Pulmonary Responses Following Quercetin Administration in Rats After Intratracheal Instillation of Amiodarone.
Amiodarone, a drug that treats arrhythmias induces pulmonary toxicity through interplay between oxidative stress and inflammation. Quercetin, a flavonoid widely occurring in natural products possesses antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the effects of quercetin on pulmonary responses in rats after amiodarone intra-tracheal instillation. Eighteen female Wistar rats (150-250 g) were randomly assigned into three groups of six animals each namely; control, amiodarone (AMI) and amiodarone + Quercetin (AMI + Quercetin) groups. AMI group received 2 intra-tracheal instillations of amiodarone (6.25mg/kg in 0.3ml of water) on days 0 and 2 and 0.4ml of 2% DMSO (Dimethyl sulfoxide) orally from day 0 for 3 weeks. AMI + Quercetin group was administered 2 intratracheal instillations of amiodarone on days 0 and 2 and 20mg/kg body weight of quercetin in 2% DMSO from day 0 for 3 weeks. Thereafter, the animals were sacrificed and bronchoalveolar lavage fluid (BALF) was collected to determine total cell polymorphonuclear (PMN) cell and macrophage counts. Inflammation of the lung tissues was also assessed. Macrophage count of AMI + Quercetin group was significantly lowered (p<0.01) compared to AMI group. Inflammation rate of the AMI + Quercetin group was significantly reduced compared to AMI group (p<0.01). Quercetin treatment markedly suppressed amiodarone induced toxicity in the pulmonary tissues.


Determination of bisphenol A in canned vegetables and fruit by high performance liquid chromatography.
A high performance liquid chromatography (HPLC) method was developed for the determination of bisphenol A (BPA) that had migrated into canned fruit and vegetables. BPA was extracted with acetonitrile from the solid portion of canned food, and with an OASIS HLB cartridge from the aqueous portion, respectively. Both extracts were cleaned up on a Florisil cartridge. The HPLC separation was carried out on a Wakosil II 3C18 RS column (4.6 x 150 mm) with acetonitrile-water (40:60, v/v) as a mobile phase with a flow rate of 0.8 ml/min. BPA was detectable by UV detector at 228 nm and determined with the similarity of chromatographic peak spectrum by multiwavelength detector (similarity index was 0.99 or above). The quantification limits were 10 ng/g for the solid portion and 5 ng/ml for the aqueous portion, respectively. BPA was mainly detected in the solid portion of canned food and found at the maximum level of 11 micrograms per can. To verify migration into the solid portion of canned food, a partitioning experiment was carried out.


Serum leptin levels in patients with nasal polyposis.
Nasal polyposis is one of the most common inflammatory pathologies of the nasal cavity. The aetiopathogenetic mechanisms of nasal polyp formation are still unclear. The aim of this study was to investigate the serum leptin levels in patients with nasal polyposis. A randomised, prospective study was performed of 28 adult patients with nasal polyposis and 22 control subjects of a similar age, sex and body mass index. Serum leptin levels were 12.10 +/- 9.39 ng/ml in the nasal polyposis patients and 6.17 +/- 7.68 ng/ml in the controls. A significant difference (p = 0.021) was observed in the mean serum leptin levels between nasal polyposis patients and controls. Serum leptin levels were found to be significantly higher in patients with nasal polyposis. Leptin, apart from its primary role in the regulation of body weight and energy expenditure, may have a role in the inflammatory response of nasal polyposis.


In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft.
Vascular endothelial growth factor (VEGF), released by tumor cells, is an important growth factor in tumor angiogenesis. The humanized monoclonal antibody bevacizumab blocks VEGF-induced tumor angiogenesis by binding, thereby neutralizing VEGF. Our aim was to develop radiolabeled bevacizumab for noninvasive in vivo VEGF visualization and quantification with the single gamma-emitting isotope 111In and the PET isotope 89Zr. Labeling, stability, and binding studies were performed. Nude mice with a human SKOV-3 ovarian tumor xenograft were injected with 89Zr-bevacizumab, 111In-bevacizumab, or human 89Zr-IgG. Human 89Zr-IgG served as an aspecific control antibody. Small-animal PET and microCT studies were obtained at 24, 72, and 168 h after injection of 89Zr-bevacizumab and 89Zr-IgG (3.5 +/- 0.5 MBq, 100 +/- 6 microg, 0.2 mL [mean +/- SD]). Small-animal PET and microCT images were fused to calculate tumor uptake and compared with ex vivo biodistribution at 168 h after injection. 89Zr- and 111In-bevacizumab ex vivo biodistribution was compared at 24, 72, and 168 h after injection (2.0 +/- 0.5 MBq each, 100 +/- 4 microg in total, 0.2 mL). Labeling efficiencies, radiochemical purity, stability, and binding properties were optimal for the radioimmunoconjugates. Small-animal PET showed uptake in well-perfused organs at 24 h and clear tumor localization from 72 h onward. Tumor uptake determined by quantification of small-animal PET images was higher for 89Zr-bevacizumab-namely, 7.38 +/- 2.06 %ID/g compared with 3.39 +/- 1.16 %ID/g (percentage injected dose per gram) for human 89Zr-IgG (P = 0.011) at 168 h and equivalent to ex vivo biodistribution studies. Tracer uptake in other organs was seen primarily in liver and spleen. 89Zr- and 111In-bevacizumab biodistribution was comparable. Radiolabeled bevacizumab showed higher uptake compared with radiolabeled human IgG in a human SKOV-3 ovarian tumor xenograft. Noninvasive quantitative small-animal PET was similar to invasive ex vivo biodistribution. Radiolabeled bevacizumab is a new tracer for noninvasive in vivo imaging of VEGF in the tumor microenvironment.


Essential role of PACSIN2/syndapin-II in caveolae membrane sculpting.
Caveolae are flask-shaped invaginations of the plasma membrane that are associated with tumor formation, pathogen entry and muscular dystrophy, through the regulation of lipids, signal transduction and endocytosis. Caveolae are generated by the fusion of caveolin-1-containing vesicles with the plasma membrane, which then participate in endocytosis via dynamin. Proteins containing membrane-sculpting F-BAR (or EFC) domains organize the membrane in clathrin-mediated endocytosis. Here, we show that the F-BAR protein PACSIN2 sculpts the plasma membrane of the caveola. The PACSIN2 F-BAR domain interacts directly with caveolin-1 by unmasking autoinhibition of PACSIN2. Furthermore, the membrane invaginations induced by the PACSIN2 F-BAR domain contained caveolin-1. Knockdown of PACSIN2 resulted in abnormal morphology of caveolin-1-associated plasma membranes, presumably as a result of decreased recruitment of dynamin-2 to caveolin-1. These results indicate that PACSIN2 mediates membrane sculpting by caveolin-1 in caveola morphology and recruits dynamin-2 for caveola fission.


[Modern detoxication methods in surgical patients].
The therapeutic possibilities of peritoneal dialysis, hemodialysis, and hemo- and lymphosorption in the treatment of the intoxication syndrome were studied in 786 patients. The causes of the intoxication syndrome were as follows: postoperative peritonitis (98), acute renal insufficiency of various etiology (493), acute hepatorenal insufficiency with exogenous poisoning (178), diffuse purulent peritonitis (11), pancreatogenic peritonitis (6). Enzymatic lavage and peritoneal dialysis were applied in 98 patients, hemodialysis methods in 493, hemosorption was conducted 360 times in 178 patients and lymphosorption in 17 patients. The efficacy of the modern methods of detoxification of the organism was demonstrated, which was evaluated from the patients' improved general condition, improvement of the values of hemodynamics, concentration of toxic metabolites and middle-mass molecules in the blood, and the results of the paramecium test.


GnRH antagonists in the treatment of advanced prostate cancer.
Analogues of the gonadotropin releasing hormone (GnRH) inhibit the hypothalamic-pituitary-gonadal axis. This has provided treatment modalities for advanced and metastatic prostate cancer. The latest group of analogues, the GnRH antagonists, make promising treatments available that avoid the transient surge in testosterone that occurs with the use of GnRH agonists. Such surges may stimulate tumor growth, causing patients to experience new or worsening cancer symptoms and potential serious adverse effects, including increased bone pain, urinary retention, and spinal cord compression and consequently delay the therapeutic benefits of agonist therapy. Degarelix, an antagonist, recently approved in the United States and Europe, achieves faster, more profound and sustained testosterone suppression and with fewer adverse effects when compared with agonists and other antagonists. This review discusses and compares the compounds degarelix, abarelix, and cetrorelix.


Diabetic hand infections and hyperbaric oxygen therapy.
The aim of this study was to discuss the clinical characteristics and results of hand infections in diabetic patients treated with hyperbaric oxygen therapy (HBOT). This retrospective study included 10 patients with diabetes mellitus who underwent HBOT due to hand infections between January 2006 and February 2011. Amputation was performed at the level of the right hand index finger proximal interphalangeal joint in 1 patient and at the level of the distal phalanx of the left hand middle finger in 1 due to necrotizing soft tissue infection. Ulcers of 8 patients healed completely without amputation. The addition of HBOT to the standard treatment may contribute to the healing of hand ulcers in diabetics by increasing the tissue oxygenation and correcting the process of disturbed wound healing.


Vaginal tactile imaging.
Changes in the elasticity of the vaginal walls, connective support tissues, and muscles are thought to be significant factors in the development of pelvic organ prolapse, a highly prevalent condition affecting at least 50% of women in the United States during their lifetimes. It creates two predominant concerns specific to the biomechanical properties of pelvic support tissues: how does tissue elasticity affect the development of pelvic organ prolapse and how can functional elasticity be maintained through reconstructive surgery. We designed a prototype of vaginal tactile imager (VTI) for visualization and assessment of elastic properties of pelvic floor tissues. In this paper, we analyze applicability of tactile imaging for evaluation of reconstructive surgery results and characterization of normal and pelvic organ prolapse conditions. A pilot clinical study with 13 patients demonstrated that VTI allows imaging of vaginal walls with increased rigidity due to implanted mesh grafts following reconstructive pelvic surgery and VTI has the potential for prolapse characterization and detection.


