Resistin is a key mediator of glucose-dependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in adipocytes.
Studies on the physiological roles of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP) have largely focused on its insulinotropic action and ability to regulate beta-cell mass. In previous studies on the stimulatory effect of GIP on adipocyte lipoprotein lipase (LPL), a pathway was identified involving increased phosphorylation of protein kinase B (PKB) and reduced phosphorylation of LKB1 and AMP-activated protein kinase (AMPK). The slow time of onset of the responses suggested that GIP may have induced release of an intermediary molecule, and the current studies focused on the possible contribution of the adipokine resistin. In differentiated 3T3-L1 adipocytes, GIP, in the presence of insulin, increased resistin secretion through a pathway involving p38 mitogen-activated protein kinase (p38 MAPK) and the stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK). The other major incretin hormone, glucagon-like peptide-1 (GLP-1), exhibited no significant effects. Chronic elevation of circulating GIP levels in the Vancouver Diabetic Fatty (VDF) Zucker rat resulted in increases in circulating resistin levels and activation of p38 MAPK or SAPK/JNK in epididymal fat tissue, suggesting the existence of identical pathways in vivo as well as in vitro. Administration of resistin to 3T3-L1 adipocytes mimicked the effects of GIP on the PKB/LKB1/AMPK/LPL pathway: increasing phosphorylation of PKB, reducing levels of phosphorylated LKB1 and AMPK, and increasing LPL activity. Knockdown of resistin using RNA interference attenuated the effect of GIP on the PKB/LKB1/AMPK/LPL pathway in 3T3-L1 adipocytes, supporting a role for resistin as a mediator.


Ab initio calculations on low-lying electronic states of SbO2- and Franck-Condon simulation of its photodetachment spectrum.
Geometry optimization and harmonic vibrational frequency calculations have been carried out on the low-lying singlet and triplet electronic states of the antimony dioxide anion (SbO2-) employing a variety of ab initio methods. Both large-core and small-core relativistic effective core potentials were used for Sb in these calculations, together with valence basis sets of up to augmented correlation-consistent polarized-valence quintuple-zeta (aug-cc-pV5Z) quality. The ground electronic state of SbO2- is determined to be the X (1)A1 state, with the a (3)B1 state, calculated to be approximately 48 kcal mole(-1) (2.1 eV) higher in energy. Further calculations were performed on the X (2)A1, A (2)B2, and B (2)A2 states of SbO2 with the aim to simulating the photodetachment spectrum of SbO(2) (-). Potential energy functions (PEFs) of the X (1)A1 state of SbO2- and the X (2)A1, A (2)B2, and B (2)A2 states of SbO2 were computed at the complete-active-space self-consistent-field multireference internally contracted configuration interaction level with basis sets of augmented correlation-consistent polarized valence quadruple-zeta quality. Anharmonic vibrational wave functions obtained from these PEFs were used to compute Franck-Condon factors between the X (1)A1 state of SbO2- and the X (2)A1, A (2)B2, and B (2)A2 states of SbO2, which were then used to simulate the photodetachment spectrum of SbO2-, which is yet to be recorded experimentally.


In vitro microbiological characterization of novel macrolide CP-163,505 for animal health specific use.
A novel 16-membered-ring macrolide agent (CP-163,505, a reductive amination derivative of repromicin) was identified as an antibacterial against Pasteurella haemolytica, P. multocida and Actinobacillus pleuropneumoniae, important etiological agents of livestock respiratory disease. In vitro MIC50/90 analysis revealed that CP-163,505 was more potent (4x) than tilmicosin against P. multocida, and equivalent to tilmicosin against P. haemolytica and A. pleuropneumoniae. In time kill kinetic studies, CP-163,505 showed bactericidal activity against P. haemolytica, P. multocida and A. pleuropneumoniae and bacteriostatic activity against E. coli at 8 times its MIC. In vitro, CP-163,505 was more potent in alkaline pH (16 approximately 32 x ) and less potent in the presence of excess cations (Mg+2 and Ca+2, 4x). EDTA and PMBN increased CP-163,505 potency against E. coli (4x) but not against the other species. Similar results were obtained with erythromycin A and tilmicosin, which were used as controls. From our data, we hypothesize that Pasteurella and Actinobacillus have an outer membrane significantly different from that of the typical enteric Gram-negative bacterium E. coli.


