Lipolytic effect of novel extracts from mulberry (Morus alba) leaves fermented with Cordyceps militaris in the primary adipocytes derived from SD rats.
Mulberry (Morus alba) leaves are known to have therapeutic effects on lipid metabolism including lipogenesis, lipolysis and hyperlipidemia. However, novel compounds with strong lipolytic ability among 27 extracts of the mulberry leaves fermented with Cordyceps militaris (EMfCs) have not yet been identified. Therefore, the cAMP concentration and cell viability were measured in the primary adipocytes of SD (Sprague Dawley) rats and 3T3-L1 cells after treatment of 27 EMfCs. Briefly, mulberry leaves powders amended with three different concentrations (0, 25 and 50%) of silkworm pupae (SWP) powder were fermented with 10% C. militaris (v/w) during three different periods (3, 4 and 6 weeks). A total of 27 extracts were obtained from the fermented mulberry leaves powders using three different solvents (dH2O, 50% EtOH and 95% EtOH). Among the 27 EMfCs treated groups, a significant increase in the concentration of cAMP was detected in primary adipocytes treated with 10 extracts when compared with the Vehicle treated group. However, their cAMP concentration did not agree completely with the non-toxicity, although most extracts showed non-toxicity. Furthermore, the concentration of cAMP and level of free glycerol gradually increased in a dose dependent manner (100, 200 and 400 µg/mL) of 4M3-95 contained cordycepin without any significant toxicity. Overall, the results of this study provide strong evidence that 4M3-95 extract derived from EMfCs can stimulate the lipolysis of primary adipocytes at an appropriate concentration and therefore have the potential for use as lipolytic agents to treat obesity.


Effect of Basicity on the Microstructure of Sinter and Its Application Based on Deep Learning.
The influence of the evolution rule of basicity (0.6∼2.4) on the mineral composition and microstructure of sinter is studied by using a polarizing microscope, and the comprehensive application analysis of the drum index, vertical sintering speed, and yield of sinter shows that, over the course of an increase in basicity (0.6∼1.0), the mineral structure changed from the original porphyritic-granular structure to a porphyritic structure. At the same time, there was no calcium ferrite phase in the bonding phase at a basicity of less than 1.0; therefore, the downward trend of the three indicators is obvious. When the basicity was further increased to approximately 1.6, the main structure of the mineral phase changed from a corrosion structure to an interweaving corrosion structure. Because of the existence of a porphyritic-granular structure, the structure of the mineral phase was extremely inhomogeneous and most complex near the basicity of 1.6; although a small amount of calcium ferrite displayed an acicular structure, the drum index appeared to show a very low value. With an increase in basicity to 2.0, the mineral phase structure was dominated by an interweaving corrosion structure with a uniform framework, and the content of calcium ferrite reached the highest value. Moreover, a clear acicular structure developed, and the drum index also increased to the highest value. At a basicity of more than 2.0, a mineral structure began to appear and the corrosion, porphyritic-granular structure, and the drum index also showed a slightly declining trend. Therefore, in the actual production process, basicity should be avoided as far as possible at around 1.0 and 1.6 and it should be controlled at around 2.0. At the same time, based on the mineral facies data set of this paper, the convolutional neural network is used to carry out a simple prediction model experiment on the basicity corresponding to the mineral facies photos, and the effect is quite good, which provides a new idea and method for the follow-up study of mineral facies.


Physical Therapists and Physicians Evaluate Nonarthritic Hip Disease Differently: Results From a National Survey.
Physical therapy and surgery are viable treatment options for nonarthritic hip disease (NAHD). Interdisciplinary collaboration can help patients make informed treatment decisions. Understanding how each provider can contribute is a critical first step in developing collaborative evaluation efforts. The objective of this study was to describe the current evaluation of NAHD by both physical therapists and physicians, and evaluate national use of expert-recommended evaluation guidelines. A national survey study distributed in the United States was implemented to accomplish the objective. A survey was distributed to 25,027 potential physical therapist and physician respondents. Respondents detailed their evaluation content for patients with NAHD across the following domains: patient-reported outcomes, patient history, special tests, movement assessment, clinical tests, and imaging. Respondents ranked importance of each domain using a 5-point Likert scale (not important, slightly important, important, very important, or extremely important). Odds ratios (ORs [95% CIs]) were calculated to identify the odds that physical therapists, compared with physicians, would report each evaluation domain as at least very important. Fisher exact tests were performed to identify statistically significant ORs. Nine hundred and fourteen participants (3.6%) completed the survey. Physical therapists were more likely to indicate movement assessment (OR: 4.23 [2.99-6.02]) and patient-reported outcomes (OR: 2.56 [1.67-3.99]) as at least very important for determining a diagnosis and plan of care. Physical therapists had lower odds of rating imaging (OR: 0.09 [0.06-0.14]) and special tests (OR: 0.72 [0.53-0.98]) as at least very important compared with physicians. This survey study did not include many orthopedic surgeons and thus, primarily represents evaluation practices of physical therapists and nonsurgical physicians. Physical therapists were more likely to consider movement assessment very important for the evaluation of patients with NAHD, whereas physicians were more likely to consider imaging and special testing very important.


Endovascular Recanalization of Symptomatic Intracranial Arterial Stenosis Despite Aggressive Medical Management.
The optimal management of intracranial arterial stenosis is unclear, particularly in patients who have failed medical management. We report a multicenter real-world experience of endovascular recanalization of intracranial atherosclerotic stenosis refractory to aggressive medical therapy. Retrospective multicenter case series of consecutive endovascularly treated patients presenting with symptomatic (transient ischemic attack [TIA] or stroke) intracranial stenosis who had failed medical therapy. Patients were divided into 2 groups: patients with recurrent TIA or stroke despite medical management (group 1) versus patients presenting with a stroke and worsening symptoms (progressive or crescendo stroke) despite medical management (group 2). A total of 101 patients were treated in 8 stroke centers from August 2009 to May 2017. Sixty-nine presented with recurrent TIA or stroke and 32 with stroke and worsening symptoms. Successful recanalization was achieved in 84% of patients. Periprocedural stroke occurred in 3 patients and 2 had a recurrent ischemic stroke at the 90-day follow-up. Symptomatic intraparenchymal hemorrhage secondary to reperfusion injury occurred in 3 patients and 1 had a hemorrhagic stroke after discharge. There were 2 periprocedural perforations that resulted in death. At 90 days, 86% of patients (64/74) did not have a recurrence of stroke and the 90-day cumulative ischemic stroke rate was 6.7% with 90-day mortality of 11.2%. The 90-day favorable outcome (modified Rankin Scale score, ≤2) rate was 77.5%. Endovascular recanalization of unstable intracranial atherosclerotic stenosis in patients who have failed medical therapy is feasible. Future randomized trials need to determine if recanalization is of any value for this population.


Enantiomers of Single Chirality Nanotube as Chiral Recognition Interface for Enhanced Electrochemical Chiral Analysis.
Although separation of single-walled carbon nanotubes (SWCNTs) according to their helicity and handedness has been attracting tremendous interest recently, exploration of the left- and right-handed SWCNT enantiomers (defined as "M" and "P") to chiral sensing still remains in the early stage. Here we presented a new electrochemical sensor for chiral discrimination, which for the first time amplified the chiral selection on the electrode surface based on the left- or right-handed semiconducting SWCNT enantiomers with (6,5)-enriched chirality. The enantioselectivity was demonstrated by different peak current response to analyte enantiomers, observed in differential pulse voltammogram (DPV). Chiral distinguishing might be a result of the formation of an efficient chiral nanospace originating from the high purity of single enantiomer of (6,5) SWCNT. The obtained chiral electrodes were also applied to determine the enantiomeric excess (ee) of DOPA. There was a good linear relationship between DPV peak currents and % ee of l-DOPA. This study is the first example showing how the structure of chiral SWCNTs influences electrochemical chiral recognition.


[Bad aftertaste caused by pine nuts].
Dysgeusia caused by the consumption of pine nuts is not widely reported in the medical literature, although much is written about this condition on the Internet. We present the case of a 46-year-old male who complained of metallic and bitter dysgeusia that started 2 days after the ingestion of approximately 70 grams of pine nuts. A literature search revealed only 3 case reports on this subject. In all cases including ours, the complaints began a few days after the ingestion of pine nuts and had spontaneously resolved after a week. No medical sequelae are known, but patients may suffer social consequences. The cause of this condition is unknown. Possible causes include the presence of toxic or inedible components in the pine nuts. Physicians should be aware of this phenomenon in order to be able to reassure patients about this benign disorder.


Two antigenically related neuronal cell adhesion molecules of different specificities mediate neuron-neuron and neuron-glia adhesion.
Previous studies in this laboratory have led to the identification of the neural cell adhesion molecule, N-CAM, a homophilic ligand that mediates adhesion between neurons as well as between neurons and striated muscle precursors. By means of a similar immunological approach but with different assays, we have now identified a cell adhesion molecule on neurons (Ng-CAM) that mediates the heterotypic adhesion between neuronal membranes and glial cells. In this paper, we compare certain aspects of the structure and function of Ng-CAM and embryonic N-CAM from the chicken. Ng-CAM was localized by specific antibodies on neurons but not on glia, and double-staining methods showed that individual neurons contained both Ng-CAM and N-CAM. Embryonic Ng-CAM migrates primarily as a single component of Mr 135,000; its apparent Mr shifted to 127,000 after neuraminidase treatment. In contrast, the embryonic form of N-CAM migrates on NaDodSO4/polyacrylamide gels in the apparent Mr range of 200,000-250,000; after neuraminidase treatment, N-CAM migrates as two components of Mr 170,000 and Mr 140,000. Although both Ng-CAM and N-CAM have calcium-independent binding mechanisms, immunologically based cell adhesion assays suggested that they have different specificities in mediating cell adhesion. Whereas 0.25 micrograms of Ng-CAM partially neutralized the ability of 0.5 mg of polyspecific antineural Fab' fragments to inhibit the heterotypic binding of neuronal membrane vesicles to glial cells and larger amounts of Ng-CAM completely neutralized this inhibition, 20 micrograms of N-CAM had no neutralization activity in this assay. Reciprocally, 0.25 micrograms of N-CAM partially neutralized the ability of 0.5 mg of the same Fab' fragments to inhibit the direct homotypic aggregation of neuronal cells, but 20 micrograms of Ng-CAM had no detectable activity. Although peptide maps of the two cell adhesion molecules differed considerably and despite the differences in binding specificity of these molecules, two independently derived monoclonal antibodies were found to crossreact with both Ng-CAM and N-CAM. Therefore, these different neuronal cell adhesion molecules with distinct binding specificities share at least one antigenic determinant, raising the possibility that they arose from a common evolutionary precursor.


