Alantolactone induces apoptosis, promotes STAT3 glutathionylation and enhances chemosensitivity of A549 lung adenocarcinoma cells to doxorubicin via oxidative stress.
Alantolactone (ALT), a sesquiterpene lactone component of Inula helenium, has been reported to exert anticancer activity in various cancers. However, the cellular targets and underlying mechanism of anticancer activity of ALT in various cancers including lung cancer has not been fully defined. In the present study, we found that ALT effectively inhibits proliferation and triggers oxidative stress mediated-apoptosis in A549 lung adenocarcinoma cells by inducing ER stress and mitochondrial dysfunction. This ALT-mediated apoptosis was inhibited by NAC while diamide potentiated it. Moreover, ALT effectively suppressed both constitutive and inducible STAT3 activation, inhibited its translocation into nucleus and decreased its DNA binding activity. Further mechanistic study revealed that ALT abrogated STAT3 activation by promoting STAT3 glutathionylation. ROS scavenger NAC reverted ALT-mediated STAT3 glutathionylation and inhibition of STAT3 phosphorylation. Finally, ALT enhanced chemosensitivity of A549 cells to doxorubicin and reversed doxorubicin resistance in A549/DR cells by inhibiting STAT3 activation and P-glycoprotein expression and increasing intracellular accumulation of doxorubicin. Suppression of STAT3 activation by targeting ROS metabolism with ALT thus discloses a previously unrecognized mechanism underlying the biological activity of ALT. Taken together; ALT induces oxidative stress-dependent apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in A549 lung cancer cells. These findings provide an in-depth insight into the molecular mechanism of ALT in the treatment of lung cancer.


Identification of a Hematopoietic Cell Population Emerging From Mouse Bone Marrow With Proliferative Potential In Vitro and Immunomodulatory Capacity.
There is continuing interest in therapeutic applications of bone marrow-derived mesenchymal stromal cells (MSC). Unlike human counterparts, mouse MSC are difficult to propagate in vitro due to their contamination with adherent hematopoietic cells that overgrow the cultures. Here we investigated the properties of these contaminating cells, referred to as bone marrow-derived proliferating hematopoietic cells (BM-PHC). The results showed that both BM-PHC and MSC had strong immunomodulatory properties on T cells in vitro, with PGE2 and NO involved in this mechanism. However, BM-PHC were stronger immunomodulators than MSC, with CCL-6 identified as putative molecule responsible for superior effects. In vivo studies showed that, in contrast to BM-PHC, MSC endorsed a more rapid xenograft tumor rejection, thus indicating a particular context in which only MSC therapy would produce positive outcomes. In conclusion, bone marrow contains two cell populations with immunomodulatory properties, which are valuable sources for therapeutic studies in specific disease-relevant contexts.


A survey of sheep and/or cattle farmers in the UK shows confusion over the diagnosis and control of rumen fluke and liver fluke.
Calicophoron daubneyi (rumen fluke) is an emerging parasitic infection of livestock across Europe. Despite increasing in prevalence, little is known about the level of awareness of rumen fluke or current control practices used by UK farmers. Fasciola hepatica (liver fluke) is a common parasitic infection of cattle and sheep in the UK. Co-infections with these parasites can present in sheep and cattle, but the only drug with reported efficacy against rumen fluke is oxyclozanide. Between December 2019 and March 2020, 451 sheep and/or cattle farmers completed an online questionnaire, capturing their awareness and current means of control for liver fluke and rumen fluke. Most respondents (70%) were aware of rumen fluke, with 14% recording its presence on their farms and 18% having previously treated for rumen fluke. Almost all respondents (99%) were aware of liver fluke and higher numbers of respondents reported its presence on farm (67%) with 88% having previously treated for liver fluke. Respondents who were aware of rumen fluke said they were concerned about the parasite (81%), although rumen fluke was less of a concern than liver fluke (p < 0.05). Of respondents who reported rumen fluke presence on their farm, 42% cited incorrect diagnostic methods, including those traditionally used to detect liver fluke. Respondents were more likely to treat annually for liver fluke, as opposed to rumen fluke (p < 0.05). The most frequently used drug for the treatment of liver fluke infection was triclabendazole (53% sheep treatments, 34% cattle treatments) and only a minority of farmers treated with a product effective against rumen fluke (oxyclozanide; 42% cattle treatments, 35% sheep treatments). A small proportion of farmers stated that they used a non-flukicide drug to treat sheep for liver fluke infection (1.6% sheep treatments). These results demonstrate a broad awareness of liver and rumen fluke in sheep and cattle, but reveal confusion amongst farmers about their diagnosis and treatment, highlighting the need to provide best practice advice to the livestock industry for the control of both parasites.


A comparative study of insight scales and their relationship to psychopathological and clinical variables.
Research on the subject of insight has been hampered by difficulties in definition and reliable measurement. We compared several rating scales to measure insight on a group of 33 psychotic patients as well as assessing patients' psychopathology, clinical characteristics and cognitive functioning. Most currently used scales showed a high degree of inter-correlation. Measures of insight related strongly to the presence of delusions; grandiosity (inversely), and depression (positively). Higher insight scores correlated with indices of treatment compliance and inversely with substance abuse. Measures of pre-morbid IQ and impaired executive functioning, including the Wisconsin Card Sorting Test were not associated with poor insight. The study highlights aspects of psychopathology and clinical variables particularly related to insight and supports the continued use of standardized scales in further research in this area.


Effects of continuously administered murine interleukin-1 alpha: tolerance development and granuloma formation.
Continuous infusion of murine recombinant interleukin-1 alpha (rIL-1 alpha) into rats by using intraperitoneally implanted osmotic pumps led to marked decreases in body weight, liver enzymes (serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, and sorbitol dehydrogenase), appetite, and mobility and increases in drinking, blood urea nitrogen, and total peripheral blood leukocytes within 3 days. Granuloma formation was found in the local area of rIL-1 alpha release. As early as day 3, a focal infiltrate of polymorphonuclear leukocytes, mononuclear leukocytes, and plasma cells filled the area; by day 6, extensive fibrosis was found. A loss of rIL-1 alpha-induced changes, with the exception of granuloma formation, occurred by day 10. A marked decrease in the response to rIL-1 alpha was also observed when animals were challenged by implantation of new pumps containing rIL-1 alpha, with monitoring of body weight, or by subcutaneous injection of rIL-1 alpha, with monitoring of serum colony-stimulating factor production. We propose that, even in the continuous presence of interleukin-1, replacement of the acute responses to interleukin-1 by restoration of more normal physiology may be advantageous upon acquisition of specific immunity.


High-Performance Small Molecule/Polymer Ternary Organic Solar Cells Based on a Layer-By-Layer Process.
The layer-by-layer process method, which had been used to fabricate a bilayer or bulk heterojunction organic solar cell, was developed to fabricate highly efficient ternary blend solar cells in which small molecules and polymers act as two donors. The active layer could be formed by incorporating the small molecules into the polymer based active layer via a layer-by-layer method: the small molecules were first coated on the surface of poly(3,4-ethylenedioxy-thiophene):poly(styrenesulfonate) ( PSS), and then the mixed solution of polymer and fullerene derivative was spin-coated on top of a small molecule layer. In this method, the small molecules in crystalline state were effectively mixed in the active layer. Without further optimization of the morphology of the ternary blend, a high power conversion efficiency (PCE) of 8.76% was obtained with large short-circuit current density (Jsc) (17.24 mA cm(-2)) and fill factor (FF) (0.696). The high PCE resulted from not only enhanced light harvesting but also more balanced charge transport by incorporating small molecules.


3,3'-Diindolylmethane, a cruciferous vegetable derived synthetic anti-proliferative compound in thyroid disease.
Considerable epidemiological evidence exists to link thyroid disease with differing patterns of dietary consumption, in particular, cruciferous vegetables. We have been studying the anti-thyroid cancer (TCa) activity of indole-3-carbinol (I3C) found in cruciferous vegetables and its acid catalyzed dimer, 3,3'-diindolylmethane (DIM). There are no studies as yet to elucidate the effect of these compounds on the altered proliferative patterns in goiter or thyroid neoplasia. In this study, we tested the anti-proliferative effects of I3C and DIM on four different thyroid cancer cell lines representative of papillary (B-CPAP and 8505-C) and follicular carcinoma of the thyroid (CGTH-W-1 and ML-1), and primary human goiter cells. Cell survival and IC50 values for I3C and DIM were calculated by the XTT assay and cell cycle distribution analysis was done by flow cytometry. DIM was found to be a better anti-proliferative agent than I3C in both papillary and follicular TCa resulting in a greater cytotoxic effect at a concentration over three fold lower than predicted by the molar ratio of DIM and I3C. The anti-proliferative activity of DIM in follicular TCa was mediated by a G1 arrest followed by induction of apoptosis. DIM also inhibited the growth of primary goiter cells by 70% compared to untreated controls. Contrary to traditional belief that cruciferous vegetables are "goitrogenic", DIM has anti-proliferative effects in glandular thyroid proliferative disease. Our preclinical studies provide a strong rationale for the clinical exploration of DIM as an adjuvant to surgery in thyroid proliferative disease.


Idiocy in nineteenth-century fiction compared with medical perspectives of the time.
Portrayals of characters with an intellectual impairment in nineteenth-century prose fiction are analyzed. In the earlier works idiocy is imprecisely differentiated from madness or eccentricity and the characters are mostly shown as socially and psychologically marginal and 'other'. In the later works a greater naturalism and a more precise notion of idiocy as a distinct condition is evident. Literary depiction of intellectual impairment or idiocy occurs in the seventeenth and eighteenth centuries but as an abstract condition; interest in the lives and personalities of people with an intellectual impairment is new to the nineteenth century. This, it is argued, is connected with a developing interest in ordinary people. The portrayals in the selected works are related to changing medical perspectives on idiocy and how it should be treated during the period, in particular to the publicizing during the eighteen forties of the view that idiocy could be ameliorated through education.