Abnormal body composition in patients with adrenal adenomas.
Increased visceral fat and sarcopenia are cardiovascular risk factors that may explain increased cardiovascular morbidity and frailty in patients with adrenal adenomas. Our objective was to compare body composition measurement of patients with adrenal adenomas to referent subjects without adrenal disease. Cross-sectional study, 2014-2018. Participants were adults with nonfunctioning adrenal tumor (NFAT), mild autonomous cortisol secretion (MACS), and Cushing syndrome (CS) and age, sex, and BMI 1:1 matched referent subjects without adrenal disorders. Main outcome measures were body composition measurements calculated from abdominal CT imaging. Intra-abdominal adipose tissue and muscle mass measurements were performed at the third lumbar spine level. Of 227 patients with adrenal adenomas, 20 were diagnosed with CS, 76 with MACS, and 131 with NFAT. Median age was 56 years (range: 18-89), and 67% were women. When compared to referent subjects, patients with CS, MACS, and NFAT demonstrated a higher visceral fat (odds ratio (OR): 2.2 (95% CI: 0.9-6.5), 2.0 (1.3-3.2), and 1.8 (1.2-2.7) and a lower skeletal muscle area (OR: 0.01 (95% CI: 0-0.09), 0.31 (0.18-0.49), and 0.3 (1.2-2.7)) respectively. For every 1 µg/dL cortisol increase after overnight dexamethasone, visceral fat/muscle area ratio increased by 2.3 (P = 0.02) and mean total skeletal muscle area decreased by 2.2 cm2 (P = 0.03). Patients with adrenal adenomas demonstrate a lower muscle mass and a higher proportion of visceral fat when compared to referent subjects, including patients with NFAT. Even a subtle abnormality in cortisol secretion may impact health of patients with adenomas.


Effect of Bathing in a 0.1% Aqueous Solution of Ethacridine Lactate on Selected Physiological Parameters of Cornu Aspersum Müller Edible Snails.
The prohibition of antibiotic use in edible snails obligates breeders to treat bacterial infections by different means, of which a common one is a bath in Gram-positive- and partially Gram-negative-bactericidal ethacridine lactate solution. The aim of the study was to determine the effect of bathing Cornu aspersum Müller snails in a 0.1% aqueous solution of ethacridine lactate on selected physiological parameters of haemolymph. The study included 80 snails, divided into two equal groups (study and control). The study group was subjected to bathing in ethacridine lactate and the control group to bathing in tap water. Both groups were treated daily for seven days. The number of haemocytes in the haemolymph, the activity of alanine (ALT) and aspartate (AST) aminotransferases, and the concentration of urea were determined. In the study group, after exposure to ethacridine lactate solution an increase in ALT activity, changes in the De Ritis ratio, an increase in the amount of haemocytes, and a decrease in body weight were found. No such changes were detected in the control group snails or in animals after the first bath. Multiple applications of a 0.1% ethacridine lactate bath may adversely affect Cornu aspersum Müller snails.


[Effects of pentagastrin and somatostatin on duodenal motility in chronic experiments].
Electromyography of the duodenums was performed in dogs, using two bipolar electrodes placed 5 and 10 cm aborally of the pylorus on the serosa of the duodenums. 10 days after implantation and 24 hours after the last meal the duodenal motility was registered in 9 bastard dogs for 5 hours. Pentagastrin, given as a 1-hour intravenous infusion, changed the interdigestive motility to an irregular (postprandial) pattern, which continued up to the end of measurement or was followed by a prolonged phase III with return to cyclic activity. Infusion of somatostatin for 1 hour interrupted the interdigestive motility leading to a prolonged phase I pattern and to partial discoordination. After the end of infusion phase III motility returning to cyclic activity or irregular activity were registered. A standard relaparotomy 10 days after implantation was performed in 3 dogs. Up to the second day of the postoperative period interdigestive cycles of duodenal motility were not obtained.


Prolactin levels are associated with lupus activity, lupus anticoagulant, and poor outcome in pregnancy.
High prolactin (PRL) levels seem to be associated with active systemic lupus erythematosus (SLE) during pregnancy. However, the association of activity, lupus anticoagulant (LA), and pregnancy outcome has not been analyzed. The objective of this study was to analyze the association among SLE activity, LA, and maternal-fetal outcome. We studied 15 pregnant SLE patients (ACR criteria), 4 of them with associated antiphospholipid syndrome (APS), and 9 healthy pregnant women. All patients were evaluated monthly with the following determinations: (a) SLE activity using modified-systemic lupus activity measurement (m-SLAM), (b) LA, and (c) PRL serum levels. Healthy controls were evaluated each trimester. Prematurity, fetal loss, low birth weight, and preeclampsia were evaluated. Chi-square test, Fisher's exact test, Student's t-test, Pearson correlation, and ANOVA were performed. The mean age of SLE patients was 30 +/- 4.9 years and 27.1 +/- 3.7 years in controls. High PRL levels were found during the second and third trimester in SLE patients in comparison with controls (186.2 +/- 54.02 ng/mL versus 119.6 +/- 31.1 ng/mL (P < 0.01) and 177.4 +/- 48.6 ng/mL versus 158.3 +/- 31.5 ng/mL. A significant linear correlation between PRL, m-SLAM, and LA in association with poor maternal-fetal outcome was observed. LA and PRL conferred risk for poor pregnancy outcome. Our study indicates for the first time a strong association among PRL, LA, SLE activity, and poor pregnancy outcome. Close rheumatologic and obstetric monitoring is mandatory in SLE pregnancy in order to avoid obstetric complications.