Computational learning techniques for intraday FX trading using popular technical indicators.
We consider strategies which use a collection of popular technical indicators as input and seek a profitable trading rule defined in terms of them. We consider two popular computational learning approaches, reinforcement learning and genetic programming, and compare them to a pair of simpler methods: the exact solution of an appropriate Markov decision problem, and a simple heuristic. We find that although all methods are able to generate significant in-sample and out-of-sample profits when transaction costs are zero, the genetic algorithm approach is superior for non-zero transaction costs, although none of the methods produce significant profits at realistic transaction costs. We also find that there is a substantial danger of overfitting if in-sample learning is not constrained.


Open Long-Tailed Recognition In A Dynamic World.
Real world data often exhibits a long-tailed and open-ended (i.e., with unseen classes) distribution. A practical recognition system must balance between majority (head) and minority (tail) classes, generalize across the distribution, and acknowledge novelty upon the instances of unseen classes (open classes). We define Open Long-Tailed Recognition++ (OLTR++) as learning from such naturally distributed data and optimizing for the classification accuracy over a balanced test set which includes both known and open classes. OLTR++ handles imbalanced classification, few-shot learning, open-set recognition, and active learning in one integrated algorithm, whereas existing classification approaches often focus only on one or two aspects and deliver poorly over the entire spectrum. The key challenges are: 1) how to share visual knowledge between head and tail classes, 2) how to reduce confusion between tail and open classes, and 3) how to actively explore open classes with learned knowledge. Our algorithm, OLTR++, maps images to a feature space such that visual concepts can relate to each other through a memory association mechanism and a learned metric (dynamic meta-embedding) that both respects the closed world classification of seen classes and acknowledges the novelty of open classes. Additionally, we propose an active learning scheme based on visual memory, which learns to recognize open classes in a data-efficient manner for future expansions. On three large-scale open long-tailed datasets we curated from ImageNet (object-centric), Places (scene-centric), and MS1M (face-centric) data, as well as three standard benchmarks (CIFAR-10-LT, CIFAR-100-LT, and iNaturalist-18), our approach, as a unified framework, consistently demonstrates competitive performance. Notably, our approach also shows strong potential for the active exploration of open classes and the fairness analysis of minority groups.


[Cholangiocarcinoma associated with Caroli's disease. Apropos of a case. Review of the literature].
This is a report of a rarely observed occurrence of complication in Caroli's disease, i.e. the emergence of a cholangiocarcinoma in the course of the disease. There are 20 observations reported in the literature, and the hypotheses of pathogenesis set forth are reviewed. The frequency of a malignant transformation during the course of Caroli's disease is compared to the frequencies of other hepatic-biliary congenital cystic tumours. The excision of the cyst resulted in an appreciable period of survival for the patient.


Long-term effects of laws governing youth access to tobacco.
We sought to examine the association between policies governing access to tobacco during adolescence and subsequent adult smoking. We analyzed adult smoking data from the 1998 through 2006-2007 administrations of the US Current Population Survey Tobacco Use Supplement by employing a quasi experimental approach. Participants (n = 105,519) were adults, aged 18 to 34 years at the time of the survey. Smoking outcomes included having ever smoked 100 cigarettes, smoking at the time of the survey, and having smoked 10 or more cigarettes a day conditioned on being an ever smoker. These were predicted from exposure to state youth access policies at age 17 years. Four of the 9 policies exhibited significant associations with reduced prevalence of 1 or more smoking outcomes, primarily among women. Lesser effects for other policies could not be ruled out. Restrictions on youth access to tobacco might lead to reduction in smoking prevalence later in adulthood. The effect might be limited to women; we estimate that having all policies in place could be associated with a 14% reduction in lifetime smoking prevalence for women, and an additional 29% reduction in heavy smoking among ever smokers.


Predominance of deterministic microbial community dynamics in salterns exposed to different light intensities.
While the dynamics of microbial community assembly driven by environmental perturbations have been extensively studied, our understanding is far from complete, particularly for light-induced perturbations. Extremely halophilic communities thriving in coastal solar salterns are mainly influenced by two environmental factors-salt concentrations and high sunlight irradiation. By experimentally manipulating light intensity through the application of shading, we showed that light acts as a deterministic factor that ultimately drives the establishment of recurrent microbial communities under near-saturation salt concentrations. In particular, the stable and highly change-resistant communities that established under high-light intensities were dominated (>90% of metagenomic reads) by Haloquadratum spp. and Salinibacter spp. On the other hand, under 37-fold lower light intensity, different, less stable and change-resistant communities were established, mainly dominated by yet unclassified haloarchaea and relatively diverse photosynthetic microorganisms. These communities harboured, in general, much lower carotenoid pigment content than their high-irradiation counterparts. Both assemblage types appeared to be highly resilient, re-establishing when favourable conditions returned after perturbation (i.e. high-irradiation for the former communities and low-irradiation for the latter ones). Overall, our results revealed that stochastic processes were of limited significance to explain these patterns.


Osmolyte regulation by TonEBP/NFAT5 during anoxia-recovery and dehydration-rehydration stresses in the freeze-tolerant wood frog (Rana sylvatica).
The wood frog, Rana sylvatica, tolerates freezing as a means of winter survival. Freezing is considered to be an ischemic/anoxic event in which oxygen delivery is significantly impaired. In addition, cellular dehydration occurs during freezing because water is lost to extracellular compartments in order to promote freezing. In order to prevent severe cell shrinkage and cell death, it is important for the wood frog to have adaptive mechanisms for osmoregulation. One important mechanism of cellular osmoregulation occurs through the cellular uptake/production of organic osmolytes like sorbitol, betaine, and myo-inositol. Betaine and myo-inositol are transported by the proteins BGT-1 and SMIT, respectively. Sorbitol on the other hand, is synthesized inside the cell by the enzyme aldose reductase. These three proteins are regulated at the transcriptional level by the transcription factor, NFAT5/TonEBP. Therefore, the objective of this study was to elucidate the role of NFAT5/TonEBP in regulating BGT-1, SMIT, and aldose reductase, during dehydration and anoxia in the wood frog muscle, liver, and kidney tissues. Wood frogs were subjected to 24 h anoxia-4 h recovery and 40% dehydration-full rehydration experiments. Protein levels of NFAT5, BGT-1, SMIT, and aldose reductase were studied using immunoblotting in muscle, liver, and kidney tissues. Immunoblotting results demonstrated downregulations in NFAT5 protein levels in both liver and kidney tissues during anoxia (decreases by 41% and 44% relative to control for liver and kidney, respectively). Aldose reductase protein levels also decreased in both muscle and kidney tissues during anoxia (by 37% and 30% for muscle and kidney, respectively). On the other hand, BGT-1 levels increased during anoxia in muscle (0.9-fold compared to control) and kidney (1.1-fold). Under 40% dehydration, NFAT5 levels decreased in liver by 53%. Aldose reductase levels also decreased by 42% in dehydrated muscle, and by 35% in dehydrated liver. In contrast, BGT-1 levels increased by 1.4-fold in dehydrated liver. SMIT levels also increased in both dehydrated muscle and liver (both by 0.8-fold). Overall, we observed that osmoregulation through an NFAT5-mediated pathway is both tissue- and stress-specific. In both anoxia and dehydration, there appears to be a general reduction in NFAT5 levels resulting in decreased aldose reductase levels, however BGT-1 and SMIT levels still increase in certain tissues. Therefore, the regulation of osmoregulatory genes during dehydration and anoxia occurs beyond the transcriptional level, and it possibly involves RNA processing as well. These novel findings on the osmoregulatory mechanisms utilized by the wood frog advances our knowledge of osmoregulation during anoxia and dehydration. In addition, these findings highlight the importance of using this model to study molecular adaptations during stress.


Transient ischemic attacks in patients with active and occult cancer.
Paraneoplastic coagulopathy can present as stroke and is associated with specific biomarker changes. Identifying paraneoplastic coagulopathy can help guide secondary prevention in stroke patients, and early cancer detection might improve outcomes. However, unlike ischemic stroke, it remains unclear whether paraneoplastic coagulopathy is associated with transient ischemic attacks (TIA). This study assessed the presence of cancer-related biomarkers in TIA patients and evaluated long-term mortality rates in patients with and without active cancer. Active cancer was retrospectively identified in consecutive TIA patients treated at a comprehensive stroke center between 2015 and 2019. An association between the presence of cancer and cancer-related biomarkers was assessed using multivariable logistic regression. Long-term mortality after TIA was analyzed using multivariable Cox regression. Among 1436 TIA patients, 72 had active cancer (5%), of which 17 were occult (1.2%). Cancer-related TIA was associated with male gender (adjusted odds ratio [aOR] 2.29, 95% CI 1.12-4.68), history of smoking (aOR 2.77, 95% CI 1.34-5.7), elevated D-dimer (aOR 1.77, 95% CI 1.26-2.49), lactate dehydrogenase (aOR 1.003, 95% CI 1.00-1.005), lower leukocyte count (aOR 1.20, 95% CI 1.04-1.38), and lower hemoglobin (aOR 1.02, 95% CI 1.00-1.04). Long-term mortality was associated with both active cancer (adjusted hazard ratios [aHR] 2.47, 95% CI 1.58-3.88) and occult cancer (aHR 3.08, 95% CI 1.30-7.32). Cancer-related TIA is not uncommon. Biomarkers known to be associated with cancer-related stroke also seem to be present in TIA patients. Early identification would enable targeted treatment strategies and could improve outcomes in this patient population.


Finite deformation near a crack tip terminated at an interface between two neo-Hookean sheets.
A crack terminating at an arbitrary angle to the interface between two neo-Hookean sheets is investigated under plane stress conditions using finite deformation theory. The asymptotic crack-tip deformation and stress fields are analyzed as a function of the ratio of the moduli and the angle of the crack relative to the interface. Full-held numerical calculations and experimental studies validate the analytical results. A stretch-based crack growth criterion is developed using crack-tip held solutions. Such criterion can predict the delay of crack growth through the bi-material interface observed in experiments and can be extended to any heterogeneity and material.


