Nanotechnology-Based Strategies for Early Cancer Diagnosis Using Circulating Tumor Cells as a Liquid Biopsy.
Circulating tumor cells (CTCs) are cancer cells that shed from a primary tumor and circulate in the bloodstream. As a form of "tumor liquid biopsy", CTCs provide important information for the mechanistic investigation of cancer metastasis and the measurement of tumor genotype evolution during treatment and disease progression. However, the extremely low abundance of CTCs in the peripheral blood and the heterogeneity of CTCs make their isolation and characterization major technological challenges. Recently, nanotechnologies have been developed for sensitive CTC detection; such technologies will enable better cell and molecular characterization and open up a wide range of clinical applications, including early disease detection and evaluation of treatment response and disease progression. In this review, we summarize the nanotechnology-based strategies for CTC isolation, including representative nanomaterials (such as magnetic nanoparticles, gold nanoparticles, silicon nanopillars, nanowires, nanopillars, carbon nanotubes, dendrimers, quantum dots, and graphene oxide) and microfluidic chip technologies that incorporate nanoroughened surfaces and discuss their key challenges and perspectives in CTC downstream analyses, such as protein expression and genetic mutations that may reflect tumor aggressiveness and patient outcome.


Direct health costs of inflammatory polyarthritis 10 years after disease onset: results from the Norfolk Arthritis Register.
To explore the change in direct medical costs associated with inflammatory polyarthritis (IP) 10 to 15 years after its onset. Patients from the Norfolk Arthritis Register who had previously participated in a health economic study in 1999 were traced 10 years later and invited to participate in a further prospective questionnaire-based study. The study was designed to identify direct medical costs and changes in health status over a 6-month period using previously validated questionnaires as the primary source of data. A representative sample of 101 patients with IP from the 1999 cohort provided complete data over the 6-month period. The mean disease duration was 14 years (SD 2.1, median 13.6, interquartile range 12.6-15.4). The mean direct medical cost per patient over the 6-month period was £1496 for IP (inflated for 2013 prices). This compared with £582 (95% CI £355-£964) inflated to 2013 prices per patient with IP 10 years earlier in their disease. The increased cost was largely associated with the use of biologics in the rheumatoid arthritis subgroup of patients (51% of total costs incurred). Other direct cost components included primary care costs (11%), hospital outpatient (19%), day care (12%), and inpatient stay (4%). The direct healthcare costs associated with IP have more than doubled with increasing disease duration, largely as a result of the use of biologics. The results showed a shift in the direct health costs from inpatient to outpatient service use.


Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex.
An important event in gene expression is the covalent modification of histone proteins. We have found that the mammalian transcriptional repressor Sin3 (mSin3) exists in a complex with histone deacetylases HDAC1 and HDAC2. Consistent with the observation that mSin3-mediated repression of transcription involves the modification of histone polypeptides, we found that the mSin3-containing complex includes polypeptides that tether the mSin3 complex to core histone proteins. In addition, two novel mSin3-associated polypeptides, SAP18 and SAP30, were identified. We isolated a cDNA encoding human SAP18 and found that SAP18 is a component of an mSin3-containing complex in vivo. Moreover, we demonstrate a direct interaction between SAP18 and mSin3. SAP18 represses transcription in vivo when tethered to the promoter, consistent with the ability of SAP18 to interact with mSin3.


Ionic currents underlying developmental regulation of repetitive firing in Aplysia bag cell neurons.
We have investigated the developmental regulation of the ability to fire repetitively in the bag cell neurons of Aplysia californica, a neuronal system in which the behavioral effects of repetitive firing are well characterized. Adult bag cell neurons exhibit an afterdischarge, consisting of prolonged depolarization and repetitive firing, which causes the release of several peptides from these neurons that induce egg-laying behaviors. Afterdischarge can be triggered in vitro by a variety of stimuli, including electrical stimulation and exposure to the potassium channel blocker tetraethyl ammonium chloride (TEA). In contrast to adults, juvenile neurons did not exhibit afterdischarge in response to pleural-abdominal connective shock or TEA. Juvenile neurons did exhibit, however, prolonged depolarizations in the presence of TEA, perhaps reflecting the anlage of the mechanism responsible for afterdischarge in the adult. To investigate developmental mechanisms underlying the regulation of repetitive firing, we compared ionic currents in adult and juvenile bag cell neurons. We found that during the period in which these neurons acquire the capacity to fire repetitively, a number of currents are regulated: (1) three K+ currents decrease (Ca2+)-dependent K+ and two components of voltage-dependent delayed-rectifier K+ current); (2) A-type K+ current increases; and (3) two Ca2+ currents increase (basal and PKC-activated). This pattern is consistent with the increase in the ability to fire repetitively that we observe during maturation: our results indicate that developmental control of repetitive firing in this system is accompanied by selective regulation of specific ionic currents which, after maturation, play important roles in generating the afterdischarge and triggering egg-laying behaviors.


Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer.
The treatment of patients with ovarian cancer is rapidly changing following the success of poly [ADP-ribose] polymerase (PARP) inhibitors in clinical trials. Olaparib is the first PARP inhibitor to be approved by the EMA and FDA for BRCA-mutated ovarian cancer. Germ line BRCA mutation status is now established as a predictive biomarker of potential benefit from treatment with a PARP inhibitor; therefore, knowledge of the BRCA status of an individual patient with ovarian cancer is essential, in order to guide treatment decisions. BRCA testing was previously offered only to women with a family or personal history of breast and/or ovarian cancer; however, almost 20% of women with high-grade serous ovarian cancer are now recognized to harbour a germ line BRCA mutation, and of these, >40% might not have a family history of cancer and would not have received BRCA testing. A strategy to enable more widespread implementation of BRCA testing in routine care is, therefore, necessary. In this Review, we summarize data from key clinical trials of PARP inhibitors and discuss how to integrate these agents into the current treatment landscape of ovarian cancer. The validity of germ line BRCA testing and other promising biomarkers of homologous-recombination deficiency will also be discussed.


Bioaccumulation and toxicity of CuO nanoparticles by a freshwater invertebrate after waterborne and dietborne exposures.
The incidental ingestion of engineered nanoparticles (NPs) can be an important route of uptake for aquatic organisms. Yet, knowledge of dietary bioavailability and toxicity of NPs is scarce. Here we used isotopically modified copper oxide ((65)CuO) NPs to characterize the processes governing their bioaccumulation in a freshwater snail after waterborne and dietborne exposures. Lymnaea stagnalis efficiently accumulated (65)Cu after aqueous and dietary exposures to (65)CuO NPs. Cu assimilation efficiency and feeding rates averaged 83% and 0.61 g g(-1) d(-1) at low exposure concentrations (<100 nmol g(-1)), and declined by nearly 50% above this concentration. We estimated that 80-90% of the bioaccumulated (65)Cu concentration in L. stagnalis originated from the (65)CuO NPs, suggesting that dissolution had a negligible influence on Cu uptake from the NPs under our experimental conditions. The physiological loss of (65)Cu incorporated into tissues after exposures to (65)CuO NPs was rapid over the first days of depuration and not detectable thereafter. As a result, large Cu body concentrations are expected in L. stagnalis after exposure to CuO NPs. To the degree that there is a link between bioaccumulation and toxicity, dietborne exposures to CuO NPs are likely to elicit adverse effects more readily than waterborne exposures.


Mutations in a dominant Nef epitope of simian immunodeficiency virus diminish TCR:epitope peptide affinity but not epitope peptide:MHC class I binding.
Viruses like HIV and SIV escape from containment by CD8(+) T lymphocytes through generating mutations that interfere with epitope peptide:MHC class I binding. However, mutations in some viral epitopes are selected for that have no impact on this binding. We explored the mechanism underlying the evolution of such epitopes by studying CD8(+) T lymphocyte recognition of a dominant Nef epitope of SIVmac251 in infected Mamu-A*02(+) rhesus monkeys. Clonal analysis of the p199RY-specific CD8(+) T lymphocyte repertoire in these monkeys indicated that identical T cell clones were capable of recognizing wild-type (WT) and mutant epitope sequences. However, we found that the functional avidity of these CD8(+) T lymphocytes for the mutant peptide:Mamu-A*02 complex was diminished. Using surface plasmon resonance to measure the binding affinity of the p199RY-specific TCR repertoire for WT and mutant p199RY peptide:Mamu-A*02 monomeric complexes, we found that the mutant p199RY peptide:Mamu-A*02 complexes had a lower affinity for TCRs purified from CD8(+) T lymphocytes than did the WT p199RY peptide:Mamu-A*02 complexes. These studies demonstrated that differences in TCR affinity for peptide:MHC class I ligands can alter functional p199RY-specific CD8(+) T lymphocyte responses to mutated epitopes, decreasing the capacity of these cells to contain SIVmac251 replication.


Estrogenic potential of certain pyrethroid compounds in the MCF-7 human breast carcinoma cell line.
Estrogens, whether natural or synthetic, clearly influence reproductive development, senescence, and carcinogenesis. Pyrethroid insecticides are now the most widely used agents for indoor pest control, providing potential for human exposure. Using the MCF-7 human breast carcinoma cell line, we studied the estrogenic potential of several synthetic pyrethroid compounds in vitro using pS2 mRNA levels as the end point. We tested sumithrin, fenvalerate, d-trans allethrin, and permethrin. Nanomolar concentrations of either sumithrin or fenvalerate were sufficient to increase pS2 expression slightly above basal levels. At micromolar concentrations, these two pyrethroid compounds induced pS2 expression to levels comparable to those elicited by 10 nM 17ss-estradiol (fivefold). The estrogenic activity of sumithrin was abolished with co-treatment with an antiestrogen (ICI 164,384), whereas estrogenic activity of fenvalerate was not significantly diminished with antiestrogen co-treatment. In addition, both sumithrin and fenvalerate were able to induce cell proliferation of MCF-7 cells in a dose-response fashion. Neither permethrin nor d-trans allethrin affected pS2 expression. Permethrin had a noticeable effect on cell proliferation at 100 microM, whereas d-trans allethrin slightly induced MCF-7 cell proliferation at 10 microM, but was toxic at higher concentrations. Overall, our studies imply that each pyrethroid compound is unique in its ability to influence several cellular pathways. These findings suggest that pyrethroids should be considered to be hormone disruptors, and their potential to affect endocrine function in humans and wildlife should be investigated.