On the characterization of three-state conical intersections using a group homomorphism approach: the two-state degeneracy spaces.
Second-order degenerate perturbation theory, in conjunction with the group homomorphism method for describing a similarity transformation, are used to characterize the subspace of two-state conical intersections contained in the branching space of a three-state conical intersection. It is shown by explicit calculation, using the lowest three-state conical intersection of (CH)3N2, that a second-order treatment yields highly accurate absolute energies, even at significant distances from the reference point of three-state intersection. The excellent agreement between the second order and ab initio results depends on the average energy component, which is computed using 5 first-order terms and 15 second-order terms. The second-order absolute energy change over the range rho = 0.0-0.3 au, where rho is the distance from the three-state conical intersection in the branching space coordinates, is approximately 6500 and 9500 cm(-1) for the E(1=2) and E(2=3) seams, respectively, with the maximum ab initio energy deviation from degeneracy of 200 cm(-1) occurring at rho = 0.3 au. The characteristic parameters gIJ and hIJ are also predicted to great accuracy, even at large rho, with the error growing to only 10-15% at rho = 0.3 au.


Monte Carlo simulations used to calculate the energy deposited in the coronary artery lumen as a function of iodine concentration and photon energy.
To better understand the risks of cumulative medical X-ray investigations and the possible causal role of contrast agent on the coronary artery wall, the correlation between iodinated contrast media and the increase of energy deposited in the coronary artery lumen as a function of iodine concentration and photon energy is investigated. The calculations of energy deposition have been performed using Monte Carlo (MC) simulation codes, namely PENetration and Energy LOss of Positrons and Electrons (PENELOPE) and Monte Carlo N-Particle eXtended (MCNPX). Exposure of a cylinder phantom, artery and a metal stent (AISI 316L) to several X-ray photon beams were simulated. For the energies used in cardiac imaging the energy deposited in the coronary artery lumen increases with the quantity of iodine. Monte Carlo calculations indicate a strong dependence of the energy enhancement factor (EEF) on photon energy and iodine concentration. The maximum value of EEF is equal to 25; this factor is showed for 83 keV and for 400 mg Iodine/mL. No significant impact of the stent is observed on the absorbed dose in the artery for incident X-ray beams with mean energies of 44, 48, 52 and 55 keV. A strong correlation was shown between the increase in the concentration of iodine and the energy deposited in the coronary artery lumen for the energies used in cardiac imaging and over the energy range between 44 and 55 keV. The data provided by this study could be useful for creating new medical imaging protocols to obtain better diagnostic information with a lower level of radiation exposure.


(3R,4S)-3,4-Isopropyl-idenedioxy-3,4-dihydro-2H-pyrrole 1-oxide.
The title compound C(7)H(11)NO(3) was prepared by intra-molecular nucleophilic displacement of 2,3-O-iso-propyl-idene-d-erythronolactol. There are two mol-ecules in the asymmetric unit, which are related by a pseudo-inversion centre. The crystal structure determination confirms unequivocally the configuration of the chiral centres as 3S,4R. In the crystal structure, inter-molecular C-H⋯O inter-actions link the mol-ecules (into infinite zigzag chains along the a axis.


68 Ga-DOTA-FAPI-04 PET/CT in the Detection of Thoracic SMARCA4-Deficient Undifferentiated Tumor.
Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare malignant disease. We present the case of a 56-year-old woman with thoracic SMARCA4-UT presenting as a mediastinal mass who underwent 68 Ga-DOTA-FAPI-04 PET/CT imaging. Intense 68 Ga-DOTA-FAPI-04 uptake was observed in the primary tumor and lymph node metastases. After 7 cycles of immune checkpoint inhibitor plus chemotherapy, the patient underwent mediastinal mass resection, and postoperative pathology confirmed a complete pathologic response. This case may provide valuable insights into the diagnosis and monitoring of the treatment response of thoracic SMARCA4-UT.


Using base rates of low scores to interpret the ANAM4 TBI-MIL battery following mild traumatic brain injury.
Base rates of low ANAM4 TBI-MIL scores were calculated in a convenience sample of 733 healthy male active duty soldiers using available military reference values for the following cutoffs: ≤2nd percentile (2 SDs), ≤5th percentile, <10th percentile, and <16th percentile (1 SD). Rates of low scores were also calculated in 56 active duty male soldiers who sustained an mTBI an average of 23 days (SD = 36.1) prior. 22.0% of the healthy sample and 51.8% of the mTBI sample had two or more scores below 1 SD (i.e., 16th percentile). 18.8% of the healthy sample and 44.6% of the mTBI sample had one or more scores ≤5th percentile. Rates of low scores in the healthy sample were influenced by cutoffs and race/ethnicity. Importantly, some healthy soldiers obtain at least one low score on ANAM4. These base rate analyses can improve the methodology for interpreting ANAM4 performance in clinical practice and research.


Pharmacology of a novel effect of gamma-aminobutyric acid on the frog optic tectum in vitro.
Excitatory postsynaptic field potentials (termed U1 and U2 waves) were extracellularly recorded from superficial layers of the frog optic tectum in vitro following stimulation of the contralateral optic nerve. gamma-Aminobutyric acid (GABA) largely enhanced the U1 and U2 waves, an effect which was progressively diminished by lowering the extracellular Cl- content. Muscimol or 3-aminopropanesulphonic acid (3-APS) was more potent than GABA in enhancing the U1 and U2 waveforms, whereas trans-4-aminocrotonic acid (TACA) was equipotent, its cis isomer (CACA) being less active. The action of GABA, TACA and CACA was relatively insensitive to bicuculline (100 microM). Pentobarbitone increased the U1 and U2 waves and antagonized the action of GABA. Midazolam did not change the GABA-induced responses. Picrotoxin antagonized both pentobarbitone and GABA effects. It is suggested that in the frog optic tectum GABA can activate an atypical receptor mechanism blocked by picrotoxin but comparatively insensitive to bicuculline.


Obesity and the school-age child.
The need for nursing involvement in the care of the obese school-age child and his family has been identified. The use of the nursing process based on the MSI Model of nursing has been discussed. The nurse plays an important role in identifying overweight children and in working with these children and their families when the need arises. the focus of nursing care may be preventing future weight gain, weight reduction, or regain after reduction. Linda, the obese child in Blubber, was ridiculed by her peers. This is a common, everyday experience for the obese child. It is hoped that the obese school-age child will have a better success rate for weight reduction and will ultimately be able to maintain the weight loss through the interventions of a professional nurse who uses this holistic approach to nursing care.


TWO PSYCHOTIC PLAYWRIGHTS AT WORK: THE LATE PLAYS OF AUGUST STRINDBERG AND TENNESSEE WILLIAMS.
August Strindberg and Tennessee Williams both became severely deranged during their playwriting careers. Both emerged from the most intense form of their derangement and wrote plays afterward. Strindberg, however, wrote his greatest plays after his psychosis; Williams, before his. Strindberg's psychosis spurred his creativity; that of Williams severely damaged his. This paper proposes that Strindberg mastered his psychosis and that in his late plays he dramatically symbolized psychotic processes. Williams, on the other hand, could neither access nor master his, and his late plays embody the repeated, unsymbolized acting out of his psychosis within an aesthetic context. These differences between the two playwrights become clear not through analysis of dramatic characters, but through changes that each playwright made to the dramatic medium itself.


Expression of miR-9a-5p in cirrhosis patients with recurrent portal hypertension after treatment.
MicroRNA (miR) influences the biological activities of cirrhotic patients with recurrent portal hypertension. The current study was designed to investigate risk factors related to the survival of cirrhosis patients and assessed the possibility of using miR-9a-5p predictability to prevent post-treatment portal hypertension. Patients with portal hypertension due to liver cirrhosis treated from January 2015 to September 2016 were included in this study. Patients without relapse after treatment were selected as the success group while patients with relapse after treatment were selected as the recurrence group. Serum samples from healthy people were also collected. The blood indexes of the 2 groups of patients before and after treatment were compared and the miR-9a-5p serum level in each group was determined. The Kaplan-Meier method was applied to analyze three-year survival, Cox univariate regression was used to analyze the risk factors for recurrence of cirrhotic portal hypertension, and the receiver operating characteristic curve (ROC) was used to evaluate the diagnostic value of serum miR-9a-5p, total bilirubin (TBIL) and platelet (PLT) levels in patients with recurrence. The miR-9a-5p level in the recurrence group was higher than that in the success group after treatment. In patients with recurrence, the miR-9a-5p level was negatively correlated with red blood cell count, TBIL, white blood cell count, and PLT count, and positively correlated with albumin. The miR-9a-5p, TBIL and PLT are potential markers of recurrent portal hypertension in liver cirrhosis. The miR-9a-5p had the highest area under the curve (AUC) value in patients with relapse. The miR-9a-5p is a risk factor for the recurrence of cirrhotic portal hypertension after treatment. It may be used as a marker of recurrence, and so has potential clinical value for the diagnosis and treatment of recurrent portal hypertension.


Serotonin transporter phosphorylation by cGMP-dependent protein kinase is altered by a mutation associated with obsessive compulsive disorder.
Human serotonin transporter (hSERT) activity expressed in HeLa cells was stimulated by agents that release nitric oxide, stimulate soluble guanylyl cyclase, or activate cGMP-dependent protein kinase (PKG). This stimulation was blocked by a PKG inhibitor. A naturally occurring mutation, I425V, associated with obsessive-compulsive disorder and other neuropsychiatric disorders, activated hSERT and eliminated stimulation via the PKG pathway. Inhibitors of soluble guanylyl cyclase or PKG decreased activity of the I425V mutant, but not wild type, indicating that both wild-type and mutant transporters could exist in both high and low activity forms. Mutation of Thr-276 in the fifth transmembrane domain (TM5) to alanine or aspartate prevented activation of wild-type hSERT through the PKG pathway and also blocked the inhibition of I425V activity by inhibitors of the pathway. The accessibility of positions in TM5 near Thr-276 was modified in T276D, but not in I425V. These results are consistent with the hypothesis that PKG phosphorylates hSERT at Thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by TM5. The effect of the I425V mutation may shift the balance of hSERT toward the phosphorylated form, possibly by interfering with the action of a phosphatase. However, association of hSERT with protein phosphatase 2A was not decreased in the I425V mutant.


Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor.
Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.