Adoptive transfer of gut intraepithelial lymphocytes protects against murine infection with Toxoplasma gondii.
Intraepithelial lymphocytes (IEL) of the gut represent a primary immune barrier against infection by orally acquired pathogens. Naturally acquired infection with Toxoplasma gondii induces the proliferation of CD8+ T cells in both the gut and spleen. Gut-derived CD8alpha/beta+ IEL exhibit MHC-restricted cytotoxicity against parasite-infected enterocytes and macrophages. In a murine model, we demonstrate that the adoptive transfer of IEL obtained from inbred mice at day 11 postinfection is able to protect against a virulent challenge in syngenic recipients. In CBA mice, the parasite cyst load within the brain of the recipients receiving primed IEL was reduced by 90%. In BALB/c and C57BL/6 mice, a 50% decrease in mortality was observed following adoptive transfer of primed IEL. To determine the T cell subset responsible for protective immunity, a purified CD8alpha/beta+ IEL population was isolated from infected mice at day 11 postinfection. These cells were able to protect naive mice by adoptive transfer against a lethal parasite challenge. RNA analysis by reverse-transcriptase PCR revealed that primed CD8alpha/beta+ IEL produce significant message for IFN-gamma, an essential cytokine for host protection against toxoplasmosis. Administration of anti-IFN-gamma at the time of adoptive transfer of primed IEL abrogated protection. The adoptive transfer of these protective IEL was not restricted to the Ld class I locus. These data demonstrate that IFN-gamma-producing IEL may be an important primary barrier against acute and perhaps recurrent infection with T. gondii.


Diffusion imaging of the human spinal cord and the vertebral column.
During the last decade, diffusion-weighted imaging (DWI) has matured from an experimental tool to a clinically useful modality that has not only significantly impacted the diagnosis of (acute) cerebral stroke but has also shown utility in other abnormalities of the brain. Although DWI should be equally sensitive to changes in the spine, it has been used far less frequently in this region of the body. This is mainly because of the inhomogeneous magnetic environment, the small size of the spinal cord, and increased motion in and around the spine. However, once these limitations are overcome, a whole range of applications can be envisioned. Already now, DWI promises to be able to differentiate between benign and malignant vertebral compression fractures. As in the brain, the immediate reduction of diffusivity following ischemic damage in the spinal cord may provide an early identification of patients with infarction. The study of diffusion anisotropy may open new avenues for the detection and better understanding of damage to the long fiber tracts with important clinical implications for disorders like multiple sclerosis and amyotrophic lateral sclerosis. It may also be possible to address, in a more refined manner, mechanisms of damage such as occur with spondylotic myelopathy. To lay the basis for future research in these areas, we will discuss the most appropriate DWI methods for the spine. Following an overview of the basic principles of DWI and associated pitfalls, the most commonly used imaging methods are addressed. Finally, experimental and clinical applications in the spinal cord and the vertebral column and their clinical relevance thus far are reviewed.


Silver nanoparticles induce apoptosis and G2/M arrest via PKCζ-dependent signaling in A549 lung cells.
The use of silver nanoparticles is one of the fastest growing product categories in the nanotechnology industry, with a focus on antimicrobial activity. However, thus far, toxicity data for silver nanoparticles are limited. In this study, we investigated the cytotoxic effects of silver nanoparticles (Ag NPs) and the pathway by which they affect A549 lung epithelial cells. The effects of Ag NPs on cell survival, cell cycle progression, and mRNA and protein alterations of selected cell cycle- and apoptosis-related genes were studied using formazan dye and LDH release assays, flow cytometric analysis, semi-quantitative RT-PCR, and Western blot analysis. Ag NPs reduced cell viability, increased LDH release, and modulated cell cycle distribution through the accumulation of cells at G2/M and sub-G1 phases (cell death), with a concurrent decrease in cells at G1. Ag NP treatment increased Bax and Bid mRNA levels and downregulated Bcl-2 and Bcl-w mRNAs in a dose-dependent manner. Furthermore, Ag NPs altered the mRNA levels of protein kinase C (PKC) family members. In particular, ectopic overexpression of PKCζ led to the enhancement of cellular proliferation and reduced sensitivity to Ag NPs in A549 cells. Together, these results suggest that Ag NPs induce strong toxicity and G2/M cell cycle arrest by a mechanism involving PKCζ downregulation in A549 cells.


Dendritic transmitter release: a comparison of two model systems.
Information flow through neurones was historically considered to be linear, with dendrites receiving information from incoming synaptic terminals, the soma processing the information and the axon carrying it to the terminal that synapses upon another cell or end organ. However, recent studies have shown that dendrites can release transmitters themselves, and thereby communicate with neighbouring structures, whether these are adjacent neurones or incoming synapses. Due to their anatomical features, the magnocellular vasopressin and oxytocin containing neurones of the hypothalamic supraoptic and paraventricular nuclei and the dopamine neurones of the substantia nigra have revealed important aspects of dendritic function including mechanisms of dendritic transmitter release.


A scanning electron-microscopic study of femoral bone surfaces from castrate rats treated with dichloromethylene biphosphonate.
This study compared SEM appearances of endosteal and periosteal surfaces of anorganic femoral diaphyses from three groups of adult male rats: (1) control; (2) castrate (osteoporotic), and (3) castrate + injections of dichloromethylene biphosphonate (Cl2 entrances; (2) area of vascular canal entrances; (3) number of osteoblast lacunae, and (4) percent area of bone surface types. Endosteal surfaces from untreated osteoporotic rats had significantly more osteoblast lacunae, larger vascular canal entrances, and less resting surface than those of the other groups. There were no differences in endosteal surfaces between controls and Cl2MBP-treated castrates. Periosteal surfaces demonstrated no significant differences in percent area of bone surface types between groups, untreated castrates had more osteoblast lacunae than other groups, and vascular canal entrances were smaller in castrate groups than in controls. Castrates treated with Cl2MBP had significantly fewer periosteal vascular canal entrances, and many canal entrances and osteoblast lacunae appeared to be plugged with mineral deposits when compared with the other groups. The results indicate that Cl2MBP treatment prevented endosteal bone surface changes that occurred with castration osteoporosis, and may have disrupted normal vascularization on periosteal surfaces.


Immunological segmentation of the rabbit distal, connecting, and collecting tubules.
To obtain monoclonal antibodies (MAB) specific for the different cell types of distal and collecting tubules, BALB/c mice were immunized with cell suspensions highly enriched in cells from the distal segments of the rabbit nephron. Nine MAB were selected and cloned. Four groups could be identified on the basis of double-labeling immunofluorescence (IF) on frozen kidney sections and on microdissected tubules. In addition, binding specificity at the cellular level was studied by immunoelectronmicroscopy (IEM) for selected MAB. A single MAB (group 1) was specific for distal bright cells and a subpopulation of cortical ascending limb cells. Six MAB (group 2) reacted with connecting and collecting tubules. Five of these (group 2A) had similar binding patterns and reacted identically with the two tubular segments. The MAB studied by IEM was specific for connecting and principal cells. One antibody (group 2B) reacted with only a fraction of the cells associated with the connecting tubule (CNT), but with all cells of the cortical collecting tubule (CCT). By IEM, this antibody was found to be specific for intercalated cells in CNT and bound both principal and intercalated cells of the CCT. Two MAB (group 3) reacted with antigen(s) expressed by the various terminal segments of renal tubule. MAB of groups 1 and 2A, which define distal bright cells and connecting-principal cells from the CNT-CCT, respectively, were used for cell fractionation experiments. Heterogeneous rabbit cortical cells were first incubated with the selected MAB. MAB-bearing renal cells were separated on plastic dishes previously coated with an affinity-purified goat anti-mouse immunoglobulin. Using these procedures it was possible to obtain highly purified subpopulations of distal, bright, or connecting-principal cells.


Interlaboratory comparison of olfactometry in Japan.
In 2000, 2001, and 2002, interlaboratory comparison of olfactometry was carried out in order to collect basic data for the establishment of a quality control procedure and the determination of quality criteria for the triangular odour bag method. In 2000, interlaboratory comparison was conducted by using a measurement method for samples taken at smoke stacks. On the other hand, the measurement method for samples taken at boundary lines was used for interlaboratory comparison in 2001. A total of seven olfactometry laboratories in Japan participated in each test, and mean values, repeatability standard deviations, reproducibility standard deviations, and standard deviations under intermediate conditions of detection threshold of ethyl acetate were calculated from the results. These values can be used in a quality control process of olfactometry. In 2002, interlaboratory comparison was carried out by using a measurement method for samples taken at smoke stacks. A total of 137 olfactometry laboratories in Japan participated in the test, and 69% of them lay within the permissible range of the odour index.


Direction-dependent activation of the insular cortex during vertical and horizontal hand movements.
The planning of any motor action requires a complex multisensory processing by the brain. Gravity - immutable on Earth - has been shown to be a key input to these mechanisms. Seminal fMRI studies performed during visual perception of falling objects and self-motion demonstrated that humans represent the action of gravity in parts of the cortical vestibular system; in particular, the insular cortex and the cerebellum. However, little is known as to whether a specific neural network is engaged when processing non-visual signals relevant to gravity. We asked participants to perform vertical and horizontal hand movements without visual control, while lying in a 3T-MRI scanner. We highlighted brain regions activated in the processing of vertical movements, for which the effects of gravity changed during execution. Precisely, the left insula was activated in vertical movements and not in horizontal movements. Moreover, the network identified by contrasting vertical and horizontal movements overlapped with neural correlates previously associated to the processing of simulated self-motion and visual perception of the vertical direction. Interestingly, we found that the insular cortex activity is direction-dependent which suggests that this brain region processes the effects of gravity on the moving limbs through non-visual signals.


Regulation of expression of microvillus membrane proteins by estrogen in baboon fetal ovarian oocytes.
We previously demonstrated that the number and height of oocyte microvilli were reduced in baboon fetuses deprived of estrogen in utero and restored to normal in animals supplemented with estradiol. Phosphorylated ezrin and Na+/H+ exchange regulatory factor 1 (NHERF, now termed SLC9A3R1) link f-actin bundles to the membrane, whereas alpha-actinin cross-links f-actin to form microvilli. Therefore, we determined whether these proteins were expressed in oocytes of the fetal baboon ovary and whether expression and/or localization were altered between mid and late gestation in association with an increase in estrogen and in late gestation in animals in which estrogen was suppressed (>95%) or restored by treatment with an aromatase inhibitor with or without estradiol. Expression of alpha-actinin was low at mid gestation, increased on the surface of oocytes of primordial follicles in late gestation, and was negligible in the ovaries of estrogen-suppressed fetuses and normal in animals treated with estrogen. Ezrin (total and phosphorylated) and SLC9A3R1 expression was localized to the surface of oocytes at mid and late gestation in estrogen-replete baboons and to the cytoplasm in late gestation after estrogen suppression. These results are the first to show that the fetal baboon oocyte expressed ezrin, SLC9A3R1, and alpha-actinin, and that these proteins were localized to the oocyte surface consistent with their role in microvilli development in epithelial cells. The current study also showed that the developmental increase in oocyte expression of alpha-actinin is regulated by estrogen and correlated with the estrogen-dependent increase in oocyte microvilli demonstrated previously. Therefore, we propose that development of oocyte microvilli requires expression of alpha-actinin and that expression of alpha-actinin and localization of ezrin-phosphate and SLC9A3R1 to the oocyte membrane are regulated by estrogen.


