Giant Faraday Rotation through Ultrasmall Fe0n Clusters in Superparamagnetic FeO-SiO2 Vitreous Films.
Magnetooptical (MO) glasses and, in particular, Faraday rotators are becoming key components in lasers and optical information processing, light switching, coding, filtering, and sensing. The common design of such Faraday rotator materials follows a simple path: high Faraday rotation is achieved by maximizing the concentration of paramagnetic ion species in a given matrix material. However, this approach has reached its limits in terms of MO performance; hence, glass-based materials can presently not be used efficiently in thin film MO applications. Here, a novel strategy which overcomes this limitation is demonstrated. Using vitreous films of xFeO·(100 - x)SiO2, unusually large Faraday rotation has been obtained, beating the performance of any other glassy material by up to two orders of magnitude. It is shown that this is due to the incorporation of small, ferromagnetic clusters of atomic iron which are generated in line during laser deposition and rapid condensation of the thin film, generating superparamagnetism. The size of these clusters underbids the present record of metallic Fe incorporation and experimental verification in glass matrices.


A DNA microarray for the versatile diagnosis of infectious diarrhea.
Several bacteria, viruses, and parasites cause diarrhea as coinfecting pathogens. We designed a DNA microarray comprising 60-bp probes spotted 194 times for the multiplex detection of 33 enteropathogenic bacteria and seven enteropathogenic viruses, and the archaeon Methanobrevibacter smithii was used as an internal positive control. Nine pathogen-free stool specimens were used as negative controls. One of these control specimens was further spiked with Salmonella enterica as a positive control. The microarray was then tested with 40 pathological stool specimens, comprising S. enterica (n = 30), Campylobacter jejuni (n = 4), pathogenic Escherichia coli (n = 2), and adenovirus (n = 4). M. smithii was detected in 47/49 (95.9%) specimens, no pathogen was detected in negative controls and S. enterica was identified in the S. enterica-spiked positive control. The overall specificity was 100% and the overall sensitivity was 97.5% because one S. enterica sample was missed by the microarray. The multiplexed detection of C. jejuni spiked into an adenovirus-positive stool sample gave positive results, with fluorescence values of 14.3 and 9.1, respectively. These data indicate that using the protocol developed in this article, the DNA array allows for the multiplexed detection of some enteropathogens in stool samples.


Early Transcriptome Signatures from Immunized Mouse Dendritic Cells Predict Late Vaccine-Induced T-Cell Responses.
Systems biology offers promising approaches for identifying response-specific signatures to vaccination and assessing their predictive value. Here, we designed a modelling strategy aiming to predict the quality of late T-cell responses after vaccination from early transcriptome analysis of dendritic cells. Using standardized staining with tetramer, we first quantified antigen-specific T-cell expansion 5 to 10 days after vaccination with one of a set of 41 different vaccine vectors all expressing the same antigen. Hierarchical clustering of the responses defined sets of high and low T cell response inducers. We then compared these responses with the transcriptome of splenic dendritic cells obtained 6 hours after vaccination with the same vectors and produced a random forest model capable of predicting the quality of the later antigen-specific T-cell expansion. The model also successfully predicted vector classification as low or strong T-cell response inducers of a novel set of vaccine vectors, based on the early transcriptome results obtained from spleen dendritic cells, whole spleen and even peripheral blood mononuclear cells. Finally, our model developed with mouse datasets also accurately predicted vaccine efficacy from literature-mined human datasets.


Role of carcinoembryonic antigen and liver function tests in the detection of recurrent colorectal carcinoma.
The optimal laboratory evaluation for the early detection of liver metastases from colorectal cancer is controversial. This investigation was undertaken to compare the efficacy of liver function tests (LFTs) with that of carcinoembryonic antigen (CEA) levels for the early detection of liver metastases. Patients who developed liver metastases after potentially curative resections of adenocarcinoma of the colorectum between 1974 and 1988 were reviewed. The following laboratory tests were serially evaluated during the follow-up period: CEA, alkaline phosphatase (AP), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and lactic dehydrogenase (LDH). These values were retrospectively assessed from the time of documented liver metastases to identify which lab value(s) were elevated initially. Ninety-two patients were available for study. Average time for the occurrence of liver metastases was 20 months (range, 3-72 months). The incidence of elevation of individual tests at the time of suspicion of liver metastasis was: CEA, 94.6 percent (P less than 0.25, chi-squared); AP, 18.5 percent; SGOT, 12.0 percent; SGPT, 5.4 percent; and LDH, 29.3 percent. When comparing CEA with a battery of LFTs at the time of suspicion of liver metastasis, CEA was elevated with normal LFTs in 64.1 percent (P less than 0.05, chi-squared), the most frequent occurrence. At least one LFT was elevated with a normal CEA in only 2.2 percent; CEA and at least one LFT were increased in 30.4 percent; and both tests were normal in only 3.3 percent. These results indicate that, of the individual laboratory tests performed, CEA elevation heralds liver metastases significantly more frequently. LDH is the liver function test most frequently elevated when liver metastases are first suspected. When CEA is directly compared with a battery of LFTs, CEA is statistically significantly more frequently elevated. In fact, suspicion of liver metastases would have been delayed by the omission of LFTs in only 2.2 percent of patients. Therefore, we conclude that LFTs should be deleted from the follow-up of colorectal cancer patients, decreasing costs without significantly decreasing accuracy.


Identification of Chlamydomonas reinhardtii endogenous genic flanking sequences for improved transgene expression.
Chlamydomonas reinhardtii is a unicellular green alga that has attracted interest due to its potential biotechnological applications, and as a model for algal biofuel and energy metabolism. Despite all the advantages that this unicellular alga offers, poor and inconsistent expression of nuclear transgenes remains an obstacle for basic and applied research. We used a data-mining strategy to identify highly expressed genes in Chlamydomonas whose flanking sequences were tested for the ability to drive heterologous nuclear transgene expression. Candidates identified in this search included two ribosomal protein genes, RPL35a and RPL23, and ferredoxin, FDX1, whose flanking regions including promoters, terminators and untranslated sequences could drive stable luciferase transgene expression to significantly higher levels than the commonly used Hsp70A-RBCS2 (AR) hybrid promoter/terminator sequences. The RPL23 flanking sequences were further tested using the zeocin resistance gene sh-ble as a reporter in monocistronic and dicistronic constructs, and consistently yielded higher numbers of zeocin-resistant transformants and higher levels of resistance than AR- or PSAD-based vectors. Chlamydomonas RPL23 sequences also enabled transgene expression in Volvox carteri. Our study provides an additional benchmark for strong constitutive expression of transgenes in Chlamydomonas, and develops a general approach for identifying flanking sequences that can be used to drive transgene expression for any organism where transcriptome data are available.


Microtetraspora malaysiensis sp. nov., isolated from Malaysian primary dipterocarp forest soil.
The taxonomic position of three actinomycete strains isolated from Malaysian soil was established by using a polyphasic approach. The isolates formed chains composed of four spores on the tip of sporophores branching from the aerial mycelium, and their chemotaxonomic properties were common to those of members of the family Streptosporangiaceae. These phenotypic properties as well as a phylogenetic analysis based on 16S rRNA gene sequences indicated that they should be classified in the genus Microtetraspora. The three isolates showed a unique pattern of cultural, physiological and biochemical properties that distinguished them from previously described species of the genus Microtetraspora. The isolates showed more than 72% DNA relatedness to each other, but only 58% or less relatedness to any previously described species. On the basis of the data presented, a new species of the genus Microtetraspora, Microtetraspora malaysiensis, is proposed. The type strain of the new species is strain H47-7(T) (=JCM 11278(T)=DSM 44579(T)).


[Promoter methylation status and protein expression of p14ARF gene in squamous cell carcinoma and adenocarcinoma of the lung].
Recently, the p14 ARF gene has emerged as a new putative tumor suppressor gene, and the alteration of p14 ARF gene is closely related to development of multiple human tumors. The aberrant promoter methylation as a mechanism of inactivation of p14 ARF gene might participate in tumorigenesis. The aim of this study is to investigate promoter methylation status and protein expression of p14 ARF gene in pulmonary squamous cell carcinoma and adenocarcinoma, and to value the role of p14 ARF promoter methylation in carcinogenesis of non-small cell lung cancer. Promoter methylation status and protein expression of p14 ARF gene were analyzed in 40 cases of pulmonary squamous cell carcinoma and adenocarcinoma by methylation specific polymerase chain reaction (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR) and immunohistochemistry (IHC). The positive rate of p14 ARF promoter methylation in tumor tissues and normal tissues adjacent to cancer was 17.5% (7/40) and 2.5% (1/40) respectively (P= 0.025 ). The results of RE-PCR were consistent with the above. The positive rate of p14 ARF protein in tumor tissues was significantly lower than that in normal tissues adjacent to cancer (P=0.003). Promoter methylation and protein expression of p14 ARF gene showed a significantly negative correlation (r=-0.56, P= 0.001 ), and both of them did not correlate statistically with the clinicopathologic characteristics of patients such as histological classification, TNM stages, differentiation grade and lymph node involvement. Promoter methylation is a crucial mechanism of inactivation of p14 ARF gene. Promoter methylation of p14 ARF gene might be involved in carcinogenesis of non-small cell lung cancer, and it is an early event in development process of non-small cell lung cancer.


A pilot phase II study of the efficacy and biosafety of doxorubicin chemotherapy in tumor-bearing equidae.
The efficacy and biosafety of a previously established tolerable dosage of doxorubicin have not been established in horses. To provide preliminary evidence of the efficacy of doxorubicin in tumor-bearing horses, explore drug pharmacokinetics profile, and estimate period of risk of exposure to drug residues. Twelve horses with 37 tumors. Treatment protocol included 6 treatments at 3-week intervals. Eight horses were uniformly treated at a dosage of 70 mg/m(2) and 4 horses received 4 of 6 treatment cycles at 70 mg/m(2) . Clinical signs, tumor responses, and toxicoses were evaluated. Drug residue concentrations were quantitated in 3 horses receiving of 65, 70, and 75 mg/m(2) by high-performance liquid chromatography with ultraviolet detection (plasma, feces) and liquid chromatography and tandem mass spectrometry (urine). Thirty tumors, including lymphomas, carcinomas, sarcoids, and melanoma, were evaluated for efficacy. The overall response rate was 47% (95% CI, 28-65%). Doxorubicin was not found to be effective against melanomas. Lymphomas and carcinomas were most responsive. Pooled serum Cmax and half-life of doxorubicin were 121.3 ng/mL and 12.9 hours, respectively. There were no detectable residues in fecal samples up to 3 weeks after treatment and in plasma and urine after 2 and 3 days, respectively. This study provides preliminary evidence that single-agent doxorubicin at a dosage of 70 mg/m(2) has a broad spectrum of activity. The risk of exposure to drug residues in plasma and feces was low. Direct contact with urine-contaminated wastes should be avoided for 2 days after treatment.