Structural evidence for non-canonical binding of Ca2+ to a canonical EF-hand of a conventional myosin.
We have previously identified a single inhibitory Ca2+-binding site in the first EF-hand of the essential light chain of Physarum conventional myosin (Farkas, L., Malnasi-Csizmadia, A., Nakamura, A., Kohama, K., and Nyitray, L. (2003) J. Biol. Chem. 278, 27399-27405). As a general rule, conformation of the EF-hand-containing domains in the calmodulin family is "closed" in the absence and "open" in the presence of bound cations; a notable exception is the unusual Ca2+-bound closed domain in the essential light chain of the Ca2+-activated scallop muscle myosin. Here we have reported the 1.8 A resolution structure of the regulatory domain (RD) of Physarum myosin II in which Ca2+ is bound to a canonical EF-hand that is also in a closed state. The 12th position of the EF-hand loop, which normally provides a bidentate ligand for Ca2+ in the open state, is too far in the structure to participate in coordination of the ion. The structure includes a second Ca2+ that only mediates crystal contacts. To reveal the mechanism behind the regulatory effect of Ca2+, we compared conformational flexibilities of the liganded and unliganded RD. Our working hypothesis, i.e. the modulatory effect of Ca2+ on conformational flexibility of RD, is in line with the observed suppression of hydrogen-deuterium exchange rate in the Ca2+-bound form, as well as with results of molecular dynamics calculations. Based on this evidence, we concluded that Ca2+-induced change in structural dynamics of RD is a major factor in Ca2+-mediated regulation of Physarum myosin II activity.


Chemosensitive neurons on the ventral medullary surface.
Central chemosensitivity is ascribed to three areas on the ventral medullary surface. The discharge frequency of neurons observed in these areas depends upon pH. Other neurons within the same areas do not change their frequency during acidosis or alkalosis. Histologically the areas are characterized by superficial nerve cells.


[The liver].
Hepatocyte transplantation has not yet reached therapeutic status, as it has proven difficult to transplant a sufficient number of functional hepatocytes able to integrate and proliferate inside liver plates. It has recently been shown that whole livers can be decellularized by portal infusion of detergents, yielding a decellularized scaffold with a well preserved vascular network and specific liver matrix. Perfusion of different combinations of cells through the portal vein of these scaffolds results in reconstitution of a complete functional organ that can be transplanted in small animals. An auto-constructed human liver could be engineered from exogenous liver scaffolds seeded with various cell populations, including autologous cells derived from induced pluripotent stem cells. Auto-constructed livers might replace conventional liver grafts in future.


Lesson of the month 1: Diabetic ketoacidosis in established renal failure.
Diabetic ketoacidosis (DKA) is a common medical emergency. The pathophysiology of DKA in patients with advanced chronic kidney disease differs significantly from patients with preserved renal function. We describe a patient with pre-dialysis renal failure who presented with DKA. This case highlights the importance of tailoring the established management guidelines appropriately.


Radiocapitellar incongruity of the radial head in magnetic resonance imaging correlates with pathologic changes of the lateral elbow stabilizers in lateral epicondylitis.
Post-traumatic posterolateral rotatory instability (PLRI) can be shown as radiocapitellar incongruity or posterior translation (PT) of the radial head in magnetic resonance imaging (MRI). We aimed to evaluate whether PT correlated with pathologic changes of lateral elbow stabilizers in patients with lateral epicondylitis. In MRIs of 160 patients with lateral epicondylitis, we measured PT of the radial head in the sagittal images. We qualitatively graded five lesions of the lateral elbow structures that included common extensor tendon (CET) lesion (grade 1-3), lateral collateral ligament complex (LCLC) insufficiency (grade 0-2), and absence or presence of bone marrow signal change, osteochondral lesion, and calcification. We analyzed whether the PT correlated with pathologic changes of the lateral elbow stabilizers and evaluated the diagnostic value of the PT for severe lesions. The average PT was 1.9 mm. The PT correlated with both the CET lesion (p < 0.001) and LCLC insufficiency (p < 0.001). The optimal cutoff values of the PT for grade 3 CET lesion and grade 2 LCLC lesion were 2.6 and 2.8 mm, respectively. When potential PLRI was defined as the PT of > 3.4mm as suggested for post-traumatic PLRI, 21 patients had potential PLRI. The positive predictive values of the PT > 3.4mm were 76% for grade 3 CET lesions and 67% for grade 2 LCLC insufficiency. This study demonstrates that PT of the radial head correlates with pathological changes of the lateral elbow stabilizers. As radiocapitellar incongruity is easy to measure quantitatively, it can be used for screening potential PLRI in patients with lateral epicondylitis.


[Tubeless superimposed high frequency jet ventilation in high grade laryngeal stenoses].
Massive stenosis of the larynx may present a potentially life-threatening situation for the patient, requiring immediate measures to ensure a patient's airway. The aim of this prospective study was to evaluate potential benefits of Superimposed High Frequency Jet Ventilation (SHFJV) in patients requiring microlaryngeal surgery due to massive stenosis of the larynx. 23 patients (age range 1.5 to 90 years) with laryngeal stenosis grade 2 and 3 according to the Cotton scale were ventilated using SHFJV. The duration of the SHFJV was 12 to 116 minutes. SHFJV was performed using a Bronchotron Respirator via a jet-laryngoscope. Arterial blood gases demonstrated paO2 between 71 and 295 mmHg and paCO2 of 28 to 81 mmHg. The mean FiO2 applied was 61.75 +/- 19.26. The airway pressure was measured at the tip of the jet-laryngoscope and was between 6 and 15 mmHg, and PEEP was 1 to 5 mmHg. In 13 patients a CO2 laser was utilised during surgery. In all patients SHFJV was performed without problems. Since the ventilation is delivered above any possible stenosis the danger of barotrauma is minimised. The surgeon obtains optimal visibility of the larynx and is not obstructed in the surgical procedure. SHFJV enables both the surgeon and the anesthetist to perform their respective duties and therefore increases the safety of the patient in the management of such a difficult problem as massive stenosis of the larynx.


[Pathology- a new revival].
The field of pathology has undergone considerable change in recent years. The editor and editorial board of this journal are to be commended for their decision to devote a special issue to the field of pathology. Pathology deals with the characterization, investigation, and diagnosis of disease and disease processes and as such, has Long been considered one of the foundations of medicine. It is a rich and multi-faceted field which has retained its breadth of scope in the face of ever-increasing specialization and sub-specialization in medicine. In addition to its classic roles in autopsy, case description, and the diagnosis of pathoLogic processes, new and innovative spheres of activity are becoming integral to the field, especially in the realm of molecular pathology. Pathology is a Leading player in the new age of "personalized cancer therapy", where pathologists are responsible not only for diagnosing disease in the tissue, but also for conducting additional tests which may predict its response to specific drug therapies. In this context, moLecular pathology has become essential to the field both in the provision of cLinical service and research. To fully implement this trend, we are witness to the rise of tissue collection and tissue banking initiatives for both diagnostic and research purposes. A national tissue banking project in Israel has recently received considerable attention.


The sarcoidosis movement and its personalities.
Sarcoidosis has been recognized for 125 years, but in every generation it makes a chameleon-like change, so updating is needed every so often. In Jonathan Hutchinson's day it was a dermatological curiosity, which gradually evolved into a multisystem disorder associated with bone cysts, and, with the introduction of X-rays, respiratory abnormalities. During the 1960s, epidemiology showed that this disorder, involving all systems of the body, was widely disseminated throughout the world. Each fresh approach, by investigators in different disciplines, has provided a new dimension, particularly in biochemistry and immunology. Each advance in knowledge brings us nearer the enigma which continues to elude us, namely the aetiology of sarcoidosis (Tables 1 and 2). This paper draws attention to the pioneers and personalities of the movement, and records the succession of congresses which have helped to define it worldwide.


Sick leaves in four factories--do characteristics of employees and work conditions explain differences in sickness absence between workplaces?
The study explored whether differences in sickness absence between four factories of a food industry company were explained by common determinants of sickness absence, such as employee health, sociodemographic characteristics, and physical and psychosocial work conditions. Survey responses of 582 employees were linked to the records of short-term (1-3 days) and long-term (>3 days) absence, as well as to records of absences due to musculoskeletal diagnoses. Multilevel models were applied in assessing the between-factory absence differences. Compared with the levels in the factory with the lowest sickness absence, in one factory the levels of short-term [rate ratio (RR) 1.72], long-term (RR 1.96), and musculoskeletal (rate ratio 2.93) absence were significantly higher. Another factory also had higher levels of long-term and musculoskeletal absence (RR 2.17 and 2.52, respectively). Adjustment for the background factors explained 35% of the difference in short-term absence, 3-9% of the differences in long-term absence, and 18-12% of the differences in musculoskeletal absence, but the between-factory differences were still highly significant. This study showed large differences in sickness absence between factories that were only partly explained by common determinants. Moreover, economic factors and formal control were unlikely explanatory factors, as the study was conducted within a single company. These results justify further research on local absence practices and cultures, including those of health service organizations and professionals.


[A case of colloid cyst of the third ventricle].
Colloid cysts of the third ventricle are rare, accounting for less than 1% of all intracranial neoplasms. However, its incidence will increase with increased use of CT scan and MRI. The symptomatology is principally acute or chronic hydrocephalus obstructing the foramen of Monro, and the origin of this cyst is controversial, neuroepithelial or endodermal. We report a case of colloid cyst of the third ventricle, associated with cavum veli interpositi. The patient, a 46-years-old female, had suffered from headache, ataxic gait and tremor lasting 6 months. CT scan and homogenous high signal intensity by SR (2450/450) MR image, detected a small round mass in the anterior part of the third ventricle that was of homogenous high density, but without the effect of enhancement. The lateral ventricle was markedly dilated, and a large cavum veli interpositi was found between the third ventricle and the corpus callosum. The cyst was totally removed by transventricular approach, and the result was satisfactory. We reviewed literatures and discussed MRI findings of colloid cysts of the third ventricle. Because of the presence of microvilli covered with coating materials seen in electron microscopic study, we suggested that the colloid cyst was endodermal in origin.


Medication Identification Device to Reduce Medication Errors in Nursing Homes: A Controlled Pilot Study.
A controlled pilot study was performed to evaluate implementation of a medication identification device intended to reduce errors in nursing homes. Naïve observation was used for data collection of medication errors on an intervention unit using the device and a control unit, along with field notes describing observation details. Ten staff were observed administering medications to 70 residents over the study time-frame. Of the 9,099 medication administrations observed (n = 4,588 intervention; n = 4,511 control), 1,068 (12%) errors were identified. The intervention unit had fewer non-time errors versus the control unit, including dose (n = 21 vs. n = 59; p < 0.01), drug (n = 4 vs. n = 21; p <0.01), route (n = 0 vs. n = 4; p < 0.01), and given without order (n = 1 vs. n = 8; p < 0.01). However, time errors were higher on the intervention unit and were often due to late start and interruptions. Non-time errors were due to reliance on memory and nursing judgment. A combination of technology and staff dedicated solely to medication administration likely affected error rate differences. [Journal of Gerontological Nursing, 48(4), 5-11.].


