[A case of successful treatment with intra-arterial infusion chemotherapy with cisplatin for advanced hepatocellular carcinoma with portal vein tumor thrombus].
A 69-year-old man with recurrent hepatocellular carcinoma (HCC) in S7/8 after radiofrequency ablation therapy (RFA)was admitted to our hospital. Serum alpha-fetoprotein and protein induced by vitamin K absence or antagonists (PIVKA-II) were elevated to 367 ng/mL and 18,973 mAU/mL, respectively. Abdominal computed tomography scan revealed that the size of the tumor was 56 mm and a portal vein tumor thrombus progressed from the right anterior branch to the left main branch(Vp3). The clinical stage was cT3N0M0, cStage III(JPS). He received 3 courses of intra-arterial infusion chemotherapy with cisplatin(CDDP IA-call)into the right hepatic artery at a dose of 65 mg/m2 every 2 months. Elevated serum alpha-fetoprotein(AFP)and PIVKA-II markedly decreased and returned to normal levels after the second course of treatment. The liver tumor and portal vein tumor thrombus disappeared, and only arterioportal shunting remained. The response to treatment was partial response (PR) and complete response (CR), according to the Response Evaluation Criteria In Solid Tumors and the modified version, respectively. He has been alive for more than 1 year without recurrence. CDDP is an effective treatment for advanced HCC with portal vein tumor thrombus.


Variation in Women's Preferences Regarding Male Facial Masculinity Is Better Explained by Genetic Differences Than by Previously Identified Context-Dependent Effects.
Women's preferences for masculine versus feminine male faces are highly variable. According to a dominant theory in evolutionary psychology, this variability results from adaptations that optimize preferences by calibrating them to certain contextual factors, including women's self-perceived attractiveness, short- versus long-term relationship orientation, pathogen disgust sensitivity, and stage of the menstrual cycle. The theory does not account for the possible contribution of genetic variation on women's facial masculinity preference. Using a large sample (N = 2,160) of identical and nonidentical female Finnish twins and their siblings, we showed that the proportion of variation in women's preferences regarding male facial masculinity that was attributable to genetic variation (38%) dwarfed the variation due to the combined effect of contextual factors (< 1%). These findings cast doubt on the importance of these context-dependent effects and may suggest a need for refocusing in the field toward understanding the wide genetic variation in these preferences and how this variation relates to the evolution of sexual dimorphism in faces.


Stable propagation of 'selfish' genetic elements.
Extrachromosomal or chromosomally integrated genetic elements are common among prokaryotic and eukaryotic cells. These elements exhibit a variety of 'selfish' strategies to ensure their replication and propagation during the growth of their host cells. To establish long-term persistence, they have to moderate the degree of selfishness so as not to imperil the fitness of their hosts. Earlier genetic and biochemical studies together with more recent cell biological investigations have revealed details of the partitioning mechanisms employed by low copy bacterial plasmids. At least some bacterial chromosomes also appear to rely on similar mechanisms for their own segregation. The 2 mm plasmid of Saccharomyces cerevisiae and related yeast plasmids provide models for optimized eukaryotic selfish DNA elements. Selfish DNA elements exploit the genetic endowments of their hosts without imposing an undue metabolic burden on them. The partitioning systems of these plasmids appear to make use of a molecular trick by which the plasmids feed into the segregation pathway established for the host chromosomes.


Pancreatic and pituitary hormonal responses to insulin-induced hypoglycaemia during muscarinic cholinergic blockade in man.
To investigate the role of muscarinic cholinergic mechanisms in mediating the pancreatic and pituitary hormonal responses to hypoglycaemia, six normal subjects were studied during acute insulin-induced hypoglycaemia under control conditions, and during blockade with intravenous atropine. During atropine blockade the response of pancreatic polypeptide was suppressed while the maximum response of plasma glucagon was significantly higher. The increment in plasma vasopressin was also increased significantly during cholinergic blockade. During blockade with atropine the responses of plasma prolactin was reduced, with a slight but significant reduction in the growth hormone response, and although a similar maximum response of plasma ACTH was achieved, this rise was delayed. These results implicate involvement of a cholinergic muscarinic inhibitory and stimulatory mechanisms in regulating the responses of pancreatic and pituitary hormones to hypoglycaemia.


[Proliferation and IFN-gamma secretion of autologous T lymphocytes stimulated by myeloid leukemia cells induced with rhGM-CSF and rhIL-4].
To observe the proliferation of T lymphocytes stimulated by CML and AML cells which were induced by rhGM-CSF and rhIL-4, and the secretion of IFN-gamma from proliferated T lymphocytes, the expression of CD80, CD86 and HLA-DR on CML and AML cells induced by GM-CSF and IL-4 was assayed by flow cytometry in vitro. Then one-way mixed lymphocyte reaction was carried out, with induced leukemia cells as stimulating cells and auto-T lymphocytes as reactive cells. The secretion of IFN-gamma from T lymphocytes was determined by double antibody sandwich ELISA. The results showed that GM-CSF and IL-4 significantly upregulated the expression of CD80, CD86 and HLA-DR on CML cells and CD80 and CD86 on AML cells, which could stimulate the T lymphocyte proliferation and high secretion of IFN-gamma (in CML group) of autologous T lymphocytes. It is concluded that the CML and AML cells induced by GM-CSF and IL-4 have the ability to present tumor specific antigen to auto-T lymphocyte.


Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction.
The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.


[Purple sulfur bacteria isolated from reservoirs of the Yavoriv sulfur deposit].
Three pure cultures of purple sulfur bacteria were isolated from reservoirs of the Yavoriv sulfur deposit. The studying of their morphology, cytology and physiology has confirmed the belonging of these bacteria to Chromatiaceae family and has allowed identifying them as Thiocapsa sp., Lamprocystis sp. and Chromatium sp.


SIGNIFICANT REDUCTION OF PERIPAPILLARY CHOROIDAL THICKNESS IN PATIENTS WITH UNILATERAL BRANCH RETINAL VEIN OCCLUSION.
To evaluate changes in peripapillary choroidal thickness in patients with branch retinal vein occlusion (BRVO) over 12 months, using spectral-domain optical coherence tomography with enhanced depth imaging. This retrospective, interventional case series included 20 treatment-naive patients with unilateral BRVO with at least 12 months follow-up. The peripapillary choroidal thickness was measured over 12 months. In BRVO-affected eyes, the mean peripapillary choroidal thickness was 213.5 ± 51.7 μm (126.1[FIGURE DASH]326.9 μm) at baseline and 129.6 ± 39.3 μm (65.9[FIGURE DASH]197.1 μm) at 12 months. In nonaffected contralateral eyes, the mean peripapillary choroidal thickness was 194.1 ± 39.8 μm (158.5[FIGURE DASH]238.3 μm) at baseline and 156.6 ± 56.2 μm (125.9[FIGURE DASH]213.9 μm) at 12 months. The mean peripapillary choroidal thickness decreased significantly over 12 months in both BRVO-affected and nonaffected eyes (P < 0.001, both eyes). Although the mean peripapillary choroidal thickness was not significantly different between groups at baseline (P = 0.472), it was significantly lower in BRVO-affected eyes than in nonaffected eyes at 12 months (P = 0.036). Peripapillary choroidal thickness decreased significantly over 12 months in BRVO-affected eyes and nonaffected eyes in patients with unilateral BRVO.


Effects of neoplastic transformation and teniposide (VM26) on protein kinase C isoform expression in rodent fibroblasts.
This study examined changes in protein kinase C (PKC) isoforms in rodent fibroblasts (rat F111 and mouse NIH3T3), transformed by the polyoma virus middle T antigen (mT) and undergoing apoptosis in response to teniposide (VM26). The mT-transformed cells up-regulated PKC delta and down-regulated both PKC epsilon and PKC lambda expression, and were more sensitive to the drug than their non-transformed counterparts. The drug treatment further lowered the expression of PKC epsilon, triggered nuclear translocation of PKC delta and its site-specific proteolysis, consistent with the notion that changes in specific PKC isoforms play a role not only in the neoplastic transformation of fibroblasts, but also in their apoptotic response.


Modulation of cytochrome P450 activity: implications for cancer therapy.
Although metabolism mediated by cytochrome P450 isoenzymes is known to play a major part in the biotransformation of anticancer agents in vivo, few clinical studies have investigated activity of cytochrome P450s and therapeutic outcome in people with cancer. Variability between individuals in the pharmacokinetics of cancer chemotherapy has important consequences in terms of therapeutic efficacy and safety. We discuss here the effect of drug metabolism mediated by cytochrome P450 on therapeutic outcome. As examples, the biotransformation pathways of cyclophosphamide, ifosfamide, tamoxifen, docetaxel, paclitaxel, and irinotecan are discussed. Since most anticancer agents are transformed by enzymes, better knowledge of their metabolic pathways could help improve treatment outcome and safety. Furthermore, a more complete understanding of the metabolism of anticancer agents through phenotyping and genotyping approaches will facilitate the prediction of interactions between drugs. More clinical evidence is needed on the metabolic transformation and drug interactions with these agents to improve cancer therapeutics.


Successful treatment of short stature and delayed puberty in congenital magnesium-losing kidney.
Bartter's syndrome is a well described but uncommon disease characterized by hypokalaemia and hyperplasia of the juxtaglomerular apparatus of the kidney. It may present in infancy with failure to thrive and muscle weakness; it commonly causes short stature. Lesions at different sites within the renal tubule have been proposed as the cause of the syndrome. However, the biochemical abnormalities in many cases can be explained by defective reabsorption of chloride in the ascending loop of Henle, with loss of sodium and water and a secondary increase in renin and aldosterone concentrations. Less severe cases have been described which present in adolescence and have tetany as a prominent feature. Primary renal loss of magnesium associated with potassium wasting has been described in such cases and it has been suggested that these can be distinguished from classical Bartter's syndrome by hypocalciuria. This less well characterized disease has been named Welt, Gitelman-Welt or Gitelman syndrome and may include deficient tubular reabsorption of chloride, but the sites of magnesium and potassium loss in the kidney are uncertain. We describe a patient with this syndrome who presented with short stature, delayed puberty and tetany and responded well to magnesium replacement.


Sunscreen Application, Safety, and Sun Protection: The Evidence.
Recently in Canada, there has been an effort to create consistent messaging about sun safety as there is a lack of up-to-date evidence-based guidelines regarding sun-protection measures. This review aimed to provide updated, evidence-based recommendations on sunscreen application, safety, and sun protection regarding the following topics for which there is clinical uncertainty: physical barriers, sunscreen properties, sunscreen application, and risk-benefit analysis.


