Inactivation of the CB2 receptor accelerated the neuropathological deterioration in TDP-43 transgenic mice, a model of amyotrophic lateral sclerosis.
The activation of the cannabinoid receptor type-2 (CB2 ) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB2 receptor through investigating the consequences of its inactivation. TDP-43(A315T) transgenic mice were crossed with CB2 receptor knock-out mice to generate double mutants. Temporal and qualitative aspects of the pathological phenotype of the double mutants were compared to TDP-43 transgenic mice expressing the CB2 receptor. The double mutants exhibited significantly accelerated neurological decline, such that deteriorated rotarod performance was visible at 7 weeks, whereas rotarod performance was normal up to 11 weeks in transgenic mice with intact expression of the CB2 receptor. A morphological analysis of spinal cords confirmed an earlier death (visible at 65 days) of motor neurons labelled with Nissl staining and ChAT immunofluorescence in double mutants compared to TDP-43 transgenic mice expressing the CB2 receptor. Evidence of glial reactivity, measured using GFAP and Iba-1 immunostaining, was seen in double mutants at 65 days, but not in TDP-43 transgenic mice expressing the CB2 receptor. However, at 90 days, both genotypes exhibited similar changes for all these markers, although surviving motor neurons of transgenic mice presented some morphological abnormalities in absence of the CB2 receptor that were not as evident in the presence of this receptor. This faster deterioration seen in double mutants led to premature mortality compared with TDP-43 transgenic mice expressing the CB2 receptor. We also investigated the consequences of a pharmacological inactivation of the CB2 receptor using the selective antagonist AM630 in TDP-43 transgenic mice, but results showed only subtle trends towards a greater deterioration. In summary, our results confirmed the potential of the CB2 receptor agonists as a neuroprotective therapy in ALS and strongly support the need to progress towards an evaluation of this potential in patients.


[Conceptions of nurses from a public university hospital regarding the cost management report].
This exploratory-descriptive study was performed with a qualitative approach, on the theoretical construct in the field of phenomenology, with the objective to identify the understanding of nurses of a public university hospital regarding the cost management report. Data collection was performed from August of 2009 to March of 2010, with 59 nurses, and consisted of three guiding questions: What is the meaning of cost management? How do you use the cost management report? What is the contribution of cost management reports? Results showed that nurses do not use this report in their practice, because they focus on the care issues, and justify this by the fact that they did not receive academic training in relation to cost management and also because they do not understand the report. The report, however, though little explored, contributes with the practice of nurses who hold a management position, in terms of cost management and control.


The effects of high levels of rumen degradable protein on rumen pH and histamine concentrations in dairy cows.
An experiment was conducted to test the hypothesis that the supplementation of crude protein (CP) results in rumen acidosis and increased histamine concentrations in dairy cows. Six ruminally fistulated, non-pregnant dry cows were fed three experimental rations in a replicated 3 × 3 Latin square design. The CP contents in the low-CP, the high rumen undegradable protein (high-RUP) and the high rumen degradable protein (high-RDP) rations were 112, 259 and 266 g/kg dry matter (DM) respectively. The cows were fed 7.7 kg DM of the concentrates and 2.7 kg DM of rice straw. High levels of RDP in the ration significantly increased the ammonia, total volatile fatty acid (VFA) and histamine concentrations in the rumen fluid. However, supplemental CP, whether degradable or undegradable, did not significantly affect the pH of rumen fluid. Plasma urea nitrogen concentration was higher in both high-RDP and high-RUP in relation to cows fed the low-CP ration. The rise in ruminal histamine concentrations was physiologically non-relevant, most likely because rumen pH was not affected by supplemental CP at the installed level of DM intake. Therefore, it can be concluded that the issue of supplemental CP, rumen pH and ruminal histamine concentrations has not yet been settled. Further research is warranted to understand these relationships.


[Guideline for stratified screening and surveillance of primary liver cancer(2020 Edition)].
The age-adjusted incidence of primary liver cancer (PLC) has been declining in China. However, PLC cases in China account for 55% globally. The disease burden is still high and the 5-year survival rate was not improved significantly in the past two decades. This guideline outlines PLC screening in the risk populations, both in hospital and community. Liver cirrhosis and chronic hepatitis B are the main causes of PLC in China. For better PLC surveillance and screening in clinical practices, it is recommended to stratify population at the risk into 4 risk levels, namely, low-risk, intermediate-risk, high-risk, and extremely high-risk.The lifelong surveillance is suggested for those at the risk of PLC. The intervals and tools for surveillance and screening are recommended based on the risk levels. Abdominal ultrasonography combined with serum alpha-fetoprotein examination (routine surveillance) every 6 months is recommended for those at a high risk of PLC.Routine surveillance every 3 months and enhanced CT/MRI examination every 6-12 months are recommended for those at an extremely high risk of PLC. The surveillance interval can be extended every 1 year or longer for those at a low-risk or at an intermediate-risk of PLC, because their annual incidence of PLC is very low. The cost-effectiveness of these recommendations remains to be evaluated.


Modulation of cell cycle control by vitamin D3 and its analogue, EB1089, in human breast cancer cells.
Examination of a panel of ER positive breast cancer cell lines showed that they were differentially growth inhibited by vitamin D3 and its analogue EB1089. EB1089 treatment of the breast cancer cell lines MCF-7 E, BT20, T47D, and ZR75 demonstrated a correlation between a reduction in Cdk2 kinase activity towards phosphorylation of histone H1 and a decrease in DNA synthesis, while no modulation of Cdk2 activity was observed in the vitamin D3 and EB1089 resistant cell line MCF-7 L. This was accompanied by a time dependent decrease in the percentage of S phase cells in the responsive lines. Characterization of the expression levels of Cdk2 and its related cell cycle proteins in MCF-7 E cells showed that after EB1089 treatment, there was a concentration and time dependent up-regulation of p21 as well as a decrease in cyclin A proteins. Paradoxically, cyclin E levels were increased as a function of treatment. Analysis of cyclin-Cdk2-Cdki complex formation showed that in EB1089 treated MCF-7 E cells, Cdk2, cyclin A and cyclin E immunoprecipitates contained an increased abundance of p21. In contrast to MCF-7 E cells, increases in both p21 and p27 as well as their complex formation with Cdk2 were observed in BT20 and ZR75 cells. These findings indicate that up-regulation of p21 as well as p27 in some cell types may account for the inactivation of Cdk2 activity and a G1 block of the cell cycle following EB1089 treatment.


A newly discovered radiation of endoparasitic gastropods and their coevolution with asteroid hosts in Antarctica.
Marine invertebrates are abundant and diverse on the continental shelf in Antarctica, but little is known about their parasitic counterparts. Endoparasites are especially understudied because they often possess highly modified body plans that pose problems for their identification. Asterophila, a genus of endoparasitic gastropod in the family Eulimidae, forms cysts in the arms and central discs of asteroid sea stars. There are currently four known species in this genus, one of which has been described from the Antarctic Peninsula (A. perknasteri). This study employs molecular and morphological data to investigate the diversity of Asterophila in Antarctica and explore cophylogenetic patterns between host and parasite. A maximum-likelihood phylogeny of Asterophila and subsequent species-delimitation analysis uncovered nine well-supported putative species, eight of which are new to science. Most Asterophila species were found on a single host species, but four species were found on multiple hosts from one or two closely related genera, showing phylogenetic conservatism of host use. Both distance-based and event-based cophylogenetic analyses uncovered a strong signal of coevolution in this system, but most associations were explained by non-cospeciation events. The prevalence of duplication and host-switching events in Asterophila and its asteroid hosts suggests that synchronous evolution may be rare even in obligate endoparasitic systems. The apparent restricted distribution of Asterophila from around the Scotia Arc may be an artefact of concentrated sampling in the area and a low obvious prevalence of infection. Given the richness of parasites on a global scale, their role in promoting host diversification, and the threat of their loss through coextinction, future work should continue to investigate parasite diversity and coevolution in vulnerable ecosystems.


Modular representation of layered neural networks.
Layered neural networks have greatly improved the performance of various applications including image processing, speech recognition, natural language processing, and bioinformatics. However, it is still difficult to discover or interpret knowledge from the inference provided by a layered neural network, since its internal representation has many nonlinear and complex parameters embedded in hierarchical layers. Therefore, it becomes important to establish a new methodology by which layered neural networks can be understood. In this paper, we propose a new method for extracting a global and simplified structure from a layered neural network. Based on network analysis, the proposed method detects communities or clusters of units with similar connection patterns. We show its effectiveness by applying it to three use cases. (1) Network decomposition: it can decompose a trained neural network into multiple small independent networks thus dividing the problem and reducing the computation time. (2) Training assessment: the appropriateness of a trained result with a given hyperparameter or randomly chosen initial parameters can be evaluated by using a modularity index. And (3) data analysis: in practical data it reveals the community structure in the input, hidden, and output layers, which serves as a clue for discovering knowledge from a trained neural network.


[A study of non-antibiotic versus antibiotic prophylaxis for recurrent urinary-tract infections in women (the NAPRUTI study)].
Patient enrolment in the 'Non-antibiotic versus antibiotic prophylaxis for recurrent urinary-tract infections' (NAPRUTI) study was started in September 2005. In this study of women with recurrent urinary-tract infections we aim to investigate the effect of 12 months of non-antibiotic prophylaxis in comparison with antibiotic prophylaxis on the rate of recurrence of urinary-tract infections and the development of antibiotic resistance. The study consists of two interlinked, randomised, clinical non-inferiority trials. In one trial, 280 premenopausal women will receive either cranberry capsules (twice daily 500 mg) or standardised antibiotic therapy (once daily 480 mg trimethoprim-sulfamethoxazole). In the other trial, 280 postmenopausal women will receive either oral lactobacilli (twice daily a capsule with > 10(9) colony-forming units of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14) or standardised antibiotic therapy. Non-inferiority of non-antibiotic prophylaxis would be attractive given its potential to reduce the prevalence of microbial resistance to antibiotics significantly.


