Is adjuvant chemotherapy for completely resected p-stage IA (>2 cm) and stage IB non-small-cell lung cancer beneficial for elderly patients? A large, retrospective cohort study based on real-world data from Japan.
The efficacy of tegafur-uracil as adjuvant chemotherapy for patients with completely resected stage I non-small-cell lung cancer is proven; however, its efficacy for elderly patients remains unclear. Herein, we evaluated the effectiveness of adjuvant chemotherapy for elderly patients with completely resected stage I non-small-cell lung cancer based on real-world Japanese data using propensity score matching. This retrospective study extracted data from a nationwide registry study, performed in 2016, on patients ≥75 years who underwent lobectomy with mediastinal nodal dissection for non-small-cell lung cancer in 2010 and were diagnosed with p-stage IA (>2 cm) or stage IB non-small-cell lung cancer. We classified the 1294 patients into two groups-Group A, postoperative adjuvant chemotherapy (n = 295, 22.8%) and Group N, no adjuvant chemotherapy (n = 999, 77.2%)-and analyzed differences in postoperative overall survival between groups. Group A showed no advantage in overall survival over Group N as a whole (hazard ratio: 0.824 [95% confidence interval: 0.631-1.076]), in p-stage IA (hazard ratio: 0.617 [95% confidence interval: 0.330-1.156]) and in p-stage IB (hazard ratio: 0.806 [95% confidence interval: 0.597-1.088]) subsets. Even after propensity score matching, Group A showed no significant advantage in overall survival over Group N as a whole (hazard ratio: 0.975 [95% confidence interval: 0.688-1.381]), in p-stage IA (hazard ratio: 1.390 [95% confidence interval: 0.539-3.586]) and in p-stage IB (hazard ratio: 0.922 [95% confidence interval: 0.633-1.343]). adjuvant chemotherapy for completely resected p-stage IA (>2 cm) and stage IB non-small-cell lung cancer showed no benefit for recommendation for elderly patients; considering the risk of adverse events, we do not recommend adjuvant chemotherapy for elderly patients.


A survey on clinical natural language processing in the United Kingdom from 2007 to 2022.
Much of the knowledge and information needed for enabling high-quality clinical research is stored in free-text format. Natural language processing (NLP) has been used to extract information from these sources at scale for several decades. This paper aims to present a comprehensive review of clinical NLP for the past 15 years in the UK to identify the community, depict its evolution, analyse methodologies and applications, and identify the main barriers. We collect a dataset of clinical NLP projects (n = 94; £ = 41.97 m) funded by UK funders or the European Union's funding programmes. Additionally, we extract details on 9 funders, 137 organisations, 139 persons and 431 research papers. Networks are created from timestamped data interlinking all entities, and network analysis is subsequently applied to generate insights. 431 publications are identified as part of a literature review, of which 107 are eligible for final analysis. Results show, not surprisingly, clinical NLP in the UK has increased substantially in the last 15 years: the total budget in the period of 2019-2022 was 80 times that of 2007-2010. However, the effort is required to deepen areas such as disease (sub-)phenotyping and broaden application domains. There is also a need to improve links between academia and industry and enable deployments in real-world settings for the realisation of clinical NLP's great potential in care delivery. The major barriers include research and development access to hospital data, lack of capable computational resources in the right places, the scarcity of labelled data and barriers to sharing of pretrained models.


Prenatal diagnosis of Tay-Sachs genotypes.
Hexosaminidase activity was determined in cultured and uncultured amniotic fluid cells taken from seven pregnant women who had previously given birth to infants with Tay-Sachs disease. Complete deficiency of hexosaminidase A was found in one case, indicating a Tay-Sachs fetus. The diagnosis was confirmed on examination of various tissues after therapeutic abortion. Of the other six cases three were considered heterozygous and three homozygous normal. These diagnoses were confirmed postnatally on examination of cord blood leucocytes, peripheral leucocytes, and urine. The activity of hexosaminidase A is appreciably decreased in dead cells and hence in uncultured amniotic fluid cells. Hence reliable identification in utero of the three genotypes may be achieved only by examining the cultured living amniotic cells.


Evaluation of the glutamine 27 glutamic acid polymorphism in the adrenoceptor β2 surface gene on obesity and metabolic phenotypes in Taiwan.
The single-nucleotide polymorphism (SNP), rs1042714 or glutamine 27 glutamic acid (Gln27Glu), in the adrenoceptor β2 surface (ADRB2) gene has previously been examined for association with obesity with inconclusive results. The objective of this study was to determine whether the ADRB2 rs1042714 SNP could influence obesity and obesity-related metabolic traits in a Taiwanese population. The ADRB2 rs1042714 SNP and obesity-related metabolic traits including blood pressure, total cholesterol, triglyceride, fasting glucose, waist circumference, and body mass index (BMI) were examined in 967 individuals with general health examinations. Our data revealed that the ADRB2 rs1042714 SNP exhibited a significant association with obesity among the subjects (P = 0.021). Furthermore, the carriers of the GG genotype had a significantly higher BMI than those with the CC genotype (26.0 ± 5.6 vs 24.3 ± 3.8 kg/m; P = 0.009) and those with the CG genotype (26.0 ± 5.6 vs 23.6 ± 3.3 kg/m; P = 0.001). We also found a nominal association with systolic blood pressure (P = 0.058) and triglyceride (P = 0.055) levels in the ADRB2 rs1042714 SNP. Our study indicates that the ADRB2 rs1042714 SNP may contribute to the risk of obesity and predict obesity-related metabolic traits such as BMI, triglyceride, and systolic blood pressure in Taiwanese subjects.


Why genetically modified crops?
This paper is intended to convey the message of the talk I gave at the Theo Murphy meeting at the Kavli Centre in July 2010. It, like the talk, is polemical, and conveys the exasperation felt by a practitioner of genetically modified (GM) plant science at its widespread misrepresentation. I argue that sustainable intensification of agriculture, using GM as well as other technologies, reduces its environmental impact by reducing pesticide applications and conserving soil carbon by enabling low till methods. Current technologies (primarily insect resistance and herbicide tolerance) have been beneficial. Moreover, the near-term pipeline of new GM methods and traits to enhance our diet, increase crop yields and reduce losses to disease is substantial. It would be perverse to spurn this approach at a time when we need every tool in the toolbox to ensure adequate food production in the short, medium and long term.


Interactions between glycine transporter type 1 (GlyT-1) and some inhibitor molecules - glycine transporter type 1 and its inhibitors (review).
Glycine is a mandatory positive allosteric modulator of N-methyl-D-aspartate (NMDA)-type ionotropic glutamate receptors in the central nervous system. Elevation of glycine concentrations by inhibition of its reuptake in the vicinity of NMDA receptors may positively influence receptor functions as glycine B binding site on NR1 receptor subunit is not saturated in physiological conditions. Synaptic and extrasynaptic concentrations of glycine are regulated by its type-1 glycine transporter, which is primarily expressed in astroglial and glutamatergic cell membranes. Alteration of synaptic glycine levels may have importance in the treatment of various forms of endogenous psychosis characterized by hypofunctional NMDA receptors. Several lines of evidence indicate that impaired NMDA receptor-mediated glutamatergic neurotransmission is involved in development of the negative (and partly the positive) symptoms and the cognitive deficit in schizophrenia. Inhibitors of glycine transporter type-1 may represent a newly developed therapeutic intervention in treatment of this mental illness. We have synthesized a novel series of N-substituted sarcosines, analogues of the glycine transporter-1 inhibitor NFPS (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine). Of the pyridazinone-containing compounds, SzV-1997 was found to be a potent glycine transporter-1 inhibitor in rat brain synaptosomes and it markedly increased extracellular glycine concentrations in conscious rat striatum. SzV-1997 did not exhibit toxic symptoms such as hyperlocomotion, restless movements, respiratory depression, and lethality, characteristic for NFPS. Besides pyridazinone-based, sarcosine-containing glycine transporter-1 inhibitors, a series of substrate-type amino acid inhibitors was investigated in order to obtain better insight into the ligand-binding characteristics of the substrate binding cavity of the transporter.


PhOTO zebrafish: a transgenic resource for in vivo lineage tracing during development and regeneration.
Elucidating the complex cell dynamics (divisions, movement, morphological changes, etc.) underlying embryonic development and adult tissue regeneration requires an efficient means to track cells with high fidelity in space and time. To satisfy this criterion, we developed a transgenic zebrafish line, called PhOTO, that allows photoconvertible optical tracking of nuclear and membrane dynamics in vivo. PhOTO zebrafish ubiquitously express targeted blue fluorescent protein (FP) Cerulean and photoconvertible FP Dendra2 fusions, allowing for instantaneous, precise targeting and tracking of any number of cells using Dendra2 photoconversion while simultaneously monitoring global cell behavior and morphology. Expression persists through adulthood, making the PhOTO zebrafish an excellent tool for studying tissue regeneration: after tail fin amputation and photoconversion of a ∼100 µm stripe along the cut area, marked differences seen in how cells contribute to the new tissue give detailed insight into the dynamic process of regeneration. Photoconverted cells that contributed to the regenerate were separated into three distinct populations corresponding to the extent of cell division 7 days after amputation, and a subset of cells that divided the least were organized into an evenly spaced, linear orientation along the length of the newly regenerating fin. PhOTO zebrafish have wide applicability for lineage tracing at the systems-level in the early embryo as well as in the adult, making them ideal candidate tools for future research in development, traumatic injury and regeneration, cancer progression, and stem cell behavior.


Soil respiration under climate warming: differential response of heterotrophic and autotrophic respiration.
Despite decades of research, how climate warming alters the global flux of soil respiration is still poorly characterized. Here, we use meta-analysis to synthesize 202 soil respiration datasets from 50 ecosystem warming experiments across multiple terrestrial ecosystems. We found that, on average, warming by 2 °C increased soil respiration by 12% during the early warming years, but warming-induced drought partially offset this effect. More significantly, the two components of soil respiration, heterotrophic respiration and autotrophic respiration showed distinct responses. The warming effect on autotrophic respiration was not statistically detectable during the early warming years, but nonetheless decreased with treatment duration. In contrast, warming by 2 °C increased heterotrophic respiration by an average of 21%, and this stimulation remained stable over the warming duration. This result challenged the assumption that microbial activity would acclimate to the rising temperature. Together, our findings demonstrate that distinguishing heterotrophic respiration and autotrophic respiration would allow us better understand and predict the long-term response of soil respiration to warming. The dependence of soil respiration on soil moisture condition also underscores the importance of incorporating warming-induced soil hydrological changes when modeling soil respiration under climate change.


