Climatic effects on niche evolution in a passerine bird clade depend on paleoclimate reconstruction method.
Climatic niches describe the climatic conditions in which species can persist. Shifts in climatic niches have been observed to coincide with major climatic change, suggesting that species adapt to new conditions. We test the relationship between rates of climatic niche evolution and paleoclimatic conditions through time for 65 Old-World flycatcher species (Aves: Muscicapidae). We combine niche quantification for all species with dated phylogenies to infer past changes in the rates of niche evolution for temperature and precipitation niches. Paleoclimatic conditions were inferred independently using two datasets: a paleoelevation reconstruction and the mammal fossil record. We find changes in climatic niches through time, but no or weak support for a relationship between niche evolution rates and rates of paleoclimatic change for both temperature and precipitation niche and for both reconstruction methods. In contrast, the inferred relationship between climatic conditions and niche evolution rates depends on paleoclimatic reconstruction method: rates of temperature niche evolution are significantly negatively related to absolute temperatures inferred using the paleoelevation model but not those reconstructed from the fossil record. We suggest that paleoclimatic change might be a weak driver of climatic niche evolution in birds and highlight the need for greater integration of different paleoclimate reconstructions.


Knowledge, attitude and practices of healthcare providers towards deep vein thrombosis prophylaxis in five teaching hospitals of Rawalpindi.
Prophylaxis of deep vein thrombosis (DVT) is underutilised in Pakistan. This cross-sectional survey was designed to evaluate knowledge, attitude and practices of healthcare providers towards DVT prophylaxis in teaching hospitals in and around Rawalpindi. Knowledge, attitude and practices was assessed by a 12-item questionnaire filled-in by healthcare providers in five teaching hospitals. Eleven out of 12 questions were multiple-choice type and one was open ended. One hundred-sixty-nine, out of 200 questionnaires were returned and were analysed. Total 43.2% of the respondents were house-officers. Although 98.8% agreed that DVT prophylaxis is clinically important, but 39.4% actually prescribed it themselves. Out of these, only 10.3% respondents did it routinely. Low molecular weight heparin (LMWH) was the preferred prophylaxis used (36.7%). Most of the respondents underestimated the prevalence and consequences of DVT in hospitalised patients. Knowledge and practices of healthcare providers about DVT prophylaxis in hospitalised patients is less than ideal. Hospitals need to develop their own guidelines for DVT prophylaxis.


Canine histiocytic diseases.
Canine histiocytic diseases are an emerging spectrum of diseases characterized by proliferations of histiocytic cells. Nonneoplastic histiocytic disease (reactive histiocytosis, comprising cutaneous and systemic histiocytosis) is uncommon. Neoplastic histiocytic diseases include cutaneous histiocytoma, which is a benign histiocytic tumor, and localized and disseminated histiocytic sarcoma (previously known as malignant histiocytosis), which are malignant diseases. The differentiation of histiocytic diseases can be challenging. This article outlines the characteristics of each disease entity and details the clinicopathologic, histologic, immunohistochemical, prognostic, and therapeutic differences among them.


Mitotic destruction of the cell cycle regulated NIMA protein kinase of Aspergillus nidulans is required for mitotic exit.
NIMA is a cell cycle regulated protein kinase required, in addition to p34cdc2/cyclin B, for initiation of mitosis in Aspergillus nidulans. Like cyclin B, NIMA accumulates when cells are arrested in G2 and is degraded as cells traverse mitosis. However, it is stable in cells arrested in mitosis. NIMA, and related kinases, have an N-terminal kinase domain and a C-terminal extension. Deletion of the C-terminus does not completely inactivate NIMA kinase activity but does prevent functional complementation of a temperature sensitive mutation of nimA, showing it to be essential for function. Partial C-terminal deletion of NIMA generates a highly toxic kinase although the kinase domain alone is not toxic. Transient induction experiments demonstrate that the partially truncated NIMA is far more stable than the full length NIMA protein which likely accounts for its toxicity. Unlike full length NIMA, the truncated NIMA is not degraded during mitosis and this affects normal mitotic progression. Cells arrested in mitosis with non-degradable NIMA are able to destroy cyclin B, demonstrating that the arrest is not due to stabilization of p34cdc2/cyclin B activity. The data establish that NIMA degradation during mitosis is required for correct mitotic progression in A. nidulans.


Recombinant protein production in yeasts.
Recombinant DNA (rDNA) technologies (genetic, protein, and metabolic engineering) allow the production of a wide range of peptides, proteins, and biochemicals from naturally nonproducing cells. These technologies, now approx 25 yr old, have become one of the most important technologies developed in the twentieth century. Pharmaceutical products and industrial enzymes were the first biotech products on the world market made by means of rDNA. Despite important advances in rDNA applications in mammalian cells, yeasts still represent attractive hosts for the production of heterologous proteins. In this review we summarize advantages and limitations of the main and most promising yeast hosts.


Helper T Cells and Cancer-Associated Inflammation: A New Direction for Immunotherapy?
CD4+ helper T cells are critical regulators in immunity and inflammation. Growing evidence has indicated their involvement in cancer, by shaping the tumor microenvironment. In this study, I summarize latest literature on Th2 and Th17 cells in cancer-associated inflammation and propose that they may be targeted for cancer immunotherapy.


The effect of finishing on the anodic polarization of high-copper amalgams.
The influence of surface finishing procedures on the corrodibility of high-copper amalgams was measured. Anodic polarization curves were determined in Ringer's solution for amalgam samples made from a dispersion and a ternary alloy. Three types of finishes were compared: as carved, burnished, and polished. The polarization curves of the burnished and polished specimens were statistically similar (P greater than 0.05) at all potentials investigated. The carved samples exhibited higher corrosion currents at most of the potentials investigated.


[Low-dose hypobaric spinal anesthesia for anorectal surgery in jackknife position: levobupivacaine-fentanyl compared to lidocaine-fentanyl].
To compare the percentage of patients who were able to bypass the postoperative intensive care recovery unit after selective spinal anesthesia with lidocaine-fentanyl versus levobupivacaine-fentanyl for anorectal surgery in jackknife position. Randomized double-blind clinical trial comparing 2 groups of 30 patients classified ASA 1-2. One group received 18 mg of 0.6% lidocaine plus 10 microg of fentanyl while the other group received 3 mg of 0.1% levobupivacaine plus 10 microg of fentanyl. Intraoperative variables were time of start of surgery, maximum extension of sensory blockade, requirement for rescue analgesics, and hemodynamic events. The level of sensory blockade was recorded at 5, 10, and 15 minutes after the start of surgery and at the end of the procedure. The degrees of postoperative motor blockade and proprioception were recorded, as were the results of the Romberg test and whether or not the patient was able to bypass the postoperative recovery unit. Also noted were times of start of ambulation and discharge, complications, and postoperative satisfaction. Intraoperative variables did not differ significantly between groups, and all patients in both groups bypassed the postoperative recovery unit. Times until walking and discharge home, complications, and overall satisfaction after surgery were similar in the 2 groups. Both spinal anesthetic solutions provide effective, selective anesthesia and are associated with similar rates of recovery care unit bypass after anorectal surgery in jackknife position.


Wnt activated β-catenin and YAP proteins enhance the expression of non-coding RNA component of RNase MRP in colon cancer cells.
RMRP, the RNA component of mitochondrial RNA processing endoribonuclease, is a non-coding RNA (ncRNA) part of the RNase MRP complex functioning in mitochondrial and ribosomal RNA processing. Even though various mutations in the RMRP gene are linked to developmental defects and pathogenesis, its relevance to cancer etiology has not been well established. Here we examined the expression of RMRP and found a significant increase in colorectal and breast cancer patient tissues. So we tested whether the oncogenic signaling pathways, Wnt/β-catenin and Hippo/YAP pathways, are relevant to the enhanced expression of RMRP in cancer cells because of the predicted β-catenin/TCF and YAP/TBX5 elements in the upstream regions of the RMRP gene. As expected, Wnt signal activation significantly induced the RMRP transcription thru β-catenin and YAP transcription factors. More importantly, YAP protein was critical for RMRP transcription by association to the proximal site near the transcription start site of the RMRP gene, a Pol III promoter, along with β-catenin and TBX5 proteins. We propose that the interplay of Wnt and Hippo signaling pathways could regulate target genes, coding or non-coding, by the β-catenin/YAP/TBX5 transcription complex in cancer cells.


Ascorbic acid insufficiency induces the severe defect on bone formation via the down-regulation of osteocalcin production.
The L-gulono-γ-lactone oxidase gene (Gulo) encodes an essential enzyme in the synthesis of ascorbic acid from glucose. On the basis of previous findings of bone abnormalities in Gulo (-/-) mice under conditions of ascorbic acid insufficiency, we investigated the effect of ascorbic acid insufficiency on factors related to bone metabolism in Gulo (-/-) mice. Four groups of mice were raised for 4 weeks under differing conditions of ascorbic acid insufficiency, namely, wild type; ascorbic acid-sufficient Gulo (-/-) mice, 3-week ascorbic acid-insufficient Gulo (-/-) mice, and 4-week ascorbic acid-insufficient Gulo (-/-) mice. Four weeks of ascorbic acid insufficiency resulted in significant weight loss in Gulo (-/-) mice. Interestingly, average plasma osteocalcin levels were significantly decreased in Gulo (-/-) mice after 3 weeks of ascorbic acid insufficiency. In addition, the tibia weight in ascorbic acid-sufficient Gulo (-/-) mice was significantly higher than that in the other three groups. Moreover, significant decreases in trabecular bone volume near to the growth plate, as well as in trabecular bone attachment to the growth plate, were evident in 3- or 4-week ascorbic acid-insufficient Gulo (-/-). In summary, ascorbic acid insufficiency in Gulo (-/-) mice results in severe defects in normal bone formation, which are closely related to a decrease in plasma osteocalcin levels.