Combining intensive practice nurse counselling or brief general practitioner advice with varenicline for smoking cessation in primary care: study protocol of a pragmatic randomized controlled trial.
Combining behavioural support and pharmacotherapy is most effective for smoking cessation and recommended in clinical guidelines. Despite that smoking cessation assistance from the general practitioner can be effective, dissemination of clinical practice guidelines and efforts on upskilling has not lead to the routine provision of smoking cessation advice among general practitioners. Intensive counselling from the practice nurse could contribute to better smoking cessation rates in primary care. However, the effectiveness of intensive counselling from a practice nurse versus usual care from a general practitioner in combination with varenicline is still unknown. A pragmatic randomized controlled trial was conducted comparing: (a) intensive individual counselling delivered by a practice nurse and (b) brief advice delivered by a general practitioner; both groups received 12-weeks of open-label varenicline. A minimum of 272 adult daily smoking participants were recruited and treated in their routine primary care setting. The primary outcome was defined as prolonged abstinence from weeks 9 to 26, biochemically validated by exhaled carbon monoxide. Data was analysed blinded according to the intention-to-treat principle and participants with missing data on their smoking status at follow-up were counted as smokers. Secondary outcomes included: one-year prolonged abstinence, short-term incremental cost-effectiveness, medication adherence, and baseline predictors of successful smoking cessation. This trial is the first to provide scientific evidence on the effectiveness, cost-effectiveness, and potential mechanisms of action of intensive practice nurse counselling combined with varenicline under real-life conditions. This paper explains the methodology of the trial and discusses the pragmatic and/or explanatory design aspects. Dutch Trial Register NTR3067.


[Surgical Resection of Solitary Brain Metastasis from Breast Cancer].
Brain metastasis from breast cancer has a poor prognosis. For solitary cerebral metastases, surgical resection may contribute to the improvement of survival and QOL. We studied the prognosis and characteristics of solitary brain metastasis from breast cancer in patients undergoing surgical resection. Seventeen patients had tumors metastatic to the brain at Kasukabe Municipal Hospital between June 2009 and May 2016, and 7 of them underwent craniotomy. Their treatment outcomes were analyzed retrospectively. The median age at diagnosis of brain metastasis was 56 years. The median survival duration was 19.6 months. With regard to radiation therapy after surgery, 3 patients received whole brain irradiation, 2 patients received stereotactic brain irradiation, and 2 patients received both. The site of brain metastasis was the cerebellum in 6 patients, and the occipital lobe in 1 patient. The number of HER2-positive breast cancer patients was 5, and lapatinib and capecitabine were administered to 4 out of these 5 patients. For solitary brain metastasis, the improvement in symptoms and the extension of the survival can be achieved using multidisciplinary treatment with surgery, radiation, and molecular targeting drugs.


Lentiviral CRISPR/Cas9-Mediated Genome Editing for the Study of Hematopoietic Cells in Disease Models.
Manipulating genes in hematopoietic stem cells using conventional transgenesis approaches can be time-consuming, expensive, and challenging. Benefiting from advances in genome editing technology and lentivirus-mediated transgene delivery systems, an efficient and economical method is described here that establishes mice in which genes are manipulated specifically in hematopoietic stem cells. Lentiviruses are used to transduce Cas9-expressing lineage-negative bone marrow cells with a guide RNA (gRNA) targeting specific genes and a red fluorescence reporter gene (RFP), then these cells are transplanted into lethally-irradiated C57BL/6 mice. Mice transplanted with lentivirus expressing non-targeting gRNA are used as controls. Engraftment of transduced hematopoietic stem cells are evaluated by flow cytometric analysis of RFP-positive leukocytes of peripheral blood. Using this method, ~90% transduction of myeloid cells and ~70% of lymphoid cells at 4 weeks after transplantation can be achieved. Genomic DNA is isolated from RFP-positive blood cells, and portions of the targeted site DNA are amplified by PCR to validate the genome editing. This protocol provides a high-throughput evaluation of hematopoiesis-regulatory genes and can be extended to a variety of mouse disease models with hematopoietic cell involvement.


Facilitation of ganglionic response to bethanechol by repetitive stimulation of the preganglionic nerve.
Repetitive stimulation of the preganglionic nerve of the rat superior cervical sympathetic ganglion potentiates the amplitude of asynchronous firing elicited by the muscarinic agonist, bethanechol. The amplitude of stimulus-induced facilitation is not related to frequency of stimulation and occurs with a stimulation frequency of 10 Hz or greater. Facilitation, but not the asynchronous firing is reduced by lowering the temperature of the bathing solution. Dibutryl cyclic adenosine monophosphate and theophylline had no effect on asynchronous firing but reduced stimulus-induced facilitation. Neither dibutryl cyclic guanosine monophosphate up to 1 mM nor nitroprusside had any significant effect on bethanechol-induced asynchronous firing or stimulus-induced facilitation. Tetraethylammonium caused a 200% increase in stimulus-induced facilitation. Acetylcholine, in a concentration that elicited maximum nicotinic firing, had no effect on the magnitude of bethanechol-induced asynchronous firing. Increased Ca++, Mg++ or Mn++ reduced both asynchronous firing and stimulus-induced facilitation. It is concluded that facilitation is a result of transmitter release, possibly not acetylcholine.


Treatment of acute abdominal pain in the emergency room: a systematic review of the literature.
Appropriate pain therapy prior to diagnosis in patients with acute abdominal pain remains controversial. Several recent studies have demonstrated that pain therapy does not negatively influence either the diagnosis or subsequent treatment of these patients; however, current practice patterns continue to favour withholding pain medication prior to diagnosis and surgical treatment decision. A systematic review of PubMed, Web-of-Science and The-Cochrane-Library from 1929 to 2011 was carried out using the key words of 'acute', 'abdomen', 'pain', 'emergency' as well as different pain drugs in use, revealed 84 papers. The results of the literature review were incorporated into six sections to describe management of acute abdominal pain: (1) Physiology of Pain; (2) Common Aetiologies of Abdominal Pain; (3) Pre-diagnostic Analgesia; (4) Pain Therapy for Acute Abdominal Pain; (5) Analgesia for Acute Abdominal Pain in Special Patient Populations; and (6) Ethical and Medico-legal Considerations in Current Analgesia Practices. A comprehensive algorithm for analgesia for acute abdominal pain in the general adult population was developed. A review of the literature of common aetiologies and management of acute abdominal pain in the general adult population and special patient populations seen in the emergency room revealed that intravenous administration of paracetamol, dipyrone or piritramide are currently the analgesics of choice in this clinical setting. Combinations of non-opioids and opioids should be administered in patients with moderate, severe or extreme pain, adjusting the treatment on the basis of repeated pain assessment, which improves overall pain management.


Clinical features, treatments and prognosis of the initial cases of pandemic influenza H1N1 2009 virus infection in Shanghai China.
As of 13 December 2009, more than 208 countries and overseas territories or communities have reported laboratory-confirmed cases of pandemic influenza H1N1 2009, which have resulted in at least 10 582 deaths. As of 7 December 2009, 4328 severe cases were reported in Mainland China, resulting in 326 deaths. This study's objective was to determine the clinical features, treatments and prognosis of the initial cases of Pandemic influenza H1N1 2009 virus infection in Shanghai, China, and how its clinical features related to patient gender. A total of 224 confirmed 2009 influenza A/H1N1-infected patients treated and discharged by Shanghai Public Health Clinical center between 24 May and 20 July 2009 were included in the study. Patients' personal information, signs and symptoms, laboratory and imagery data, disease course, hospitalization period and seroconversion duration for viral nucleic acid after antiviral treatment were analyzed. Among the 224 patients, 118 were male and 106 were female, yielding a sex ratio of 1.1:1. Approximately 52% of the patients came from Australia, and 63.8% were between 18 and 40 years old. Clinical manifestations included fever, cough and congestion of the throat, and lab findings were characterized by elevated C-reaction protein (CRP) and neutrophils. Female patients had significantly lower serum Prealbumin (PA) levels than male patients (P < 0.05). The patients' serum CRF levels significantly decreased after treatment (P < 0.05), while the levels of CD3, CD4 and CD8 significantly increased after treatment (P < 0.01). Approximately 29.9% of the patients had abnormal signs on chest computer tomography scan, and 21.9% had obvious signs indicating pneumonia. However, blood cultures were negative in these patients. The average disease course was 3.9 +/- 1.4 days, the average hospitalization period was 5.0 +/- 1.7 days, and the seroconversion duration for viral nucleic acid after antiviral treatment was 3.8 +/- 1.3 days. Initial cases of pandemic influenza H1N1 2009 were characterized by fever, cough and throat congestion, with elevated CRP and neutrophils being the most significant lab findings. The pandemic influenza H1N1 2009 strain was able to affect multiple organs, including the hepatic synthesis of PA and immune functioning. The novel 2009 Influenza A/H1N1 virus was mild clinically, with a short disease course and good prognosis.