Agricultural by-products and oyster shell as alternative nutrient sources for microbial sealing of early age cracks in mortar.
Bio-concrete using bacterially produced calcium carbonate can repair microcracks but is still relatively expensive due to the addition of bacteria, nutrients, and calcium sources. Agricultural by-products and oyster shells were used to produce economical bio-concrete. Sesame meal was the optimal agricultural by-product for low-cost spore production of the alkaliphilic Bacillus miscanthi strain AK13. Transcriptomic dataset was utilized to compare the gene expressions of AK13 strain under neutral and alkaline conditions, which suggested that NaCl and riboflavin could be chosen as growth-promoting factors at alkaline pH. The optimal levels of sesame meal, NaCl, and riboflavin were induced with the central composite design to create an economical medium, in which AK13 strain formed more spores with less price than in commercial sporulation medium. Calcium nitrate obtained from nitric acid treatment of oyster shell powder increased the initial compressive strength of cement mortar. Non-ureolytic calcium carbonate precipitation by AK13 using oyster shell-derived calcium ions was verified by energy-dispersive X-ray spectroscopy and X-ray diffraction analysis. Stereomicroscope and field emission scanning electron microscopy confirmed that oyster shell-derived calcium ions, along with soybean meal-solution, increased the bacterial survival and calcium carbonate precipitation inside mortar cracks. These data suggest the possibility of commercializing bacterial self-healing concrete with economical substitutes for culture medium, growth nutrient, and calcium sources.


Contamination of rural surface and ground water by endosulfan in farming areas of the Western Cape, South Africa.
In South Africa there is little data on environmental pollution of rural water sources by agrochemicals. This study investigated pesticide contamination of ground and surface water in three intensive agricultural areas in the Western Cape: the Hex River Valley, Grabouw and Piketberg. Monitoring for endosulfan and chlorpyrifos at low levels was conducted as well as screening for other pesticides. The quantification limit for endosulfan was 0.1 microg/L. Endosulfan was found to be widespread in ground water, surface water and drinking water. The contamination was mostly at low levels, but regularly exceeded the European Drinking Water Standard of 0.1 microg/L. The two most contaminated sites were a sub-surface drain in the Hex River Valley and a dam in Grabouw, with 0.83 +/- 1.0 microg/L (n = 21) and 3.16 +/- 3.5 microg/L (n = 13) average endosulfan levels respectively. Other pesticides including chlorpyrifos, azinphos-methyl, fenarimol, iprodione, deltamethrin, penconazole and prothiofos were detected. Endosulfan was most frequently detected in Grabouw (69%) followed by Hex River (46%) and Piketberg (39%). Detections were more frequent in surface water (47%) than in groundwater (32%) and coincided with irrigation, and to a lesser extent, to spraying and trigger rains. Total dietary endosulfan intake calculated from levels found in drinking water did not exceed the Joint WHO/FAO Meeting on Pesticide Residues (JMPR) criteria. The study has shown the need for monitoring of pesticide contamination in surface and groundwater, and the development of drinking water quality standards for specific pesticides in South Africa.


Why don't some men with banked sperm respond to letters about their stored samples?
Abstract Long-term storage of banked sperm, especially when it is not needed, for reproductive purposes, is costly and poses practical problems for sperm banks. For sperm banks to function efficiently, men must understand the implications of unnecessary storage, and make timely decisions about disposal of their own samples. Men who bank sperm prior to cancer treatment are routinely offered follow-up consultations to test their fertility, update consent and, where necessary, expedite referral for Assisted Conception. Yet sperm banks report that men do not respond to letters, suggesting samples are stored needlessly. We conducted semi-structured interviews with six men with a history of not responding to letters, to document reasons for non-response. Interviews were transcribed and analysed using Interpretive Phenomenological Analysis. Men's reasons for not responding are a complex interplay between past, present and future perspectives. In terms of their past, information is important on diagnosis, because men must understand that fertility can change after treatment. Present and future concerns focus on fears of being told fertility has not recovered and being pressured to dispose of banked sperm. The challenge is to devise invitation letters that address men's concerns while offering them tangible benefits and peace of mind.


Density functional theory for the study of the multimode Jahn-Teller effect.
The Jahn-Teller (JT) theorem states that in a molecule with a degenerate electronic state, a structural distortion must occur that lowers the symmetry, removes the degeneracy and lowers the energy. The multideterminental-DFT method performed to calculate the JT parameters for JT active molecules is described. Within the harmonic approximation the JT distortion can be analyzed as a linear combination of all totally symmetric normal modes in any of the low symmetry minimum energy conformation, which allows the intrinsic distortion path (IDP) to be calculated, exactly from the high symmetry point to the low symmetry configuration. Results obtained by the approach described here give direct insight into the coupling of electronic structure and nuclear movements.


Tissue motion assessment from 3D echographic speckle tracking.
The potential of ultrasonic image speckle tracking to characterize tissue dynamics has been illustrated and validated elsewhere. In this paper we wish to extend this speckle tracking methodology to 3D. To investigate the feasibility of such an approach we first model the image formation process and simulate the 3D speckle motion inherent to tissue linear transformations (translation, rotation and deformation). It is shown that tissue axial rotation and translation are perfectly correlated with the tissue speckle motion while tissue deformation and non-axial rotations corrupt the speckle pattern with a motion-induced noise and are therefore more difficult to track when large motions are concerned. Furthermore, in the framework of our model, our results indicate that short ultrasound pulses with low frequencies and small beamwidths are more desirable for a speckle tracking methodology. The feasibility of speckle tracking is illustrated with an optical flow algorithm. A theoretical study of the correlation between various linear transformations of the tissue and the corresponding ultrasonic speckle motions is also performed.


A Visual Analytics Framework for Spatiotemporal Trade Network Analysis.
Economic globalization is increasing connectedness among regions of the world, creating complex interdependencies within various supply chains. Recent studies have indicated that changes and disruptions within such networks can serve as indicators for increased risks of violence and armed conflicts. This is especially true of countries that may not be able to compete for scarce commodities during supply shocks. Thus, network-induced vulnerability to supply disruption is typically exported from wealthier populations to disadvantaged populations. As such, researchers and stakeholders concerned with supply chains, political science, environmental studies, etc. need tools to explore the complex dynamics within global trade networks and how the structure of these networks relates to regional instability. However, the multivariate, spatiotemporal nature of the network structure creates a bottleneck in the extraction and analysis of correlations and anomalies for exploratory data analysis and hypothesis generation. Working closely with experts in political science and sustainability, we have developed a highly coordinated, multi-view framework that utilizes anomaly detection, network analytics, and spatiotemporal visualization methods for exploring the relationship between global trade networks and regional instability. Requirements for analysis and initial research questions to be investigated are elicited from domain experts, and a variety of visual encoding techniques for rapid assessment of analysis and correlations between trade goods, network patterns, and time series signatures are explored. We demonstrate the application of our framework through case studies focusing on armed conflicts in Africa, regional instability measures, and their relationship to international global trade.


Evidence-based nutrition for the malnourished, hospitalised patient: one bite at a time.
Although malnutrition is a highly prevalent condition in the inpatient setting, particularly in older patients with multiple morbidities, the medical community has struggled to find efficient, evidence-based approaches for its prevention and treatment. From an evolutionary perspective, illness-related low appetite may be seen as a protective response with the goals to accelerate recovery from disease by improving autophagy. In line with this, earlier trials in the intensive care setting including severely ill patients have demonstrated unwarranted effects of overnutrition on patient outcomes. Uncertainties regarding the best approach to the malnourished inpatient in conjunction with a lack of strong trial data may, in part, explain the low level of attention that hospital medical staff have paid to the issue of malnutrition in the non-critical care inpatient setting. The recent Effect of early nutritional support on Frailty, Functional Outcomes and Recovery of malnourished medical inpatients Trial (EFFORT) study, however, has shown that individualized nutritional support reduces severe complications and improves mortality in medical inpatients, with positive effects on functional outcomes and quality of life. These results from a high quality effectiveness trial in conjunction with other studies, such as the NOURISH trial, should prompt us to improve our management of malnutrition in the inhospital setting. This procedure should start with a systematic screening for risk of malnutrition of admitted patients, effective assessment of nutritional status in multidisciplinary teams including dieticians, nurses and physicians, and early start of individualized adequate nutritional support of at risk patients to reach nutritional goals. Understanding the optimal use of nutritional support in patients with acute illness is complex because timing, route of delivery, and the amount and type of nutrients may all affect patient outcomes. Also, particularly for patients on the medical ward, factors like the logistics of catering, staffing to provide food and support the patient (i.e., number of nurses and dieticians), motivation/understanding of the patient to eat in defiance of appetite, the empathic human factor of nutritional care, the quality of meals, the taste of supplements, and unnecessary fasting for diagnostic or therapeutic procedures have a strong influence on nutritional care of patients. Further research and clinical trials are required to better understand, step by step, how we can use clinical nutrition best to maximize recovery of our patient and improve their functional status and their quality of life. Such evidence regarding nutritional therapy may allow us to implement personalized nutrition-driven interventions in the future.


Comparative Genomics of Carriage and Disease Isolates of Streptococcus pneumoniae Serotype 22F Reveals Lineage-Specific Divergence and Niche Adaptation.
Streptococcus pneumoniae is a major cause of meningitis, sepsis, and pneumonia worldwide. Pneumococcal conjugate vaccines have been part of the United Kingdom's childhood immunization program since 2006 and have significantly reduced the incidence of disease due to vaccine efficacy in reducing carriage in the population. Here we isolated two clones of 22F (an emerging serotype of clinical concern, multilocus sequence types 433 and 698) and conducted comparative genomic analysis on four isolates, paired by Sequence Type (ST) with one of each pair being derived from carriage and the other disease (sepsis). The most compelling observation was of nonsynonymous mutations in pgdA, encoding peptidoglycan N-acetylglucosamine deacetylase A, which was found in the carriage isolates of both ST433 and 698. Deacetylation of pneumococcal peptidoglycan is known to enable resistance to lysozyme upon invasion. Althought no other clear genotypic signatures related to disease or carriage could be determined, additional intriguing comparisons between the two STs were possible. These include the presence of an intact prophage, in addition to numerous additional phage insertions, within the carriage isolate of ST433. Contrasting gene repertoires related to virulence and colonization, including bacteriocins, lantibiotics, and toxin--antitoxin systems, were also observed.