Quality of life in young adults with cerebral palsy.
Little is known about the quality of life (QOL) of young adults with cerebral palsy. This cross-sectional analysis compares the QOL of a cohort of young Australian adults with CP with a cohort of able-bodied peers to explore the relationship between QOL and impairments, functioning, and social participation. Young adults identified from the Victorian Cerebral Palsy Register were invited to complete a survey about QOL, gross motor function, independence in self-care, and social participation. QOL was assessed with the Quality of Life Instrument for Young Adults (YAQOL). A general population sample of young North American adults, who had completed the YAQOL was selected for comparison. Surveys and consent forms were completed by 335 young adults or their proxies, an overall participation rate of 63% of those located. The mean age of the study participants was 24.7 [s.d = 2.8] years; 51% were male and 49% female. Two hundred and seven (62%) of the 335 participants self-reported their QOL. When compared with the general population sample, self-reporting participants had similar QOL scores for the social relationship and environmental context domains (p > 0.05), while QOL scores were lower for the physical health, psychological well-being, and role function domains (p < 0.001). There was no association between psychological well-being and variables related to body structure and gross motor function in young adults with CP. Contrary to the assumption that young adults with severe CP have low psychosocial well-being, it is apparent that these individuals can have good psychosocial well-being regardless of their disability.


Spectrum of genetic diversity and networks of clonal organisms.
Clonal reproduction characterizes a wide range of species including clonal plants in terrestrial and aquatic ecosystems, and clonal microbes such as bacteria and parasitic protozoa, with a key role in human health and ecosystem processes. Clonal organisms present a particular challenge in population genetics because, in addition to the possible existence of replicates of the same genotype in a given sample, some of the hypotheses and concepts underlying classical population genetics models are irreconcilable with clonality. The genetic structure and diversity of clonal populations were examined using a combination of new tools to analyse microsatellite data in the marine angiosperm Posidonia oceanica. These tools were based on examination of the frequency distribution of the genetic distance among ramets, termed the spectrum of genetic diversity (GDS), and of networks built on the basis of pairwise genetic distances among genets. Clonal growth and outcrossing are apparently dominant processes, whereas selfing and somatic mutations appear to be marginal, and the contribution of immigration seems to play a small role in adding genetic diversity to populations. The properties and topology of networks based on genetic distances showed a 'small-world' topology, characterized by a high degree of connectivity among nodes, and a substantial amount of substructure, revealing organization in subfamilies of closely related individuals. The combination of GDS and network tools proposed here helped in dissecting the influence of various evolutionary processes in shaping the intra-population genetic structure of the clonal organism investigated; these therefore represent promising analytical tools in population genetics.


SU-E-J-141: Assessment of the Magnitude and Impact of Trigger Delay in Respiratory Triggered Real-Time Imaging during Radiotherapy.
To assess the trigger delay in respiratory triggered real-time imaging and its impact on image guided radiotherapy (IGRT) with Varian TrueBeam System. A sinusoidal motion phantom with 2cm motion amplitude was used. The trigger delay was determined directly with video image, and indirectly by the distance between expected and actual triggering phantom positions. For the direct method, a fluorescent screen was placed on the phantom to visualize the x-ray. The motion of the screen was recorded at 60 frames/second. The number of frames between the time when the phantom reached expected triggering position and the time when the screen was illuminated by the x-ray was used to determine the trigger delay. In the indirect method, triggered kV x-ray images were acquired in real-time during 'treatment' with triggers set at 25% and 75% respiratory phases where the phantom moved at the maximum speed. 39-40 triggered images were acquired continuously in each series. The distance between the expected and actual triggering points, d, was measured on the images to determine the delay time t by d=Asin(wt), where w=2π/T, T=period and A=amplitude. Motion periods of 2s and 4s were used in the measurement. The trigger delay time determined with direct video imaging was 125ms (7.5 video frames). The average distance between the expected and actual triggering positions determined by the indirect method was 3.93±0.74mm for T=4s and 7.02±1.25mm for T=2s, yielding mean trigger delay times of 126±24ms and 120±22ms, respectively. Although the mean over-travel distance is significant at 25% and 75% phases, clinically, the target over-travel resulted from the trigger delay at the end of expiration (50% phase) is negligibly small(< 0.5mm). The trigger delay in respiration-triggered imaging is in the range of 120-126ms. This delay has negligible clinical effect on gated IGRT.


Addiction Research Training Programs: Four Case Studies and Recommendations for Evaluation.
: The presence of structured addiction research training programs helps to ensure that the scientific workforce includes well-trained, diverse scientists necessary to reduce the negative impact of alcohol, drug, and tobacco use disorders. Although the field has made significant progress in the development of standards for clinical training in addiction medicine, there remains significant room for improvement in the training of addiction researchers, and also opportunities to synergize across addiction research training programs. The purpose of this commentary is to describe 4 National Institutes of Health (NIH)-sponsored addiction research training programs, highlight critical components, and provide recommendations for more comprehensive and effective program evaluation. Moving forward, evaluation of addiction research training programs would be enhanced by the use of conceptual models to inform process and outcome evaluations, the application of innovative methods to ensure long-term data collection, the improvement of mentorship evaluation measures, and the integration of training methods from other fields of study. We encourage NIH and others in the field to be proactive in establishing core metrics for evaluation across programs. Furthermore, centralized tracking of NIH-funded addiction research trainees, analysis of aggregate data across programs, and innovative methods to effectively disseminate program materials and processes are recommended.


Two-component schedules of differential-reinforcement-of-low-rate.
Two-component schedules of differential-reinforcement-of-low-rate were presented, where the contingencies specified separately two minimum interresponse times, t(1) and t(2), required for reinforcement, depending on whether the interresponse time was initiated by, in one case, a reinforced response (t(1)) or, in the other, a nonreinforced response (t(2)). A distinctive pattern of responding developed on each of the two contingencies. Duration of an interresponse time approximated t(1) when the t(1) contingency was in effect, and t(2) when the t(2) contingency was in effect. This relationship persisted even when t(2) was shorter than t(1), and responding at a higher rate on the t(1) contingency would have greatly increased the rate of reinforcement. Increasing the value of t(2) resulted in both longer interresponse times on the t(1) contingency, and a higher probability of a response-burst on those occasions when the contingency switched from t(1) to t(2). The results indicated that both reinforced and nonreinforced responses functioned as discriminative events in determining the duration of following interresponse times.


Crystal structure and antitumor activity of the novel zwitterionic complex of tri-n-butyltin(IV) with 2-thiobarbituric acid.
A novel tri-n-butyl(IV) derivative of 2-thiobarbituric acid (HTBA) of formula [(n-Bu)(3)Sn(TBA) H(2)O] (1) has been synthesized and characterized by elemental analysis and (119)Sn-NMR and FT-IR spectroscopic techniques. The crystal structure of complex 1 has been determined by single crystal X-ray diffraction analysis at 120(2) K. The geometry around Sn(IV) is trigonal bipyramidal. Three n-butyl groups and one oxygen atom from a deprotonated 2-thiobarbituric ligand are bonded to the metal center. The geometry is completed with one oxygen from a water molecule. Compound 1 exhibits potent, in vitro, cytotoxicity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (PAH, benzo[a]pyrene) carcinogenesis. In addition, the inhibition caused by 1, in the rate of lipoxygenase (LOX) catalyzed oxidation reaction of linoleic acid to hyperoxolinoleic acid, has been also kinetically and theoretically studied. The results are compared to that of cisplatin.


Origins of the 2009 H1N1 influenza pandemic in swine in Mexico.
Asia is considered an important source of influenza A virus (IAV) pandemics, owing to large, diverse viral reservoirs in poultry and swine. However, the zoonotic origins of the 2009 A/H1N1 influenza pandemic virus (pdmH1N1) remain unclear, due to conflicting evidence from swine and humans. There is strong evidence that the first human outbreak of pdmH1N1 occurred in Mexico in early 2009. However, no related swine viruses have been detected in Mexico or any part of the Americas, and to date the most closely related ancestor viruses were identified in Asian swine. Here, we use 58 new whole-genome sequences from IAVs collected in Mexican swine to establish that the swine virus responsible for the 2009 pandemic evolved in central Mexico. This finding highlights how the 2009 pandemic arose from a region not considered a pandemic risk, owing to an expansion of IAV diversity in swine resulting from long-distance live swine trade.


Intraarterial contrast-enhanced computed tomography of the equine distal extremity.
A technique for regional delivery of contrast medium to the foot of the horse to increase the diagnostic utility of computed tomography (CT) for the characterization of soft tissue structures within the hoof capsule was developed. An intraarterial catheter was placed under ultrasound guidance into the medial palmar artery at the level of the carpus to facilitate a steady-state infusion of iodinated contrast medium. Two 5 mm collimated contiguous acquisition CT scans were performed in 10 horses without lameness or radiographic evidence of distal sesamoid bone degeneration. CT examination was performed before and during regional arterial infusion of iodinated contrast medium administered at a rate of 2 ml/s. Cross-sectional area and mean pre- and post-contrast attenuation of the deep digital flexor tendon and the collateral ligaments of the distal interphalangeal joint were quantified from CT images. Soft tissue anatomy of the foot was also qualitatively characterized from pre- and postcontrast images. Catheterization was successful and without complication in all horses. The evaluated tendons and ligaments were clearly visible and had a small (8-20 Hounsfield Unit) but significant (P < 0.05, paired t-test) increase in attenuation during the steady-state infusion of contrast medium. This study should enhance the diagnostic potential of CT by providing baseline quantitative data for comparison with horses affected with soft tissue injuries in the distal extremity causing lameness that is alleviated with a palmar digital nerve block.