Recent advances in porous Pt-based nanostructures: synthesis and electrochemical applications.
Porous Pt-based nanostructured materials possess intriguing physical and chemical properties to generate promising potential for various important applications such as fuel cells, sensors, stimulation electrodes, mechanical actuators and catalysis. With the great advances in material science and nanotechnology, porous Pt-based nanomaterials with well-controlled composition, shape, and geometrical configuration have been rationally designed and fabricated. Importantly, their superior properties including unique pore structure, large specific surface area and excellent structural stability have fuelled up great interest to improve their current performance and to explore new applications. This tutorial review attempts to summarize the recent important progress towards the development of porous Pt-based nanostructured materials, with special emphasis on fabrication methods and advanced electrochemical applications, such as electrocatalysis and electrochemical sensors. The correlations between the composition and morphology of the catalysts and their catalytic properties are discussed based on some important and representative examples. Some key scientific issues and potential future directions of research in this field are also discussed.


Rapid and sensitive detection of nodularin-R in water by a label-free BLI aptasensor.
Contamination of freshwater with nodularin-R (NOD-R) represents a significant global environmental and public health concern. However, ethical problems and technical difficulties surrounding the current detection methods for NOD-R necessitate further studies to devise appropriate alternatives within a regulatory monitoring regime. In this work, we employed an aptamer as a specific recognition element and developed a biolayer interferometry (BLI) biosensor platform for NOD-R detection. The aptasensor we propose displayed a broad detection range from 40 to 600 nM NOD-R (and a linear response range from 40 to 200 nM), and achieved a detection limit as low as 167 pM. In addition, the aptamer-based biosensor was shown to possess high selectivity, as well as good reproducibility and stability. We believe that this novel aptamer-based biosensor provides a potential alternative for the sensitive and rapid detection of NOD-R.


The effect of short sleep duration on coronary heart disease risk is greatest among those with sleep disturbance: a prospective study from the Whitehall II cohort.
Short sleep duration is associated with increased CHD (coronary heart disease) mortality and morbidity, although some evidence suggests that sleep disturbance is just as important. We investigated whether a combination of short sleep duration and sleep disturbance is associated with a higher risk of CHD than their additive effects. The Whitehall II study. The Whitehall II study recruited 10,308 participants from 20 civil service departments in London, England. Participants were between the ages of 35 and 55 years at baseline (1985-1988) and were followed up for an average of 15 years. N/A. Sleep hours and sleep disturbance (from the General Heath Questionnaire-30) were obtained from the baseline survey. CHD events included fatal CHD deaths or incident nonfatal myocardial infarction or angina (ICD-9 codes 410-414 or ICD-10 120-25). Short sleep duration and sleep disturbance were both associated with increased hazards for CHD in women as well as in men, although, after we adjusted for confounders, only those reporting sleep disturbance had a raised risk. There was some evidence for an interaction between sleep duration and sleep disturbance. Participants with short sleep duration and restless disturbed nights had the highest hazard ratios (HR) of CHD (relative risk:1.55, 95% confidence interval:1.33-1.81). Among participants who did not report any sleep disturbance, there was little evidence that short sleep hours increased CHD risk. The effect of short sleep (< or = 6 hours) on increasing CHD risk is greatest among those who reported some sleep disturbance. However, among participants who did not report any sleep disturbance, there was little evidence that short sleep hours increased CHD risk.


New HIV-1 circulating recombinant form 94: from phylogenetic detection of a large transmission cluster to prevention in the age of geosocial-networking apps in France, 2013 to 2017.
BackgroundEnding the HIV pandemic must involve new tools to rapidly identify and control local outbreaks and prevent the emergence of recombinant strains with epidemiological advantages.AimThis observational study aimed to investigate in France a cluster of HIV-1 cases related to a new circulating recombinant form (CRF). The confirmation this CRF's novelty as well as measures to control its spread are presented.MethodsPhylogenetic analyses of HIV sequences routinely generated for drug resistance genotyping before 2018 in French laboratories were employed to detect the transmission chain. The CRF involved was characterised by almost full-length viral sequencing for six cases. Cases' clinical data were reviewed. Where possible, epidemiological information was collected with a questionnaire.ResultsThe transmission cluster comprised 49 cases, mostly diagnosed in 2016-2017 (n = 37). All were infected with a new CRF, CRF94_cpx. The molecular proximity of this CRF to X4 strains and the high median viraemia, exceeding 5.0 log10 copies/mL, at diagnosis, even in chronic infection, raise concerns of enhanced virulence. Overall, 41 cases were diagnosed in the Ile-de-France region and 45 were men who have sex with men. Among 24 cases with available information, 20 reported finding partners through a geosocial networking app. Prevention activities in the area and population affected were undertaken.ConclusionWe advocate the systematic use of routinely generated HIV molecular data by a dedicated reactive network, to improve and accelerate targeted prevention interventions. Geosocial networking apps can play a role in the spread of outbreaks, but could also deliver local targeted preventive alerts.


Evaluation of the marketing methods and handling of live shellfish (American lobsters) for the purpose of sale as food: First evaluations in Piedmont, Italy.
Some species of crustaceans pose problems during marketing, being sold alive. Food Business Operators (FBO) have the need to adopt specific measures based on opinions and guidelines of national and international associations. This investigation was aimed at evaluating the practices in use in the marketing of live crustaceans in Piedmont. Twenty-three plants were analyzed using checklists and through physical and chemical measurements of the water in the holding tanks. The situation appears uneven in the application of Good Handling Practices (GHP), management of animals and knowledge of FBO. Only 48% of the Hazard Analysis and Critical Control Point plans had a dedicated section. Immobilization of the claws was the option identified to control aggressiveness. Dead animals are mainly identified as Category 3 instead of other hygienically safe options. Only 1/3 of interviewed can indicate the slaughtering methods recognized as most suitable for these animals. The aquariums show a good state of maintenance and most of evaluated parameters complaint to GHP except for nitrites (35%). In conclusion, the situation reflects the different levels of knowledge of the FBOs. Therefore the veterinarian of the public health service can propose itself as a reference point for specific training.


Prevention of cisplatin-induced hearing loss in children: Informing the design of future clinical trials.
Cisplatin is an essential chemotherapeutic agent in the treatment of many pediatric cancers. Unfortunately, cisplatin-induced hearing loss (CIHL) is a common, clinically significant side effect with life-long ramifications, particularly for young children. ACCL05C1 and ACCL0431 are two recently completed Children's Oncology Group studies focused on the measurement and prevention of CIHL. The purpose of this paper was to gain insights from ACCL05C1 and ACCL0431, the first published cooperative group studies dedicated solely to CIHL, to inform the design of future pediatric otoprotection trials. Use of otoprotective agents is an attractive strategy for preventing CIHL, but their successful development must overcome a unique constellation of methodological challenges related to translating preclinical research into clinical trials that are feasible, evaluate practical interventions, and limit risk. Issues particularly important for children include use of appropriate methods for hearing assessment and CIHL severity grading, and use of trial designs that are well-informed by preclinical models and suitable for relatively small sample sizes. Increasing interest has made available new funding opportunities for expanding this urgently needed research.


ST-elevation myocardial infarction, thrombus aspiration, and different invasive strategies. A TASTE trial substudy.
The clinical effect of thrombus aspiration in ST-elevation myocardial infarction may depend on the type of aspiration catheter and stenting technique. The multicenter, prospective, randomized, open-label trial Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia (TASTE) did not demonstrate a clinical benefit of thrombus aspiration compared to percutaneous coronary intervention alone. We assessed the effect of type of aspiration device, stent type, direct stenting, and postdilatation on outcomes at 1 year. There was no difference in all-cause mortality, between the 3 most frequently used aspiration catheters (Eliminate [Terumo] 5.4%, Export [Medtronic] 5.0%, Pronto [Vascular Solutions] 4.5%) in patients randomized to thrombus aspiration. There was no difference in mortality between directly stented patients randomized to thrombus aspiration compared to patients randomized to percutaneous coronary intervention only (risk ratio 1.08, 95% CI 0.70 to 1.67, P=0.73). Similarly, there was no difference in mortality between the 2 randomized groups for patients receiving drug-eluting stents (risk ratio 0.89, 95% CI 0.63 to 1.26, P=0.50) or for those treated with postdilation (risk ratio 0.72, 95% CI 0.49 to 1.07, P=0.11). Furthermore, there was no difference in rehospitalization for myocardial infarction or stent thrombosis between the randomized arms in any of the subgroups. In patients with ST-elevation myocardial infarction randomized to thrombus aspiration, the type of aspiration catheter did not affect outcome. Stent type, direct stenting, or postdilation did not affect outcome irrespective of treatment with thrombus aspiration and percutaneous coronary intervention or percutaneous coronary intervention alone. URL: ClinicalTrials.gov. Unique identifier: NCT01093404, https://clinicaltrials.gov/ct2/show/NCT01093404.


Unhealthy assimilation: why do immigrants converge to American health status levels?
It is well documented that immigrants are in better health upon arrival in the United States than their American counterparts but that this health advantage erodes over time. We study the potential determinants of this "healthy immigrant effect, " with a particular focus on the tendency of immigrants to converge to unhealthy American BMI levels. Using data from the National Health Interview Survey, we find that average female and male immigrants enter the United States with BMIs that are approximately two and five percentage points lower than native-born women and men, respectively. Consistent with the declining health status of immigrants the longer they remain in the United States, we also find that female immigrants almost completely converge to American BMIs within 10 years of arrival, and men close a third of the gap within 15 years.