Ferulsinaic acid attenuation of advanced glycation end products extends the lifespan of Caenorhabditis elegans.
Ferulsinaic acid is the first member of a new rearranged class of sesquiterpene coumarins of the genus Ferula. The genus Ferula can be used for the treatment of skin infections, hysteria and for stomach disorders, such as a febrifuge and a carminative agent. The effect of ferulsinaic acid on the lifespan of the nematode Caenorhabditis elegans has been examined. Novel data explaining the effect of ferulsinaic acid on the lifespan of C. elegans and its antioxidant power were obtained. C. elegans was cultivated under standard laboratory conditions in absence and presence of different ferulsinaic acid. Also, animals were cultivated under heat and chemical stress conditions in absence and presence of ferulsinaic acid. Life span assay, determination of protein concentration, assay of malondialdehyde and ELISA for determination of AGEs were performed. Under standard laboratory conditions and in presence of ferulsinaic acid (500 nm, 10 µm and 100 µm), mean life span of wild type animals was significantly lengthened in a dose-dependent manner from 18.64 ± 0.19 days (control) to 19 ± 0.19 (P = 0.695), 20.76 ± 0.25 (P = 0.043) and 22.3 ± 0.29 (P = 0.0291), respectively. Interestingly, in C. elegans resistance for heat stress at 35°C and oxidative stress induced by paraquat were significantly improved with ferulsinaic acid. Ferulsinaic acid was found to significantly attenuate both lipid peroxidation and the formation of advanced glycation end products in the wild-type animals under standard laboratory conditions. Ferulsinaic acid had therapeutic efficacy as an antioxidant with the possibility of its use as an antioxidant drug.


Effects of clenbuterol on central beta-1 and beta-2 adrenergic receptors of the rat.
Repeated administration of the centrally acting beta adrenoceptor agonist, clenbuterol, to rats reduced the ability of isoproterenol to increase the concentration of cyclic AMP (cAMP) in slices of cerebellum. This reduced responsiveness to isoproterenol was accompanied by a marked reduction in the density of beta adrenoceptors as measured by the binding of the beta adrenoceptor antagonist [125I]iodopindolol. In addition, the agonist-binding properties of remaining cerebellar beta adrenoceptors were altered after clenbuterol treatment. The clenbuterol-induced reduction in the density of beta adrenoceptors in the cerebellum is in marked contrast to its inability to do this in cerebral cortex. Comparison of the ability of clenbuterol to that of isoproterenol to increase levels of cAMP in slices of cerebral cortex or cerebellum showed that clenbuterol is a weakly potent agonist in both brain regions. The increase in cAMP induced by isoproterenol in the cortex was significantly reduced in the presence of the selective beta-1 adrenoceptor antagonist, ICI 89,406. In contrast, the clenbuterol-induced increase in cortical cAMP was unchanged by ICI 89,406 but was reduced significantly by the beta-2 adrenoceptor antagonist, ICI 118,551. In cerebellum, both isoproterenol- and clenbuterol-stimulated accumulation of cAMP were antagonized much more potently by ICI 118,551 than by ICI 89,406. Furthermore, clenbuterol antagonized the cAMP response induced by isoproterenol in the presence of ICI 118,551 in a concentration-dependent manner. In terms of measurement of cAMP in brain slices, clenbuterol is weakly potent as an agonist at beta-2 adrenoceptors and has antagonist properties at beta-1 adrenoceptors.


A dietary supplement for female sexual dysfunction, Avlimil, stimulates the growth of estrogen-dependent breast tumors (MCF-7) implanted in ovariectomized athymic nude mice.
Avlimil, a dietary supplement advertised to ameliorate female sexual dysfunction, is a mixture of eleven herbal components, and some herbal constituents of Avlimil (including black cohosh, licorice, red raspberry, red clover and kudzu) contain phenolic compounds, which are suggested to have estrogenic, anti-estrogenic, or androgenic potential for relieving menopausal symptoms. We hypothesize that Avlimil could modulate the growth of estrogen receptor positive human breast cancer (MCF-7) cells in vitro and in vivo. A dimethylsulfoxide (DMSO) extract of Avlimil (0.001-100 microg Avlimil powder equivalents/mL media) was tested for its estrogenic and anti-estrogenic effects on the growth of MCF-7 cells in vitro. We observed that the DMSO extract of Avlimil at low concentrations (0.1-50 microg/mL media) dose-dependently increased MCF-7 cell proliferation in vitro, and Avlimil DMSO extract at 100 microg/mL inhibited the growth of MCF-7 cells in vitro. Avlimil and some constituents (black cohosh and licorice roots) of Avlimil were fractionated by using sequential solvent extraction (hexane, ethyl acetate, and methanol) and the activities of the fractions were monitored by effects on the growth of MCF-7 cells. Depending on dosage (0.1-100 microg/mL media) both stimulatory and inhibitory effects of the extracts on the growth of MCF-7 cells were observed. The effect of dietary Avlimil at dosages approximating human intake was evaluated using ovariectomized mice implanted with MCF-7 cells. Animals were fed diets containing 500 ppm or 1000 ppm Avlimil for 16 weeks. Dietary Avlimil at 500 ppm stimulated MCF-7 tumors, but Avlimil at 1000 ppm had no apparent effect on the growth of MCF-7 tumors. The observation of stimulated tumor growth in the absence of uterine wet weight gains suggest that estrogenic/anti-estrogenic effects of Avlimil we observed may be dosage- and target tissue-specific and that Avlimil may not be safe for women with estrogen-dependent breast cancer. The different biological effects of fractionated Avlimil components and the different concentration dependencies warrant further compound identification and dose-response studies, especially at recommended intake levels that could have estrogenic effects in women.


Investigating the impact of eating norms and collective autonomy support vs. collective control on unhealthy eating and its internalization.
Our eating behaviors are highly influenced by those of individuals surrounding us and the groups we belong to. The first goal of this experiment was to determine how social norms that encourage (pro-) vs. discourage (anti-) unhealthy eating influence people's intentions and motivations to eat unhealthily. Since these norms can be conveyed by one's group in a manner that either promotes group members' autonomy (i.e., collective autonomy support), or pressures them into eating certain foods (i.e., collective control), the experiment also tests which of these types of messages promotes the highest conformity to group norms. Hence, the second goal of this experiment was to investigate this synergetic effect of pro- vs anti-unhealthy eating norms and of collective autonomy support vs. collective control on participants' unhealthy eating intentions and their motivations for unhealthy eating. An experimental study (N = 341) using a 2 (eating norm: pro-unhealthy eating norm vs. anti-unhealthy eating norm) x 3 (type of group support: collective autonomy support vs. collective control vs. no support) design was conducted. Results showed that pro-unhealthy eating norms increased participants' intentions to eat salty and fatty food, but also their amotivation (i.e., lack of motivation) for unhealthy eating relative to anti-unhealthy eating norms. In addition, when pro-unhealthy eating was encouraged in a controlling (vs. in an autonomy supportive) manner, participants reported higher intentions to eat tofu tacos. Finally, when pro-unhealthy eating was promoted by supporting group members' autonomy, participants reported higher integrated regulation, i.e., a highly internalized motivation, for unhealthy eating. These results demonstrate that eating norms do not impact all types of unhealthy food consumption in the same manner, and that collective control may be motivating in uncertain contexts; furthermore, when individuals' autonomy is supported and promoted by other group members, they are more susceptible to integrate unhealthy eating in their life.


Kondo effect of molecular complexes at surfaces: ligand control of the local spin coupling.
The spin state of single magnetic atoms and molecules at surfaces is of fundamental interest and may play an important role in future atomic-scale technologies. We demonstrate the ability to tune the coupling between the spin of individual cobalt adatoms with their surroundings by controlled attachment of molecular ligands. The strength of the coupling is determined via the Kondo resonance by low-temperature scanning tunneling spectroscopy. Spatial Kondo resonance mapping is introduced as a novel imaging tool to localize spin centers in magnetic molecules with atomic precision.


Limited Utility of Pulmonary Nodule Risk Calculators for Managing Large Nodules.
The optimal management of large pulmonary nodules, at higher risk for lung cancer, has not been determined, and it remains unclear as to which patients should undergo follow-up imaging vs invasive tissue diagnosis via biopsy or surgical resection. Through search of radiology reports, 86 nodules from our institution were identified using the inclusion criterion of solid nodules measuring greater than 8mm. We evaluated these nodules with a number of risk prediction calculators, including the Brock University model, and compared these against the proven diagnosis. Of 86 nodules, 59 (69%) nodules were malignant. The most accurate predictive model, the Brock University calculator, underestimated the risk for this group at 33%. At its optimal threshold, this model had a positive predictive value of 81% and negative predictive value of 53%. Notwithstanding the low negative predictive value, the positive predictive value was no better than patients clinically selected for biopsy (86% of biopsies were malignant). Existing nodule risk prediction calculators are of limited usage in guiding the management of large pulmonary nodules. At present, the accuracy of these models in this setting is inferior to expert clinical judgment, and future work is needed to develop management algorithms for higher-risk nodules.


Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression.
Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein-coupled receptors (S1P1-5) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis. SphK1 depletion in HeLa cells caused prometaphase arrest, whereas its overexpression or activation accelerated mitosis. Increasing the abundance of S1P promoted mitotic progression, overrode the spindle assembly checkpoint (SAC), and led to chromosome segregation defects. S1P was secreted through the transporter SPNS2 and stimulated mitosis by binding to and activating S1P5 on the extracellular side, which then activated the intracellular phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Knockdown of S1P5 prevented the S1P-induced spindle defect phenotype. RNA interference assays revealed that the mitotic kinase Polo-like kinase 1 (PLK1) was an important effector of S1P-S1P5 signaling-induced mitosis in HeLa cells. Our findings identify an extracellular signal and the downstream pathway that promotes mitotic progression and may indicate potential therapeutic targets to inhibit the proliferation of cancer cells.


Origin of ferroelectricity in high-T(c) magnetic ferroelectric CuO.
Cupric oxide is a unique magnetic ferroelectric material with a transition temperature significantly higher than the boiling point of liquid nitrogen. However, the mechanism of high-T(c) multiferroicity in CuO remains puzzling. In this Letter, we clarify the mechanism of high-T(c) multiferroicity in CuO by using combined first-principles calculations and an effective hamiltonian model. We find that CuO contains two magnetic sublattices, with strong intrasublattice interactions and weakly frustrated intersublattice interactions. The weak spin frustration leads to incommensurate spin excitations that dramatically enhance the entropy of the multiferroic phase and eventually stabilize that phase in CuO.