The spatiotemporal structure of control variables during catching.
The discrepancy between traditional (force scaling models) and the more recently conceived dynamic explanations of load compensation (lambda model) was the departure point for the present study. By using the complex "open" motor skill of catching a ball--rather than the traditional "closed" skills--under "normal" (baseline) conditions and under conditions where a spring load was applied to the catching hand (thereby changing the dynamics of the skeletomuscular system) it was hoped to provide further clarification of this issue. Traditional force scaling models, in this respect, would predict that maximal closing velocity of the grasp action, and movement time would not be significantly different between a control and a spring-load condition. In contrast, a dynamic system perspective would maintain that spring loading would be compensated for by a change in the rate of shift of the reciprocal command (R-command). The obtained results showed a significant difference for conditions with regard to the maximal closing velocity of the grasp action, the baseline condition being higher than the two spring-load conditions. Furthermore, a significant difference was found for the aperture at moment of catch, the aperture at moment of catch being smaller in the baseline condition than that under the two spring-load conditions. With regard to the temporal variables, no significant differences were obtained. A comprehensive overall explanation of the obtained data in terms of the force scaling models was not realisable. It may be that findings supporting such theories are task specific and that for constrained tasks--such as catching a ball--different underlying organisational principles apply. The lambda model, however, could explain adequately the obtained results. It was concluded that, except for the preparatory phase associated with load compensation before the onset of the movement of the ball, the spatiotemporal structure of the control pattern underlying catching remains the same (invariant) in both baseline and load conditions. Thereby, the spatiotemporal structure of the resulting movement changes under the influence of the load and thus is not the same for load and baseline condition.


Tutorship process in health care professions: a survey investigation in Emilia Romagna.
The areas that we wanted to investigate include: tasks performed, tools used, formalization of the assignment, workload, empowerment and satisfaction of the function performed, and training. The results clearly show that the processes of tutoring are different for physicians and non-physician healthcare professionals. The first interesting difference is the method of assignment of mentoring. While among medical professions the function is assigned by others, tutors are often non-medical volunteers. This evidence leads to two unanswered questions: what are the criteria by which they are chosen as tutors? Do volunteers really possess the skills and ability to carry out this role? Future research should be directed towards clearly defining the profile of the "tutor" among both doctors and non-medical professionals. Another difference is the way the work of the mentor is formalized. If they are doctors, the task is assigned to them; this is not the case for non-medical professions. Despite this difference, a high percentage of both medical professionals and doctors said they did not feel valued for their role of tutor. However, differences emerge: physicians see their role as a paid tutor and / or recognized in their curriculum vitae. For non-medical professions, however, the only reward is a recognition of ECM (Educazione Continua in Medicina)credits. A common feature among professionals is that for both physicians and non-physician healthcare tutors, a system of evaluation is rarely reported. Another common feature is the skills that professionals would like to see improved. Both groups of professionals, in fact, would like to see improved teaching methods, communication strategies and reporting and evaluation systems. Finally, non-physician tutors report the same level of satisfaction, although the non-physician professionals are more satisfied in their relationship with colleagues. The degree of empowerment reveals perceived differences and similarities among the professionals. In fact, both professional groups reported the same levels of competence and impact, but differ in meaning and self-determination. More specifically, the non-medical professionals show high scores, while doctors get a higher score for self-determination. These results suggest that for increased attention to the system of evaluation and enhancement of the function tutorial we need not only to increase the satisfaction of those who act as tutors, but also to improve the tutorial process itself. Furthermore, the results suggest the carrying out of training projects for teaching and assessment methods that represent the issues that are most in demand by tutors. The training should include the use of tools for the governance process that project tutorial and apprenticeships. The responses indicate that these tools are already in use, although not as widespread and continuous.


The relationship between specific cognitive functions and falls in aging.
The current study examined the relationship between cognitive function and falls in older people who did not meet criteria for dementia or mild cognitive impairment (N = 172). To address limitations of previous research, the authors controlled for the confounding effects of gait measures and other risk factors by means of associations between cognitive function and falls. A neuropsychological test battery was submitted to factor analysis, yielding 3 orthogonal factors (Verbal IQ, Speed/Executive Attention, Memory). Single and recurrent falls within the last 12 months were evaluated. The authors hypothesized that Speed/Executive Attention would be associated with falls. Additionally, the authors assessed whether associations between different cognitive functions and falls varied depending on whether single or recurrent falls were examined. Multivariate logistic regressions showed that lower scores on Speed/Executive Attention were associated with increased risk of single and recurrent falls. Lower scores on Verbal IQ were related only to increased risk of recurrent falls. Memory was not associated with either single or recurrent falls. These findings are relevant to risk assessment and prevention of falls and point to possible shared neural substrates of cognitive and motor function.


Daily variations in deaths in Lithuania: the possible contribution of binge drinking.
During the early 1990s the countries of the Former Soviet Union experienced a dramatic rise in mortality, especially from cardiovascular diseases. Although still poorly understood there is evidence, particularly from Russia, that this mortality crisis is partly linked to alcohol consumption. In this paper we use data from Lithuania to explore the daily variations of deaths and the probable relationship with binge drinking. Computerized death certificates for those aged 20-59 years were analysed according to the day of death, place of death, and cause of death for the years 1988-1997. There is a marked increase in deaths from accidents, violence, and alcohol poisoning at the weekend, suggesting a pattern of binge drinking in Lithuania. There is also a significant increase in ischaemic heart disease (IHD) deaths on Saturdays, Sundays and Mondays. If the analysis is performed separately according to place of death, the day of the week effect is strengthened for cardiovascular deaths outside of hospital; consistent with the idea of a sudden cardiac death. The increase in mortality from cardiovascular diseases observed at the weekend in Lithuania is similar to that observed in Moscow and other populations. The relationship with alcohol consumption is supported by the available physiological evidence. We propose that bingeing can be solely responsible for, or acts as a 'catalyst' for, pathophysiological events by increasing blood pressure, cardiac rhythm and coagulability. The increased IHD mortality observed throughout the weekend and on Monday in Lithuania may reflect the influence of alcohol consumption patterns in a population already subject to high psychosocial stress.


Strain engineering of electronic structures and photocatalytic responses of MXenes functionalized by oxygen.
The structural, electronic, and photocatalytic properties of two-dimensional Ti2CO2, Zr2CO2, and Hf2CO2 MXenes were investigated by first-principles (PBE and hybrid) calculations. Transition from an indirect to a direct band gap was achieved for the biaxial tensile strain of 3% for Ti2CO2, 8% for Zr2CO2, and 13% for Hf2CO2 while the nature of the band gap remained indirect in the case of the compressive strain. The size of the band gap passed through a maximum under tensile strain and decreased monotonically under compressive strain. Analysis of Bader charge distribution showed that the tensile strain decreased the transfer of charge from the Ti, Zr, and Hf atoms to the C atom. Phonon spectra suggested that these systems are stable under a wide range of strains from compression to tension. The photocatalytic properties showed that unstrained and biaxial tensile strained Ti2CO2, Zr2CO2, and Hf2CO2 systems can be used to oxidize H2O into O2.


Postsynaptic expression of a new calcium pathway in hippocampal CA3 neurons and its influence on mossy fiber long-term potentiation.
Long-term potentiation (LTP) in the CA1 region of the hippocampus is induced by postsynaptic Ca(2+) influx via NMDA receptors (NMDARs). However, this synaptic plasticity occurs independently of NMDARs when Ca(2+)-permeable AMPA receptors (AMPARs) are expressed at postsynaptic sites using various genetic techniques, indicating that an increase in Ca(2+) level at critical postsynaptic sites, regardless of its entry pathway, triggers the induction of LTP at CA1 synapses. In contrast, NMDARs are sparsely distributed on mossy fiber (MF) synapses in CA3 hippocampal neurons, and most evidence favors the presynaptic mechanism for LTP induction, although some reports suggested a postsynaptic mechanism. In this study, we examined whether Ca(2+) influx through the newly produced postsynaptic receptors during high-frequency stimulation affects the induction of MF LTP. For this purpose, we expressed Ca(2+)-permeable AMPARs in CA3 pyramidal neurons by Sindbis viral-mediated gene transfer of the unedited form of the glutamate receptor 2 (GluR2Q) subunit, as a new pathway for postsynaptic Ca(2+) entry, in rat hippocampal organotypic cultures. Virally expressed myc-tagged GluR2Q was detected at the complex spines known as the thorny excrescences, which serve as postsynaptic targets for MF synaptic input, on the proximal apical dendrites of CA3 pyramidal cells. Furthermore, endogenous Ca(2+)-impermeable AMPARs at MF synapses were converted into Ca(2+)-permeable receptors by GluR2Q expression. However, the postsynaptic expression of Ca(2+)-permeable AMPARs had no significant influence on the two types of MF LTP induced by different stimulus protocols. These results supported the notion that MF LTP is independent of postsynaptic Ca(2+).


Evaluating depressive symptom interactions on adolescent smoking prevention program mediators: a mediated moderation analysis.
Smoking prevention interventions have been shown to be effective in reducing smoking prevalence in the United States. Further work is needed to address smoking in China, where over one third of the world's current smokers reside. China, with more than 60% of the male population being smokers, also presents a unique opportunity to test cognitive processes involved in depression, social influences, and smoking. Adolescents at-risk for developing depression may process social information differently from low-risk counterparts. The Wuhan Smoking Prevention Trial was a school-based longitudinal randomized controlled trial aimed at preventing initiation and escalation of adolescent smoking behaviors. Thousand three hundred and ninety-one male seventh-grade students were assessed with a 200-item paper-and-pencil baseline survey, and it was readministered 1 year later following program implementation. Friend prevalence estimates were significantly higher among 30-day smokers and among those at highest risk for depression symptoms. The program appeared to be successful in changing the perception of friend smoking prevalence only among adolescents with a comorbidity of high scores of depression symptoms and who have experimented previously with smoking. This Program x Comorbidity interaction on perceived friend smoking prevalence was significant in predicting 30-day smoking 1 year after program implementation. This study provides evidence that those adolescents with high levels of depressive symptoms may be more sensitive to social influences associated with smoking prevalence. Individual Disposition x Social Environmental Influences may be important when developing future effective prevention programming.