Multiply fully recyclable carbon fibre reinforced heat-resistant covalent thermosetting advanced composites.
Nondestructive retrieval of expensive carbon fibres (CFs) from CF-reinforced thermosetting advanced composites widely applied in high-tech fields has remained inaccessible as the harsh conditions required to recycle high-performance resin matrices unavoidably damage the structure and properties of CFs. Degradable thermosetting resins with stable covalent structures offer a potential solution to this conflict. Here we design a new synthesis scheme and prepare a recyclable CF-reinforced poly(hexahydrotriazine) resin matrix advanced composite. The multiple recycling experiments and characterization data establish that this composite demonstrates performance comparable to those of its commercial counterparts, and more importantly, it realizes multiple intact recoveries of CFs and near-total recycling of the principal raw materials through gentle depolymerization in certain dilute acid solution. To our best knowledge, this study demonstrates for the first time a feasible and environment-friendly preparation-recycle-regeneration strategy for multiple CF-recycling from CF-reinforced advanced composites.


Novel charm of 2D materials engineering in memristor: when electronics encounter layered morphology.
The family of two-dimensional (2D) materials composed of atomically thin layers connected via van der Waals interactions has attracted much curiosity due to a variety of intriguing physical, optical, and electrical characteristics. The significance of analyzing statistics on electrical devices and circuits based on 2D materials is seldom underestimated. Certain requirements must be met to deliver scientific knowledge that is beneficial in the field of 2D electronics: synthesis and fabrication must occur at the wafer level, variations in morphology and lattice alterations must be visible and statistically verified, and device dimensions must be appropriate. The authors discussed the most recent significant concerns of 2D materials in the provided prose and attempted to highlight the prerequisites for synthesis, yield, and mechanism behind device-to-device variability, reliability, and durability benchmarking under memristors characteristics; they also indexed some useful approaches that have already been reported to be advantageous in large-scale production. Commercial applications, on the other hand, will necessitate further effort.


Inappropriate prescribing in outpatient healthcare: an evaluation of respiratory infection visits among veterans in teaching versus non-teaching primary care clinics.
A recent study led by the Centers for Disease Control and Prevention (CDC) revealed at least 30% of antibiotic prescriptions in the outpatient setting were inappropriate. In this study of all ages, among adult patients, results were similar to the overall population, with the majority of inappropriate prescribing relating to respiratory infections. We applied the same methodology to investigate rates of antibiotic prescribing for respiratory tract infections in outpatient primary care clinics at the Providence Veterans Affairs Medical Center. The results of our evaluation reflected comparable rates of inappropriate prescribing, but when stratified by teaching versus non-teaching primary care clinics, inappropriate prescribing was significantly higher in non-teaching clinics (17.6% vs 44.0%, p < .0001). Respiratory infection visits in non-teaching outpatient clinics may be a pragmatic target for antimicrobial stewardship programs.


What lessons can we learn from the Japanese sarin attacks?
On 27 June 1994 a Japanese terrorist group, Aum Shinrikyo, released sarin in Matsumoto. Some 600 people were exposed: 58 were admitted to six hospitals and all recovered: seven casualties living close to the sarin release died outside hospital. This release followed an earlier attempt by Aum Shinrikyo to use sarin to kill the head of a religious sect perceived as a threat. In December 1994, a former supporter of the group was murdered by Aum Shinrikyo using VX. On 20 March 1995, Aum Shinrikyo launched a coordinated attack using sarin on the Tokyo subway system. Over 5000 "casualties" sought medical attention of whom 984 were moderately poisoned and 54 were severely poisoned; 12 died. Despite some initial difficulties, Japanese emergency units and local hospitals were able to respond reasonably rapidly. Analysis of the events reveals a number of important lessons for authorities as well as physicians to consider when preparing for such incidents.


Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis.
Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.