Th2-biased immune system promotion of allogeneic corneal epithelial cell survival after orthotopic limbal transplantation.
The Th2-biased immune system can promote penetrating keratoplasty survival in mice. A series of experiments were performed to determine whether this system could prolong corneal limbal transplant (LT) survival. BALB/c (H-2d) mice were immunized with 50 microg of keyhole limpet hemocyanin (KLH) in incomplete Freud's adjuvant. Four weeks later, the corneal epithelium, including the limbal area, was removed, and the mice received LT from B10.D2 (H-2d), C57BL/10 (H-2b), or enhanced green fluorescence protein (EGFP) transgenic (H-2b) donor mice. Immediately thereafter, recipient mice were immunized with 50 micro g of KLH or Hanks' balanced salt solution (HBSS; control) in complete Freund's adjuvant. The allograft fates were assessed clinically. Lymphocytes of recipients were examined for donor-specific proliferation and for donor-specific cytokine production in vitro. The regenerated epithelia of all C57BL/10 (n=14) and B10.D2 (n=18) grafts were rejected swiftly in control mice, whereas 66.6% of C57BL/10 grafts (8/12, P<0.001) and 62.8% of B10.D2 grafts (22/35, P<0.001) in the KLH immune group remained significantly clear for 8 weeks. Moreover, EGFP donor epithelial cells were detected from the healthy corneas of KLH-immunized mice. As for the in vitro assay, at 1 week after B10.D2 grafting, lymphocytes from KLH-immunized groups showed neither proliferation nor increased cytokine secretion. The Th2-biased immune system can support LT prolongation irrespective of donor disparity and can suppress corneal neovascularization. This prolongation is not due to induction of donor-specific regulatory cells, but is presumably at least associated with the suppression of allosensitization.


The protein-binding potential of C2H2 zinc finger domains.
There are over 10,000 C2H2-type zinc finger (ZF) domains distributed among more than 1,000 ZF proteins in the human genome. These domains are frequently observed to be involved in sequence-specific DNA binding, and uncharacterized domains are typically assumed to facilitate DNA interactions. However, some ZFs also facilitate binding to proteins or RNA. Over 100 Cys2-His2 (C2H2) ZF-protein interactions have been described. We initially attempted a bioinformatics analysis to identify sequence features that would predict a DNA- or protein-binding function. These efforts were complicated by several issues, including uncertainties about the full functional capabilities of the ZFs. We therefore applied an unbiased approach to directly examine the potential for ZFs to facilitate DNA or protein interactions. The human OLF-1/EBF associated zinc finger (OAZ) protein was used as a model. The human O/E-1-associated zinc finger protein (hOAZ) contains 30 ZFs in 6 clusters, some of which have been previously indicated in DNA or protein interactions. DNA binding was assessed using a target site selection (CAST) assay, and protein binding was assessed using a yeast two-hybrid assay. We observed that clusters known to bind DNA could facilitate specific protein interactions, but clusters known to bind protein did not facilitate specific DNA interactions. Our primary conclusion is that DNA binding is a more restricted function of ZFs, and that their potential for mediating protein interactions is likely greater. These results suggest that the role of C2H2 ZF domains in protein interactions has probably been underestimated. The implication of these findings for the prediction of ZF function is discussed.


Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance.
In the nematode Caenorhabditis elegans, formation of the long-lived dauer larva and adult aging are both controlled by insulin/insulin-like growth factor-1 signaling. Potentially, increased adult life span in daf-2 insulin/insulin-like growth factor-1 receptor mutants results from mis-expression in the adult of a dauer larva longevity program. By using oligonucleotide microarray analysis, we identified a dauer transcriptional signature in daf-2 mutant adults. By means of a nonbiased statistical approach, we identified gene classes whose expression is altered similarly in dauers and daf-2 mutants, which represent potential determinants of life span. These include known determinants of longevity; the small heat shock protein/alpha-crystallins are up-regulated in both milieus. The cytochrome P450, short-chain dehydrogenase/reductase, UDP-glucuronosyltransferase, and glutathione S-transferase (in daf-2 mutants) gene classes were also up-regulated. These four gene classes act together in metabolism and excretion of toxic endobiotic and xenobiotic metabolites. This suggests that diverse toxic lipophilic and electrophilic metabolites, disposed of by phase 1 and phase 2 drug metabolism, may be the major determinants of the molecular damage that causes aging. In addition, we observed down-regulation of genes linked to nutrient uptake, including nhx-2 and pep-2. These work together in the uptake of dipeptides in the intestine, implying dietary restriction in daf-2 mutants. Some gene groups up-regulated in dauers and/or daf-2 were enriched for certain promoter elements as follows: the daf-16-binding element, the heat shock-response element, the heat shock-associated sequence, or the hif-1-response element. By contrast, the daf-16-associated element was enriched in genes down-regulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated.


UBIQUITIN-SPECIFIC PROTEASE 26 is required for seed development and the repression of PHERES1 in Arabidopsis.
The Arabidopsis mutant Atubp26 initiates autonomous endosperm at a frequency of approximately 1% in the absence of fertilization and develops arrested seeds at a frequency of approximately 65% when self-pollinated. These phenotypes are similar to those of the FERTILIZATION INDEPENDENT SEED (FIS) class mutants, mea, fis2, fie, and Atmsi1, which also show development of the central cell into endosperm in the absence of fertilization and arrest of the embryo following fertilization. Atubp26 results from a T-DNA insertion in the UBIQUITIN-SPECIFIC PROTEASE gene AtUBP26, which catalyzes deubiquitination of histone H2B and is required for heterochromatin silencing. The paternal copy of AtUBP26 is able to complement the loss of function of the maternal copy in postfertilization seed development. This contrasts to the fis class mutants where the paternal FIS copy does not rescue aborted seeds. As in the fis class mutants, the Polycomb group (PcG) complex target gene PHERES1 (PHE1) is expressed at higher levels in Atubp26 ovules than in wild type; there is a lower level of H3K27me3 at the PHE1 locus. The phenotypes suggest that AtUBP26 is required for normal seed development and the repression of PHE1.


The Impact of Isocyanate Index and Filler Functionalities on the Performance of Flexible Foamed Polyurethane/Ground Tire Rubber Composites.
The structure and performance of polyurethane (PU) foams are strongly driven by the stoichiometry of the polyaddition reaction, quantitatively described by the isocyanate index. It determines the balance between isocyanate and hydroxyl groups in the reacting system and is affected by the introduction of additional functionalities originated, e.g., from applied fillers. Nevertheless, this issue is hardly taken into account in research works. Herein, the structure and performance of PU/ground tire rubber (GTR) composites differing in their isocyanate index (from 0.8 to 1.2) and prepared with and without considering the GTR functionalities in formulation development were investigated. Incorporating GTR into the PU matrix led to a reduction in average cell diameter (from 2 to 30% depending on the isocyanate index) compared to unfilled foams. However, formulation adjustments did not show a significant impact on cellular structure. The only decrease in open cell content was noted, from 10% for the 0.9 index to 40% for 1.2. Such changes were related to the increasing strength of the PU cellular structure able to maintain inside the increasing amount of carbon dioxide. On the other hand, considering hydroxyl values of GTR noticeably affected the thermomechanical performance of composites. The shift of glass transition temperature (Tg), even by 10 °C for 1.2 isocyanate index, enhanced the performance of materials, which was expressed in an 8-62% drop in the composite performance factor, pointing to the enhanced reinforcing effect resulting from filler incorporation. The stiffening of foams, related to the variations in PU segmental structure, also caused minor changes in the course of thermal degradation of PU/GTR composites due to the inferior thermal stability of hard segments. The obtained results provide important insights into the development of formulations of PU composites filled with materials containing reactive functional groups able to disrupt the stoichiometric balance of the polyaddition reaction.


Threshold effects in synaptosomal and nonsynaptic mitochondria from hippocampal CA1 and paramedian neocortex brain regions.
After a brief period of global ischemia, the hippocampal CA1 region is more susceptible to irreversible damage than the paramedian neocortex. To test whether primary differences in bioenergetic parameters may be present between these regions, respiration rates and respiratory control activities were measured. In synaptosomal and nonsynaptic mitochondria isolated from the hippocampal CA1 region, state 3 respiration rates and complex IV activities were significantly lower than those present in synaptosomal and nonsynaptic mitochondria from the paramedian neocortex. These results suggest that mitochondria from the CA1 hippocampal area differ in some properties of metabolism compared with the neocortex area, which may render them more susceptible to a toxic insult such as that of ischemia. In addition, when complex I and IV activities were titrated with specific inhibitors, thresholds in ATP synthesis and oxygen respiration became apparent. Complex I and IV activities were decreased by 60% in nonsynaptic mitochondria from the hippocampal CA1 region and paramedian neocortex before oxidative phosphorylation was severely compromised; however, in synaptosomes from these regions, complex I activities had a threshold of 25%, indicating heterogenous behaviour for brain mitochondria. Reduced complex I thresholds in mitochondria, in association with other constitutive defects in energy metabolism, may induce a decreased ATP supply in the synaptic region. The implications of these findings are discussed in relation to delayed neuronal death and processes of neurodegeneration.