[Isolated agenesis of the gallbladder: case report].
The gallbladder agenesis is a rare congenital abnormality which is frequently mistaken with cholecystolithiasis, regardless of the imaging modality used. The diagnosis is confirmed at laparoscopic surgery with intraoperative sonography and intraoperative cholangiography and postoperative MRI-cholangiography. Intraoperative cholangiography may be risky because the absence of normal anatomical structures and the impossibility of pulling on the gallbladder to dissect the triangle of Calot represents an increased risk of iatrogenic injury to biliary or portal structures. Therefore postoperative MRI-cholangiography seems to be a more suitable approach to confirm the diagnosis.


Dietary cholecalciferol and 25-hydroxycholecalciferol supplementation interact to modulate reproductive performance, egg quality, serum antioxidant capacity, intestinal morphology and tibia quality of breeder geese.
1. A study was conducted to evaluate the effects of dietary cholecalciferol (vitamin D3) and 25-hydroxycholecalciferol (25-OH-D3) supplementation on the reproductive performance, egg quality, eggshell ultrastructure, serum hormone level and antioxidant capacity, intestinal morphology and tibia quality of breeder geese during the laying period.2. The trial was designed as a 3 × 3 factorial arrangement with three levels (300, 400 and 500 IU/kg) of vitamin D3 supplementation and three levels (25, 50 and 75 μg/kg) of 25-OH-D3 supplementation in a 10-wk feeding trial.3. The results showed that the combined supplementation of 400 IU/kg vitamin D3 and 50 μg/kg 25-OH-D3 had a better feed conversion ratio and a higher egg laying rate than the other groups. Vitamin D3 supplementation significantly increased the rate of qualified eggs for hatching, eggshell strength and thickness, serum testosterone and progesterone levels, serum total superoxide dismutase and glutathione peroxidase activities, tibia ash content and bone mineral density (P < 0.05). Dietary 25-OH-D3 supplementation significantly increased serum glutathione peroxidase activity and duodenal villus height and villus height-to-crypt-depth ratio (P < 0.05). The geese receiving 500 IU/kg vitamin D3 and 75 µg/kg 25-OH-D3 had the highest tibia calcium and phosphorous content among all groups (P < 0.05).4. Feeding 400 IU/kg vitamin D3 plus 50 µg/kg 25-OH-D3 gave optimal effects on feed conversion ratio and egg laying rate. This combination could be a nutritional strategy for increasing the laying rate, eggshell quality, serum hormone levels and serum antioxidant function regardless of 25-OH-D3 supplementation. Supplementation of 50 μg/kg 25-OH-D3 could be a recommended dose for improving the serum antioxidant capacity and intestinal morphology regardless of vitamin D3 supplementation.


Selective COX-2 inhibitors and the surgical patient.
The identification of COX-2 less than a decade ago has been followed by an unprecedented period of discovery and drug development (Golden & Abramson, 1999). Clinical studies thus far have established that the selective COX-2 inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx) are effective in the treatment of OA and RA, as are conventional NSAIDs. However, they do not cause the same adverse effects on the GI mucosa nor do they increase bleeding time as do conventional NSAIDs. Therefore, their use is not contraindicated in pre or postsurgical patients. Further investigation is underway to fully elucidate the role of COX-2 and to determine any additional benefits of selective COX-2 inhibition.


Neonatal mortality in Argentina. Situation analysis from 2005 to 2014.
Neonatal mortality (NM) refers to deaths occurring between birth and 27 days of life. This component of infant mortality has shown the least reduction over the past 50 years. The objective of this study was to analyze the course and characteristics of NM in Argentina. This was a descriptive, ecological study of NM in Argentina conducted between 2005 and 2014 to analyze its course, causes, and the relevance of prematurity and a low birth weight. Records of the Health Statistics and Information Department of the Ministry of Health of Argentina were used. The neonatal mortality rate reduced by 19.2% (2005: 8.9‰; 2014: 7.2‰); the early component (between birth and 6 days of life), by 20% (2005: 6.5‰; 2014: 5.2‰); and the late component (between 7 and 27 days of life), by 13% (2005: 2.3‰; 2014: 2‰). Disorders originating in the perinatal period and congenital malformations were the cause of more than 95% of neonatal deaths in this period. The relative significance of disorders originating in the perinatal period reduced, but that of congenital malformations increased. Preterm and low birth weight live births had the greatest risk of neonatal death. A younger gestational age and a lower birth weight resulted in a lower reduction of specific neonatal mortality rate. In the past 10 years, NM has reduced significantly. Disorders originating in the perinatal period and congenital malformations were the cause of almost all deaths in this age group. NM was associated with a low birth weight and prematurity.


Unification of Protein Abundance Datasets Yields a Quantitative Saccharomyces cerevisiae Proteome.
Protein activity is the ultimate arbiter of function in most cellular pathways, and protein concentration is fundamentally connected to protein action. While the proteome of yeast has been subjected to the most comprehensive analysis of any eukaryote, existing datasets are difficult to compare, and there is no consensus abundance value for each protein. We evaluated 21 quantitative analyses of the S. cerevisiae proteome, normalizing and converting all measurements of protein abundance into the intuitive measurement of absolute molecules per cell. We estimate the cellular abundance of 92% of the proteins in the yeast proteome and assess the variation in each abundance measurement. Using our protein abundance dataset, we find that a global response to diverse environmental stresses is not detected at the level of protein abundance, we find that protein tags have only a modest effect on protein abundance, and we identify proteins that are differentially regulated at the mRNA abundance, mRNA translation, and protein abundance levels.


Diagnostic reliability of needle biopsy of the parietal pleura. A review of 272 biopsies.
The clinical charts and histologic preparations from 245 patients who had pleural biopsies to evaluate pleural effusions of unknown etiology were reviewed. This represents an experience with 272 biopsies, as some patients underwent multiple biopsies. In 57 per cent of the cases of suspected or proven granulomatous disease involving the pleura, the pleural biopsy was positive. Similarly, in 48 per cent of the cases of suspected or proven pleural involvement by carcinoma, tumor was identified in the biopsy specimen. Only two false-positive diagnoses (one of granulomatous pleuritis and one of neoplastic disease) were made. The other 35 histologic diagnoses of granulomatous inflammation and 43 histologic diagnoses of carcinoma were verified. In this study, the authors found that the major limiting factor in establishing a diagnosis is the accuracy in random sampling of the parietal pleural surface. Thus, a negative pleural biopsy should not give the clinician a false sense of security.


[Clinical effects of Dynesys system and transfacet decompression through Wiltse approach in the treatment of lumbar degenerative diseases].
Objective: To investigate the early clinical effects of Dynesys system and transfacet decompression by Wiltse approach in the treatment of lumbar degenerative diseases. Methods: From January 2010 to December 2013, 48 patients suffering from lumbar degenerative diseases were treated with Dynesys system in addition to transfacet decompression through Wiltse approach.There were 28 males and 20 females with age of (51.8±6.8). The preoperative diagnosis included lumbar spinal stenosis(10 cases); lumber intervertebral disc herniation (38 cases). There were 23 cases in L4/5, 16 cases in L5/S1 and 9 cases in both of L4/5 and L5/S1.Posterolateral fixation with Dynesys pedicle screw through Wiltse approach.Unilateral resection of the inferior articular facet of the superior vertebra and the superior articular facet of the inferior vertebra.Decompression of the vertebral canal until the never root was decompressed satisfactorily.In the end, Dynesys was performed according to normal procedure.VAS, ODI evaluating standards were applied to evaluate the therapeutic effect.The intervertebral space and ROM of the lumbar were observed by X ray. Results: All patients underwent surgery safely without severe complications occurred.The average following up time was 33.5 (24-60) months.Compared with preoperative parameters (7.7±1.3, 70.8±13.5), the scores of VAS and ODI decreased significantly after surgery (2.3±1.5, 23.6±12.2) and at the final follow-up (2.2±1.4, 20.0±9.8) (P<0.05). There were significant difference in the height of intervertebral space and ROM at the stabilized segment (P<0.05), but no significant changes were seen at the adjacent segments (P>0.05). X-ray scan showed neither instability or internal fixation loosen, breakage or distortion in follow-up. Conclusion: Dynesys system in addition to transfacet decompression through Wiltse approach is a therapy option for mild lumbar degenerative disease.This method can retention the structure of lumbar posterior complex and the activity of the fixed segment, reduce the risk of low back pain together with nerve root decompressed.The early clinical results are satisfactory.


Everyday Racial Discrimination, Everyday Non-racial Discrimination, and Physical Health Among African Americans.
Past research has identified a link between discrimination and health outcomes among people of color. Perceptions of the cause of discrimination (racial vs. other) seem to be important for mental health; however, this relationship has not been fully examined for physical health. Using data from the National Survey of American Life, we find that, among African Americans, racial discrimination and overall discrimination regardless of attribution are associated with negative health outcomes while non-racial discrimination is not. The results suggest that racial discrimination has a unique adverse effect on physical health for African Americans that practitioners need to better understand.


[Evaluation of cellular immunity in a selected sample of aged subjects].
The immune system in the aging man is known to show age-related defects; the study of the subpopulations in human blood has yielded conflicting results. This mostly seems to be due to the heterogeneity of the subjects admitted to immunogerontological studies. We investigated a group of aged persons fulfilling the admission criteria described in the "SENIEUR" protocol and strictness criteria dietetics. We found a decrease in the number of T cells, while the number of B cells and, above all, the report of the T4/T8 remained constant. There individuals should be considered as optimally healthy and immunologically uncompromised.


Tissue-specific effects of castration and ovariectomy on murine epidermal growth factor and its mRNA.
The polypeptide mitogen, epidermal growth factor (EGF), was originally isolated from mouse submaxillary gland (SMG). In mice, these glands are sexually dimorphic; the SMG of male animals typically contains up to 400 pmol EGF/mg protein whereas EGF concentrations in the SMG of female mice are only 5-20 pmol/mg protein. When mice were castrated at 8 weeks of age, EGF mRNA levels in the SMG fell rapidly to the low levels observed in control female animals. Although the concentration of EGF in the SMG, measured by radioimmunoassay, also fell to very low levels (13.8 +/- 0.7 (S.E.M.) pmol/mg protein) in the castrated mice, the rate of decrease was considerably slower than that of the mRNA. In contrast to the loss of EGF and EGF mRNA from mice following castration, ovariectomy led to a rise in EGF mRNA levels in SMG, with a maximal increase (approximately 100-fold) 4-6 weeks after ovariectomy. Concentrations of EGF in the SMG also rose markedly in the ovariectomized animals, from a control value of 5.4 +/- 0.8 to 34.7 +/- 7.9 pmol/mg protein at 6 weeks. In mice, the kidney displays the second highest level of EGF gene expression. However, in contrast to the effects on SMG, kidney EGF mRNA was not affected by either castration or ovariectomy. These results provide further evidence for the tissue-specific control of EGF gene expression in response to steroid hormones.