Role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in autophagy activation following subarachnoid hemorrhage.
Early brain injury (EBI) refers to a severe brain injury that occurs within hours to days after subarachnoid hemorrhage (SAH). Neuronal damage in EBI is considered a key factor leading to poor prognosis. Currently, our understanding of the mechanisms of neuronal damage, such as neuronal autophagy, is still incomplete. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in metabolism and plays an important role in autophagy. Based on this, this study will further explore the regulation of autophagy by GAPDH after SAH, which may provide a new treatment strategy for improving the prognosis of SAH patients. The rat SAH model was established by endovascular puncturing, and the trend of autophagy in hippocampal neurons at different time points was discussed. Additionally, an in vitro SAH model was created using the oxygenated hemoglobin and hippocampal neuronal HT22 cell line. Through siRNA and overexpression adenovirus techniques, we further investigated the relationship between the key enzyme GAPDH and autophagy in the in vitro SAH model. We observed significant neuronal damage in the hippocampus 24 h after SAH, and the proteomics showed significant enrichment of autophagy-related pathways at this time point. Further studies showed that the expression of LC3 and Beclin1 peaked at 24 h, and the nuclear translocation of GAPDH occurred simultaneously with SAH-induced neuronal autophagy. Our in vitro SAH model confirmed the role of GAPDH in regulating the level of autophagy in HT22 cells. Knockdown of GAPDH significantly reduced the level of autophagy, while overexpression of GAPDH increased the level of autophagy. This study shows the trend of autophagy in hippocampal neurons after SAH, and reveals the regulatory role of GAPDH in SAH-induced autophagy. However, further studies are needed to reveal the exact mechanism of GAPDH in the nuclear translocation regulation of autophagy and validate in animal models.


Proteogenomic Annotation of Chinese Hamsters Reveals Extensive Novel Translation Events and Endogenous Retroviral Elements.
A high-quality genome annotation greatly facilitates successful cell line engineering. Standard draft genome annotation pipelines are based largely on de novo gene prediction, homology, and RNA-Seq data. However, draft annotations can suffer from incorrect predictions of translated sequence, inaccurate splice isoforms, and missing genes. Here, we generated a draft annotation for the newly assembled Chinese hamster genome and used RNA-Seq, proteomics, and Ribo-Seq to experimentally annotate the genome. We identified 3529 new proteins compared to the hamster RefSeq protein annotation and 2256 novel translational events (e.g., alternative splices, mutations, and novel splices). Finally, we used this pipeline to identify the source of translated retroviruses contaminating recombinant products from Chinese hamster ovary (CHO) cell lines, including 119 type-C retroviruses, thus enabling future efforts to eliminate retroviruses to reduce the costs incurred with retroviral particle clearance. In summary, the improved annotation provides a more accurate resource for CHO cell line engineering, by facilitating the interpretation of omics data, defining of cellular pathways, and engineering of complex phenotypes.


Small molecule inhibition of microbial natural product biosynthesis-an emerging antibiotic strategy.
A variety of natural products modulate critical biological processes in the microorganisms that produce them. Thus, inhibition of the corresponding natural product biosynthesis pathways represents a promising avenue to develop novel antibiotics. In this tutorial review, we describe several recent examples of designed small molecule inhibitors of microbial natural product biosynthesis and their use in evaluating this emerging antibiotic strategy.


Presumed circle area ratio of the prostate in a community-based group of men.
OBJECTIVE To determine the normal values for the presumed circle area ratio (PCAR) in a group of community-based men, and to determine whether PCAR is associated with specific urological outcomes. PATIENTS AND METHODS The study was a cross-sectional analysis among 328 Caucasian men (94% participation) residing in Olmsted County, Minnesota, USA. The PCAR was measured during prostatic ultrasonography. Lower urinary tract symptoms (LUTS) were measured using the American Urologic Association Symptom Index. The peak urinary flow rate was measured by a uroflowmeter, and the postvoid residual volume (PVR) was assessed using the BladderScan(TM) BVM 6500 (Verathon, Bothell, WA, USA). Correlations between PCAR and presence of LUTS, peak urinary flow rate, and PVR were determined using Spearman correlation coefficients. Unadjusted and adjusted odds ratios (ORs) were calculated using logistic regression to determine the associations between PCAR thresholds and categorical urological outcomes. RESULTS The median (interquartile range) PCAR was 0.85 (0.81-0.88). After adjusting for age and total prostate volume, men who had PCARs of >0.90 were more likely to have elevated overall and obstructive symptom scores (OR 2.95, 95% confidence interval 1.39-6.25, and 3.47, 1.63-7.39, respectively). CONCLUSION PCAR might add further information beyond total prostate volume when predicting the development of obstructive LUTS.


Correlation of Serum M-CSF, CER, and TIMP-1 Levels with Liver Fibrosis in Viral Hepatitis.
This research is aimed at investigating the relationship between liver fibrosis in viral hepatitis and macrophage colony-stimulating factor (M-CSF), tissue inhibitor of matrix metalloproteinase (TIMP-1), and ceruloplasmin (CER) in serum level. Patients were randomly selected among those admitted to our hospital, and 60 healthy volunteers were chosen to serve as control participants. The levels of serum M-CSF, CER, and TIMP-1 were compared. According to the severity of their liver fibrosis, patients with CHB were separated into four groups: S1, S2, S3, and S4. Serum levels of M-CSF, CER, and TIMP-1 were correlated with liver fibrosis and hepatitis markers, and the diagnostic usefulness of the three indices was assessed with liver cirrhosis patients. Increases in M-CSF and TIMP-1 in the CHB group but decreases in CER were statistically significant (P < 0.05). Serum levels of M-CSF, CER, TIMP-1, HA, PC-III, C-IV, and LN differed significantly across the four study groups (P < 0.05). Over time, as liver fibrosis worsened, we observed a progressive uptick in M-CSF, TIMP-1, LN, HA, C-IV, and PC-III levels and a progressive downtick in CER levels, with significant (P < 0.05) differences between the groups. There was a significant positive correlation between liver fibrosis and serum M-CSF, PC-III, TIMP-1, HA, LN, and C-IV levels in the CHB group (P < 0.05) and a significant negative correlation between serum CER and these same factors (P < 0.05). The AUC of 0.956 for diagnosing the S4 stage was greater than that of 0.857, 0.851, and 0.817 for M-CSF, CER, and TIMP-1, respectively. In CHB patients, the liver fibrosis degree is associated with the M-CSF, CER, and TIMP-1 levels, and the combined clinical detection of these three markers has better diagnostic significance.


A Scoping Review of Rodent Studies Investigating the Epigenetic Mechanisms in the Brain Underlying the Effects of Diet on Depressive-like Behaviour.
A healthy diet has been highly associated with a decreased risk for mental health problems such as major depression. Evidence from human studies shows that diet can influence mood but there is a poor understanding of the molecular mechanisms behind these effects, especially the role of epigenetic alterations in the brain. Our objective was to use the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) format to gather all recent studies using animal models that investigate direct or indirect (on the offspring) effects of diet on depressive symptoms, including studies that assess epigenetic mechanisms in the brain. In this format, two authors conducted independent database searches of PubMed, Web of Science, and Academic search premier using one search block "diet epigenetics depression" to find papers published between 2000 and 2022. Relevant studies were selected using pre-defined inclusion/exclusion criteria that were performed independently by the two authors before a subset of studies were selected for qualitative analysis. A total of 11 studies met the inclusion criteria for this systematic scoping review. We found that the literature focuses primarily on the effects of individual nutrients, instead of a specific diet, on despair-like behaviour and anxiety. Studies are heterogenous with the techniques used to asses epigenetic changes in the brain and therefore making it hard to reach common mechanistic explanations. However, all studies report diet-induced changes in the epigenome mainly by the action of DNA methylation, histone acetylation and microRNAs that are parallelel with changes in behaviour. Moreover studies show that inadequate maternal diets can make the offspring more susceptible to develop anxiety and depressive-like behaviour later in life, which is paralleled with changes in the epigenome. Overall, this systematic review shows that there is some literature suggesting a role of brain epigenetics on the diet-induced protective or detrimental effects, specifically on anxiety and depressive-like behaviour. However, studies are limited, lacking the study of some types of diets, behavioural tasks or epigenetic mechanisms. Nevertherless, it shows the importance of genome-environment interactions, bringing new insights towards mechanisms that could be involved in the pathophysiology of mood disorders as well as putative therapeutic targets.


Health economic research on vaccinations and immunisation practices--an introductory primer.
The economic importance of vaccines lies partly in the burden of disease that can be avoided and partly in the competition for resources between vaccines and other interventions. Up to the 1980s only few economic evaluations had been carried out. Since then the confrontation of most countries with escalating health care costs and tighter budgets have awakened the interest in pharmacoeconomic analysis. Resources used to provide health care are vast but not limitless. When clinicians are asked to participate in decisions for large groups of patients (in a managed care context, in an institution, or at the level of local health authorities), the balance between consumption of resources and the benefits of an intervention is important. Clinicians may use cost-effectiveness and cost-benefit studies to inform such decisions (but not to make them). Because of differences in methods, the presentation of results, and country-specific parameters, economic evaluations of the same vaccination strategy by different groups may have divergent results. Vaccines differ from classical medicines in at least three ways: firstly, there is a longer tradition of economic evaluations for vaccines than for medicines. Some of the most earliest economic studies were carried out in the field of vaccines in the public health arena. Secondly, comparatively fewer central decision makers need to be convinced as compared to drugs. The reason for this being a more centralised process of recommending vaccines and vaccination policies. Thirdly, externalities are more relevant in the field of vaccines. Such externalities may be positive or negative. Positive externalities are present in the case where herd immunity prevents the spread of the disease in the community. We are now undoubtedly in an era of assessment and accountability for all new technologies in healthcare. However, sufficient economic data are still lacking to support the formulation of health policy and a particular challenge for the future is to conduct further health economic research on immunisation. Specific areas for such study include: effectiveness under field conditions (i.e., not under the conditions of a randomised controlled trial); the real value of economic production losses; the conditions for implementing novel immunization programmes; cost estimates for more ambitious immunization programmes; the economic benefits of combination vaccines. From this research, it will be important to disseminate the data and to adapt the findings to other countries. Nevertheless, the source of funding for research and its application in clinical trials programmes represent some of the practical problems faced by medical economics today within academia and the industry.


Splanchnic ischaemia and multiple organ failure in the critically ill.
The development of a safe and simple tonometric method of monitoring the adequacy of gastrointestinal mucosal perfusion has provided a new perspective of splanchnic ischaemia in the critically ill. It would appear that splanchnic hypoxia, identified by the presence of intramucosal acidosis in the gut, may be one of the most consistent and earliest indications of impaired tissue perfusion in the critically ill and be causally related to the development of sepsis and multiple organ failure.