[A pseudo-triangle technique for redshift identification of celestial spectra].
In this paper, we present a novel technique for redshift identification. Redshift is a key parameter of celestial spectra. In the literature, there are few reports on redshift identification due to either no many people working on the problem or perhaps industrial confidentiality. Our technique is a pseudo-triangle technique. It consists of the following three major steps: in the first step, the three wavelengths corresponding to the three highest intensity values of an unknown spectrum are selected to construct a pseudo-triangle, and the largest angle of this triangle is calculated which is independent of redshift value. In the second step, the obtained angle is used as an index to retrieve the corresponding three model wavelengths via a pre-calculated look-up-table, which is composed of all the combinations of all the feature wavelengths of the model spectrum. And finally, based on the three corresponding wavelengths, the corresponding redshift value is derived. The main characteristic of our technique is its simplicity and efficiency, which is demonstrated by experiments on simulated data as well as on real celestial spectra. It is shown that the correct identification rate can reach as high as 86%. Taking into account the high noisy nature of celestial spectra, such a result is considered a good one.


Oral graft-versus-host disease.
Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in patients receiving hematopoietic cell transplant. It is estimated that 40-70% of engrafted patients surviving the initial transplant eventually develop chronic GVHD (cGVHD), which can persist for months to years and require long-term management from multiple disciplines. This review describes the oral component of this transplant complication. The search related to GVHD patho-biology, salivary gland disease after hematopoietic cell transplant and treatments for oral GVHD encompassed literature from 1966 through 2008. Searches were limited to the MEDLINE/PubMed database and English language literature in peer-reviewed journals. Our understanding of the patho-biology of oral cGVHD is based on studies of other affected tissues. It is difficult to determine the prevalence and incidence of salivary gland disease after transplant because there is no universally accepted case definition. In general, clinical trials for treatment of oral cGVHD have been too small to make strong recommendations for use in clinical practice. Larger well-designed clinical studies are needed to understand the patho-biology of oral cGVHD and determine best treatments for this disease.


Workload measurement: A survey of computerized data collection.
The results of a national survey which examined current computer usage and occupational therapist direct entry of Workload Measurement Data is presented. Results indicated an almost equal distribution of departments using computers versus not using computers. A variety of software packages are used for the purposes of collecting workload measurement data, but the majority of departments use customized in-house programmes. The most common method of data entry was a clerk in a central location, however, a number of departments are considering a switch to therapist direct entry. Advantages and disadvantages of both methods were described by survey respondents.


Influence of oxidized purine processing on strand directionality of mismatch repair.
Replicative DNA polymerases are high fidelity enzymes that misincorporate nucleotides into nascent DNA with a frequency lower than [1/10(5)], and this precision is improved to about [1/10(7)] by their proofreading activity. Because this fidelity is insufficient to replicate most genomes without error, nature evolved postreplicative mismatch repair (MMR), which improves the fidelity of DNA replication by up to 3 orders of magnitude through correcting biosynthetic errors that escaped proofreading. MMR must be able to recognize non-Watson-Crick base pairs and excise the misincorporated nucleotides from the nascent DNA strand, which carries by definition the erroneous genetic information. In eukaryotes, MMR is believed to be directed to the nascent strand by preexisting discontinuities such as gaps between Okazaki fragments in the lagging strand or breaks in the leading strand generated by the mismatch-activated endonuclease of the MutL homologs PMS1 in yeast and PMS2 in vertebrates. We recently demonstrated that the eukaryotic MMR machinery can make use also of strand breaks arising during excision of uracils or ribonucleotides from DNA. We now show that intermediates of MutY homolog-dependent excision of adenines mispaired with 8-oxoguanine (G(O)) also act as MMR initiation sites in extracts of human cells or Xenopus laevis eggs. Unexpectedly, G(O)/C pairs were not processed in these extracts and failed to affect MMR directionality, but extracts supplemented with exogenous 8-oxoguanine DNA glycosylase (OGG1) did so. Because OGG1-mediated excision of G(O) might misdirect MMR to the template strand, our findings suggest that OGG1 activity might be inhibited during MMR.


[Veterinary dentistry in dogs and cats; a survey among veterinarians].
To gain an insight into the prevalence of dental disease in dogs and cats and forms of dental treatment, a postal survey was conducted among veterinarians in the Netherlands. Seventy per cent of the veterinarians replied that they made routine oral examinations of dogs and cats. Of dental diseases observed in dogs and cats periodontal diseases were stated to be the most common dental problem. Dental treatments, such as removal of calculus and extractions, were performed by nearly all veterinarians. Fifty per cent of the veterinarians asked for assistance of a dentist when a dental treatment could not be carried out by themselves. More education in veterinary dentistry to veterinary students and veterinarians is required.


Evaluation of hypopharyngeal suction to eliminate aspiration: the Retro-Esophageal Suction (REScue) catheter.
Profound oropharyngeal dysphagia (OPD) is common and costly. Treatment options are limited. The purpose of this investigation was to evaluate the utility of hypopharyngeal suction at the upper esophageal sphincter (UES) to eliminate aspiration. Five different catheters were passed retrograde up the esophagus and positioned at the UES in a cadaver model of profound OPD. Suction was affixed to each catheter. 10 cc of barium was administered into the pyriform sinus, and videofluoroscopy was utilized to evaluate the presence of aspiration. 6 trials were administered per catheter and for a no catheter control. The outcome measures were the incidence of aspiration, the NIH Swallow Safety Scale (NIH-SSS), and UES opening. Control trials with no suction resulted in an aspiration rate of 100 % (6/6 trials). Negative pressure through 16, 18, 24, and 30 Fr catheter resulted in an aspiration rate of 0 % (0/24 trials; p < 0.001), and suction through a 12-Fr catheter resulted in an aspiration rate of 33 % (2/6 trials; p > 0.05). The mean NIH-SSS improved from 7.0 (±0.0) in the control to 0 (±0.0) with hypopharyngeal suction (18 Fr nasogastric catheter; p < 0.001). Mean UES opening improved from 0.0 (±0.0) mm in the control condition to 8.6 (±0.2) mm with a hypopharyngeal catheter (16 Fr Foley catheter; p < 0.001). Negative pressure applied through retro-esophageal suction catheters (>12 Fr) at the level of the UES reduced aspiration by 100 % and significantly increased UES opening in a cadaveric model of profound oropharyngeal dysphagia.


Histochemical and histopathological study of the gastric mucosa in the portal hypertensive gastropathy.
It has been studied "in situ" the action of NADH2-cytochrome C reductase, an aerobe oxidative enzyme, in comparison to lactate dehydrogenase, a glycolitic enzyme in the gastric mucosa and with portal hypertensive gastropathy (PHG) accompanied by morpho-pathological observations. In the normal gastric mucosa, the aerobe oxidative metabolism is predominant over the anaerobe one in all types of cells, but in different intensities (medium in the surface epithelium and low in the vascular endothelium, weak, medium, intense and very intense in fibroblasts and in secretory cells of fundic glands and macrophages). In the portal hypertensive gastropathy, this type of metabolism decreases and the anaerobe metabolism increases, tending to equal the first, especially in the glandular cells. The oxidative activity decreases in the surface epithelium and in the vascular endothelium, increases in cells of the inflammatory infiltrate and in fibroblasts and mast cells.


Experiments reveal limited top-down control of key herbivores in southern California kelp forests.
Predator responses to gradients in prey density have important implications for population regulation and are a potential structuring force for subtidal marine communities, particularly on rocky reefs where herbivorous sea urchins can drive community state shifts. On rocky reefs in southern California where predatory sea otters have been extirpated, top-down control of sea urchins by alternative predators has been hypothesized but rarely tested experimentally. In laboratory feeding assays, predatory spiny lobsters (Panulirus interruptus) demonstrated a saturating functional response to urchin prey, whereby urchin proportional mortality was inversely density-dependent. In field experiments on rocky reefs near San Diego, California, predators (primarily the labrid fish California sheephead, Semicossyphus pulcher) inflicted highly variable mortality on purple urchin (Strongylocentrotus purpuratus) prey across all density levels. However, at low to moderate densities commonly observed within kelp forests, purple urchin mortality increased to a peak at a density of ~11 urchins/m2 . Above that level, at densities typical of urchin barrens, purple urchin mortality was density-independent. When larger red urchins (Mesocentrotus franciscanus) were offered to predators simultaneously with purple urchins, mortality was density-independent. Underwater videography revealed a positive relationship between purple urchin density and both the number and richness of fish predators, but these correlations were not observed when red urchins were present. Our results demonstrate highly variable mortality rates across prey densities in this system and suggest that top-down control of urchins can occur only under limited circumstances. Our findings provide insight into the dynamics of alternate community states observed on rocky reefs.


Combined Effects of High-Speed Railway Noise and Ground Vibrations on Annoyance.
The Shinkansen super-express railway system in Japan has greatly increased its capacity and has expanded nationwide. However, many inhabitants in areas along the railways have been disturbed by noise and ground vibration from the trains. Additionally, the Shinkansen railway emits a higher level of ground vibration than conventional railways at the same noise level. These findings imply that building vibrations affect living environments as significantly as the associated noise. Therefore, it is imperative to quantify the effects of noise and vibration exposures on each annoyance under simultaneous exposure. We performed a secondary analysis using individual datasets of exposure and community response associated with Shinkansen railway noise and vibration. The data consisted of six socio-acoustic surveys, which were conducted separately over the last 20 years in Japan. Applying a logistic regression analysis to the datasets, we confirmed the combined effects of vibration/noise exposure on noise/vibration annoyance. Moreover, we proposed a representative relationship between noise and vibration exposures, and the prevalence of each annoyance associated with the Shinkansen railway.