Residence of Streptococcus pneumoniae and Moraxella catarrhalis within polymicrobial biofilm promotes antibiotic resistance and bacterial persistence in vivo.
Otitis media (OM) is an extremely common pediatric ailment caused by opportunists that reside within the nasopharynx. Inflammation within the upper airway can promote ascension of these opportunists into the middle ear chamber. OM can be chronic/recurrent in nature, and a wealth of data indicates that in these cases, the bacteria persist within biofilms. Epidemiological data demonstrate that most cases of OM are polymicrobial, which may have significant impact on antibiotic resistance. In this study, we used in vitro biofilm assays and rodent infection models to examine the impact of polymicrobial infection with Moraxella catarrhalis and Streptococcus pneumoniae (pneumococcus) on biofilm resistance to antibiotic treatment and persistence in vivo. Consistent with prior work, M. catarrhalis conferred beta-lactamase-dependent passive protection from beta-lactam killing to pneumococci within polymicrobial biofilms. Moreover, pneumococci increased resistance of M. catarrhalis to macrolide killing in polymicrobial biofilms. However, pneumococci increased colonization in vivo by M. catarrhalis in a quorum signal-dependent manner. We also found that co-infection with M. catarrhalis affects middle ear ascension of pneumococci in both mice and chinchillas. Therefore, we conclude that residence of M. catarrhalis and pneumococci within the same biofilm community significantly impacts resistance to antibiotic treatment and bacterial persistence in vivo.


Protective effect of Aquilegia vulgaris (L.) on carbon tetrachloride-induced oxidative stress in rats.
The ethyl ether extract of A. vulgaris inhibited in vitro microsomal lipid peroxidation (IC50 58.8 microg/ml) and showed moderate ability to scavenge superoxide radicals and to chelate iron ions. The extract (100 mg/kg body weight, po) decreased uninduced and enzymatic microsomal lipid peroxidation in the liver of male rats pretreated with CCl4 (1 ml/kg body weight) by 27 and 40%, respectively. Activity of antioxidant and related enzymes (catalase and glucose-6-phosphate dehydrogenase) inhibited by CCl4 was significantly restored after administration of the extract. The extract itself significantly enhanced superoxide dismutase activity. There was no effect of the extract on hepatic glutathione level and cytochrome P450 content, both were decreased by CCl4. Neither CCl4 nor the tested extract affected activities of NADPH-cytochrome P450 reductase and two monooxygenases, aniline hydroxylase and aminopyrine n-demethylase. It can be concluded that the protective effect of the A. vulgaris extract in CCl4-induced liver injury is mediated by inhibition of microsomal lipid peroxidation and restoring activity of some antioxidant and related enzymes.


Dialysis Dependence Predicts Complications, Intensive Care Unit Care, Length of Stay, and Skilled Nursing Needs in Elective Primary Total Knee and Hip Arthroplasty.
Limited data describe risks and perioperative resource needs of total joint arthroplasty (TJA) in dialysis-dependent patients. Retrospective multiple cohort analysis of dialysis-dependent American College of Surgeons National Surgical Quality Improvement Program patients undergoing primary elective total hip and knee arthroplasty compared to non-dialysis-dependent controls from 2005 to 2015. Relative risks (RRs) of 30-day adverse events were determined by multivariate regression adjusting for baseline differences. Six hundred forty-five (0.2%) dialysis-dependent patients of 342,730 TJA patients were dialysis-dependent and more likely to be dependent, under weight, anemic, hypoalbuminemic, and have cardiopulmonary disease. In total hip arthroplasty patients, dialysis was associated with greater risk of any adverse event (RR = 1.1, P < .001), mortality (RR = 2.8, P = .012), intensive care unit (ICU) care (RR = 9.8, P < .001), discharge to facility (RR = 1.3, P < .001), and longer admission (1.5×, P < .001). In total knee arthroplasty patients, dialysis conferred greater risk of any adverse event (RR = 1.1, P < .001), ICU care (RR = 6.0, P < .001), stroke (RR = 7.6, P < .001), cardiac arrest (RR = 4.8, P = .014), discharge to facility (RR = 1.5, P < .001), readmission (RR = 1.8, P = .002), and longer admission (1.3×, P < .001). Dialysis-dependence is an independent risk factor for 30-day adverse events, ICU care, longer admission, and rehabilitation needs in TJA patients. Thirty days is not sufficient to detect infectious complications among these patients. These findings inform shared decision-making, perioperative resource planning, and risk adjustment under alternative reimbursement models.


Educational Video on Pain Management and Subsequent Opioid Use After Cesarean Delivery: A Randomized Controlled Trial.
To evaluate whether viewing an educational video on pain management reduces opioid use after cesarean delivery. We conducted a randomized, controlled trial of women aged 18 years or older who underwent cesarean delivery at a tertiary care center. Eligible women were randomized in a 1:1 ratio to usual discharge pain medication instructions plus an educational video on pain management or to usual discharge pain medication instructions alone. All women received the same opioid prescription at discharge: Twenty 5-mg oxycodone tablets. Participants were contacted at 7 days and at 14 days after delivery to assess the number of oxycodone tablets used, adjunct medication (acetaminophen and ibuprofen) use, pain scores, and overall satisfaction of pain control. The primary outcome was the number of oxycodone tablets used from discharge through postpartum day 14. A sample size of 23 per group (n=46) was planned to detect a 25% difference in mean number of oxycodone tablets used between groups, as from 20 to 15. From July 2019 through December 2019, 61 women were screened and 48 were enrolled-24 in each group. Women who viewed the educational video used significantly fewer opioid tablets from discharge through postpartum day 14 compared with women who received usual pain medication instructions (median 1.5, range 0-20 vs median 10, range 0-24, P<.001). Adjunct medication use, pain scores, and satisfaction with pain control did not differ significantly between groups. Among women who underwent cesarean delivery, viewing an educational video on pain management reduced postdischarge opioid use. ClinicalTrials.gov, NCT03959969.


Isolation and characterization of Shiga toxin-producing Escherichia coli O157:H7 and non-O157 from beef carcasses at a slaughter plant in Mexico.
The contamination of beef carcasses with Shiga toxin-producing O157:H7 and non-O157 Escherichia coli (STEC) obtained from a slaughter plant in Guadalajara, Mexico was investigated. A total of 258 beef carcasses were sampled during a 12-month period. All samples were assayed for STEC by selective enrichment in modified tryptone soy broth supplemented with cefixime, cefsulodin and vancomycin, followed by plating on Sorbitol MacConkey Agar supplemented with cefixime and tellurite (CT-SMAC). Simultaneously, all samples were assayed by immunomagnetic separation (IMS) and plated on CT-SMAC and CHROMagar. The presence of the stx1, stx2, eaeA and hly933 genes, recognized as major virulence factors of STEC, was tested for O157:H7 and non-O157 E. coli isolates by multiplex polymerase chain reaction (PCR). STEC was detected in two (0.8%) samples. One of these STEC isolates corresponded to the serotype O157:H7 showing stx2, eaeA and hyl933 genes. The other isolate corresponded to non-O157 STEC and only had the stx1 gene. Thirteen carcasses (5%) were positive for nonmotile E. coli O157 and 7 (2.7%) were positive for E. coli O157:H7. The presence of O157:H7 and non-O157 STEC on beef carcasses in this slaughter plant in Guadalajara, Mexico, emphasizes the importance of implementing the Hazard Analysis and Critical Control Point (HACCP) system, as well as the need for implementing, evaluating, and validating antimicrobial interventions to reduce the presence of potential pathogenic microorganisms.


Pathological analysis of lesions in the exocrine pancreas of rats induced by Zinc Maltol.
The pancreas plays an important role in the homeostasis of zinc (Zn), a nutritionally essential metal. In several previous studies, Zn ions induced inflammatory changes in the exocrine pancreas; however, little is known about Zn complexes. In this study, we microscopically, immunohistochemically, and ultrastructurally examined pancreatic lesions in Sprague-Dawley (SD) rats induced by a 4-week repeated oral dose toxicity study of Zinc Maltol (ZM), a zinc (II) complex. ZM induces acinar atrophy and increases the number of duct-like structures. Immunohistochemistry revealed a decrease in the number of trypsin-positive cells, and an increase in the number of SOX9-positive cells. Interstitial fibrosis and macrophage infiltration also correlated with the degree of acinar atrophy. Electron microscopic evaluation revealed that the acinar cells that lost granules were surrounded by fibroblasts and collagen fibers. In conclusion, we provided a detailed description of ZM-induced pancreatic lesions in SD rats.


Solving a nomenclatural conundrum: Cernosvitovia crainensis (Mršić, 1989) and Aporrectodea macvensis Šapkarev in Mršić, 1991 (Lumbricidae).
This contribution deals with the names and authorship of two lumbricid taxa endemic to the Balkans (see Stojanović et al., this volume). Although their validity has never been questioned, it has been unclear up to now which publication has made these two species-group names available according to the rules of the International Code of Zoological Nomenclature (Articles in "the Code," ICZN 1999). In the following, we review the somewhat intricate history of these names and explain why the correct citation and spelling of these names are "Cernosvitovia crainensis (Mršić, 1989)" and "Aporrectodea macvensis Šapkarev in Mršić, 1991," respectively.