Postmortem blood cadmium, lead, and mercury concentrations: comparisons with regard to sampling location and reference ranges for living persons.
This study's goal was to determine cadmium (Cd), lead (Pb), total mercury (THg), and inorganic mercury (IHg) levels in human cadavers to compare measured levels with established reference ranges for living persons and to determine whether blood levels varied with time from death to sample collection or by body collection site. Subjects (n = 66) recruited from the Fulton County Medical Examiner's Office in Atlanta, GA, were 20 years of age or older, had no penetrating trauma, no obvious source of environmental contamination of the vasculature, and had whole blood accessible from the femoral (F) site, the cardiac (C) site, or both. Geometric mean results were as follows: 2.59 microg/L F-Cd; 11.81 microg/L C-Cd; 1.03 microg/L F-THg; 2.01 microg/L C-THg; 0.29 microg/L F-IHg; 0.49 microg/L C-IHg; 1.78 microg/dL F-Pb; and 1.87 microg/dL C-Pb. Both F- and C-Cd levels as well as C-THg levels were significantly higher than reference values among living persons (C- and F-Cd, p < 0.0001 and C-THg, p = 0.0001, respectively). Based on regression modeling, as the postmortem interval increased, blood Cd levels increased (p < 0.006). Postmortem blood Cd concentrations were elevated compared to population values and varied with respect to sampling location and postmortem interval.


Effects of postnatal dexamethasone on blood-brain barrier permeability and brain water content in newborn lambs.
We showed that antenatal corticosteroids reduced blood-brain barrier permeability in fetuses at 60 and 80%, but not 90% of gestation, and decreased brain water content in fetuses. Our objective was to examine the effects of postnatal corticosteroids on regional blood-brain barrier permeability and brain water content in newborn lambs. Three dexamethasone treatment groups were studied in 3- to 5-day-old lambs. A 0.01 mg/kg dose was selected to estimate the amount of dexamethasone that might have reached fetuses via antenatal treatment of ewes in our previous studies. The other doses (0.25 and 0.5 mg/kg) were chosen to approximate those used clinically to treat infants with bronchopulmonary dysplasia. Lambs were randomly assigned to receive four intramuscular injections of dexamethasone or placebo given 12 h apart on days 3 and 4 of age. Blood-brain barrier function was measured with the blood-to-brain transfer constant (K(i)) to alpha-aminoisobutyric acid, brain plasma volume was measured with polyethylene glycol for the calculation of K(i,) and brain water was measured by wet-to-dry tissue weights. Postnatal treatment with corticosteroids did not reduce barrier permeability in newborn lambs. Brain blood volume was higher in the 0.25 and 0.5 mg/kg dose dexamethasone groups than in the placebo group. Brain water content did not differ among the groups. We conclude that postnatal treatment with corticosteroids did not reduce regional blood-brain barrier permeability or brain water content but increased the brain plasma volume in newborn lambs. These findings are consistent with our previous work indicating that barrier permeability is responsive to corticosteroids at 60 and 80% of gestation and brain water regulation at 60% of gestation, but not in near-term fetuses or newborn lambs.


Seroepidemiology of Toxoplasma gondii in zoo animals in selected zoos in the midwestern United States.
Toxoplasma gondii infections in zoo animals are of interest because many captive animals die of clinical toxoplasmosis and because of the potential risk of exposure of children and elderly to T. gondii oocysts excreted by cats in the zoos. Seroprevalence of T. gondii antibodies in wild zoo felids, highly susceptible zoo species, and feral cats from 8 zoos of the midwestern United States was determined by using the modified agglutination test (MAT). A titer of 1:25 was considered indicative of T. gondii exposure. Among wild felids, antibodies to T. gondii were found in 6 (27.3%) of 22 cheetahs (Acynonyx jubatus jubatus), 2 of 4 African lynx (Caracal caracal), 1 of 7 clouded leopards (Neofelis nebulosa), 1 of 5 Pallas cats (Otocolobus manul), 12 (54.5%) of 22 African lions (Panthera leo), 1 of 1 jaguar (Panthera onca), 1 of 1 Amur leopard (Panthera pardus orientalis), 1 of 1 Persian leopard (Panthera pardus saxicolor), 5 (27.8%) of 18 Amur tigers (Panthera tigris altaica), 1 of 4 fishing cats (Prionailurus viverrinus), 3 of 6 pumas (Puma concolor), 2 of 2 Texas pumas (Puma concolor stanleyana), and 5 (35.7%) of 14 snow leopards (Uncia uncia). Antibodies were found in 10 of 34 feral domestic cats (Felis domesticus) trapped in 3 zoos. Toxoplasma gondii oocysts were not found in any of the 78 fecal samples from wild and domestic cats. Among the macropods, antibodies were detected in 1 of 3 Dama wallabies (Macropus eugenii), 1 of 1 western grey kangaroo (Macropus fuliginosus), 1 of 2 wallaroos (Macropus robustus), 6 of 8 Bennett's wallabies (Macropus rufogriseus), 21 (61.8%) of 34 red kangaroos (Macropus rufus), and 1 of 1 dusky pademelon (Thylogale brunii). Among prosimians, antibodies were detected in 1 of 3 blue-eyed black lemurs (Eulemur macaco flavifrons), 1 of 21 ring-tailed lemurs (Lemur catta), 2 of 9 red-ruffed lemurs (Varecia variegata rubra), and 2 of 4 black- and white-ruffed lemurs (Varecia variegata variegata). Among the avian species tested, 2 of 3 bald eagles (Haliaeetus leucocephalus) were seropositive. Among 7 possible risk factors, sex, freezing meat temperature (above -13 C vs. below -13 C), washing vegetables thoroughly, frequency of feral cat sightings on zoo grounds (occasionally vs. frequently), frequency of feral cat control programs, capability of feral cats to enter hay/grain barn, and type of animal exhibit, exhibiting animals in open enclosures was the only factor identified as a significant risk (OR 3.22, P = 0.00).


Direct-to-consumer genetic testing: failure is not an option.
Direct-to-consumer genetic testing is an unavoidable consequence of our ability to cheaply and accurately measure the genome. Some are troubled by the loss of control over how and when this information is disclosed to individuals, but it is difficult to imagine any way to prevent the wide availability of these data. Therefore, the key challenge is to set up social, educational, and technical means to support individuals who have access to their genome.


Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer's disease.
Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood-brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects.


Thiol protecting agents and antioxidants inhibit the mitochondrial permeability transition promoted by etoposide: implications in the prevention of etoposide-induced apoptosis.
Etoposide (VP-16) is known to promote cell apoptosis either in cancer or in normal cells as a side effect. This fact is preceded by the induction of several mitochondrial events, including increase in Bax/Bcl-2 ratio followed by cytochrome c release and consequent activation of caspase-9 and -3, reduction of ATP levels, depolarization of membrane potential (DeltaPsi) and rupture of the outer membrane. These events are apoptotic factors essentially associated with the induction of the mitochondrial permeability transition (MPT). VP-16 has been shown to stimulate the Ca2+-dependent MPT induction similarly to prooxidants and to promote apoptosis by oxidative stress mechanisms, which is prevented by glutathione (GSH) and N-acetylcysteine (NAC). Therefore, the aim of this work was to study the effects of antioxidants and thiol protecting agents on MPT promoted by VP-16, attempting to identify the underlying mechanisms on VP-16-induced apoptosis. The increased sensitivity of isolated mitochondria to Ca2+-induced swelling, Ca2+ release, depolarization of DeltaPsi and uncoupling of respiration promoted by VP-16, which are prevented by cyclosporine A proving that VP-16 induces the MPT, are also efficiently prevented by ascorbate, the primary reductant of the phenoxyl radicals produced by VP-16. The thiol reagents GSH, dithiothreitol and N-ethylmaleimide, which have been reported to prevent the MPT induction, also protect this event promoted by VP-16. The inhibition of the VP-16-induced MPT by antioxidants agrees with the prevention of etoposide-induced apoptosis by GSH and NAC and suggests the generation of oxidant species as a potential mechanism underlying the MPT that may trigger the release of mitochondrial apoptogenic factors responsible for apoptotic cascade activation.


Consequences of Paternal Nutrition on Offspring Health and Disease.
It is well established that the maternal diet during the periconceptional period affects the progeny's health. A growing body of evidence suggests that the paternal diet also influences disease onset in offspring. For many years, sperm was considered only to contribute half of the progeny's genome. It now appears that it also plays a crucial role in health and disease in offspring's adult life. The nutritional status and environmental exposure of fathers during their childhood and/or the periconceptional period have significant transgenerational consequences. This review aims to describe the effects of various human and rodent paternal feeding patterns on progeny's metabolism and health, including fasting or intermittent fasting, low-protein and folic acid deficient food, and overnutrition in high-fat and high-sugar diets. The impact on pregnancy outcome, metabolic pathways, and chronic disease onset will be described. The biological and epigenetic mechanisms underlying the transmission from fathers to their progeny will be discussed. All these data provide evidence of the impact of paternal nutrition on progeny health which could lead to preventive diet recommendations for future fathers.


Cardio-renal interaction: impact of renal function and anemia on the outcome of chronic heart failure.
The purpose of this study is to investigate the effects of renal function and anemia on the outcome of chronic heart failure (CHF). We targeted 711 consecutive patients who were hospitalized at the Division of Cardiology of Fujita Health University Hospital during a 5-year period. The subjects were divided into four groups according to their estimated glomerular filtration rate (e-GFR) calculated using the Modification of Diet in Renal Disease (MDRD) formula. Intergroup comparisons were conducted for underlying heart diseases, clinical findings at the time of hospitalization, treatment, and outcome. Moreover, the patients were divided into two groups according to their serum hemoglobin concentration at the time of hospitalization, using 12.0 g/dl as the dividing point, to study the effects of anemia on the outcome. In the group with decreased renal function, the average age was higher, and ischemic heart disease and associated conditions such as hypertension and diabetes mellitus were observed in most of the patients. In addition, the rate of anemia development and the plasma B-type natriuretic peptide concentration were also high. The greater the deterioration in renal function, the poorer the outcome became (P < 0.0001). Chronic heart failure complicated by anemia showed an especially poor outcome (P < 0.0001). As this study showed that renal function and anemia significantly affected the outcome of CHF, it is clear that the preservation of renal function and the management of anemia are important in addition to the conventional treatments for CHF.