Voltage-Gated Sodium Channel Blockers: Synthesis of Mexiletine Analogues and Homologues.
Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the treatment of myotonia, myotonic dystrophy and amyotrophic lateral sclerosis is now widely recognized. Nevertheless, it has been retired from the market in several countries because of its undesired effects. Thus, several papers were reported in the last years about analogues and homologues of mexiletine being endowed with a wider therapeutic ratio and a more selectivity of action. Some of them showed sodium channel blocking activity higher than the parent compound. It is noteworthy that mexiletine is used in therapy as a racemate even though a difference in the activities of the two enantiomers was widely demonstrated, with (-)-(R)-enantiomer being more active: this finding led several research groups to study mexiletine and its analogues and homologues in their optically active forms. This review summarizes the different synthetic routes used to obtain these compounds. They could represent an interesting starting point to new mexiletine-like compounds without common side effects related to the use of mexiletine.


Hypercalcemia of cancer: an update.
Hypercalcemia of cancer is due to secretion of substances with parathyroid hormone (PTH)-like activity from tumours of the respiratory, gastrointestinal and urogenital tract as well as hematologic malignancies and breast cancer. PTH-related Protein (PTHrP) is secreted mainly from solid tumours and it has been recently recognized as being responsible for hypercalcemia mediated primarily via an increased renal reabsorption of calcium and secondly by an increased bone resorption. PTHrP-mRNA is expressed in a variety of normal tissues and has multiple physiologic and paracrine actions. Bone resorbing factors like the cytokines-lymphokines, interleukins, prostaglandins, TNF-alpha/TNF-beta, GM-CSF/G-CSF, TGF-alpha and TGF-beta are produced by certain solid and hematologic cancers and have also been implicated in tumour-induced hypercalcemia. The recently introduced PTHrP antagonists are hopeful therapeutic measures for the future.


Laparoscopic appendectomy in an adult patient with situs inversus totalis.
Left-sided appendicitis is usually caused by situs inversus totalis or midgut malrotation. Clinical and imaging diagnoses have been presented relatively fully in the literature. However, this is a rare condition, and each related case should be further reported to help the day-to-day clinician better investigate and understand. Therefore, in this paper, we present a case of left-sided acute appendicitis in an adult male patient with situs inversus totalis. In addition, we also discuss the laparoscopic technique of the left-sided appendectomy as it is technically more difficult because of the mirror nature of the anatomy.


Update on TB, waterlines, ventilation and ergonomics.
As the study of diseases changes, the focus must remain the same: To provide the highest quality of care in the safest healthcare environment. It is absolutely necessary to continue a relentless pursuit to keep current with new emerging diseases and adapt solutions that eliminate waterline contamination, support ventilation standards, and ergonomic practices as they apply to dentistry. It's not enough to eliminate the symptom, we must prevent the cause. The standard of care must be constantly challenged with an awareness and acceptance to improve modes of operation as they become necessary. This commitment, in and of itself, allows us to take a proactive approach in ensuring not only our own futures, but also those of whom we serve.


Biomimetic human lung-on-a-chip for modeling disease investigation.
The lung is the primary respiratory organ of the human body and has a complicated and precise tissue structure. It comprises conductive airways formed by the trachea, bronchi and bronchioles, and many alveoli, the smallest functional units where gas-exchange occurs via the unique gas-liquid exchange interface known as the respiratory membrane. In vitro bionic simulation of the lung or its microenvironment, therefore, presents a great challenge, which requires the joint efforts of anatomy, physics, material science, cell biology, tissue engineering, and other disciplines. With the development of micromachining and miniaturization technology, the concept of a microfluidics-based organ-on-a-chip has received great attention. An organ-on-a-chip is a small cell-culture device that can accurately simulate tissue and organ functions in vitro and has the potential to replace animal models in evaluations of drug toxicity and efficacy. A lung-on-a-chip, as one of the first proposed and developed organs-on-a-chip, provides new strategies for designing a bionic lung cell microenvironment and for in vitro construction of lung disease models, and it is expected to promote the development of basic research and translational medicine in drug evaluation, toxicological detection, and disease model-building for the lung. This review summarizes current lungs-on-a-chip models based on the lung-related cellular microenvironment, including the latest advances described in studies of lung injury, inflammation, lung cancer, and pulmonary fibrosis. This model should see effective use in clinical medicine to promote the development of precision medicine and individualized diagnosis and treatment.


Regulatory claims made by US businesses engaged in direct-to-consumer marketing of purported stem cell treatments and exosome therapies.
Aim: This study investigated whether US businesses engaged in direct-to-consumer online marketing of purported stem cell therapies and stem cell-derived exosome products made claims concerning the regulatory status of these interventions. Methods: We used data mining and content analysis of company websites to examine regulatory-related representations made by US businesses marketing stem cell treatments and exosome therapies. Results: More than two thirds of such businesses did not make explicit representations about the regulatory status of their marketed products. Businesses that made claims about the regulatory status of the stem cell and exosome products they sold used range of representations concerning the legal standing of these interventions. Conclusion: The absence of information addressing the regulatory status of stem cell interventions and exosome products and the use of what appeared to be inaccurate information concerning the regulatory status of numerous products likely complicates efforts by customers to make informed health-related decisions.


Power and sample size computations in simultaneous tests for non-inferiority based on relative margins.
In this paper, we address the problem of calculating power and sample sizes associated with simultaneous tests for non-inferiority. We consider the case of comparing several experimental treatments with an active control. The approach is based on the ratio view, where the common non-inferiority margin is chosen to be some percentage of the mean of the control treatment. Two power definitions in multiple hypothesis testing, namely, complete power and minimal power, are used in the computations. The sample sizes associated with the ratio-based inference are also compared with that of a comparable inference based on the difference of means for various scenarios. It is found that the sample size required for ratio-based inferences is smaller than that of difference-based inferences when the relative non-inferiority margin is less than one and when large response values indicate better treatment effects. The results are illustrated with examples.


Purification and subunit structure of RNA polymerase II from different stages of Artemia development.
RNA polymerase II has been purified from different stages of Artemia development: cryptobiotic gastrulae, developing embryos and nauplii. RNA polymerase from dormant and developing embryos consists of 12 subunits of 205 000, 140 000, 32 500, 25 600, 22 000, 19 400, 18 000, 16 800, 147 000, 14 000, 12 700 and 11 500 daltons, as determined by dodecyl sulphate polyacrylamide gel electrophoresis. The enzyme from larvae contains the same polypeptides except for the higher-molecular-mass component: the larval enzyme has a subunit of 172 kDa instead of the 205-kDa subunit present in the enzyme purified from embryos. Incubation of embryonic RNA polymerase II with larval extracts results in the conversion of the 205-kDa subunit into the 172-kDa one. This conversion is inhibited by soybean trypsin inhibitor, a compound which inhibits three proteases induced during Artemia early larval development. RNA polymerase II purified from a mixture of embryos and larvae contain only the 172-kDa subunit. Our results indicate that the 172-kDa subunit present in RNA polymerase II purified from larvae is produced by proteolysis of the 205-kDa subunit during the extraction and purification of the enzyme and therefore that Artemia has only one class of RNA polymerase II.


Effect of catheter position on thermodilution cardiac output during continuous positive-pressure ventilation.
PEEP may decrease regional perfusion to nondependent lung regions, thereby creating different zones of thermal dissipation in dependent and nondependent zones of the lung. Under these conditions, the measurement of cardiac output by thermodilution may, thus, be influenced by the vertical position of the pulmonary artery catheter in the lung. We investigated this hypothesis in 7 healthy, anesthetized pigs by comparing cardiac output measurements from thermistors located in dependent and nondependent lung regions at varying levels of PEEP. Our data from thermistors in these 2 positions were similar, suggesting that the measurement of cardiac output by thermodilution is not influenced by the vertical position of the thermal sensor with respect to the left atrium.


Longitudinal change of HBsAg in HBeAg-negative patients with genotype B or C infection.
Quantitative HBsAg has been recognized to assist in the management of chronic hepatitis B virus (HBV) infection. However, its role in disease monitoring of HBeAg-negative patients remains unclear. We aimed to investigate the longitudinal HBsAg change in HBeAg-negative carriers with HBV genotype B or C infection. This is a retrospective cohort study conducted in a university hospital. Treatment-naïve HBeAg-negative carriers followed for more than 3 years were recruited. Their hepatitis activities were categorized by longitudinal HBV-DNA levels into high viral-load (HVL: HBV-DNA >/ =2000 IU/mL persistently), low viral-load (LVL: HBV-DNA <2000 IU/mL persistently) and fluctuated viral-load (FVL: HBV-DNA between HVL and LVL). The baseline and end-of-follow-up (EOF) HBsAg levels were quantified for analyses. We recruited 187 patients with a median follow-up of 8 years. LVL patients had a significantly lower HBsAg at baseline and EOF and a significantly greater annualized HBsAg decline compared with the FVL and HVL. The longitudinal HBsAg change was independent of genotype B or C. The lower baseline HBsAg level predicted the HBsAg decline and HBsAg loss, whereas the higher baseline HBV-DNA predicted the hepatitis flare. A baseline HBsAg <50 IU/mL predicted subsequent HBsAg loss with a sensitivity of 82% and specificity of 67%. The annualized HBsAg decline appeared non-linear, and accelerated as the HBsAg level lowered (0.054, 0.091, 0.126 log(10) IU/mL in patients with baseline HBsAg >1000, 100-999, <100 IU/mL, respectively, P for trend= .014). In genotype B or C HBeAg-negative carriers, baseline HBsAg levels correlate with future disease activities and help to predict HBsAg decline or loss. Inactive carriers with lower baseline HBsAg levels have a greater and accelerating HBsAg decline over time, regardless of HBV genotypes.


Sugarcane Pulp Take-Out Containers Produce More Microparticles in Acidic Foods.
In the current study, the production of microparticles released from fifteen commercial sugarcane pulp (SCP) take-out containers into different food simulants under different conditions was investigated, where deionized water (DI water), 4% acetic acid (4% HAc), and 95% ethanol (95% EtOH) were used to simulate aqueous, acidic, and fatty foods, respectively. Results showed that compared with DI water and 95% EtOH, 4% HAc caused the degradation of sugarcane fibers, thereby releasing the highest number of microparticles. The overall migration values of the sugarcane pulp take-out containers in 4% HAc were above the prescribed limit of 10 mg/dm2. Furthermore, it was estimated that consumers may intake 36,400-231,700 microparticles in a take-out container at one time, of which the proportion of particles with a particle size between 10 and 500 μm was the highest, ranging from 26,470 to 216,060 items. Moreover, the Al and Fe are the main metals in these take-out containers, ranging between 35.16 and 1244.04 and 44.71 and 398.52 mg/kg, respectively, followed by Pb, Ti, and Sr. This study provides important information that the safety of both the production of microparticles and the metallic elements should be considered for SCP take-out containers when in contact with food.