[Risk factors for osteoarthritis of the knee: current status].
The development of arthrosis is best understood paradigmatically as the result of an interaction between individual and systemic risk factors. This review of the current literature on the subject identifies overweight, occupational exposure to repeated daily lifting and the postmenopausal decline in gonadal steroids in women as significant risk factors for the development of symptomatic and radiologic osteoarthritis of the knee.


Giant Osteolipoma Fixed to the Greater Trochanter of the Femur in a Seventy-Year-Old Elderly Woman.
A lipoma containing mature osseous elements is called osteolipoma. This article describes a giant osteolipoma fixed to the periosteum of the greater trochanter of the femur. A seventy-year-old woman presented with a large subcutaneous mass in the right buttock which had been present for six years. On local examination, a giant mass that was ovoid, firm, non-tender, well demarcated, subcutaneous, and relatively fixed to the greater trochanter was palpated in the right buttock. A medical imaging and fluoro-deoxy-glucose (FDG) bone scan revealed a large lipomatous and metabolically active lesion arising from the periosteum of the greater trochanter of femur. The excisional mass of 17 × 8 × 7 cm3 was well encapsulated and had an osseous basal portion. Cut sections of the mass revealed mainly yellow fatty tissue surrounded by a thin fibrous capsule with numerous interlacing thin lamellar bony structures. The definitive pathological diagnosis was osteolipoma without evidence of malignancy. No recurrence was observed at eight months follow-up. Osteolipoma with an osseous basal portion is rare. Surgical excision is the treatment of choice and the prognosis is good. To the best of our knowledge, this is the first report of an unusual giant osteolipoma fixed to the periosteum of the greater trochanter of the femur.


Evaluation of CD44 Expression in Prostatic Adenocarcinoma: An Institutional Study.
Prostate adenocarcinoma is the second-most common cause of cancer. Globally, many cancer-related deaths among men were noted due to prostate adenocarcinoma. CD44 plays a key role in mediating cell-to-cell and cell-to-matrix interaction, which further helps to maintain the integrity of tissue and also inhibits tumor metastasis. Cross-sectional study was done on chips from transurethral resections of the prostate (TURP) and prostatic core biopsy specimens. All specimens with clinically diagnosed and histopathologically confirmed prostatic adenocarcinoma were included in the study. Prostatic intraepithelial neoplasia (PIN), recurrent cases, and patients who had undergone radiotherapy/ chemotherapy prior to biopsy were excluded from the study. The sample size for the current study was 57 with an 8% prevalence value, 95% confidence interval, and 8% absolute error. Immunoreaction to CD44 antibody is membranous and was evaluated by calculating positively stained cell percentage and staining intensity. These two parameters were added to obtain a final score; a score of 0-3 was considered as negative, and a score of 4-6 was regarded as positive. A statistically significant difference was only found between Gleason grade (p<0.001), clinical staging (p<0.002), nodal metastasis (p<0.015), and distant metastasis (p<0.020) with CD44 positive expression. The rest of the parameters like PSA (p=0.642) and age (p=0.051) did not correlate with CD44-positive expression. Out of 29 cases with positive CD44 expression, 100% positivity was seen in Gleason's grades 1, 2, and 3. This indicates that CD44 expression showed lesser positivity in poorly differentiated carcinoma. CD44 positivity was seen in 83.3% in the T2 stage. An inverse relationship between tumor staging and CD44 expression was observed with positive CD44 expression in lower tumor staging which implies loss of CD44 expression was associated with greater tumor aggressiveness. Lymph node metastasis cases showed more negative CD44 expression (59.5%) and the same was noted in patients without distant metastasis, that is in 61% of the subjects. Conclusion: Cells tend to lose the ability of CD44 expression as they progress from well-differentiated adenocarcinoma to poorly differentiated adenocarcinoma. CD44 expression suggests that the tumor is in a well-differentiated and gland-forming state as compared to Gleason's grade. Loss of CD44 expression suggests tumor aggressiveness. Thus, the upregulation of CD44 expression can be considered as a potential target for targeted therapy. As many targeted and gene therapies are in clinical trials, large-scale multicentered studies are needed for a better understanding of the clinical course of the disease.