Safety and efficacy of weight training soon after acute myocardial infarction.
To determine if weight training used during cardiac rehabilitation as soon as 4 weeks after myocardial infarction (MI) is safe, and if weight training combined with aerobic exercise improves aerobic fitness and muscle strength more than aerobic exercise alone. Twenty-three men within 6 weeks of an acute MI and without exercise-induced ischemia, complex arrhythmias, anterior Q wave MI, or ejection fraction < 40% were randomly assigned to combined weight and cycle training versus cycle training for 10 weeks. The main measures were change in maximal oxygen uptake (VO2max), muscle strength, resting left ventricular (LV) wall segment motion and early diastolic filling by resting echocardiograms, exercise ECG, heart rate, and blood pressure responses [corrected]. VO2max increased 14% (P < 0.01) and cycle time increased 10% (P < 0.01) in the combined training group. The 8% increases in VO2max (P = 0.15) and cycle time (P = 0.08) in the cycling group were not significant. Arm and leg strength increased (P < 0.01) in each group. However, the change was greater for the combined training group--31% versus 16% (P < 0.03) for leg strength and 20% versus 10% (P < 0.001) for arm strength. There were no changes for either group in resting hemodynamics, body weight and composition, LV wall segment motion, LV fractional shortening, and early diastolic function, and no adverse clinical events or exercise-related complications. Combined training soon after MI improved aerobic and muscle fitness more than cycling alone, and was performed without complication.


[Motor evacuatory function of the stomach and the absorptive capacity of the intestines in patients with extensive suppurative wounds receiving tube feeding].
Radionuclide gastroscopy conducted in patients with vast purulent wounds and sepsis disclosed reduced motor-evacuatory function of the stomach and the rate of its fractional emptying, that supports the necessity of continuous administration of nutrient mixtures by a drip method. A significant improvement of the motor evacuatory function and the rate of fractionated emptying of the stomach, 9-12 days after the commencement of the enteral (tube) nutrition, has shown the necessity of its use at the early stages of the course of severe purulent infection. The investigation of the absorptive capacity of the intestine with the use of the D-xylose test has revealed that it is insignificantly decreased in 82.6% of patients with severe purulent infection, and tube nutrition in such patients could be successfully conducted. Only in 17.4% of the patients the adsorptive capacity of the intestine was significantly decreased, and in these cases predominantly parenteral nutrition was recommended.


Food chain model based on field data to predict westslope cutthroat trout (Oncorhynchus clarkii lewisi) ovary selenium concentrations from water selenium concentrations in the Elk Valley, British Columbia.
Previous studies conducted in the Elk River watershed showed that selenium concentrations are higher in aquatic biota in lentic compared to lotic habitats of the system having similar water selenium concentrations. Studies have also shown that water selenium concentrations have increased over time (~10% per year) and recent annual average concentrations have ranged up to 0.044 mg/L in areas downstream from mine discharges. For the present study, trophic transfer of selenium was characterized in lotic versus lentic habitats using concentrations measured in field-collected samples and assuming a three-step food chain of water to the base of the food web (biofilm), to benthic invertebrates, and then to westslope cutthroat trout (WCT) ovaries. Food chain models were developed for each habitat type (lotic and lentic) by combining linear regression equations for the three transfer relationships, allowing for prediction of fish ovary concentrations from water concentrations. Greater accumulation of selenium in lentic areas was mostly attributable to greater uptake at the base of the food chain compared to lotic areas. Enrichment/trophic transfer factors for selenium at all levels of the lotic and lentic food chains decreased and then became near constant as exposure concentrations increased. The lotic model predicted little increase in WCT ovary selenium concentrations over an eightfold increase in water concentrations (~0.005-0.040 mg/L), accounting for the lack of observed increase in within-area fish tissue concentrations over time despite increasing trends in water concentrations.


Controlled evaluation of the volume of blood cultured in detection of bacteremia and fungemia.
To evaluate the role of the volume of blood cultured in the detection of clinically important bacteremia and fungemia in adults, we evaluated the yield and speed of detection of microorganisms from 5,317 paired 2- and 5-ml samples of blood. The same kind of medium (supplemented peptone broth with 0.03% sodium polyanetholsulfonate) and atmosphere of incubation (open venting units) were used for all blood cultures. Only adequately filled (less than or equal to 80% of stated volume) sets (20-ml tube and 50-ml bottle) were compared statistically. Significantly more bacteria (p less than 0.01), Pseudomonas spp. In particular (P less than 0.05), were isolated from the 5-ml samples of blood. We conclude that the volume of blood cultured is a critical factor in the detection of septicemia. Consequently, valid evaluation of other factors influencing the detection of septicemia must be based on comparisons in which equal volumes of blood are cultured.


Spinal efference copy signaling and gaze stabilization during locomotion in juvenile Xenopus frogs.
In swimming Xenopus laevis tadpoles, gaze stabilization is achieved by efference copies of spinal locomotory CPG output that produce rhythmic extraocular motor activity appropriate for minimizing motion-derived visual disturbances. During metamorphosis, Xenopus switches its locomotory mechanism from larval tail-based undulatory movements to bilaterally synchronous hindlimb kick propulsion in the adult. The change in locomotory mode leads to body motion dynamics that no longer require conjugate left-right eye rotations for effective retinal image stabilization. Using in vivo kinematic analyses, in vitro electrophysiological recordings and specific CNS lesions, we have investigated spino-extraocular motor coupling in the juvenile frog and the underlying neural pathways to understand how gaze control processes are altered in accordance with the animal's change in body plan and locomotor strategy. Recordings of extraocular and limb motor nerves during spontaneous "fictive" swimming in isolated CNS preparations revealed that there is indeed a corresponding change in spinal efference copy control of extraocular motor output. In contrast to fictive larval swimming where alternating bursts occur in bilateral antagonistic horizontal extraocular nerves, during adult fictive limb-kicking, these motor nerves are synchronously active in accordance with the production of convergent eye movements during the linear head accelerations resulting from forward propulsion. Correspondingly, the neural pathways mediating spino-extraocular coupling have switched from contralateral to strictly ipsilateral ascending influences that ensure a coactivation of bilateral extraocular motoneurons with synchronous left-right limb extensions. Thus, adaptive developmental plasticity during metamorphosis enables spinal CPG-driven extraocular motor activity to match the changing requirements for eye movement control during self-motion.


ChemPix: automated recognition of hand-drawn hydrocarbon structures using deep learning.
Inputting molecules into chemistry software, such as quantum chemistry packages, currently requires domain expertise, expensive software and/or cumbersome procedures. Leveraging recent breakthroughs in machine learning, we develop ChemPix: an offline, hand-drawn hydrocarbon structure recognition tool designed to remove these barriers. A neural image captioning approach consisting of a convolutional neural network (CNN) encoder and a long short-term memory (LSTM) decoder learned a mapping from photographs of hand-drawn hydrocarbon structures to machine-readable SMILES representations. We generated a large auxiliary training dataset, based on RDKit molecular images, by combining image augmentation, image degradation and background addition. Additionally, a small dataset of ∼600 hand-drawn hydrocarbon chemical structures was crowd-sourced using a phone web application. These datasets were used to train the image-to-SMILES neural network with the goal of maximizing the hand-drawn hydrocarbon recognition accuracy. By forming a committee of the trained neural networks where each network casts one vote for the predicted molecule, we achieved a nearly 10 percentage point improvement of the molecule recognition accuracy and were able to assign a confidence value for the prediction based on the number of agreeing votes. The ensemble model achieved an accuracy of 76% on hand-drawn hydrocarbons, increasing to 86% if the top 3 predictions were considered.


Dual-mode infrared laser-excited synergistic effect in NaGdF4:Er3+ nano-glass ceramics: a kinetic model.
Realization of the absorption and conversion of wide band infrared light have been a challenge in the field of upconversion luminescence. Herein, a facile physical approach is reported to realize the cooperative absorption and conversion of dual-band infrared light by NaGdF4:Er3+ nano-glass ceramics by employing a dual-mode excitation source (980 nm + 1545 nm). A synergistic effect of infrared photons induced by dual-wavelength infrared excitation is observed. The dual-mode excited red emission intensity is 2.76 times the total red emission intensities from 980 nm and 1545 nm single excitation. This upconversion synergistic effect can be modulated by adjusting the single excitation power, and it is proved to originate from ground and excited state absorption, in which the Er3+ ions in metastable states excited by 980 nm (or 1545 nm) photons are excited again by the 1545 nm (or 980 nm) infrared photons. A rate equation model is established to simulate the dynamic process in the dual-mode infrared upconversion process. The synergistic effect provides us with a way to convert two low-energy infrared photons into middle-energy visible photons to enhance the upconversion efficiency of rare earth ion doped glass ceramics.


[Dr. Sackett & "Mr. Sacketeer"... Enchantment and disenchantment in the land of expertise in evidence-based medicine].
In May 2000, Prof. David L. Sackett, one of the founders of the evidence-based medicine movement (EBM), published an article in the British Medical Journal in which he renounced writing, teaching, or serving as a referee for topics related to EBM. He justified his stance based on his frustration over what he considered the harmful effects of an alleged excess of experts in this field. Sackett's position was the raw material whereby we approached aspects linked to the definition and scope of EBM as well as related critiques. We also stress the movement's various rhetorical strategies. In addition, we discuss both the notion of expertise and the role of "expert systems" and "specialized competence" in our societal milieu, developed respectively by Anthony Giddens and Zygmunt Bauman. The main focus of this commentary is to emphasize that while we are dealing with a progressive trend towards acquiring control and intelligibility vis-à-vis the objects of our research, we must consider the possibility of dimensions that cannot be reached by way of the rationalistic Western mode of thought.


Molecular characterization of Escherichia coli strains that cause symptomatic and asymptomatic urinary tract infections.
The differences between Escherichia coli strains associated with symptomatic and asymptomatic urinary tract infections (UTIs) remain to be properly determined. Here we examined the prevalence of plasmid types and bacteriocins, as well as genetic relatedness, in a defined collection of E. coli strains that cause UTIs. Comparative analysis identified a subgroup of strains with a high number of virulence genes (VGs) and microcins M/H47. We also identified associations between microcin genes, VGs, and specific plasmid types.