Lipid and cell membranes in the presence of gadolinium and other ions with high affinity to lipids. 1. Dipole and diffuse components of the boundary potential.
Two methods were used for monitoring the changes in the boundary and surface potentials induced by Gd3+ adsorption--the method of intramembranous field compensation applied to planar BLM and electrophoresis of liposomes, respectively. The data of both methods agree well in the case of membranes made from phosphatidylcholine (PC), in contrast to those made from phosphatidylserine (PS). In the latter case, they show a significant discrepancy between potential amplitudes even within the micromolar range of Gd3+ concentrations because of cation-induced changes in the dipole component of the boundary potential. The adsorption of these cations with extremely high affinities to lipids was described by the theory of diffuse double layer (Gouy-Chapman-Stern) combined with the condition of mass balance, which is essential in the case of limited volumes of real systems. The electrokinetic data for PS and PC liposomes are in good agreement with the modified theory and correlate well with the Gd3+ association constants of 5.10(4) and 10(3) M-1, respectively. The same theory was used to extract the changes in the dipole component from the measured changes in the PS membrane boundary potential. The dependence of this component on the number of binding sites occupied by cation was shown to be nonlinear but cooperative with the step-like increase of dipole potential up to about 140 mV (positive inside the membrane) at the Gd3+ concentration around the zero charge point of the PS membranes. This potential corresponds to the structural changes in the lipid bilayers which are discussed with respect to the Gd3+ blocking effects on the mechanosensitive channels.


Getting Real about body image: A qualitative investigation of the usefulness of the Aerie Real campaign.
This study qualitatively examined perceptions of the Aerie Real campaign that utilized images that had not been digitally modified, as well as its capacity to contribute to positive body image. A sample of 35 college women, of mean age of 19.48 (range = 18-23 years) participated in individual interviews focused on their perceptions and reactions to the images included in the Aerie Real campaign. They also described the impact of the campaign on their brand perceptions and consumer intentions, as well as their attitudes towards social policy targeting the use of digital airbrushing. Most participants reacted to the images positively and perceived them as representing body diversity across several dimensions. In addition, the majority of participants found the images to be helpful for promoting positive body image and acceptance, through both appearance comparisons, and the modeling of body confidence. In addition, many participants expressed being more likely to purchase products from Aerie and support for the brand. Overwhelmingly, participants called for widespread portrayals of diverse bodies in media, although only partial support emerged for achieving this through policy. These findings support the usefulness of increasing body diversity in media and limiting thin-ideal images as means of promoting positive body image.


Good publication practice as a prerequisite for comparable enzyme data?
Systems level investigation of genomic and proteomic scale information requires incomparably higher demands for data quality than in previous decades. Truly integrated databases that deal with heterogeneous data need to be developed to be able to retrieve properties of genes, for kinetics of enzymes, for behaviour of complex networks and for the analysis and modelling of complex biological processes. Despite the fast paced global efforts in biological systems research, the current analyses are limited by the lack of available systematic collections of comparable functional enzyme data. Besides its reliability, these data have to provide defined minimum experimental information, they must be available from the literature along with their accepted enzyme names, and must be as comprehensive as possible. However, the reality reveals a different picture: the quality of experimental data of enzymes is insufficient for the needs of systems level investigations. A 2003 founded working group, called STRENDA, recently published suggestions which intend both to improve the quality of reporting functional enzyme data and to support the comparability of inter alia enzyme kinetics for their application in the in silico investigation of biological systems.


The effect of temporal perception on weight perception.
A successful catch of a falling ball requires an accurate estimation of the timing for when the ball hits the hand. In a previous experiment in which participants performed ball-catching task in virtual reality environment, we accidentally found that the weight of a falling ball was perceived differently when the timing of ball load force to the hand was shifted from the timing expected from visual information. Although it is well known that spatial information of an object, such as size, can easily deceive our perception of its heaviness, the relationship between temporal information and perceived heaviness is still not clear. In this study, we investigated the effect of temporal factors on weight perception. We conducted ball-catching experiments in a virtual environment where the timing of load force exertion was shifted away from the visual contact timing (i.e., time when the ball hit the hand in the display). We found that the ball was perceived heavier when force was applied earlier than visual contact and lighter when force was applied after visual contact. We also conducted additional experiments in which participants were conditioned to one of two constant time offsets prior to testing weight perception. After performing ball-catching trials with 60 ms advanced or delayed load force exertion, participants' subjective judgment on the simultaneity of visual contact and force exertion changed, reflecting a shift in perception of time offset. In addition, timing of catching motion initiation relative to visual contact changed, reflecting a shift in estimation of force timing. We also found that participants began to perceive the ball as lighter after conditioning to 60 ms advanced offset and heavier after the 60 ms delayed offset. These results suggest that perceived heaviness depends not on the actual time offset between force exertion and visual contact but on the subjectively perceived time offset between them and/or estimation error in force timing.


Automated osteoporosis risk assessment by dentists: a new pathway to diagnosis.
General dental practitioners use a vast amount of panoramic radiography in their routine clinical work, but valuable information about patients' osteoporotic status is not collected. There are many reasons for this, but one of the prime reasons must be the disruption involved in clinical routine with lengthy manual radiographic assessment. We have developed computer software, based on active shape modeling that will automatically detect the mandibular cortex on panoramic radiographs, and then measure its width. Automatic or semi-automatic measurement of the cortical width will indicate the osteoporotic risk of the patient. The aim of our work was to assess the computer search technique's ability to measure the mandibular cortical width and to assess its potential for detection of osteoporosis of the hip, spine and femoral neck. Mandibular cortical width was measured using the manually initialized (semi-automatic) method and, when assessed for diagnosing osteoporosis at one of the three measurement sites, gave an area under the ROC curve (A(z))=0.816 (95% CI=0.784 to 0.845) and for the automatically initialized searches, A(z)=0.759 (95% CI=0.724 to 0.791). The difference between areas=0.057 (95% Confidence interval=0.025 to 0.089), p<0.0001. For diagnosing osteoporosis at the femoral neck, mandibular cortical width derived from the manually initialized fit gave an area under the ROC curve (A(z))=0.835 (95% CI=0.805 to 0.863) and for the automatically initialized searches A(z)=0.805 (95% CI=0.773 to 0.835). The difference in A(z) values between active shape modeling search methods=0.030 (95% CI=-0.010 to 0.070), and this was not significant, p=0.138. We concluded that measurement of mandibular cortical width using active shape modeling is capable of diagnosing skeletal osteoporosis with good diagnostic ability and repeatability.


Intrinsic proteins and their effect upon lipid hydrocarbon chain order.
We present evidence that at temperatures greater than their main transition temperature, phospholipid molecules that are trapped within clusters of intrinsic molecules such as polypeptides or proteins have the ends of their hydrocarbon chains more statically disordered than those of lipid molecules far from such intrinsic molecules. We have constructed a model in which the lipids are divided into three populations: (i) those that are not adjacent to any protein ("free" lipids), (ii) those that are adjacent to only one protein ("adjacent" lipids), and (iii) those that are "trapped" between two or three proteins. We applied this model to study deuterium nuclear magnetic resonance of dimyristoyl-3-sn-phosphatidylcholine (DMPC) bilayers containing gramicidin A' or cytochrome oxidase and found that while the methyl groups of adjacent lipids are slightly more statically ordered than those of free lipids, the methyl groups of trapped lipids are more statically disordered than those of free lipids. We propose a physical explanation for this and show that phosphorus-31 nuclear magnetic resonance data for DMPC-cytochrome oxidase bilayers can be understood as a consequence of changes in the polar region of only trapped lipids.


Therapy of experimental meningeal and disseminated cryptococcosis.
This study evaluated the efficacy of itraconazole, a broad-spectrum triazole antifungal drug, which has previously been demonstrated to exhibit activity against Candida albicans C. krusei, C. glabrata, Aspergillus, Histoplasma and Blastomyces as a potential treatment for cryptococcosis. The susceptibility of 62 strains of Cryptococcus neoformans was tested in vitro. All strains were inhibited by itraconazole 0.1 microgram ml-1. Itraconazole was fungicidal after replenishment at a concentration that can easily be achieved in vivo. When mice were infected intracerebrally with Cr. neoformans all control animals died, whereas only 11% and 26% of itraconazole-treated animals died. In a group treated with ketoconazole, 67% died. After intravenous infection, 30% of control guinea pigs died, while other animals treated with itraconazole (5 or 10 mg kg-1) or amphotericin B (1.25 or 2.5 mg kg-1) all survived. Itraconazole 10 mg kg-1 produced the best results, with brain and meningeal cultures becoming negative in 55-64% of animals. In addition, intravenously infected guinea pigs received oral or intraperitoneal treatment with itraconazole or fluconazole (each 5 or 10 mg kg-1) as monotherapy or in combination. Although both treatments were active, itraconazole 10 mg kg-1 was the most effective. In two out of six immunosuppressed guinea pigs infected with Cr. neoformans oral itraconazole was effective, resulting in negative brain and meningeal cultures. A combination of itraconazole (5 mg kg-1) with flucytosine or amphotericin B was more efficacious than monotherapy. Therefore, itraconazole is a potentially effective therapy for the treatment of Cryptococcus infection when administered either alone or in combination with other antifungal drugs. It may also be effective in immunocompromised patients.