Cost-effectiveness of therapeutics for COVID-19 patients: a rapid review and economic analysis.
Severe acute respiratory syndrome coronavirus 2 is the virus that causes coronavirus disease 2019. Over six million deaths worldwide have been associated with coronavirus disease 2019. To assess the cost-effectiveness of treatments used for the treatment of coronavirus disease 2019 in hospital or used in the community in patients with coronavirus disease 2019 at high risk of hospitalisation. Treatments provided in United Kingdom hospital and community settings. Clinical effectiveness estimates were taken from the coronavirus disease-network meta-analyses initiative and the metaEvidence initiative. A mathematical model was constructed to explore how the interventions impacted on patient health, measured in quality-adjusted life-years gained. The costs associated with treatment, including those of hospital care, were also estimated and used to form a cost per quality-adjusted life-year gained value which was compared with thresholds published by the National Institute for Health and Care Excellence. Estimates of cost-effectiveness compared against current standard of care were produced in both the hospital and community settings at three different levels of efficacy: mean, low and high. Public list prices were used for interventions with neither confidential patient access schemes nor confidential list prices considered. Results incorporating confidential pricing data were provided to the National Institute for Health and Care Excellence appraisal committee. The treatments were estimated to be clinically effective although not all reached statistical significance. All treatments in the hospital setting, or community, were estimated to plausibly have a cost per quality-adjusted life-year gained value below National Institute for Health and Care Excellence's thresholds when compared with standard of care. However, almost all drugs could plausibly have cost per quality-adjusted life-years above National Institute for Health and Care Excellence's thresholds. However, there is considerable uncertainty in the results as the prevalent severe acute respiratory syndrome coronavirus 2 variant, vaccination status, history of being infected with severe acute respiratory syndrome coronavirus 2 and standard of care have all evolved since the pivotal studies were conducted which could have significant impact on the efficacy of each drug. For drugs used in high-risk patients in the community setting, the proportion of people at high risk who need hospital admission was a large driver of the cost per quality-adjusted life-year. No studies were identified that were conducted in current conditions. This may be a large limitation as the severe acute respiratory syndrome coronavirus 2 variant changes. No head-to-head studies of interventions were identified. The results produced could be informative to decision-makers, although conclusions regarding the most clinical - and cost-effectiveness of each intervention should be tentative due to the evolving nature of the decision problem and, in this report, the use of list prices only. Comparisons between interventions should also be treated with caution due to potentially large heterogeneity between studies. Research assessing the relative clinical effectiveness of interventions within head-to-head studies in current conditions would be beneficial. Contemporary information related to the probability of hospital admission and death for patients at high risk in the community would improve the precision of the estimates generated. This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR135564) and will be published in full in Health Technology Assessment; Vol. 27, No. 14. See the NIHR Journals Library website for further project information.


Diagnosis and natural history of Ebstein's anomaly.
Thirty five cases of Ebstein's anomaly were diagnosed by cardiac catheter study or echocardiography between 1962 and 1984. The anomaly was an isolated abnormality in 27 patients; the remainder had additional heart lesions. Six patients have died and four of these had other cardiac lesions. Thirteen are currently symptom free. Twelve cases presented with cyanosis and heart murmur on the first day of life. Eight of these had associated thrill which is a rare finding in neonates. As pulmonary vascular resistance fell there was clinical improvement. This was assisted by oxygen treatment. Another two cases presented in the first week of life and 10 in the first decade with a murmur or supraventricular tachycardia. Eleven cases presented as adolescents or adults with a murmur, cardiomegaly, or cardiac symptoms. Three patients were seen initially in the sixth decade. Clinical diagnosis was correct in only one adult. Twenty five patients had cardiac catheterisation. Important arrhythmias occurred in 10 cases, and two required cardioversion. Difficulty was experienced in entering the pulmonary artery in 11 infants and children. Diagnosis at initial catheter study was incorrect in four patients. Echocardiograms were recorded in 29 cases. Earlier M mode measurements of time delay of tricuspid closure compared with mitral closure did not always lead to the correct diagnosis. Cross sectional studies gave good images of tricuspid leaflet displacement, its tethering, and the atrialised portion of the right ventricle and have facilitated the diagnosis of more cases in recent years. Echocardiography is the procedure of choice for diagnosis of Ebstein's anomaly.


Enhanced detection of respiratory viruses using cryopreserved R-Mix ReadyCells.
R-Mix, which contains a fresh mixture of two cell lines, Mv1Lu (mink lung cells) and A549 cells, has shown good sensitivity and specificity for respiratory virus culture. However, it has until recently only been available in North America, in part due to the shipping constraints associated with cell aging and the difficulty in providing these cells to hard to reach regions. Recently, cryopreserved R-Mix ReadyCells for longer storage were developed. These cells, which are shipped on dry ice and have a shelf life as long as 6 months from date of manufacture, can be thawed and used as needed with minimal addition of refeeding media. Assess the potential for cryopreserved R-Mix ReadyCells to replace conventional culture. Two hundred and twenty-three nasopharyngeal aspirates confirmed as respiratory virus-positive by conventional culture were inoculated into cryopreserved R-Mix ReadyCells and re-inoculated into conventional culture cells simultaneously. After 1 and 3 days of incubation cryopreserved R-Mix ReadyCells and conventional culture cells were screened using a respiratory virus fluorescent antibody pool for the detection of seven major respiratory viruses (influenza A and B viruses, parainfluenza 1, 2 and 3 viruses, respiratory syncytial virus and adenovirus). Positive pool results were further differentiated with specific monoclonal antibodies against the individual viruses. After 1 day of incubation detection rates for conventional culture were 25%, 39%, 39%, 49%, and 10% for influenza A virus, influenza B virus, parainfluenza viruses, respiratory syncytial virus, and adenovirus, respectively. Corresponding detection rates for cryopreserved R-Mix ReadyCells were 78%, 91%, 72%, 81%, and 65%. Average detection rates of cryopreserved R-Mix ReadyCells for all respiratory viruses were 80% after 1 day incubation and 95% after 3 days incubation, compared to 35% and 70% by conventional culture. The cryopreserved R-Mix ReadyCells system offers a highly sensitive and rapid method for detection of respiratory viruses that may allow it to replace conventional cell culture systems.


Radiation sensitivity of the hemopoietic stem cell.
The LD50/30 after total-body irradiation (TBI) indicates the radiosensitivity of any animal species and is determined by the number and radiosensitivity of the hemopoietic stem cells, in particular those that are pluripotent. The most extensive information exists for the mouse because in the species the pluripotential stem cells can be enumerated by the spleen colony assay. Stem cells of various species can also be quantified in vitro by the CFU-S and CFU-C assays. With the latter assay, the reported values for D0 and N vary by factors of 2-3 and up to 5, respectively. In both assays the upper level of the range of doses is about 5 Gy. A theoretical approach for the calculation of the D0 of hemopoietic stem cells was previously developed by comparing the number of autologous or syngeneic bone marrow cells required to protect 50% of supralethally irradiated animals with the known LD50/30 of the species and the estimates of total number of bone marrow cells present before irradiation. Using the rate of repopulation of peripheral blood cells in monkeys following high-dose TBI and the repopulation of the spleen and the bone marrow in mice, we have derived estimates of the surviving fractions of hemopoietic stem cells at radiation doses between 5 and 10 Gy. The resulting data suggest, among other possibilities, the presence of a small subpopulation of hemopoietic stem cells with higher radioresistance than the majority of the stem cells. It was postulated that this small subpopulation may exist under hypoxic conditions. To test this hypothesis, RBEs for fission neutrons have been determined for CFU-S survival and for LD50/30 in BCBA mice. Both RBEs were very similar, which proves that the radioresistance of the subpopulation responsible for survival at high doses is not due to hypoxic conditions.


Comparison of lidocaine and lidocaine-xylazine for distal paravertebral anesthesia in dairy cattle.
To determine the time of onset and duration of action of distal paravertebral blocks (DPB) in dairy cattle using lidocaine and lidocaine plus xylazine (LX). 10 healthy adult Holstein cows. Unilateral DPB were performed in 6 cows at L1, L2, and L4. They received 2 treatments (lidocaine and LX) in a blinded random crossover design. Due to treatment failure, 4 additional cows were enrolled. The lidocaine treatment received 1,800 mg (90 mL) of lidocaine, and treatment LX received 1,784 mg (89.2 mL) of lidocaine and 16 mg (0.8 mL) of xylazine. Anesthesia was assessed by response (rapid movements of the tail, directed movements of the feet, or turning of the head towards the site of the needle pricks) to 6 approximately 1-cm deep needle pricks to the paralumbar fossa with a 22-gauge hypodermic needle. The time of onset, duration of action, maximum sedation score, and average heart rate (HR) were compared between treatments. Duration of anesthesia was significantly prolonged after DPB in cows treated with LX (251.6 ± 96.94 minutes) compared to lidocaine (105.8 ± 35.9 minutes; P = .01). Treatment with LX was associated with significantly lower average heart rate (56 ± 3 beats/min) compared to cows treated with lidocaine (59 ± 3 beats/min; P = .045). The LX treatment was associated with mild sedation but was not significant (P = .063). The addition of xylazine to a lidocaine DPB provides a longer duration of anesthesia, is inexpensive and practical, and can be implemented with ease.


Systemic and regional hemodynamic effects of perindopril in experimental heart failure.
The effects of converting-enzyme inhibition by perindoprilat (0.5 mg/kg, intravenously, short-term administration) or perindopril (2 mg/kg, orally, long-term administration once a day for 21 days) on systemic and regional hemodynamics were studied on a new rat model of heart failure, which was induced by microembolization of coronary vessels by 15 microns plastic microspheres. Cardiac output and regional blood flows were measured by microsphere technique; the tone of the venous vessels was determined as mean circulatory filling pressure in conscious, freely moving rats. Perindoprilat evoked a much more prominent increase in kidneys, adrenal glands, intestine, and skin blood flows in embolized rats than in sham-operated rats. The differences between the effects of long-term treatment with perindopril in sham-operated and embolized rats were highly significant. Mean circulatory filling pressure was decreased by short-term and long-term administration of an angiotensin-converting enzyme inhibitor. It is concluded that venous vessels could be one of the target sites for the effects of perindopril-like drugs.