Nonlinear irreversible thermodynamics of single-molecule experiments.
Irreversible thermodynamics of single-molecule experiments subject to external constraining forces of a mechanical nature is presented. Extending Onsager's formalism to the nonlinear case of systems under nonequilibrium external constraints, we are able to calculate the entropy production and the general nonlinear kinetic equations for the variables involved. In particular, we analyze the case of RNA stretching protocols obtaining critical oscillations between different configurational states when forced by external means to remain in the unstable region of its free-energy landscape, as observed in experiments. We also calculate the entropy produced during these hopping events and show how resonant phenomena in stretching experiments of single RNA macromolecules may arise. We also calculate the hopping rates using Kramer's approach obtaining a good comparison with experiments.


Evaluation of targeting errors in ultrasound-assisted radiotherapy.
A method for validating the start-to-end accuracy of a 3-D ultrasound (US)-based patient positioning system for radiotherapy is described. A radiosensitive polymer gel is used to record the actual dose delivered to a rigid phantom after being positioned using 3-D US guidance. Comparison of the delivered dose with the treatment plan allows accuracy of the entire radiotherapy treatment process, from simulation to 3-D US guidance, and finally delivery of radiation, to be evaluated. The 3-D US patient positioning system has a number of features for achieving high accuracy and reducing operator dependence. These include using tracked 3-D US scans of the target anatomy acquired using a dedicated 3-D ultrasound probe during both the simulation and treatment sessions, automatic 3-D US-to-US registration and use of infrared LED (IRED) markers of the optical position-sensing system for registering simulation computed tomography to US data. The mean target localization accuracy of this system was 2.5 mm for four target locations inside the phantom, compared with 1.6 mm obtained using the conventional patient positioning method of laser alignment. Because the phantom is rigid, this represents the best possible set-up accuracy of the system. Thus, these results suggest that 3-D US-based target localization is practically feasible and potentially capable of increasing the accuracy of patient positioning for radiotherapy in sites where day-to-day organ shifts are greater than 1 mm in magnitude.


Relationships Between Violent Sexual Victimization and Muscle-Building Exercise among Adolescents from the 2019 Youth Risk Behavior Survey.
This study aimed to investigate the association between violent sexual victimization and muscle-building exercise among adolescents. Cross-sectional data from the 2019 National Youth Risk Behavior Survey (N = 8408) were analyzed. Two indicators of non-dating-related sexual violence (lifetime, past 12 months), along with one indicator of adolescent sexual violence (past 12 months), were assessed. Days of muscle-building in the past week were reported. Multinomial logistic regression analyses were conducted to determine the associations between the three violent sexual victimization variables and muscle-building exercise. Among the sample (50.3% girls), lifetime violent sexual victimization (relative risk ratio [RRR] 1.87, 95% confidence interval [CI] 1.29 to 2.72), past 12-month violent sexual victimization (RRR 1.60, 95% CI 1.15 to 2.22), and past 12-month sexual dating violence (RRR 1.60, 95% CI 1.03 to 2.51) were associated greater relative risk of high engagement (ie, 6 to 7 days) in muscle-building exercise relative to no engagement. A history of violent sexual victimization is associated with greater involvement in muscle-building exercise, particularly among adolescent girls. Engagement in muscle-building exercise in relation to violent sexual victimization may be a means of emotion regulation and occur due to body dissatisfaction resulting from experiencing violence.


Differential modulation of the lipoxygenase cascade during typical and latent Pectobacterium atrosepticum infections.
Plant diseases caused by Pectobacterium atrosepticum are often accompanied by extensive rot symptoms. In addition, these bacteria are able to interact with host plants without causing disease for long periods, even throughout several host plant generations. There is, to date, no information on the comparative physiology/biochemistry of symptomatic and asymptomatic plant-P. atrosepticum interactions. Typical (symptomatic) P. atrosepticum infections are associated with the induction of plant responses mediated by jasmonates, which are one of the products of the lipoxygenase cascade that gives origin to many other oxylipins with physiological activities. In this study, we compared the functioning of the lipoxygenase cascade following typical and latent (asymptomatic) infections to gain better insight into the physiological basis of the asymptomatic and antagonistic coexistence of plants and pectobacteria. Tobacco plants were mock-inoculated (control) or infected with the wild type P. atrosepticum (typical infection) or its coronafacic acid-deficient mutant (latent infection). The expression levels of the target lipoxygenase cascade-related genes were assessed by Illumina RNA sequencing. Oxylipin profiles were analysed by GC-MS. With the aim of revising the incorrect annotation of one of the target genes, its open reading frame was cloned to obtain the recombinant protein, which was further purified and characterized using biochemical approaches. The obtained data demonstrate that when compared to the typical infection, latent asymptomatic P. atrosepticum infection is associated with (and possibly maintained due to) decreased levels of 9-lipoxygenase branch products and jasmonic acid and increased level of cis-12-oxo-10,15-phytodienoic acid. The formation of 9-oxononanoic acid and epoxyalcohols in tobacco plants was based on the identification of the first tobacco hydroperoxide lyase (HPL) with additional epoxyalcohol synthase (EAS) activity. Our results contribute to the hypothesis of the oxylipin signature, indicating that different types of plant interactions with a particular pathogen are characterized by the different oxylipin profiles of the host plant. In addition, the tobacco LOC107825278 gene was demonstrated to encode an NtHPL (CYP74C43) enzyme yielding volatile aldehydes and aldoacids (HPL products) as well as oxiranyl carbinols (EAS products).


Midline extraperitoneal approach to upper urinary tract surgery: anatomical basis of surgical technique.
To overcome the disadvantages inherent in the standard surgical approach to the kidney, we introduced a novel surgical technique via a midline extraperitoneal approach. The surgical technique is not substantially different from that of the standard midline transperitoneal approach, except no entry is made into the peritoneal cavity. Although the peritoneum itself is extremely thin and fragile, the peritoneum together with underlying subperitoneal fascia can be dissected readily as a substantial layer, if the proper plane is dissected. Further medial mobilization of the peritoneal sac en bloc by pursuing the fusion fascia plane allows full exposure of the kidney, ureter and great vessels. This approach was adopted for consecutive 51 patients during a 10-month period in 2003. All operations, including 33 radical nephrectomies and 11 nephroureterectomies were completed successfully without significant technical difficulties and differences in operation time and estimated blood loss compared to the transperitoneal approach. No intra- or perioperative complication occurred. All patients did seem to have a much more comfortable postoperative period with minor pain and few abdominal complaint, and the clinical impression was that they resumed the physical activity and oral intake earlier than those after the transperitoneal approach (P = 0.056). There are no operation-related problems such as intra-abdominal adhesion or abdominal muscle weakness resulting in some deformity at 2-year or more follow up. This approach combines the advantages of the transperitoneal midline and extraperitoneal flank approach. Its use will undoubtedly reduce the complications inherent in the transperitoneal approach or the flank approach.


Endoscopic transorbital surgery for Meckel's cave and middle cranial fossa tumors: surgical technique and early results.
OBJECTIVETumors involving Meckel's cave remain extremely challenging because of the surrounding complex neurovascular structures and deep-seated location. The authors investigated a new minimal-access technique using the endoscopic transorbital approach (eTOA) through the superior eyelid crease to Meckel's cave and middle cranial fossa lesions and reviewed the most useful surgical procedures and pitfalls of this approach.METHODSBetween September 2016 and January 2018, the authors performed eTOA in 9 patients with tumors involving Meckel's cave and the middle cranial fossa. The lesions included trigeminal schwannoma in 4 patients, meningioma in 2 patients, metastatic brain tumor in 1 patient, chondrosarcoma in 1 patient, and dermoid cyst in 1 patient. In 7 of the 9 patients, eTOA alone was performed, while the other 2 patients underwent a combined eTOA and endoscopic endonasal approach or retrosigmoid craniotomy. Data including details of surgical techniques and clinical outcomes were recorded.RESULTSGross-total resection was performed in 7 of the 9 patients (77.8%). Four patients underwent extended eTOA (with lateral orbital rim osteotomy). Drilling of the trapezoid sphenoid floor, a middle fossa "peeling" technique, and full visualization of Meckel's cave were applied to approach the lesions. Tumors were exposed and removed extradurally in 3 patients and intradurally in 6 patients. There was no postoperative CSF leak.CONCLUSIONSThe eTOA affords a direct route to access Meckel's cave and middle cranial fossa lesions. With experience, this novel approach can be successfully applied to selected skull base lesions. To achieve successful removal of the tumor, emphasis should be placed on the importance of adequately removing the greater sphenoid wing and vertical crest. However, because of limited working space eTOA may not be an ideal approach for posterior fossa lesions.


Comparison of facially amphiphilic biaryl dendrimers with classical amphiphilic ones using protein surface recognition as the tool.
Facially amphiphilic biaryl dendrimers are compared with the more classical benzyl ether amphiphilic dendrimers for molecular recognition, using protein binding as the probe. The protein used for the proposed study is chymotrypsin (ChT). A generation-dependent binding affinity was observed with the benzyl ether dendrimers, while the affinities were independent of generation in the case of the biaryl dendrimers. Similarly, although the ligands incorporated in both dendrons are the same, the biaryl dendrimers are able to bind more proteins compared to the benzyl ether dendrimers. For example, G3-dendron of biaryl dendrimer can bind six molecules of chymotrypsin, whereas G3-analogue of benzyl ether dendrimers can bind only three molecules of chymotrypsin. This result is consistent with our hypothesis that the internal layers of the facially amphiphilic biaryl dendrons are solvent-exposed and accessible for recognition. In addition, the systematic size differences in dendrons were also used to gain insights into the substrate selectivity that the enzyme gains upon binding to a ligand scaffold.