Evaluation of efforts in untrained Wistar rats following exercise on forced running wheel at maximal lactate steady state.
We aimed to examine the effect of running speed on metabolic responses associated with maximal lactate steady state (MLSS) in rats during forced running wheel (FRW) exercise. Forty male adult Wistar rats were divided into seven groups. The blood lactate threshold and peak running speed were determined for an incremental power test group. Five groups participated in constant power tests at intensities 10, 13, 14.5, 16, and 17.5 m/min to determine MLSS and a non-exercise group was chosen as the control. Animals were euthanized immediately after constant power tests and their corticosterone, non-esterified fatty acid (NEFA), blood glucose, and creatine kinase (CK) levels analyzed. The differences among groups were identified by one-way analysis of variance (p < 0.05). Blood lactate threshold corresponded a running intensity of 15 m/min, while MLSS was determined to be 16 m/min. Serum corticosterone concentrations were significantly higher in 14.5, 16, and 17.5 m/min groups (298.8±62, 338.3±65, and 354±26 nM, respectively) as compared to that in the control group (210.6±16 nM). Concentrations of NEFA observed in groups 13, 14.5, 16, and 17.5 m/min (662.8±24, 702.35±69, 718.4±34, and 752.8±77 μM, respectively) were significantly higher than those in 10 m/min and control groups (511.1±53 and 412.1±56 μM, respectively). The serum CK concentration recorded for group 17.5 m/min (372.4±56 U/L) was higher than those recorded for other groups. The speed above 16 m/min on FRW resulted in increased physiological demands and muscle damage in untrained healthy Wistar rats.


[Mitral valve prolapse syndrome and arrhythmias].
In patients with mitral valve prolapse syndrome various disturbances of cardiac rhythm can be observed such as atrial arrhythmias, ventricular tachycardias and conduction disturbances. Of timely interest are the questions of which etiology is at the basis of the arrhythmias, what is their relevance with respect to sudden cardiac death, what are the indications for treatment and which therapeutic results can be anticipated. Cardiac arrhythmias represent the most frequent complication of mitral valve prolapse. Holter ECG monitoring has assumed the central role in detection of all types of arrhythmias. As compared with normal persons, in patients with mitral valve prolapse, both ventricular and supraventricular arrhythmias can be found more frequently. Atrial arrhythmias: Supraventricular arrhythmias can be found less frequently than ventricular arrhythmias (Table 1). Premature atrial contractions can be observed in 35% of those with mitral valve prolapse but also in a similar number of normal individuals such that their presence is not of clinical relevance. There is only a tendency to more frequently incurred supraventricular couplets in mitral valve prolapse. Supraventricular tachycardias can be observed in 10.5 to 32% of which sinus tachycardia (heart rate greater than 120 beats per minute), paroxysmal atrial tachycardia and intermittent atrial fibrillation at about 5 to 6% each are not more common than in control subjects. Atrial fibrillation was seen more frequently in mitral valve prolapse with mitral regurgitation or, conversely, in mitral regurgitation due to mitral valve prolapse more frequently than in mitral regurgitation due to other causes.(ABSTRACT TRUNCATED AT 250 WORDS)


Arthroscopic Anatomic Coracoclavicular Ligament Repair Using a 6-Strand Polyester Suture Tape and Cortical Button Construct.
Acromioclavicular separations are common injuries. Low-grade separations are typically managed with nonoperative treatment. However, surgical treatment is recommended for high-grade separations, as well as for chronic low-grade separations that remain symptomatic. Multiple fixation techniques have been described over the past several decades, including Kirschner wires, hook plates, and coracoclavicular screws. More recently, a single-tunnel suture-graft repair and an anatomic reconstruction reproducing both the conoid and trapezoid ligaments have been described. All described techniques have reported complications, including implant migration, need for implant removal, clavicle or coracoid fracture, and loss of reduction. As a result, there is no single optimal method of operative fixation. We describe our technique for an arthroscopically assisted anatomic coracoclavicular repair using a 6-strand suture tape and cortical button construct.


ROR1 Is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells.
The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often observed in primary refractory DLBCL, Richter's syndrome and transformed follicular lymphoma than in relapsed and non-relapsed DLBCL patients (p < 0.001). A survival effect of ROR1 expression was preliminarily observed in relapsed/refractory patients independent of gender and stage but not of age, cell of origin and international prognostic index. A second generation small molecule ROR1 inhibitor (KAN0441571C) induced apoptosis of ROR1+ DLBCL cell lines, similar to venetoclax (BCL-2 inhibitor) but superior to ibrutinib (BTK inhibitor). The combination of KAN0441571C and venetoclax at EC50 concentrations induced almost complete killing of DLBCL cell lines. Apoptosis was accompanied by the downregulation of BCL-2 and MCL-1 and confirmed by the cleavage of PARP and caspases 3, 8, 9. PI3Kδ/AKT/mTOR (non-canonical Wnt pathway) as well as β-catenin and CK1δ (canonical pathway) were inactivated. In zebra fishes transplanted with a ROR1+ DLBCL cell line, KAN0441571C induced a significant tumor reduction. New drugs with mechanisms of action other than those available for DLBCL are warranted. ROR1 inhibitors might represent a novel promising approach.


Single-trial dynamics of hippocampal spatial representations are modulated by reward value.
Reward value is known to modulate learning speed in spatial memory tasks, but little is known about its influence on the dynamical changes in hippocampal spatial representations. Here, we monitored the trial-to-trial changes in hippocampal place cell activity during the acquisition of place-reward associations with varying reward size. We show a faster reorganization and stabilization of the hippocampal place map when a goal location is associated with a large reward. The reorganization is driven by both rate changes and the appearance and disappearance of place fields. The occurrence of hippocampal replay activity largely followed the dynamics of changes in spatial representations. Replay patterns became more selectively tuned toward behaviorally relevant experiences over the course of learning via the refined contributions of specific cell subpopulations. These results suggest that high reward value enhances memory retention by accelerating the formation and stabilization of the hippocampal cognitive map and selectively enhancing its reactivation during learning.


[The nosological structure of the mortality of fetuses\infants with extremely low weight (acccording to the 2004-2008 records of the Kursk Regional Morbid Anatomy Bureau)].
The authors present the results of studying the mortality of fetuses/infants with extremely low weight from the 2004-2008 records of the Children Pathology Department, Kursk Regional Morbid Anatomy Bureau. The nosological structure of pathology in late miscarriages points to the potential possibilities of reducing mortality rates, by rendering medical aid to pregnant women. The problems of early detection of fetal malformations and those of postmortem diagnosis of intrauterine infections retain their topicality.


Dyskinesia analysis. Histogram analysis of cineseismograms of human dyskinesia.
The report presents a method developed to analyze strip chart records generated by a system previously described and termed cineseismography which makes available quantitative records of abnormal involuntary movements in the human. In this report, method for converting measurements made on the strip chart record is described. Application of the method is made in three cases with diagnosis of Huntington's disease (chorea). Case histories are presented for each subject detailing the medications and dosage, and the quantitative data together with the histograms derived are provided. Preliminary trials indicate that movement decomposition, as in ataxia, can also be detected and quantified.


[Early childhood oligoarthritis (antinuclear antibody positive) in alpha 1-antitrypsin deficiency of the PiIZ type].
A 15 months old girl with gonarthritis, and positive antinuclear autoantibodies was found to have a genetically determined alpha 1-antitrypsin deficiency of the rare protease inhibitory (Pi) type IZ. The possible significance of a disturbed equilibrium of cellular inflammation-promoting proteases and extracellular protease inhibition for the pathogenesis of chronic arthritis is discussed using as illustration the presented case.


Role of intra- and extracellular calcium in histamine release from rat peritoneal mast cells.
The present study provides evidence for a number of calcium pools important in histamine secretion from the mast cell. Firstly, calcium loosely bound to the cell membrane, and in rapid equilibrium with the extracellular environment, may be utilized for histamine release induced by most secretagogues. Secondly, all inducers are able to mobilize deeply buried or internal stores of calcium to initiate exocytosis. Finally, calcium bound to regulatory sites in the membrane may modulate the secretory process. Removal of calcium from the latter sites by brief treatment with chelating agents markedly enhances the secretory response in the absence of extracellular calcium, probably by facilitating the mobilization of bound stores of the ion. Saturation of these sites in the presence of excess calcium inhibits the release process and may restrict influx of the cation.


Dr. X: the consequences of untreated addiction.
The following case example shows the difficulty dentists face when their alcohol or drug dependence causes them to violate laws or the Dental Practice Act. In this case, the dentist is charged with driving while intoxicated (DWI) and is in possession of inappropriately prescribed medications.


Shifting to a control diet after a high-fat, high-sucrose diet intake induces epigenetic changes in retroperitoneal adipocytes of Wistar rats.
The aim of the study was to analyze the phenotypic and epigenetic changes induced by the shift to a chow diet after an obesogenic environment. Animals were randomized to fed chow (control group) or high-fat-sucrose diet (HFS). After 10 weeks, half of the rats fed with HFS diet were reassigned to a chow diet (rest group) while the other half continued with the obesogenic diet (HFS group) until week 20. Changes in fat content, biochemical profile, and DNA methylation levels of several gene promoters from retroperitoneal adipocytes were analyzed. HFS diet intake for 10 weeks induced obese phenotype in the animals, increasing body weight and fat content. These effects were maintained until the end of the trial in HFS group, where an increase in liver fat content, a modification of lipid profile, and retroperitoneal adipose tissue hypertrophy were also observed. Changing the dietary pattern reversed these parameters. Epigenetic analysis showed that HFS diet intake for 20 weeks hypermethylated several CpG sites (6.7 and 29.30) and hypomethylated CpG site 15 from leptin gene promoter. Moreover, the obesogenic diet also hypomethylated CpG site 1 from Fasn (fatty acid synthase) gene promoter, without changes on Ppargc1a (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), Srebf1 (sterol regulatory element-binding transcription factor 1), and aquaporin 7. Shifting to a chow diet reverted HFS-induced DNA methylation levels of some CpG sites of leptin promoter. Changing the dietary pattern hypomethylated a CpG site of Srebf1 and hypermethylated other CpGs on Ppargc1a and Fasn promoter. This study shed light on the reversibility of phenotypical and epigenetic changes induced by a HFS diet intake.


Balance of coordination and hydrophobic interaction in the formation of bilayers in metal-coordinated surfactant mixtures.
Metal-ligand coordination and hydrophobic interaction are two significant driving forces in the aggregation of mixtures of M(n+) surfactants and alkyldimethylamine oxide (CnDMAO) in aqueous solutions. The coordinated systems exhibit rich aggregation behavior. This study investigated the effect of M(n+) ions (Zn(2+), Ca(2+), Ba(2+), Al(3+), Fe(3+), La(3+), Eu(3+), and Tb(3+)) and hydrophobic chains (hydrocarbon and fluorocarbon) on the formation of metal-coordinated bilayers. We found that fluorocarbon chains and branched hydrocarbon chains are preferable to the corresponding linear hydrocarbon chains for the formation of an Lα phase. Moreover, Lα phases formed by fluorocarbon chains exhibited higher viscoelasticity than ones formed by the hydrocarbons, and the bilayers formed by branched chains were rather flexible, revealing obvious undulation. The construction of bilayers was also strongly affected by metal ions due to their variable coordination ability with CnDMAO. Our results contribute to the understanding of the formation of metal-coordinated bilayers, which is driven by the interplay of noncovalent forces.