Blue-green eggshell coloration is not a sexually selected signal of female quality in an open-nesting polygynous passerine.
It has been proposed that blue-green egg colours have evolved as a post-mating signal of female quality, selected by males allocating their parental effort in response to the strength of this signal. We tested two main assumptions of the sexually selected egg coloration hypothesis: (1) whether the intensity of eggshell blue-green chroma (BGC) reflects female quality; and (2) whether males make their decisions on the level of parental care that they provide according to the intensity of eggshell BGC. As a model species, we chose the facultatively polygynous great reed warbler (Acrocephalus arundinaceus). In this species, females simultaneously paired with the same male, compete for his nest attendance and could benefit from signalling their quality through egg coloration. However, we found no association between the variation in eggshell BGC and the measures of female quality (physical condition, mean egg volume and age). Moreover, great reed warbler males did not adjust their investment (as measured in terms of nest defence against a brood parasite) in relation to the eggshell BGC. We conclude that blue-green egg coloration in this open-nesting passerine is unlikely to have a signalling function. Rather, the large colour variation among clutches of individual females may depend on yearly fluctuations in environmental conditions.


An AND-Gated Drug and Photoactivatable Cre-loxP System for Spatiotemporal Control in Cell-Based Therapeutics.
While engineered chimeric antigen receptor (CAR) T cells have shown promise in detecting and eradicating cancer cells within patients, it remains difficult to identify a set of truly cancer-specific CAR-targeting cell surface antigens to prevent potentially fatal on-target off-tumor toxicity against other healthy tissues within the body. To help address this issue, we present a novel tamoxifen-gated photoactivatable split-Cre recombinase optogenetic system, called TamPA-Cre, that features high spatiotemporal control to limit CAR T cell activity to the tumor site. We created and optimized a novel genetic AND gate switch by integrating the features of tamoxifen-dependent nuclear localization and blue-light-inducible heterodimerization of Magnet protein domains (nMag, pMag) into split Cre recombinase. By fusing the cytosol-localizing mutant estrogen receptor ligand binding domain (ERT2) to the N-terminal half of split Cre(2-59aa)-nMag, the TamPA-Cre protein ERT2-CreN-nMag is physically separated from its nuclear-localized binding partner, NLS-pMag-CreC(60-343aa). Without tamoxifen to drive nuclear localization of ERT2-CreN-nMag, the typically high background of the photoactivation system was significantly suppressed. Upon blue light stimulation following tamoxifen treatment, the TamPA-Cre system exhibits sensitivity to low intensity, short durations of blue light exposure to induce robust Cre-loxP recombination efficiency. We finally demonstrate that this TamPA-Cre system can be applied to specifically control localized CAR expression and subsequently T cell activation. As such, we posit that CAR T cell activity can be confined to a solid tumor site by applying an external stimulus, with high precision of control in both space and time, such as light.


Radiological ageing process in the cervical spine of Nigerian women.
The study was designed to determine the age of commencement of ageing process in Nigerian women Four hundred (400) consecutive women requesting for cervical spine radiographs where recruited for this study. A study chart was made showing different variables like osteoarthrosis, detached osteophytes, postural ulterations and disk degenerations in a four year period from 1st January, 1993 to 31st December, 1996 the modified Kellgren and Lawrence grading system was used to assess radiographic changes. The highest rate of osteoarthrosis (31.13%) was found in the fifth decade. Incidence of postural alterations of the cervical spine rose sharply in the 5th and 6th decades of life. Grade 2 osteoarthrosis (Kellgren and Lawrence) was commonest (61.3%); Grades 3 and 4 had the lowest incidence (3.45%). Disc degeneration was commonest in the 5th; the most involved disc was C5/C6 and the least involved was C2/C3. It is concluded that the ageing process in the Nigerian women commences in the fourth decade of life, and apparently shows no difference with caucasian women.


Membrane-bound ribosomes of myeloma cells. I. Preparation of free and membrane-bound ribosomal fractions. Assessment of the methods and properties of the ribosomes.
A cell fractionation procedure is described which allowed, by use of MOPC 21 (P3K) mouse plasmocytoma cells in culture, the separation of the cytoplasmic free and membrane-bound ribosomes in fractions devoid of mutual cross-contamination, and in which the polyribosomal structure was entirely preserved. This was achieved by sedimentation on a discontinuous sucrose density gradient in which the two ribosome populations migrate in opposite directions. A variety of controls (electron microscopy, labeling of membrane lipids, further repurification of the isolated fractions) provided no evidence of cross-contamination of these populations. However, when an excess of free 60S or 40S subunits, labeled with a different isotope, was added to the cytoplasmic extract before fractionation, the possibility of a small amount of trapping and/or adsorption of free ribosomal particles by the membrane fraction was detected, especially in the case of the 60S subunits; this could be entirely prevented by the use of sucrose gradients containing 0.15 M KC1. EDTA treatment of the membrane fraction detached almost all the 40S subunits, and about 70% of the 60S subunits. 0.5 M KC1 detached only 10% of the ribosomal particles, which consist of the native 60S subunits and the monoribosomes, i.e. the bound particles inactive in protein synthesis. Analysis in CsC1 buoyant density gradients of the free and membrane-bound polyribosomes and of their derived 60S and 40S ribosomal subunits showed that the free and membrane-bound ribosomal particles have similar densities.


Microbubble enhanced ozonation process for advanced treatment of wastewater produced in acrylic fiber manufacturing industry.
This work investigated microbubble-ozonation for the treatment of a refractory wet-spun acrylic fiber wastewater in comparison to macrobubble-ozonation. CODcr, NH3-N, and UV254 of the wastewater were removed by 42%, 21%, and 42%, respectively in the microbubble-ozonation, being 25%, 9%, and 35% higher than the removal rates achieved by macrobubble-ozonation at the same ozone dose. The microbubbles (with average diameter of 45μm) had a high concentration of 3.9×10(5) counts/mL at a gas flow rate of 0.5L/min. The gas holdup, total ozone mass-transfer coefficient, and average ozone utilization efficiency in the microbubble-ozonation were 6.6, 2.2, and 1.5 times higher than those of the macrobubble-ozonation. Greater generation of hydroxyl radicals and a higher zeta potential of the bubbles were also observed in the microbubble ozonation process. The biodegradability of the wastewater was also significantly improved by microbubble-ozonation, which was ascribed to the enhanced degradation of alkanes, aromatic compounds, and the many other bio-refractory organic compounds in the wastewater. Microbubble-ozonation can thus be a more effective treatment process than traditional macrobubble-ozonation for refractory wastewater produced by the acrylic fiber manufacturing industry.


Pubertal development, spare time activities, and adolescent delinquency: testing the contextual amplification hypothesis.
Extensive evidence supports associations between early pubertal timing and adolescent externalizing behavior, but how and under which conditions they are linked is not fully understood. In addition, pubertal development is also characterized by variations in the relative speed at which individuals mature, but studies linking pubertal 'tempo' and outcomes are scarce. This study examined the mediating and moderating roles of spare time activities in associations between pubertal development and later delinquency, using data from a large (4,327 girls, 4,250 boys) longitudinal UK cohort (Avon Longitudinal Study of Parents and Children). Self-reports of Tanner stage were available from ages 9 to 14, spare time activities at age 12 and delinquency at age 15. Pubertal development was examined using latent growth models. Spare time activities were categorized using factor analyses, yielding four types (hanging out at home, hanging out outside, consumerist behavior, and sports/games), which were examined as mediators and moderators. Earlier and faster maturation predicted delinquency in boys and girls. Spare time activities partially mediated these links such that early maturing girls more often engaged in hanging out outside, which placed them at greater risk for delinquency. In addition, compared to their later and slower maturing counterparts, boys who matured earlier and faster were less likely to engage in sports/games, a spare time activity type that is linked to lower delinquency risk. No moderation effects were found. The findings extend previous research on outcomes of early maturation and show how spare time activities act as proxies between pubertal development and delinquency.


Stem cell therapy for retinal disease.
Stem cell therapy holds great promise for the treatment of retinal diseases. This review summarizes recent advances in stem cell biology, outlines ongoing clinical trials and details the obstacles that must be overcome for stem cell therapy to be a viable treatment for retinal disease. Stem cells can now be directed to specific retinal cell fates with high yields and acceptable purity for clinical trials. New stem cell sources have been discovered including induced pluripotent stem cells that can be derived from adult tissues then differentiated into multiple retinal cell types. The initial results of clinical trials of subretinal transplantation of human embryonic stem cell-derived retinal pigment epithelium cells in patients with Stargardt's macular dystrophy and dry age-related macular degeneration showed preliminary safety and possible visual acuity benefits. A phase I trial of intravitreally injected autologous bone marrow-derived mononuclear cells for hereditary retinal dystrophy demonstrated no evidence of toxicity with possible visual acuity benefits but no structural or functional changes. Ongoing trials are examining the trophic effects of undifferentiated umbilical cells for the treatment of geographic atrophy in age-related macular degeneration. Stem cell therapy is a promising treatment under active investigation in multiple retinal diseases. Ongoing clinical trials should yield further insights into the potential for stem cell-based retinal therapies.