Rare electrosurgical complications in tonsillectomy: Analysis of national adverse event reporting.
To identify U.S. Food and Drug Administration (FDA)-reported adverse events related to electrosurgical devices during tonsillectomy and characterize the most common devices and patient/provider sequelae. Retrospective analysis of FDA database of device-related adverse events. Data were extracted from the OpenFDA database for all adverse events reported for electrosurgical devices used in tonsillectomies from January 2008 to December 2017. Adverse events were classified by device, event type, etiology, complication severity, and patient disposition. Six hundred fifty-two adverse events were identified, with 195 events (30%) leading to known bodily injury to patient/provider. Device failure was the most common adverse event (202 events, 31%), followed by burns in 187 patient (98% of burns) and three provider events (2%). Burn injuries occurred most frequently with coblation devices (78 events, 42% of burns), monopolar electrocautery (48 events, 25%), and electrosurgical generators (23 events, 13%). Burn injuries most commonly occurred in the oral cavity (144 events, 76% of burn events) and were most commonly first-degree (28 events, 15%). Complications related to burns were managed conservatively for 36% of burn events (68 events), and secondary surgery was rarely required (8 events, 4%). Postoperative bleeding (173 events, 26%; 3 deaths) and intraoperative fire (73 events, 11%) were also reported. Device failures caused significant OR delay or cancellation in 17% of occurrences (35 events). Numerous complications may occur with various devices used during tonsillectomy and can result in significant patient/provider harm and sequelae. Surgeons must understand the nature of such complications to facilitate safe perioperative care and inform preoperative patient discussions. NA Laryngoscope, 2019.


Effects of Ichthyophonus hoferi on condition indices and blood chemistry of experimentally infected rainbow trout (Oncorhynchus mykiss).
Body condition, hepatosomatic index and blood chemistry of Oncorhynchus mykiss experimentally infected with a tissue dwelling fish pathogenic fungus, Ichthyophonus hoferi, were monitored over a 6 wk period. This was to determine whether the infection constituted a stress manifest by changes in the hypothalamic-pituitary interrenal axis, and especially plasma cortisol levels. Infection caused anaemia and leucopenia but did not change the condition, hepatosomatic indices, or plasma chloride, cholesterol, cortisol, creatinine, glucose, osmolarity, potassium, total protein, sodium and T4. It is suggested that increased cortisol levels may not be a normal component of the stress response of fish to disease caused by invasive infectious agents.


Ischemic necrosis of the breast following septic shock: A case report.
Fat necrosis of the breast is a common and benign entity, often secondary to trauma, surgery, radiation therapy, or unknown etiologies. Critically ill patients with septic shock may experience end-organ hypoperfusion and tissue infarction and necrosis, which may result in breast fat necrosis, however, to the best of our knowledge this has not been previously described. We report a case of biopsy-proven breast fat necrosis secondary to septic shock following an emergency surgery in a postmenopausal female.


Intracranial Meningioma Surgery: Value-Based Care Determinants in New York State, 1995-2015.
Intracranial meningiomas are the most commonly diagnosed brain tumor in the United States. With increasing incidence, efficient allocation of limited health care resources is a critical component of emerging value-based models of care. The purpose of this study was to evaluate the effect of patient and hospital variables on metrics of value-based care. The Statewide Planning and Research Cooperative System database was queried for records of patients undergoing intracranial meningioma surgery in New York State from 1995 to 2015. Multivariate logistic regression was used to investigate the effect of hospital volume and patient demographics on 30-day readmissions, 30-day mortality, prolonged length of stay (pLOS), and excess hospital charges. Among the 14,239 patients included, 10,252 (72%) cases were performed at high-volume centers (HVC) (>75th percentile). HVC were associated with lower rates of readmissions, mortality, and pLOS, but higher hospital charges. In the multivariate analysis, HVC had reduced odds of pLOS (odds ratio, 0.56; P < 0.0001) and 30-day mortality (odds ratio, 0.39; P < 0.0001). Patient variables associated with adverse outcomes in the multivariate model included advanced age, male gender, higher Charlson Comorbidity Index, lower socioeconomic status (low income, Medicaid, and Medicare insurance), black race, and Hispanic ethnicity. These populations were more likely to undergo treatment at lower-volume centers. This statewide population analysis of readmissions, mortality, length of stay, and hospital charges after intracranial meningioma surgery identified patient predictors of adverse outcomes. These determinants may be used by hospitals to develop improved systems of care in at-risk populations.


Sex role psychodynamics in psychotherapy supervision.
Supervision of the female psychotherapy neophyte is discussed in relation to sex role-exacerbated ambivalence toward the transition from classroom passive-dependency to self-reliance as a professional clinician. Supervisors are alerted to hostile-dependent strategies, such as seductive flattery, that serve immediate ego-protective needs but ultimately block the attainment of fuller professional functioning.


Using memories to understand others: the role of episodic memory in theory of mind impairment in Alzheimer disease.
Theory of mind (TOM) refers to the ability to infer one's own and other's mental states. Growing evidence highlighted the presence of impairment on the most complex TOM tasks in Alzheimer disease (AD). However, how TOM deficit is related to other cognitive dysfunctions and more specifically to episodic memory impairment - the prominent feature of this disease - is still under debate. Recent neuroanatomical findings have shown that remembering past events and inferring others' states of mind share the same cerebral network suggesting the two abilities share a common process .This paper proposes to review emergent evidence of TOM impairment in AD patients and to discuss the evidence of a relationship between TOM and episodic memory. We will discuss about AD patients' deficit in TOM being possibly related to their difficulties in recollecting memories of past social interactions.


WY-14,643-mediated promotion of hepatocarcinogenesis in connexin32-wild-type and connexin32-null mice.
Connexin32 (Cx32) is the major gap junction forming protein in liver and lack of functional Cx32 enhances hepatocarcinogenesis. Many tumour-promoting agents block gap junctional intercellular communication, which may favour clonal expansion of neoplastic cells. We recently demonstrated that liver tumourigenesis is accelerated in Cx32-wild-type but not in Cx32-null mice by the model tumour promoter phenobarbital (PB). In the present study, male Cx32-wild-type and Cx32-null mice were treated with a single injection of 90 micro g/g body wt of N-nitrosodiethylamine (DEN) at 6 weeks of age and were subsequently kept on a diet containing the peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) or on control diet. Thirty-eight weeks after DEN treatment, mice were killed, frozen liver sections were prepared and (pre)-neoplastic lesions were identified by alterations in glucose-6-phosphatase (G-6-Pase) and glutamine synthetase (GS) staining. G-6-Pase-deficient lesions were generally small in size and were observed in all groups of mice. Large focal pre-neoplastic and benign neoplastic lesions, however, which demonstrated increased rather than decreased activity in G-6-Pase were exclusively present in DEN/Wy-14,643-treated mice. G-6-Pase-positive lesions were strongly promoted by Wy-14,643, both in Cx32-wild-type and Cx32-null mice without significant difference in response between mice of the two genotypes. This contrasts G-6-Pase-negative lesions and lesions over-expressing GS, which were both increased by WY-14,643 treatment in number and size in Cx32-wild-type but not in Cx32-null mice. GS-positive lesions from WY-14,643-treated mice harboured beta-catenin mutations, a hallmark of lesions selected during promotion by PB, while G-6-Pase-positive lesions, which displayed negative or diffuse GS staining, did not show beta-catenin mutations. Our results demonstrate significant differences between mouse liver lesions of differing phenotype and genotype in their response towards selection by Wy-14,643 during the promotional phase of hepatocarcinogenesis.


Quantitative analysis of visually induced courtship elements in Drosophila subobscura.
We developed a new paradigm for quantitative analysis of courtship behavior in flies, Fly Motion-detector with an Actuator-Coupled Stimulator (FlyMacs), in which the stimulation of a fly with a moving visual target and recording of induced behaviors are automated under computer control. We employ FlyMacs for the identification of motion features that trigger specific courtship elements in Drosophila subobscura, whose mating is suggested to be strongly vision dependent. A female abdomen attached to the actuator, when moved in an appropriate pattern, evokes in the test male tapping-like foreleg motions, midleg swing and proboscis extension, which are considered to be elementary actions in male courtship behavior. Tapping is primarily induced when the target is moving, whereas midleg swing and proboscis extension are most frequently observed after the target stops moving. In contrast to midleg swing, which tends to occur immediately after target cessation (∼3000 ms), the incidence of proboscis extension gradually increases with time after target cessation, reaching a plateau at 3000 ms. The results suggest that tapping, midleg swing and proboscis extension are each induced by different movement features of the visual target. These findings do not support the view that a single key stimulus induces the entire courtship ritual. Rather, courtship behaviors in D. subobscura are correlated with movement and position of the target, which suggests that D. subobscura uses sensory information to pattern its courtship.


Truncus arteriosus with double aortic arch: A rare association.
Yıldırım SV, Yıldırım A. Truncus arteriosus with double aortic arch: A rare association. Turk J Pediatr 2017; 59: 221-223. Truncus arteriosus (TA) is a congenital heart defect often diagnosed in neonatal period; it represents 0.7% of all congenital heart lesions. The pulmonary arteries originate generally above the coronary ostium. Aorto-pulmonary and interventricular defects are believed to represent an abnormality of conotruncal septation. TA is classified into four types, according to Van Praagh and Colette Edwards. Some of congenital heart defects may be associated with TA, such as aortic interruption. In literature, TA with a double aortic arch is observed as a very rare condition. We present here a newborn diagnosed with a combination of TA type 1 and double aortic arch.