Do hospitalist physicians improve the quality of inpatient care delivery? A systematic review of process, efficiency and outcome measures.
Despite more than a decade of research on hospitalists and their performance, disagreement still exists regarding whether and how hospital-based physicians improve the quality of inpatient care delivery. This systematic review summarizes the findings from 65 comparative evaluations to determine whether hospitalists provide a higher quality of inpatient care relative to traditional inpatient physicians who maintain hospital privileges with concurrent outpatient practices. Articles on hospitalist performance published between January 1996 and December 2010 were identified through MEDLINE, Embase, Science Citation Index, CINAHL, NHS Economic Evaluation Database and a hand-search of reference lists, key journals and editorials. Comparative evaluations presenting original, quantitative data on processes, efficiency or clinical outcome measures of care between hospitalists, community-based physicians and traditional academic attending physicians were included (n = 65). After proposing a conceptual framework for evaluating inpatient physician performance, major findings on quality are summarized according to their percentage change, direction and statistical significance. The majority of reviewed articles demonstrated that hospitalists are efficient providers of inpatient care on the basis of reductions in their patients' average length of stay (69%) and total hospital costs (70%); however, the clinical quality of hospitalist care appears to be comparable to that provided by their colleagues. The methodological quality of hospitalist evaluations remains a concern and has not improved over time. Persistent issues include insufficient reporting of source or sample populations (n = 30), patients lost to follow-up (n = 42) and estimates of effect or random variability (n = 35); inappropriate use of statistical tests (n = 55); and failure to adjust for established confounders (n = 37). Future research should include an expanded focus on the specific structures of care that differentiate hospitalists from other inpatient physician groups as well as the development of better conceptual and statistical models that identify and measure underlying mechanisms driving provider-outcome associations in quality.


Selective complex fractionated atrial electrograms targeting for atrial fibrillation study (SELECT AF): a multicenter, randomized trial.
This study compared generalized complex fractionated atrial electrograms (CFAE) ablation versus a selective CFAE ablation strategy targeting areas of continuous electric activity. Subjects with symptomatic, persistent/high-burden paroxysmal atrial fibrillation (AF) were enrolled at 6 centers (n=86) and randomized to 1 of 2 arms. For group I, all CFAE regions with an interval confidence level >7 were ablated followed by pulmonary vein isolation (PVI). For group II, only CFAE sites with continuous electric activity were ablated followed by PVI. For PVI, all 4 PV antra were isolated with confirmed entrance block. Subjects were followed for 1 year with a visit, ECG, and 48-hour Holter every 3 months. Symptoms were confirmed by loop recording. The primary end point was freedom from arrhythmia >30 seconds at 1 year. For both group I and II, CFAE ablation prolonged AF cycle length (25±33 versus 23±33 ms; P=0.78) and resulted in similar rates of AF termination (37% versus 28%; P=0.42). Radiofrequency duration during CFAE ablation was significantly less in group II (23±20 versus 38±20 minutes; P=0.002). At 1-year follow-up, freedom from AF/atrial flutter/atrial tachycardia recurrence was significantly higher in group I versus group II after 1 procedure (50% versus 28%; P=0.03). There were also significantly fewer repeat procedures in group I (13% versus 36%; P=0.021). Continuous electric activity ablation+PVI result in a similar incidence of acute AF termination with significantly less radiofrequency time. However, incidence of repeat procedures and long-term recurrence of AF/atrial flutter/atrial tachycardia are significantly lower using generalized CFAE ablation+PVI. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00926783.


Organophosphate pesticides-induced changes in the redox status of rat tissues and protective effects of antioxidant vitamins.
Organophosphates (OPs) pesticides are among the most toxic synthetic chemicals purposefully added in the environment. The common use of OP insecticides in public health and agriculture results in an environmental pollution and a number of acute and chronic poisoning events. Present study was aimed to evaluate the potential of monocrotophos and quinalphos to effect the redox status and glutathione (GSH) homeostasis in rat tissues and find out whether antioxidant vitamins have some protection on the pesticide-induced alterations. The results showed that these pesticides alone or in combination, caused decrease in the levels of GSH and the corresponding increase in the levels of GSSG, decreasing the GSH/GSSG ratio. The results also showed that NADPH/NADP(+) and NADH/NAD(+) ratios were decreased in the liver and brain of rats on exposure with mococrotophos, quinalphos, and their mixture. These pesticides, alone or in combination, caused alterations in the activities of GSH reductase and glucose-6-phosphate dehydrogenase in the rat tissues. However, the expression of the GSH recycling enzymes did not show significant alterations as compared to control. From the results, it can be concluded that these pesticides generate oxidative stress but their effects were not synergistic when given together and prior feeding of antioxidant vitamins tend to reduce the toxicities of these pesticides.


Validation of the child and youth resilience measure among South African adolescents.
Resilience is a dynamic, interactive process between resources that contribute to safeguarding a person and the adversities they experience. Within this promotional framework of resilience, this study sought to validate the Child and Youth Resilience Measure (CYRM-28) among a sample of South African adolescents (N = 1854). Confirmatory factor analysis supported a superior level of fit for a 24-item, three-factor model (i.e., individual/social, familial, and community/spiritual). Internal consistency and test-retest reliability estimates at a 12-month interval (N = 648) supported the reliability of the scales. Higher scores on the scales were associated with feeling more connected at school, greater parental monitoring perceptions, and lower sexual risk, confirming the convergent and criterion validity of the instrument. Partial discriminative power was evidenced based on selected scale distinctions according to age and sex groupings. Collectively, the findings suggest the 24-item CYRM is a valid and reliable self-report measure to assess the availability of resources associated with resilience in South African youth.


Glycoprotein 96 perpetuates the persistent inflammation of rheumatoid arthritis.
The mechanisms that contribute to the persistent activation of macrophages in rheumatoid arthritis (RA) are incompletely understood. The aim of this study was to determine the contribution of endogenous gp96 in Toll-like receptor (TLR)-mediated macrophage activation in RA. RA synovial fluid was used to activate macrophages and HEK-TLR-2 and HEK-TLR-4 cells. Neutralizing antibodies to TLR-2, TLR-4, and gp96 were used to inhibit activation. RA synovial fluid macrophages were isolated by CD14 negative selection. Cell activation was measured by the expression of tumor necrosis factor α (TNFα) or interleukin-8 messenger RNA. Arthritis was induced in mice by K/BxN serum transfer. The expression of gp96 was determined by immunoblot analysis, enzyme-linked immunosorbent assay, and immunohistochemistry. Arthritis was treated with neutralizing anti-gp96 antiserum or control serum. RA synovial fluid induced the activation of macrophages and HEK-TLR-2 and HEK-TLR-4 cells. RA synovial fluid-induced macrophage and HEK-TLR-2 activation was suppressed by neutralizing anti-gp96 antibodies only in the presence of high (>800 ng/ml) rather than low (<400 ng/ml) concentrations of gp96. Neutralization of RA synovial fluid macrophage cell surface gp96 inhibited the constitutive expression of TNFα. Supporting the role of gp96 in RA, joint tissue gp96 expression was induced in mice with the K/BxN serum-induced arthritis, and neutralizing antibodies to gp96 ameliorated joint inflammation, as determined by clinical and histologic examination. These observations support the notion that gp96 plays a role as an endogenous TLR-2 ligand in RA and identify the TLR-2 pathway as a therapeutic target.


Human papillomavirus and penile cancers in Rio de Janeiro, Brazil: HPV typing and clinical features.
To determine the prevalence of human papillomavirus (HPV) DNA in penile cancers in Rio de Janeiro, Brazil. We studied, prospectively, 80 consecutive cases of patients with penile cancers who underwent surgical treatment at three different Hospitals in Rio de Janeiro between March 1995 and June 2000. Of these patients, 72 were diagnosed with invasive squamous cell carcinoma and 8 patients with verrucous carcinoma. The following parameters were observed: presence or absence of HPV DNA viral type, histological subtypes, clinical stage and overall survival. HPV DNA was detected in 75% of patients with invasive carcinomas and in 50% of patients with verrucous carcinomas. High risk HPVs were detected in 15 of 54 (27.8%) patients with HPV positive invasive tumors and in 1 of 4 (25%) patients with HPV positive verrucous tumors. HPV 16 was the most frequent type observed. No correlation was observed between HPV status and histological subtype (p = 0.51) as well as HPV status and stage stratification (p = 0.88). HPV status was also not significantly associated with the presence of regional metastases (p = 0.89). The overall survival was related to the presence of lymph node metastases (p < 0.0001). HPV infection may have contributed to malignant transformation in a large proportion of our penile cancer cases but only inguinal metastasis was a prognostic factor for survival in these patients with penile carcinoma.


Alcohol risk reduction for fraternity and sorority members.
The primary objective of this study is to evaluate the effectiveness of "Talking about Alcohol and Drugs... Among Greeks" (TAAD), a lifestyle risk reduction program that is research- and theory-based, protocol-driven, and targeted for fraternity and sorority members. One fraternity and two sororities on five campuses participated in the program. A total of 780 participants completed pre- and posttest questionnaires. Posttest data were collected 1 academic year after pretest data collection. Results indicate that the program decreased positive attitudes toward alcohol consumption among program participants, with participants in the true experimental condition indicating greater disagreement than control participants (F = 3.05, 2/701 df, p < .05). Belief in myths about the etiology of alcoholism was reduced among experimental participants who did not actually attend the program, with those participants indicating greater disagreement than control or true experimental participants (F = 10.92, 2/702 df, p < .0001). The program had no apparent effect on alcohol consumption by experimental participants. The program's ability to influence behavior was hindered by systemic problems, such as trainer credibility and implementation infidelity, and probable participant psychological reactance. Training by professionals and mandatory attendance would set the stage for improved program effectiveness. Beyond that, an approach that emphasized how high-risk drinking norms jeopardize the goals of the fraternities and sororities might be better received than the current approach, which focuses on how individual attitudes, beliefs and behaviors lead to alcohol-related problems and alcoholism.


Association of the G-2548A polymorphism in the 5' region of the LEP gene with overweight.
Mutations in the translated part of the leptin gene (LEP) have been found in only two families. Nevertheless DNA polymorphisms in the LEP region are linked to extreme obesity. We previously found in the 5' region of LEP a polymorphism, G-2548A, associated with a differerce in BMI reduction following a low calorie diet in overweight women. Recently, this polymorphism was associated with extreme obesity in women. In this work, we genotyped a new sample from the general population including 314 normal weight (BMI < 27 kg/m2) and 109 overweight subjects (BMI > or = 27 kg/m2). The genotype and allele frequencies were significantly different between groups, with the G-2548 allele being more frequent in the overweight subjects (p < 0.01). In men, carriers of this allele had lower leptin concentrations adjusted for fat mass (p = 0.05). Our results indicate that variations at the leptin locus are associated with common obesity phenotypes, and not only with extreme obesity or the rare mendelian obesity syndromes.