Positron emission tomography using [(18)F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy.
To determine whether [(18)F]-fluorodeoxy-D-glucose ([(18)F]-FDG) positron emission tomography (PET) can predict the pathologic response of primary and metastatic breast cancer to chemotherapy. Thirty patients with noninflammatory, large (> 3 cm), or locally advanced breast cancers received eight doses of primary chemotherapy. Dynamic PET imaging was performed immediately before the first, second, and fifth doses and after the last dose of treatment. Primary tumors and involved axillary lymph nodes were identified, and the [(18)F]-FDG uptake values were calculated (expressed as semiquantitative dose uptake ratio [DUR] and influx constant [K]). Pathologic response was determined after chemotherapy by evaluation of surgical resection specimens. Thirty-one primary breast lesions were identified. The mean pretreatment DUR values of the eight lesions that achieved a complete microscopic pathologic response were significantly (P =.037) higher than those from less responsive lesions. The mean reduction in DUR after the first pulse of chemotherapy was significantly greater in lesions that achieved a partial (P =.013), complete macroscopic (P =.003), or complete microscopic (P =.001) pathologic response. PET after a single pulse of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph node metastases. Mean pretreatment DUR values in the metastatic lesions that responded did not differ significantly from those that failed to respond (P =.076). However, mean pretreatment K values were significantly higher in ultimately responsive cancers (P =.037). The mean change in DUR and K after the first pulse of chemotherapy was significantly greater in responding lesions (DUR, P =.038; K, P =.012). [(18)F]-FDG PET imaging of primary and metastatic breast cancer after a single pulse of chemotherapy may be of value in the prediction of pathologic treatment response.


[Studies on rapid multi-residue analysis of pesticides in agricultural products by LC-MS/MS].
Rapid multi-residue analysis of pesticides in agricultural products was studied by using LC-MS/MS. Pesticide residues in 10 g of homogenized agricultural products were extracted with 30 mL of acetonitrile and salted out with 4 g of anhydrous magnesium sulfate and 1 g of sodium chloride in the presence of citrate salts for buffering in a disposable tube. Co-extractives were removed by use of our original triple layered column (C18/GC/PSA; 60/30/60 mg). According to the method validation guideline of the Ministry of Health, Labour and Welfare of Japan, we conducted recovery tests in 5 kinds of agricultural products (brown rice, kiwi, cabbage, sweet potato and spinach) spiked with 60 pesticides at the level of 0.01 or 0.1 μg/g. Each concentration of pesticide spiked was extracted from 2 samples per day on 5 days. Pesticides in the test solution were determined by two types of LC-MS/MS using scheduled MRM. Using this method, 58 out of 60 pesticides satisfied the guideline criteria in brown rice, 59 in kiwi, 55 in cabbage, 55 in sweet potato and 56 in spinach. This method is applicable for routine examination of pesticide residues in agricultural products.


Platelet activating factor does not release histamine from human dispersed cutaneous mast cells.
Histamine H1-antagonists inhibit the weal-and-flare responses to the intradermal injection of platelet activating factor (PAF) in humans, and PAF response is reduced in histamine-depleted skin sites. This indicates that mast cell histamine release is likely to be the mechanism of this response. We have therefore studied the interaction of PAF with cutaneous mast cells by observing whether it releases histamine directly from human dispersed foreskin mast cells, potentiates the activity of known mast cell stimulants or liberates histamine releasing factors (HRFs) from human platelets and leucocytes to release mast cell histamine by an indirect mechanism. At a concentration of 100 microM both PAF C18 and PAF C16 caused near maximal release (83.5 +/- 4.3% and 88.2 +/- 4.5% respectively) of the total histamine content of the cell. This release was not inhibited in the absence of extracellular Ca2+, by the lack of metabolic energy or in the presence of the PAF antagonists WEB 2086 (100 nM-3 microM) or BN 52021 (100 nM-10 microM). These results indicate a cytotoxic mechanism of histamine release by PAF 100 microM. PAF (10 nM-1 microM) failed to potentiate the mast cell-stimulating activity of anti-IgE, calcium ionophore A23187 or substance P and it did not induce the release of HRFs for skin mast cells when incubated with platelets and leucocytes in concentrations up to 1 microM.


Glomerular filtration rate-estimating equations for patients with advanced chronic kidney disease.
Renal function is often estimated using one of several glomerular filtration rate (GFR) estimating equations. However, there is no consensus which estimating equation performs best in patients with advanced renal failure. We compared the performance of five different estimated GFR (eGFR) equations [Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease (CKD) Epidemiology collaboration (CKD-EPI) and Mayo Clinic and Lund-Malmö] with measured GFR (plasma iohexol clearance) in 2098 referred CKD patients with mGFR <30 mL/min/1.73 m(2). There were 398 patients with an mGFR ≤ 10 mL/min/1.73 m(2), 1974 with a measured GFR (mGFR) 11-20 mL/min/1.73 m(2) and 749 patients with mGFR 21-30 mL/min/1.73 m(2). Across the entire range, the median bias of eGFR was lowest for the Lund-Malmö equation (0.7 mL/min/1.73 m(2)), followed by the CKD-EPI (1.2 mL/min/1.73 m(2)), the MDRD (1.6 mL/min/1.73 m(2)), Mayo Clinic equation (1.7 mL/min/1.73 m(2)) and Cockcroft-Gault equation (4.6 mL/min/1.73 m(2)). The best accuracy within 30% of mGFR was also for Lund-Malmö (76%), while it was similar for CKD-EPI, MDRD and Mayo (65-67%). The Cockcroft-Gault had the worst accuracy of only ∼54%.The median bias was stable across mGFR categories, while the accuracy within 30% of mGFR became worse with decreasing mGFR. All equations performed best among patients with hereditary kidney diseases and tubulointerstitial disease. Accuracy was generally worse for patients >65 years of age and for those with diabetic nephropathy. In patients with advanced renal failure, the GFR-estimating equations show reasonably good performance on the population level. On the individual patient level, they are inaccurate, especially in elderly patients and those with diabetic nephropathy.


Microbiome in the hair follicle of androgenetic alopecia patients.
Androgenetic alopecia is the most common form of hair loss in males. It is a multifactorial condition involving genetic predisposition and hormonal changes. The role of microflora during hair loss remains to be understood. We therefore analyzed the microbiome of hair follicles from hair loss patients and the healthy. Hair follicles were extracted from occipital and vertex region of hair loss patients and healthy volunteers and further dissected into middle and lower compartments. The microbiome was then characterized by 16S rRNA sequencing. Distinct microbial population were found in the middle and lower compartment of hair follicles. Middle hair compartment was predominated by Burkholderia spp. and less diverse; while higher bacterial diversity was observed in the lower hair portion. Occipital and vertex hair follicles did not show significant differences. In hair loss patients, miniaturized vertex hair houses elevated Propionibacterium acnes in the middle and lower compartments while non-miniaturized hair of other regions were comparable to the healthy. Increased abundance of P. acnes in miniaturized hair follicles could be associated to elevated immune response gene expression in the hair follicle.


Management of chronic hepatitis B in children: an unresolved issue.
Although a rather benign course of chronic hepatitis B virus (HBV) infection during childhood has been described, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9-24% and the incidence of cirrhosis to 2-3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer-reviewed journals from January 1980 to February 2013. The search terms used included "Hepatitis B virus infection," "children," "HBV," "interferon," "lamivudine," "adefovir," "entecavir," and "tenofovir." Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune-tolerant phase or in the inactive carrier state. For children in the immune-active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies.


Repeated courses of antenatal corticosteroids have adverse effects on aspects of brain development in naturally delivered baboon infants.
Repeated courses of antenatal steroids in women at risk of preterm delivery have beneficial effects on lung maturation, but concern exists about the effects on brain development. We aimed to determine whether repeated courses of corticosteroids increased the risk of neuropathology as compared with single courses or no treatment. Single-course animals received a 6-mg dose of steroids at 123 and 124 d of gestation (dg; term, 185 dg; n = 6). Repeated-course animals received additional doses at 137 and 138 dg (n = 7). Controls received no steroids (n = 5). Baboons delivered naturally at term and necropsy was performed. Brains were assessed histologically for parameters of development and neuropathology. Body weights did not differ between the groups (P > 0.05); neither did brain/body weight ratio. Density of glial fibrillary acidic protein (GFAP)-immunoreactive (IR) astrocytes in white matter (WM) was increased in the single- (P < 0.05) and repeated-course (P < 0.01) groups as compared with controls. Density of myelin basic protein (MBP)-IR oligodendrocytes was reduced in the repeated-course animals as compared with both the control and single-course groups (P < 0.05); oligodendrocyte transcription factor 2 (Olig2)-IR showed no difference between groups. Repeated courses of antenatal corticosteroids have effects on myelination in the developing nonhuman primate brain, which should be taken into account when determining a dosing regimen.


Mapping whole brain connectivity changes: The potential impact of different surgical resection approaches for temporal lobe epilepsy.
In neurosurgery there are several situations that require transgression of the temporal cortex. For example, a subset of patients with temporal lobe epilepsy require surgical resection (most typically, en-bloc anterior temporal lobectomy). This procedure is the gold standard to alleviate seizures but is associated with chronic cognitive deficits. In recent years there have been multiple attempts to find the optimum balance between minimising the size of resection in order to preserve cognitive function, while still ensuring seizure freedom. Some attempts involve reducing the distance that the resection stretches back from the temporal pole, whilst others try to preserve one or more of the temporal gyri. More recent advanced surgical techniques (selective amygdalo-hippocamptectomies) try to remove the least amount of tissue by going under (sub-temporal), over (trans-Sylvian) or through the temporal lobe (middle-temporal), which have been related to better cognitive outcomes. Previous comparisons of these surgical techniques focus on comparing seizure freedom or behaviour post-surgery, however there have been no systematic studies showing the effect of surgery on white matter connectivity. The main aim of this study, therefore, was to perform systematic 'pseudo-neurosurgery' based on existing resection methods on healthy neuroimaging data and measuring the effect on long-range connectivity. We use anatomical connectivity maps (ACM) to determine long-range disconnection, which is complementary to existing measures of local integrity such as fractional anisotropy or mean diffusivity. ACMs were generated for each diffusion scan in order to compare whole-brain connectivity with an 'ideal resection', nine anterior temporal lobectomy and three selective approaches. For en-bloc resections, as distance from the temporal pole increased, reduction in connectivity was evident within the arcuate fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and the uncinate fasciculus. Increasing the height of resections dorsally reduced connectivity within the uncinate fasciculus. Sub-temporal amygdalohippocampectomy resections were associated with connectivity patterns most similar to the 'ideal' baseline resection, compared to trans-Sylvian and middle-temporal approaches. In conclusion, we showed the utility of ACM in assessing long-range disconnections/disruptions during temporal lobe resections, where we identified the sub-temporal resection as the least disruptive to long-range connectivity which may explain its better cognitive outcome. These results have a direct impact on understanding the amount and/or type of cognitive deficit post-surgery, which may not be obtainable using local measures of white matter integrity.