Meiosis-activating sterol and the maturation of isolated mouse oocytes.
This study was carried out to examine the effects of the meiosis-activating C(29) sterol, 4,4-dimethyl-5 alpha-cholesta-8,14, 24-trien-3 beta-ol (FF-MAS), on mouse oocyte maturation in vitro. Cumulus cell-enclosed oocytes (CEO) and denuded oocytes (DO) from hormonally primed, immature mice were cultured 17-18 h in minimum essential medium (MEM) containing 4 mM hypoxanthine plus increasing concentrations of FF-MAS. The sterol induced maturation in DO with an optimal concentration of 3 microg/ml but was without effect in CEO, even at concentrations as high as 10 microg/ml. Some stimulation of maturation in hypoxanthine-arrested CEO was observed when MEM was replaced by MEMalpha. Interestingly, the sterol suppressed the maturation of hypoxanthine-arrested CEO in MEM upon removal of glucose from the medium. FF-MAS also failed to induce maturation in DO when meiotic arrest was maintained with dibutyryl cAMP (dbcAMP). The rate of maturation in FF-MAS-stimulated, hypoxanthine-arrested DO was slow, as more than 6 h of culture elapsed before significant meiotic induction was observed, and this response required the continued presence of the sterol. Although the oocyte took up radiolabeled lanosterol, such accumulation was restricted by the presence of cumulus cells. In addition, lanosterol failed to augment FSH-induced maturation and was even inhibitory at a high concentration. Moreover, the downstream metabolite, cholesterol, augmented the inhibitory action of dbcAMP on maturation in both CEO and DO. Two inhibitors of 14 alpha-demethylase, ketoconazole, and 14 alpha-ethyl-5 alpha-cholest-7-ene-3 beta, 15 alpha-diol that can suppress FF-MAS production from lanosterol failed to block consistently FSH-induced maturation. These results confirm the stimulatory action of FF-MAS on hypoxanthine-arrested DO but do not support a universal meiosis-inducing function for this sterol.


[Mechanisms of compensatory hypertrophy of the kidney].
The paper presents the actual state of knowledge on compensatory renal growth. The following problems are discussed: 1) hemodynamical, biochemical and morphological alternations in different models compensatory renal growth, 2) mechanisms of induction and modification kidney growth, 3) hormonal control of kidney growth.


Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009-2015.
The Food and Drug Administration (FDA) approved quadrivalent human papillomavirus vaccine (4vHPV) for use in females and males aged 9-26 years, since 2006 and 2009 respectively. We characterized reports to the Vaccine Adverse Event Reporting System (VAERS), a US spontaneous reporting system, in females and males who received 4vHPV vaccination. We searched VAERS for US reports of adverse events (AEs) following 4vHPV from January 2009 through December 2015. Signs and symptoms were coded using Medical Dictionary for Regulatory Activities (MedDRA). We calculated reporting rates and conducted empirical Bayesian data mining to identify disproportional reports. Clinicians reviewed available information, including medical records, and reports of selected pre-specified conditions. VAERS received 19,760 reports following 4vHPV; 60.2% in females, 17.2% in males, and in 22.6% sex was missing. Overall, 94.2% of reports were non-serious; dizziness, syncope and injection site reactions were commonly reported in both males and females. Headache, fatigue and nausea were commonly reported serious AEs. More than 60 million 4vHPV doses were distributed during the study period. Crude AE reporting rates were 327 reports per million 4vHPV doses distributed for all reports, and 19 per million for serious reports. Among 29 verified reports of death, there was no pattern of clustering of deaths by diagnosis, co-morbidities, age, or interval from vaccination to death. No new or unexpected safety concerns or reporting patterns of 4vHPV with clinically important AEs were detected. Safety profile of 4vHPV is consistent with data from pre-licensure trials and postmarketing safety data.


C1QTNF1-AS1 regulates the occurrence and development of hepatocellular carcinoma by regulating miR-221-3p/SOCS3.
The aim of our study was to explore how C1QTNF1-AS1 regulated miR-221-3p/SOCS3 axis in human hepatocellular carcinoma (HCC). Differentially expressed lncRNAs and genes were examined via RNA-seq. GO analysis and KEGG pathway enrichment analysis were carried out based on the function of dys-regulated mRNAs. RT-qPCR was employed to detect the relative mRNA expression level of C1QTNF1-AS1, miR-221-3p, SOCS3 and key genes in the JAK/STAT signaling pathway in HCC tissues and cells, and western blot analysis was conducted to detect the relative protein expression levels of SOCS3 and key proteins in the JAK/STAT signaling pathway in HCC tissues and cells. MTT assay, transwell assay and flow cytometry were utilized to assess HCC cell proliferation, invasion, migration and apoptosis. Dual luciferase reporter gene assay was used to verify the targeted relationship between C1QTNF1-AS1 and miR-221-3p, as well as between miR-221-3p and SOCS3. A tumorigenicity assay in nude mice was conducted to investigate the effects of C1QTNF1-AS1 on HCC tumor growth in vivo. C1QTNF1-AS1 and SOCS3 were down-regulated, while miR-221-3p was up-regulated in HCC tissues and cells. In HepG2 and Huh7 cells, overexpression of C1QTNF1-AS1 or SOCS3, as well as silence of miR-221-3p inhibited HCC cell proliferation, migration, and invasion and promoted HCC cell apoptosis. The results of the dual luciferase reporter gene assay indicated that miR-221-3p could directly target both C1QTNF1-AS1 and SOCS3. In addition, up-regulation of C1QTNF1-AS1 suppressed HCC tumor growth in vivo. Overexpression of C1QTNF1-AS1 down-regulated miR-221-3p and subsequently up-regulated SOCS3, thereby inhibiting HCC cell proliferation, migration and invasion and promoting apoptosis through the JAK/STAT signaling pathway.


Role of mast cells and basophils in pruritus.
To protect our body systems, there is a constant interactive conversation between the skin nervous and immune system. Important elements of this conversation in the skin include mast cells, basophils, and sensory nerve fibers. These cells employ a vast array of sensors that detect danger and react accordingly. This reaction, summarized as neurogenic inflammation, manifests at the conscious level as sensations including pain and itch. Here we provide a perspective on the blossoming knowledge that is illuminating connections between mast cells, basophils, and sensory nerve fibers in the mediation of itch. We discuss established mediators and receptors, in particular cytokine and neuropeptide pathways, upstream proteases, and proteinase-activated receptors, and the emerging role of mas-related G-protein-coupled receptors in itch.


Quantitative analysis of immobilized penicillinase using enzyme-modified AlGaN/GaN field-effect transistors.
Penicillinase-modified AlGaN/GaN field-effect transistors (PenFETs) are utilized to systematically investigate the covalently immobilized enzyme penicillinase under different experimental conditions. We demonstrate quantitative evaluation of covalently immobilized penicillinase layers on pH-sensitive field-effect transistors (FETs) using an analytical kinetic PenFET model. This kinetic model is explicitly suited for devices with thin enzyme layers that are not diffusion-limited, as it is the case for the PenFETs discussed here. By means of the kinetic model it was possible to extract the Michaelis constant of covalently immobilized penicillinase as well as relative transport coefficients of the different species associated with the enzymatic reaction which, exempli gratia, give information about the permeability of the enzymatic layer. Based on this analysis we quantify the reproducibility and the stability of the analyzed PenFETs over the course of 33 days as well as the influence of pH and buffer concentration on the properties of the enzymatic layer. Thereby the stability measurements reveal a Michalis constant KM of (67 ± 13)μM while the chronological development of the relative transport coefficients suggests a detachment of physisorbed penicillinase during the first two weeks since production. Our results show that AlGaN/GaN PenFETs prepared by covalent immobilization of a penicillinase enzyme layer present a powerful tool for quantitative analysis of enzyme functionality.


Radiosensitization by a new potent nucleoside analog: 1-(1',3',4'-trihydroxy-2'-butoxy)methyl-2-nitroimidazole(RP-343).
A new hypoxic cell sensitizer has been synthesized; this is a 2-nitroimidazole nucleoside analog having erythritol as a sugar moiety at the N-1 position of the imidazole ring (RP-343). Its possibility as a potent hypoxic cell sensitizer was compared with those of RP-170 and etanidazole. Radiosensitization was tested in two murine tumors, EMT6 using in vitro and in vivo-in vitro assays and SCCVII using growth delay and TCD50 assays. Pharmacokinetic study was performed in Balb/c mice bearing EMT6 tumors and in Beagle dogs. LD50 of each sensitizer was obtained with ICR mice. As might be expected from the almost identical electron affinities of the three sensitizers, they were equally effective against hypoxic EMT6 cells in vitro. While having the lowest partition coefficient (0.035), RP-343 exhibited almost equally effective distribution to tumors and sensitizing radiation activity. An intravenous (i.v.) injection of 100 mg/kg of RP-343, RP-170 and etanidazole showed an almost equal sensitizer enhancement ratio (SER) of about 1.4 to solid EMT6 tumor under in vivo-in vitro assay and a virtually equal SER of 1.33-1.44 to solid SCCVII tumor under both tumor growth delay assay and TCD50 assay. A great advantage of RP-343 over RP-170 and etanidazole is its very much lower toxicity; their LD50 in mice were > 6.0, 4.3 and 4.8 g/kg, respectively, on i.v. injection. The lower toxicity of RP-343 was supported by its lower concentrations in the brain; the RP-343 AUC for brain was 0.43 times that of RP-170. Three indices were selected to compare the three nitroimidazoles. SER at 5% LD50 doses of RP-343, RP-170 and etanidazole was 1.66, 1.59 and 1.56. At the same toxicity levels, RP-343 was found to have better sensitization of solid tumors over both etanidazole and RP-170. The maximum tumor concentration/AUC for brain (Cmax,tumor/AUCbrain) ratios for RP-343 and RP-170 were 9.62 and 3.98. This extremely high ratio of RP-343 could explain its lower toxicity than RP-170 or etanidazole. The therapeutic risk index defined as D1.5/LD50 (D1.5 is the sensitizer dose to obtain the SER of 1.5 in vivo) for RP-343, RP-170 and etanidazole were 0.022, 0.033 and 0.036, respectively. Especially, the effectively lower therapeutic risk index for RP-343 presents the possibility of clinical advantage over etanidazole.


Role of regulatory T cells in long-term immune dysfunction associated with severe sepsis.
To investigate the role of regulatory T cells in the modulation of long-term immune dysfunction during experimental sepsis. It is well established that sepsis predisposes to development of a pronounced immunosuppression. Nevertheless, the mechanisms underlying the immune dysfunction after sepsis are still not well understood. Prospective experimental study. University research laboratory. Wild-type mice underwent cecal ligation and puncture and were treated with antibiotic during 3 days after surgery. On days 1, 7, or 15 after cecal ligation and puncture, the frequency of regulatory T cells, proliferation of CD4 T cells and bacterial counts were evaluated. Fifteen days after cecal ligation and puncture, surviving mice underwent secondary pulmonary infection by intranasal inoculation of nonlethal dose of Legionella pneumophila. Some mice received agonistic glucocorticoid-induced tumor necrosis factor receptor antibody (DTA-1) before induction of secondary infection. Mice surviving cecal ligation and puncture showed a markedly increased frequency of regulatory T cells in thymus and spleen, which was associated with reduced proliferation of CD4 T cells. Fifteen days after cecal ligation and puncture, all sepsis-surviving mice succumbed to nonlethal injection of L. pneumophila. Treatment of mice with DTA-1 antibody reduced frequency of regulatory T cells, restored CD4 T cell proliferation, reduced the levels of bacteria in spleen, and markedly improved survival of L. pneumophila infection. These findings suggest that regulatory T cells play an important role in the progression and establishment of immune dysfunction observed in experimental sepsis.


JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin.
Erythropoietin (EPO) regulates the proliferation and differentiation of erythroid cells through interaction with its receptor (EPOR). Although EPOR is a member of the cytokine receptor superfamily and lacks a kinase domain, EPO induces tyrosine phosphorylation, which is correlated with gene transcription and mitogenesis. Here we demonstrate that EPO induces tyrosine phosphorylation of JAK2 kinase and activates its in vitro autophosphorylation. Using EPOR mutants, phosphorylation and activation of kinase activity correlate with the induction of mitogenesis. Furthermore, JAK2 physically associates with a membrane-proximal region of the EPOR cytoplasmic domain that is required for biological activity. The results support the hypothesis that JAK2 is the kinase that couples EPO binding to tyrosine phosphorylation and mitogenesis.


Is Lateral Femoral Nailing Associated With Increased Intensive Care Unit Days? A Propensity-Matched Analysis of 848 Cases.
The purpose of this study is to determine if lateral patient position during femoral nailing is associated with increases in intensive care unit (ICU) length of stay (LOS) or ventilator days when compared with femoral nailing in a supine position. Retrospective cohort study. Level 1 trauma center. Patients with femoral shaft fractures treated with intramedullary fixation were identified. Propensity matching was performed to minimize selection bias using factors thought to be associated with surgeon selection of supine nailing at our institution (Injury Severity Score, Abbreviated Injury Score brain, and bilateral fractures). After matching, 848 patients were included in the analysis. Femoral nailing in the lateral position compared with the supine position. Our primary outcome measure was ICU LOS. Ventilator days were the secondary outcome. Treating patients with femoral nailing in the lateral position was associated with a 1.88 days (95% confidence interval, 0.73-3.02; P = 0.001) reduction in ICU LOS in our adjusted model. Intramedullary nailing in the lateral position was associated with a 1.29 days (95% confidence interval, -0.12 to 2.69) decrease in postoperative time on a ventilator. However, this finding was not statistically significant (P = 0.07). Lateral femoral nailing was associated with decreased ICU LOS (P = 0.001) even after accounting for selection bias using propensity score matching. Our data indicate that lateral femoral nailing is likely not associated with the increased risk of pulmonary complication. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Degree of population diversity - a perspective on premature convergence in genetic algorithms and its Markov chain analysis.
In this paper, a concept of degree of population diversity is introduced to quantitatively characterize and theoretically analyze the problem of premature convergence in genetic algorithms (GAs) within the framework of Markov chain. Under the assumption that the mutation probability is zero, the search ability of GA is discussed. It is proved that the degree of population diversity converges to zero with probability one so that the search ability of a GA decreases and premature convergence occurs. Moreover, an explicit formula for the conditional probability of allele loss at a certain bit position is established to show the relationships between premature convergence and the GA parameters, such as population size, mutation probability, and some population statistics. The formula also partly answers the questions of to where a GA most likely converges. The theoretical results are all supported by the simulation experiments.


Bio-inspired production of chitosan/chitin films from liquid crystalline suspensions.
Inspired by chitin based hierarchical structures observed in arthropods exoskeleton, this work reports the capturing of chitin nanowhiskers' chiral nematic order into a chitosan matrix. For this purpose, highly crystalline chitin nanowhiskers (CTNW) with spindle-like morphology and average aspect ratio of 24.9 were produced by acid hydrolysis of chitin. CTNW were uniformly dispersed at different concentrations in aqueous suspensions. The suspensions liquid crystalline phase domain was determined by rheological measurements and polarized optical microscopy (POM). Chitosan (CS) was added to the CTNW isotropic, biphasic and anisotropic suspensions and the solvent was evaporated to allow films formation. The Films' morphologies as well as the mechanical properties were explored. A correlation between experimental results and a theoretical model, for layered matrix' structures with fibers acting as a reinforcement agent, was established. The results evidence the existence of two different layered structures, one formed by chitosan layers induced by the presence of chitin and another formed by chitin nanowhiskers layers. By playing on the ratio chitin/chitosan one layered structure or the other can be obtained allowing the tunning of materials' mechanical properties.


Study of the neuroprotective effect of ginseng on superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels in experimental diffuse head trauma.
The purpose of our study was to investigate the effect of ginseng on antioxidant enzyme levels in brain damage following experimental diffuse head trauma in rats. The neuroprotective effect of ginseng was also studied. In this study, rats were divided into four groups, and the rats in group 1 received no intervention. In group 2, the rats were administered 50 mg/kg ginseng, injected intraperitoneally at 1, 24 and 48 h, and the effect of ginseng on normal tissues was studied. No drugs were administered to the rats in group 3 who had previously experienced diffuse head trauma using Feeney's falling weight method. In group 4, rats underwent Feeney's falling weight method, leading to diffuse head trauma, and they were given 50 mg/kg ginseng intraperitoneally 1, 24 and 48 h after head trauma. Rats were killed 72 h after head trauma and their brain tissues extracted for histopathological and biochemical studies. Histopathological study of brain cross sections in the trauma group demonstrated neurons in the trauma region and surrounding area, which generally had a dark-colored eosinophilic cytoplasm and a pyknotic nucleus, while the nuclei of neurons were located peripherally. However, brain cross sections in group 4 from rats given ginseng after head trauma showed fewer neurons with eosinophilic cytoplasm, pyknotic and peripheral nuclei in the trauma region and surrounding area. No statistically significant difference in the tissue SOD level was observed; however, the GSH Px level in group 4 was significantly reduced compared to that in group 3. After affecting the GSH Px level and reducing histopathological scores, ginseng was found to display antioxidant and neuroprotective activity.


Epigenetic regulation of proprotein convertase PACE4 gene expression in human ovarian cancer cells.
Proprotein convertases (PC) are a family of serine endoproteases that play important roles in regulating cell function by converting proproteins to biologically active molecules. Several lines of evidence suggest that overexpression of PCs contributes to tumor formation and progression in various types of cancer. In this study, we examined PC expression in six normal ovarian surface epithelium (OSE) cultures, nine primary ovarian cancer (OC) cultures, and three established OC cell lines (Hey, HeyC2, and OCC-1). Our results show that furin and PC7 expression in OC cells was comparable to that in normal OSE. However, PACE4 expression was greatly reduced in all OC samples studied. PACE4 promoter activity was measured in HeyC2 and OCC-1 cells using transiently transfected luciferase reporter plasmids. Both cell lines supported PACE4 promoter activity, showing that the transcription factors critical for PACE4 expression are present in OC cells. The observation that established OC cell lines have reduced PACE4 expression, but maintained the ability to support PACE4 promoter activity, led to the hypothesis that reduced expression may be due to epigenetic modification of the PACE4 gene, such as DNA methylation and histone deacetylation. Methylation analysis of 79 CpG dinucleotides within the PACE4 promoter and exon I (-196/+340) revealed that the percentage of methylated cytosine nucleotides was 8-9% in normal OSE, but 58-93% in OC cells. Treatment with the demethylating agent 5-aza-2'-deoxycytidine and/or the histone deacetylase inhibitor trichostatin A greatly increased PACE4 expression in OC cells. These data suggest that the reduction of PACE4 expression in OC cells is caused, in part, by DNA hypermethylation and histone deacetylation.


Isozyme pattern of glycogen phosphorylase in the rat nervous system and rat astroglia-rich primary cultures: electrophoretic and polymerase chain reaction studies.
Of the three isozymes of glycogen phosphorylase (GP) known, the brain (B) and muscle (M) isoforms have been reported to occur in brain. We investigated the regional and cellular occurrence of the three isozymes in various parts of the rat nervous system, fetal brain and astroglia-rich primary cultures by means of electrophoresis of native proteins with subsequent activity stain and by reverse transcriptase polymerase chain reaction. In the cortex, cerebellum, olfactory bulb, brainstem, spinal cord and dorsal root ganglia, both mRNA and enzyme protein were found for the B and M isozymes. In addition, the liver (L) isoform mRNA was detected in fetal brain and cultured astrocytes. Our studies indicate that there is no regional difference in distribution pattern between brain regions, spinal cord and dorsal root ganglia. In immature brain and cultured glial cells, the additional presence of the L isozyme is possible. These results support the idea that astrocytes express two or even three GP isozymes simultaneously.


Home-based exercise to alleviate fatigue and improve functional capacity among breast cancer survivors.
This pilot study examined the efficacy of two home-based exercise programs on alleviating fatigue and improving functional capacity in breast cancer survivors. Participants were randomly assigned into one of three groups: aerobic exercise (AE), resistance exercise (RE), or usual care control (CON). After receiving individualized instruction and training, participants assigned to the AE and RE groups were asked to perform the prescribed exercise(s) 3 times per week for 12 weeks at home. Both groups were instructed to keep their perceived exercise intensity in the "fairly light" to "somewhat hard" range using the Borg Perceived Exertion Scale. All participants completed the revised Piper Fatigue Scale (PFS) and the 6-minute walk test (6MWT) at baseline and 12-week post-exercise program. Analysis of pre- and post-training data revealed a significant reduction in fatigue levels on the PFS among participants in the AE group (Z=2.521, one-tailed P=0.006), and a significant improvement in the distance of the 6MWT for the RE group (Z=2.366, one-tailed P=0.009) at the end of 12-week study period. No significant changes in fatigue or functional status were observed in the CON group. Findings provide preliminary support for RE as a viable strategy for improving functional capacity in breast cancer survivors, while AE may be more effective in attenuating cancer-related fatigue. Incorporating RE training for future research may help advance the growing body of knowledge in symptom management for breast cancer survivors.