Variations of the C2H2 zinc finger motif in the yeast genome and classification of yeast zinc finger proteins.
The PROSITE pattern Zinc_Finger_C2H2 was extended to permit the detection of all C2H2 zinc fingers and their parent proteins in the recently completed sequence of the yeast genome. Additionally, a new computer program was written that extracts other zinc binding motifs (non C2H2 'fingers'), overlapping with the classical zinc finger pattern, from the found set of yeast C2H2 fingers. The complete and correct detection of all fingers is a prerequisite for the classification of the yeast zinc finger proteins in functional terms. The detected 53 yeast C2H2 zinc finger proteins do not contain finger clusters with 10 or more repeats, as is frequently found in higher eukaryotes. Only three proteins contain four or more fingers in a cluster. Moreover, nearly all 27 yeast proteins with tandem arrays of two or three finger domains can be classified into nine subgroups with high sequence conservation in their finger clusters, in particular of their DNA recognition helices. These results and application of the recently elaborated finger/DNA recognition rules suggest that the yeast proteins belonging to the same subgroup may recognize identical or very similar DNA sites.


[Image characterization of Alzheimer's disease associated with the E280A-PS1 mutation. Case-control study: MRI findings].
In order to compare the magnetic resonance image characteristics of individuals belonging to pedigrees carrying the mutation E280A-PS1 associated to early onset Alzheimer disease, coming from Antioquia, Colombia, 78 individuals were studied. 47 of them were carriers of the mutation, 23 of those presented symptoms and 31 individuals being controls (non carriers of the mutation). In summary, significative differences were appreciated between symptomatic individuals and those asymptomatic. There was not significant difference between asymptomatic carriers and the controls. The presence of the perihippocampal fissure constituted a difference statistically significant between the symptomatic individuals and those carriers asymptomatic and between the symptomatic ones and the controls. The interuncal distance increased significantly was another difference between symptomatic and asymptomatic individuals and among symptomatic and control group. The lobar atrophy and the ventriculomegaly were found in symptomatic individuals and they correlate with the disorder graveness. There was not significance in the presence of infarcts and/or hippocampal hyperintensities. These results corroborate the statement that magnetic resonance image is very useful in the diagnosis and follow-up of individuals affected by early onset Alzheimer disease.


Flail chest syndrome and pulmonary contusion.
Controlled mechanical ventilation has been the mainstay of treatment in the flail chest syndrome for more than 20 years, retrospective studies have recently suggested that the technique is unnecessary, and they infer that spontaneous ventilation or intermittent mandatory ventilation are equally effective. The common theme of these investigations is that mechanical ventilation is required only to relieve hypoxemia associated with the underlying contusion. In two cases of flail chest, spontaneous respiratory efforts resulted in complete disruption of the fracture sites and thus prolonged the duration of mechanical ventilation that was required. In severe cases of flail chest syndrome, there is still a need for controlled mechanical ventilation to splint the rib fractures in a position which facilitates union of the fragments.


PET/MRI, Part 1: Establishing a PET/MRI Facility.
The emergence of PET and MRI as a hybrid modality has generated widespread interest in the technology and techniques. Although adoption and use are unlikely to be as expansive as for PET and CT hybrid systems, PET/MRI is an important modality that requires broad insight for nuclear medicine professions generally and deeper insight for those engaged in PET/MRI practice. This article provides insight into the considerations and challenges associated with establishing a PET/MRI facility. Each clinical site will present unique requisites for establishing a PET/MRI facility, and indeed, each PET/MRI vendor will have specific site requirements. Nonetheless, this article provides general insight into common considerations but should not be considered exhaustive. Here, development of the facility, staffing of the facility, and implications of both radiation and MRI safety are considered from the context of facility design. Given that the nature of PET is well established among the readership of this journal, the article provides an emphasis on MRI factors. This article is the first in a 4-part integrated series sponsored by the PET/MR and Publication Committees of the Society of Nuclear Medicine and Molecular Imaging-Technologist Section. In the subsequent 3 parts, PET/MRI will be explored on the basis of technology principles (part 2), protocols and procedures (part 3), and applications and clinical cases (part 4).


Development of replication-defective adenovirus serotype 5 containing the capsid and 3C protease coding regions of foot-and-mouth disease virus as a vaccine candidate.
A recombinant replication-defective human adenovirus serotype 5 vector containing FMDV capsid, P1-2A, and viral 3C protease coding regions was constructed. Two viral clones were isolated, Ad5-P12X3CWT, containing the wild-type (WT) 3C protease that processes capsid polyprotein precursor into mature capsid proteins, and Ad5-P12X3CMUT, containing a point mutation in the protease coding region that inhibits processing. In 293 cells infected with either virus, synthesis of the FMDV capsid polyprotein precursor occurred, but processing of the polyprotein into structural proteins VP0, VP3, and VP1 occurred only in 3CWT virus-infected cells. Immunoprecipitation with monospecific and monoclonal antibodies indicates possible higher order structure formation in Ad5-P12X3CWT virus-infected cells. The viruses were used to elicit immune responses in mice inoculated intramuscularly (im). Only virus containing the 3CWT elicited a neutralizing antibody response. After boosting, this neutralizing antibody response increased. Swine inoculated im with Ad5-P12X3CWT virus developed a neutralizing antibody response and were either completely or partially protected from contact challenge with an animal directly inoculated with virulent FMDV. This adenovirus vector may be an efficient system for the delivery of FMDV cDNA into animals, leading to a high level of neutralizing antibody production and protection from FMDV challenge.


[The effects of family history of colorectal cancer on the development of colorectal adenoma].
Early detection of polyp is important for the prevention of colorectal cancer (CRC). There have been few studies to investigate the relationship between colorectal adenoma and family history of CRC (FHCRC) in Korea. The aim of this study was to identify the relationship between colorectal adenoma and FHCRC. Between March 2009 and September 2010, 225 patients with adenomatous polyps were included. Their medical records with clinical history and size, numbers, histology of polyps were reviewed. Immunohistochemical staining using Bcl-2, Bax, p-AKT, NF-κB, and β-catenin antibodies were performed. We compared the histology of adenoma and expression of immunohistochemical staining according to the existence of FHCRC. The incidence of colorectal adenoma increased in case of FHCRC (p=0.029). In patients with FHCRC, the mean age of patients was 49 years old and younger than patients without FHCRC. In addition in patients with FHCRC, the incidence of advanced adenoma was significantly higher than in patients without FHCRC (p=0.001). The expression of Bax was significantly lower in patients with FHCRC than without FHCRC (p=0.046). There was a tendency for polyp to develop in their younger ages and to be more advanced adenomas in patients with FHCRC. The low expression of Bax, tumor suppressor gene, might be associated with the development of polyps in patient with FHCRC. Therefore, patients with FHCRC may be better to start screening colonoscopy earlier than patient without FHCRC.


Knowledge of sexual partner's HIV serostatus and the practice of safer sex among heterosexual men of African descent in London, Ontario.
Objective: Poor knowledge of sexual partners' HIV status is a major contributing factor in the heterosexual spread of HIV in Canada. This study examined knowledge of sexual partner's HIV serostatus and the practice of safer sex among self-identified heterosexual African, Caribbean and Black (ACB) men in London, Ontario.Design: A cross-sectional data was collected from 156 heterosexual ACB men in London. The negative log-log link function was fitted to estimate the relationship between knowledge of sexual partner's HIV status and condom use among ACB men.Results: Findings show that ACB men who know their sexual partner's HIV status are less likely to use condoms compared to men who do not know the serostatus of their sexual partner, controlling for other theoretically relevant covariates. In addition, the findings show that sexually active, single ACB men are less likely to use condoms. On the other hand, ACB men with higher education, employed and with income over 60 thousand dollars a year have a higher likelihood of using condoms.Conclusions: Heterosexual ACB men who used condoms even when they did not know their sexual partners' HIV status could be explained as a resilience-building strategy in response to their increasing HIV vulnerabilities. Heterosexual ACB men's use of condoms is further associated with socioeconomic factors including income, employment and education that need to be addressed for an improved safer sex.


Chlamydia diagnosis rate in England in 2012: an ecological study of local authorities.
Local authorities (LAs) in England commission chlamydia screening as part of the National Chlamydia Screening Programme. It is recommended that LAs achieve a chlamydia diagnosis rate of ≥2300 cases per 100 000 population aged 15-24. We describe national patterns in attainment of the chlamydia diagnosis rate recommendation and possible implications of using it to measure LA-level performance. We used publicly available data sets from England (2012) to explore the association between LAs attaining the recommended chlamydia diagnosis rate and population size, socioeconomic deprivation, test setting and sex. We used data from 1 197 121 recorded chlamydia tests in females and 564 117 in males. The chlamydia diagnosis rate recommendation was achieved by 22% (72/324) of LAs overall (43% female population; 8% male population). LAs in the highest deprivation quintile were more likely to reach the recommendation than those in the least-deprived quintile for both sexes (women: unadjusted prevalence ratio (UPR) 7.43, 95% CI 3.65 to 15.11; men: UPR 7.00, 95% CI 1.66 to 29.58). The proportion of tests performed in genitourinary medicine clinics was negatively associated with attainment of the recommended diagnosis rate (UPR 0.95, 0.93 to 0.97). Chlamydia diagnosis rate recommendations that reflect local area deprivation (as a proxy for disease burden) may be more appropriate than a single national target if the aim is to reduce health inequalities nationally. We suggest LAs monitor their chlamydia diagnosis rate, test coverage and test positivity across a range of measures (including setting and sex) and pre/post changes to commissioned services. Critical evaluation of performance against the recommendation should be reflected in local commissioning decisions.