Defining the role of Porphyromonas gingivalis peptidylarginine deiminase (PPAD) in rheumatoid arthritis through the study of PPAD biology.
Antibodies to citrullinated proteins are a hallmark of rheumatoid arthritis (RA). Porphyromonas gingivalis peptidylarginine deiminase (PPAD) has been implicated in the initiation of RA by generating citrullinated neoantigens and due to its ability to autocitrullinate. To define the citrullination status and biology of PPAD in P gingivalis and to characterise the anti-PPAD antibody response in RA and associated periodontal disease (PD). PPAD in P gingivalis cells and culture supernatant were analysed by immunoblotting and mass spectrometry to detect citrullination. Recombinant PPAD (rPPAD), inactive mutant PPAD (rPPAD(C351S)), and N-terminal truncated PPAD (rPPAD(Ntx)) were cloned and expressed in Escherichia coli. Patients with RA and healthy controls were assayed for IgG antibodies to citrullinated rPPAD and unmodified rPPAD(C351S) by ELISA. Anti-PPAD antibodies were correlated with anti-cyclic citrullinated peptide (third-generation) antibody levels, RA disease activity and PD status. PPAD from P gingivalis is truncated at the N-terminal and C-terminal domains and not citrullinated. Only when artificially expressed in E coli, full-length rPPAD, but not truncated (fully active) rPPAD(Ntx), is autocitrullinated. Anti-PPAD antibodies show no heightened reactivity to citrullinated rPPAD, but are exclusively directed against the unmodified enzyme. Antibodies against PPAD do not correlate with anti-cyclic citrullinated peptide levels and disease activity in RA. By contrast, anti-PPAD antibody levels are significantly decreased in RA patients with PD. PPAD autocitrullination is not the underlying mechanism linking PD and RA. N-terminal processing protects PPAD from autocitrullination and enhances enzyme activity. Anti-PPAD antibodies may have a protective role for the development of PD in patients with RA.


Comparison of self-report, hospital discharge codes, and adjudication of cardiovascular events in the Women's Health Initiative.
Limited information is available from large clinical investigations about the agreement among sources of diagnoses for endpoints. The authors used data from the Women's Health Initiative clinical trials and observational study from January 1994 to November 2000 to evaluate the agreement among self-report, hospital discharge codes, and two different levels of physician review of medical records for cardiovascular endpoints. For myocardial infarction, stroke, pulmonary embolism, and venous thrombosis, the agreement of hospital discharge codes or self-report with review by study physicians at clinical centers was substantial (kappa = 0.64-0.84). For coronary revascularization, agreement among these sources of information was substantial to almost perfect (kappa = 0.79-0.92), but for angina, congestive heart failure, and peripheral vascular disease, concordance was only fair to moderate (kappa = 0.37-0.56), indicating that these endpoints remain difficult to classify reliably. Agreement between physician adjudicators at clinical centers and central physician adjudicators was substantial to almost perfect (kappa = 0.67-0.94). The findings also suggest that, for the endpoint of myocardial infarction, physician review of events with hospital discharge codes for angina and congestive heart failure is an important source of validated events, and for stroke, review of all events with cerebrovascular codes is important.


Harvesting changes mating behaviour in European lobster.
Removing individuals from a wild population can affect the availability of prospective mates and the outcome of competitive interactions, with subsequent effects on mating patterns and sexual selection. Consequently, the rate of harvest-induced evolution is predicted to be strongly dependent on the strength and dynamics of sexual selection, yet there is limited empirical knowledge on the interplay between selective harvesting and the mating systems of exploited species. In this study, we used genetic parentage assignment to compare mating patterns of the highly valued and overexploited European lobster (Homarus gammarus) in a designated lobster reserve and nearby fished area in southern Norway. In the area open to fishing, the fishery is regulated by a closed season, a minimum legal size and a ban on the harvest of egg-bearing females. Due to the differences in size and sex-specific fishing mortality between the two areas, males and females are of approximately equal average size in the fished area, whereas males tend to be larger in the reserve. Our results show that females would mate with males larger than their own body size, but the relative size difference was significantly larger in the reserve. Sexual selection acted positively on both body size and claw size in males in the reserve, while it was nonsignificant in fished areas. This strongly suggests that size truncation of males by fishing reduces the variability of traits that sexual selection acts upon. If fisheries continue to target large individuals (particularly males) with higher relative reproductive success, the weakening of sexual selection will likely accelerate fisheries-induced evolution towards smaller body size.


Partitioning of heat production in growing pigs as a tool to improve the determination of efficiency of energy utilization.
In growing pigs, the feed cost accounts for more than 60% of total production costs. The determination of efficiency of energy utilization through calorimetry measurements is of importance to sustain suitable feeding practice. The objective of this paper is to describe a methodology to correct daily heat production (HP) obtained from measurements in respiration chamber for the difference in energy expenditure related to physical activity between animals. The calculation is based on a preliminary published approach for partitioning HP between HP due to physical activity (AHP), thermic effect of feeding (TEF) and basal metabolic rate (fasting HP; FHP). Measurements with male growing pigs [mean body weight (BW): 115 kg] which were surgically castrated (SC), castrated through immunization against GnRH (IC), or kept as entire male (EM) were used as an example. Animals were fed the same diet ad-libitum and were housed individually in two 12-m(3) open-circuit respiration chambers during 6 days when fed ad-libitum and one supplementary day when fasted. Physical activity was recorded through interruption of an infrared beam to detect standing and lying positions and with force transducers that recorded the mechanical force the animal exerted on the floor of the cage. Corrected AHP (AHPc), TEF (TEFc), and HP (HPc) were calculated to standardize the level of AHP between animals, assuming that the ratio between AHPc and ME intake should be constant. Inefficiency of energy utilization (sum of AHPc and TEFc) was lower than the inefficiency estimated from the slope of the classical relationship between HPc and ME intake but was associated with higher requirements for maintenance. Results indicate that EM pigs had higher FHP but lower TEFc than IC and SC pigs. These results agree with the higher contents in viscera of EM pigs that stimulate their basal metabolic rate and with the reduced utilization of dietary protein to provide energy for maintenance energy requirements and fat deposition (FD).


Interferometric inverse synthetic aperture ladar target detection method.
To improve the target detection performance of inverse synthetic aperture ladar (ISAL) under the situation that there is Doppler bandwidth ambiguity, we consider energy accumulation of echo signals along a range through matched illumination. However, since the target impulse responses change with the target aspect angle, the phase shifts along slow-time between range cells are different, and the output of matched illumination fluctuates along slow-time. To reduce the slow-time fluctuation of matched illumination under additive white Gaussian noise assumption, we have proposed an interferometric ISAL (InISAL) target detection method based on interferometry processing and principal component analysis (PCA) in this paper. After the interferometry processing, the interferometric phase shifts along slow-time of all range cells are approximately the same. Then PCA is introduced to reduce the impact of noise, interference, and cross-terms of interferometry processing. Thus, the slow-time fluctuation of matched illumination can be decreased, and the target detection performance is improved. The proposed method has been validated with both simulated data of InISAL and real data of millimeter-wave interferometric synthetic aperture radar.


Phloxine B effect on immature stages of the Mediterranean fruit fly, Ceratitis capitata (Diptera: Tephritidae) (Wiedemann).
A laboratory bioassay was developed to determine both the chemical toxicity and the phototoxicity of the xanthene dye, phloxine B (D&C Red No 28), to the immature stages of the Mediterranean fruit fly, Certitis capitata (Wiedemann). An additional goal was to find out which main tissues are affected first. A low, but significant, level of toxicity was observed when the insects were maintained in the dark: at the point of adult ecdysis, the LC50 was 11.03 mM. As expected, after 8-h exposure of late larva III to light, a high level of mortality was produced (LC50 at ecdysis: 0.45 mM) as a dose-dependent function of dye concentration. At sublethal concentrations of the dye, the surviving insects showed a number of physiological abnormalities. Phloxine B appeared to mainly affect the larval longitudinal muscles as well as the abdominal muscles of ecdysing adults, giving rise to abnormal puparia and failed adult ecdysis, respectively. Moreover, a significant phloxine B-dependent delay in the jumping of surviving larvae for dispersal was documented. This could be attributed to a delay in attaining a threshold weight for jumping and/or to abnormalities in neuromuscular coordination, thus reinforcing the idea of pleiotropic effects of the dye.


Effects of unemployment on mental health in the contemporary family.
This article summarizes research conducted in the past 20 years concerning mental health effects of involuntary job loss. The majority of studies and previous reviews focus on unemployment effects on men. Although these studies are also reviewed, this article highlights studies of (a) the involuntarily unemployed woman, (b) the spouse of the unemployed person, and (c) their children. Within each of these research areas, the authors consider studies grouped according to their methodological strength for drawing causal inferences about the impact of job loss on psychological status, ranging from cross-sectional to longitudinal to prospective studies. The implications of the unemployment literature not only for future research but also for clinical practice are addressed. Knowledge of family effects of this stressful life circumstance is critical to developing effective treatment plans for patients who, although perhaps not the direct victims of job loss themselves, may nevertheless present with problems indirectly caused or exacerbated by unemployment within the family.


Experimental determination of bone cortex holding power of orthopedic screw.
Cylindrical specimens of bone measuring 15 mm in diameter were obtained from the lateral cortical layer of 10 pairs of femurs and tibias. A central hole 3.2 mm in diameter was drilled in each specimen. The hole was tapped, and a 4.5 mm cortical bone screw was inserted from the outer surface. The montage was submitted to push-out testing up to a complete strip of the bone threads. The cortical thickness and rupture load were measured, and the shear stress was calculated. The results were grouped according to the bone segment from which the specimen was obtained. The results showed that bone cortex screw holding power is dependent on the bone site. Additionally, the diaphyseal cortical bone tissue is both quantitatively and qualitatively more resistant to screw extraction than the metaphyseal tissue.


Direct local solvent probing by transient infrared spectroscopy reveals the mechanism of hydrogen-bond induced nonradiative deactivation.
The fluorescence quenching of organic dyes via H-bonding interactions is a well-known phenomenon. However, the mechanism of this Hydrogen-Bond Induced Nonradiative Deactivation (HBIND) is not understood. Insight into this process is obtained by probing in the infrared the O-H stretching vibration of the solvent after electronic excitation of a dye with H-bond accepting cyano groups. The fluorescence lifetime of this dye was previously found to decrease from 1.5 ns to 110 ps when going from an aprotic solvent to the strongly protic hexafluoroisopropanol (HFP). Prompt strengthening of the H-bond with the dye was identified by the presence of a broad positive O-H band of HFP, located at lower frequency than the O-H band of the pure solvent. Further strengthening occurs within a few picoseconds before the excited H-bonded complex decays to the ground state in 110 ps. The latter process is accompanied by the dissipation of energy from the dye to the solvent and the rise of a characteristic hot solvent band in the transient spectrum. Polarization-resolved measurements evidence a collinear alignment of the nitrile and hydroxyl groups in the H-bonded complex, which persists during the whole excited-state lifetime. Measurements in other fluorinated alcohols and in chloroform/HFP mixtures reveal that the HBIND efficiency depends not only on the strength of the H-bond interactions between the dye and the solvent but also on the ability of the solvent to form an extended H-bond network. The HBIND process can be viewed as an enhanced internal conversion of an excited complex consisting of the dye molecule connected to a large H-bond network.