MR Imaging Measurements of Altered Placental Oxygenation in Pregnancies Complicated by Fetal Growth Restriction.
Purpose To evaluate oxygen-enhanced and blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging parameters in normal pregnancies and those complicated by fetal growth restriction (FGR). Materials and Methods This case-control study was approved by the local research ethics committee. Informed consent was obtained from all subjects. From October 2010 to October 2015, 28 women with uncomplicated pregnancies (individualized birthweight ratio [IBR] >20th percentile and delivery >37 weeks) and 23 with pregnancies complicated by FGR (IBR <5th percentile and abnormal Doppler ultrasonography [US] studies) underwent MR imaging. Differences in placental longitudinal R1 (1/T1) and transverse R2* (1/T2*) were quantified, with subjects breathing either air or oxygen. The difference in R1 (ΔR1) after hyperoxia was converted to change in partial pressure of oxygen (ΔPo2). Data were acquired prospectively, with retrospective interpretation of group differences (unpaired t tests). Diagnostic models were developed by using logistic regression analysis with gestational age as a covariate. Results The mean baseline R1 and R2* for normal pregnancies (R1: 0.59 sec-1, 95% confidence interval [CI]: 0.58 sec-1, 0.60 sec-1; R2*: 17 sec-1, 95% CI: 14 sec-1, 20 sec-1) were significantly different from those of pregnancies complicated by FGR (R1: 0.63 sec-1, 95% CI: 0.62 sec-1, 0.65 sec-1; R2*: 26 sec-1, 95% CI: 22 sec-1, 32 sec-1) (P < .0001). The ΔR1 showed a significant negative association with gestational age (P < .0001) in the combined cohort, with the FGR group having a ΔR1 that was generally 61.5% lower than that in the normal pregnancy group (P = .003). The area under the receiver operating characteristic curve for the differentiation between pregnancy complicated by FGR and normal pregnancy by using ΔPo2, baseline R1, and baseline R2* was 0.91 (95% CI: 0.82, 0.99). Conclusion R1, R2*, and ΔPo2 were significantly different between normal pregnancies and those complicated by severe FGR. MR imaging parameters have the potential to help identify placental dysfunction associated with FGR and may have clinical utility in correctly identifying FGR among fetuses that are small for gestational age. A larger prospective study is needed to assess the incremental benefit beyond that offered by US. © RSNA, 2017.


An Evaluation of the Clinical Therapeutic Effect of Lixisenatide in Type 2 Diabetes Patients: A Systematic Literature Review.
With cardiovascular disease accounting for approximately 50% of deaths in patients diagnosed with type 2 diabetes, it is pertinent to initiate anti-diabetic medications with cardiovascular benefits. This systematic clinical review critically examines the clinical therapeutic effect of lixisenatide. Data were gathered from articles indexed in PubMed, Google Scholar and Medline from 2010 - 2017, with the following search terms, "lixisenatide" and "GLP-1 receptor agonist". Studies written in the English language were included. Thirteen clinical studies which evaluated the efficacy of lixisenatide were analyzed. Results from these studies showed that lixisenatide is an effective monotherapy in the reduction of glycated hemoglobin (A1C), Postprandial Glucose (PPG) and Fasting Blood Glucose (FPG). As an add-on therapy to metformin or sulfonylureas and insulin, it was found to be clinically effective compared to placebo. In all reviewed trials, there were higher proportions of patients who achieved A1C < 7% or < 6.5% compared to placebo without a corresponding increase in weight. Finally, the use of lixisenatide was not associated with an increased risk of cardiovascular events. The most common adverse events in all lixisenatide groups were nausea, vomiting, and diarrhea. Lixisenatide appears to be safe and effective therapy for the management of type 2 diabetes mellitus. It is not associated with either the risk of cardiovascular events or symptomatic hypoglycemia. Finally, lixisenatide may be best used as an adjunct therapy for patients who are inadequately controlled with other diabetic medications, or select group of patients at risk of insulin induced obesity, hypertension or heart failure.


Seroprevalence of anti-Helicobacter pylori and anti-CagA antibodies among healthy children according to age, sex, ABO blood groups and Rh status in south-east of Iran.
The aim of this study was to evaluate the seroprevalence of anti-H. pylori and anti-CagA antibodies in healthy children and to investigate those relation with age, sex, ABO blood groups and Rh status. Serum samples from 386 children (187 males; 199 females), aged 1-15 years were tested for the presence of antibody to H. pylori and its virulence factor (CagA) by use of ELISA. ABO blood grouping were also done by hemagglutination test . The overall seroprevalence of H. pylori infection was 46.6%. The prevalence of anti-H. pylori antibody was significantly (p<0.05) higher in males (51.9%) compare to females (41.7%). The prevalence of anti-CagA antibody in infected children was 72.8%. Although, the prevalence of anti-CagA antibody was higher in males (78.4%) compared to females (66.3%), but the difference was not statistically significant (p=0.07). In age subgroups of 1-5 years, 6-10 years and 11-15 years, the prevalence of anti-H. pylori was 37.6%, 46.9% and 54.9% and regarding infected-children the prevalence and the mean titer of anti-CagA antibody were 63.8%, 75.94 Uarb/ml; 75%, 63.32 Uarb/ml and 79.45%, 57.11 Uarb/ml; respectively. The seroprevalence of anti-H. pylori and anti-CagA (in infected children) were 53% and 77.3% in blood group A, 50.5% and 64.7% in blood group B, 44.4% and 62.5% in blood group AB, 41.6 % and 76.8% in blood group O, 45.9% and 73% in Rh(+) phenotype and 54.84% and 70.6% in Rh(-) phenotype, respectively. The prevalence of both antibodies did not significantly differ between ABO blood groups or Rh status. However, within blood group A, the prevalence of anti-H. pylori and anti-CagA was significantly higher in males compare to females (p<0.05). These results showed that almost half of the children acquire H. pylori infection. Anti-CagA antibody are also common in the children. The seroprevalence of anti-H. pylori and anti-CagA antibodies were higher in males and increased with age. However, the mean titer of anti-CagA antibodies decreased with age, inversely. ABO blood groups may partly influence the prevalence of H. pylori infection, especially in male gender.


[Role of adherence to long-term drug therapy in patients with cardiovascular disease: an Italian intersocietary consensus document].
Chronic therapy with statins, antihypertensive and antiplatelet drugs is one of the most important interventions for primary and secondary prevention of cardiovascular disease. Adherence to drug treatment is key to successful therapeutic intervention, especially in chronic conditions. This holds particularly true in the setting of cardiovascular diseases, because poor adherence may have serious adverse effects in terms of morbidity and mortality. Many factors may contribute to poor adherence, which can be either patient-related or dependent on the healthcare system, the physician and the environment. The identification and appropriate correction of these factors may result in both clinical and economic benefits. In this setting it is also important to assess the implications of the increasing use of generic or equivalent drugs on adherence to pharmacological therapy.


Antitumor effects of interleukin-12 in pre-clinical and early clinical studies (Review).
Interleukin-12 (IL-12) previously called cytotoxic lymphocyte maturation factor (CLMF) or NK cell stimulatory factor (NKSF) is a recently characterized heterodimeric cytokine composed of two subunits. Although identified no more than 10 years ago IL-12 has already proved efficacious in numerous pre-clinical tumor immunotherapy studies. Animal studies revealed that IL-12 has powerful antitumor, anti-metastatic and anti-angiogenic activities and seems to be less toxic than other immunotherapeutics such as interferons or IL-2. A number of pre-clinical studies with IL-12 prompted the evaluation of this cytokine in the treatment of human cancers. Results of phase I and early phase II clinical trials have already been reported and these are described here together with a brief discussion concerning IL-12-related toxicities and potential methods of their prevention.


Role of Intelligent Management Systems in Surgical Punctuality and Quality of Care.
The main objective is to illustrate the role of intelligent management systems in surgical punctuality and quality of care. 72 registered nurses were selected from our operating room, and 180 patients who needed surgery were randomly divided into the control group and the observation group for satisfaction survey and satisfaction analysis. The correct rate of surgical clothing distribution and the qualified rate of clothing recovery were improved, and the punctuality rate of the operation was enhanced than before the implementation of the intelligent management system. The accurate positioning of surgical items and the accurate statistics of equipment use time were enhanced than before implementation. The error rate of surgical item preparation after implementation was lessened than before implementation. Both nursing satisfaction and patient satisfaction after implementation were increased than before implementation. The intelligent management system improves the punctuality of surgery and the quality of care in the operating room.


catena-Poly[[(2,2'-bipyridine)-manganese(II)]-μ(3)-4,4'-sulfonyl-dibenzoato].
In the title compound, [Mn(C(14)H(8)O(6)S)(C(10)H(8)N(2))](n), the Mn(II) ion is coordinated by four O atoms from three 4,4'-sulfonyl-dibenzoate (sdba) ligands and two N atoms from one 2,2'-bipyridine (2,2'-bipy) ligand in a distorted octa-hedral geometry. The manganese atoms are alternately bridged either by two sdba ligands, with an Mn⋯Mn separation of 12.284 (1) Å, or by two carboxyl-ate groups from two sdba ligands, with an Mn⋯Mn separation of 4.064 (1) Å, thus producing polymeric chains propagated in [101]. Weak inter-molecular C-H⋯O hydrogen bonds and π-π inter-actions [centroid-centroid distance of 3.730 (3) Å between the aromatic rings of neighbouring polymeric chains] further stabilize the crystal packing.


The minus 35-recognition region of Escherichia coli sigma 70 is inessential for initiation of transcription at an "extended minus 10" promoter.
It is known that Escherichia coli promoters having the major minus 10 consensus sequence TATAAT, but lacking significant resemblance to consensus in the minus 35 region, allow transcriptional initiation in vivo and in vitro if they have an additional TGn motif immediately upstream of minus 10. To determine whether region 4.2 of sigma 70, whose normal role is sequence recognition at minus 35, is unnecessary for initiation of transcription at such "extended minus 10" promoters, we modified the sigma 70 gene so as to generate a carboxy-truncated polypeptide lacking the last 84 amino acids and therefore missing region 4.2. Our results show that both the intact and truncated sigma 70 allow purified RNA polymerase to initiate efficiently and specifically at an extended minus 10 promoter, whereas only the intact sigma 70 permits efficient initiation at normal promoters (defined by minus 35 and minus 10 hexamer sequences).


Testicular Volume in a Cohort of Prepubertal Indian Children.
There are orchidometer-based testicular volume nomograms for Indian children; however, accurate and reliable values measured by ultrasound are lacking. The aim of this study was to (1) measure the testicular volumes of boys from birth to 8 years and generate reference values and (2) to identify factors if any that may influence variation in testicular volumes. This was a prospective observational study conducted on 320 children in the Department of Pediatric Surgery, Christian Medical College, Vellore, India. A total of 320 boys without any genital abnormalities were studied. The testes were scanned using a linear transducer, and the length, width, and depth of each testis were recorded. Testicular volume was calculated using Lambert's equation - length × width × depth × 0.71. Mean testicular volumes and standard deviation for every year of age were calculated. The centile values for testicular volume were computed using R software. Age-specific nomogram of each testis was created separately. Interobserver variability of the measurement was shown to be up to 0.3 ml. No difference was demonstrated in the testicular volumes between the right and left testis. No correlation was found between body weight and body mass index with testicular volume. From the data on differences in size between the two sides, a volume differential index of 27% corresponds to the 95th centile. Reference values have been created for testicular volumes in prepubertal Indian children that could be used to assess the effects of disease and surgical interventions in this age group.