Treatment and clinical management of primary mediastinal large B-cell lymphoma with sclerosis: MACOP-B regimen and mediastinal radiotherapy monitored by (67)Gallium scan in 50 patients.
To evaluate the efficacy of a combined modality treatment (MACOP-B plus mediastinal radiotherapy) and the advantages of Gallium-67-citrate single-photon emission ((67)GaSPECT) over computed tomography (CT) for restaging in patients with primary mediastinal large B-cell lymphoma (PMLBCL) with sclerosis. Between 1989 and 1998, 50 previously untreated patients with PMLBCL with sclerosis (70% with bulky mass) were treated with MACOP-B regimen plus mediastinal radiotherapy. The radiologic clinical stage with evaluation of tumor size included CT and (67)GaSPECT at diagnosis, after chemotherapy, and after radiotherapy. Forty-three patients (86%) achieved a complete response and 7 were nonresponders to treatment. For the imaging evaluation, only 47 patients were evaluable because 3 had disease progression during chemotherapy. After treatment, 3/5 (60%) patients with positive (67)GaSPECT and negative CT scan relapsed, as against 0/21 (0%) with negative (67)GaSPECT and CT scan. Twenty-one patients had a positive CT scan: of these, the 4 with positive (67)GaSPECT all progressed, whereas there were no relapses among the 17 with negative (67)GaSPECT. After radiotherapy, there was a decrease of positive CT (from 33 to 21 cases) and of positive (67)GaSPECT (from 31 to 9 cases). Relapse-free survival rate was 93% at 96 months (median 39 months). In patients with PMLBCL with sclerosis, MACOP-B plus radiation therapy is a very useful first-line treatment and radiation therapy may play an important role. As regards restaging, (67)GaSPECT should be considered the imaging technique of choice at least in patients who show CT positivity.


A comprehensive model for predicting burnout in Korean nurses.
Although burnout among nurses has been studied in a great deal, this work has not included Korean nurses. Furthermore, the role of personal resources such as empathy and empowerment in predicting the variance in burnout has never been examined. The purpose of this study was to understand the phenomenon of burnout among Korean nurses. A comprehensive model of burnout was examined to identify significant predictors among individual characteristics, job stress and personal resource, with the intention of providing a basis for individual and organizational interventions to reduce levels of burnout experienced by Korean nurses. A cross-sectional correlational design was used. A sample of 178 nurses from general hospitals in southern Korea was surveyed from May 1999 to March 2000. The data were collected using paper and pencil self-rating questionnaires and analysed using descriptive statistics, Pearson correlations, and hierarchical multiple regression. Korean nurses reported higher levels of burnout than nurses in western countries such as Germany, Canada, the United Kingdom and the United States of America. Nurses who experienced higher job stress, showed lower cognitive empathy and empowerment, and worked in night shifts at tertiary hospitals were more likely to experience burnout. Identifying a comprehensive model of burnout among Korean nurses is an essential step to develop effective managerial strategies to reduce the problem. Suggestions to reduce the level of burnout include enhancing nurses' cognitive empathy and perceived power, providing clear job descriptions and work expectations, and exploring nurses' shift preferences, especially at tertiary hospitals. In future research we recommend recruiting nurses from broader geographical areas using random selection in order to increase the generalizability of the findings.


Are some therapists better at facilitating and consolidating sudden gains than others?
Changes during psychotherapy often include sudden symptom improvements, called sudden gains (SGs), which have been identified as being superior to gradual symptom change with regard to treatment success. This study investigates the role of therapists in initiating and/or consolidating SGs. The analyses are based on a sample of patients (N = 1937) who were seen by 155 therapists and received individual psychotherapy at a university outpatient clinic. First, the therapist effect (TE) on SG was investigated using multilevel modeling (MLM). Second, MLM was used to explore the relative importance of patient and therapist variability in SGs as they relate to outcome. The TE on SGs accounted for 1.8% of variance, meaning that therapists are accountable for inter-individual differences in their patients' likelihood to experience SGs. Furthermore, results revealed a significant effect of SGs on outcome for both levels, while therapist differences regarding the consolidation of SGs were not significant. The analyses indicated that some therapists are better in facilitating and initiating SGs. The process of triggering SGs seems to be a therapist skill or competence, which opens up an additional pathway to positive outcomes that could be used to improve clinical training.


Interplay between the NO pathway and elevated [Ca2+]i enhances ciliary activity in rabbit trachea.
1. Average intracellular calcium concentration ([Ca2+]i) and ciliary beat frequency (CBF) were simultaneously measured in rabbit airway ciliated cells in order to elucidate the molecular events that lead to ciliary activation by purinergic stimulation. 2. Extracellular ATP and extracellular UTP caused a rapid increase in both [Ca2+]i and CBF. These effects were practically abolished by a phospholipase C inhibitor (U-73122) or by suramin. 3. The effects of extracellular ATP were not altered: when protein kinase C (PKC) was inhibited by either GF 109203X or chelerythrine chloride, or when protein kinase A (PKA) was inhibited by RP-adenosine 3', 5'-cyclic monophosphothioate triethylamine (Rp-cAMPS). 4. Activation of PKC by phorbol 12-myristate, 13-acetate (TPA) had little effect on CBF or on [Ca2+]i, while activation of PKA by forskolin or by dibutyryl-cAMP led to a small rise in CBF without affecting [Ca2+]i. 5. Direct activation of protein kinase G (PKG) with dibutyryl-cGMP had a negligible effect on CBF when [Ca2+]i was at basal level. However, dibutyryl-cGMP strongly elevated CBF when [Ca2+]i was elevated either by extracellular ATP or by ionomycin. 6. The findings suggest that the initial rise in [Ca2+]i induced by extracellular ATP activates the NO pathway, thus leading to PKG activation. In the continuous presence of elevated [Ca2+]i the stimulated PKG then induces a robust enhancement in CBF. In parallel, activated PKG plays a central role in Ca2+ influx via a still unidentified mechanism, and thus, through positive feedback, maintains CBF close to its maximal level in the continuous presence of ATP.


Relationship among performance, carcass, and feed efficiency characteristics, and their ability to predict economic value in the feedlot.
A 4-yr study was conducted using 736 steers of known Angus, Simmental, or Simmental × Angus genetics to determine performance, carcass, and feed efficiency factors that explained variation in economic performance. Steers were pen fed and individual DMI was recorded using a GrowSafe automated feeding system (GrowSafe Systems Ltd., Airdrie, Alberta, Canada). Steers consumed a similar diet and received similar management each year. The objectives of this study were to: 1) determine current economic value of feed efficiency and 2) identify performance, carcass, and feed efficiency characteristics that predict: carcass value, profit, cost of gain, and feed costs. Economic data used were from 2011 values. Feed efficiency values investigated were: feed conversion ratio (FCR; feed to gain), residual feed intake (RFI), residual BW gain (RG), and residual intake and BW gain (RIG). Dependent variables were carcass value ($/steer), profit ($/steer), feed costs ($/steer • d(-1)), and cost of gain ($/kg). Independent variables were year, DMI, ADG, HCW, LM area, marbling, yield grade, dam breed, and sire breed. A 10% improvement in RG (P < 0.05) yielded the lowest cost of gain at $0.09/kg and highest carcass value at $17.92/steer. Carcass value increased (P < 0.05) as feed efficiency improved for FCR, RG, and RIG. Profit increased with a 10% improvement in feed efficiency (P < 0.05) with FCR at $34.65/steer, RG at $31.21/steer, RIG at $21.66/steer, and RFI at $11.47/steer. The carcass value prediction model explained 96% of the variation among carcasses and included HCW, marbling score, and yield grade. Average daily gain, marbling score, yield grade, DMI, HCW, and year born constituted 81% of the variation for prediction of profit. Eighty-five percent of the variation in cost of gain was explained by ADG, DMI, HCW, and year. Prediction equations were developed that excluded ADG and DMI, and included feed efficiency values. Using these equations, cost of gain was explained primarily by FCR (R(2) = 0.71). Seventy-three percent of profitability was explained, with 55% being accounted for by RG and marbling. These prediction equations represent the relative importance of factors contributing to economic success in feedlot cattle based on current prices.


A report of congenital indifference to pain as diagnosed in infancy.
As physicians and nurses, we have a fundamental obligation to consider patient welfare above all else. The case presented demonstrates the depth of this obligation. Our patient, who was diagnosed during infancy with congenital indifference to pain, can neither feel nor perceive the meaning of pain. Congenital indifference to pain is a rare disorder, which is characterized by normal intelligence, development, and sensation despite an absence of pain perception. There is no cure and treatment difficulties are plentiful. Educating and maintaining an open, consistent relationship with the family and caregivers is essential to reduce the morbidity of this condition.


Clinical hypoxemia score for outpatient child pneumonia care lacking pulse oximetry in Africa and South Asia.
Pulse oximeters are not routinely available in outpatient clinics in low- and middle-income countries. We derived clinical scores to identify hypoxemic child pneumonia. This was a retrospective pooled analysis of two outpatient datasets of 3-35 month olds with World Health Organization (WHO)-defined pneumonia in Bangladesh and Malawi. We constructed, internally validated, and compared fit & discrimination of four models predicting SpO2 < 93% and <90%: (1) Integrated Management of Childhood Illness guidelines, (2) WHO-composite guidelines, (3) Independent variable least absolute shrinkage and selection operator (LASSO); (4) Composite variable LASSO. 12,712 observations were included. The independent and composite LASSO models discriminated moderately (both C-statistic 0.77) between children with a SpO2 < 93% and ≥94%; model predictive capacities remained moderate after adjusting for potential overfitting (C-statistic 0.74 and 0.75). The IMCI and WHO-composite models had poorer discrimination (C-statistic 0.56 and 0.68) and identified 20.6% and 56.8% of SpO2 < 93% cases. The highest score stratum of the independent and composite LASSO models identified 46.7% and 49.0% of SpO2 < 93% cases. Both LASSO models had similar performance for a SpO2 < 90%. In the absence of pulse oximeters, both LASSO models better identified outpatient hypoxemic pneumonia cases than the WHO guidelines. Score external validation and implementation are needed.


The early proximal tubule: a high-capacity delivery-responsive reabsorptive site.
The proximal convoluted tubule is responsible for reclaiming almost all of the filtered bicarbonate, glucose, and amino acids, as well as 40% or more of the filtered sodium, fluid, chloride, and phosphate. Walker and co-workers demonstrated the importance of this nephron segment as a high-capacity transport site in the first mammalian micropuncture studies, and they suggested that the first portion of the proximal tubule played a particularly important role in the ability of the nephron to adapt to variations in filtered load. Since then, many studies using micropuncture and in vivo and in vitro microperfusion techniques have confirmed that the early proximal tubule has a higher transport capacity than the late proximal tubule for a number of solutes. Moreover, at least for bicarbonate, fluid, and chloride, the transport capacity is not static, but is in a dynamic state, adapting in response to changes in filtration. In this review we have focused on the high capacity and load dependence of early proximal bicarbonate and fluid reabsorption. In addition, we summarize the evidence for axial heterogeneity along the proximal convoluted tubule for transport of a variety of other solutes.