CD8+ T cells are effector cells of contact dermatitis to common skin allergens in mice.
Allergic contact dermatitis (ACD) to strong experimental haptens is mediated by specific CD8+ T cells. Here, we show that similar mechanisms occur for weak haptens, which comprise the vast majority of chemicals responsible for human ACD. We used a model of ACD, that is, the contact hypersensitivity reaction, to test for the allergenicity of three weak haptens involved in fragrance allergy. ACD to weak haptens could not be induced in normal mice. In contrast, mice acutely depleted in CD4+ T cells developed a typical ACD reaction to the three weak fragrance allergens that peaked 24 hours after challenge. Priming of CD8+ T cells was observed in draining lymph nodes 5 days after sensitization and development of ACD was associated with the infiltration of activated CD8+ T cells in the challenged skin. CD8+ T cells were effectors of the ACD reaction as in vivo treatment with depleting anti-CD8 mAbs abrogated the ACD responses and as purified CD8+ T cells could adoptively transfer ACD to naive recipients. In conclusion, our data demonstrate a dominant role of CD8+ T cells as initiators of ACD to weak haptens, and suggest that CD8+ T cells may represent potential targets for preventing or treating ACD.


Multiple metabolomics of uropathogenic E. coli reveal different information content in terms of metabolic potential compared to virulence factors.
No single analytical method can cover the whole metabolome and the choice of which platform to use may inadvertently introduce chemical selectivity. In order to investigate this we analysed a collection of uropathogenic Escherichia coli. The selected strains had previously undergone extensive characterisation using classical microbiological methods for a variety of metabolic tests and virulence factors. These bacteria were analysed using Fourier transform infrared (FT-IR) spectroscopy; gas chromatography mass spectrometry (GC-MS) after derivatisation of polar non-volatile analytes; as well as reversed-phase liquid chromatography mass spectrometry in both positive (LC-MS(+ve)) and negative (LC-MS(-ve)) electrospray ionisation modes. A comparison of the discriminatory ability of these four methods with the metabolic test and virulence factors was made using Procrustes transformations to ascertain which methods produce congruent results. We found that FT-IR and LC-MS(-ve), but not LC-MS(+ve), were comparable with each other and gave highly similar clustering compared with the virulence factors tests. By contrast, FT-IR and LC-MS(-ve) were not comparable to the metabolic tests, and we found that the GC-MS profiles were significantly more congruent with the metabolic tests than the virulence determinants. We conclude that metabolomics investigations may be biased to the analytical platform that is used and reflects the chemistry employed by the methods. We therefore consider that multiple platforms should be employed where possible and that the analyst should consider that there is a danger of false correlations between the analytical data and the biological characteristics of interest if the full metabolome has not been measured.


Embolism to the central nervous system from cardiac myxoma. Report of two cases.
Two cases of left atrial myxoma are reviewed, both presenting as embolic phenomena. Neither patient gave a history compatible with pre-existent cardiac dysfunction. Sudden collapse and subsequent right hemiplegia resulted in one patient when an embolus lodged in the left middle cerebral artery. The second patient presented with headache and transient visual obscuration in the left eye. She showed evidence of embolism to the central retinal artery, and particulate matter could be seen within the retinal arterioles. Attention is drown to the fact that echocardiography now constitutes a simple, noninvasive, and highly reliable method of making this diagnosis. The propensity for embolic tumor fragments to grow and invade cerebral arterial walls is discussed along with its possible neurosurgical significance.


Ankyrin exposure induced by activated protein kinase C plays a potential role in erythrophagocytosis.
In physiological and pathological conditions activated protein kinace C (PKC) has been observed in the erythrocytes. Externalization of ankyrin followed by Arg-Gly-Asp (RGD)/integrin recognition also triggers erythrophagocytosis. In the present study, to test whether activated PKC is associated with ankyrin exposure in erythrophagocytosis. Phorbol 12-myristate-13-acetate (PMA)-induced PKC activation and ankyrin phosphorylation were tested, and under different treatment conditions the subpopulation of erythrocytes with ankyrin exposure and the levels of intracellular calcium were analyzed by flow cytometry. Results showed that treatment of erythrocytes with PMA in a calcium-containing buffer led to ankyrin exposure. In the absence of extracellular calcium, no ankyrin exposure was observed. PKC inhibition with calphostin C, a blocker of the PMA binding site, completely prevented the calcium entry, protein phosphorylation and ankyrin exposure. PKC inhibition with chelerythrine chloride, an inhibitor of the active site, diminished the level of ankyrin-exposing cells and ankyrin phosphorylation; however it even led to a higher percentage of cells with increased levels of calcium than with PMA treatment alone. Although PKC was activated and ankyrin phosphorylation occurred, no ankyrin exposure was observed in the absence of extracellular calcium. Analyses of results suggested that PMA induces calcium influx into the erythrocytes, leading to the activation of calcium-dependent enzymes and the phosphorylation of membrane proteins, ultimately inducing ankyrin exposure and erythrophagocytosis. This study may provide insights into the molecular mechanisms of removing aged or diseased erythrocytes.


TRPC6 Mutational Analysis in Iranian Children With Focal Segmental Glomerulosclerosis.
Focal segmental glomerulosclerosis (FSGS) ranks among nephrotic syndromes. Research shows that FSGS is brought about by several genes including transient receptor potential cation channel subfamily c member 6 (TRPC6). This study aimed to investigate TRPC6 gene in Iranian FSGS children. Twenty-six FSGS patients were included. They were all under 16 years old. Polymerase chain reaction amplification and sequencing were performed to examine exons 2 and 13 of TRPC6 gene. Sampling was performed when the patients had a mean age of 9.26 ± 3.19 years. Sixteen children were boys (61.5%); male-female ratio was 1.35:1. Four patients (15.4%) were diagnosed with TRPC6 variants. Three missense nonsynonymous mutations (C121S, D130V, and G162R) and 1 synonymous mutation (I111I) were detected. All variants were novel; in silico analysis predicted D130V and G162R as pathogenic. Patients with and without mutations were not different significantly regarding age at disease onset, sex, consanguinity, hypertension, hematuria, serum creatinine and albumin, rate of progression to kidney failure, response to steroids, and resistance to cyclosporine A and cyclophosphamide. This study examined exons 2 and 13 of TRPC6 gene in Iranian FSGS children. Four novel TRPC6 variants were detected; in silico analysis showed that 2 variants (D130V and G162R) could be pathogenic. It could be concluded that TRPC6 may be useful for genetic screening in Iranian FSGS children.


Ex vivo organ culture of adipose tissue for in situ mobilization of adipose-derived stem cells and defining the stem cell niche.
In spite of the advances in the knowledge of adipose-derived stem cells (ASCs), in situ location of ASCs and the niche component of adipose tissue (AT) remain controversial due to the lack of an appropriate culture system. Here we describe a fibrin matrix-supported three-dimensional (3D) organ culture system for AT which sustains the ASC niche and allows for in situ mobilization and expansion of ASCs in vitro. AT fragments were completely encapsulated within the fibrin matrix and cultured under dynamic condition. The use of organ culture of AT resulted in a robust outgrowth and proliferation in the fibrin matrix. The outgrown cells were successfully recovered from fibrin by urokinase treatment. These outgrown cells fulfilled the criteria of mesenchymal stem cells, adherence to plastic, multilineage differentiation, and cell surface molecule expression. In vitro label retaining assay revealed that newly divided cells during the culture resided in interstitium between adipocytes and capillary endothelial cells. These interstitial stromal cells proliferated and outgrew into the fibrin matrix. Both in situ mobilized and outgrown cells expressed CD146 and alpha-smooth muscle actin (SMA), but no endothelial cell markers (CD31 and CD34). The structural integrity and spatial approximation of CD31(-)/CD34(-)/CD146(+)/SMA(+) interstitial stromal cells, adipocytes, and capillary endothelial cells were well preserved during in vitro culture. Our results suggest that ASCs are natively associated with the capillary wall and more specifically, belong to a subset of pericytes. Furthermore, organ culture of AT within a fibrin matrix-supported 3D environment can recapitulate the ASC niche in vitro.


Daily egg production of Ascaris lumbricoides: the distribution of eggs in the faeces and the variability of egg counts.
Fifteen children aged from 6 to 12 years who were infected with Ascaris lumbricoides were selected for the study. The number of eggs/g (e.p.g.) of stool was determined using Beaver's direct smear technique, Stoll's dilution egg count technique and Katz's modified thick smear technique. Beaver's direct smear method consistently gave a higher e.p.g. than the other two methods. Results of this study show that Katz's modified thick smear technique was the best of the three methods used. The e.p.g. depends on several factors: the amount of stool passed daily, the concentration of eggs within a stool sample, the daily egg output, the worm load, the age of the worm and the technique used for determining the egg load. The daily average egg output/female A. lumbricoides was estimated to be 238 722 (range 134 462-358 750) with an average e.p.g. of 3540. The estimation of worm load based on egg count is useful in determining the intensity of infection in an individual. The male/female worm ratio was estimated to be 1:1.4.


In Vitro Validation of the Hippo Pathway as a Pharmacological Target for Canine Mammary Gland Tumors.
Canine mammary tumors (CMTs) are the most common neoplasms in intact female dogs. Some clinical and molecular similarities between certain CMT subtypes and breast cancer make them a potential model for the study of the human disease. As misregulated Hippo signaling is thought to play an important role in breast cancer development and also occurs in CMTs, we sought to determine if Hippo represents a valid pharmacological target for the treatment of CMTs. Six CMT cell lines were assessed for their expression of the Hippo pathway effectors YAP and TAZ and for their sensitivity to verteporfin, an inhibitor of YAP-mediated transcriptional coactivation. Four cell lines that expressed YAP (CMT-9, -12, -28, -47) were found to be very sensitive to verteporfin treatment, which killed the cells through induction of apoptosis with ED50 values of 14-79 nM. Conversely, two YAP-negative cell lines (CF-35, CMT-25) were an order of magnitude more resistant to verteporfin. Verteporfin suppressed the expression of YAP/TAZ target genes, particularly CYR61 and CTGF, which play important roles in breast cancer development. Verteporfin was also able to inhibit cell migration and anchorage-independent growth. Likewise, verteporfin efficiently suppressed tumor cell invasiveness in the CMT-28 and -47 lines, but not in CF-35 cells. Together, our findings provide proof of principle that pharmacological targeting of the Hippo pathway compromises the viability and attenuates the malignant behavior of CMT cells. These results will serve as the basis for the development of novel chemotherapeutic approaches for CMTs that could translate to human medicine.