The Charcot foot: pathophysiology, diagnosis and classification.
Neuropathic changes in the foot are common with a prevalence of approximately 1%. The diagnosis of neuropathic arthropathy is often delayed in diabetic patients with harmful consequences including amputation. The appropriate diagnosis and treatment can avoid an extensive programme of treatment with significant morbidity for the patient, high costs and delayed surgery. The pathogenesis of a Charcot foot involves repetitive micro-trauma in a foot with impaired sensation and neurovascular changes caused by pathological innervation of the blood vessels. In most cases, changes are due to a combination of both pathophysiological factors. The Charcot foot is triggered by a combination of mechanical, vascular and biological factors which can lead to late diagnosis and incorrect treatment and eventually to destruction of the foot. This review aims to raise awareness of the diagnosis of the Charcot foot (diabetic neuropathic osteoarthropathy and the differential diagnosis, erysipelas, peripheral arterial occlusive disease) and describe the ways in which the diagnosis may be made. The clinical diagnostic pathways based on different classifications are presented. Cite this article: Bone Joint J 2016;98-B:1155-9.


Slip-free processing of (001) silicon wafers under 1064 nm laser ablation.
Slip phenomenon on a (001) silicon surface under 1064 nm laser ablation was studied by experiments and simulations. The surface morphologies of the silicon wafers after laser irradiation were observed using an optical microscope. The slip patterns showed that slip that occurred before melting was responsible for a low-quality ablation surface. The slip damage was predicted by a three-dimensional finite element model based on heat transfer and thermoelasticity theory. The judging criterion of slip was explained in detail. The numerical results gave a better understanding of slip phenomenon in experiments. It is shown that low laser irradiances cause slip and high laser irradiances are helpful in preventing slip. The threshold irradiance is ∼1 MW/cm2. Lasers with higher irradiance are essential to obtain a slip-free ablation on a (001) silicon surface.


661W Photoreceptor Cell Line as a Cell Model for Studying Retinal Ciliopathies.
The retina contains several ciliated cell types, including the retinal pigment epithelium (RPE) and photoreceptor cells. The photoreceptor cilium is one of the most highly modified sensory cilia in the human body. The outer segment of the photoreceptor is a highly elaborate primary cilium, containing stacks or folds of membrane where the photopigment molecules are located. Perhaps unsurprisingly, defects in cilia often lead to retinal phenotypes, either as part of syndromic conditions involving other organs, or in isolation in the so-called retinal ciliopathies. The study of retinal ciliopathies has been limited by a lack of retinal cell lines. RPE1 retinal pigment epithelial cell line is commonly used in such studies, but the existence of a photoreceptor cell line has largely been neglected in the retinal ciliopathy field. 661W cone photoreceptor cells, derived from mouse, have been widely used as a model for studying macular degeneration, but not described as a model for studying retinal ciliopathies such as retinitis pigmentosa. Here, we characterize the 661W cell line as a model for studying retinal ciliopathies. We fully characterize the expression profile of these cells, using whole transcriptome RNA sequencing, and provide this data on Gene Expression Omnibus for the advantage of the scientific community. We show that these cells express the majority of markers of cone cell origin. Using immunostaining and confocal microscopy, alongside scanning electron microscopy, we show that these cells grow long primary cilia, reminiscent of photoreceptor outer segments, and localize many cilium proteins to the axoneme, membrane and transition zone. We show that siRNA knockdown of cilia genes Ift88 results in loss of cilia, and that this can be assayed by high-throughput screening. We present evidence that the 661W cell line is a useful cell model for studying retinal ciliopathies.


Telomerase activity in prostate cancer, prostatic intraepithelial neoplasia, and benign prostatic epithelium.
Telomerase is a ribonucleoprotein that synthesizes telomeric DNA on chromosomal ends. Telomerase activation has been seen in many immortal cell lines and cancers. Telomerase activity was analyzed in prostate carcinoma; in coexistent prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), atrophy and normal tissue; and in benign prostate glands. Telomerase activity was detected in 80 of 87 (92%) prostate cancers. Forty-one matched samples (from a total of 32 cases) were available for comparative analysis. The presence of telomerase activity in adjacent PIN, BPH, and normal tissue was correlated with telomerase activity in the malignant epithelium. In these adjacent tissues, telomerase activity was found in 11 of 15 (73%) PINs, 13 of 26 (50%) BPHs, and 1 of 6 (16%) atrophy and 4 of 11 (36%) normal tissues. In contrast to the BPH tissue from cancer-bearing glands, all 16 BPH specimens from patients only diagnosed with BPH were telomerase activity negative. In cancer samples, there was no correlation between telomerase activity and Gleason grade or preoperation prostate-specific antigen level. Our data indicate that telomerase activity is present in most prostate cancers. The high rate of telomerase activity in the benign-appearing areas of these glands may be attributed either to the presence of occult cancer cells or to early molecular alterations of cancer that were histologically inapparent.


Balance in chronic traumatic brain injury: correlations between clinical measures and a self-report measure.
To assess associations among commonly used self-report and clinical measures of balance in chronic TBI. Cross-sectional analysis of balance in a convenience sample of individuals at least one year post TBI. Activities-Specific Balance Confidence Scale (ABC) (self-reported balance impairment), Community Balance and Mobility Scale (CB&M) (clinical measure validated in TBI), and Balance Evaluation Systems Test (BESTest) (clinical measure not validated in TBI). Fifty-nine individuals (64% male, mean age 48.2 years) ambulating independently within the home participated in testing. Pearson correlation coefficients were used to quantify the direction and magnitude of the relationships among the three balance impairment measures. A significant positive correlation was noted between the ABC and CB&M (r = 0.42, p = 0.0008), between the ABC and BESTest (r = 0.46, p = 0.0002), and between the CB&M and BESTest (r = 0.86, p < 0.0001). This is the first study we are aware of in the chronic moderate to severe TBI population directly comparing patient's self-reported balance impairment with clinical measures. Positive correlations were found between the self-report measure and both clinical measures. Overall, individuals with chronic TBI tend to self-report less impaired balance than clinical measures indicate. These results provide preliminary evidence to support the need for validation of the BESTest in this population. ABC: Activities-specific balance confidence scale; BESTest: balance evaluation systems test; BOS: base of support; COM: center of mass; CB&M: community balance and mobility scale; CI: confidence interval; IQR: interquartile range; PTs: physical therapists; SD: standard deviation; SE: standard error; TBI: traumatic brain injury.


Control Beliefs Mediate the Within-Person Relationship Between Everyday Activity Volition and Daily Subjective Age.
Appraisal and interpretation of personal experiences resulting from interaction with situational contexts might play an important role in shaping subjective age at the within-person level, but it is unclear how this process unfolds. We propose that older adults evaluate situational contexts and reflect on their general psychological resources when determining their subjective age, and tested this proposal with volition of daily activities as a proxy for appraisal of situational contexts and control beliefs as a proxy for psychological resources. We hypothesize that appraising daily activities one engaged in as obligatory would deplete one's perceived control and concomitantly make one feel older. Older adults (n = 116) ranging in age from 60 to 90 (M = 64.84) completed a 9-day daily diary study online, resulting in 743 total days. Participants reported their sociodemographic characteristics on Day 1 and major daily activities, volition of every reported activity, felt age, and control beliefs on Days 2-9. On days when older adults felt that activities they engaged in were of their own volition, they also felt more in control. A lower-level mediation result suggested that within-person control beliefs mediated the relationship between volition of daily activities and subjective age. Our findings suggest that older adults evaluate situational contexts and reflect on their control beliefs as a general psychological resource when determining their subjective age. These findings show the important role psychological resources play in determining subjective age from a within-person perspective and extended the within-person process proposed in previous theoretical models.


Serum antibodies to periodontal pathogens are related to allergic symptoms.
The association between periodontitis and allergic symptoms has been investigated. However, the difference in immune signatures between them remains poorly understood. This cross-sectional study assessed the relationship between serum immunoglobulin G (IgG) antibodies to periodontal pathogens and allergic symptoms in a nationwide population cohort. Two phases of the Third National Health and Nutrition Examination Survey (NHANES III) were used as discovery dataset (n = 3700) and validation dataset (n = 4453), respectively. Based on the antibodies against 19 periodontal pathogens, we performed an unsupervised hierarchical clustering to categorize the population into three clusters. In the discovery dataset, cluster 1 (n = 2847) had the highest level of IgG antibodies, followed by clusters 2 (n = 588) and 3 (n = 265). Data on allergic symptoms (asthma, hay fever, and wheezing) were obtained using a self-reported questionnaire. Survey-weighted multivariable logistic regression evaluated the association between these clusters and allergic symptoms. In the discovery dataset, the participants with lower levels of antibodies to periodontal pathogens exhibited a higher risk of asthma (odds ratio [OR]cluster 3 vs. cluster 1 = 1.820, 95% confidence interval [CI]: 1.153-2.873) and wheezing (ORcluster 3 vs. cluster 1 = 1.550, 95% CI: 1.095-2.194) compared to those with higher periodontal antibodies, but the non-significant association with hay fever. Consistent results were found in the validation dataset. Serum IgG titers to periodontal pathogens were inversely associated with the risk of asthma and wheezing, suggesting the potentially protective role against allergic conditions.