Long-range allosteric transitions in carbamoyl phosphate synthetase.
Carbamoyl phosphate synthetase plays a key role in both pyrimidine and arginine biosynthesis by catalyzing the production of carbamoyl phosphate from one molecule of bicarbonate, two molecules of MgATP, and one molecule of glutamine. The enzyme from Escherichia coli consists of two polypeptide chains referred to as the small and large subunits, which contain a total of three separate active sites that are connected by an intramolecular tunnel. The small subunit harbors one of these active sites and is responsible for the hydrolysis of glutamine to glutamate and ammonia. The large subunit binds the two required molecules of MgATP and is involved in assembling the final product. Compounds such as L-ornithine, UMP, and IMP allosterically regulate the enzyme. Here, we report the three-dimensional structure of a site-directed mutant protein of carbamoyl phosphate synthetase from E. coli, where Cys 248 in the small subunit was changed to an aspartate. This residue was targeted for a structural investigation because previous studies demonstrated that the partial glutaminase activity of the C248D mutant protein was increased 40-fold relative to the wild-type enzyme, whereas the formation of carbamoyl phosphate using glutamine as a nitrogen source was completely abolished. Remarkably, although Cys 248 in the small subunit is located at approximately 100 A from the allosteric binding pocket in the large subunit, the electron density map clearly revealed the presence of UMP, although this ligand was never included in the purification or crystallization schemes. The manner in which UMP binds to carbamoyl phosphate synthetase is described.


Matching seed to site by climate similarity: Techniques to prioritize plant materials development and use in restoration.
Land management agencies are increasing the use of native plant materials for vegetation treatments to restore ecosystem function and maintain natural ecological integrity. This shift toward the use of natives has highlighted a need to increase the diversity of materials available. A key problem is agreeing on how many, and which, new accessions should be developed. Here we describe new methods that address this problem. Our methods use climate data to calculate a climate similarity index between two points in a defined extent. This index can be used to predict relative performance of available accessions at a target site. In addition, the index can be used in combination with standard cluster analysis algorithms to quantify and maximize climate coverage (mean climate similarity), given a modeled range extent and a specified number of accessions. We demonstrate the utility of this latter feature by applying it to the extents of 11 western North American species with proven or potential use in restoration. First, a species-specific seed transfer map can be readily generated for a species by predicting performance for accessions currently available; this map can be readily updated to accommodate new accessions. Next, the increase in climate coverage achieved by adding successive accessions can be explored, yielding information that managers can use to balance ecological and economic considerations in determining how many accessions to develop. This approach identifies sampling sites, referred to as climate centers, which contribute unique, complementary, climate coverage to accessions on hand, thus providing explicit sampling guidance for both germplasm preservation and research. We examine how these and other features of our approach add to existing methods used to guide plant materials development and use. Finally, we discuss how these new methods provide a framework that could be used to coordinate native plant materials development, evaluation, and use across agencies, regions, and research groups.


Long-term marginal periimplant bone loss in edentulous patients.
The aim of this study was to examine the long-term periimplant bone loss in patients treated with implant-supported fixed prostheses in both jaws. The participants comprised 44 edentulous patients who have been followed for a 15-year period after treatment with a fixed implant-supported prosthesis in the mandible. Thirteen of them also received an implant-supported fixed prosthesis in the maxilla, on average 4.5 years after the mandibular treatment. The periimplant bone level was measured on intraoral radiographs. The long-term results of the implant treatment were successful, and only 1% (3/273) of the implants were lost in the mandible and 7% (5/75) in the maxilla. All but one of the failures occurred before the connection of the prostheses. The mean marginal bone loss around the implants was small (less than 1 mm for a 10-year period after implant placement), and was of similar magnitude in both jaws. However, the individual variation was relatively great. There was no significant difference in marginal bone loss between those who had a maxillary complete denture during the entire observation period and those who had received a fixed implant-supported maxillary prosthesis. Smokers lost more periimplant bone than did the nonsmokers; the difference was significant in the mandible but small and nonsignificant in the maxilla. The long-term periimplant bone loss was small and of similar magnitude in the mandible and the maxilla in subjects who had received implant-supported fixed prostheses in both jaws. The prosthetic status in the maxilla, i.e., complete denture or fixed implant-supported prosthesis, had no significant influence on the mandibular periimplant bone loss.


Converting surface plasmon to spatial Airy beam by graded grating on metal surface.
A well-developed phase modulation method is utilized to design a nanogroove grating for a desired diffraction process, which gives rise to the conversion of a surface plasmon wave to an Airy-like radiation beam. Experiments and simulations revealed the unique characteristics of the generated Airy-like beam, such as nonspreading, self-bending, and self-healing. Our result confirms the validation of the diffraction strategy for beam engineering in conversions and possibly indicates wider applications in broader areas.


[Current status of illegal trade in pharmaceutical products on Internet auction sites in Japan and responses of site administrators to such transactions].
In Japan, it is illegal to sell pharmaceuticals on Internet auction sites, although a considerable number of pharmaceuticals are listed on such sites. We investigated the current situation regarding the illegal trade in pharmaceuticals on Japanese Internet auction sites and the responses of site administrators to such transactions. We searched for pharmaceuticals and "gray" items that were suspected of being pharmaceuticals on Yahoo-oku! (Yahoo! Auctions, Japan) over a 37-day period and then submitted violation reports indicating that selling pharmaceuticals is illegal or that the description of an item was insufficient. The reports were directed to the site administrators and forwarded to the sellers. One hundred and six pharmaceutical products and 34 gray items were identified during the study period. After the submission of the violation reports, only 28 of the pharmaceutical products and one of the gray items were deleted by the administrator, while 18 of the pharmaceutical products and 7 of the gray items were withdrawn by their sellers. However, 41 pharmaceuticals and 20 gray items were sold. Most of the gray items were listed using characteristic terms or abbreviations without photographic images. More than 70% of the identified pharmaceuticals had a contraindication(s) other than hypersensitivity. In conclusion, the illegal trade in pharmaceuticals on Internet auction sites remains a serious problem in Japan, and the responses of site administrators to such transactions are inadequate. The government and pharmaceutical industry may have to take measures such as providing public and administrative guidance to stop the illegal trade in pharmaceuticals on the Internet.


Health inequalities experienced by children and young people with intellectual disabilities: a review of literature from the United Kingdom.
This literature review aimed to synthesize evidence on the prevalence and determinants of health conditions and impairments among children and young people with intellectual disability in the United Kingdom. Several databases were systematically searched for studies conducted with children under the age of 18 living in the United Kingdom and published in 2010-11. Evidence from a 2002 and a 2010 literature review on health inequalities among individuals of all ages with intellectual disability was also reviewed. We conclude there is an increased prevalence of a number of health conditions and impairments among children with intellectual disability and evidence that these health inequalities are associated with several preventable environmental determinants.


Protein Hpn: cloning and characterization of a histidine-rich metal-binding polypeptide in Helicobacter pylori and Helicobacter mustelae.
Helicobacter pylori is a human gastrointestinal pathogen involved in gastritis, duodenal ulcers, and gastric neoplasia. This microorganism produces large amounts of a urease which, like all known ureases, has nickel in the active site. We have identified a protein in clinical isolates of H. pylori and an identical protein in the ferret pathogen Helicobacter mustelae that strongly binds Ni2+ and Zn2+. This protein has been named Hpn to emphasize its origins in H. pylori and its affinity for nickel. The encoding hpn gene, cloned and expressed in Escherichia coli ER1793, has an open reading frame (180 bp) that specifies a protein with a calculated molecular mass of 7,077 Da and with the same amino-terminal sequence as that of wild-type Hpn. The deduced sequence of Hpn consists of 60 amino acids, of which 28 (47%) are histidines. The hpn gene does not map with the urease gene cluster on the H. pylori chromosome. An Hpn-negative, isogenic H. pylori strain, generated by hpn gene deletion and grown on blood agar, had the same urease activity that wild-type cells did. Thus, the role of Hpn in helicobacters is unknown.


Spontaneous innovation for future deception in a male chimpanzee.
The ability to invent means to deceive others, where the deception lies in the perceptually or contextually detached future, appears to require the coordination of sophisticated cognitive skills toward a single goal. Meanwhile innovation for a current situation has been observed in a wide range of species. Planning, on the one hand, and the social cognition required for deception on the other, have been linked to one another, both from a co-evolutionary and a neuroanatomical perspective. Innovation and deception have also been suggested to be connected in their nature of relying on novelty. We report on systematic observations suggesting innovation for future deception by a captive male chimpanzee (Pan troglodytes). As an extension of previously described behaviour--caching projectiles for later throwing at zoo visitors--the chimpanzee, again in advance, manufactured concealments from hay, as well as used naturally occurring concealments. All were placed near the visitors' observation area, allowing the chimpanzee to make throws before the crowd could back off. We observed what was likely the first instance of this innovation. Further observations showed that the creation of future-oriented concealments became the significantly preferred strategy. What is more, the chimpanzee appeared consistently to combine two deceptive strategies: hiding projectiles and inhibiting dominance display behaviour. The findings suggest that chimpanzees can represent the future behaviours of others while those others are not present, as well as take actions in the current situation towards such potential future behaviours. Importantly, the behaviour of the chimpanzee produced a future event, rather than merely prepared for an event that had been reliably re-occurring in the past. These findings might indicate that the chimpanzee recombined episodic memories in perceptual simulations.


Cardiac involvements in myasthenia gravis associated with anti-Kv1.4 antibodies.
There is no general consensus as to whether autoimmune myasthenia gravis (MG) is associated with heart diseases, despite the fact that myocarditis, a serious cardiac involvement treatable by immunotherapy, is a complication of MG. It has been observed previously that MG patients with clinically suspected myocarditis had anti-Kv1.4 antibodies. The purpose of this study was to disclose the association between anti-Kv1.4 antibodies and cardiac involvements in MG patients. Anti-Kv1.4 antibody was detected by an immunoprecipitation assay using (35) S-labeled rhabdomyosarcome cellular extract as the antigen source. Cardiac findings including electrocardiography (ECG) and clinical features of clinically suspected myocarditis in MG patients with anti-Kv1.4 antibodies were investigated. Ultrasound echocardiography (UCG) of ex vivo chick embryos was performed to determine the suppressive effects of sera with or without anti-Kv1.4 antibodies on heart muscle functions. Seventy (10.8%) of 650 MG patients had anti-Kv1.4 antibodies and 60% of them had abnormal ECG findings with high frequencies of T-wave abnormality and QT prolongation. Clinically suspected myocarditis was found in eight MG patients with anti-Kv1.4 antibodies but in none of the MG patients without anti-Kv1.4 antibodies. Most patients showed rapid deterioration with lethal arrhythmias such as ventricular tachycardia, sick sinus syndrome, or complete atrial ventricular block and severe heart failure. It was concluded using UCG of ex vivo chick embryos that MG serum with anti-Kv1.4 antibodies suppressed heart muscle functions. It has been demonstrated that anti-Kv1.4 antibodies are possible markers for cardiac involvements in MG patients.