Natural uterine Mycoplasma pulmonis infection in female rats.
Uterine washings from 124 apparently healthy and non-pregnant female Wistar rats of different ages were cultured for mycoplasmas and bacteria. The animals originated from four conventional breeding colonies which were known to be chronically infected with M. pulmonis from the previous microbiological examination. Mycoplasmas were isolated from the uterus in 30.6% of examined females. All the isolates were biochemically and seriologically identified as M. pulmonis. Uterine colonization with this organism was first evidenced in non-mated female rats at the age of three months. After mating the number of infected females rapidly increased. This observation points out the microbiologically uncontrolled mating as an important factor in the distribution of genital infection within the colony. Bacterial examination of uterine washings revealed only ubiquitous organisms in some animals. Gross lesions in the form of purulent salpingitis and mild endometritis were observed only in two animals.


Green microalgae in marine coastal waters: The Ocean Sampling Day (OSD) dataset.
The ecology and distribution of green phytoplankton (Chlorophyta) in the ocean is poorly known because most studies have focused on groups with large cell size such as diatoms or dinoflagellates that are easily recognized by traditional techniques such as microscopy. The Ocean Sampling Day (OSD) project sampled surface waters quasi-simultaneously at 141 marine locations, mostly in coastal waters. The analysis of the 18S V4 region OSD metabarcoding dataset reveals that Chlorophyta are ubiquitous and can be locally dominant in coastal waters. Chlorophyta represented 29% of the global photosynthetic reads (Dinoflagellates excluded) and their contribution was especially high at oligotrophic stations (up to 94%) and along the European Atlantic coast. Mamiellophyceae dominated most coastal stations. At some coastal stations, they were replaced by Chlorodendrophyceae, Ulvophyceae, Trebouxiophyceae or Chlorophyceae as the dominating group, while oligotrophic stations were dominated either by Chloropicophyceae or the uncultured prasinophytes clade IX. Several Chlorophyta classes showed preferences in terms of nitrate concentration, distance to the coast, temperature and salinity. For example, Chlorophyceae preferred cold and low salinity coastal waters, and prasinophytes clade IX warm, high salinity, oligotrophic oceanic waters.


Evaluation of bridging institution and housing--a joint consumer-care provider initiative.
1. The most common alternative housing choice in the community for individuals with serious mental illness was a boarding home. 2. Community consumers noted that being with other people was the most important benefit of the teaching apartment, followed by eating, learning new skills, and entertainment. 3. Although they reported negative aspects about the homes, most consumers did not want to change anything about their boarding home.


Evaluation of a hybrid artificial liver module with liver lobule-like structure in rats with liver failure.
We studied the recovery of rats with fulminant hepatic failure (FHF) by treating them with our original hybrid artificial liver support system (HALSS). We developed an original artificial liver module having a liver lobule-like structure (LLS). This module consists of many hollow fibers regularly arranged in close proximity and hepatocyte aggregates (organoids) induced into the extra capillary space of the module by centrifugal force. The LLS module can express some liver specific functions at high levels and maintain them for several months in vitro. In this study, we evaluated the efficacy of our LLS-HALSS by using rats with FHF induced by a method that combined partial hepatectomy with hepatic ischemia. In the animal experiments, blood ammonia levels rapidly increased in the control group (sham-HALSS group). These rats died during or immediately after application of the sham-HALLS. On the other hand, in the LLS module application group (LLS-control group), the increase in blood ammonia was completely suppressed and all rats recovered. Blood constituents at 4 weeks after application were at normal levels, and the weight of the liver was the same as that of a normal rat. These results indicate that HALSS may be useful for treating liver failure patients until liver transplantation can be performed or until regeneration of the native liver occurs.


Patterns of pigment accumulation in Plasmodium falciparum trophozoites in peripheral blood samples.
Ninety-five samples of peripheral blood from patients with Plasmodium falciparum malaria in southwest Saudi Arabia were examined by Giemsa staining and darkfield microscopy under flow condition. Eighty-four samples contained trophozoites (ring forms) only and 11 samples contained gametocytes and trophozoites. Two patterns of pigmentation were observed in the trophozoite-containing samples: 48 (57%) contained trophozoites in which no pigment could be detected, 32 (38%) contained trophozoites with clearly detectable pigment, and 4 (5%) contained both pigmented and nonpigmented forms. Trophozoite pigmentation did not correlate with percent parasitemia or age or sex of the patients. These results indicate that microscopically observable pigment accumulation in trophozoites of P. falciparum is not required during the asexual multiplication cycle. Pigment accumulation may be triggered later in infection, perhaps as a feature of the differentiation process leading to the formation of gametocytes.


Nonenzymatic glycosylation of basement membranes: in vitro studies.
Incubation of purified rat glomerular basement membrane (GBM) with [14C]-glucose in vitro resulted in the incorporation of [14C] into acid-precipitable radioactivity in a reaction that was time and temperature dependent. Findings with rat lens capsule basement membrane (LCBM), an anatomically distinct but chemically similar extracellular matrix, incubated for varying times at different temperatures with [14C]-glucose at constant specific activity were similar. Nonenzymatic glycosylation of basement membrane, documented by hydroxymethylfurfuraldehyde generation after incubation with unlabeled glucose, increased in proportion to the ambient glucose concentration over a range of 5--100 mM. Acid-precipitable radioactivity also increased in proportion to [14C]-glucose concentration, although this method overestimated glycosylation about 15-fold at 5--20 mM glucose and 50-fold at 50--100 mM glucose. Coupled with recent in vivo studies, these findings indicate that exposure to increased glucose concentration alters the chemistry of glomerular and other basement membranes. Since accumulation of basement membrane characterizes several of the microangiopathic sequelae of diabetes, the role of increased nonenzymatic glycosylation on the structure, function, and metabolism of basement membrane warrants investigation.


A three-dimensional mathematical and computational model of necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is a severe disease that affects the gastrointestinal (GI) tract of premature infants. Different areas of NEC research have often been isolated from one another and progress on the role of the inflammatory response in NEC, on the dynamics of epithelial layer healing, and on the positive effects of breast feeding have not been synthesized to produce a more integrated understanding of the pathogenesis of NEC. We seek to synthesize these areas of research by creating a mathematical model that incorporates the current knowledge on these aspects. Unlike previous models that are based on ordinary differential equations, our mathematical model takes into account not only transient effects but also spatial effects. A system of nonlinear transient partial differential equations is solved numerically using cell-centered finite differences and an explicit Euler method. The model is used to track the evolution of a prescribed initial injured area in the intestinal wall. It is able to produce pathophysiologically realistic results; decreasing the initial severity of the injury in the system and introducing breast feeding to the system both lead to healthier overall simulations, and only a small fraction of epithelial injuries lead to full-blown NEC. In addition, in the model, changing the initial shape of the injured area can significantly alter the overall outcome of a simulation. This finding suggests that taking into account spatial effects may be important in assessing the outcome for a given NEC patient. This model can provide a platform with which to test competing hypotheses regarding pathological mechanisms of inflammation in NEC, suggest experimental approaches by which to clarify pathogenic drivers of NEC, and may be used to derive potential intervention strategies.


[Colorectal Crohn's disease: indications to surgical treatment].
Colorectal Crohns Disease (CRCD) represents the 25% of all cases of Crohns Disease (CD). Between January 1984 and December 2000 we have operated 68 patients with CRCD, that represent 10.3% of the patients operated for CD. Thirtythree patients (48.5%) were men and 35 (51.5%) were women. The median age at diagnosis was 37.3 +/- 13.1 years, with the highest incidence during the fourth decade. In most cases the disease involved the left colon and rectum (65.9%), while in 6.3% and in 3.8% of cases the right and the transverse colon respectively. In the 27.9% of cases the entire colon was involved. At the time of surgery, the disease behaviour was stenosing in 30.9% of patients, inflammatory in 22.1%, and penetrating in 47% of cases with the presence of fistulae (coloenteric in 6 patients, colo-bladder in 2 cases, rectouretral in 1 case, colo-cutaneous in 4 cases and intramesenteric in 2 cases) and abscesses (23.5% of patients). In three patients the CRCD had led to neoplastic transformation. Fourteen patients had undergone an emergency surgical procedure for severe acute colitis, 2 for toxic megacolon, 1 for an intraabdominal abscess and one for intestinal occlusion. In the segmentary forms we have always practiced a resection of the diseased colonic segment without total colectomy. In the cases with diffuse colonic involvement in which the rectum was free from disease a total colectomy with ileorectal anastomosis was performed. In the cases with rectal disease (26 cases) the sphinteric function was preserved with low rectal resection or with colo-anal anastomosis. In 4 patients with rectal disease and in 4 cases with fistulae, we complited the intervention with a permanent stoma. During the median follow-up of 83.7 months (12-207) the surgical relapse was of 27.3%. We suggest to treat CRCD with resections limited to the diseased segment. Moreover, it is possible to preserve the sphinteric function every time the rectum or the anal canal are normal, without postoperative complications or early relapses.


The Value of the Prostate Health Index and Derived Indexes in the Diagnosis of Prostate Cancer with PI-RADS-3 Lesions.
The purpose of this article was to evaluate the diagnostic value of prostate health index (PHI) and its derivatives in prostate cancer (PCa) with prostate imaging reporting and data system (PI-RADS)-3 lesions. Patients with benign prostatic hyperplasia (BPH) (n = 155) were included in the BPH group, while all patients with PCa (n = 49) were enrolled in the PCa group. Between the groups, the serum concentrations of total prostate-specific antigen (TPSA), percent-free prostate-specific antigen (%fPSA), prostate health index (PHI), prostate health index density (PHID), and prostate-specific antigen density (PSAD) were compared. On average, 49 (24%) of 204 men had PCa on biopsy, with 81.63% of those cases being clinically serious. Age, prostate volume, TPSA, and PSAD did not significantly differ between the PCa group and the BPH group. In contrast, [-2]pro prostate-specific antigen (p2PSA) (17.10 ± 4.77 vs. 13.93 ± 3.22, p < 0.001), PHI (33.88 ± 8.81 vs. 25.83 ± 5.63, p < 0.001), and PHID (0.52 ± 0.15 vs. 0.38 ± 0.11, p < 0.001) showed a statistically significant difference between the two groups. Compared to conventional PSA, PHI (AUC = 0.786, 95% CI: 0.705-0.867) and PHID (AUC = 0.763, 95% CI: 0.684-0.843) were considerably better predictors of all PCa. The TPSA, %fPSA, p2PSA, PHI, PHID, and PSAD areas under the receiver operating characteristic for clinically significant PCa (csPCa) were 0.587, 0.650, 0.696, 0.823, 0.796, and 0.614, respectively. Out of all the various parameters, PHI and PHID performed very well in this cohort's biopsy outcome prediction. PHI offers the best diagnostic value for detecting PCa in cases of PI-RADS-3 lesions. Additionally, PHID raised the possibility of csPCa PI-RADS-3 lesions. However, more investigation is required to confirm our results by using multicenter collaboration.