The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities.
Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes and most of the corresponding proteins are localized in the cytosol. To test for possible functional differences and/or substrate specificity, we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment. Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation. This was not related to client specificity itself, as the polyQ aggregation inhibitors often also suppressed heat-induced aggregation of luciferase. Surprisingly, the exclusively heat-inducible HSPA6 lacks both luciferase refolding and polyQ aggregation-suppressing activities. Furthermore, whereas overexpression of HSPA1A protected cells from heat-induced cell death, overexpression of HSPA6 did not. Inversely, siRNA (small interfering RNA)-mediated blocking of HSPA6 did not impair the development of heat-induced thermotolerance. Yet, HSPA6 has a functional substrate-binding domain and possesses intrinsic ATPase activity that is as high as that of the canonical HSPA1A when stimulated by J-proteins. In vitro data suggest that this may be relevant to substrate specificity, as purified HSPA6 could not chaperone heat-unfolded luciferase but was able to assist in reactivation of heat-unfolded p53. So, even within the highly sequence-conserved HSPA family, functional differentiation is larger than expected, with HSPA6 being an extreme example that may have evolved to maintain specific critical functions under conditions of severe stress.


New developments in the treatment of patients with multiple myeloma.
Much progress has been made in the treatment of patients with multiple myeloma (MM). The introduction of new drugs such as thalidomide, bortezomib and lenalidomide has created more possibilities for patients than many years before. In addition, autologous peripheral blood stem cell transplantation after high-dose melphalan has become the standard of care for younger patients. Allogeneic stem cell transplantation is an experimental option for those younger patients with a human leucocyte antigen identical donor. Because of these rapid developments and many treatment options we need good quality clinical studies that can guide us in what to do in everyday practice. This review will focus on those studies that have changed the treatment guidelines for patients with MM.


Screening and brief interventions for hazardous and harmful alcohol use among patients with active tuberculosis attending primary care clinics in South Africa: a cluster randomized controlled trial protocol.
In 2008 the World Health Organization (WHO) reported that South Africa had the highest tuberculosis (TB) incidence in the world. This high incidence rate is linked to a number of factors, including HIV co-infection and alcohol use disorders. The diagnosis and treatment package for TB and HIV co-infection is relatively well established in South Africa. However, because alcohol use disorders may present more insidiously, making it difficult to diagnose, those patients with active TB and misusing alcohol are not easily cured from TB. With this in mind, the primary purpose of this cluster randomized controlled trial is to provide screening for alcohol misuse and to test the efficacy of brief interventions in reducing alcohol intake in those patients with active TB found to be misusing alcohol in primary health care clinics in three provinces in South Africa. Within each of the three selected health districts with the highest TB burden in South Africa, 14 primary health care clinics with the highest TB caseloads will be selected. Those agreeing to participate will be stratified according to TB treatment caseload and the type of facility (clinic or community health centre). Within strata from 14 primary care facilities, 7 will be randomly selected into intervention and 7 to control study clinics (42 clinics, 21 intervention clinics and 21 control clinics). At the clinic level systematic sampling will be used to recruit newly diagnosed TB patients. Those consenting will be screened for alcohol misuse using the AUDIT. Patients who screen positive for alcohol misuse over a 6-month period will be given either a brief intervention based on the Information-Motivation-Behavioural Skills (IMB) Model or an alcohol use health education leaflet.A total sample size of 520 is expected. The trial will evaluate the impact of alcohol screening and brief interventions for patients with active TB in primary care settings in South Africa. The findings will impact public health and will enable the health ministry to formulate policy related to comprehensive treatment for TB and alcohol misuse, which will result in reduction in alcohol use and ultimately improve the TB cure rates. PACTR: PACTR201105000297151.


UVS is rare in seabirds.
Ultraviolet-sensitive vision (UVS), believed to have evolved from an ancestral state of violet-sensitive vision (VS), is widespread among terrestrial birds, where it is thought to play a role in orientation, foraging, and sexual selection. Less is known, however, about the distribution and significance of UVS in seabirds. To date UVS has been definitively demonstrated only in two families (Laridae and Sternidae), although indirect evidence has been used to argue for a more widespread occurrence. In this study we analyzed short-wavelength sensitive (SWS1) opsin DNA sequences to determine the distribution of ancestral (VS) and derived (UVS) amino acid spectral tuning sites in 16 seabird species representing 8 families with diverse ecological niches. Our results revealed sequences associated with UVS pigments (UVSs) in the Black-backed gull (Larus dominicanus), providing further evidence of its widespread occurrence within the Laridae. The Caspian tern (Hydroprogne caspia) and White-fronted tern (Sterna striata), however, were found to have VSs, suggesting an evolutionary reversion to the ancestral state within Sternidae. VSs were also detected in an additional six families. Our results raise interesting questions about the functions of UV vision in marine environments.


Development and validation of the Four-Item Mentalising Index.
Mentalising, also known as "Theory of Mind", is the ability to understand and infer the cognitions of others, such as their perceptions, intentions, and beliefs. Although several tools have been designed to measure mentalising in adults, there exist methodological and practical limitations. Many of the existing measures conflate mentalising with similar constructs (e.g., empathy), and most are lengthy measures that are unsuitable for large population-based studies and clinical practice. These issues are currently hampering clinical and non-clinical investigations into mentalising and related social-cognitive abilities. Drawing on questionnaire measures of social cognition, we conceived a self-report mentalising scale, the Four-Item Mentalising Index (FIMI; Studies 1a and b). The FIMI was developed through a series of studies examining its factor structure and reliability (Studies 2a and b) and by testing its construct validity against a cognitive mentalising task, autistic traits, and comparing scores in autistic and non-autistic people (Studies 3a and b). Together, we demonstrate that the FIMI is a conceptually and methodologically robust tool for measuring mentalising ability in the general population, including autistic and non-autistic people. Future research directions and practical (clinical) applications of the scale are discussed, with a focus on improving understanding and management of (a)typical mentalising ability. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Evaluation of murine cytomegalovirus antibody detection by serological techniques.
Naturally acquired murine cytomegalovirus (MCMV) infection in laboratory strains of mice induces antibody levels which are generally undetectable by standard techniques; therefore, MCMV has not been included routinely in mouse viral antibody screening programs. The relative sensitivity of three assay systems, the nuclear anticomplement immunofluorescence (NACIF), the enzyme-linked immunosorbent assay (ELISA), and the complement fixation (CF) test, was evaluated for the detection of MCMV antibodies. Sera were harvested from CD1 male mice (33 days old) infected intraperitoneally with salivary gland-passaged MCMV (Smith strain). The sera were assayed separately at weeks 1 through 8, and at week 11, 16, and 25 post-inoculation; a total of 167 mice in 11 groups were tested. The animals tested at 1 week post-inoculation had low levels of antibodies to MCMV as measured by the NACIF test (1:10), whereas only 25% were positive by ELISA, and none was positive by CF until 5 weeks post-inoculation. A higher titer of MCMV antibodies was measured by CF (1:640) than by NACIF (1:40) at 6 months post-inoculation; yet, a titer of 1:3,200 was detected by ELISA from the same serum. The ELISA technique was more sensitive for detecting persistent infection with MCMV, and NACIF was more useful for detecting acute MCMV infection. Since MCMV can have significant long-term effects on the immune system, it is recommended that testing for antibodies to MCMV be included in mouse viral antibody screening protocols.


[Effect of serotonin on the electrical activity of the cerebral cortex in the rabbit].
Application of serotonin on the rabbit cerebral cortex produced prolonged (minutes) periodical oscillations of the activation level and the level of spatial synchronization of neocortical biopotentials. Periodical changes of biopotentials correlation were due above all to a significant reorganization of phasic correlation of the EEG theta-components of remote neocortex points. The changes may be explained by the appearance, due to serotonin, of slow oscillations of the excitation level of the cortical neurones, as a systemic transitional reaction to the change in the balance of excitatory and inhibitory processes. The ability of serotonin to influence phasic relationships of the distantly-synchronous cortical theta-rhythm is of considerable significance for conditioned activity.


A randomized, double-blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients.
The aim of this study was to examine the effect of a specific cyclooxygenase-2 inhibitor, rofecoxib, on rectal polyps in familial adenomatous polyposis patients. This was a randomized, double-blind, placebo-controlled study of the efficacy and safety of rofecoxib in the rectum. Initially, 21 patients were assigned randomly in a 1:1 ratio to receive either 25 mg rofecoxib once a day or a placebo p.o. for 9 months. Patients underwent endoscopy at the beginning of the study and then every 3 months thereafter. We reviewed the videotapes to measure the number and size of polyps in the same area throughout the study period in each individual patient. The polyp number, measured as the percentage of change from the baseline values, was significantly decreased in the rofecoxib group at 3, 6, and 9 months. At 9 months, the polyp number in the rofecoxib group decreased by 6.8% from the baseline values, whereas that in the placebo group increased by 3.1%. The 9.9% difference between the rofecoxib and placebo groups was statistically significant (P = 0.004). At 9 months, the rofecoxib group showed a significant reduction from the baseline in polyp size as compared with the placebo group (-16.2% versus 1.5%; P < 0.001). There was no statistically significant increase in the incidence of any adverse events in treatment with rofecoxib compared with placebo (P = 0.922). In this study, once-daily treatment with 25 mg rofecoxib, a cyclooxygenase 2-specific inhibitor, significantly decreased the number and size of rectal polyps in familial adenomatous polyposis patients.


An in vivo translation-reporter system for the study of protein synthesis in zebrafish embryos.
Control of gene expression at the translation level is increasingly regarded as a key feature in many biological processes. Simple, inexpensive and reliable procedures to visualize sites of protein production are required to allow observation of the spatiotemporal patterns of mRNA translation at subcellular resolution. We present a method, named SPoT (for Subcellular Patterns of Translation), developed upon the original TimeStamp technique ( Lin et al., 2008), consisting in the expression of a fluorescent protein fused to a tagged, self-cleavable protease domain. The addition of a cell-permeable protease inhibitor instantly stabilizes newly produced tagged protein allowing us to distinguish recently synthesized proteins from pre-existing ones. After a brief protease inhibitor treatment, the ratio of tagged versus non-tagged forms is highest at sites where proteins are the most recent, i.e. sites of synthesis. Therefore, by comparing tagged and non-tagged proteins it is possible to spotlight sites of translation. By specifically expressing the SPoT cassette in neurons of transgenic zebrafish embryos, we reveal sites of neuronal protein synthesis in diverse cellular compartments during early development.