Failure to prevent selective CA1 neuronal death and reduce cortical infarction following cerebral ischemia with inhibition of nitric oxide synthase.
We investigated the putative role of nitric oxide in the expression of neuronal injury following both transient severe forebrain ischemia (CA1 neuronal injury) and transient or permanent middle cerebral artery occlusion (neocortical pannecrosis). Using the four-vessel occlusion model and increasing doses of N-omega-nitro-L-arginine, 2-40 mg/kg, we were unable to demonstrate any reduction in the percentage of CA1 cells injured following 10 min of transient severe forebrain ischemia followed by seven days of reperfusion. Higher doses proved toxic insofar as they increased the mortality following the ischemic insult. Saline-treated animals (n = 8) had 77 +/- 10% CA1 injury while those treated with 2 mg/kg of nitro-arginine i.v. had 80 +/- 7% (n = 7), and those with 10 mg/kg i.v. had 78 +/- 11% (n = 8). Two of five rats given 20 mg/kg i.v., three of eight given 40 mg/kg i.v., and two of six given 10 mg/kg i.v. followed by 3 x 10 mg/kg i.p., died. Of those treated with high-dose nitro-arginine and which survived ischemia and seven days' reperfusion, no significant reduction in CA1 injury was detected. Wistar rats and spontaneously hypertensive rats treated with either saline or nitro-arginine i.v. were exposed to 2 h of transient middle cerebral artery occlusion followed by 22 h of reperfusion. There were seven animals in each group. Wistars treated with saline had 198 +/- 67 mm3 (mean +/- S.D.) of neocortical infarction, and those treated with 10 m/kg of nitro-arginine i.v. had 199 +/- 93 mm3. Spontaneously hypertensive rats, transiently ischemic, treated with saline had 164 +/- 25 mm3 of infarct volume, while those treated with 2 mg/kg i.v. had 151 +/- 53 mm3, and those treated with 10 mg/kg i.v. had 145 +/- 29 mm3. Animals treated with 40 mg/kg i.v. had a nonsignificantly larger mean infarct volume (191 +/- 81 mm3). High dose nitro-arginine caused an increase in hypertension in the spontaneously hypertensive rats and increased the severity of focal ischemia as measured by intra-ischemic regional cerebral blood flows. A final group of seven spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion and repeated dosing with N-omega-nitro-L-arginine i.p. In these animals an infarct volume of 234 +/- 60 mm3 was observed, which was again not statistically different from saline-treated controls (208 +/- 43 mm3, n = 7).(ABSTRACT TRUNCATED AT 400 WORDS)


Communication With Limited English-Proficient Families in the PICU.
Health care disparities have been described for children of limited English-proficient (LEP) families compared with children of English-proficient (EP) families. Poor communication with the medical team may contribute to these worse health outcomes. Previous studies exploring communication in the PICU have excluded LEP families. We aimed to understand communication experiences and preferences in the 3 primary communication settings in the PICU. We also explored LEP families' views on interpreter use in the PICU. EP and Spanish-speaking LEP families of children admitted to the PICU of a large tertiary pediatric hospital completed surveys between 24 hours and 7 days of admission. A total of 161 of 184 families were surveyed (88% response rate); 52 were LEP and 109 EP. LEP families were less likely to understand the material discussed on rounds (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.11-0.90), to report that PICU nurses spent enough time speaking with them (OR 0.15, 95% CI 0.05-0.41), and to report they could rely on their nurses for medical updates (OR 0.07, 95% CI 0.02-0.25) controlling for covariates, such as education, insurance type, presence of a chronic condition, PICU length of stay, and mortality index. LEP families reported 53% of physicians and 41% of nurses used an interpreter "often." Physician and nurse communication with LEP families is suboptimal. Communication with LEP families may be improved with regular use of interpreters and an increased awareness of the added barrier of language proficiency.


Health worker migration from South Africa: causes, consequences and policy responses.
This paper arises from a four-country study that sought to better understand the drivers of skilled health worker migration, its consequences, and the strategies countries have employed to mitigate negative impacts. The four countries-Jamaica, India, the Philippines, and South Africa-have historically been "sources" of skilled health workers (SHWs) migrating to other countries. This paper presents the findings from South Africa. The study began with a scoping review of the literature on health worker migration from South Africa, followed by empirical data collected from skilled health workers and stakeholders. Surveys were conducted with physicians, nurses, pharmacists, and dentists. Interviews were conducted with key informants representing educators, regulators, national and local governments, private and public sector health facilities, recruitment agencies, and professional associations and councils. Survey data were analyzed using descriptive statistics and regression models. Interview data were analyzed thematically. There has been an overall decrease in out-migration of skilled health workers from South Africa since the early 2000s largely attributed to a reduced need for foreign-trained skilled health workers in destination countries, limitations on recruitment, and tighter migration rules. Low levels of worker satisfaction persist, although the Occupation Specific Dispensation (OSD) policy (2007), which increased wages for health workers, has been described as critical in retaining South African nurses. Return migration was reportedly a common occurrence. The consequences attributed to SHW migration are mixed, but shortages appear to have declined. Most promising initiatives are those designed to reinforce the South African health system and undertaken within South Africa itself. In the near past, South Africa's health worker shortages as a result of emigration were viewed as significant and harmful. Currently, domestic policies to improve health care and the health workforce including innovations such as new skilled health worker cadres and OSD policies appear to have served to decrease SHW shortages to some extent. Decreased global demand for health workers and indications that South African SHWs primarily use migratory routes for professional development suggest that health worker shortages as a result of permanent migration no longer pertains to South Africa.


Left Ventricular Hypertrophy and Mortality Risk in Male Veteran Patients at High Cardiovascular Risk.
Several studies addressed cardiovascular risk and mortality in the general population, but data in veteran patients is lacking. This study was designed to investigate the association between echocardiographic left ventricular hypertrophy (LVH) and all-cause mortality in a male, high-risk group of veterans. Valid echocardiograms were evaluated in 10,406 male veterans, mean age 68.3 ± 13 years. Using the left ventricular mass/body surface area (LVM/BSA) method 6,575 (63.1%) patients had normal left LVMI and 3,831 (37.9%) had LVH, defined as LVMI ≥116 g/m2. Of those 1,371 (13.2%) had mild LVH, 1,025 (9.9%) moderate LVH, 605 (5.8%) severe, and 830 (8%) had extreme LVH. After a mean follow up of 5.9 ± 4.4 years, a total of 3,550 (34.1%) patients died. Cox proportional hazard analyses adjusted for co-morbidities revealed increased risk for individuals with mild LVH (hazard ratios [HR] 1.21; 95% confidence intervals [CI]: 1.09 to 1.33); moderate LVH (HR 1.37; 95% CI: 1.23 to 1.52); severe (HR = 1.36; 95% CI: 1.19 to 1.56); and extreme LVH, (HR = 1.95; 95% CI: 1.74 to 2.17). Similar findings were observed when LVMI was defined by LVM/m2.7. When LVM index was introduced as a continuous variable, mortality risk was 6.2% higher per 10-unit change in LVMI, and 9.4% higher when defined by the m2.7 method. There was no difference in mortality risk between black and white patients, or patients with concentric or eccentric LVH. We conclude that increased LVMI was associated with increased risk of all-cause mortality. The incremental risk was significantly higher in patients with extreme LVH.


Urban microbiomes and urban ecology: how do microbes in the built environment affect human sustainability in cities?
Humans increasingly occupy cities. Globally, about 50% of the total human population lives in urban environments, and in spite of some trends for deurbanization, the transition from rural to urban life is expected to accelerate in the future, especially in developing nations and regions. The Republic of Korea, for example, has witnessed a dramatic rise in its urban population, which now accounts for nearly 90% of all residents; the increase from about 29% in 1955 has been attributed to multiple factors, but has clearly been driven by extraordinary growth in the gross domestic product accompanying industrialization. While industrialization and urbanization have unarguably led to major improvements in quality of life indices in Korea and elsewhere, numerous serious problems have also been acknowledged, including concerns about resource availability, water quality, amplification of global warming and new threats to health. Questions about sustainability have therefore led Koreans and others to consider deurbanization as a management policy. Whether this offers any realistic prospects for a sustainable future remains to be seen. In the interim, it has become increasingly clear that built environments are no less complex than natural environments, and that they depend on a variety of internal and external connections involving microbes and the processes for which microbes are responsible. I provide here a definition of the urban microbiome, and through examples indicate its centrality to human function and wellbeing in urban systems. I also identify important knowledge gaps and unanswered questions about urban microbiomes that must be addressed to develop a robust, predictive and general understanding of urban biology and ecology that can be used to inform policy-making for sustainable systems.


Clinical evaluation of the safety and efficacy of enoxaparin in patients with COVID-19.
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), increases thrombotic risk in hospitalised patients. The rate of thrombosis in patients with COVID-19 is unclear. The role of heparin, frequently used in the management of hospitalised patients, also needs to be clarified. In this study, we investigated the efficacy and safety of enoxaparin given at prophylactic or therapeutic dose in hospitalised patients with COVID-19, and evaluated its role in the development of disease in terms of mortality, and incidence of thrombotic and bleeding events. We included 141 patients with SARS-CoV-2 infection, admitted to five different wards (one intensive care unit, 2 sub-intensive care units, and 2 general infectious disease units) of Cotugno Hospital, a tertiary care hospital in Naples, Italy, between March and May 2020. Over a median time of 17 days (IQR 11-25), enoxaparin was given to 90/141 patients (63.8%) of whom 65 took a prophylactic and 25 a therapeutic dose. We documented 14 episodes of thrombosis (9.9%); almost all were cases of pulmonary embolism. No significant difference in terms of thromboembolic prevention was found between those patients not receiving anticoagulants and those on prophylactic or therapeutic dose of enoxaparin. Five episodes of major bleeding occurred (3.5%); therapeutic dose of enoxaparin was associated with a greater bleeding risk than prophylactic dose (p=0.002). During follow-up, 31 patients (22%) died; these were mostly elderly men with two or more comorbidities at admission. No advantages of enoxaparin, either as prophylaxis or at high doses, in terms of mortality were observed. At multivariate analysis, low estimated glomerular filtration rate, and high total bilirubin and fasting hyperglycemia were independently associated with a higher mortality. We did not observe advantages in terms of either thromboembolic prevention or mortality of enoxaparin, which however was more frequently used in patients with more severe disease. Prophylactic enoxaparin was not seen to be associated with bleeding risk.