Molecular cloning of bovine papillomavirus genomes and comparison of their sequence homologies by heteroduplex mapping.
The genomic DNAs of bovine papillomavirus (BPV) type 1, type 2 and type 4 were cloned in pAT153. BPV1 and BPV2 genomes were cloned using the single HindIII sites of the vector and virus DNAs, and BPV4 was cloned using the single BamHI sites. The orientation of the recombinant DNAs was established by restriction enzyme digestion, hybridization and heteroduplex analysis. The results showed that: (i) BPV1 and BPV2 DNAs are in register and are broadly homologous throughout most of their length when aligned at their single HindIII sites; (ii) depending on the degree of hybridization stringency used, the two DNAs show one major region and several minor regions of partial homology, mainly residing in the segment of the genomes believed to contain the structural genes; (iii) BPV4 DNA shares no homology with either BPV1 or BPV2 DNA.


Linking behavioral and neurophysiological indicators of perceptual tuning to language.
Little is known about the neural mechanisms that underlie tuning to the native language(s) in early infancy. Here we review language tuning through the lens of type and amount of language experience and introduce a new manner in which to conceptualize the phenomenon of language tuning: the relative speed of tuning hypothesis. This hypothesis has as its goal a characterization of the unique time course of the tuning process, given the different components (e.g., phonology, prosody, syntax, semantics) of one or more languages as they become available to infants, and biologically based maturational constraints. In this review, we first examine the established behavioral findings and integrate more recent neurophysiological data on neonatal development, which together demonstrate evidence of early language tuning given differential language exposure even in utero. Next, we examine traditional accounts of sensitive and critical periods to determine how these constructs complement current data on the neural mechanisms underlying language tuning. We then synthesize the extant infant behavioral and neurophysiological data on monolingual, bilingual, and sensory deprived tuning, thereby scrutinizing the effect of these three different language profiles on the specific timing, progression, and outcome of language tuning. Finally, we discuss future directions researchers might pursue to further understand this aspect of language development, advocating our relative speed of tuning hypothesis as a useful framework for conceptualizing the complex process by which language experience works together with biological constraints to shape language development.


Generating a three-dimensional dark focus from a single conically refracted light beam.
We report here the generation of a three-dimensional (3D) dark focus from a single focused monochromatic Gaussian beam that undergoes conical refraction when it propagates along one of the optic axes of a biaxial crystal. We study the resulting ring intensity pattern behind the crystal as a function of the ratio between the ring radius and the beam waist and derive the particular parameter values for which a 3D dark focus with null intensity at the ring center is formed. We have performed experiments with a KGd(WO(4))(2) biaxial crystal, reporting the generation of a bottle beam in full agreement with our theoretical investigations.


Leaking Umbilical Hernias in Cirrhotic Patients, Repair or Observe?
Umbilical hernias (UHs) in cirrhotic patients are common, can be quite complicated and are associated with significant morbidity and mortality. Leakage of ascites is a challenging entity and poses significant risks. This is a retrospective study of patients with cirrhosis and UHs with ascitic leakage. Patients were divided into two groups: patients managed operatively during index admission (Group 1) and those managed non-surgically during index admission (Group 2). Group 2 was further divided into those that subsequently underwent repair of UH and those managed medically. Of 47 cirrhotic patients with leaking UHs, 19 patients were managed surgically during index admission (Group 1). In Group 2, 15 patients were managed non-surgically and 13 subsequently underwent surgery. The groups had comparable demographics, MELD-Na and Child-Pugh class. Group 2 had a higher rate of emergency surgery (92% vs 58%, P = .04) and higher rate of recurrence (31 vs. 0%, P = .02). The non-surgical patients in Group 2 had higher 1-year mortality (67%) compared to Group 1 (21%) and surgical patients in Group 2 (31%, P = .007). Multi-variable logistic regression for 1-year mortality demonstrated MELD-Na as the most significant risk factor (OR = 1.2, P = .05) and undergoing UH repair as the most significant protective factor (OR = .16, P = .02). Cirrhotic patients with leaking UHs should undergo urgent repair. Non-operative management confers high risk of continued or increased ascitic leakage necessitating more emergent surgery. Despite high rate of post-operative complications related to cirrhosis, there is a clear mortality benefit to the repair of leaking UHs in cirrhotic patients.


Independent Living Alternatives.
Independent Living Alternatives (ILA) advocate the rights of people with disabilities. Run by the clients it serves, the organisation provides a comprehensive range of personal assistance services.


Mechanism of enzymatic fluorination in Streptomyces cattleya.
Recently a fluorination enzyme was identified and isolated from Streptomyces cattleya, as the first committed step on the metabolic pathway to the fluorinated metabolites, fluoroacetate and 4-fluorothreonine. This enzyme, 5'-fluoro-5'-deoxy adenosine synthetase (FDAS), has been shown to catalyze C-F bond formation by nucleophilic attack of fluoride ion to S-adenosyl-l-methionine (SAM) with the concomitant displacement of l-methionine to generate 5'-fluoro-5'-deoxy adenosine (5'-FDA). Although the structures of FDAS bound to both SAM and products have been solved, the molecular mechanism remained to be elucidated. We now report site-directed mutagenesis studies, structural analyses, and isothermal calorimetry (ITC) experiments. The data establish the key residues required for catalysis and the order of substrate binding. Fluoride ion is not readily distinguished from water by protein X-ray crystallography; however, using chloride ion (also a substrate) with a mutant of low activity has enabled the halide ion to be located in nonproductive co-complexes with SAH and SAM. The kinetic data suggest the positively charged sulfur of SAM is a key requirement in stabilizing the transition state. We propose a molecular mechanism for FDAS in which fluoride weakly associates with the enzyme exchanging two water molecules for protein ligation. The binding of SAM expels remaining water associated with fluoride ion and traps the ion in a pocket positioned to react with SAM, generating l-methionine and 5'-FDA. l-methionine then dissociates from the enzyme followed by 5'-FDA.


Phase separation of a plant virus movement protein and cellular factors support virus-host interactions.
Both cellular and viral proteins can undergo phase separation and form membraneless compartments that concentrate biomolecules. The p26 movement protein from single-stranded, positive-sense Pea enation mosaic virus 2 (PEMV2) separates into a dense phase in nucleoli where p26 and related orthologues must interact with fibrillarin (Fib2) as a pre-requisite for systemic virus movement. Using in vitro assays, viral ribonucleoprotein complexes containing p26, Fib2, and PEMV2 genomic RNAs formed droplets that may provide the basis for self-assembly in planta. Mutating basic p26 residues (R/K-G) blocked droplet formation and partitioning into Fib2 droplets or the nucleolus and prevented systemic movement of a Tobacco mosaic virus (TMV) vector in Nicotiana benthamiana. Mutating acidic residues (D/E-G) reduced droplet formation in vitro, increased nucleolar retention 6.5-fold, and prevented systemic movement of TMV, thus demonstrating that p26 requires electrostatic interactions for droplet formation and charged residues are critical for nucleolar trafficking and virus movement. p26 readily partitioned into stress granules (SGs), which are membraneless compartments that assemble by clustering of the RNA binding protein G3BP following stress. G3BP is upregulated during PEMV2 infection and over-expression of G3BP restricted PEMV2 RNA accumulation >20-fold. Deletion of the NTF2 domain that is required for G3BP condensation restored PEMV2 RNA accumulation >4-fold, demonstrating that phase separation enhances G3BP antiviral activity. These results indicate that p26 partitions into membraneless compartments with either proviral (Fib2) or antiviral (G3BP) factors.


Reliability of a novel thermal imaging system for temperature assessment of healthy feet.
Thermal imaging is a useful modality for identifying preulcerative lesions ("hot spots") in diabetic foot patients. Despite its recognised potential, at present, there is no readily available instrument for routine podiatric assessment of patients at risk. To address this need, a novel thermal imaging system was recently developed. This paper reports the reliability of this device for temperature assessment of healthy feet. Plantar skin foot temperatures were measured with the novel thermal imaging device (Diabetic Foot Ulcer Prevention System (DFUPS), constructed by Photometrix Imaging Ltd) and also with a hand-held infrared spot thermometer (Thermofocus® 01500A3, Tecnimed, Italy) after 20 min of barefoot resting with legs supported and extended in 105 subjects (52 males and 53 females; age range 18 to 69 years) as part of a multicentre clinical trial. The temperature differences between the right and left foot at five regions of interest (ROIs), including 1st and 4th toes, 1st, 3rd and 5th metatarsal heads were calculated. The intra-instrument agreement (three repeated measures) and the inter-instrument agreement (hand-held thermometer and thermal imaging device) were quantified using intra-class correlation coefficients (ICCs) and the 95% confidence intervals (CI). Both devices showed almost perfect agreement in replication by instrument. The intra-instrument ICCs for the thermal imaging device at all five ROIs ranged from 0.95 to 0.97 and the intra-instrument ICCs for the hand-held-thermometer ranged from 0.94 to 0.97. There was substantial to perfect inter-instrument agreement between the hand-held thermometer and the thermal imaging device and the ICCs at all five ROIs ranged between 0.94 and 0.97. This study reports the performance of a novel thermal imaging device in the assessment of foot temperatures in healthy volunteers in comparison with a hand-held infrared thermometer. The newly developed thermal imaging device showed very good agreement in repeated temperature assessments at defined ROIs as well as substantial to perfect agreement in temperature assessment with the hand-held infrared thermometer. In addition to the reported non-inferior performance in temperature assessment, the thermal imaging device holds the potential to provide an instantaneous thermal image of all sites of the feet (plantar, dorsal, lateral and medial views). Diabetic Foot Ulcer Prevention System NCT02317835, registered December 10, 2014.