Experimental validation of dose calculation algorithms for the GliaSite RTS, a novel 125I liquid-filled balloon brachytherapy applicator.
This paper compares experimentally measured and calculated dose-rate distributions for a novel 125I liquid-filled brachytherapy balloon applicator (the GliaSite RTS), designed for the treatment of malignant brain-tumor resection-cavity margins. This work is intended to comply with the American Association of Physicists in Medicine (AAPM) Radiation Therapy Committee's recommendations [Med. Phys. 25, 2269-2270 (1998)] for dosimetric characterization of low-energy photon interstitial brachytherapy sources. Absolute low dose-rate radiochromic film (RCF) dosimetry measurements were performed in coronal planes about the applicator. The applicator was placed in a solid water phantom, machined to conform to the inflated applicator's surface. The results were used to validate the accuracy of Monte Carlo photon transport (MCPT) simulations and a point-source dose-kernel algorithm in predicting dose to water. The absolute activity of the 125I solution was determined by intercomparing a National Institute of Standards and Technology (NIST) 125I standard with a known mass of radiotherapy solution (Iotrex) in an identical vial and geometry. For the two films not in contact with applicator, the average agreement between RCF and MCPT (specified as the mean absolute deviation in successive 4 mm rings) was found to be within +/-5% at distances 0.2-25 mm from the film centers. For the two films touching the catheter, the mean agreement was +/-14.5% and 7.5% near the balloon surface but improving to 7.5% and 6% by 3.5 mm from the surface. These errors, as large as 20% in isolated pixels, are likely due to trim damage, 125I contamination, and poor conformance with the balloon. At larger distances where the radiation doses were very low, the observed discrepancies were significantly larger than expected. We hypothesize that they are due to a dose-rate dependence of the RCF response. A 1%-10% average difference between a simple one-dimensional path-length semiempirical dose-kernel model and the MCPT calculations was observed over clinically relevant distances.


Pelvic Venous Disorders (PeVD).
Pelvic venous disorders (PeVDs) have replaced the concept of pelvic congestion syndrome encompassing venous origin chronic pelvic pain (VO-CPP) in women. The evaluation of women with VO-CPP includes the assessment for other causes of pelvic pain as well as imaging evaluation for pelvic varicosities measuring greater than 5 mm diameter, ovarian vein diameter, and flow direction, as well as iliac vein diameter and signs of compression. Proper identification of these patients can lead to high degrees of success eliminating chronic pelvic pain following ovarian vein embolization and/or iliac vein stenting. Strong encouragement is provided to use the symptoms, varices, pathophysiology classification for these patients and upcoming research studies on the specific symptoms of patients with VO-CPP will help elucidate patient selection for intervention. Additional future randomized controlled trials are also upcoming to evaluate for outcomes of ovarian vein embolization and iliac vein.


Tophaceous Gout of the Lumbar Spine Mimicking Malignancy on FDG PET/CT.
A 46-year-old man with over a 10-year history of gout complained of progressive bilateral buttock pain with numbness of legs for 4 months. Serum uric acid level was elevated. Lumbar radiographs showed decreased density of the bilateral L4-L5 facet joints. CT showed lytic lesions of the facet joints with hyperdense periarticular lesions. Enhanced MRI showed marked enhancement of these lesions. FDG PET/CT showed avid FDG uptake of the bony and periarticular lesions with SUVmax of 16.8. A decompressive posterior lumbar laminectomy with periarticular lesion resection was performed. Histopathologic findings of the periarticular lesions were consistent with tophaceous gout.


Peripheral Muscle Near-Infrared Spectroscopy Variables are Altered Early in Septic Shock.
Noninvasive evaluation of muscle perfusion using near-infrared spectroscopy (NIRS) coupled with a vascular occlusion test (VOT) may provide an early and simple marker of altered perfusion and microcirculatory function in sepsis. The aim of the study was to compare the time-course of NIRS-derived variables with systemic measures of perfusion in an experimental model of peritonitis. Peritonitis was induced in eight anesthetized, mechanically ventilated, adult sheep (24-34 kg), by injecting autologous feces into the peritoneal cavity. Animals were followed until death or for a maximum of 30 h. Muscle tissue oxygen saturation (StO2) was determined using NIRS on the right posterior leg and arterial VOTs were performed by intermittent intra-aortic balloon inflation. Microdialysis was used to measure muscle lactate and pyruvate levels. Muscle StO2 was significantly lower than baseline values from 8 h after sepsis induction, but with considerable intersubject variability. The NIRS VOT ascending (Asc) slope decreased to values <120%/min in most animals from 12 h after sepsis induction. Muscle lactate/pyruvate ratios were higher than baseline from 16 h after sepsis induction. Mixed venous oxygen saturation (SvO2) decreased to <70% and blood lactate levels increased to >2 mmol/L in most of the animals only 24 and 28 h after sepsis induction, respectively. Muscle NIRS StO2 correlated strongly with femoral venous oxygen saturation (r = 0.820) and moderately with SvO2 (r = 0.436). The muscle NIRS Asc slope after a VOT is altered earlier than global markers of tissue hypoperfusion during sepsis. This simple noninvasive test can detect early changes in peripheral perfusion in sepsis.


The new low-toxic histone deacetylase inhibitor S-(2) induces apoptosis in various acute myeloid leukaemia cells.
Histone deacetylase inhibitors (HDACi) induce tumour cell cycle arrest and/or apoptosis, and some of them are currently used in cancer therapy. Recently, we described a series of powerful HDACi characterized by a 1,4-benzodiazepine (BDZ) ring hybridized with a linear alkyl chain bearing a hydroxamate function as Zn(++)--chelating group. Here, we explored the anti-leukaemic properties of three novel hybrids, namely the chiral compounds (S)-2 and (R)-2, and their non-chiral analogue 4, which were first comparatively tested in promyelocytic NB4 cells. (S)-2 and partially 4--but not (R)-2--caused G0/G1 cell-cycle arrest by up-regulating cyclin G2 and p21 expression and down-regulating cyclin D2 expression, and also apoptosis as assessed by cell morphology and cytofluorimetric assay, histone H2AX phosphorylation and PARP cleavage. Notably, these events were partly prevented by an anti-oxidant. Moreover, novel HDACi prompted p53 and α-tubulin acetylation and, consistently, inhibited HDAC1 and 6 activity. The rank order of potency was (S)-2 > 4 > (R)-2, reflecting that of other biological assays and addressing (S)-2 as the most effective compound capable of triggering apoptosis in various acute myeloid leukaemia (AML) cell lines and blasts from patients with different AML subtypes. Importantly, (S)-2 was safe in mice (up to 150 mg/kg/week) as determined by liver, spleen, kidney and bone marrow histopathology; and displayed negligible affinity for peripheral/central BDZ-receptors. Overall, the BDZ-hydroxamate (S)-2 showed to be a low-toxic HDACi with powerful anti-proliferative and pro-apototic activities towards different cultured and primary AML cells, and therefore of clinical interest to support conventional anti-leukaemic therapy.


Optimizing Dosing of Vagus Nerve Stimulation for Stroke Recovery.
Vagus nerve stimulation (VNS) paired with rehabilitative training enhances recovery of function in models of stroke and is currently under investigation for use in chronic stroke patients. Dosing is critical in translation of pharmacological therapies, but electrical stimulation therapies often fail to comprehensively explore dosing parameters in preclinical studies. Varying VNS parameters has non-monotonic effects on plasticity in the central nervous system, which may directly impact efficacy for stroke. We sought to optimize stimulation intensity to maximize recovery of motor function in a model of ischemic stroke. The study design was preregistered prior to beginning data collection (DOI: https://doi.org/10.17605/OSF.IO/BMJEK ). After training on an automated assessment of forelimb function and receiving an ischemic lesion in motor cortex, rats were separated into groups that received rehabilitative training paired with VNS at distinct stimulation intensities (sham, 0.4 mA, 0.8 mA, or 1.6 mA). Moderate-intensity VNS at 0.8 mA enhanced recovery of function compared with all other groups. Neither 0.4 mA nor 1.6 mA VNS was sufficient to improve functional recovery compared with equivalent rehabilitation without VNS. These results demonstrate that moderate-intensity VNS delivered during rehabilitation improves recovery and defines an optimized intensity paradigm for clinical implementation of VNS therapy.


Preadmission self-instruction booklets, postadmission exercise performance, and teaching time.
The relative effects of preadmission self-instructional information on levels of performance and time needed to achieve level of mastery of exercise behaviors were examined using a sample of 130 presurgical cholecystectomy and herniorrhaphy patients. Experimental interventions were (1) no preadmission information, (2) specific preadmission instructions, and (3) nonspecific preadmission instructions. Preadmission instructions consisting of either a specific or nonspecific booklet mailed to patients focused on techniques for coughing, deep breathing exercises leg movements, and ambulatory behaviors. During hospitalization, patients' exercise behaviors and the length of teaching time required for patients to perform the exercise steps were measured. Findings showed that subjects in the specific exercise instruction group performed significantly more of the exercise behaviors common to both booklets than subjects in the nonspecific exercise instruction group. Subjects in the specific instruction group also performed significantly more of the behaviors available to them than the nonspecific instruction group. Required postadmission teaching time did not differ significantly between the specific and nonspecific information groups, but both the groups required significantly less teaching time in the hospital than the no-preadmission instruction group.