Moisture-Enabled Germination of Heat-Activated Bacillus Endospores for Rapid and Practical Bioelectricity Generation: Toward Portable, Storable Bacteria-Powered Biobatteries.
Small-scale battery-like microbial fuel cells (MFCs) are a promising alternative power source for future low-power electronics. Controllable microbial electrocatalytic activity in a miniaturized MFC with unlimited biodegradable energy resources would enable simple power generation in various environmental settings. However, the short shelf-life of living biocatalysts, few ways to activate the stored biocatalysts, and extremely low electrocatalytic capabilities render the miniature MFCs unsuitable for practical use. Here, heat-activated Bacillus subtilis spores are revolutionarily used as a dormant biocatalyst that can survive storage and rapidly germinate when exposed to special nutrients that are preloaded in the device. A microporous, graphene hydrogel allows the adsorption of moisture from the air, moves the nutrients to the spores, and triggers their germination for power generation. In particular, forming a CuO-hydrogel anode and an Ag2 O-hydrogel cathode promotes superior electrocatalytic activities leading to an exceptionally high electrical performance in the MFC. The battery-type MFC device is readily activated by moisture harvesting, producing a maximum power density of 0.4 mW cm-2 and a maximum current density of 2.2 mA cm-2 . The MFC configuration is readily stackable in series and a three-MFC pack produces enough power for several low-power applications, demonstrating its practical feasibility as a sole power source.


Superior mesenteric artery syndrome: an uncommon cause of upper intestinal obstruction.
A previously healthy young boy who was operated for upper gastrointestinal obstruction, 12 weeks earlier, without relief of his symptoms of projectile bilious emesis and colicky pain, is described. He underwent upper gastrointestinal contrast studies, suggesting duodenal obstruction at its third part and superior mesenteric artery syndrome, which was confirmed by selective superior mesenteric arteriography. Duodenojejunostomy was carried out. The patient was symptom-free with normal built and growth after 4 years of follow-up.


Radiographs in the office: is a second reading always needed?
We evaluated the frequency, nature, and importance of the changes in patient care that occurred as a result of differences in outpatient radiograph readings for cases in which the primary care clinician, hypothetically, would not request a second reading by a radiologist. During 4 months, 1393 pairs of radiographic readings were collected from 9 volunteer primary care practices with 86 clinicians and a second reading by one of 42 radiologists. For 553, hypothetically, the clinician would not request a consultation from a radiologist. Review analysis of the 553 pairs revealed 100 (18.1%) radiographs in which the radiologist's reading did not agree with the clinician's reading. Data from the original visit and subsequent related care were abstracted from patient charts and reviewed. Changes in clinical care resulting from the radiologist's reading were identified. The radiologists' second reading of these 553 sets of radiographs resulted in 14 (2.5% of 553 and 14% of 100) cases of one or more changes in care. We found 38 documented or presumed changes in care and zero substantial changes in care. Primary care clinicians are able to identify radiographs for which a second reading by a radiologist will not result in substantial changes in care.


[Congenital diaphragmatic hernia diagnosed in adulthood--a case report and review of the literature].
Congenital diaphragmatic hernia (CDH) is a rare anomaly (1 of 2-4000 live births) where abdominal organs can enter the thoracic cavity. It is usually diagnosed shortly after birth, often associated with pulmonary hypoplasia and pulmonary hypertension causing life threatening condition. In approximately one out of four patients CDH is diagnosed later in life, usually within several weeks or months from birth. CDH diagnosed in adulthood is very uncommon. Here we describe a 45 year old previously healthy woman that was diagnosed with a large tumor in her right hemithorax, after having symptoms of chronic cough and chest pain for several months. At thoracotomy the tumor was found to be omentum covered with a hernial sac that had penetrated the chest through a small diaphragmatic hernia. Six months postoperatively she was doing well with no respiratory or abdominal symptoms.


The landscape of transposable elements in the finished genome of the fungal wheat pathogen Mycosphaerella graminicola.
In addition to gene identification and annotation, repetitive sequence analysis has become an integral part of genome sequencing projects. Identification of repeats is important not only because it improves gene prediction, but also because of the role that repetitive sequences play in determining the structure and evolution of genes and genomes. Several methods using different repeat-finding strategies are available for whole-genome repeat sequence analysis. Four independent approaches were used to identify and characterize the repetitive fraction of the Mycosphaerella graminicola (synonym Zymoseptoria tritici) genome. This ascomycete fungus is a wheat pathogen and its finished genome comprises 21 chromosomes, eight of which can be lost with no obvious effects on fitness so are dispensable. Using a combination of four repeat-finding methods, at least 17% of the M. graminicola genome was estimated to be repetitive. Class I transposable elements, that amplify via an RNA intermediate, account for about 70% of the total repetitive content in the M. graminicola genome. The dispensable chromosomes had a higher percentage of repetitive elements as compared to the core chromosomes. Distribution of repeats across the chromosomes also varied, with at least six chromosomes showing a non-random distribution of repetitive elements. Repeat families showed transition mutations and a CpA → TpA dinucleotide bias, indicating the presence of a repeat-induced point mutation (RIP)-like mechanism in M. graminicola. One gene family and two repeat families specific to subtelomeres also were identified in the M. graminicola genome. A total of 78 putative clusters of nested elements was found in the M. graminicola genome. Several genes with putative roles in pathogenicity were found associated with these nested repeat clusters. This analysis of the transposable element content in the finished M. graminicola genome resulted in a thorough and highly curated database of repetitive sequences. This comprehensive analysis will serve as a scaffold to address additional biological questions regarding the origin and fate of transposable elements in fungi. Future analyses of the distribution of repetitive sequences in M. graminicola also will be able to provide insights into the association of repeats with genes and their potential role in gene and genome evolution.


Protein Requirements in Critically Ill Older Adults.
Critically ill elderly patients' nutritional needs are not well understood and vary with the phase of illness and recovery. Patients' nutritional needs should be assessed early in hospitalization and re-assessed throughout the stay with additional attention during the transitions from critical illness, to severe illness, to post-hospital rehabilitation. In this review, we summarize recent findings and highlight recommendations for protein supplementation in critically ill geriatric patients throughout the stages of recovery. Future research specifically focusing on protein dose, its relationship with caloric needs, and delivery modality must be conducted to provide more specific guidelines for clinical practice.


Salivary Markers in Patients with Chronic Kidney Disease.
Aim of the study: To determine the possibility of using saliva as a diagnostic and prognostic tool for screening and monitoring kidney function. Methods: This study included 32 patients with different stages of chronic kidney disease (CKD) and 20 healthy examinees for the control group. Saliva was collected using the spitting method, and on the same day blood was also drawn from the examinees to determine serum concentrations of urea and creatinine. The salivary values of uric acid, urea, creatinine and albumin were determined with a spectrophotometer, as well as the serum concentrations of urea and creatinine. Results: Our results showed a statistically significant positive correlation between salivary and serum levels of urea and creatinine in patients with CKD (Pearson's correlation coefficient for urea was r =0.6527, p = 0.000, while for creatinine it was r = 0.5486, p = 0.001). We detected a statistically significant positive correlation between the salivary levels of urea and the clinical stage of CKD (r = 0.4667, p = 0.007). We did not register a significant correlation between the salivary levels of creatinine and the clinical stage of CKD (r = 0.1643, p = 0.369). Conclusion : Salivary urea is a valid marker for determining kidney function and a potential salivary marker for screening and monitoring kidney function. Salivary creatinine can be used as a qualitative marker, only indicating the existence of a disease.


A new generator for proposing flexible lifetime distributions and its properties.
In this paper, we develop a generator to propose new continuous lifetime distributions. Thanks to a simple transformation involving one additional parameter, every existing lifetime distribution can be rendered more flexible with our construction. We derive stochastic properties of our models, and explain how to estimate their parameters by means of maximum likelihood for complete and censored data, where we focus, in particular, on Type-II, Type-I and random censoring. A Monte Carlo simulation study reveals that the estimators are consistent. To emphasize the suitability of the proposed generator in practice, the two-parameter Fréchet distribution is taken as baseline distribution. Three real life applications are carried out to check the suitability of our new approach, and it is shown that our extension of the Fréchet distribution outperforms existing extensions available in the literature.


Immunoexpression of MMP-8, MMP-9 and TIMP-2 in dilated cardiomyopathy.
Alteration of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) expression has been studied for various cardiac diseases, including dilated cardiomyopathy (DCM), with the significance of surrogate markers of extracellular matrix (ECM) remodeling. In this study, we determined the MMP-8, MMP-9 and TIMP-2 immunoexpression in the heart of patients diagnosed with DCM in relation to a histological composite score (HCS). The study included 40 cases of heart fragments that were processed by the usual paraffin inclusion technique, followed by a semi-quantitative evaluation of histopathological parameters, which summed, allowed the establishment of a HCS. Subsequently, the cases were immunohistochemically processed for MMP-8, MMP-9 and TIMP-2, followed by the semi-quantitative evaluation of their expression intensity. MMP-8 was identified only in myocardiocytes, while MMP-9 and TIMP-2 were present in both myocardiocytes and stroma, but with different intensity. The increasing intensity of MMP-8 and TIMP-2 immunoreactions was significantly associated with low HCS. In case of MMP-9, the immunostaining intensity analysis in relation to the HCS level revealed insignificant differences, but we found an association of increased and moderate intensity with low HCS. The imbalance between TIMPs and MMPs disrupts the ECM architecture and contributes to the remodeling process in DCM, aspect that can be used in the development of new clinical therapies.