Kidney biopsy chronicity grading in antineutrophil cytoplasmic antibody-associated vasculitis.
Kidney biopsy is valuable for prognostic assessment of renal outcomes in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) but the impact of chronic changes is not determined. We conducted a retrospective cohort study of myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA-positive patients with AAV and active renal disease. We applied the Mayo Clinic Chronicity Score (MCCS) and validated and evaluated its implications on outcome prediction in AAV-GN. We analyzed 329 patients with kidney biopsies available to score. The extent of chronicity was graded by MCCS as minimal [102 (31.0%)], mild [106 (32.2%)], moderate [86 (26.1%)] and severe [35 (10.6%)]. The MCCS grades correlated with the degree of renal function impairment at presentation [mean estimated glomerular filtration rate (eGFR) 48.3 versus 29.2 versus 23.7 versus 18.5 mL/min/1.73 m2, respectively; P < 0.0001]. Higher degrees of the individual components of the MCCS (glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriosclerosis) were associated with lower median eGFR (P < 0.0001) and decreased event-free [kidney failure (KF) and death] survival (P = 0.002, P < 0.0001, P < 0.0001 and P = 0.017, respectively). Patients with lower MCCS grades recovered renal function more frequently (P < 0.0001). Increasing MCCS grades were associated with decreased renal recovery (P = 0.001), more frequent events and shorter time to KF (P < 0.0001), KF and death (P < 0.0001) and death (P = 0.042), independent of the remission induction treatment used (cyclophosphamide or rituximab). The MCCS stratified renal outcomes for each MCCS grade and can be used in clinical practice as a cutoff for KF prediction (MCCS ≥4). Chronic changes on kidney histology independently predict renal function, outcomes and response to treatment in AAV-GN.


Rates, perceptions and predictors of depression, anxiety and Post Traumatic Stress Disorder (PTSD)-like symptoms about Covid-19 in adolescents.
Increasing evidence has shown that the Covid-19 outbreak, and subsequent school closures and exam cancellations that followed, has impacted adolescent mental health. The current cross-sectional study examined rates of depression, anxiety and Post Traumatic Stress Disorder (PTSD)-like symptoms about Covid-19 in adolescents and whether current or past mental health support, additional support in school, keyworker status, poorer household relationships since the outbreak of Covid-19 or reduced physical activity were associated with elevated levels of depression, anxiety or PTSD-like symptoms. Lastly, it examined perceived changes in mental health due to the Covid-19 pandemic, school closures and the cancellation of exams. A total of 899 adolescents (14-18 years) took part in the 'in isolation instead of in school' (INISS) project. Findings indicated that older adolescents, females, those who currently or previously received mental health support or additional support in school and adolescents who reported poorer relationships at home since Covid-19 were more likely to meet clinical threshold levels for their mental health. Adolescents highlighted worsening of their mental health due to Covid-19 and school closures with mixed positive and negative impact of exam cancellations. Adolescents experiencing clinical threshold levels of depression and anxiety uniquely reported worsening of their mental health since the Covid-19 pandemic, school closures and exam cancellations. Understanding the rates, perceptions and factors associated with increases in depression, anxiety and PTSD-like symptoms in adolescents during the Covid-19 pandemic will inform national policy in supporting adolescent mental health and recovery from the Covid-19 pandemic.


From "low hanging" to "user ready": initial steps into a HealthGrid.
Grids offer powerful infrastructures and promising concepts for the development and deployment of advanced applications in medical research and healthcare. The construction of HealthGrids in practice, however, is challenging due to reasons of scientific, technical, and cultural nature, among them the large gap between communities that develop and use the technology. Whereas grid developments focus mostly on functionality, usability issues are also very important to enable the potential of grids to be fully exploited by those who could mostly benefit from it, the end-users. In this paper we make a retrospective of our efforts to develop the Virtual Lab for functional Magnetic Resonance Imaging (fMRI). This project aims at providing for the end-users a grid-based system to facilitate research and clinical usage of fMRI data for study of brain activation. We present the evolution of this project in three phases coined "low hanging fruit", "trying out" and "end-user ready", and the lessons learnt in each one. The evolution of the software architecture, which had a large impact on the user front-end, is discussed in more detail. The current architecture facilitates the construction of front-ends that enable users to access the grid infrastructure from a single user-friendly GUI. All (local and grid) resources are accessed directly by the users from a virtual desktop implemented by the Virtual Resource Browser (VBrowser).


The plant mitochondrial protein import apparatus - the differences make it interesting.
Mitochondria play essential roles in the life and death of almost all eukaryotic cells, ranging from single-celled to multi-cellular organisms that display tissue and developmental differentiation. As mitochondria only arose once in evolution, much can be learned from studying single celled model systems such as yeast and applying this knowledge to other organisms. However, two billion years of evolution have also resulted in substantial divergence in mitochondrial function between eukaryotic organisms. Here we review our current understanding of the mechanisms of mitochondrial protein import between plants and yeast (Saccharomyces cerevisiae) and identify a high level of conservation for the essential subunits of plant mitochondrial import apparatus. Furthermore, we investigate examples whereby divergence and acquisition of functions have arisen and highlight the emerging examples of interactions between the import apparatus and components of the respiratory chain. After more than three decades of research into the components and mechanisms of mitochondrial protein import of plants and yeast, the differences between these systems are examined. Specifically, expansions of the small gene families that encode the mitochondrial protein import apparatus in plants are detailed, and their essential role in seed viability is revealed. These findings point to the essential role of the inner mitochondrial protein translocases in Arabidopsis, establishing their necessity for seed viability and the crucial role of mitochondrial biogenesis during germination. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.


Defined covalent attachment of three cancer drugs to DNA origami increases cytotoxicity at nanomolar concentration.
DNA nanostructures have captured great interest as drug delivery vehicles for cancer therapy. Despite rapid progress in the field, some hurdles, such as low cellular uptake, low tissue specificity or ambiguous drug loading, remain unsolved. Herein, well-known antitumor drugs (doxorubicin, auristatin, and floxuridine) were site-specifically incorporated into DNA nanostructures, demonstrating the potential advantages of covalently linking drug molecules via structural staples instead of incorporating the drugs by noncovalent binding interactions. The covalent strategy avoids critical issues such as an unknown number of drug-DNA binding events and premature drug release. Moreover, covalently modified origami offers the possibility of precisely incorporating several synergetic antitumor drugs into the DNA nanostructure at a predefined molar ratio and to control the exact spatial orientation of drugs into DNA origami. Additionally, DNA-based nanoscaffolds have been reported to have a low intracellular uptake. Thus, two cellular uptake enhancing mechanisms were studied: the introduction of folate units covalently linked to DNA origami and the transfection of DNA origami with Lipofectamine. Importantly, both methods increased the internalization of DNA origami into HTB38 and HCC2998 colorectal cancer cells and produced greater cytotoxic activity when the DNA origami incorporated antiproliferative drugs. The results here present a successful and conceptually distinct approach for the development of DNA-based nanostructures as drug delivery vehicles, which can be considered an important step towards the development of highly precise nanomedicines.


Hemolytic uremic syndrome following hemorrhagic colitis caused by verotoxin-producing Escherichia coli O157:H7: early signs of hemolytic uremic syndrome.
Ten cases of hemolytic uremic syndrome (HUS) following hemorrhagic colitis caused by verotoxin T2-producing Escherichia coli O157:H7 (VTEC) occurred in a Kindergarten. Slight changes in results of peripheral blood and blood chemistry studies an average of 4 days after onset suggested HUS, and within the following 12 hours platelet counts and levels of haptoglobin and lactic dehydrogenase decreased. Treatment was mainly directed toward the management of renal failure and included supportive therapy and anticoagulant and antiplatelet treatment. Although neurological complications occurred in some cases, all patients eventually recovered completely.


Cs frequency synthesis: a new approach.
The paper describes a new approach to synthesizing the Cs hyperfine frequency of 9.192 GHz that is designed to be sufficiently rugged for use in space, specifically for the Primary Atomic Reference Clock in Space (PARCS) planned for the International Space Station, as well as ground applications. This new approach requires no narrow band filters or frequency multiplication, and the primary source of cooling is conduction. Instead of frequency multiplication, it uses a custom regenerative divider stage followed by two commercial binary dividers and several mixing stages. A fractional frequency step of 2x10(-17) is achieved by mixing the output of a 48-bit numerically controlled oscillator with the microwave signal. Preliminary tests on the new synthesizer design indicate an internal fractional frequency stability of 1x10(-15) at 10 s and 1x10 (-18) at 1 d, dominated by the daily room temperature variations. The phase and amplitude noise are similar to our previous designs that used frequency multiplication and narrow band filters. The temperature coefficient is less than 0.2 ps/K.


Improved detection of delirium, implementation and validation of the CAM-ICU in elderly Emergency Department patients.
To evaluate the effect of routine use of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) on the diagnosis rate of delirium in elderly Emergency Department (ED) patients and the validity of the CAM-ICU in the ED setting. This was a prospective observational study in a tertiary care academic ED. We compared the diagnosis rate of delirium before implementation of the CAM-ICU, without routine use of a screening tool, with the diagnosis rate after implementation of the CAM-ICU. All consecutive patients aged 70 years or older were enrolled. The diagnosis rate before implementation was based on chart review and after implementation on a positive CAM-ICU score. In a subsample, the presence of delirium was evaluated independently according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) criteria to assess the validity of the CAM-ICU. The total study population included 968 patients: 490 before and 478 after implementation of the CAM-ICU. The two groups were not significantly different in patient characteristics. Before implementation of the CAM-ICU, delirium was diagnosed in 14 patients (3%) and after implementation in 48 patients (10%) (P<0.001). The sensitivity of the CAM-ICU for delirium in the ED setting was 100%, specificity was 98%, positive predictive value was 92%, and negative predictive value was 100%. The diagnosis rate of delirium after implementation of the CAM-ICU was three-fold higher than before. The CAM-ICU is a reliable screening tool in the ED, with high sensitivity, specificity, and positive and negative predictive value.


v-Src induces constitutive macropinocytosis in rat fibroblasts.
The role of v-Src as regulator of fluid-phase pinocytosis was investigated in Rat-1 cells expressing a stable (Rat-1/BB16) or a thermosensitive (Rat-1/tsLA29) v-Src protein. In the second cell line, this protein is inactive when cells are cultured at 40 degrees C but recovers its tyrosine kinase activity upon transfer to 34 degrees C, resulting into a transformed phenotype. The rate of fluid-phase pinocytosis of the tracer horseradish peroxidase was 2-fold higher in v-Src-transformed fibroblasts (Rat-1/BB16, Rat-1/tsLA29 cultured at 34 degrees C) as compared to non-transformed cells (Rat-1, Rat-1/tsLA29 kept at 40 degrees C). In contrast, receptor-mediated endocytosis of transferrin was poorly affected, suggesting that structures distinct from clathrin-coated pits are involved in pinocytosis stimulation. By light and electron microscopy, transformed cells frequently contained large peroxidase-labeled pinocytic vesicles located near to membrane ruffles, demonstrating that stimulation of pinocytosis corresponds to induction of constitutive macropinocytosis. Stimulation of pinocytosis occurred more than 8 hours after transfer to the permissive temperature, whereas transfer to the non-permissive temperature partially reversed the stimulation within 2 hours. Protein synthesis inhibition for 6 hours abrogated pinocytosis stimulation in transformed cells, indicating that constitutive macropinocytosis induced by v-Src depends on continuous synthesis of a short-lived regulatory machinery.