Thermal Requirements and Performance of the Parasitoid Trichogramma pretiosum (Hymenoptera: Trichogrammatidae) on Helicoverpa armigera (Lepidoptera: Noctuidae) Eggs Under Variable Temperatures.
Temperature causes physiological and behavioral changes in egg parasitism. Egg parasitoids are a possible alternative for the control of Lepidoptera pests. The cotton bollworm Helicoverpa armigera (Hübner) is a generalist pest that has recently been introduced into Brazil. We evaluated the suitability of H. armigera eggs as hosts for Trichogramma pretiosum Riley and the effects of temperature (18-33°C) on its survival and development. We assessed the developmental time (egg adult), thermal requirements, age-specific fertility, and parasitism rate upon eggs of H. armigera at six different temperatures. Linear and nonlinear (Brière2) models were fitted to our data in order to describe the relationship between developmental rate and temperature for the immature stages of T. pretiosum and estimate the thermal constant (K), lower developmental temperature threshold (LT), optimum temperature for development (Topt), and upper developmental temperature threshold (Tmax). The estimated K and LT estimated by linear model were 130.38 degree days and 10.3°C, respectively. The T0, Topt, and Tmax by Brière model were 11.52, 32.89, and 41.1°C, respectively. Females of T. pretiosum developed at each temperature were assessed, and parasitism rate was above 75% on the first day, except at 30°C where it took 2 d to reach 75%. At 33°C, the highest rate of parasitism was 38%. The life table parameters predict population increases across the temperature range evaluated. The results demonstrated that T. pretiosum are suitable for the control of H. armigera, and the best performance will be achieved when used in regions with temperatures up to 30°C.


Tissue distribution of sex steroids: concentration of 17beta-oestradiol and cyproterone acetate in selected organs of female Wistar rats.
The tissue distribution of 17beta-oestradiol and cyproterone acetate was investigated after intravenous and intragastric administration to female Wistar rats by measuring the time course of the concentration of the sex steroids in plasma, liver, kidney, brain, and heart by radioimmunoassay. Test substances were administered intravenously in doses of 0.1 mg/kg each and intragastrically in doses of 10 mg/kg (17beta-oestradiol) and 0.1 mg/kg (cyproterone acetate) corresponding to the expected oral bioavailability. Tissue distribution was assessed within each mode of administration by AUCorgan/AUCplasma-quotients (Q-values), and between both routes of administration by F-values representing (bio- and organ availability) and R-values, which express the organ load after intragastric compared to intravenous administration if the same amount of drug has been made bioavailable in the plasma after both routes (for explanation see next page). The absolute bioavailability of 17beta-oestradiol after intragastric administration of 10 mg/kg was ca. 8%. The oestradiol liver load after intragastric administration was about 20 times higher than after intravenous administration, whereas the drug load of other organs was independent of the administration route. Cyproterone acetate was completely bioavailable after intragastric administration in a dose of 0.1 mg/kg. Cyproterone acetate levels and AUC-values in all organs investigated were higher when compared to the plasma with highest levels in the liver. The organ distribution of cyproterone acetate including the drug liver load was independent of the route of administration.


Time and energy constraints in pinniped lactation.
Previous reviews have recognized patterns of lactation in pinnipeds divided along phylogenetic lines. This study extended previous models of lactation in pinnipeds by explicitly taking into account all the energetic costs to mothers. Based on an analysis of time-energy budgets, the feasible lactation strategy for a species can be shown to depend on body mass. Due to increased metabolic costs of maintenance, species with a large body mass cannot normally sustain lactation by foraging during lactation unless they have access to rich local prey resources. Consequently, large pinnipeds must normally sustain lactation from body reserves. This disadvantage is compensated in large pinnipeds by freedom to forage in support of offspring at greater range whereas small pinnipeds are restricted to foraging within the locality of the pupping colony. In the absence of correlations between major life-history variables and body mass in pinnipeds, the principal patterns of lactation are likely to be different solutions to the trade-off between foraging on a relatively rich prey resource at long range and foraging on a poorer prey resource within a restricted range. Hence phylogeny may be less important than adaptation in the evolution of pinniped lactation.


Carisbamate (RWJ-333369).
Carisbamate (RWJ-333369) is a novel neuromodulator, initially developed by SK Biopharmaceuticals (Fairlawn, NJ), under development by Johnson & Johnson Pharmaceutical Research and Development (La Jolla, CA). Carisbamate displays high potency in a broad range of rodent seizure models at doses well below those that produce CNS toxicity. Its mechanism of action has not been elucidated. Acute and chronic nonclinical toxicological studies have not revealed any significant abnormalities other than dose-related CNS toxicity. It is extensively metabolized, chiefly through glucuronidation and oxidation of the aliphatic side chain. There is little evidence of CYP metabolism. It has linear pharmacokinetics. Its clearance is increased by carbamazepine and to a lesser degree by oral contraceptives. Carisbamate slightly increases the clearance of valproic acid and lamotrigine. The most common adverse events in humans are headaches, dizziness, and somnolence, generally mild to moderate, occurring at doses of 1000 mg/day or more. A recently completed phase 2 study for adjunctive use in partial onset seizures showed efficacy at a dose that was well tolerated.


[Borrelia burgdorferi sensu lato in ixodid ticks from Ostrava slag heaps].
In 2005 and 2006, Ixodes ricinus ticks were collected on two slag (waste rock) heaps from coal mines in the Ostrava area (North Moravia/Silesia, Czech Republic), Oskar (site A) and Emma (site B), partially covered by vegetation including trees, and at a control forest site near Hlucín (site C). The mean numbers of L. ricinus nymphs and imagoes flagged per person-hour were high: 35.3 nymphs and 12.7 imagoes, at site A, 23.3 and 26.0, respectively, at site B, and 25.4 and 16.8, respectively, at control site C. Using dark-field microscopy, 100 nymphs and 100 imagoes (50 females and 50 males) from each site were examined for borreliae. The mean prevalence rates of Borrelia burgdorferi sensu lato in nymphs and imagoes were 10.0% and 12.0%, respectively, at site A, 10.0% and 24.0%, respectively, at site B, and 13.0% and 17.0%, respectively, at site C. Differences in the prevalence of borreliae in nymphal and adult ticks from the slag heaps and control site were insignificant, but adult ticks from site B compared to site A contained borreliae significantly more frequently. The mean numbers of nymphs and imagoes infected with borreliae flagged per person-hour were 3.3 and 1.2, respectively at site A, 1.5 and 2.9, respectively, at site B, and 3.1 and 2.6, respectively, at site C. Isolation experiments for borreliae were carried out only in 16 ticks containing higher numbers of borreliae, with eight of these being culture-positive. The cultured borreliae were identified by PCR-RFLP as B. garinii (3 isolates: two from site B, one from site C), B. afzelii (4 isolates: one from site A, three from site B) and B. burgdorferi s.s. (one isolate from site A). Surprisingly, the results suggest that slag heaps, when covered by woody vegetation and frequented by humans, could theoretically pose roughly the same LB transmission risk to humans as common forest biotopes.


Lung alveolar epithelial cells synthesize interstitial collagenase and gelatinases A and B in vitro.
Type II pneumocytes are multifunctional alveolar epithelial cells that play a major role in the maintenance of lung structure and function. Recent evidence supports that these cells can synthesize a variety of extracellular matrix components in vitro, suggesting an active participation in connective tissue remodeling. However, their possible role in extracellular matrix degradation is unknown. In this study the production of matrix metalloproteinases (MMPs) was examined in primary cultures of rat alveolar type II pneumocytes after 2 and 7 days in culture. Under basal conditions, at both periods type II cells expressed interstitial collagenase mRNA. The immunoreactive protein was detected both in the cells and in conditioned media, and collagenolytic activity was revealed after trypsin activation. Gelatinolytic activity was detected by zymography showing a relative molecular mass of approximately 72 and 92 kDa (gelatinases A and B). Phorbol treatment increased collagenase and gelatinase activities. In addition, three alveolar epithelial cell lines were analysed for MMP production: MLE-12 (mice), L2 (rat), and A549 (human). The cell lines A549 and MLE-12 revealed collagenase and gelatinase A and B activities whereas the L2 cell line only exhibited gelatinase A activity, even after PMA induction. These findings demonstrate that alveolar epithelial cells synthesize in vitro several MMPs that confer on them the ability to degrade extracellular matrix and basement membrane components, a capacity of considerable importance for the remodeling of the stromal/epithelial interface.


Effect of patient position and hypotensive anesthesia on inferior vena caval pressure.
This is a prospective study to measure the inferior vena caval pressure of 20 patients in different positions and different states of blood pressure. Because the inferior vena caval pressure could affect the vertebral venous pressure, which in turn may influence blood loss during lumbar spinal surgery, this study was designed to provide the quantitative data necessary to stress the importance of patient positioning and to assess the effect of controlled hypotension on inferior vena caval pressure. Positioning patients with a pendulous abdomen and controlled hypotension has been practiced widely during lumbar spinal surgery. It is generally believed that the former will help reduce vertebral venous engorgement and the latter will produce a bloodless surgical wound. However, there have been no complete studies in which quantitative changes of inferior vena caval pressure resulting from different positions was examined. In addition, it would be interesting to know what happens to inferior vena caval pressure during induced hypotension. Could there be an adverse effect on the inferior vena caval pressure during the hypotensive state? An intravenous catheter was introduced into the inferior vena cava in each of 20 patients undergoing spinal surgery. In each patient, the inferior vena caval pressure was measured when the patient was supine, prone on a conventional pad, and prone on a Relton-Hall frame. It was followed by isoflurane-induced hypotension with reduction of mean arterial pressure by 20 mm Hg. In this series, the inferior vena caval pressure ranged from 8.2 to 23.4 mm Hg (with a mean of 15.3 mm Hg) when patients were positioned prone on a conventional pad. However, when they were subsequently positioned prone on a Relton-Hall frame, the inferior vena caval pressure decreased dramatically to a range of 4.6 to 13.6 mm Hg (with a mean of 8.2 mm Hg). In each patient the measured inferior vena caval pressure when positioned prone on a conventional pad was 1.5 times greater than that measured with the patient positioned on a Relton-Hall frame. There was a statistically significant difference between these two positions (F = 75.996; P < 0.05). The patients' mean arterial pressure ranged from 92 to 105 mm Hg before induced hypotension. During this time, the inferior vena caval pressure ranged from 4.1 to 13.1 mm Hg (mean, 8.2 mm Hg). During the hypotensive state, the patients' inferior vena caval pressure was found to range from 4.2 to 13.6 mm Hg (mean, 8.1 mm Hg). In each patient the hypotensive interior vena caval pressure may be slightly higher or lower than the baseline pressure. However, the variation never exceeded 1.7 mm Hg. Statistically, there was no significant difference between these two periods (t = 0.956; P > 0.05). A device allowing the patient's abdominaL viscera to hang freely while the patient is in a prone position significantly reduces their inferior vena caval pressure. The patients also has a constant inferior vena caval pressure during isoflurane-induced hypotension.