Is Neck Circumference an Indicator for Metabolic Complication of Childhood Obesity?
The possible role of neck circumference (NC) for screening childhood obesity and its complication is not well characterized. To assess NC and to explore its increase as risk factor with metabolic syndrome (MS) variables. Cross sectional case-control study included 50 obese children (BMI ≥95(th) percentile) and 50 healthy (BMI 15(th)-‹85(th) percentile). All were subjected to clinical examination, measuring blood pressure (BP), body weight, height, NC, waist (WC) and hip (HC)., fasting blood glucose, insulin and lipid profile. MS was detected among 52% of obese participants, but not among controls (0%). Clinical parameters and most of the laboratory values were higher in subjects with MS than in non-metabolic subjects, with statistical significance only in blood pressure and triglycerides. Among obese without MS, NC showed significantly positive correlations with age, weight, height, WC, HC and negative with LDL. While among Obese with MS, NC showed significantly positive correlations with age, weight, height, BMI-SDS, WC, HC and DBP. NC can be considered as a good indicator and predictor for obesity, especially central obesity. However, NC has no relation with lipid profile or fasting blood sugar.


Instantaneous flow rate of vitreous cutter probes.
We report on instantaneous volumetric flow rate of vitreous cutters measured by means of particle image velocimetry (PIV). In an in vitro experimental study, vitreous cutters mounting a regular blade (RB) or modified Twedge blade (TB) engineered for higher flow were connected to a console machine equipped with a double peristaltic and Venturi pump, and immersed in balanced salt solution (BSS). Instantaneous flow was measured on aspiration tubing sections proximal to the cutter hand piece. Measures settings were as follows: (1) regular functioning at 3000 and 6000 cuts per minute (cpm) with 300 mm Hg aspiration with both pumps, (2) aspiration tubing clamped proximal to pump cassette, and (3) aspiration tubing clamped proximal to hand piece, and (4) flow fluctuation as a function of cut rate also was calculated. For main outcome measures, instantaneous volumetric flow rate in mL/min and flow fluctuation measured as the standard deviation of flow rate were measured. Regular functioning shows sinusoidal flow oscillating at cut rate frequency, with amplitude between ±50 mL/min at 3000 cpm and ±35 mL/min at 6000 cpm. The TB always determined a bimodal wave and neither blade nor pump type influenced the sinusoidal pattern of flow. Clamping aspiration tubing zeroes flow, but does not influence fluctuation frequency or amplitude. Clamping at the hand piece determined a significantly higher oscillation. Oscillation amplitude retain a typical resonance pattern with significant changes in function of cut rate and resonance occurs at approximately 4000 cpm. Cutter blade action determines instantaneous flow rate fluctuation that interferes significantly with cutter suction and hampers a steady suction through cutter port. In a surgical scenario, this translates into a higher risk of inadvertent retinal entrapment and lower predictability of cutter behavior, especially at frequency approaching resonance.


Activity-based Therapies in Spinal Cord Injury:: Clinical Focus and Empirical Evidence in Three Independent Programs.
This article summarizes presentations of a symposium examining the potential impact of activity-based therapies (ABT) in promoting neurological and functional recovery after spinal cord injury (SCI). The symposium addressed 3 key questions concerning activity-based therapy in SCI: (1) What clinical approaches are used? (2) Is there empirical evidence supporting efficacy of ABT in promoting neurological recovery and improving overall function, health, and quality of life? (3) What are the issues related to long-term viability of ABT?


Seed rain and soil seed bank in Chinese fir plantations and an adjacent natural forest in southern China: Implications for the regeneration of native species.
The natural regeneration of native broadleaved species underneath forest monoculture plantations is important to recover ecosystem functions and to mitigate adverse environmental effects. To understand how seed rain and soil seed bank facilitate natural regeneration, we surveyed their density and composition in a monoculture Chinese fir plantation, a mixed Chinese fir-broadleaf plantation, and an adjacent natural broadleaved forest for two years in southern China. Twenty-eight species (16 families) were in seed rain, and 45 species (27 families) were in soil seed bank. Seed rain density did not differ significantly across stands; however, the number of taxa in seed rain was highest in the mixed plantation and lowest in the natural forest. Seed bank density was significantly higher in the mixed plantation than in the other stands (p < .05). The Sørensen similarity index of species composition between seed sources and aboveground vegetation were relatively low (<.50). The seeds of various native tree species were common in the seed bank of the plantations, indicating that seed rain and seed bank played an important role in native forest regeneration. We recommend that managers interested in sustainable forestry should take into consideration the presence of existing soil seed bank when developing their management strategies. In addition, with regard to forest regeneration process, we also recommend supplementation of the species composition by direct seeding or planting of desired species.


A pilot study-is there a role for mitoxantrone pleurodesis in the management of pleural effusion due to lung cancer?
Lung cancer is the leading cause of malignant pleural effusion (MPE). Management of MPEs remains a clinical challenge due to recurrence and poor quality of life. An ideal sclerosing agent has yet to be found. The aim of this cohort pilot study was to evaluate the role of mitoxantrone pleurodesis (MP) as an alternative to talc sclerotherapy for managing MPEs in lung cancer patients. A retrospective chart review was conducted on consecutively admitted patients with MPE to the Department of Post-Intensive Care at the Clinic for Respiratory Diseases "Jordanovac", University Hospital Centre Zagreb, in Croatia. Of 34 patients with MPE, twenty-one (64.8±9.46 years; 47-84 years) with primary lung carcinoma who received MP (30 mg of mitoxantrone) between December 2003 and February 2009 were included in this study. Chest radiographs taken prior to sclerotherapy and at 1-, 2-, and 3-month follow-up were compared. At the post-sclerotherapy evaluation periods, overall success (OS) rates of MP were 88.2% [17.6%, complete response (CR); 70.6%, partial response (PR)], 53.9% (7.7% CR; 46.2% PR), and 45.5% (PR), respectively. Kaplan-Meier median survival from MP until death was 5.2 months, while that from diagnosis of primary lung cancer was 12.3 months. MP may be a safe and effective method of managing MPE due to lung cancer. Future randomized controlled studies comparing mitoxantrone and talc pleurodesis in lung cancer patients are warranted to elucidate whether a significant difference exists between these agents. Factors affecting success, survival probability, and quality of life also require further investigation.


Vitiligo: Focus on Clinical Aspects, Immunopathogenesis, and Therapy.
Vitiligo is an acquired chronic depigmenting disorder of the skin, with an estimated prevalence of 0.5% of the general population, characterized by the development of white macules resulting from a loss of epidermal melanocytes. The nomenclature has been revised after an extensive international work within the vitiligo global issues consensus conference, and vitiligo (formerly non-segmental vitiligo) is now a consensus umbrella term for all forms of generalized vitiligo. Two other subsets of vitiligo are segmental vitiligo and unclassified/undetermined vitiligo, which corresponds to focal disease and rare variants. A series of hypopigmented disorders may masquerade as vitiligo, and some of them need to be ruled out by specific procedures including a skin biopsy. Multiple mechanisms are involved in melanocyte disappearance, namely genetic predisposition, environmental triggers, metabolic abnormalities, impaired renewal, and altered inflammatory and immune responses. The auto-immune/inflammatory theory is the leading hypothesis because (1) vitiligo is often associated with autoimmune diseases; (2) most vitiligo susceptibility loci identified through genome-wide association studies encode immunomodulatory proteins; and (3) prominent immune cell infiltrates are found in the perilesional margin of actively depigmenting skin. However, other studies support melanocyte intrinsic abnormalities with poor adaptation of melanocytes to stressors leading to melanocyte instability in the basal layer, and release of danger signals important for the activation of the immune system. Recent progress in the understanding of immune pathomechanisms opens interesting perspectives for innovative treatment strategies. The proof of concept in humans of targeting of the IFNγ /Th1 pathway is much awaited. The interplay between oxidative stress and altered immune responses suggests that additional strategies aiming at limiting type I interferon activation pathway as background stabilizing therapies could be an interesting approach in vitiligo. This review covers classification and clinical aspects, pathophysiology with emphasis on immunopathogenesis, and promising therapeutic approaches.


An outbreak in 1996 of cyclosporiasis associated with imported raspberries. The Cyclospora Working Group.
Cyclospora cayetanensis is a parasite that causes gastroenteritis. Until last year most of the documented cases of cyclosporiasis in North America were in overseas travelers. In 1996, a large outbreak of cyclosporiasis occurred in North America. We investigated this outbreak. Health departments solicited information from clinicians and laboratories on cases of cyclosporiasis, which were then reported to the Centers for Disease Control and Prevention and to Health Canada. We conducted retrospective cohort studies for the cases associated with events (e.g., luncheons) and attempted to identify the sources of the implicated food. A total of 1465 cases of cyclosporiasis were reported by 20 states, the District of Columbia, and 2 provinces. Of these cases, 978 (66.8 percent) were laboratory confirmed and 725 (49.5 percent) were associated with 55 events that were held from May 3 through June 14. Raspberries were definitely served at 50 events and may have been served at 4 events. For 27 of the 41 events for which adequate data were available (65.8 percent), the associations between the consumption of berries (raspberries with or without other berries) and cyclosporiasis were statistically significant (P<0.05). For all 29 events for which there were good data, the raspberries definitely came from Guatemala (21 events, 72.4 percent) or may have come from Guatemala (8 events, 27.6 percent). As few as five Guatemalan farms could have accounted for the 25 events for which the raspberries could be traced to a single exporter per event. The mode of contamination of the raspberries remains unclear. This large outbreak of cyclosporiasis in North America in 1996 was associated with the consumption of Guatemalan raspberries. The outbreak illustrates the need to consider that a local cluster of foodborne illness may be part of a widespread outbreak and to pursue investigations to the source of the implicated vehicle.