Untying the FIV frameshifting pseudoknot structure by MS3D.
The structure of the putative feline immunodeficiency virus (FIV) ribosomal frameshifting pseudoknot (PK) has been investigated by a mass spectrometric three-dimensional (MS3D) approach, which involves the application of established solvent-accessibility probes and chemical crosslinkers with detection by electrospray ionization (ESI) Fourier transform mass spectrometry (FTMS). Regardless of their size, probed substrates can be treated with ribonucleases and analyzed by ESI-FTMS to obtain the correct position of chemically modified nucleotides. Protection maps and distance information can be utilized to generate 3D models using the constraint satisfaction algorithm provided by MC-SYM and the energy minimization modules included in CNS. Control experiments were performed on a mutant of mouse mammary tumor virus pseudoknot (VPK), for which an NMR structure is available. Comparison between the MS3D model and the high-resolution structure provided a approximately 3A root-mean-square deviation calculated from all the atoms present in double-stranded regions. Applied to FIV-PK, the MS3D approach confirmed that the selected sequence could fold into an actual pseudoknot, supporting the sequence alignment predictions. Characteristic features of H-type pseudoknots were recognized immediately, but a putative A13-U30 pair was not observed at the stem junction, making FIV-PK resemble VPK more closely than the initially suggested simian retrovirus type-1 pseudoknot. In our model, the unpaired U30 protrudes into the medium, while the hinging A13 assumes a stacked conformation that enables the stems to form a approximately 60 degrees bend and relieve the strain caused by a short loop 1. The model provided the basis to explain the different alkylation patterns observed in the absence and presence of Mg(2+), suggesting the possible formation of a specific metal-binding site between loop 1 and stem 2. This instance illustrates how the MS3D model of FIV-PK can be utilized effectively to generate hypotheses and support functional observations in the absence of a high-resolution structure.


The Global Regulon sarA Regulates β-Lactam Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus In Vitro and in Endovascular Infections.
The global regulator sarA modulates virulence of methicillin-resistant Staphylococcus aureus (MRSA) via regulation of principal virulence factors (eg, adhesins and toxins) and biofilm formation. Resistance of S. aureus strains to β-lactam antibiotics (eg, oxacillin) depends on the production of penicillin-binding protein 2a (PBP2a), encoded by mecA METHODS: In the present study, we investigated the impact of sarA on the phenotypic and genotypic characteristics of oxacillin resistance both in vitro and in an experimental endocarditis model, using prototypic healthcare- and community-associated MRSA parental and their respective sarA mutant strain sets. All sarA mutants (vs respective MRSA parental controls) displayed significant reductions in oxacillin resistance and biofilm formation in vitro and oxacillin persistence in an experimental endocarditis model in vivo. These phenotypes corresponded to reduced mecA expression and PBP2a production and an interdependency of sarA and sigB regulators. Moreover, RNA sequencing analyses showed that sarA mutants exhibited significantly increased levels of primary extracellular proteases and suppressed pyrimidine biosynthetic pathway, argininosuccinate lyase-encoding, and ABC transporter-related genes as compared to the parental strain. These results suggested that sarA regulates oxacillin resistance in mecA-positive MRSA. Thus, abrogation of this regulator represents an attractive and novel drug target to potentiate efficacy of existing antibiotic for MRSA therapy.


Lack of shunt response in suspected idiopathic normal pressure hydrocephalus with Alzheimer disease pathology.
To determine the impact of cortical Alzheimer disease pathology on shunt responsiveness in individuals treated for idiopathic normal pressure hydrocephalus (iNPH), 37 patients clinically diagnosed with iNPH participated in a prospective study in which performance on neurologic, psychometric, and gait measures before and 4 months after shunting was correlated with amyloid β plaques, neuritic plaques, and neurofibrillary tangles observed in cortical biopsies obtained during shunt insertion. No complications resulted from biopsy acquisition. Moderate to severe pathology was associated with worse baseline cognitive performance and diminished postoperative improvement on NPH symptom severity scales, gait measures, and cognitive instruments compared to patients lacking pathology.


Gestational weight gain as a predictor of macrosomia and low birth weight: a systematic review.
To evaluate the predictive capacity of gestational weight gain recommendations regarding low birth weight (LBW) and neonatal macrosomia, proposed by the Institute of Medicine (IOM) and the Latin American Center of Perinatology (CLAP). The bibliographic search was performed in PubMed, Embase (via Ovid), Cochrane Library, EBSCOhost, Sco pus, LILACS and SciELO. Methodological quality was evaluated using QUADAS 2. A total of 1,192 articles were identified, only 5 articles met the inclusion criteria, no study evluated the CLAP recomendations. Sensitivity and specificity to predict LBW and macrosomia varied widely depending on which country the study took place. In the Latin American cohorts, the sensitivity for predicting LBW ranged from 62.8% to 74% and the specificity from 61.7% to 68%, while the sensitivity for predicting macrosomia was 28.8% and the specificity 43.8%. In most studies the positive predictive value was less than 25%, and the negative predictive va lue was more than 90%. Most studies had high risk of bias and applicability problems in patient selection. The limited methodological quality and representativeness of the studied cohorts, probable unadjusted confounding factors and modest values of sensitivity and specificity suggest the need to develop studies aimed at providing recommendations that fit the epidemiological characteristics of the Peruvian population.


Cancer rehabilitation indicators for Europe.
Little is known of cancer rehabilitation needs in Europe. EUROCHIP-3 organised a group of experts to propose a list of population-based indicators used for describing cancer rehabilitation across Europe. The aim of this study is to present and discuss these indicators. A EUROCHIP-3 expert panel reached agreement on two types of indicators. (a) Cancer prevalence indicators. These were proposed as a means of characterising the burden of cancer rehabilitation needs by time from diagnosis and patient health status. These indicators can be estimated from cancer registry data or by collecting data on follow-up and treatments for samples of cases archived in cancer registries. (b) Indicators of rehabilitation success. These include: return to work, quality of life, and satisfaction of specific rehabilitation needs. Studies can be performed to estimate these indicators in individual countries, but to obtain comparable data across European countries it will be necessary to administer a questionnaire to randomly selected samples of patients from population-based cancer registry databases. However, three factors complicate questionnaire studies: patients may not be aware that they have cancer; incomplete participation in surveys could lead to bias; and national confidentiality laws in some cases prohibit cancer registries from approaching patients. Although these studies are expensive and difficult to perform, but as the number of cancer survivors increases, it is important to document their needs in order to provide information on cancer control.


Varian HDR surface applicators - commissioning and clinical implementation.
The purpose of this study was to validate the dosimetric performance of Varian surface applicators with the source vertically positioned and develop procedures for clinical implementation. The Varian surface applicators with the source vertically positioned provide a wide range of apertures making them clinically advantageous, though the steep dose gradient in the region of 3-4 mm prescription depth presents multiple challenges. The following commissioning tests were performed: 1) verification of functional integrity and physical dimensions; and 2) dosimetric measurements to validate data provided by Varian as well as data obtained using the Acuros algorithm for heterogeneity corrected dose calculation. A solid water (SW) phantom was scanned and the Acuros algorithm was used to compute the dose at 5 mm depth and at surface for all applicators. Two sets of reference dose measurements were performed, with the source positioned at (i) -10 mm and (ii) -15 mm from the center of the first nominal dwell position. Measurements were taken at 5 mm depth in a SW phantom and in air at the applicator surface. The results were then compared to the vendor's data and to the Acuros calculated dose. Relative dose measurements using Gafchromic films were taken at a depth of 4 mm in SW. Percent depth ionization (PDI) measurements using ion chamber were performed in SW. The profiles generated from film measurements and the PDI plots were compared with those computed using the Acuros algorithm and vendor's data, when available. Preliminary leakage tests were performed using optically stimulated luminescence dosimeters (OSLDs) and the results were compared with Acuros predictions. All applicators were found to be functional with physical dimensions within 1 mm of specifications. For scenario (ii) measurements taken in SW at 5 mm depth and in air at the surface of each applicator were within 10% and 4% agreement with vendor's data, respectively. Compared with Acuros predictions, these measurements were within 6% and 5%, respectively. Measurements taken for scenario (i) showed reduced agreement with both the vendor's data as well as the Acuros calculations, especially when using the 10 mm applicator. The full widths of the measured dose profiles were within 2 mm of those predicted by Acuros at the 90% dose level. The PDI plots and measured leakage dose were in good agreement with vendor's data and Acuros predictions. Based on the dosimetric results, a quality assurance program and procedures for clinical implementation were developed. Treatment planning will be performed using scenario (ii). The 10mm applicator will not be released for clinical use. A prescription depth of 4mm is recommended, to ensure full coverage at 3 mm and a minimum dose of 90% of prescribed dose at 4 mm depth.