Altered transport properties of pentamidine-resistant Leishmania donovani and L. amazonensis promastigotes.
Pentamidine-resistant clones of Leishmania donovani and L. amazonensis promastigotes were developed by increase of the drug pressure in the culture medium and characterized. The resistant clones could grow in 40 and 20 microM pentamidine as determined for L. donovani and L. amazonensis, respectively, with 50% inhibitory concentrations (IC50 values) being 140 and 60 microM, which were 18 and 75 times higher than those recorded for the parental clones, respectively. Biochemical analysis of the clones showed that the acquired pentamidine resistance was specific (no cross-resistance to unrelated drugs and no reversibility with verapamil) and stable in vitro and in vivo. Pentamidine resistance is related to decreased drug uptake and highly increased efflux in both clones of Leishmania spp., accompanied by an alteration in polyamine carriers. Furthermore, a modification of the uptake of pyrimidine nucleosides and several amino acids by these resistant clones indicates alterations in the surface membrane.


MultiNet PyGRAPPA: Multiple neural networks for reconstructing variable density GRAPPA (a 1H FID MRSI study).
Magnetic resonance spectroscopic imaging (MRSI) is a powerful tool for mapping metabolite levels across the brain, however, it generally suffers from long scan times. This severely hinders its application in clinical settings. Additionally, the presence of nuisance signals (e.g. the subcutaneous lipid signals close to the skull region in brain metabolite mapping) makes it challenging to apply conventional acceleration techniques to shorten the scan times. The goal of this work is, therefore, to increase the overall applicability of high resolution metabolite mapping using 1H MRSI by introducing a novel GRAPPA acceleration acquisition/reconstruction technique. An improved reconstruction method (MultiNet) is introduced that uses machine learning, specifically neural networks, to reconstruct accelerated data. The method is further modified to use more neural networks with nonlinear hidden layers and is then combined with a variable density undersampling scheme (MultiNet PyGRAPPA) to enable higher in-plane acceleration factors of R = 5.6 and R = 7 for a non-lipid suppressed ultra-short TR and TE 1H FID MRSI sequence. The proposed method is evaluated for high resolution metabolite mapping of the human brain at 9.4T. The results show that the proposed method is superior to conventional GRAPPA: there is no significant residual lipid aliasing artifact in the images when the proposed MultiNet method is used. Furthermore, the MultiNet PyGRAPPA acquisition/reconstruction method with R = 5.6 results in reproducible high resolution metabolite maps (with an in-plane matrix size of 64 × 64) that can be acquired in 2.8 min on 9.4T. In conclusion, using multiple neural networks to predict the missing points in GRAPPA reconstruction results in a more reliable data recovery while keeping the noise levels under control. Combining this high fidelity reconstruction with variable density undersampling (MultiNet PyGRAPPA) enables higher in-plane acceleration factors even for non-lipid suppressed 1H FID MRSI, without introducing any structured aliasing artifact in the image.


Occupational exposure to silica and lung cancer: pooled analysis of two case-control studies in Montreal, Canada.
Respirable crystalline silica is a highly prevalent occupational exposure and a recognized lung carcinogen. Most previous studies have focused on selected high-exposure occupational groups. This study examines the relationship between occupational exposure to silica and lung cancer in an occupationally diverse male population. Two large population-based case-control studies of lung cancer were conducted in Montreal, one in 1979-1986 (857 cases, 533 population controls, 1,349 cancer controls) and the second in 1996-2001 (738 cases and 899 controls). Interviews provided descriptive lifetime job histories, smoking histories, and other information. Industrial hygienists translated job histories into histories of exposure to a host of occupational substances, including silica. Relative risk was estimated, adjusting for several potential confounders, including smoking. The odds ratio for substantial exposure to silica was 1.67 (95% confidence interval, 1.21-2.31) and for any exposure was 1.31 (95% confidence interval, 1.08-1.59). Joint effects between silica and smoking were between additive and multiplicative, perhaps closer to the latter. In this population, it is estimated that approximately 3% of lung cancers were attributable to substantial silica exposure. The carcinogenicity of inhaled crystalline silica was observed in a population with a wide variety of exposure circumstances. The finding of carcinogenicity across a wide range of occupations complements prior studies of specific high-exposure occupations. This suggests that the burden of cancer induced by silica may be much greater than previously thought.


Systematic analysis of domain motions in proteins from conformational change: new results on citrate synthase and T4 lysozyme.
Methods developed originally to analyze domain motions from simulation [Proteins 27:425-437, 1997] are adapted and extended for the analysis of X-ray conformers and for proteins with more than two domains. The method can be applied as an automatic procedure to any case where more than one conformation is available. The basis of the methodology is that domains can be recognized from the difference in the parameters governing their quasi-rigid body motion, and in particular their rotation vectors. A clustering algorithm is used to determine clusters of rotation vectors corresponding to main-chain segments that form possible dynamic domains. Domains are accepted for further analysis on the basis of a ratio of interdomain to intradomain fluctuation, and Chasles' theorem is used to determine interdomain screw axes. Finally residues involved in the interdomain motion are identified. The methodology is tested on citrate synthase and the M6I mutant of T4 lysozyme. In both cases new aspects to their conformational change are revealed, as are individual residues intimately involved in their dynamics. For citrate synthase the beta sheet is identified to be part of the hinging mechanism. In the case of T4 lysozyme, one of the four transitions in the pathway from the closed to the open conformation, furnished four dynamic domains rather than the expected two. This result indicates that the number of dynamic domains a protein possesses may not be a constant of the motion.


The ventral tegmental area is required for the behavioral and nucleus accumbens neuronal firing responses to incentive cues.
Reward-predictive cues exert powerful control over behavioral choice and may be a critical factor in drug addiction. Reward-seeking elicited by predictive cues is facilitated by the release of dopamine in the nucleus accumbens (NAc), yet the contribution of dopamine to the specific NAc firing patterns that underlie goal-directed behavior has remained elusive. We present evidence that subpopulations of NAc neurons that respond to predictive cues require the dopaminergic projection from the ventral tegmental area (VTA) to promote reward-seeking behavior. Rats trained to perform an operant response to a cue to obtain a sucrose reward were implanted with both multiunit recording electrodes in the NAc and microinjection cannulas in the VTA. Both the behavioral response to cues and the cue-evoked firing of NAc neurons were blocked by injection of the GABA(B) agonist baclofen into the VTA. An additional group of rats was trained on the same task and then implanted with microinjection cannulas in the NAc. Like VTA baclofen injection, injection of dopamine receptor antagonists into the NAc profoundly reduced cue-elicited reward seeking. Together, these results support the conclusion that both the behavioral response to the cue and the specific NAc neuronal firing that promotes the response depend on dopamine release within the NAc. Our findings suggest a neural mechanism by which the dopamine-dependent firing of NAc neurons mediates goal-directed behavior.


Expert evaluation of different infection types in dairy cow quarters naturally infected with Staphylococcus aureus or Streptococcus agalactiae.
The purpose of this study was to improve the diagnostic recommendations for Staphylococcus aureus and Streptococcus agalactiae control using bacterial culture (BC), polymerase chain reaction (PCR) and somatic cell count (SCC) as diagnostic methods. The study was carried out in three steps: firstly, diagnostic test patterns for naturally infected quarters with Staph. aureus (24 quarters) and Strep. agalactiae (16 quarters) were created by sampling the quarters each day for 21 days and analysing the daily quarter milk samples using BC, PCR and SCC. Secondly, 30 mastitis experts were asked to group and describe the diagnostic test patterns and to establish a diagnosis for each group. The experts' statements regarding the groups they established were subsequently examined using qualitative content analysis to assign "infection types" to the statements. Lastly, the test performance was estimated for BC, PCR and SCC using generalised logistic regression models with the interpreted statements as a reference for infection. The experts mainly identified the Staph. aureus quarter-patterns as persistent infections, while some had more dynamic patterns. Strep. agalactiae quarter-patterns mainly involved persistent infection, yet some appeared hard to diagnose and were assigned to almost all different infection types, while experts did not agree on the interpretation. Estimates of Se for detection of Staph. aureus infection were 95.9% [93.7; 97.3] for BC, 99.5% [98.3; 99.8] for PCR, and 96.1% [94.0; 97.5] for SCC. The corresponding Sp estimates were 74.5% [65.7; 81.7], 66% [57.2; 73.8] and 43.7% [36.2; 51.5] for BC, PCR and SCC, respectively. The Se estimates of BC and PCR for Strep. agalactiae infection were 100% [83.5; 100] and 99.9% [99.6; 100], respectively, whereas the Se of SCC detecting Strep. agalactiae infection was only 34.3% [26.4; 43.3]. This indicated that Strep. agalactiae-positive BC and PCR test results were more important than SCC results to the experts when diagnosing a quarter as infected. The Sp estimates of BC, PCR and SCC for Strep. agalactiae infection were 99% [72.8; 100], 97.7% [62.1; 99.9], and 65.7% [56.7; 73.7], respectively. We conclude that PCR and BC are highly sensitive in the detection of persistent and new infections as defined by the experts, although the Se was not always 100%. An accepted lower Sp suggests that experts place less emphasis on false-positive results. We recommend that efforts are made to develop consistent terminology to characterise intramammary infections over time so that the course of infection can be taken into account at diagnosis.