Iron-saturated lactoferrin and pathogenic protozoa: could this protein be an iron source for their parasitic style of life?
Iron is an essential nutrient for the survival of pathogens inside a host. As a general strategy against microbes, mammals have evolved complex iron-withholding systems for efficiently decreasing the iron accessible to invaders. Pathogens that inhabit the respiratory, intestinal and genitourinary tracts encounter an iron-deficient environment on the mucosal surface, where ferric iron is chelated by lactoferrin, an extracellular glycoprotein of the innate immune system. However, parasitic protozoa have developed several mechanisms to obtain iron from host holo-lactoferrin. Tritrichomonas fetus, Trichomonas vaginalis, Toxoplasma gondii and Entamoeba histolytica express lactoferrin-binding proteins and use holo-lactoferrin as an iron source for growth in vitro; in some species, these binding proteins are immunogenic and, therefore, may serve as potential vaccine targets. Another mechanism to acquire lactoferrin iron has been reported in Leishmania spp. promastigotes, which use a surface reductase to recognize and reduce ferric iron to the accessible ferrous form. Cysteine proteases that cleave lactoferrin have been reported in E. histolytica. This review summarizes the available information on how parasites uptake and use the iron from lactoferrin to survive in hostile host environments.


Determinants of directional specificity in the regeneration of lamprey spinal axons.
The projection patterns of regenerating spinal axons in the larval sea lamprey (Petromyzon marinus) were determined by intracellular injection of HRP. Four hundred and eighty-six of 562 stained axons and axon-like neurites (87%) arising from Muller and Mauthner axons, giant interneurons, and dorsal cells terminated in an orientation similar to that of their counterpart control cells. Therefore, lamprey spinal axons regenerate selectively along their normal projection paths. During the first 4 weeks of recovery, i.e., before any had regenerated beyond the transection site, 91 of 114 axons and long neurites (80%) projected in the proper direction. Thus, the correctness of the final projection patterns did not result from selective retraction of randomly directed long neurites. When the cords were doubly transected 1 cm apart, orientation of regenerating neurites remained normal both within the 1 cm island and in the adjacent spinal cord. This suggests that the directional specificity of axonal regeneration was determined neither by the location of the scar nor by the availability of channels formed by the degenerating fibers. Finally, removing 1 cm of spinal cord eliminated potential synaptic targets for regenerating axons on either side of the lesion, but did not affect the direction of axonal growth. These findings are consistent with the hypothesis that the regeneration of lamprey spinal axons is guided by local chemical cues that persist long after the pathways are formed early in development.


[Influence of combination on the specific chromatogram of Glycyrrhiza in sini decoctions by HPLC].
The paper is to report the establishment of an HPLC specific chromatogram of Glycyrrhiza in Sini decoctions and the influence of combination on the specific chromatogram. The RP-HPLC method was used with a Phenomenex Gemini C18 column (250 mm x 4.6 mm ID, 5 microm), and acetonitrile-0.05% trifluoroacetic acid (gradient elution) as mobile phase. Flow rate was 0.8 mL x min(-1) and the detection wavelength was set at 232 nm. The temperature of column was 30 degrees C. The method is stable and reliable with a good reproducibility, it can be used to determine the specific chromatogram of Glycyrrhiza in Sini Decoctions. Twenty peaks were selected as specific peaks in Sini Decoction with liquiritin peak as the reference peak. Six of them were from Glycyrrhiza and the other 6 peaks were from both Glycyrrhiza and Ganjiangfuzi Decoction. The areas of specific peaks of Sini Decoctions were smaller than those in the chromatogram of Glycyrrhiza. The specific chromatogram of Glycyrrhiza in Sini Decoctions is markedly influenced by Radix Aconiti Carmichaeli and Rhizoma Zingiberis. The areas of the specific peaks in Sini Decoctions were reduced obviously. The method is stable and reliable with a good reproducibility, it can be used to determine the specific chromatogram of Glycyrrhiza in Sini Decoctions.


Modern freshwater microbialite analogues for ancient dendritic reef structures.
Microbialites are organosedimentary structures that can be constructed by a variety of metabolically distinct taxa. Consequently, microbialite structures abound in the fossil record, although the exact nature of the biogeochemical processes that produced them is often unknown. One such class of ancient calcareous structures, Epiphyton and Girvanella, appear in great abundance during the Early Cambrian. Together with Archeocyathids, stromatolites and thrombolites, they formed major Cambrian reef belts. To a large extent, Middle to Late Cambrian reefs are similar to Precambrian reefs, with the exception that the latter, including terminal Proterozoic reefs, do not contain Epiphyton or Girvanella. Here we report the discovery in Pavilion Lake, British Columbia, Canada, of a distinctive assemblage of freshwater calcite microbialites, some of which display microstructures similar to the fabrics displayed by Epiphyton and Girvanella. The morphologies of the modern microbialites vary with depth, and dendritic microstructures of the deep water (> 30 m) mounds indicate that they may be modern analogues for the ancient calcareous structures. These microbialites thus provide an opportunity to study the biogeochemical interactions that produce fabrics similar to those of some enigmatic Early Cambrian reef structures.


Familial subepithelial corneal amyloidosis (gelatinous drop-like corneal dystrophy): exclusion of linkage to lactoferrin gene.
Because corneal tissue with familial subepithelial corneal amyloidosis (FSCA; gelatinous drop-like dystrophy of the cornea) contains lactoferrin the possibility that the FSCA gene was the human lactoferrin (hLF) gene was investigated. Due to contradictory published information we also mapped the hLF gene. We mapped the hLF gene using a genomic clone of the entire hLF gene as a probe by fluorescence in situ hybridization (FISH). Utilizing PCR primers that are specific to the hLF gene, we also mapped the hLF via radiation somatic cell hybrid analysis. Linkage of the FSCA gene to the hLF gene was evaluated by genetic linkage analysis using polymorphic markers within and in the vicinity of the hLF gene. The hLF gene mapped to the short arm of chromosome 3 at 3p21. Linkage analysis using polymorphic markers for hLF and haplotype analysis of the 3p21 loci indicates that the FSCA gene is not linked to the 3p21 locus. The gene for FSCA is not the hLF gene in these families.


Deleterious metabolic effects of high-carbohydrate, sucrose-containing diets in patients with non-insulin-dependent diabetes mellitus.
The effects of variations in dietary carbohydrate and fat intake on various aspects of carbohydrate and lipid metabolism were studied in patients with non-insulin-dependent diabetes mellitus (NIDDM). Two test diets were utilized, and they were consumed in random order over two 15-day periods. One diet was low in fat and high in carbohydrate, and corresponded closely to recent recommendations made by the American Diabetes Association (ADA), containing (as percent of total calories) 20 percent protein, 20 percent fat, and 60 percent carbohydrate, with 10 percent of total calories as sucrose. The other diet contained 20 percent protein, 40 percent fat, and 40 percent carbohydrate, with sucrose accounting for 3 percent of total calories. Although plasma fasting glucose and insulin concentrations were similar with both diets, incremental glucose and insulin responses from 8 a.m. to 4 p.m. were higher (p less than 0.01), and mean (+/- SEM) 24-hour urine glucose excretion was significantly greater (55 +/- 16 versus 26 +/- 4 g/24 hours p less than 0.02) in response to the low-fat, high-carbohydrate diet. In addition, fasting and postprandial triglyceride levels were increased (p less than 0.001 and p less than 0.05, respectively) and high-density lipoprotein (HDL) cholesterol concentrations were reduced (p less than 0.02) when patients with NIDDM ate the low-fat, high-carbohydrate diet. Finally, since low-density lipoprotein (LDL) concentrations did not change with diet, the HDL/LDL cholesterol ratio fell in response to the low-fat, high-carbohydrate diet. These results document that low-fat, high-carbohydrate diets, containing moderate amounts of sucrose, similar in composition to the recommendations of the ADA, have deleterious metabolic effects when consumed by patients with NIDDM for 15 days. Until it can be shown that these untoward effects are evanescent, and that long-term ingestion of similar diets will result in beneficial metabolic changes, it seems prudent to avoid the use of low-fat, high-carbohydrate diets containing moderate amounts of sucrose in patients with NIDDM.


Novel murine model of pneumococcal pneumonia: use of temperature as a measure of disease severity to compare the efficacies of moxifloxacin and levofloxacin.
Surface temperature measured by an infrared temperature-scanning thermometer was used to evaluate disease severity and predict imminent death in a murine model of pneumococcal pneumonia. We showed that a decrease in temperature was associated with increasing severity of disease and concomitant histological changes and also that a temperature of 30 degrees C or less was a predictor of death. Furthermore, viable bacterial counts in the lungs of mice euthanized at a temperature of < or = 30 degrees C were not significantly different from those seen in the lungs of mice allowed to die without intervention. These data support temperature change as a more subtle indicator of outcome than death and demonstrate that this could be used as a reliable end point for euthanasia. To test the utility of our model in a drug trial, we examined the efficacies of moxifloxacin and levofloxacin by using temperature as a measure of disease severity prior to and during treatment. Regardless of the antibiotic used, mice assessed as moderately ill (temperature > or = 32 degrees C) at the start of treatment had better clinical and bacteriological outcomes than mice assessed as severely ill (temperature < 32 degrees C). However, moxifloxacin offered better protection and greater bacterial clearance than did levofloxacin in all infected mice independent of disease severity. This model not only allows a more subtle evaluation of drug efficacy but also ensures a better degree of standardization and a more humane approach to drug efficacy studies involving animals.


The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species.
Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund's adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund's adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6-7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction.


CIB1 regulates endothelial cells and ischemia-induced pathological and adaptive angiogenesis.
Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process on a molecular level. CIB1 (calcium- and integrin-binding protein), a 22-kDa EF-hand-containing protein, modulates the activity of p21-activated kinase 1 in fibroblasts. Because p21-activated kinase 1 also contributes to endothelial cell function, we hypothesized that CIB1 may have a role in angiogenesis. We found that endothelial cells depleted of CIB1 by either short hairpin RNA or homologous recombination have reduced migration, proliferation, and tubule formation. Moreover, loss of CIB1 in these cells decreases p21-activated kinase 1 activation, downstream extracellular signal-regulated kinase 1/2 activation, and matrix metalloproteinase 2 expression, all of which are known to contribute to angiogenesis. Consistent with these findings, tissues derived from CIB1-deficient (CIB1-/-) mice have reduced growth factor-induced microvessel sprouting in ex vivo organ cultures and in vivo Matrigel plugs. Furthermore, in response to ischemia, CIB1-/- mice demonstrate decreased pathological retinal and adaptive hindlimb angiogenesis. Ischemic CIB1-/- hindlimbs also demonstrate increased tissue damage and significantly reduced p21-activated kinase 1 activation. These data therefore reveal a critical role for CIB1 in ischemia-induced pathological and adaptive angiogenesis.