Cisplatin Eligibility Issues and Alternative Regimens in Locoregionally Advanced Head and Neck Cancer: Recommendations for Clinical Practice.
Well-designed randomized trials provide the highest level of scientific evidence to guide clinical decision making. In chemoradiotherapy of locally advanced squamous cell carcinoma of the head and neck (SCCHN), data support the use of three cycles of 100 mg/m2 cisplatin given every 3 weeks concurrently with conventionally fractionated external beam radiotherapy, although a full compliance with all three cycles is reserved to only about two thirds of initially eligible cases. On an individual patient level, practicing oncologists have to determine whether the patient is a suitable candidate for this treatment or whether contraindications exist. In the latter case, an adequate alternative has to be offered. In this regard, to facilitate triaging of medical information, we reviewed available publications on this topic and prepared practice-oriented recommendations for systemic treatment concurrent to definitive and post-operative radiotherapy. Even if no contraindications for the standard-of-care cisplatin apply, clinicians may opt for alternative regimens by adjusting the peak dose, cumulative dose, or timing of cisplatin. Relative contraindications pose the major issue in clinical practice, as very limited data is available in the literature and final decisions are usually based on an expert opinion or retrospective cohort studies. In the case of absolute interdiction of cisplatin, several alternative regimens incorporating carboplatin, 5-fluorouracil, cetuximab, and docetaxel are available. At the same time, it should be kept in mind that radiotherapy alone represents a viable option with hyperfractionation being particularly beneficial in the definitive management of limited nodal disease. Ideally, all treatment propositions should be discussed within multidisciplinary tumor boards taking into account the patient- and disease-related characteristics as well as local logistics and reimbursement policies.


[Long-term exposure to PCB in broiler chickens--metabolic and immunotoxic effects].
Even though it has been forbidden to produce and commerically use polychlorinated biphenyls (PCB) in this country, their stocks and contaminated refuses continue to be a source of danger at present. Hence prevention of environment and food chain contamination is being focused on, along with their monitoring in various commodities. In the poultry operations random contacts of poultry with PCB-containing materials may be expected (paints, plasters, litter). In our experiment we investigated metabolic and immunotoxic effects of low PCB doses on broiler chickens. A hundred and twenty sexed straight-run chicks randomly divided themselves into three departments on deep litter. Cockerels had an ad libitum access to feeds and water, and they were reared under a continuous lighting regime. A feed mix BR-2 (ME 12.8 i.u., crude protein 19.9%) was used as an experimental diet. The experimental groups received a contaminated mix (equal portions of original commercial PCB preparations--Delor 103 and Delor 105 manufactured by the firm Chemko Strázske) at doses of 5 and 50 mg/kg. Chick exposure to PCB lasted from the first to 42nd day of their life. Chick weight, relative organ weight and vitamin A and E levels in liver were determined at the end of the experiment (42 days). The concentrations of cholesterol, triglycerides, proteins, calcium and lysozyme were determined in the blood serum. The concentrations of antibodies to chick repeated immunization with a vaccine against Newcastle disease (AVIPEST) and the blood picture of chicks were also evaluated. Chronical PCB applications in broiler diet resulted in a significant decrease in the weight of broiler chicks at the age of 21 and 28 days (P < 0.01). The weight differences were compensated later on, and the chick weight of the different groups at the age of 42 days was not significantly affected by this treatment. Hepatitis and hydropericarditis were found in affected chicks at their dissection (age of 42 days). Liver weight significantly increased after administration of both PCB doses (P < 0.01), but the relative weight of lymphoreticular organs (thymus, spleen, bursa Fabricii) decreased (P < 0.05). There were serious metabolic disorders in the blood serum after 42-day PCB applications. Cholesterol and triglyceride concentrations (P < 0.01) were significantly increasing (P < 0.01), while the content of serum calcium significantly dropped (28 and 35 days of age). PCB exposed cockerels had the significantly lower titre of antibodies to repeated immunization against Newcastle disease.(ABSTRACT TRUNCATED AT 400 WORDS)


Effect of verapamil on electrical activities of SA node, ventricular muscle and Purkinje fibers in isolated rabbit hearts.
In the isolated rabbit heart, verapamil reduced the rate of rise and the slopes of diastolic slow depolarization, the maximum diastolic potential (Ed) and the membrane potential at the peak of depolarization (Ea) of the SA node without preventing regenerative responses in ventricular and Purkinje fibers. This effect of verapamil on SA node was counteracted by raising the extracellular calcium ion concentration. On the other hand, tetrodotoxin (TTX) had almost no effect on these parameters of the SA node, but it reduced the maximum rate of rise of the ventricular and Purkinje fibers markedly and eventually rendered these tissues non-excitable. The difference in the actions of verapamil and TTX on the SA node suggests that the SA nodal action potential comes from a different ionic channel (slow channel) from that of the Purkinje fibers or the working myocardium, and the effect of calcium ion suggests that this ion plays an important role in the generation of the SA nodal action potential. The difference in the effect of verapamil on the repolarization phase between ventricular and Purkinje fibers was pointed out and the possible participation of calcium ion in the repolarization phase of these two tissues was discussed.


The effects of in utero exposure to a migrant, 4,4'-butylidenebis(6-t-butyl-m-cresol), from nitrile-butadiene rubber gloves on monoamine neurotransmitter in rats.
4,4'-Butylidenebis(6-t-butyl-m-cresol) (BBBC) can be eluted from disposable gloves made of nitrile-butadiene rubber and possibly also detected in food. We have reported that BBBC is an androgen and estrogen antagonist. In this report, BBBC (0.1, 1.0 mg/kg body weight (bw)/day) was subcutaneously administered to pregnant rats from gestation days 11 through 18 and the effects on male offspring (postnatal day (PND) 102) were examined. Body weight at lactation and brain weight at PND 102 were decreased in the 1.0 mg/kg bw BBBC-treated group. Altered levels and turnover of the monoamines dopamine (DA), serotonin (5-HT), and noradrenalin (NA) as well as their metabolites were detected. In the prefrontal cortex DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA) levels were significantly increased, but homovanillic acid (HVA)/DA was decreased. In the striatum NA level, DOPAC/DA and HVA/DA were significantly increased, but 3-methoxy-4-hydrophenylglycol hemipiperazinium (MHPG) level and MHPG/NA were decreased. In hippocampus MHPG level was significantly decreased. In hypothalamus 5-HIAA level and 5-HIAA/5-HT were significantly increased. These results suggested that prenatal exposure to BBBC affects the central nervous system of male rat offspring, and BBBC may be an endocrine disrupting-chemical during the fetal periods.


An automated robotic platform for rapid profiling oligosaccharide analysis of monoclonal antibodies directly from cell culture.
Oligosaccharides attached to Asn297 in each of the CH2 domains of monoclonal antibodies play an important role in antibody effector functions by modulating the affinity of interaction with Fc receptors displayed on cells of the innate immune system. Rapid, detailed, and quantitative N-glycan analysis is required at all stages of bioprocess development to ensure the safety and efficacy of the therapeutic. The high sample numbers generated during quality by design (QbD) and process analytical technology (PAT) create a demand for high-performance, high-throughput analytical technologies for comprehensive oligosaccharide analysis. We have developed an automated 96-well plate-based sample preparation platform for high-throughput N-glycan analysis using a liquid handling robotic system. Complete process automation includes monoclonal antibody (mAb) purification directly from bioreactor media, glycan release, fluorescent labeling, purification, and subsequent ultra-performance liquid chromatography (UPLC) analysis. The entire sample preparation and commencement of analysis is achieved within a 5-h timeframe. The automated sample preparation platform can easily be interfaced with other downstream analytical technologies, including mass spectrometry (MS) and capillary electrophoresis (CE), for rapid characterization of oligosaccharides present on therapeutic antibodies.


Stability of Octastatin, a somatostatin analog cyclic octapeptide, in aqueous solution.
In this study, the degradation of Octastatin, a cyclic octapeptide analog of somatostatin, was examined as a function of pH, temperature, buffer, and ionic strength by reversed-phase gradient high-performance liquid chromatography. Degradation of Octastatin followed a first-order kinetics. Various buffer species such as acetate, ammonium acetate, citrate, glutamate, phosphate, and borate showed differing effects on the degradation of the octapeptide. Good stability was found in glutamate and acetate buffer of pH 4.0. Degradation of Octastatin was greater in citrate- or phosphate-containing buffers than in glutamate or acetate buffers. With phosphate buffer, higher buffer concentration caused greater degradation, while in acetate buffer, the effect of buffer concentration and ionic strength was negligible. In addition, the degradation of Octastatin was markedly inhibited by increasing the concentration of glutamate buffer. This study allows the prediction of good stability in acetate buffer (0.01 M, pH 4.0) with a t90% of 84.1 days at 20 degrees C.


Investigation of mtDNA control region sequences in a Tibetan population sample from China.
Mitochondrial hypervariable region sequences including HVI and HVII (15,751-520) were investigated from 174 unrelated Tibetan individuals living in Tibet Autonomous Region in People's Republic of China. The resulted sequences were aligned and compared with revised Cambridge sequence (rCRS). This sequence variability rendered a high gene diversity value (0.9940 ± 0.0021) and a high random match probability (0.0118) was determined with PIC of 0.9882. Among a total of 174 samples, 217 polymorphic sites were identified, which defined 135 haplotypes. A total of 135 different haplotypes were detected, 113 of them were unique and 22 were shared. The most common haplogroup was M9a1a1c1b1 (16.09%), followed by A11 (6.32%), A (5.17%), R (4.60%), A15 (4.60%), and G3a1 (3.45). The proportions of macro-haplogroups M, N, and L were 54.60%, 42.53%, and 2.87%, respectively. By principal component analysis (PCA), there was no special cluster between Tibetans and other populations except that the structure of Tibetans closely resembled that of Uygur in component 2.


Using the UPLC-ESI-Q-TOF-MSE method and intestinal bacteria for metabolite identification in the nonpolysaccharide fraction from Bletilla striata.
Bletilla striata (Thunb.) Reichb. f. (Orchidaceae), also known as Bai-ji, is a traditional Chinese herb that is widely used in Asia to treat hematemesis, hemoptysis, traumatic bleeding and other similar disorders. Most studies have focused on the pharmacological activities of polysaccharide extracts from B. striata. Our previous studies found that the nonpolysaccharide fraction from B. striata extract also has a hemostatic effect; however, the active constituents responsible for this pharmacological action are unclear. Thus, the metabolic profiles of the nonpolysaccharide fraction were investigated in Sprague-Dawley rats and intestinal bacteria models using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Mass data were acquired by the MSE method. Eight components including five prototypes and three metabolites were identified in rat biofluids after oral administration of the nonpolysaccharide fraction. The parent compounds underwent various metabolic processes, including hydrolysis, deglucosylation, glycosylation and sulfate conjugation. The results not only reveal the possible metabolic pathway, but also indicate the potential pharmacological components. Further mechanistic studies using nonpolysaccharide compounds of the B. striata extract are required to obtain potential candidate compounds.