Time series of EIT chest images using singular value decomposition and Fourier transform.
The aim of this study is to propose a useful method for exploring regional ventilation and perfusion in the chest. The paper describes two methods based on singular value decomposition (SVD) and Fourier transform (FT) respectively. This work shows that power spectral density (PSD) and phase images (derived from the Fourier transform) are easier to interpret and more useful tools for exploiting in vivo EIT data in healthy volunteers in order to explore the cardiovascular and respiratory systems.


Recovery of metabolic acidosis in term infants with postasphyxial hypoxic-ischemic encephalopathy.
To describe the base deficit (BD) values and the rate of postnatal recovery of the BD of infants with hypoxic ischemic encephalopathy due to intrapartum asphyxia; and to explore the relationships between the rate of recovery of BD, severe adverse outcome and different time patterns (acute total vs prolonged partial) of asphyxia. Clinical and laboratory data were collected from the neonatal period (n = 244) and outcome data to a minimal age of 1 y (n = 218). Rates of recovery of BD were described in four 60 min blocks of time. The values of rate of recovery were compared between the outcome groups, ignoring correlation structure within subjects and with adjustment by the generalized estimating equations method. The BD normalized within 4 h of birth in all but 9 of 244 infants. The rates of recovery of BD in infants with good and severe adverse outcome respectively were 0.11 [95% confidence interval (95% CI) 0.07, 0.14] and 0.09 (95% CI 0.07, 0.12) mmol l(-1) min(-1) over the first 4 h after birth. The rates of recovery were similar with or without buffer therapy, and after acute near-total and prolonged partial asphyxia. The BD in the great majority of infants with severe intrapartum asphyxia normalizes within 4 h of birth. The BD recovery rate of infants with adverse outcomes was similar to those with relatively good outcome. The different time patterns of asphyxial episode were not associated with differential recovery profiles.


Central airway stabilization for tracheobronchomalacia improves quality of life in patients with COPD.
Tracheobronchomalacia (TBM) is characterized by excessive collapsibility of the central airways, typically during expiration. TBM may be present in as many as 50% of patients evaluated for COPD. The impact of central airway stabilization on symptom pattern and quality of life is poorly understood in this patient population. Patients with documented COPD were identified from a cohort of 238 patients assessed for TBM at our complex airway referral center. Pulmonary function testing, exercise tolerance, and health-related quality-of-life (HRQOL) measures were assessed at baseline and 2 to 4 weeks following tracheal stent placement/operative tracheobronchoplasty (TBP). Severity of COPD was classified according to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) staging system. One hundred three patients (48 women) with COPD and moderately severe to severe TBM were identified. Statistically and clinically significant improvements were seen in HRQOL measures, including the transitional dyspnea index (stent, P = .001; TBP, P = .008), the St. George Respiratory Questionnaire (stent, P = .002; TBP, P < .0001), and the Karnofsky performance score (stent, P = .163; TBP, P < .0001). The improvement appeared greatest following TBP and was seen in all GOLD stages. Clinical improvement was also seen in measured FEV(1) and exercise capacity as assessed by 6-min walk test. Central airway stabilization may provide symptomatic benefit for patients with severe COPD and concomitant severe airway malacia. Operative airway stabilization appears to impart the greatest advantage. Long-term follow-up study is needed to fully ascertain the ultimate efficacy of both stenting and surgical airway stabilization in this patient group.


The role of humoral factors in the mechanisms of graft-versus-host induced host cell proliferation and lymph node hyperplasia in the rat.
The effect of humoral factors released during systemic graft-versus-host (GVH) reactions on cell proliferation and lymph node enlargement was investigated as follows: 1) Thoracic duct lymphocytes of host origin were cultured in diffusion chambers in the peritoneal cavity of rats undergoing a systemic GVH reaction. On day 7 of the response chamber cell proliferation (as judged by 3H thymidine incorporation) was increased two to four fold over that seen in normal hosts. 2) Serum from (H0 x DA) F1 hybrid rats being repeatedly injected with parental (HO) cells contained a factor that, when preincubated with such parental cells in vitro, was able to augment their ability to produce lymph node enlargement in a local GVH reaction. These results suggest that the host cell proliferation and lymphoid hyperplasia observed during GVH reactions might be the results of long range humoral mechanisms acting alone or in addition to the direct interaction between donor and host cells.


Post-replication repair: Rad5/HLTF regulation, activity on undamaged templates, and relationship to cancer.
The eukaryotic post-replication repair (PRR) pathway allows completion of DNA replication when replication forks encounter lesions on the DNA template and are mediated by post-translational ubiquitination of the DNA sliding clamp proliferating cell nuclear antigen (PCNA). Monoubiquitinated PCNA recruits translesion synthesis (TLS) polymerases to replicate past DNA lesions in an error-prone manner while addition of K63-linked polyubiquitin chains signals for error-free template switching to the sister chromatid. Central to both branches is the E3 ubiquitin ligase and DNA helicase Rad5/helicase-like transcription factor (HLTF). Mutations in PRR pathway components lead to genomic rearrangements, cancer predisposition, and cancer progression. Recent studies have challenged the notion that the PRR pathway is involved only in DNA lesion tolerance and have shed new light on its roles in cancer progression. Molecular details of Rad5/HLTF recruitment and function at replication forks have emerged. Mounting evidence indicates that PRR is required during lesion-less replication stress, leading to TLS polymerase activity on undamaged templates. Analysis of PRR mutation status in human cancers and PRR function in cancer models indicates that down regulation of PRR activity is a viable strategy to inhibit cancer cell growth and reduce chemoresistance. Here, we review these findings, discuss how they change our views of current PRR models, and look forward to targeting the PRR pathway in the clinic.


Vertex algebras, Kac-Moody algebras, and the Monster.
It is known that the adjoint representation of any Kac-Moody algebra A can be identified with a subquotient of a certain Fock space representation constructed from the root lattice of A. I define a product on the whole of the Fock space that restricts to the Lie algebra product on this subquotient. This product (together with a infinite number of other products) is constructed using a generalization of vertex operators. I also construct an integral form for the universal enveloping algebra of any Kac-Moody algebra that can be used to define Kac-Moody groups over finite fields, some new irreducible integrable representations, and a sort of affinization of any Kac-Moody algebra. The "Moonshine" representation of the Monster constructed by Frenkel and others also has products like the ones constructed for Kac-Moody algebras, one of which extends the Griess product on the 196884-dimensional piece to the whole representation.


Propulsion mechanisms for Leidenfrost solids on ratchets.
We propose a model for the propulsion of Leidenfrost solids on ratchets based on viscous drag due to the flow of evaporating vapor. The model assumes pressure-driven flow described by the Navier-Stokes equations and is mainly studied in lubrication approximation. A scaling expression is derived for the dependence of the propulsive force on geometric parameters of the ratchet surface and properties of the sublimating solid. We show that the model results as well as the scaling law compare favorably with experiments and are able to reproduce the experimentally observed scaling with the size of the solid.


Quantification of collagen and elastic fibers using whole-slide images of liver biopsy specimens.
Histological evaluation of fibrosis after a liver biopsy is crucial for evaluating the pathology of patients with chronic liver disease. Previous studies have reported quantitative analyses of fibrosis using images of collagen-stained sections. However, analysis of these studies requires manual selection of the region of interest. In addition, the quantification of elastic fibers is not considered. The present study was conducted in order to measure both the collagen and elastic fiber area ratios using Elastica van Gieson-stained whole-slide images (WSIs) of liver biopsy specimens. High-resolution WSIs provide precise color classification, enabling accurate detection of even fine collagen and elastic fibers. To minimize the influence of pre-existing fibrous tissue, median area ratios of the collagen and elastic fibers were independently calculated from the image tiles of the WSIs. These median area ratios were highly concordant with area ratios after the pre-existing fibrous tissues were manually trimmed from the WSI. Further, these median area ratios were correlated with liver stiffness as measured by transient elastography (collagen: r = 0.73 [P < 0.01], elastic: r = 0.53 [P < 0.01]). Our approach to quantifying liver fibrosis will serve as an effective tool to evaluate liver diseases in routine practice.


First evidence of sphingosine 1-phosphate lyase protein expression and activity downregulation in human neoplasm: implication for resistance to therapeutics in prostate cancer.
This is the first report of sphingosine 1-phosphate lyase (SPL) protein expression and enzymatic activity in human neoplasm. This enzyme drives irreversible degradation of sphingosine 1-phosphate (S1P), a bioactive lipid associated with resistance to therapeutics in various cancers, including prostate adenocarcinoma. In fresh human prostatectomy specimens, a remarkable decrease in SPL enzymatic activity was found in tumor samples, as compared with normal adjacent tissues. A significant relationship between loss of SPL expression and higher Gleason score was confirmed in tissue microarray (TMA) analysis. Moreover, SPL protein expression and activity were inversely correlated with those of sphingosine kinase-1 (SphK1), the enzyme producing S1P. SPL and SphK1 expressions were independently predictive of aggressive cancer on TMA, supporting the relevance of S1P in prostate cancer. In human C4-2B and PC-3 cell lines, silencing SPL enhanced survival after irradiation or chemotherapy by decreasing expression of proteins involved in sensing and repairing DNA damage or apoptosis, respectively. In contrast, enforced expression of SPL sensitized cancer cells to irradiation or docetaxel by tilting the ceramide/S1P balance toward cell death. Interestingly, the S1P degradation products failed to sensitize to chemo- and radiotherapy, supporting the crucial role of ceramide/S1P balance in cancer. Of note, the combination of SPL enforced expression with a SphK1 silencing strategy by further decreasing S1P content made prostate cancer cells even more sensitive to anticancer therapies, suggesting that a dual strategy aimed at stimulating SPL, and inhibiting SphK1 could represent a future approach to sensitize cancer cells to cancer treatments.