(D-Ala2)deltorphin II: D1-dependent stereotypies and stimulation of dopamine release in the nucleus accumbens.
In order to investigate the relative role of central delta- and mu-opioid receptors in behavior, the effects of (D-Ala2)deltorphin II, a natural delta-opioid peptide, and PL017, a beta-casomorphin derivative specific for mu receptors, were compared after local intracerebral and intraventricular administration. Intracerebral infusion of the two peptides was done bilaterally in the limbic nucleus accumbens and in the ventral and dorsal caudate putamen of freely moving rats through chronic intracerebral cannulas. After intra-accumbens infusion, the two peptides elicited marked but opposite behavioral effects: while (D-Ala2)deltorphin II evoked dose-dependent motor stimulation characterized by locomotion, sniffing, and oral stereotypies, PL017 elicited motor inhibition with rigidity and catalepsy. These effects were site specific because they could not be evoked from the ventral or from the dorsal caudate. Low doses of naloxone (0.1 mg/kg, s.c.) blocked the effects of PL017 but not those of (D-Ala2)deltorphin II, which instead were reduced by high doses of naloxone (1.0 mg/kg) and by the putative delta-antagonist naltrindole; this drug failed to affect the catalepsy induced by PL017. Therefore, while (D-Ala2)deltorphin II effects were delta-mediated, PL017 effects were mu-mediated. Blockade of dopamine D1 receptors by SCH 23390 abolished (D-Ala2)deltorphin II effects, while blockade of dopamine D2 receptors by raclopride or by haloperidol was without effect. Local application by reverse dialysis of (D-Ala2)deltorphin II (5 microM) to the accumbens resulted in a naloxone-sensitive increase of extracellular dopamine concentrations; these effects could not be evoked from the caudate, nor by PL017 in the accumbens. Intracerebroventricular administration of (D-Ala2)deltorphin II or of PL017 elicited behavioral effects qualitatively similar to those obtained from the accumbens.


QTL mapping for Mediterranean corn borer resistance in European flint germplasm using recombinant inbred lines.
Ostrinia nubilalis (ECB) and Sesamia nonagrioides (MCB) are two maize stem borers which cause important losses in temperate maize production, but QTL analyses for corn borer resistance were mostly restricted to ECB resistance and maize materials genetically related (mapping populations derived from B73). Therefore, the objective of this work was to identify and characterize QTLs for MCB resistance and agronomic traits in a RILs population derived from European flint inbreds. Three QTLs were detected for stalk tunnel length at bins 1.02, 3.05 and 8.05 which explained 7.5% of the RILs genotypic variance. The QTL at bin 3.05 was co-located to a QTL related to plant height and grain humidity and the QTL at bin 8.05 was located near a QTL related to yield. Our results, when compared with results from other authors, suggest the presence of genes involved in cell wall biosynthesis or fortification with effects on resistance to different corn borer species and digestibility for dairy cattle. Particularly, we proposed five candidate genes related to cell wall characteristics which could explain the QTL for stalk tunnelling in the region 3.05. However, the small proportion of genotypic variance explained by the QTLs suggest that there are also many other genes of small effect regulating MCB resistance and we conclude that MAS seems not promising for this trait. Two QTLs detected for stalk tunnelling overlap with QTLs for agronomic traits, indicating the presence of pleitropism or linkage between genes affecting resistance and agronomic traits.


Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy: the D: A: D study.
The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. Participants were followed from the latest of D:A:D study entry or January 1, 2004, until the earliest of a first cancer diagnosis, February 1, 2012, death, or 6 months after the last visit. Multivariable Poisson regression models assessed associations between cumulative (per year) use of either any cART or PI/NNRTI, and the incidence of any cancer, non-AIDS-defining cancers (NADC), AIDS-defining cancers (ADC), and the most frequently occurring ADC (Kaposi sarcoma, non-Hodgkin lymphoma) and NADC (lung, invasive anal, head/neck cancers, and Hodgkin lymphoma). A total of 41,762 persons contributed 241,556 person-years (PY). A total of 1832 cancers were diagnosed [incidence rate: 0.76/100 PY (95% confidence interval: 0.72 to 0.79)], 718 ADC [0.30/100 PY (0.28-0.32)], and 1114 NADC [0.46/100 PY (0.43-0.49)]. Longer exposure to cART was associated with a lower ADC risk [adjusted rate ratio: 0.88/year (0.85-0.92)] but a higher NADC risk [1.02/year (1.00-1.03)]. Both PI and NNRTI use were associated with a lower ADC risk [PI: 0.96/year (0.92-1.00); NNRTI: 0.86/year (0.81-0.91)]. PI use was associated with a higher NADC risk [1.03/year (1.01-1.05)]. Although this was largely driven by an association with anal cancer [1.08/year (1.04-1.13)], the association remained after excluding anal cancers from the end point [1.02/year (1.01-1.04)]. No association was seen between NNRTI use and NADC [1.00/year (0.98-1.02)]. Cumulative use of PIs may be associated with a higher risk of anal cancer and possibly other NADC. Further investigation of biological mechanisms is warranted.


Charge localization increases chemical expansion in cerium-based oxides.
In this work, we demonstrate the mechanism by which electronic charge localization increases the chemical expansion coefficient in two model systems, CeO(2-δ) and BaCeO(3-δ). Using Density Functional Theory calculations, we predict that this coefficient is increased by more than 70% when charge is fully localized, consistent with the observation that materials with a smaller degree of charge localization have smaller chemical expansion coefficients. This finding has important consequences for devising materials with smaller chemical expansion coefficients and for the reliability of the widely-used Shannon's ionic radii.


The cholinergic blockade of both thermally and non-thermally induced human eccrine sweating.
Thermally induced eccrine sweating is cholinergically mediated, but other neurotransmitters have been postulated for psychological (emotional) sweating. However, we hypothesized that such sweating is not noradrenergically driven in passively heated, resting humans. To test this, nine supine subjects were exposed to non-thermal stimuli (palmar pain, mental arithmetic and static exercise) known to evoke sweating. Trials consisted of the following four sequential phases: thermoneutral rest; passive heating to elevate (by ~1.0°C) and clamp mean body temperature and steady-state sweating (perfusion garment and footbath); an atropine sulphate infusion (0.04 mg kg(-1)) with thermal clamping sustained; and following clamp removal. Sudomotor responses from glabrous (hairless) and non-glabrous skin surfaces were measured simultaneously (precursor and discharged sweating). When thermoneutral, these non-thermal stimuli elicited significant sweating only from the palm (P < 0.05). Passive heating induced steady-state sweating ranging from 0.20 ± 0.04 (volar hand) to 1.40 ± 0.14 mg cm(-2) min(-1) (forehead), with each non-thermal stimulus provoking greater secretion (P < 0.05). Atropine suppressed thermal sweating, and it also eliminated the sudomotor responses to these non-thermal stimuli when body temperatures were prevented from rising (P > 0.05). However, when the thermal clamp was removed, core and skin temperatures became further elevated and sweating was restored (P < 0.05), indicating that the blockade had been overcome, presumably through elevated receptor competition. These observations establish the dependence of both thermal and non-thermal eccrine sweating from glabrous and non-glabrous surfaces on acetylcholine release, and challenge theories concerning the psychological modulation of sweating. Furthermore, no evidence existed for the significant participation of non-cholinergic neurotransmitters during any of these stimulations.


Measuring rough optical surfaces using scanning long-wave optical test system. 1. Principle and implementation.
Current metrology tools have limitations when measuring rough aspherical surfaces with 1-2 μm root mean square roughness; thus, the surface cannot be shaped accurately by grinding. To improve the accuracy of grinding, the scanning long-wave optical test system (SLOTS) has been developed to measure rough aspherical surfaces quickly and accurately with high spatial resolution and low cost. It is a long-wave infrared deflectometry device consisting of a heated metal ribbon and an uncooled thermal imaging camera. A slope repeatability of 13.6 μrad and a root-mean-square surface accuracy of 31 nm have been achieved in the measurements of two 4 inch spherical surfaces. The shape of a rough surface ground with 44 μm grits was also measured, and the result matches that from a laser tracker measurement. With further calibration, SLOTS promises to provide robust guidance through the grinding of aspherics.


Hyperphosphorylation of JNK-interacting protein 1, a protein associated with Alzheimer disease.
The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases are activated by pleiotropic signals including environmental stresses, growth factors, and hormones. JNK-interacting protein 1 (JIP1) is a scaffold protein that assembles and facilitates the activation of the mixed lineage kinase-dependent JNK module and also establishes an interaction with beta-amyloid precursor protein that has been partially characterized. Here we show that, similarly to other proteins involved in various neurological diseases, JIP1 becomes hyperphosphorylated following activation of stress-activated and MAP kinases. By immobilized metal affinity chromatography and a combined microcapillary LC/MALDI-TOF/ESI-ion trap mass spectrometry approach, we identified 35 sites of mitotic phosphorylation within JIP1, among which eight were present within (Ser/Thr)-Pro sequence. This motif is modified by various kinases in aggregates of the microtubule-associated protein tau, which generates typical intraneuronal lesions occurring in Alzheimer disease. Most of the post-translational modifications found were located within the JNK, MAP kinase kinase, and RAC-alpha Ser/Thr protein kinase binding regions; no modifications occurred in protein Src homology 3 and phosphotyrosine interaction domains, which are essential for binding to kinesin, beta-amyloid precursor protein, and MAP kinase kinase kinase. Protein phosphorylation is known to affect stability and protein-protein interactions. Thus, the findings that JIP1 is extensively phosphorylated after activation of stress-activated and MAP kinases indicate that these signaling pathways might modulate JIP1 signaling by regulating its stability and association with some, but not all, interacting proteins.