An item response theory analysis of the Problem Gambling Severity Index.
Increases in the availability of gambling heighten the need for a short screening measure of problem gambling. The Problem Gambling Severity Index (PGSI) is a brief measure that allows for the assessment of characteristics of gambling behavior and severity and its consequences. The authors evaluate the psychometric properties of the PGSI using item response theory methods in a representative sample of the urban adult population in South Africa (N = 3,000). The PGSI items were evaluated for differential item functioning (DIF) due to language translation. DIF was not detected. The PGSI was found to be unidimensional, and use of the nominal categories model provided additional information at higher values of the underlying construct relative to a simpler binary model. This study contributes to the growing literature supporting the PGSI as the screen of choice for assessing gambling problems in the general population.


Uniparental isodisomy of chromosome 14 in two cases: an abnormal child and a normal adult.
Uniparental disomy (UPD) of a number of different chromosomes has been found in associated with abnormal phenotypes. A growing body of evidence for an imprinting effect involving chromosome 14 has been accumulating. We report on a case of paternal UPD of chromosome 14 studied in late gestation due to polyhydramnios and a ventral wall hernia. A prenatal karyotype documented a balanced Robertsonian 14:14 translocation. The baby was born prematurely with hairy forehead, retrognathia, mild puckering of the lips and finger contractures. Hypotonia has persisted since birth and at age one year, a tracheostomy for laryngomalacia and gastrostomy for feeding remain necessary. Absence of maternal VNTR polymorphisms and homozygosity of paternal polymorphisms using chromosome 14 specific probes at D14S22 and D14S13 loci indicated paternal uniparental isodisomy (pUPID). Parental chromosomes were normal. We also report on a case of maternal UPD in a normal patient with a balanced Robertsonian 14:14 translocation and a history of multiple miscarriages. Five previous reports of chromosome 14 UPD suggest that an adverse developmental effect may be more severe whenever the UPD is paternal in origin. This is the second reported patient with paternal UPD and the fifth reported with maternal UPD, and only few phenotypic similarities are apparent. Examination of these chromosome 14 UPD cases of maternal and paternal origin suggests that there are syndromic imprinting effects.


Real-world evidence of adjuvant gemcitabine plus capecitabine vs gemcitabine monotherapy for pancreatic ductal adenocarcinoma.
The added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC-4 trial. Real-world data on the effectiveness of gemcitabine plus capecitabine (GEMCAP), in patients ineligible for mFOLFIRINOX, are lacking. Our study assessed whether adjuvant GEMCAP is superior to GEM in a nationwide cohort. Patients treated with adjuvant GEMCAP or GEM after resection of PDAC without preoperative treatment were identified from The Netherlands Cancer Registry (2015-2019). The primary outcome was overall survival (OS), measured from start of chemotherapy. The treatment effect of GEMCAP vs GEM was adjusted for sex, age, performance status, tumor size, lymph node involvement, resection margin and tumor differentiation in a multivariable Cox regression analysis. Secondary outcome was the percentage of patients who completed the planned six adjuvant treatment cycles. Overall, 778 patients were included, of whom 21.1% received GEMCAP and 78.9% received GEM. The median OS was 31.4 months (95% CI 26.8-40.7) for GEMCAP and 22.1 months (95% CI 20.6-25.0) for GEM (HR: 0.71, 95% CI 0.56-0.90; logrank P = .004). After adjustment for prognostic factors, survival remained superior for patients treated with GEMCAP (HR: 0.73, 95% CI 0.57-0.92, logrank P = .009). Survival with GEMCAP was superior to GEM in most subgroups of prognostic factors. Adjuvant chemotherapy was completed in 69.5% of the patients treated with GEMCAP and 62.7% with GEM (P = .11). In this nationwide cohort of patients with PDAC, adjuvant GEMCAP was associated with superior survival as compared to GEM monotherapy and number of cycles was similar.


Prognostic significance of immune checkpoints in the tumour-stromal microenvironment of sebaceous gland carcinoma.
Immune checkpoint blockade strategies have gained attention in the treatment/prognosis of cancers by targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway alone or in combination with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade and are currently in clinical trials. The present study investigated the expression of the PD-1, PD-L1, CTLA-4, CD4 and CD8 proteins and their prognostic value in the tumour microenvironment of sebaceous gland carcinoma (SGC). The expression levels of PD-1, PD-L1, CTLA-4, CD4 and CD8 proteins were assessed in 52 cases of SGC by immunohistochemistry and validated by western blotting. mRNA expression was measured by quantitative real-time PCR. Kaplan-Meier curves and Cox proportional hazard models were used to analyse the correlation of protein expression with clinicopathological parameters and disease-free survival. The expression of PD-L1 was found to be higher in tumour cells than in stromal cells. In univariate analysis, the expression of PD-1 in tumour-infiltrating lymphocytes (tPD-1) and PD-L1 in tumour cells was associated with reduced disease-free survival, whereas PD-L1 expression in stromal lymphocyte infiltration (sPD-L1) was associated with the increased survival of patients (p<0.05). However, by multivariate analysis, the expression of tPD-1 was found to be an independent prognostic factor for poor survival. Our study highlights the prognostic outcome of PD-1 and PD-L1 protein expression in cells of tumour-stromal compartments. These results indicate that the PD-1/PD-L1 pathway mediates important interactions within the tumour microenvironment in SGC.


Hepatitis A seroprevalence in a population of immigrants at a French vaccination center.
Hepatitis A vaccination is recommended to people traveling to countries where the disease is endemic. Until recently, people originating from developing countries were considered to be "naturally" immunized. Because of improving socioeconomic conditions, hepatitis A incidence has decreased in most previously highly endemic countries during the last three decades, especially in the younger age groups. We analyzed hepatitis A seroprevalence of 989 travelers who had been born and lived at least 1 year in a developing country, wanted to travel to a hepatitis A endemic area, and consulted at the vaccination center of the Institut Pasteur of Paris between September 1, 2008 and February 28, 2010. Hepatitis A serology results were available for 646 subjects. Overall seroprevalence was 82.4%. A total of 90, 82.6, 81.2, 68.4, 56.9, and 50% of people of sub-Saharan African, Near and Middle Eastern, North African, Asian, Latin American, and Eastern European origin had hepatitis A antibodies, respectively. The difference in seroprevalence according to the continent of origin, age, and length of stay in an endemic country was significant (p < 0.0001). More than 75% of seronegatives and less than 50% of seropositives were younger than 36 years. Almost three quarters of the positive group (while less than half of the negative group) lived longer than 18 years in a developing country. Multivariate analysis showed that seroprevalence increases with age, length of stay in a country at risk, and varies significantly from one continent to another. We recommend extending serologic confirmation of immigrants' hepatitis A immunity. If time is lacking, vaccination should be considered.


An Improved Spatiotemporal Fusion Approach Based on Multiple Endmember Spectral Mixture Analysis.
High spatial and temporal resolution remotely sensed data is of great significance for the extraction of land use/cover information and the quantitative inversion of biophysical parameters. However, due to the limitation of sensor performance and the influence of rain cloud weather, it is difficult to obtain remote sensing images with both high spatial and temporal resolution. The spatiotemporal fusion model is a crucial method to solve this problem. The spatial and temporal adaptive reflectivity fusion model (STARFM) and its improved models are the most widely used spatiotemporal adaptive fusion models. However, the existing spatiotemporal adaptive reflectivity fusion model and its improved models have great uncertainty in selecting neighboring similar pixels, especially in spatially heterogeneous areas. Therefore, it is difficult to effectively search and determine neighboring spectrally similar pixels in STARFM-like models, resulting in a decrease of imagery fusion accuracy. In this research, we modify the procedure of neighboring similar pixel selection of ESTARFM method and propose an improved ESTARFM method (I-ESTARFM). Based on the land cover endmember types and its fraction values obtained by spectral mixing analysis, the neighboring similar pixels can be effectively selected. The experimental results indicate that the I-ESTARFM method selects neighboring spectrally similar pixels more accurately than STARFM and ESTARFM models. Compared with the STARFM and ESTARFM, the correlation coefficients of the image fused by the I-ESTARFM with that of the actual image are increased and the mean square error is decreased, especially in spatially heterogeneous areas. The uncertainty of spectral similar neighborhood pixel selection is reduced and the precision of spatial-temporal fusion is improved.


Use of an amikacin-infused collagen sponge concurrent with implant removal for treatment of tibial plateau leveling osteotomy surgical site infection in 31 cases.
To report the use and long-term outcome of dogs with surgical site infection (SSI) after tibial plateau leveling osteotomy (TPO), treated with an amikacin-infused collagen sponge and implant removal. Retrospective study. Thirty-one client-owned dogs. Medical records were reviewed for dogs with SSI after a TPLO that were treated with surgical implant removal and concurrent implantation of an amikacin-infused collagen sponge. Relevant clinical and surgical data were recorded. The TPLO implants were routinely removed; the surgical site was swabbed for culture. The sponge was aseptically infused with amikacin prior to implantation. Postprocedure examinations consisted of visual inspection of the incision by the surgeon and lameness scoring. Thirty-one dogs met all inclusion criteria. Median follow-up time was 687 days. Short-term examination after implant removal and sponge implantation revealed uneventful incisional healing in 24 dogs. Six (19.4%) dogs exhibited inflamed incision sites a median of 4 days (range, 3-9) postoperatively that resolved without additional treatment. One (3.2%) dog required empirical antibiotic treatment 7 days postoperatively but was lost to long-term follow-up. Long-term follow-up examination revealed no clinical evidence of SSI recurrence and no lameness in the remaining 30 cases. Surgical implant removal and implantation of an absorbable collagen sponge infused with amikacin alone was an effective treatment for postoperative TPLO SSI. This procedure had a 96.8% long-term resolution of SSI. It should be considered as a treatment option for TPLO SSI.