Model matters: Differential outcomes in traumatic optic neuropathy pathophysiology between blunt and blast-wave mediated head injuries.
Over 3 million people in the United States live with long-term disability because of a traumatic brain injury (TBI). The purpose of this study was to characterize and compare two different animal models of TBI (blunt head trauma and blast TBI) to determine common and divergent characteristics of these models. With recent literature reviews noting the prevalence of visual system injury in animal models of TBI, coupled with clinical estimates of 50-75% of all TBI cases, we decided to assess commonalities, if they existed, through visual system injury. A unilateral (left directed) blast and repeat blast model injury with coup-contra-coup injury patterns were compared to a midline blunt injury. Injuries were induced in adult male mice to observe and quantify visual deficits. Retinal ganglion cell loss and axonal degeneration in the optic tract, superior colliculus, and lateral geniculate nuclei were examined to trace injury outcomes throughout major vision-associated areas. Optokinetic response, immunohistochemistry, and western blots were analyzed. Where a single blunt injury produces significant visual deficits a single blast injury appears to have less severe visual consequences. Visual deficits after repeat blasts are similar to a single blast. Single blast injury induces contralateral damage to the right optic chiasm and tract whereas bilateral injury follows a single blunt TBI. Repeat blast injuries are required to see degeneration patterns in downstream regions similar to the damage seen in a single blunt injury. This finding is further supported by amyloid precursor protein (APP) staining in injured cohorts. Blunt injured groups present with staining 1.2 mm ahead of the optic nerve, indicating axonal breakage closer to the optic chiasm. In blast groups, APP was identifiable in a bilateral pattern only in the geniculate nucleus. Evidence for unilateral neuronal degeneration in brain tissue with bilateral axonal ruptures are pivotal discoveries in this model differentiation. Analysis of the two injury models suggests that there is a significant difference in the histological outcomes dependent on injury type, though visual system injury is likely present in more cases than are currently diagnosed clinically.


Retinoic acid receptors alpha, beta and gamma, and cellular retinol binding protein-I expression in breast fibrocystic disease and cancer.
Retinoids seem to act as agents of chemoprevention and differentiation in breast diseases. Their action is mediated by nuclear receptors, retinoic acid receptors (RAR alpha, RAR beta, RAR gamma) and retinoid X receptors (RXR alpha, RXR beta, RXR gamma) and modulated by cellular retinol binding proteins (CRBP). There are few published data on CRBP expression. In this study, we evaluated the expression of RAR alpha, beta and gamma and CRBP type I (CRBP-I) gene expression in fibrocystic disease (FD) and in breast cancer (BC), studying 14 FD and 20 BC surgical samples by reverse transcription (RT)-PCR. We also evaluated mRNA concentrations in cancer samples by a semiquantitative PCR method, co-amplifying RAR alpha, RAR beta and CRBP-I genes with an unrelated gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), as internal control. All benign and malignant breat tissues expressed RAR alpha, beta and gamma, and CRBP-I mRNAs. A greater concentration of RAR beta mRNA was detected in cancer tissues with lower oestrogen and progesterone receptor concentrations, whereas RAR alpha was detected in variable concentrations that were not related to those of steroid receptors. The CRBP-I concentration was similar in all samples studied. We demonstrated that all three RARs and CRBP-I transcripts are expressed in FD, and that RAR beta, RAR gamma and CRBP-I mRNAs also are present in BC tissues. This indicates that both malignant and benign breast tissues may be target for retinoids, justifying the use of natural and synthetic vitamin A derivatives in the chemoprevention of breast disease.


A polyepitope DNA vaccine targeted to Her-2/ErbB-2 elicits a broad range of human and murine CTL effectors to protect against tumor challenge.
A cDNA vaccine (pVax1/pet-neu) was designed to encode 12 different Her-2/ErbB-2-derived, HLA-A*0201-restricted dominant and high-affinity heteroclitic cryptic epitopes. Vaccination with pVax1/pet-neu triggered multiple and ErbB-2-specific CTL responses in HLA-A*0201 transgenic HHD mice and in HLA-A*0201 healthy donors in vitro. Human and murine CTL specific for each one of the 12 ErbB-2 peptides recognized in vitro both human and murine tumor cells overexpressing endogenous ErbB-2. Furthermore, vaccination of HHD mice with pVax1/pet-neu significantly delayed the in vivo growth of challenged ErbB-2-expressing tumor (EL4/HHD/neu murine thymoma) more actively when compared with vaccination with the empty vector (pVax1) or vehicle alone. These data indicate that the pVax1/pet-neu cDNA vaccine coding for a poly-ErbB-2 epitope is able to generate simultaneous ErbB-2-specific antitumor responses against dominant and cryptic multiple epitopes.


A phase II study of estramustine, docetaxel, and exisulind in patients with hormone- refractory prostate cancer: results of cancer and leukemia group B trial 90004.
Docetaxel/estramustine is a known active regimen in hormonerefractory prostate cancer (HRPC). A phase II study was conducted to assess the safety and efficacy of docetaxel/estramustine combined with exisulind, an apoptotic antineoplastic drug. Eighty men with chemotherapy-naive HRPC were enrolled in a multicenter, cooperative group study. The treatment regimen consisted of oral estramustine (280 mg 3 times daily for 5 days), docetaxel 70 mg/m2, oral exisulind (250 mg twice daily), oral dexamethasone (8 mg twice daily for 3 days), and oral warfarin (2 mg daily). Seventy-five eligible patients were treated with a median of 6 cycles of therapy. Fortyseven patients (62.7%; 95% CI, 50.7%-73.6%) had a > or = 50% decline in prostate-specific antigen levels. Forty-six patients had measurable disease with 6 partial responses (13%; 95% CI, 4.9%-26.3%). The main grade 3/4 toxicities were neutrophils (79%), fatigue (15%), and thrombosis/embolism (10%). The median time to first progression was 5.1 months (95% CI, 4.4-6.3 months) and the median survival time was 17.8 months (95% CI, 14.7-20.1 months). The combination of estramustine/docetaxel/exisulind was associated with significant thomboembolic toxicity despite prophylactic warfarin. The contribution of exisulind to toxicity is uncertain. Prostate-specific antigen decline, response rates, and progression-free and overall survival are similar to those reported with docetaxel/estramustine.


Agrobacterium tumefaciens VirB9, an outer-membrane-associated component of a type IV secretion system, regulates substrate selection and T-pilus biogenesis.
Agrobacterium tumefaciens translocates DNA and protein substrates between cells via a type IV secretion system (T4SS) whose channel subunits include the VirD4 coupling protein, VirB11 ATPase, VirB6, VirB8, VirB2, and VirB9. In this study, we used linker insertion mutagenesis to characterize the contribution of the outer-membrane-associated VirB9 to assembly and function of the VirB/D4 T4SS. Twenty-five dipeptide insertion mutations were classified as permissive for intercellular substrate transfer (Tra+), completely transfer defective (Tra-), or substrate discriminating, e.g., selectively permissive for transfer only of the oncogenic transfer DNA and the VirE2 protein substrates or of a mobilizable IncQ plasmid substrate. Mutations inhibiting transfer of DNA substrates did not affect formation of close contacts of the substrate with inner membrane channel subunits but blocked formation of contacts with the VirB2 and VirB9 channel subunits, which is indicative of a defect in assembly or function of the distal portion of the secretion channel. Several mutations in the N- and C-terminal regions disrupted VirB9 complex formation with the outer-membrane-associated lipoprotein VirB7 or the inner membrane energy sensor VirB10. Several VirB9.i2-producing Tra+ strains failed to elaborate T pilus at detectable levels (Pil-), and three such Tra+ Pil- mutant strains were rendered Tra- upon deletion of virB2, indicating that the cellular form of pilin protein is essential for substrate translocation. Our findings, together with computer-based analyses, support a model in which distinct domains of VirB9 contribute to substrate selection and translocation, establishment of channel subunit contacts, and T-pilus biogenesis.


Red-absorbing visual pigment of butterflies.
Noninvasive photochemical and physiological experiments with intact butterflies of 17 species showed that nine species have a rhodopsin absorbing maximally at 610 nanometers, contained in retinular cells that are maximally sensitive at 610 nanometers. This is the longest-wavelength visual pigment known for an invertebrate. Eight species of butterflies lack the 610-nanometers rhodopsin. All species possess a rhodopsin absorbing maximally in the green region of the spectrum.


Association of pleomorphic xanthoastrocytoma with cortical dysplasia and neuronal tumors. A report of three cases.
Several recent publications indicate that pleomorphic xanthoastrocytoma (PXA) may occasionally express ganglionic cell differentiation, linking this type of tumor to other benign, mixed glioneuronal neoplasms. Furthermore, ganglionic tumors and less frequently some benign glial tumors in the central nervous system, could be associated with a variety of mild developmental abnormalities of the cerebral cortex that are classified under the broad term cortical dysplasia. The association of cortical dysplasia with PXA and a neuronal pattern of differentiation has not been reported previously. The authors present clinical, radiologic, immunohistochemical, and ultrastructural findings in three patients with cortical dysplasia. The cortical dysplasia was continuous with PXA, displaying an additional component of neuronal cell differentiation. The ages of the patients were 23, 47, and 52 years. Resection of the tumors was predated by temporal lobe seizures by 6 years in 1 patient and by more than 30 years in the others. In all 3 cases, radiologic studies conducted 3-6 years before surgery showed either no abnormality or lesions that were initially nonprogressing. The longstanding clinical history of seizures and the existence of radiologically documented dormant lesions several years before tumor removal both suggest that PXA in these patients very likely developed in benign hamartomatous cortical lesions or in preexisting cortical dysplasia. The authors' findings, along with the consistent occurrence of PXA in the gray matter in the majority of the reported cases, indicate that these tumors may originate either from a subclass of astrocytes histogenetically and topographically associated with neurons or from multipotential neuroectodermal precursor cells common to neurons and astrocytes.


Strategy for Conditional Orthogonal Sequential CuAAC Reactions Using a Protected Aromatic Ynamine.
A method for conditional control of orthogonal sequential Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reactions is reported. The inherent reactivity of an aromatic ynamine is controlled by a silyl protecting group that allows the selective CuAAC reaction of less reactive alkynes. Alternatively, the same protected ynamine undergoes selective CuAAC reaction via silyl deprotection in situ to give the ynamine click products. This allows complete orthogonal control of dialkyne systems and provides a unifying strategy for chemoselective CuAAC ligations in multialkyne/azide systems.