Administering ascorbic acid to rats undergoing ageing processes: effects on myosin-V immunoreactive myenteric neurons.
During the ageing process the enteric nervous system undergoes morphofunctional changes, such as enteric neurodegeneration. Neuronal death can be attributed to increase radicals free, and ascorbic acid (AA), known antioxidant, could minimize damage cause by oxidative stress. The objective of this study is to analyse the behaviour of morphoquantative myenteric neurons in the duodenum of adult Wistar rats with aged 90 (C90), 345 (E345) and 428 (E428) days, as well as animals of the same age who received ascorbic acid supplementation for 120 days (EA345 and EA428). Whole-mount preparations of muscle layer from the duodenum of the animals were immunostained by the method myosin V. 80 microscopic fields were quantified (14.8 mm2/animal) and measured 100 neuronal cell bodies per animal. During the aging process, there was a reduction in neuronal density in all animals groups, indicating that the effects of age were not attenuated with AA supplementation. The increase in the neuronal area of the cell bodies in 428-day-old animals proved the influence of age on this parameter. There was no observed a neuroprotective effect of AA (1 mL/g body weight) on the neuronal population myenteric myosin V immunoreactive.


Synthesis and NMR spectroscopy of peptides containing either phosphorylated or phosphonylated cis- or trans-4-hydroxy-L-proline.
Many proteins are regulated by reversible O-glycosylation and O-phosphorylation. Whereas O-glycosylation of hydroxy-L-proline is common and well investigated, phosphorylation has not been proved so far in vivo, but this post-translational modification is entirely possible. As a first step to identify this phosphoamino acid, we describe both the syntheses of peptides phosphorylated at 4-hydroxy-L-proline and the 1H and 31P NMR parameters of these phosphopeptides. The model peptides were synthesized on solid-phase using Fmoc-strategy. Both natural isomers of 4-hydroxy-L-proline (containing the hydroxyl group in either the cis or trans position) were introduced without side-chain protection. All peptides were globally phosphorylated with O,O'-tert-butyl-N,N-diethylphosphoramidite on the solid phase and cleaved with trifluoroacetic acid. Additionally, we synthesized two classes of phosphonopeptides that mimic phosphopeptides, namely H- and methylphosphonopeptides. The NMR data were based on the model peptide Gly-Gly-Hyp-Ala, which is regarded as a typical random-coil sequence. The NMR parameters showed a significant influence of the phosphate group on the cis-trans isomerization of the Gly-Hyp bond, which may reflect a possible regulation of proteins by changing their local conformations. The 1H and 31P NMR parameters differed for each isomer, and were distinct from the parameters of phosphorylated serine, threonine and tyrosine. These known shifts can be used to identify both cis- and trans-O-phospho-4-hydroxy-L-proline in vivo.


Palytoxin induces an increase in the cation conductance of red cells.
Palytoxin (PTX), isolated from the marine soft coral Palythoa tuberculosa, increases the cation conductance of human red cell membranes. In the presence of 10(-10) M PTX and 10(-5) M DIDS, the membrane potential approximates the equilibrium potential for Na+ or K+ rather than Cl-. Even in the absence of DIDS, the Na+ and K+ conductances were greater than the Cl- conductance. The selectivity of the PTX-induced cation conductance is K+ greater than Rb+ greater than Cs+ greater than Na+ greater than Li+ much greater than choline+ greater than TEA+ much greater than Mg2+. Measurements of K+ efflux revealed two apparent sites for activation by PTX, one with a Kal of 0.05 nM and a maximum flux, nu max1, of 1.4 mol/liter of cells per h and another with a Ka2 of 98 nM and a nu max2 of 24 mol/liter of cells per h. These effects of PTX are completely blocked by external ouabain (300 microM) and prevented by internal vanadate (100 microM). When the PTX channels are open, the Na,K pumps do not catalyze ATP hydrolysis. Upon thorough washout of cells exposed to about five molecules of PTX/pump, the Na,K pump of these cells operates normally. Blockage of the positively charged NH2 terminus of PTX with a p-bromobenzoyl group reduces the potency of the compound to induce Na and K fluxes by at least a factor of 100, and to compete with the binding of [3H]ouabain by at least a factor of 10. These data are consistent with the conclusion that PTX binds reversibly to the Na,K pumps in the red cell membrane and opens a (10-pS) channel equally permeable to Na and K at or near each pump site.


Pulmonary mucormycosis diagnosed by convex probe endobronchial ultrasound-guided fine needle aspiration of cavity wall.
Pulmonary mucormycosis is an opportunistic fungal infection in immunocompromised individuals. It is difficult to diagnose as it requires tissue biopsy, and generally these patients are unfit to undergo invasive lung biopsies. We describe a novel technique in a case with uncontrolled diabetes mellitus with nonresolving pulmonary cavitary disease where convex probe endobronchial ultrasound (EBUS)-guided aspiration of lung cavity wall showed classical histopathological picture establishing the diagnosis of mucorale infection. EBUS being real-time, minimally invasive technique with minimal risk of complications, led to early diagnosis, and prompt treatment. This appears to be a novel diagnostic modality in pulmonary mucormycosis with minimal complications as compared with other biopsy methods with very high complication risk.


Continuous abdominal paracentesis for management of late type severe ovarian hyperstimulation syndrome.
The ovarian hyperstimulation syndrome (OHSS) is often observed in patients undergoing assisted reproductive technology (ART). In severe form OHSS is a serious and potentially life-threatening. Here we report a 36-year-old woman with primary infertility due to endometriosis who underwent controlled ovarian hyperstimulation. Ten days later, severe late-onset ovarian hyperstimulation syndrome, severe ascites and pulmonary effusion, developed. Continuous abdominal paracentesis of 5000 mL/day was performed on the third day. With this procedure, ascitic fluid was drained efficiently and the patient's condition improved. This report suggests that early continuous abdominal paracentesis with drainage of ascitic fluid is an efficacious procedure for management of the severe ovarian hyperstimulation syndrome as soon as euvolemia is achieved clinically.


A Health Assessment Survey of Veteran Students: Utilizing a Community College-Veterans Affairs Medical Center Partnership.
To assess health status among student veterans at a community college utilizing a partnership between a Veterans Affairs Medical Center and a community college. Student veterans at Cuyahoga Community College in Cleveland, Ohio, in January to April 2013. A health assessment survey was sent to 978 veteran students. Descriptive analyses to assess prevalence of clinical diagnoses and health behaviors were performed. Logistic regression analyses were performed to assess for independent predictors of functional limitations. 204 students participated in the survey (21% response rate). Self-reported depression and unhealthy behaviors were high. Physical and emotional limitations (45% and 35%, respectively), and pain interfering with work (42%) were reported. Logistic regression analyses confirmed the independent association of self-reported depression with functional limitation (odds ratio [OR] = 3.3, 95% confidence interval [CI] 1.4-7.8, p < 0.05, and C statistic 0.72) and of post-traumatic stress disorder with pain interfering with work (OR 3.9, CI 1.1-13.6, p < 0.05, and C statistic 0.75). A health assessment survey identified priority areas to inform targeted health promotion for student veterans at a community college. A partnership between a Veterans Affairs Medical Center and a community college can be utilized to help understand the health needs of veteran students.


Neuroleptic malignant syndrome: long-term follow-up of 20 cases.
The authors obtained long-term follow-up data on 20 (91%) of the 22 patients who had experienced index episodes of neuroleptic malignant syndrome (NMS) at McLean Hospital between 1983 and 1990. Eleven of the 20 patients resumed neuroleptic treatment after the index episode and have now collectively received more than 16 years of neuroleptic exposure with no recurrences of the syndrome. Furthermore, 14 of the 20 patients had already collectively accumulated more than 71 additional years of neuroleptic exposure before their index episodes; only 1 had experienced a possible episode of NMS in the past. These findings suggest that NMS may not predictably develop even in predisposed individuals upon neuroleptic exposure and that additional cofactors must be present for the full syndrome to evolve.


Prosthetic Mitral Valve Endocarditis Complicated by Left Ventricular Pseudoaneurysm.
Left ventricular pseudoaneurysm is a rare complication that can result from mitral valve replacement. Proper follow-up imaging can help to detect this potentially fatal complication and identify areas of concern. Infective endocarditis following mitral valve replacement can occur and further lead to the development of a pseudoaneurysm. We describe a case of left ventricular aneurysm in the setting of infective endocarditis following mitral valve replacement and present radiologic images from various modalities detailing the major findings.


Impacts of rTMS on Refractory Depression and Comorbid PTSD Symptoms at a Military Treatment Facility.
Repetitive transcranial magnetic stimulation (rTMS) as a treatment for depression has been studied for over two decades. Repetitive TMS was approved by the Food and Drug Administration in 2008 for the treatment of depression after at least one failed trial of an antidepressant medication of adequate dose and duration. This study evaluated whether rTMS treatments may be associated with measurable improvements in depression and post-traumatic stress disorder (PTSD) symptoms for treated military beneficiaries in Hawaii suffering from depression. It also examined the number of failed medication trials that patients underwent before rTMS treatment. A retrospective chart review of 77 rTMS patients who received and completed treatment between January 1, 2010 and October 31, 2016 was performed. Under a typical treatment regimen, patients receive rTMS for 6 weeks as well as weekly psychiatric assessments, which included completion of Beck's Depression Inventory (BDI) and PTSD Checklist (PCL). A mixed model repeated measures analysis was done assuming an autoregressive order one covariance structure to evaluate changes over time. Adjusted analyses were done to assess whether changes over time differed by age, prior diagnosis of PTSD, active duty status, and gender. The majority of patients were from the army (74%) and 56% were on active duty. Just over half (53%) were male. Most patients (52%) had completed trials of three or more different antidepressant medications before initiation of treatment with rTMS. The mean number of antidepressant trials was 2.7. BDI and PCL scores were significantly lower at end of treatment on average compared to the pretreatment baseline scores. Mean differences for BDI and PCL were significant with P < 0.001 15, 30, and 45 days after TMS treatment was initiated. Overall, 44% of patients experienced a reduction ≥10 points on BDI, and 38% experienced a reduction ≥10 points on PCL. Additionally, scores fell similarly regardless of whether or not patients had a comorbid diagnosis of PTSD. Our research suggests that rTMS treatments may produce a reduction in symptoms of both depression and PTSD in patients with refractory depression and comorbid PTSD. It may be a useful alternative to antidepressants in the treatment of depression in the military population, including those with comorbid PTSD. Broader implementation of this treatment modality may prove beneficial for the purposes of military readiness, given current policies and restrictions on service members who are initiated on antidepressant medications.