Adherence to therapy with oral antineoplastic agents.
With the rise in availability and increasing use of oral anticancer agents, concerns about adherence to prescribed regimens will become an increasingly important issue in oncology. Few published studies have focused on adherence to oral antineoplastic therapy, in part because the vast majority of chemotherapy is delivered intravenously in physicians' offices or hospitals. In this article, we review current knowledge of adherence behavior with regard to oral medications in general, including factors associated with adherence and methods for measuring adherence. We also review published studies of adherence to oral antineoplastic agents in adult and pediatric populations and adherence issues in cancer prevention. The available evidence reveals that patient adherence to oral chemotherapy recommendations is variable and not easily predicted. Adherence rates ranging from less than 20% to 100% have been reported, and certain populations, such as adolescents, pose particular challenges. Future efforts should focus on improving measurement and prediction of adherence and on developing interventions to improve adherence for both patients in clinical trials and patients being treated outside of the research setting. Assessment of adherence among individuals with cancer and implementation of interventions in situations of poor adherence should improve clinical outcomes.


Naturally occurring mutation, Asp70his, in human butyrylcholinesterase.
People with genetic variants of butyrylcholinesterase can have hours of prolonged apnoea after a normal dose of succinylcholine or mivacurium. Serum samples from 308 persons living in mid-USA were phenotyped to identify the atypical and fluoride variants. 308 samples were analysed for the K variant by DNA amplification, digestion with Mae III and gel electrophoresis. Amplified DNA from 16 samples was sequenced to identify the D70G, T243M and D70H mutations. Values for kcat and Km were determined for the D70H mutant BChE expressed in 293T cells. A new mutation, Asp70His, was identified. This mutation is located in the peripheral anionic site of butyrylcholinesterase, where it causes a 10-fold decrease in binding affinity for positively charged substrates. People homozygous for the Asp70His mutation are expected to have prolonged apnoea in response to succinylcholine or mivacurium, similar to people with the Asp70Gly mutation.


Maximized virulence in a sterilizing pathogen: the anther-smut fungus and its co-evolved hosts.
Host sterilization is a common feature of sexually transmitted diseases (STDs). Because host reproductive failure may free up resources for pathogen reproduction and transmission, theory predicts that selection on sterilizing pathogens will favour maximum virulence (i.e. complete sterilization). We examined patterns of infection in sexually transmitted anther-smut fungi (Microbotryum) on four of their host species in the Caryophyllaceae. Using controlled fungal matings and experimental inoculations, we compared disease expression in inoculations ranging from host-specific pathogens to hybrids and cross-species treatments. Our data support the existence of host-specific sibling species within the genus Microbotryum based on a low infection rate from cross-inoculations and reduced fitness for hybrid pathogens. These patterns of host specificity and reproductive isolation, however, were not absolute. We did observe some successful cross-species and hybrid infections, but the expression of disease was frequently incomplete, including only partial host sterilization and the failed dehiscence of pathogen spores. The prevalence of these maladapted disease phenotypes may greatly inhibit the emergence of novel host pathogen combinations. Infections by hybrid pathogen genotypes were intermediate, in terms of both infection rate and the normality of disease symptoms, between host-specific and cross-inoculated pathogens. In addition, the frequency with which hybrid and cross-inoculated anther-smut pathogens were able to infect but not sterilize new hosts supports the prediction that sterilizing STDs are under selection to maximize virulence in natural populations.


Reference standards for gene fusion molecular assays on cytological samples: an international validation study.
Gene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated. Cell lines harbouring EML4(13)-ALK(20) and SLC34A2(4)-ROS1(32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides. Four (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms. Reference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches.


A comparison of stapedial reflex fatigue with repetitive stimulation and single-fiber EMG in myasthenia gravis.
The pattern of stapedial reflex fatigue in response to pulsed acoustic stimulation was measured and compared to results of repetitive nerve stimulation and single-fiber electromyography (EMG) in 89 patients with myasthenia gravis. Studies were also made on 22 patients with other neuromuscular disorders and 40 control subjects with no evidence of neuromuscular impairment. Stapedial reflex fatigue exceeded normal control values in 84% of the patients with myasthenia gravis. Repetitive stimulation and single-fiber EMG measurements were abnormal in 56% and 91% of this same population, respectively. Stapedial reflex abnormalities were most prevalent in patients with mild forms of myasthenia (predominantly ocular or oropharyngeal weakness). Of 22 nonmyasthenic patients with neuromuscular disease tested, 6 had abnormal stapedial reflex fatigue according to our normal values, indicating that this form of testing also detects other diseases of the motor unit. The measurement of stapedial reflex fatigue is painless, is easy to perform, and requires minimal patient cooperation. Due to the relatively high occurrence of abnormal stapedial reflex fatigue in patients with myasthenia gravis, this procedure appears to have considerable potential value in screening and monitoring patients for the presence of defects in neuromuscular transmission.


Differential expression of chemokine receptors on uveal melanoma cells and their metastases.
To determine the expression of the chemokine receptors CXCR4 and CCR7 on human uveal melanoma cells and their metastases and the effect of liver-borne factors on the chemotactic responses of uveal melanoma cells. Four human uveal melanoma cell lines and three cell lines of uveal melanoma metastases were examined by RT-PCR and flow cytometry for their constitutive expression of CXCR4 and CCR7. The effect of the liver and liver-borne factors on the expression of CXCR4 and CCR7 was determined after intracameral, intrasplenic, and subcutaneous transplantation of uveal melanoma cells in nude mice. Chemotactic responses of melanoma cells to liver-borne factors were determined by in vitro chemotaxis assays using protein extracts of hepatocytes and striated muscle tissue. All the primary uveal melanoma cell lines expressed CXCR4 and CCR7 message and protein, whereas the metastases cell lines expressed little or no chemokine receptor. Extracts of human liver cells stimulated chemotaxis of uveal melanoma cells, which could be inhibited by anti-CXCR4 antibody. Liver-borne factors also induced the downregulation of CXCR4 and CCR7 on uveal melanoma cells. Uveal melanoma cells maintained their high expression of CXCR4 and CCR7 after intracameral transplantation. However, CXCR4 and CCR7 expression was sharply reduced in liver metastases arising from intraocular melanomas. CXCR4 and CCR7 provide directional migration of uveal melanoma cells toward the liver, the most common site for the formation of uveal melanoma metastases. However, soluble factors elaborated by hepatocytes induce the downregulation of CXCR4 and CCR7 on metastatic uveal melanoma cells.


Treatment with aripiprazole and N-acetylcysteine affects anaerobic cysteine metabolism in the hippocampus and reverses schizophrenia-like behavior in the neurodevelopmental rat model of schizophrenia.
Preclinical and clinical studies have shown that the antipsychotic drug aripiprazole and the antioxidant N-acetylcysteine have unique biological properties. The aim of the study was to investigate, in a rat model of schizophrenia, the effects of chronic administration of these drugs on schizophrenia-like behaviors and anaerobic cysteine metabolism in the hippocampus (HIP). The schizophrenia-type changes were induced in Sprague-Dawley rats by repeated administration of the glutathione synthesis inhibitor l-butionine-(S,R)-sulfoximine in combination with the dopamine reuptake inhibitor GBR 12909 in the early postnatal period. Adult model rats were chronically treated with aripiprazole (0.3 mg·kg-1 , i.p.) or N-acetylcysteine (30 mg·kg-1 , orally), and their effects on schizophrenia-like behaviors were assessed using the social interaction test and novel object recognition test. In the HIP, the level of anaerobic cysteine metabolites, H2 S, and bound sulfane sulfur were determined by a fluorescence method, while the expression of H2 S-synthetizing enzymes: cystathionine β-synthase (CBS) and mercaptopyruvate sulfurtransferase (MST) by western blot. Long-term treatment with aripiprazole or N-acetylcysteine reversed social and cognitive deficits and reduced the exploratory behaviors. In the HIP of 16-day-old model pups, H2 S levels and MST protein expression were significantly decreased. In adult model rats, H2 S levels remained unchanged, bound sulfane sulfur significantly increased, and the expression of CBS and MST slightly decreased. The studied drugs significantly reduced the level of bound sulfane sulfur and the expression of tested enzymes. The reduction in bound sulfane sulfur level coincided with the attenuation of exploratory behavior, suggesting that modulation of anaerobic cysteine metabolism in the HIP may have therapeutic potential in schizophrenia.


Incidence of cesarean section and analysis of risk factors for failed conversion of labor epidural to surgical anesthesia: A prospective, observational study in a tertiary care center.
This study aimed to analyze the effect of labor epidural (LE) on the incidence of cesarean section (CS) and assess the risk factors involved in failed conversion of LE to surgical anesthesia for CS. A prospective observational study of 18 months from January 2012 to June 2013 was conducted on all patients who had delivered in the labor room suit of our hospital. The data collected for all 4694 patients included their demographics, parity and mode of delivery. In addition a predesigned proforma, with additional information was used for 629 parturient with LE. During the study period, total numbers of deliveries performed in our hospital were 4694, with an epidural rate of 13.4% (629/4694). No significant difference (P = 0.06) was observed in the rate of CS among women with or without LE (28 % [n = 176/629] vs. 31.7 % [n = 1289/4065]), however, a statistically significant difference (P < 0.01) was observed in the rate of assisted delivery in patients receiving LE as compared to those delivering without it (8.7% [n = 55/629] vs. n = 3.7% [154/4065]). For 176 patients requiring CS, LE utilization for surgical anesthesia was 52.8% (93/176) and factors identified for not utilizing LE in 47% (83/176) were; failure to achieve surgical anesthesia in 6.8% (12/176), emergency CS in 28.4% (50/176), patient preference in 6.8% (12/176) and inadequate labor pain relief with LE in 5.1% (9/176) patients. Non-obstetric anesthesiologists were involved in 59% (49/83) of cases where LE was not used for CS. LE had no effect on the rate of CS; however it significantly increased (P < 0.01) the rate of assisted delivery. Factors like inadequate LE, emergency situations and non-obstetric anesthesiologists can all be responsible for failed conversion of LE to surgical anesthesia for CS.