Usefulness of turbo-fluid-attenuated inversion-reovery (tFLAIR) sequence in diagnosing meningioma.
We evaluated qualitatively and quantitatively the usefulness of turbo-FLAIR (tFLAIR) in diagnosing meningioma in comparison with the T2-weighted turbo spin echo (T2W-TSE) sequence. Forty-eight patients diagnosed with meningioma were studied. In the qualitative study, we evaluated tumor delineation, contrast (Co) of tumor-to-CSF (cerebrospinal fluid), Co of tumor-to-brain parenchyma, Co of peripheral edema-to-brain parenchyma, and detectability of tumor margin. In quantitative study-1, using signal intensity (SI), we measured SI and calculated Co-SI of tumor-to-gray matter, Co-SI of tumor-to-white matter, Co-SI of peripheral edema-to-white matter, and Co-SI of tumor-to-CSF. In quantitative study-2, using film density, we measured density (De) on hard-copy film images and calculated Co-De for the same items as in quantitative study-1. In the qualitative study, tFLAIR was superior to T2W-TSE in tumor delineation, Co of tumor-to-CSF, Co of tumor-to-brain parenchyma, and Co of peripheral edema-to-brain parenchyma. In quantitative study-1, tFLAIR was superior to T2W-TSE in Co-SI of tumor-to-CSF, however, T2W-TSE was superior to tFLAIR in Co-SI of tumor-to-white matter. In quantitative study-2, tFLAIR was superior to T2W-TSE in all Co-De. tFLAIR was superior to T2W-TSE in the depiction of meningioma.


PPAR ligands for metabolic disorders.
As master regulators of lipid metabolism the peroxisome proliferator activated receptor (PPAR) family controls a wide variety of cellular processes, and thus it is not surprising that a large effort has focussed on discovering agents to pharmacologically modulate activity of these receptors. Early generation PPAR ligands, such as the fibrates and the thiazolidinediones (TZDs), were discovered empirically through an in vivo structure activity relationship exercise, whereas currently PPAR ligands are more often identified through target based structural design using cloned and expressed receptors. Regardless of how they were discovered, the development and clinical use of PPAR ligands throughout the last decade has greatly advanced understanding of the physiological function and therapeutic value of modulating these receptors. This review will briefly examine the PPAR family and then outline in greater detail select PPAR ligands indicated for the treatment of metabolic disorders.


Dense junctures of ethical concern.
A collection of stories by bioethicists writing about their own illnesses displays the importance of microethics. From this perspective, ethics happens not in the application of principles to specific decisions, but rather in the moment-to-moment flow of clinical interaction, as healthcare workers and patients make decisions, especially in their use of language. Microethical issues that are common to multiple stories are described as dense junctures of ethical concern. Three junctures are discussed in detail: conflicts between medical and patient rationalities, issues of how clinicians represent patients, and practices of truth telling. These junctures are illustrated with examples from the bioethicists' personal stories of treatment.


Structural diversities and related properties of four coordination polymers synthesized from original ligand of 3,3',5,5'-azobenzenetetracarboxylic acid.
Four new coordination polymers, namely [Co(H2O2abtc)(bibp)]n (), {[Mn1.5(Oabtc)(H2O)2]·(H2bmib)0.5·H2O}n (), {[Cd1.5(O2abtc)]·(H2bmib)0.5·2H2O}n (), and {[Cd(nip)(bibp)]·0.5H2O}n (),were constructed under solvothermal conditions in the presence of two bis(imidazole) bridging linkers (bimb = 1,4-bis(2-methylimidazol-1-ylmethyl)benzene, bibp = 4,4'-bis(imidazol-1-yl)biphenyl). The unstable azo ligand of 3,3',5,5'-azobenzenetetracarboxylic acid (H4abtc) could be oxidized and resulted in three oxidized derivatives of H4Oabtc (one N atom was oxidized), H4O2abtc (two N atoms were oxidized), and H2nip (one H4abtc was oxidized to two 5-nitroisophthalic acids). Their structures were determined by single-crystal X-ray diffraction and further characterized by elemental analyses, IR spectroscopy, powder X-ray diffraction (PXRD), and thermogravimetric (TG) analysis. Complex exhibited an interestingly 2D + 2D → 3D parallel entangled network based on 4-connected (4(4)·6(2))-sql sheets. Complex was found to be a {Mn3(COO)6} trinuclear SBU based 2D (3,6)-connected (4(3))2(4(6)·6(6)·8(3))-kgd sheet. While complex displays a {Cd3(COO)8} trinuclear SBUs based 3D (4,8)-connected (4(6))2(4(12)·6(12)·8(4))-flu network. Complex can be regard as a {Cd2(COO)2} binuclear SBUs based 6-connected (4(4)·6(11))-6T8 framework. In addition, the magnetic property of complexes , and the luminescence properties of complexes , were investigated.


Bone marrow precursors of nonobese diabetic mice develop into defective macrophage-like dendritic cells in vitro.
The NOD mouse spontaneously develops autoimmune diabetes. Dendritic cells (DC) play a crucial role in the autoimmune response. Previous studies have reported a defective DC generation in vitro from the NOD mouse bone marrow (BM), but a deviated development of myeloid precursors into non-DC in response to GM-CSF was not considered. In this study, we demonstrate several abnormalities during myeloid differentiation of NOD BM precursors using GM-CSF in vitro. 1) We found reduced proliferation and increased cell death in NOD cultures, which explain the previously reported low yield of DC progeny in NOD. Cell yield in NOR cultures was normal. 2) In a detailed analysis GM-CSF-stimulated cultures, we observed in both NOD and NOR mice an increased frequency of macrophages, identified as CD11c(+)/MHCII(-) cells with typical macrophage morphology, phenotype, and acid phosphatase activity. This points to a preferential maturation of BM precursors into macrophages in mice with the NOD background. 3) The few CD11c(+)/MHCII(high) cells that we obtained from NOD and NOR cultures, which resembled prototypic mature DC, appeared to be defective in stimulating allogeneic T cells. These DC had also strong acid phosphatase activity and elevated expression of monocyte/macrophage markers. In conclusion, in this study we describe a deviated development of myeloid BM precursors of NOD and NOR mice into macrophages and macrophage-like DC in vitro. Potentially, these anomalies contribute to the dysfunctional regulation of tolerance in NOD mice yet are insufficient to induce autoimmune diabetes because they occurred partly in NOR mice.


Analysis of the xylem sap proteome of Brassica oleracea reveals a high content in secreted proteins.
Xylem plays a major role in plant development and is considered part of the apoplast. Here, we studied the proteome of Brassica oleracea cv Bartolo and compared it to the plant cell wall proteome of another Brassicaceae, the model plant Arabidopsis thaliana. B. oleracea was chosen because it is technically difficult to harvest enough A. thaliana xylem sap for proteomic analysis. We studied the whole proteome and an N-glycoproteome obtained after Concanavalin A affinity chromatography. Altogether, 189 proteins were identified by LC-MS/MS using Brassica EST and cDNA sequences. A predicted signal peptide was found in 164 proteins suggesting that most proteins of the xylem sap are secreted. Eighty-one proteins were identified in the N-glycoproteome, with 25 of them specific of this fraction, suggesting that they were concentrated during the chromatography step. All the protein families identified in this study were found in the cell wall proteomes. However, proteases and oxido-reductases were more numerous in the xylem sap proteome, whereas enzyme inhibitors were rare. The origin of xylem sap proteins is discussed. All the experimental data including the MS/MS data were made available in the WallProtDB cell wall proteomic database.


Impact of autonomic nerve preservation and lateral node dissection on male urogenital function after total mesorectal excision for lower rectal cancer.
Urogenital dysfunction is a well recognized complication of rectal cancer surgery. The aim of this study was to assess the impact of autonomic nerve preservation (ANP) and lateral node dissection (LND) on male urogenital function after total mesorectal excision for lower rectal cancer. We studied, using a questionnaire, preoperative and current urogenital function in 47 male patients who underwent total mesorectal excision with the ANP technique for lower rectal cancer. Patients with and without LND were analyzed separately. A total of 37 patients (78.7%) (22 patients without LND, 15 with LND) returned the questionnaire. Among the 15 patients with LND, 2 underwent unilateral ANP. One patient without LND had urinary dysfunction preoperatively, and among the other 21 patients only 2 (9.5%) reported minor urinary complications postoperatively. After LND, 5 patients (33%) reported minor complications; there were no severe complications. Among patients who were sexually active prior to the operation, 90% and 70% of patients without LND and 50% and 10% of those with LND maintained sexual activity and ejaculation, respectively. However, 50% of patients who underwent low anterior resection or Hartmann resection without LND and all patients with abdominoperineal resection or LND reported reduced overall sexual satisfaction. The ANP technique offers the great advantage of maintaining urogenital function after rectal cancer surgery. After LND, although the ANP technique minimized urinary dysfunction, sexual function, particularly ejaculation, was often damaged. Careful follow-up is important even after ANP to improve postoperative sexual satisfaction.


Optimal management of central venous catheters for hemodialysis.
Good medical practices for optimizing the management of central venous catheters (CVCs) can be summarized in the following ten commandments: (1) the indications of CVC use you will restrict; (2) the choice of the catheter type and site venous you will discuss; (3) an experienced operator you will choose; (4) validated protocols of use and maintenance of catheters you will respect; (5) caring and nursing staff of the dialysis unit you will train and control; (6) the patients you will educate; (7) monitoring and maintenance care of CVC you will apply; (8) the duration of CVC use you will restrict; (9) specific patient risk factors you will evaluate and correct, and (10) a continuous quality improvement care process for CVC you will establish and apply in your dialysis unit.


Oligonucleotides containing modified bases. I. Inhibition of DNA and RNA polymerases by partially thiolated oligocytidylic acids.
A series of oligomers of cytidylic acid were prepared and partially (6-9% of the bases) thiolated in the 5 positions. The modified oligomers showed increasing inhibition with increasing chain length of both the DNA polymerase-alpha from regenerating rat liver and the DNA-dependent RNA polymerase of E. coli, but the minimum chain length for observable inhibitory activity was 5 nucleotide units for the DNA polymerase-alpha and 16 units for the RNA polymerase.