Distinct Contributions of Autophagy Receptors in Measles Virus Replication.
Autophagy is a potent cell autonomous defense mechanism that engages the lysosomal pathway to fight intracellular pathogens. Several autophagy receptors can recognize invading pathogens in order to target them towards autophagy for their degradation after the fusion of pathogen-containing autophagosomes with lysosomes. However, numerous intracellular pathogens can avoid or exploit autophagy, among which is measles virus (MeV). This virus induces a complete autophagy flux, which is required to improve viral replication. We therefore asked how measles virus interferes with autophagy receptors during the course of infection. We report that in addition to NDP52/CALCOCO₂ and OPTINEURIN/OPTN, another autophagy receptor, namely T6BP/TAXIBP1, also regulates the maturation of autophagosomes by promoting their fusion with lysosomes, independently of any infection. Surprisingly, only two of these receptors, NDP52 and T6BP, impacted measles virus replication, although independently, and possibly through physical interaction with MeV proteins. Thus, our results suggest that a restricted set of autophagosomes is selectively exploited by measles virus to replicate in the course of infection.


Inhibition of aberrant cyclin-dependent kinase 5 activity attenuates isoflurane neurotoxicity in the developing brain.
Aberrant CDK5 activity is implicated in a number of neurodegenerative disorders. Isoflurane exposure leads to neuronal apoptosis, and subsequent learning and memory defects in the developing brain. The present study was designed to examine whether and how CDK5 activity plays a role in developmental isoflurane neurotoxicity. Rat pups and hippocampal neuronal cultures were exposed to 1.5% isoflurane for 4 h. The protein and mRNA levels of CDK5, p35 and p25 were detected by western blot and QReal-Time PCR. CDK5 activity was evaluated in vitro using Histone H1 as a substrate. Roscovitine (an inhibitor of CDK5) was applied before isoflurane treatment, cleaved Caspase-3, Bcl-2, Bax, MEF2 and phospho-MEF2A-Ser-408 expressions were determined. Dominant-Negative CDK5 was transfected before isoflurane treatment. Neuronal apoptosis was evaluated by Flow cytometry (FCM) and TUNEL-staining. Cognitive functions were assessed by Morris water maze. We found that isoflurane treatment led to an aberrant CDK5 activation due to its activator p25 that was cleaved from p35 by calpain. Inhibition of CDK5 activity with Roscovitine enhanced Bcl-2, and decreased cleaved Caspase-3 and Bax expressions. In addition, isoflurane exposure resulted in a decrease of MEF2 and increase of phospho-MEF2A-Ser-408, which were rescued by Roscovitine or Dominant-Negative CDK5 transfection. Dominant-Negative CDK5 transfection also decreased the percentage of TUNEL-positive cells in isoflurane neurotoxicity. Moreover, Roscovitine remarkably alleviated the learning and memory deficits induced by postnatal isoflurane exposure. These results indicated that aberrant CDK5 activity-dependent MEF2 phosphorylation mediates developmental isoflurane neurotoxicity. Inhibition of CDK5 overactivation contributes to the relief of isoflurane neurotoxicity in the developing brain.


Role of a BCL9-related beta-catenin-binding protein, B9L, in tumorigenesis induced by aberrant activation of Wnt signaling.
Wnt signaling plays a crucial role in a number of developmental processes and in tumorigenesis. beta-Catenin is stabilized by Wnt signaling and associates with the TCF/LEF family of transcription factors, thereby activating transcription of Wnt target genes. Constitutive activation of beta-catenin-TCF-mediated transcription resulting from mutations in adenomatous polyposis coli (APC), beta-catenin, or Axin is believed to be a critical step in tumorigenesis among divergent types of cancers. Here we show that the transactivation potential of the beta-catenin-TCF complex is enhanced by its interaction with a BCL9-like protein, B9L, in addition to BCL9. We found that B9L is required for enhanced beta-catenin-TCF-mediated transcription in colorectal tumor cells and for beta-catenin-induced transformation of RK3E cells. Furthermore, expression of B9L was aberrantly elevated in about 43% of colorectal tumors, relative to the corresponding noncancerous tissues. These results suggest that B9L plays an important role in tumorigenesis induced by aberrant activation of Wnt signaling.


Responsive hydrogels for label-free signal transduction within biosensors.
Hydrogels have found wide application in biosensors due to their versatile nature. This family of materials is applied in biosensing either to increase the loading capacity compared to two-dimensional surfaces, or to support biospecific hydrogel swelling occurring subsequent to specific recognition of an analyte. This review focuses on various principles underpinning the design of biospecific hydrogels acting through various molecular mechanisms in transducing the recognition event of label-free analytes. Towards this end, we describe several promising hydrogel systems that when combined with the appropriate readout platform and quantitative approach could lead to future real-life applications.


Preoperative patient selection with magnetic resonance imaging, computed tomography, and electroencephalography: does the test predict outcome after cervical surgery?
The objective of this systematic review was to use evidence-based medicine to assess whether preoperative imaging or electromyography (EMG) predicts surgical outcomes in patients undergoing cervical surgery. The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to the preoperative imaging and EMG. Abstracts were reviewed after which studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Preoperative MR imaging and CT myelography are successful in confirming clinical radiculopathy (Class II). Multilevel T2 hyperintensity, T1 focal hypointensity combined with T2 focal hyperintensity, and spinal cord atrophy each convey a poor prognosis (Class III). There is conflicting data concerning whether focal T2 hyperintensity or cervical stenosis are associated with a worse outcome. Electromyography has mixed utility in predicting outcome (Class III). Magnetic resonance imaging or CT myelography are important for preoperative assessment. Magnetic resonance imaging may be helpful in assessing prognosis, whereas EMG has mixed utility in assessing outcome.


Local vasodilator response to mobile phones.
The use of mobile phones with the resulting generation of potentially harmful electromagnetic fields (EMF) is the focus of public interest. Heat generation and the activation of the inducible form of nitric oxide (NO) synthase may be possible causes of the biological effects of EMF exposure. We investigated if a mobile telephone conversation can modify skin temperature, NO, and nasal resistance. We studied the effect of an EMF (900 MHz) generated by a commercially available cellular phone during a 30-minute telephone conversation on skin temperature, nasal NO measured by chemiluminescence, and nasal minimal cross-sectional area (MCA) measured by rhinometry. Eleven normal subjects (mean age +/- standard error of mean [SEM], 32 +/- 5 y; 10 male) were studied. There was a similar and significant increase in skin temperature of the nostril and occipital area on the same side as the telephone (maximal increase 2.3 +/- 0.2 degrees C at 6 min) as well as a tendency for higher nasal NO levels (maximal increase 12.9 +/- 4.9% at 10 min), whereas the MCA was significantly reduced (maximal decrease -27 +/- 6% at 15 min). Such changes were not recorded when an earpiece was used to avoid the direct exposure to the electromagnetic field. There were no changes in the skin temperature and nasal NO measured on the opposite side to the mobile phone, whereas the MCA was significantly increased (38 +/- 10%). Exposure to EMF produced by a mobile phone produces biological effects that can be easily measured. Microwaves may increase skin temperature and therefore cause vasodilation and reduce MCA. Further studies are needed to study the long-term effects of mobile phone use and the relation among NO production, vasodilation, and temperature.


Emergent features in the crowding zone: When target-flanker grouping surmounts crowding.
Crowding is the impairment of target identification when the target is surrounded by nearby flankers. Two hallmarks of crowding are that it is stronger when the flankers are close to the target and when the target strongly groups with the flankers. Here we show the opposite of both. A chevron target (pointing up or down) was presented at 8° eccentricity in the right visual field. It was surrounded by four flankers. Three of the flankers varied (pointing left or right). The fourth, the critical flanker (CF), was fixed in one orientation (left, right, up, down), yielding different configurations with the target. The CF's distance to the target was varied. Target identification depended strongly on the distance and the orientation of the CF. Remarkably, when the target and the CF grouped into a good configuration and elicited an emergent feature, performance was high if the CF was close to the target. This effect was particularly strong when participants were informed about the different CF-target configurations before the experiment. Reducing crowding and grouping by asynchronous presentation of the CF and the other items abolished the effect. When participants reported the entire configuration of the CF and the target, performance rapidly decreased with increasing spacing when the CF and the target were different but not when they were the same, indicating different spatial extents of the corresponding grouping processes. Our results show that the features emerging from the configurations of the target and a flanker strongly modulate crowding. Strong target-flanker grouping can benefit performance.


Total energy expenditure and physical activity measured with the bicarbonate-urea method in patients with human immunodeficiency virus infection.
1. Our objectives were to measure total energy expenditure, the daily variation in total energy expenditure and the physical activity level in a group of HIV-positive subjects using the bicarbonate-urea method. The study also aimed to asses the practicalities of using the bicarbonate-urea technique in free-living conditions. 2. Total energy expenditure was measured with the bicarbonate-urea method over 2 consecutive days (1 day in one subject) in 10 male patients with HIV infection (median CD4 count = 30). Resting energy expenditure was measured by indirect calorimetry. Physical activity level (total energy expenditure/resting energy expenditure) was calculated from these measurements and from activity diaries. 3. Resting energy expenditure was found to be 7.46 +/- 0.87 MJ/day, 5% higher than predicted values. Total energy expenditure was 10.69 +/- 1.95 MJ/day with an intra-individual day-to-day variation of 6 +/- 6%. The measured physical activity level was 1.42 +/- 0.14, higher than the diary estimate of 1.34 +/- 0.16 (P = 0.029), and there were large intermethod differences in individual values. The subcutaneous infusion of bicarbonate was well tolerated and did not seem to restrict normal activities. 4. Total energy expenditure was not elevated in the group of HIV-positive subjects when compared with reference values for normal subjects. The physical activity level of the patients in this study was lower than that measured using other techniques in healthy young men, but was compatible with that expected for people leading a sedentary lifestyle. Reductions in physical activity in patients with HIV are likely to contribute to the wasting process and physical activity level may thus be a clinically useful measure. This study has also provided the first tracer estimate of the day-to-day variation in total energy expenditure. The bicarbonate-urea method represents an important new investigative tool for measuring total energy expenditure which has previously only been possible within the confines of a whole-body calorimeter or using the expensive doubly labelled water method.