Repetitive shock wave therapy for lateral elbow tendinopathy (tennis elbow): a systematic and qualitative analysis.
Pooled meta-analyses of statistically and clinically heterogeneous data of randomised-controlled studies are difficult to interpret. Therefore, a qualitative study-by-study assessment was thought to be of greater relevance, to physicians confronted with a therapy-resistant tennis elbow patient, to determine the effectiveness of shock wave therapy (SWT) for lateral elbow tendinopathy. Orthopaedic clinic. Randomized trials were identified from a current search of The Cochrane Bone, Joint and Muscle Trauma Group specialized register of trials, the Cochrane Central Register of Controlled Trials, MEDLINE and reference lists of articles and dissertations. We included 10 trials that randomized 948 participants to SWT or placebo or treatment control. For each trial, two independent reviewers assessed the methodological quality and extracted data. Methodological quality criteria included appropriate randomization, allocation concealment, blinding, number lost to follow-up and intention-to-treat analysis. Conflicting results of the 10 studies were found. There was considerable heterogeneity in terms of methodological quality; treatment regimen; patient selection and follow-up period, precluding pooled analyses. Instead, individual trial results were described in the text. Only six trials had a high-quality methodology. Two independent high-quality randomized placebo-controlled trials (196 participants) reported significant success of SWT over placebo (65 versus 28%; 61 versus 29%). Design of both trials included enrolment of chronic recalcitrant patients only; 1500-2000 shocks of low-energy flux density (0.1 mJ/mm(2)) applied to the site of maximal discomfort (clinical focusing) in weekly intervals; no use of local anaesthesia and main follow-up at least 3 months after the last application. Three other independent high-quality trials (406 participants) did not find any benefit of SWT over placebo (32 versus 33%; 35 versus 34%; 39 versus 31%). In these three trials, study designs deviated from the design described earlier, enrolling acute patients or applying SWT under local anaesthesia or expanding the application intervals to 4 weeks, while reducing the main follow-up to 4 weeks. With current studies heterogeneous in terms of the duration of the disorder; type, frequency and total dose of SWT; period of time between SWT; type of management and control group; timing of follow-up and outcomes assessed, a pooled meta-analysis of SWT for lateral elbow tendinopathy was considered inappropriate. In a qualitative systematic per-study analysis identifying common and diverging details of 10 randomized-controlled trials, evidence was found for effectiveness of shock wave treatment for tennis elbow under well-defined, restrictive conditions only.


Feedback control of unsupported standing in paraplegia--part II: experimental results.
This is the second of a pair of papers which describe an investigation into the feasibility of providing artificial balance to paraplegics using electrical stimulation of the paralyzed muscles. By bracing the body above the shanks, only stimulation of the plantar flexors is necessary. This arrangement prevents any influence from the intact neuromuscular system above the spinal cord lesion. In this paper, we present experimental results from intact and paraplegic subjects.


Risk factors associated with liver injury and impact of liver injury on transplantation-related mortality in pediatric recipients of allogeneic hematopoietic stem cell transplantation.
In adults, hepatic complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with significant morbidity and transplantation-related mortality (TRM). However, there is a paucity of parallel data on the incidence of, and risk factors for, liver injury (LI) and the impact of LI on TRM in pediatric allo-HSCT recipients. We compared total bilirubin, direct bilirubin, and alanine aminotransferase values before allo-HSCT and at 1 month, day +100, and 12 months after allo-HSCT in 248 patients who received either a myeloablative conditioning (MAC) regimen (n = 109) or a reduced-toxicity/reduced-intensity conditioning (RTC/RIC) regimen (n = 139). LI was defined as grade ≥ 2 hyperbilirubinemia according to the National Cancer Institute's Common Terminology Criteria for Adverse Events 3.0/4.0 (total bilirubin, >1.95 mg/dL, 1.5 times above the upper limit of normal for our laboratory). Univariate and multivariate logistic regression models were used to identify risk factors for LI and TRM. The incidence of LI at 1 month after allo-HSCT was 14.1%. The median bilirubin level was 3.5 mg/dL (range, 1.97 to 32.2 mg/dL). Only LI as defined by total bilirubin level, but not by direct bilirubin or alanine aminotransferase level, was found to be a significant predictor for TRM. The 1-year TRM was 60.7% (95% confidence interval, 42.6% to 78.7%) in patients with LI at 1 month after allo-HSCT, compared with 14.6% (95% confidence interval, 9.9% to 19.4%) (P < .0001) in patients those who did not have liver injury. Multivariate analysis identified age (P = .03), total body irradiation (P = .007), bacterial bloodstream infection (BBSI) (P = .001), and invasive fungal infection (IFI) (P = .002) as significant risk factors for developing LI at 1 month. On multivariate analysis for risk factors for TRM, only LI at 1 month after allo-HSCT (P < .0001), primary graft failure (P = .001), BBSI (P = .003), and systemic viral infection (P = .04) were identified as significant risk factors for TRM. LI before allo-HSCT conditioning was not associated with higher TRM. Although the incidence of LI in pediatric allo-HSCT recipients is low, LI is associated with very high TRM. BBSI and IFI are the primary risk factors for LI.


Managing incidental findings in human subjects research: analysis and recommendations.
No consensus yet exists on how to handle incidental findings (IFs) in human subjects research. Yet empirical studies document IFs in a wide range of research studies, where IFs are findings beyond the aims of the study that are of potential health or reproductive importance to the individual research participant. This paper reports recommendations of a two-year project group funded by NIH to study how to manage IFs in genetic and genomic research, as well as imaging research. We conclude that researchers have an obligation to address the possibility of discovering IFs in their protocol and communications with the IRB, and in their consent forms and communications with research participants. Researchers should establish a pathway for handling IFs and communicate that to the IRB and research participants. We recommend a pathway and categorize IFs into those that must be disclosed to research participants, those that may be disclosed, and those that should not be disclosed.


Development of a new mouse model for coxsackievirus-induced myocarditis by attenuating coxsackievirus B3 virulence in the pancreas.
The coxsackievirus B3 (CVB3) mouse myocarditis model is the standard model for investigation of virus-induced myocarditis but the pancreas, rather than the heart, is the most susceptible organ in mouse. The aim of this study was to develop a CVB3 mouse myocarditis model in which animals develop myocarditis while attenuating viral infection of the pancreas and the development of severe pancreatitis. We developed the recombinant CVB3 variant H3N-375TS by inserting target sites (TS) of miR-375, which is specifically expressed in the pancreas, into the 3'UTR of the genome of the pancreo- and cardiotropic CVB3 variant H3. In vitro evaluation showed that H3N-375TS was suppressed in pancreatic miR-375-expressing EndoC-βH1 cells >5 log10, whereas its replication was not suppressed in isolated primary embryonic mouse cardiomyocytes. In vivo, intraperitoneal (i.p.) administration of H3N-375TS to NMRI mice did not result in pancreatic or cardiac infection. In contrast, intravenous (i.v.) administration of H3N-375TS to NMRI and Balb/C mice resulted in myocardial infection and acute and chronic myocarditis, whereas the virus was not detected in the pancreas and the pancreatic tissue was not damaged. Acute myocarditis was characterized by myocardial injury, inflammation with mononuclear cells, induction of proinflammatory cytokines, and detection of replicating H3N-375TS in the heart. Mice with chronic myocarditis showed myocardial fibrosis and persistence of H3N-375TS genomic RNA but no replicating virus in the heart. Moreover, H3N-375TS infected mice showed distinctly less suffering compared with mice that developed pancreatitis and myocarditis after i.p. or i.v application of control virus. In this study, we demonstrate that by use of the miR-375-sensitive CVB3 variant H3N-375TS, CVB3 myocarditis can be established without the animals developing severe systemic infection and pancreatitis. As the H3N-375TS myocarditis model depends on pancreas-attenuated H3N-375TS, it can easily be used in different mouse strains and for various applications.


Hunting the Snark: the flawed search for mythical Jurassic angiosperms.
Several recent palaeobotanical studies claim to have found and described pre-Cretaceous angiosperm macrofossils. With rare exceptions, these papers fail to define a flower, do not acknowledge that fossils require character-based rather than group-based classification, do not explicitly state which morphological features would unambiguously identify a fossil as angiospermous, ignore the modern conceptual framework of phylogeny reconstruction, and infer features in the fossils in question that are interpreted differently by (or even invisible to) other researchers. This unfortunate situation is compounded by the relevant fossils being highly disarticulated two-dimensional compression-impressions lacking anatomical preservation. Given current evidence, all supposed pre-Cretaceous angiosperms are assignable to other major clades among the gymnosperms sensu lato. By any workable morphological definition, flowers are not confined to, and therefore cannot delimit, the angiosperm clade. More precisely defined character states that are potentially diagnostic of angiosperms must by definition originate on the phylogenetic branch that immediately precedes the angiosperm crown group. Although the most reliable candidates for diagnostic characters (triploid endosperm reflecting double fertilization, closed carpel, bitegmic ovule, and phloem companion cells) are rarely preserved and/or difficult to detect unambiguously, similar characters have occasionally been preserved in high-quality permineralized non-angiosperm fossils. The angiosperm radiation documented by Early Cretaceous fossils involves only lineages closely similar to extant taxonomic families, lacks obvious morphological gaps, and (as agreed by both the fossil record and molecular phylogenies) was relatively rapid-all features that suggest a primary radiation. It is unlikely that ancestors of the crown group common ancestor would have fulfilled a character-based definition of (and thereby required expansion of the concept of) an angiosperm; they would instead form a new element of the non-angiosperm members of the 'anthophyte' grade, competing with Caytonia to be viewed as morphologically determined sister group for angiosperms. Conclusions drawn from molecular phylogenetics should not be allowed to routinely constrain palaeobotanical inferences; reciprocal illumination between different categories of data offers greater explanatory power than immediately resorting to Grand Syntheses. The Jurassic angiosperm-essentially a product of molecular phylogenetics-may have become the holy grail of palaeobotany but it appears equally mythical.