RNA synthesis in rabbit endometrial nuclei. Hormonal regulation of transcription of the uteroglobin gene.
Endometrical nuclei, prepared from rabbits subjected to different hormonal treatments, were used for the cell-free synthesis of RNA. Optimal conditions for the incorporation of [3H]UMP into RNA are described, leading to the synthesis of relatively undegraded RNA molecules. Under these conditions there is virtually no initiation of new RNA chains in vitro, and RNA chain elongation is inhibited up to 60% by low concentrations of alpha-amanitin and up to 90% by actinomycin D. The synthesis of RNA is slightly inhibited in the presence of Hg-CTP and monothioglycerol, but newly synthesized mercurated RNA can be efficiently separated from endogenous RNA upon chromatography on sulfhydryl-Sepharose under stringent conditions. The RNA synthesized in vitro by endometrial nuclei from pseudopregnant rabbits contains RNA sequences transcribed from the uteroglobin gene, as demonstrated by hybridization to an excess of purified preuteroglobin cDNA. In endometrial cells from pseudopregnant animals the number of RNA polymerase II molecules transcribing the uteroglobin gene is 12-fold higher than in control animals, demonstrating that at least part of the hormonally induced accumulation of preuteroglobin mRNA is due to an increased rate of transcription of the uteroglobin gene.


Infiltration and inflow in combined sewer systems: long-term analysis.
A study was conducted on 34 German combined sewer systems including combined sewer overflow (CSO) tanks and treatment plant to show up actual hidden reserves and bottlenecks in stormwater treatment. The study gave also a general insight into the water pathways in urban hydrology. A special focus was given to undesired non-polluted water infiltrating into the sewer, labelled infiltration and inflow (I/I) or infiltration inflows, which is widely underestimated. It leads to a bad performance of the drainage system although the parasite waters are themselves non-polluted. In existing combined systems, pollution control can be considerably improved by reducing I/I. It is equivalent to the reduction of surface runoff e.g. by a separate drainage as frequently proposed alternative. Artificial infiltration of surface runoff may even increase infiltration inflows.


Development of a Selective Medium for the Fungal Pathogen Cylindrocarpon destructans Using Radicicol.
The soil-borne ascomycete fungus Cylindrocarpon destructans causes ginseng root rot disease and produces various secondary metabolites such as brefeldin A and radicicol. The slow growth of this fungus compared with other plant pathogenic and saprophytic fungi in soil disturbs isolation of this fungus from soil and infected ginseng. In this study, we developed a selective medium for C. destructans using radicicol produced by this fungus. Supplementing 50 mg/L of radicicol to medium inhibited the mycelia growth of other fungi including Botrytis cinerea, Rhizoctonia solani and Alternaria panax, but did not affect the growth of C. destructans. In addition, conidia germination of other fungal species except for C. destructans was inhibited in submerged culture supplemented with radicicol. This medium provides a very efficient tool for isolating C. destructans and also can be used as an enrichment medium for this fungus.


Histopathological maladaptive changes in the explanted human mitral leaflets correlate with changes in echocardiographic leaflet morphology and the severity of ischaemic mitral regurgitation.
Several changes of the mitral valve (MV) morphology have been previously documented in ischaemic mitral regurgitation (IMR) upon macro and microscopic examination. This study aimed to correlate echocardiographic MV thickening with IMR severity and to delineate the histopathological basis of valve thickening from the explanted leaflets. Two hundred and fifty patients were included in the echo-group; of these, 48 patients (19.2%) underwent surgical mitral valve replacement (MVR), including them in the histology-group. By echocardiography, the thickness of the anterior and posterior leaflet was more extensive in moderate to severe IMR, P < 0.001. Histology-group: patients were divided into two groups based on the median thickness: those with cusp thickness <0.42 cm in Group 1, and ≥0.42 cm in Group 2. The thickness of the base and cusp was more significant in Group 2, P < 0.05 in both. Group 2 biopsies were characterized by involvement of the three leaflet segments, myxoid tissue, and fibrosis deposition. Thicker leaflets were associated with a greater degree of mitral regurgitation (MR), P < 0.0001. In the echo-group, a median leaflet thickness of 3.5 mm of the anterior and posterior MV was independently associated with moderate to severe ischaemic MR [odds ratio (OR) 2.88, P < 0.01] and (OR 10.8, P < 0.001), respectively. In ischaemic MR, the thicker the cusps, the worse the MR. Leaflet thickening was due to the myxoid and fibrosis deposition and was detected by echocardiography. Therefore, this method can be helpful in the evaluation of valve remodelling.


Developmental cost of leg-regenerated Coccinella septempunctata (Coleoptera: Coccinellidae).
As larval cannibalism is common under intensive rearing conditions, leg regeneration can help ladybugs adapt to the competitive environment, but whether the leg regeneration leads to side effects on development remains unclear. To analyze the potentially developmental cost of leg regeneration, the developmental period and weight of leg-regenerated Coccinella septempunctata were studied in the laboratory. The results showed that, when the time intervals between the emergency of 4th-instar larva and leg amputation increased, the developmental period of leg-regenerated 4th-instar larvae was gradually prolonged. Significantly developmental delay were also examined at prepupal and pupal stages, and various timings of leg amputation affected the periods of leg-regenerated prepupae/pupae similarly. After the leg was amputated at different larval instars, the developmental delay only occurred at the larval instar when the leg was amputated, whereas other larval instars failed to be extended, and the developmental periods of leg-regenerated prepupae/pupae were affected similarly by the instars of leg amputation. Developmental delays possibly resulted in more consumption by leg-regenerated larvae, and then weight gains at prepupal/pupal stages, but different larval instars of leg amputation affected the weight gain similarly. Both the developmental delay (at 4th-instar larval, prepupal and pupal stages) and weight gain (at pupal and adult stages) in complete/bilateral amputation were longer or greater than those in half/unilateral amputation. However, the thoracic locations of leg amputation impacted the developmental delay and weight gain similarly. Our study indicates that although leg regeneration triggers the developmental cost decreasing the competitive superiority or agility, C. septempunctata larvae still choose to completely regenerate the leg to adapt to complex environments. Thus, in order to remain competitive at adult stages, leg-impaired larvae may make an investment tradeoff between leg regeneration and developmental cost.


Descending necrotizing mediastinitis after sequestrectomy in a patient with bisphosphonate-induced osteonecrosis of the jaw: A case report.
An 83-year-old woman underwent mastectomy for breast cancer of the right breast in 2008. In addition to hormone therapy and irradiation, zoledronate was started for bone metastasis 6 months postoperatively. Five years after the operation, the patient developed osteonecrosis of the jaw, and underwent sequestrectomy because of uncontrollable pain in the mandible. The patient visited our hospital for a 1-week history of fever and right facial swelling with pain, and was diagnosed with right mandibular cellulitis. Despite antibiotic therapy, the patient fell into shock. Follow-up computed tomography showed gas formation extending down to the posterior mediastinum, which was compatible with descending necrotizing mediastinitis (DNM). The patient succumbed to septicemia on the third hospital day. The mortality rate of DNM greatly increases in patients with advanced cancer because clinicians cannot perform radical treatment due to the impaired general condition and limited life expectancy. DNM advances by the hour; therefore, repeated computed tomography is essential when antibiotic therapy does not improve the patient's condition. Attention must be paid to detect signs of DNM in such patients. To the best of our knowledge, this is the first report in English regarding DNM caused by bisphosphonate-induced osteonecrosis of the jaw.


The production and immunostimulatory activity of double-stranded CpG-DNA.
CpG-DNA, which contains unmethylated CpG dinucleotides in the context of specific sequences, has remarkable and diverse immunological effects, including induction of proinflammatory cytokine expression and regulation of the Th1/Th2 immune response. Here, we examined the immunostimulatory activities of double-stranded (ds) CpG-DNA in the human B cell line RPMI8226. To investigate whether dsCpG-DNA stimulates immune cells, we constructed a plasmid containing repeated dsCpG-DNA and produced dsCpG-DNA by PCR amplification and EcoR I digestion. PCR-amplified dsCpG-DNA alone did not have immmunostimulatory activity. However, dsCpGDNA encapsulated with lipofectin induced IL-8 promoter activation, HLA-DRA expression, and IL-8 expression in a CG sequence- independent manner. The effects of encapsulated dsCpGDNA were independent of minor endotoxin contamination. These findings suggest the potential use of dsCpG-DNA as a therapy for immune response regulation.


Aging Exacerbates Neuroinflammatory Outcomes Induced by Acute Ozone Exposure.
The role of environmental stressors, particularly exposure to air pollution, in the development of neurodegenerative disease remains underappreciated. We examined the neurological effects of acute ozone (O3) exposure in aged mice, where increased blood-brain barrier (BBB) permeability may confer vulnerability to neuroinflammatory outcomes. C57BL/6 male mice, aged 8-10 weeks or 12-18 months were exposed to either filtered air or 1.0 ppm O3 for 4 h; animals received a single IP injection of sodium fluorescein (FSCN) 20 h postexposure. One-hour post-FSCN injection, animals were transcardially perfused for immunohistochemical analysis of BBB permeability. β-amyloid protein expression was assessed via ELISA. Flow cytometric characterization of infiltrating immune cells, including neutrophils, macrophages, and microglia populations was performed 20 h post-O3 exposure. Flow cytometry analysis of brains revealed increased microglia "activation" and presentation of CD11b, F4/80, and MHCII in aged animals relative to younger ones; these age-induced differences were potentiated by acute O3 exposure. Cortical and limbic regions in aged brains had increased reactive microgliosis and β-amyloid protein expression after O3 insult. The aged cerebellum was particularly vulnerable to acute O3 exposure with increased populations of infiltrating neutrophils, peripheral macrophages/monocytes, and Ly6C+ inflammatory monocytes after insult, which were not significantly increased in the young cerebellum. O3 exposure increased the penetration of FSCN beyond the BBB, the infiltration of peripheral immune cells, and reactive gliosis of microglia. Thus, the aged BBB is vulnerable to insult and becomes highly penetrable in response to O3 exposure, leading to greater neuroinflammatory outcomes.