Retrotranspositions in orthologous regions of closely related grass species.
Retrotransposons are commonly occurring eukaryotic transposable elements (TEs). Among these, long terminal repeat (LTR) retrotransposons are the most abundant TEs and can comprise 50-90% of the genome in higher plants. By comparing the orthologous chromosomal regions of closely related species, the effects of TEs on the evolution of plant genomes can be studied in detail. Here, we compared the composition and organization of TEs within five orthologous chromosomal regions among three grass species: maize, sorghum, and rice. We identified a total of 132 full or fragmented LTR retrotransposons in these regions. As a percentage of the total cumulative sequence in each species, LTR retrotransposons occupy 45.1% of the maize, 21.1% of the rice, and 3.7% of the sorghum regions. The most common elements in the maize retrotransposon-rich regions are the copia-like retrotransposons with 39% and the gypsy-like retrotransposons with 37%. Using the contiguous sequence of the orthologous regions, we detected 108 retrotransposons with intact target duplication sites and both LTR termini. Here, we show that 74% of these elements inserted into their host genome less than 1 million years ago and that many retroelements expanded in size by the insertion of other sequences. These inserts were predominantly other retroelements, however, several of them were also fragmented genes. Unforeseen was the finding of intact genes embedded within LTR retrotransposons. Although the abundance of retroelements between maize and rice is consistent with their different genome sizes of 2,364 and 389 Mb respectively, the content of retrotransposons in sorghum (790 Mb) is surprisingly low. In all three species, retrotransposition is a very recent activity relative to their speciation. While it was known that genes re-insert into non-orthologous positions of plant genomes, they appear to re-insert also within retrotransposons, potentially providing an important role for retrotransposons in the evolution of gene function.


Milk-substitutes comparable to rat's milk; their preparation, composition and impact on development and metabolism in the artificially reared rat.
1. Procedures are described to prepare nutritionally adequate rat milk-substitutes by modifying commercially available processed cow's milk, rich in carbohydrate and low in protein and fat compared with rat's milk. 2. Premilk formulas, prepared as intermediates in the preparation of rat milk-substitutes, are rich in protein but low in their concentration of fat, carbohydrate, and minerals when compared with rat's milk. 3. Premilks were supplemented with lactose, vitamins, minerals, fat as oil mixtures, certain amino acids and other constituents to yield rat milk-substitutes which resemble the known composition of rat's milk in their properties and composition. 4. Detailed analyses of the milk-substitutes show them to be comparable to rat's milk in energy content, pH, osmolarity, the concentration of the macronutrients, fat, protein and carbohydrate, and the major minerals. 5. Rat pups were artificially reared from postnatal day 4 or 5 until days 16-18 by fitting them with gastric cannulas through which the milk-substitutes could be infused automatically. 6. The nutritional impact of the milk-substitutes was assessed by a comparison of growth and metabolic characteristics for artificially reared rats with age-matched sucking rats reared by their mother. 7. Indices which were taken to be appropriate included (a) body-weight gain; (b) the concentration in blood of protein, amino acids, ketone bodies, carnitine, glucose, galactose, lactate, insulin, and the electrolytes calcium, sodium, potassium and chloride; (c) the turnover of glucose and 3-hydroxybutyrate; (d) the concentration in brain of protein, cholesterol, cerebroside sulphate and the activities of the enzymes pyruvate dehydrogenase (EC 126.96.36.199), 3-oxo-acid-CoA transferase (EC 22.214.171.124) and acetoacetyl-CoA ligase (EC 18.104.22.168). 8. The studies suggest that milk-substitutes approximating to rat's milk in composition promote acceptable metabolism in the artificially reared rat pup.


A systematic review on the impact of gestational Lyme disease in humans on the fetus and newborn.
Lyme disease (LD), caused by bacteria of the Borrelia burgdorferi sensu lato species complex, is the most common vector-borne disease in North America and Europe. A systematic review (SR) was conducted to summarize the global literature on adverse birth outcomes associated with gestational LD in humans. The SR followed an a priori protocol of pretested screening, risk of bias, and data extraction forms. Data were summarized descriptively and random effects meta-analysis (MA) was used where appropriate. The SR identified 45 relevant studies, 29 describing 59 cases reported as gestational LD in the United States, Europe, and Asia (1969-2017). Adverse birth outcomes included spontaneous miscarriage or fetal death (n = 12), newborn death (n = 8), and newborns with an abnormal outcome (e.g. hyperbilirubinemia, respiratory distress and syndactyly) at birth (n = 16). Only one report provided a full case description (clinical manifestations in the mother, negative outcome for the child, and laboratory detection of B. burgdorferi in the child) that provides some evidence for vertical transmission of B. burgdorferi that has negative consequences for the fetus. The results of 17 epidemiological studies are included in this SR. Prevalence of adverse birth outcomes in an exposed population (defined by the authors as: gestational LD, history of LD, tick bites or residence in an endemic area) was compared to that in an unexposed population in eight studies and no difference was reported. A meta-analysis of nine studies showed significantly fewer adverse birth outcomes in women reported to have been treated for gestational LD (11%, 95%CI 7-16) compared to those who were not treated during pregnancy (50%, 95%CI 30-70) providing indirect evidence of an association between gestational LD and adverse birth outcomes. Other risk factors investigated; trimester of exposure, length of LD during pregnancy, acute vs. disseminated LD at diagnosis, and symptomatic LD vs. seropositive women with no LD symptoms during pregnancy were not significantly associated with adverse birth outcomes. This SR summarizes evidence from case studies that provide some limited evidence for transplacental transmission of B. burgdorferi. There was inconsistent evidence for adverse birth outcomes of gestational LD in the epidemiological research, and uncommon adverse outcomes for the fetus may occur as a consequence of gestational LD. The global evidence does not fully characterize the potential impact of gestational LD, and future research that addresses the knowledge gaps may change the findings in this SR. Given the current evidence; prompt diagnosis and treatment of LD during pregnancy is recommended.


Efficacy of Preoperative Chemotherapy for High Risk Upper Tract Urothelial Carcinoma.
The impact of preoperative chemotherapy in patients with upper urinary tract urothelial carcinoma remains poorly investigated. We assessed the rates of pathological complete response (pT0N0/X) and downstaging (pT1N0/X or less) at radical nephroureterectomy after preoperative chemotherapy and evaluated their impact on survival. This was an international observational study of patients who underwent preoperative chemotherapy and radical nephroureterectomy for high risk upper tract urothelial carcinoma between 2005 and 2017. Multiple imputation of chained equations was applied to account for missing values. Logistic regression analyses were performed to identify predictors of pathological response. Cox proportional hazard regression models were used to estimate recurrence-free survival, cancer specific survival and overall survival. A total of 267 patients met our inclusion criteria. Among included patients 82 (31%) received methotrexate, vinblastine, doxorubicin and cisplatin; 123 (46%) gemcitabine and cisplatin; 25 (9%) gemcitabine and carboplatin; and 32 (12%) other regimens. The overall rates of pathological complete response and pathological downstaging were 10.1% and 44.9%, respectively. On multivariable analysis the use of gemcitabine and cisplatin, and gemcitabine and carboplatin was not statistically different from methotrexate, vinblastine, doxorubicin and cisplatin in achieving pathological complete response and pathological downstaging, respectively. The number of administered cycles did not appear to have an effect on pathological responses. Pathological downstaging was the strongest prognostic factor for recurrence-free survival (HR 0.2, p <0.001), cancer specific survival (HR 0.19, p <0.001) and overall survival (HR 0.40, p <0.001). Pathological downstaging after preoperative chemotherapy is a robust prognostic factor at radical nephroureterectomy and is associated with improved survival outcomes. Although preoperative chemotherapy appears to be effective, well designed prospective studies are still needed.


Wound infection in gynecologic surgery.
We sought to determine the wound infection rate among patients undergoing elective gynecologic surgery at a single tertiary care center and to determine the predictive value of various factors that contribute to infection. We further investigated the adequacy of hospital records in documenting infection rates as well as the timing of presentation of wound infections. The records of 115 patients undergoing elective gynecologic surgery at our institution were reviewed. Patients were further subdivided based on route of surgery. We analyzed the importance of antibiotic prophylaxis, route of surgery, smoking, diabetes, and body mass index (BMI). The overall wound infection rate was 12.17% with no significant difference in the subgroups by route of surgery. Overall, antibiotic prophylaxis significantly decreased infection rates (P = 0.0118), but the route of surgery, BMI, smoking, and diabetes were not significant predictors of infection. Only one case of infection was detected during the initial hospital stay (6.1%). Fifty percent of the patients with infection required readmission, and of these 35.7% required an additional surgical procedure. The average length of hospital stay was 2.4 days longer in patients with infection. Antibiotic prophylaxis has a role in the management of patients undergoing abdominal gynecologic surgery. In today's environment of cost containment, an increased hospital stay and the added likelihood of additional surgical intervention associated with wound infection are important targets for prevention. Most patients with wound infection were diagnosed after discharge from the hospital. In our population, among whom transportation problems and remote residence are prevalent, strategies for infection surveillance should be integral to discharge planning.


Effect of gain dispersion and stimulated Raman scattering on soliton amplification in fiber amplifiers.
Amplification of ultrashort solitons in fiber amplifiers is discussed by considering a general model that includes gain saturation, gain dispersion, and intrapulse stimulated Raman scattering. The numerical results show that an interplay between gain dispersion and intrapulse Raman scattering can lead to novel temporal and spectral features. Under high-gain conditions the input pulse is found to split into several subpulses propagating at different speeds. Each subpulse evolves toward a chirped soliton whose width is governed by the gain bandwidth and is ~50 fsec for erbium-doped fiber amplifiers.