Second-line systemic therapies for metastatic urothelial carcinoma: a population-based cohort analysis.
Patients with urothelial carcinoma (uc) have a poor prognosis after progression on first-line cisplatin-based chemotherapy. Real-world data about second-line cytotoxic therapies are limited. We sought to characterize patients with metastatic uc who receive more than 1 line of systemic therapy and to describe their treatments and outcomes. Using BC Cancer's pharmacy database, we identified patients with documented metastatic uc who had received more than 1 line of systemic therapy. A retrospective chart review was then performed to collect clinicopathologic, treatment, and outcomes data. The 51 included patients, of whom 42 were men (82%), had a median age of 65 years (range: 38-81 years). Sites of metastasis included lymph nodes (n = 30), bone (n = 7), lung (n = 9), and peritoneum (n = 2). Second-line chemotherapy regimens included gemcitabine-cisplatin [gc (n = 14)], paclitaxel (n = 24), docetaxel (n = 12), and an oral topoisomerase i inhibitor (n = 1). Median time to progression (ttp) and overall survival (os) were 2.0 and 6.83 months respectively. Compared with patients who received a different agent, patients who had experienced a prior response to first-line gc and who were re-challenged with second-line gc had a better median ttp (11.0 months vs. 6.0 months, p = 0.02) and survived longer (4.0 months vs. 1.0 months, p = 0.02). No differences in os between non-gc regimens were evident. In patients with metastatic uc, overall outcomes remain poor, but compared with patients receiving other agents, the subgroup of patients re-challenged with second-line gc demonstrated improved ttp. Conventional chemotherapy regimens provide only modest benefits in the second-line setting and have largely been replaced with immunotherapy.


Involvement of arachidonic acid and the lipoxygenase pathway in mediating luteinizing hormone-induced testosterone synthesis in rat Leydig cells.
Evidence has been introduced linking the lipoxygenase products and steroidogenesis in Leydig cells, thereby supporting that this pathway may be a common event in the hormonal control of steroid synthesis. On the other hand, it has also been reported that lipoxygenase products of arachidonic acid (AA) may not be involved in Leydig cells steroidogenesis. In this paper, we investigated the effects of PLA2 and lipoxygenase pathway inhibitors on steroidogenesis in rat testis Leydig cells. The effects of two structurally unrelated PLA2 inhibitors (4-bromophenacyl bromide (BPB) and quinacrine) were determined. BPB blocked the LH- and Bt2cAMP-stimulated testosterone production but had no effect on 22(4)-OH-cholesterol conversion to testosterone. Quinacrine caused a dose-dependent inhibition of LH- and Bt2cAMP-induced steroidogenesis. The effects of different lipoxygenase pathway inhibitors (nordihydroguaiaretic acid (NDGA), 5,8,11,14-eicosatetraynoic acid (ETYA), caffeic acid and esculetin) have also been determined. Both NDGA and ETYA inhibited LH- and Bt2cAMP-stimulated steroid synthesis in a dose-related manner. Furthermore caffeic acid and esculetin also blocked the LH-stimulated testosterone production. Moreover, exogenous AA induced a dose-dependent increase of testosterone secretion which was inhibited by NDGA. Our results strongly support the previous concept that the lipoxygenase pathway is involved in the mechanism of action of LH on testis Leydig cells.


Functions of cholera toxin B-subunit as a raft cross-linker.
Lipid rafts are putative complexes of lipids and proteins in cellular membranes that are proposed to function in trafficking and signalling events. CTxB (cholera toxin B-subunit) has emerged as one of the most studied examples of a raft-associated protein. Consisting of the membrane-binding domain of cholera toxin, CTxB binds up to five copies of its lipid receptor on the plasma membrane of the host cell. This multivalency of binding gives the toxin the ability to reorganize underlying membrane structure by cross-linking otherwise small and transient lipid rafts. CTxB thus serves as a useful model for understanding the properties and functions of protein-stabilized domains. In the present chapter, we summarize current evidence that CTxB associates with and cross-links lipid rafts, discuss how CTxB binding modulates the architecture and dynamics of membrane domains, and describe the functional consequences of this cross-linking behaviour on toxin uptake into cells via endocytosis.


Urine C-peptide as index of integrated insulin secretion in hypocaloric states in obese human subjects.
To determine the effects of different hypocaloric diets on insulin secretion, 24-h urine C-peptide was measured in 11 obese subjects on a weight-maintaining baseline diet, and the results were compared with values obtained during 14-day periods of diets containing 400 kcal/day of only protein (n = 6) or glucose (n = 5), followed by 14 days of fasting and 14 days of refeeding on 800-1000 kcal/day. A significant positive correlation between total caloric intake and urine C-peptide excretion was found once the C-peptide excretion reached steady state after several days on each diet. Multiple regression analysis showed no contribution of body weight to urine C-peptide during the different diets. In contrast, a significant correlation was found between body weight and urine C-peptide in the fasting state. A marked and identical decrease of approximately 75% in urine C-peptide occurred over the first 5-7 days of the two 400-kcal diets, followed by a further decrease during fasting to 5% of baseline values. Refeeding was associated with a progressive increase. Plasma insulin and C-peptide followed the same trends as found for urine C-peptide, although the magnitude of change was much smaller. C-peptide clearance was not assessed because of the variation in plasma levels on eating meals. However, the same responses were found when C-peptide excretion was factored for creatinine excretion. Thus, the major determinant of urine C-peptide excretion appears to be food intake, and adaptations take 5-7 days to reach steady state.(ABSTRACT TRUNCATED AT 250 WORDS)


Management of primary skin cancer during a pandemic: Multidisciplinary recommendations.
During the coronavirus disease 2019 (COVID-19) pandemic, providers and patients must engage in shared decision making regarding the pros and cons of early versus delayed interventions for localized skin cancer. Patients at highest risk of COVID-19 complications are older; are immunosuppressed; and have diabetes, cancer, or cardiopulmonary disease, with multiple comorbidities associated with worse outcomes. Physicians must weigh the patient's risk of COVID-19 complications in the event of exposure against the risk of worse oncologic outcomes from delaying cancer therapy. Herein, the authors have summarized current data regarding the risk of COVID-19 complications and mortality based on age and comorbidities and have reviewed the literature assessing how treatment delays affect oncologic outcomes. They also have provided multidisciplinary recommendations regarding the timing of local therapy for early-stage skin cancers during this pandemic with input from experts at 11 different institutions. For patients with Merkel cell carcinoma, the authors recommend prioritizing treatment, but a short delay can be considered for patients with favorable T1 disease who are at higher risk of COVID-19 complications. For patients with melanoma, the authors recommend delaying the treatment of patients with T0 to T1 disease for 3 months if there is no macroscopic residual disease at the time of biopsy. Treatment of tumors ≥T2 can be delayed for 3 months if the biopsy margins are negative. For patients with cutaneous squamous cell carcinoma, those with Brigham and Women's Hospital T1 to T2a disease can have their treatment delayed for 2 to 3 months unless there is rapid growth, symptomatic lesions, or the patient is immunocompromised. The treatment of tumors ≥T2b should be prioritized, but a 1-month to 2-month delay is unlikely to worsen disease-specific mortality. For patients with squamous cell carcinoma in situ and basal cell carcinoma, treatment can be deferred for 3 months unless the individual is highly symptomatic.


A questionnaire investigation on factors of importance for the development of anthelmintic resistance of nematodes in sow herds in Denmark.
A questionnaire survey on the use of anthelmintics and presence of other potential risk factors for the development of anthelmintic resistance of nematodes in 136 Danish sow herds was carried out between November 1992-February 1993. Twenty one veterinarians who specialize in diseases of pigs administered the questionnaire in personal interviews during their regular visits to the respective pig farmers. In the study population, 91% of the farmers currently treated their sows with anthelmintics, while only 38% and 14% treated their weaners and fatteners, respectively. Most respondents treated their sows either before or after farrowing (40%) or once every 6 months (27%). Benzimidazole and pro-benzimidazole (Class I) anthelmintics were the most used in sows by the farmers (39%, 47%, 49%, 50%, 46%, and 47% during the years 1987, 1988, 1989, 1990, 1991 and 1992, respectively). When sows were treated, fenbendazole was the most frequently used anthelmintic during the period 1987-1992 (30%-39%). The proportion of farmers that used Class II (pyrantel and levamisole) or Class III (ivermectin and piperazine) anthelmintics during the year 1992 were 25% and 13%, respectively. Of the 70 farmers who used anthelmintics from either Class I, II or III during the study period, 44 farmers always used the same class of drugs. Eight herd owners among those 44, had changed the pharmaceutical product within the same class. Sixty nine percent of the farmers did not weight the sows, but used visual appraisal of average body.


Perinatal Risks in "Late Motherhood" Defined Based On Parity and Preterm Birth Rate - an Analysis of the German Perinatal Survey (20th Communication).
Aim: "Late motherhood" is associated with greater perinatal risks but the term lacks precise definition. We present an approach to determine what "late motherhood" associated with "high risk" is, based on parity and preterm birth rate. Materials and Methods: Using data from the German Perinatal Survey of 1998-2000 we analysed preterm birth rates in women with zero, one, or two previous live births. We compared groups of "late" mothers (with high preterm birth rates) with "control" groups of younger women (with relatively low preterm birth rates). Data of 208 342 women were analysed. For women with zero (one; two) previous live births, the "control" group included women aged 22-26 (27-31; 29-33) years. Women in the "late motherhood" group were aged > 33 (> 35; > 38) years. Results: The "late motherhood" groups defined in this way were also at higher risk of adverse perinatal events other than preterm birth. For women with zero (one; two) previous live births, normal cephalic presentation occurred in 89 % (92.7 %; 93.3 %) in the "control" group, but only in 84.5 % (90 %; 90.4 %) in the "late motherhood" group. The mode of delivery was spontaneous or at most requiring manual help in 71.3 % (83.4 %; 85.8 %) in the "control" group, but only in 51.4 % (72.2 %; 76.4 %) in the "late motherhood" group. Five-minute APGAR scores were likewise worse for neonates of "late" mothers and the proportion with a birth weight ≤ 2499 g was greater. Conclusion: "Late motherhood" that is associated with greater perinatal risks can be defined based on parity and preterm birth rate.


Superresolution along extended depth of focus with binary-phase filters for the Gaussian beam.
In the paraxial Debye regime, simple and power-efficient pupil filters are designed to break the diffraction limit along a large depth of focus (DOF) for the Gaussian beam. Dependences of the superresolution factor, DOF gain, Strehl ratio, sidelobe strength, and axial intensity nonuniformity on the Gaussian profile in the pupil plane are characterized using the numerical method. Optimal filter designs are proposed for either high-resolution or ultra-large-DOF applications followed by experimental verifications.