Effect of hexachlorobenzene on haem synthesis.
Several drugs are known to induce the liver microsomal mixed-function oxidase system when administered in vivo or even in vitro in cell culture. A sequence of events has been suggested in which the drug is visualized to induce delta-aminolaevulinate synthetase, the first and rate-limiting enzyme of the haem-biosynthetic pathway, which is followed by enhanced haem synthesis and cytochrome P-450 content, facilitating the increase in the drug-metabolizing activity of the liver microsomal fraction. The present studies show that the fungicide hexachlorobenzene, when administered to female rats, can lead to enhanced amounts and rate of synthesis of cytochrome P-450 under conditions when the rate of total haem synthesis has not appreciably altered. The subsequent increase in the rate of total haem synthesis as well as the initial increase in amounts of cytochrome P-450 are brought about under conditions when delta-aminolaevulinate synthetase activity remains constant. However, manifestation of porphyria due to prolonged drug administration is accompanied by a twofold increase in delta-aminolaevulinate synthetase activity. The increase in enzyme activity appears to be due to a decreased degradation rate of the enzyme.


Diversity of anopheline species and their Plasmodium infection status in rural Bandarban, Bangladesh.
Historically, the Chittagong Hill Tracts (CHT) of Bangladesh was considered hyperendemic for malaria. To better understand the contemporary malaria epidemiology and to develop new and innovative control strategies, comprehensive epidemiologic studies are ongoing in two endemic unions of Bandarban district of CHT. Within these studies entomological surveillance has been undertaken to study the role of the existing anopheline species involved in the malaria transmission cycle throughout the year. CDC miniature light traps were deployed to collect anopheline mosquitoes from the sleeping room of the selected houses each month in a single union (Kuhalong). Molecular identification was carried out for available Anopheles species complexes. Circumsporozoite proteins (CSP) for Plasmodium falciparum, Plasmodium vivax-210 (Pv-210) and Plasmodium vivax-247(Pv-247) were detected by Enzyme-linked immunosorbent assay (ELISA) from the female anopheline mosquitoes. To confirm CSP-ELISA results, polymerase chain reaction (PCR) was also performed. A total of 2,837 anopheline mosquitoes, of which 2,576 were female, belonging to 20 species were collected from July 2009-June 2010. Anopheles jeyporiensis was the most abundant species (18.9%), followed by An. vagus (16.8%) and An. kochi (14.4%). ELISA was performed on 2,467 female mosquitoes of 19 species. 15 (0.6%) female anophelines belonging to eight species were found to be positive for Plasmodium infection by CSP-ELISA. Of those, 11 (0.4%) mosquitoes were positive for P. falciparum and four (0.2%) for Pv-210. No mosquito was found positive for Pv-247. An. maculatus (2.1%, 2/97) had the highest infection rate followed by An. umbrosus (1.7%, 2/115) and An. barbirostris (1.1%, 2/186). Other infected species were An. nigerrimus, An. nivipes, An. jeyporiensis, An. kochi, and An. vagus. Out of 11 P. falciparum CSP positive samples, seven turned out to be positive by PCR. None of the samples positive for Pv-210 was positive by PCR. In terms of abundance and incrimination, the results suggest that An. maculatus, An. jeyporiensis and An. nivipes play important roles in malaria transmission in Kuhalong. The findings of this study suggest that even in the presence of an insecticide impregnated bed-net intervention, a number of Anopheles species still play a role in the transmission of malaria. Further investigations are required to reveal the detailed biology and insecticide resistance patterns of the vector mosquito species in endemic areas in Bangladesh in order to assist with the planning and implementation of improved malaria control strategies.


Toxoplasma gondii infection in two common wombats (Vombatus ursinus).
Toxoplasmosis is a common cause of death in wild and captive Australian marsupials, yet descriptions of clinical disease, diagnosis and pathological lesions are limited and incomplete. Infection with Toxoplasma gondii was diagnosed, using immunohistochemical techniques, following the acute death of a juvenile common wombat, Vombatus ursinus, that was being bottle raised by wildlife carers. This animal's cage mate developed dyspnoea, tachycardia and anorexia 3 weeks later. Serum was collected prior to euthanasia and necropsy examination. Pathological lesions in both animals were similar and toxoplasma cysts were seen in most organs examined but particularly in the neurological and respiratory systems. Serological testing of the second wombat supported the histological diagnosis and indicated that the tests have valuable roles in both diagnosing infections ante-mortem and in distinguishing between acute and chronic infections.


Panel-Based Population Next-Generation Sequencing for Inherited Retinal Degenerations.
Inherited retinopathies affect approximately two and a half million people globally, yet the majority of affected patients lack clear genetic diagnoses given the diverse range of genes and mutations implicated in these conditions. We present results from a next-generation sequencing study of a large inherited retinal disease patient population, with the goal of providing clear and actionable genetic diagnoses. Targeted sequencing was performed on 539 individuals from 309 inherited retinal disease pedigrees. Causative mutations were identified in the majority (57%, 176/309) of pedigrees. We report the association of many previously unreported variants with retinal disease, as well as new disease phenotypes associated with known genes, including the first association of the SLC24A1 gene with retinitis pigmentosa. Population statistics reporting the genes most commonly implicated in retinal disease in the cohort are presented, as are some diagnostic conundrums that can arise during such studies. Inherited retinal diseases represent an exemplar group of disorders for the application of panel-based next-generation sequencing as an effective tool for detection of causative mutations.


A Framework for Engineering the Collective Behavior of Complex Rhythmic Systems.
We have developed an engineering framework which utilizes experiment-based phase models to tune complex dynamic structures to desired states; weak, non-destructive signals are employed to alter interactions among nonlinear rhythmic elements. In this manuscript we present an integrated overview and discussion of our recent studies in this area. Experiments on electrochemical reactions were conducted using multi-electrode arrays to demonstrate the use of mild model-engineered feedback to achieve a desirable system response. Application is made to the tuning of phase difference between two oscillators, generation of sequentially-visited dynamic cluster patterns, engineering dynamically differentiated cluster states, and to the design of a nonlinear anti-pacemaker for the destruction of synchronization of a population of interacting oscillators.


Glycolytic enzymes in mammalian spermatozoa. Activities and stabilities of hexokinase and phosphofructokinase in various fractions from sperm homogenates.
1. Methods of homogenizing suspensions of washed mammalian spermatozoa were studied. The most useful methods were those using sonication and those using a French press. 2. Hexokinase, phosphofructokinase, glucose phosphate isomerase and adenosine triphosphatase activities in ram, bull and boar spermatozoa were investigated by using these two homogenization methods. Glucose phosphate isomerase, representative of soluble cytoplasmic material, was very readily extracted and remained entirely in the supernatant after centrifugation at 145000g for 60min. In contrast, the other three activities were less easily extracted and were sedimented in various proportions under the described conditions of centrifugation. 3. Attempts to obtain subcellular fractions from sperm homogenates by ;classical' methods failed, owing apparently to the inhomogeneity of subcellular particles in the homogenates. It is concluded that, after removal of sperm heads, the only meaningful fractionation is a separation of spermatozoal material which sediments at 145000g during 60min from that which does not. 4. The stabilities of hexokinase and phosphofructokinase activities in bull, boar and ram sperm homogenates were investigated. Hexokinases showed very little dependence on the various environments tested, whereas the optimum conditions for phosphofructokinase stability were: a minimum of sonication, the presence of phosphate ions and of a thiol-group protectant, and a pH7.5. Activities of hexokinase, phosphofructokinase and glucose phosphate isomerase per sperm cell were compared with published data on rates of fructolysis by spermatozoa; the potential catalytic activities were shown to be considerably in excess of these rates. However, phosphofructokinase may be the rate-limiting enzyme of glycolysis in vivo in bull and ram spermatozoa.


Tolerance of acid-adapted and non-adapted Escherichia coli O157:H7 cells to reduced pH as affected by type of acidulant.
A study was carried out to determine if three strains of Escherichia coli O157:H7 grown (18 h) in Tryptic Soy Broth (TSB) and TSB supplemented with 1.25% glucose (TSBG), i.e. unadapted and acid-adapted cells, respectively, exhibited changes in tolerance to reduced pH when plated on Tryptic Soy Agar (TSA) acidified (pH 3.9, 4.2, 4.5, 4.8, 5.1 and 5.4) with acetic, citric or malic acids. All test strains grew well on TSA acidified with acetic acid at pH > or = 5.4 or malic acid at pH > or = 4.5; two strains grew on TSA acidified with citric acid at pH > or = 4.5, while the third strain grew at pH > or = 4.8. Acid-adapted and control (unadapted) cells differed little in their ability to form visible colonies on TSA containing the same acid at the same pH. However, on plates not showing visible colonies, acid-adapted cells retained higher viability than unadapted cells when plated on acidified TSA. Growth of acid-adapted and control cells of E. coli O157:H7 inoculated into TSB containing acetic acid (pH 5.4 and 5.7) and citric or malic acids (pH 4.2 and 4.5) was also studied. There was essentially no difference in growth characteristics of the two types of cells in TSB acidified at the same pH with a given acid. Tolerance of acid-adapted and control cells on subsequent exposure to low pH is influenced by the type of acidulant. The order of sensitivity at a given pH is acetic > citric > malic acid. When performing acid challenge studies to determine survival and growth characteristics of E. coli O157:H7 in foods, consideration should be given to the type of acid to which cells have been exposed previously, the procedure used to achieve acidic environments and possible differences in response among strains. The use of strains less affected by pH than type of acidulant or vice versa could result in an underestimation of the potential for survival and growth of E. coli O157:H7 in acid foods.


Health supervision for children with achondroplasia.
Achondroplasia is the most common condition associated with disproportionate short stature. Substantial information is available concerning the natural history and anticipatory health supervision needs in children with this dwarfing disorder. Most children with achondroplasia have delayed motor milestones, problems with persistent or recurrent middle-ear dysfunction, and bowing of the lower legs. Less often, infants and children may have serious health consequences related to hydrocephalus, craniocervical junction compression, upper-airway obstruction, or thoracolumbar kyphosis. Anticipatory care should be directed at identifying children who are at high risk and intervening to prevent serious sequelae. This report is designed to help the pediatrician care for children with achondroplasia and their families.