Potentially hazardous residues of non-ortho chlorine substituted coplanar PCBs in human adipose tissue.
The non-ortho chlorine substituted coplanar polychlorinated biphenyls (PCBs), namely, 3,3',4,4'-tetra-(T4CB), 3,3'4,4',5-penta-(P5CB), and 3,3',4,4',5,5', hexachlorobiphenyl (H6CB) are found to be the most toxic congeners of PCBs eliciting toxic and biological responses typical of 2,3,7,8-tetrachloro dibenzo-p-dioxin (T4CDD). Analyses of human adipose tissues for these congeners revealed 94-860 pg/g of T4CB, 120-730 pg/g of P5CB, and 36-200 pg/g of H6CB on wet weight basis. These were significantly higher than 2,3,7,8-T4CDD detected in the same samples (less than 1-18 pg/g). On the basis of in vitro and in vivo induction of hepatic microsomal benzo(a)pyrene hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD), "T4CDD toxic equivalents" were calculated for coplanar PCBs in humans. "T4CDD toxic equivalent" for 3,3',4,4',5-P5CB was one order of magnitude higher than 2,3,7,8-T4CDD. Considering the extreme toxic potential and persistence of coplanar PCBs, their presence in the human body may pose a greater toxic threat than dioxins and dibenzofurans.


Unexplained lymphadenopathy in family practice. An evaluation of the probability of malignant causes and the effectiveness of physicians' workup.
This study reported here was undertaken to determine the probability of malignancy in patients presenting with unexplained lymphadenopathy in primary care practice and to estimate the effectiveness of current referral patterns by family physicians in relation to malignant disease. Clinical characteristics that may be discriminatory for malignant causes were also investigated. A retrospective analysis was performed of 82 patients who underwent biopsy for unexplained lymphadenopathy from 1982 to 1984; data regarding the incidence of unexplained lymphadenopathy and the referral rate for this problem were obtained from registration projects. A total of 29 malignant lymphadenopathies were identified for a prior probability of 1.1 percent and a posterior (after referral) probability of 11 percent. The ability of the family physician to refer malignant cases within four weeks after initial consultation (sensitivity of referral) was 80 to 90 percent; 91 to 98 percent of benign cases were not referred (specificity of referral). An increased likelihood of malignancy was associated with age over 40 years (4 percent) and supraclavicular lymphadenopathy (50 percent). The incidence of malignancy in patients presenting with unexplained lymphadenopathy to the family physicians is very low (1 to 2 percent). Nevertheless, despite the paucity of validated discriminatory factors, the family physicians perform a reasonably effective selection process toward referral and biopsy.


Mahogunin ring finger 1 suppresses misfolded polyglutamine aggregation and cytotoxicity.
Polyglutamine diseases are a family of inherited neurodegenerative diseases caused by the expansion of CAG repeats within the coding region of target genes. Still the mechanism(s) by which polyglutamine proteins are ubiquitinated and degraded remains obscure. Here, for the first time, we demonstrate that Mahogunin 21 ring finger 1 E3 ubiquitin protein ligase is depleted in cells that express expanded-polyglutamine proteins. MGRN1 co-immunoprecipitates with expanded-polyglutamine huntingtin and ataxin-3 proteins. Furthermore, we show that MGRN1 is predominantly colocalized and recruits with polyglutamine aggregates in both cellular and transgenic mouse models. Finally, we demonstrate that the partial depletion of MGRN1 increases the rate of aggregate formation and cell death, whereas the overexpression of MGRN1 reduces the frequency of aggregate formation and provides cytoprotection against polyglutamine-induced proteotoxicity. These observations suggest that stimulating the activity of MGRN1 ubiquitin ligase might be a potential therapeutic target to eliminate the cytotoxic threat in polyglutamine diseases.


Huffmanela lata n. sp. (Nematoda: Trichosomoididae: Huffmanelinae) from the shark Carcharhinus amblyrhynchos (Elasmobranchii: Carcharhinidae) off New Caledonia.
Huffmanela lata n. sp. is described from eggs only, which were found in a small black spot on the skin near the gill opening of a shark, Carcharhinus amblyrhynchos, caught off Nouméa, New Caledonia, South-West Pacific. The eggs are 77-88 (mean 84) microm in length and 52-63 (mean 57) microm in width, with a thick (6-8 microm) shell, apparently spinose. Mobile larvae, 200-250 microm in length, were visible in the eggs. The species is distinguished from other members of the genus by the dimensions and shape of its eggs, which are the broadest ever reported. This is the second species of Huffmanela described from a shark, after H. carcharhini (MacCallum, 1925), to which it appears closely related in terms of its site in the skin and the nature of the egg surface.


[Effect of niflumic acid on the components of inactivation of the sodium channels of the Ranvier node membrane].
In voltage clamp experiments on the frog Ranvier node, niflumic acid did not alter fast or slow inactivation time courses in the wide range of membrane potentials but reduced the amplitude of the fast phase of inactivation. Fast and slow currents, corresponding respectively to fast and slow phases of inactivation, reversed at the same voltage, revealed different activation- and inactivation-voltage dependences both in intact fibre and after application of niflumic acid. The latter induced a shift of the steady-state inactivation curves for both components of inactivation towards more negative potentials without changing their steepness. The validity of suggestion of the existence of two populations of sodium channels in nerve membrane, is discussed.


Synthesis and structural revision of symbiodinolide C23-C34 fragment.
Stereoselective synthesis of the C23-C34 fragment of symbiodinolide, which possesses the originally proposed stereochemistry, and its diastereomers was achieved in 19 steps from L-aspartic acid, respectively. Comparison of spectroscopic data of the synthetic products with those of the degraded product of symbiodinolide led to a structural revision of the C23-C34 fragment.


ASO Author Reflections: Dialysis and Recurrence in Urothelial Cancer.


Solution-Phase Synthesis of Branched Metallic Nanoparticles for Plasmonic Applications.
This review discusses wet processes to synthesize metallic nanoparticles with many surface projections. Such projections can be formed by the aggregation of seed nanoparticles or by anisotropic crystal growth from specific facets on a base nanoparticle. The aggregation process can be controlled by protecting agents, which also play a key role in determining the morphology of the projections and the size of the nanoparticles. The reducing agents used for this purpose are mostly moderate and therefore allow seed aggregation before crystal growth. Some reducing agents act catalytically on specific crystal facets to promote anisotropic crystal growth. Branched nanostructures with high symmetry can be prepared from monocrystalline nanoparticles by site-selective growth and etching. The optical and plasmonic properties of the nanoparticles thus obtained can be used for various applications in surface-enhanced spectroscopy and in plasmon photocatalysts.


Potentiation of GABA-induced inhibition by 20-hydroxyecdysone, a neurosteroid, in cultured rat cortical neurons.
Effects of 20-hydroxyecdysone (20-HE), a neurosteroid, on cultured rat cortical neurons were examined using the whole cell recording technique. Under the voltage and current clamp conditions, brief application (5 sec) of 20-HE alone did not produce current changes nor any changes in the membrane potential. However, the chemical dose-dependently potentiated the GABA-induced current and hyperpolarization, which were blocked by bicuculline. These results suggest that 20-HE acts on the modulatory site of the GABAA receptor and potentiates GABAergic inhibition in rat cortical neurons.


The recovery from alcohol problems over the life course: the Lundby longitudinal study, Sweden.
The aim of this paper is to 'look behind the statistics' and to study alcohol-related problems over time and to portray the recovery (treated and untreated) from these problems over the life course in a subset of 41 males, defined as DSM-IV alcoholics from the Lundby general population project. The subjects were interviewed with semi-structured interviews by a psychiatrist. There was only minimal attrition. An analysis was made of the distribution of alcohol-related problems among the current alcoholic group compared to the recovered one at follow-up. Due to the limited number of subjects the calculations were mainly descriptive. The dominant problems were medical (64% vs. 25%), mental (45% vs. 17%), family (27% vs. 0%) and work (18% vs. 8%). The overall functioning assessed by the GAF scale implied a change from continuous to transient symptoms and problems in the recovered group. The subjects' attributions of reasons for recovery were social stabilization (84%), treatment (58%), family and peer pressure (58%) and medical complications (33%). It is argued that the qualitative findings might be used to complement the large statistical investigations in order to understand how to link alcohol-related problems and social consequences to the life course studies.


Finite element simulation of nonlinear wave propagation in thermoviscous fluids including dissipation.
A recently developed finite element method (FEM) for the numerical simulation of nonlinear sound wave propagation in thermoviscous fluids is presented. Based on the nonlinear wave equation as derived by Kuznetsov, typical effects associated with nonlinear acoustics, such as generation of higher harmonics and dissipation resulting from the propagation of a finite amplitude wave through a thermoviscous medium, are covered. An efficient time-stepping algorithm based on a modification of the standard Newmark method is used for solving the non-linear semidiscrete equation system. The method is verified by comparison with the well-known Fubini and Fay solutions for plane wave problems, where good agreement is found. As a practical application, a high intensity focused ultrasound (HIFU) source is considered. Impedance simulations of the piezoelectric transducer and the complete HIFU source loaded with air and water are performed and compared with measured data. Measurements of radiated low and high amplitude pressure pulses are compared with corresponding simulation results. The obtained good agreement demonstrates validity and applicability of the nonlinear FEM.


p53 regulates autophagic activity in senescent rat mesenchymal stromal cells.
The tumor suppressor protein p53 is an important player in the regulation of cell senescence, its functions are largely carried out by modulating its downstream genes. Emerging evidence has suggested that senescence and autophagy appear to be regulated by overlapping signaling pathways. Furthermore, autophagy markers have been observed in senescent cells. In this study, we sought to explore the effects of the expression pattern and function of p53 on the activity of autophagy and replicative senescence in bone marrow derived mesenchymal stromal cells (BMSCs). We found that more than 85% of BMSCs stained positive for SA-β-gal at passage 6 (senescent BMSCs) with increased expressions of senescence related genes (p16(ink4a) and p21(waf1)). These results were accompanied by the up-regulation of p53, down-regulation of mammalian target of rapamycin (mTOR) and phosphorylation of Rb. Senescent BMSCs displayed an increased monodansylcadaverine (MDC) staining and autophagy related genes (LC3 and atg12) level compared with BMSCs at passage 2. Knockdown of p53 alleviated the senescent state and reduced autophagic activity during the progression of BMSC senescence, which was accompanied by significantly up-regulated levels of mTOR and phosphorylation of Rb. These results demonstrate that autophagy increases when BMSCs enter the replicative senescence state, and p53 contributes a crucial role in the up-regulation of autophagy in this state.