Constrained cups appear incapable of meeting the demands of revision THA.
Failure rates of constrained cups for treating recurrent dislocation in revision THA range from 40% to 100%. Although constrained liners are intended to stabilize the hip by mechanically preventing dislocation, the resulting loss of range of motion may lead to impingement and, ultimately, implant failure. We therefore documented the mechanisms of failure of constrained acetabular cups in revision THA and determined the type and severity of damage (wear, fracture, and impingement) that occurs in situ. We retrieved 57 constrained components of four different designs at revision THA and examined for the presence of rim impingement, oxidation, cracks within the liner, backside wear, pitting, scratching, abrasion, burnishing, and the presence of embedded particles. Articular wear was calculated from the volume of the concave articular bearing surface, which was measured using the fluid displacement method. Failure of the locking ring was responsible for 51% of failures, whereas 28% of revisions were the result of acetabular cup loosening, 6% backside wear, and 22% infection. Impingement damage of the rim of the polyethylene liner was seen in all retrievals with moderate or severe damage in 54%. The average volumetric wear rate of the articular surface was 95 mm(3)/year. Failure of the locking liner ring and loosening of the acetabular cup are the primary causes of mechanical failure with constrained liners; polyethylene is an inadequate material for restricting motion of the hip to prevent instability. The durability of these devices is unlikely to improve unless the mechanical demands are modified through increased range of motion leading to less frequent rim impingement.


Biomarkers in vasculitis.
Biomarkers are considered to be helpful in diagnosing, monitoring, predicting treatment response, and prognosis in clinical practice and as outcomes in clinical trials. In this article, we review the recent literature on new biomarkers and the expanding use of older ones in vasculitic conditions. In antineutrophil cytoplasmic antibody-associated vasculitis patients antineutrophil cytoplasmic antibody type may be useful as a predictor of relapse and response to rituximab. Moreover, serial measurements of proteinase-3 titer may help to predict relapse. Urinary soluble CD163 levels are promising for identifying active renal vasculitis. Imaging modalities such as positron emission tomography, computerized angiography tomography, and temporal artery ultrasound maintain their role in diagnosis and disease assessment in large vessel vasculitis. Fecal calprotectin is a useful marker of active gastrointestinal involvement in Behçet's syndrome. The publications reviewed here potentially may help to move the field of biomarkers in vasculitis management. However, more work toward understanding the underlying pathophysiology and effects of an intervention on the disease process are needed before true biomarkers can be realized. Further studies with appropriate control groups, using good definitions for disease states such as activity and remission are needed to guide our use of these markers correctly in the management of our patients.


Role of microRNA-150 in solid tumors.
MicroRNAs (miRNAs) are a family of small endogenous noncoding RNAs and their altered expression has been associated with various cellular functions, including cell development, proliferation, differentiation, apoptosis, signal transduction, tumorigenesis and cancer progression. Accumulating evidence has indicated that miRNA (miR)-150 plays an essential regulatory role in normal hematopoiesis and tumorigenesis; therefore, miR-150 may be a potential biomarker and therapeutic target in the diagnosis and treatment of various malignancies. The aim of the present review was to summarize the current knowledge on the functions and regulatory mechanism of miR-150 as an oncogene or tumor suppressor gene in solid tumors. In addition, its potential application as a tumor biomarker, targeted therapeutic strategy and index of prognosis in various cancer types was investigated.


Peripheral cholinesterase activity is not correlated with postoperative delirium in urological surgery.
The value of biomarkers, such as acetylcholinesterase and butyrylcholinesterase, for guiding perioperative patients suffering from postoperative delirium and/or (possibly related) postoperative cognitive dysfunction is unclear. Only recently have different biomarkers are being explored to assess postoperative delirium's occurrence and/or course. The aim of this work is to investigate whether acetylcholinesterase and butyrylcholinesterase can help detect increased risks of the development and course of postoperative delirium in urological patients undergoing surgery. In total, 45 urology patients were screened. During five perioperative time points (meaning preoperative and postoperative), acetylcholinesterase or butyrylcholinesterase concentrations from serum were correlated with three perioperative postoperative delirium and two perioperative postoperative cognitive dysfunction investigations. Results showed neither a significant decline of either acetylcholinesterase or butyrylcholinesterase concentration before and after surgery, nor a significant correlation with postoperative delirium. Furthermore, significant postoperative cognitive dysfunction could not be detected in this perioperative urological collective.


Influence of estrogen deficiency on bone around osseointegrated dental implants: an experimental study in the rat jaw model.
The aim of this study was to evaluate the influence of estrogen deficiency on bone around osseointegrated dental implants in a rat jaw model. This study used 16 female rats that had the first molars bilaterally extracted and were allowed to heal for 30 days before implant placement. Sixty days after implant placement, the animals were randomly subjected to sham surgery or ovariectomy (OVX). The animals were euthanized 90 days after OVX. Bone-to-implant contact, bone area fraction occupancy between implant threads, mineral density, turnover markers, and cells positive for tartrate-resistant acid phosphatase were assessed for the 2 groups. The results showed that OVX group presented a decrease of systemic bone density, alterations in bone turnover markers, and an increase of cells positive for tartrate-resistant acid phosphatase compared with the sham-surgery group. However, no difference relative to bone-to-implant contact and bone area fraction occupancy was observed between groups. The findings of this study demonstrate that estrogen deficiency may not be considered a risk factor for osseointegrated implant failure in jaw bone.


Bovine papilloma virus contains an activator of gene expression at the distal end of the early transcription unit.
Bovine papilloma virus (BPV) contains a cis-acting DNA element which can enhance transcription of distal promoters. Utilizing both direct and indirect transient transfection assays, we showed that a 59-base-pair DNA sequence from the BPV genome could activate the simian virus 40 promoter from distances exceeding 2.5 kilobases and in an orientation-independent manner. In contrast to the promoter 5'-proximal localization of other known viral activators, this element was located immediately 3' to the early polyadenylation signal in the BPV genome. Deletion of these sequences from the BPV genome inactivated the transforming ability of BPV recombinant plasmids. Orientation-independent reinsertion of this 59-base-pair sequence, or alternatively of activator DNA sequences from simian virus 40 or polyoma virus, restored the transforming activity of the BPV recombinant plasmids. Furthermore, the stable transformation frequency of the herpes simplex virus type 1 thymidine kinase gene was enhanced when linked to restriction fragments of BPV DNA which included the defined activator element. This enhancement was orientation independent with respect to the thymidine kinase promoter. The enhancement also appeared to be unrelated to the establishment of the recombinant plasmids as episomes, since in transformed cells these sequences are found linked to high-molecular-weight DNA. We propose that the enhancement of stable transformation frequencies and the activation of transcription units are in this case alternate manifestations of the same biochemical events.


[Effect of ileo-jejunal transposition (IJT) on gastrointestinal hormones and intestinal structure in dogs].
The effects of ileo-jejunal transposition (IJT) on gastro-intestinal hormones and intestinal structure have been studied in 9 mongrel dogs. IJT was performed by isoperistaltic interposition of the distal fourth of the small bowel in the jejunum 15 cm distal from the ligament of Treitz. A test meal (carbohydrate- and fat-rich) loading was carried out in 5 dogs before and 4 and 12 weeks after the operation. Plasma concentrations of gastrointestinal hormones (GLI, GI, GIP and gastrin) were measured by radioimmunoassay using the antibodies. The six mongrel dogs were used for the histological studies. Following IJT hyperenteroglucagonemia was observed, especially in postprandial state. An increase of the mucosal thickness in the whole intestine was observed after IJT. This suggested the possibility that enteroglucagon stimulates intestinal mucosal growth as a circulating hormone. Postprandial plasma GIP levels after IJT were significantly lower at the 90, 120 and 150 min after the test meal loading than those of the preoperative state. Plasma gastrin levels were no significant differences before and after surgery. These observations lead us to conclude that enteroglucagon may play an important role in intestinal adaptation mechanisms after IJT.


Unravelling Conformational Aspects of Milk Protein Structure-Contributions from Nuclear Magnetic Resonance Studies.
Changes in the molecular structure and association of milk proteins lead to many desirable (under controlled conditions) or undesirable characteristics of dairy products. Several methods have been used to study the structure of milk proteins and changes therein in different environments. Whey proteins are an excellent model for secondary structure studies using circular dichroism (CD), Fourier-transform infrared spectroscopy (FTIR) and tertiary structure studies using X-ray crystallography and nuclear magnetic resonance (NMR). However, caseins, the most abundant protein class in milk, are far more difficult to characterize. The tertiary structure of caseins cannot be observed by X-ray crystallography due to the inability to crystallize caseins. However, NMR is an appropriate approach for structural elucidation. Thus far, NMR was applied on specific peptides of individual caseins of the molecules including phosphoserine centers and colloidal calcium phosphate. The literature focuses on these parts of the molecule due to its importance in building the sub-unit particles involving individual caseins and calcium phosphate nanoclusters. This review focuses on present structural studies of milk proteins using NMR and their importance in dairy processing.


Effects of age and comorbidity on treatment and survival of patients with muscle-invasive bladder cancer.
Our study assessed whether rising age, socioeconomic status (SES) and the presence of serious comorbidity affected treatment choice and survival in a population-based series of patients with muscle-invasive bladder cancer (MIBC) in The Netherlands. Therefore, a consecutive series was studied, including all patients diagnosed with MIBC between 1995 and 2009 in the Eindhoven Cancer Registry, preceding centralization of cystectomy. The independent effects of age, SES and serious comorbidity on therapy choice and their effects on overall survival were estimated by multivariate logistic regression and multivariate Cox proportional hazard analyses, respectively. Out of the 2,445 patients, 38% were aged ≥ 75 years at diagnosis and 63% had at least one serious comorbid condition. Higher age and serious comorbidity were independent predictors for abstaining from cystectomy, where SES was not (61-74 vs. ≤ 60: odds ratio [OR], 0.8; 95% confidence interval [CI], 0.6-1.0; ≥ 75 vs. ≤ 60: OR, 0.1; 95% CI,0.1-0.2; one comorbid condition vs. none: OR, 0.7; 95% CI, 0.5-0.9; two vs. none: OR, 0.6; 95% CI, 0.5-0.8). Patients undergoing cystectomy, external beam radiotherapy or interstitial radiotherapy survived longer independent of age, SES and serious comorbidity (hazard ratio [HR]: 0.4; 95% CI: 0.4-0.5; HR: 0.8; 95% CI: 0.7-0.9; HR: 0.4; 95% CI: 0.3-0.5, respectively). Consequently, preceding centralization of cystectomy, higher age and serious comorbidity were independent predictors for abstaining from cystectomy owing to an expected high rate of short-term medical problems. As cystectomy is associated with a better survival, independently of age, SES and serious comorbidity, it can be questioned whether cystectomy has been underutilised in elderly and in patients with serious comorbidity. Centralization might be a solution for this suggested underutilisation.