Possible molecular exploration of herbal pair Haizao-Kunbu in the treatment of Graves' disease by network pharmacology, molecular docking, and molecular dynamic analysis.
To promote the development and therapeutic application of new medications, it is crucial to conduct a thorough investigation into the mechanism by which the traditional Chinese herb pair of Haizao-Kunbu (HK) treats Graves' disease (GD). Chemical ingredients of HK, putative target genes, and GD-associated genes were retrieved from online public databases. Using Cytoscape 3.9.1, a compound-gene target network was established to explore the association between prosperous ingredients and targets. STRING, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses visualized core targets and disease pathways. Additionally, we conducted a refined analysis of the binding interactions between active ingredients and their respective targets. To visualize these findings, we employed precise molecular docking techniques. Furthermore, we carried out molecular dynamics simulations to gain insights into the formation of more tightly bound complexes. We found that there were nine key active ingredients in HK, which mainly acted on 21 targets. These targets primarily regulated several biological processes such as cell population proliferation, protein phosphorylation, and regulation of kinase activity, and acted on PI3K-AKT and MAPK pathways to treat GD. Analysis of the molecular interaction simulation under computer technology revealed that the key targets exhibited strong binding activity to active ingredients, and Fucosterol-AKT1 and Isofucosterol-AKT1 complexes were highly stable in humans. This study demonstrates that HK exerts therapeutic effects on GD in a multi-component, multi-target, and multi-pathway manner by regulating cell proliferation, differentiation, inflammation, and immunomodulatory-related targets. This study provides a theoretical foundation for further investigation into GD.


Preparation of manganese doped cadmium sulfide nanoparticles in zincblende phase and their magnetic properties.
In this study, the random dope of Mn into CdS nanoparticles in zincblende phase has been carried out under the mild reaction condition. The resulting nanoparticles were characterized by energy dispersive X-ray analysis (EDX), transmission electron microscopy (TEM), X-ray diffractometer (XRD), UV-Vis spectrometer, PL spectrometer, and SQUID. EDX showed that the compositions of Mn doped CdS nanoparticles were readily controlled. TEM showed the particle sizes were not significantly affected by the compositions, retaining to be ca. 3 nm with a narrow size distribution. UV-Vis and PL spectra of the resulting nanoparticles showed the intra-Mn level may be affected by the quantum size effect. SQUID measurement showed that the resulting nanoparticles showed diamagnetism, paramagnetism and superparamagnetism dependent on Mn content.


[Appearance of extended-spectrum beta-lactamases].
Extended-spectrum beta-lactamases (ESBLs) are enzymes which hydrolyze broad-spectrum beta-lactam antibiotics by expanding the substrate spectra into the so-called anti-beta-lactamase beta-lactams such as oxyimino-cephalosporins, cephamycins, oxacephems, carbapenems and monobactams, conferring resistance to many kinds of beta-lactams on pathogenic bacteria. Recently, ESBLs have been demonstrated from various types of beta-lactamases phylogenetically belonging to the molecular class, A, B, C, or D. The genes coding for ESBLs are chromosome- or plasmid-mediated and some of them have developed by point or insertion mutations in the parental genes coding for the narrow-spectrum beta-lactamase. If the genes are plasmid-mediated, the dissemination among various species of pathogenic bacteria would cause hospital-acquired infections by ESBL-producing bacteria.


Protein patterns in serum and peritoneal fluid in Crohn's disease and ulcerative colitis.
The protein content in serum and peritoneal fluid has been determined and analysed electrophoretically in patients with Crohn's disease and ulcerative colitis and the data obtained compared with previously published data on serum and ascites content in liver cirrhosis, heart failure and intestinal tuberculosis. Ascites fluid in liver cirrhosis and heart failure, representing a true transudate, had a comparatively low protein content while the ascites fluid in inflammatory bowel diseases including Crohn's disease had high protein content. There was no difference in ascites protein content or ascites/serum protein ratio between patients with Crohn's disease and patients with ulcerative colitis. An exudative nature of both these inflammatory bowel conditions appears to be the main cause to the peritoneal fluid often observed at laparotomy. It cannot be excluded, however, that a lymphatic stasis, which is thought to be involved in Crohn's disease, might at least partly contribute to the development when larger quantities of ascitic fluid are at hand in this disease.


Carcinoid tumor of the kidney: case report and review of the literature.
Carcinoid tumors are low-grade malignant tumors that arise from neuroendocrine cells. Primary renal carcinoid tumors are extremely uncommon. They seem to be more indolent than renal cell carcinomas, although metastases to regional lymph nodes, liver, and bone have been described. The presence of metastases seems to indicate a more malignant course; however, even with metastases a patient might live for 3 or 4 years. Renal carcinoid tumors should be managed by radical or partial nephrectomy, and good outcomes have been obtained for organ-confined disease after radical excision. Conventional methods of imaging are inadequate for detecting smaller carcinoids, so somatostatin receptor scintigraphy should complement computed tomography and magnetic resonance imaging when searching for occult or metastatic disease. Close follow-up after surgery is necessary.


Structure of trabeculated detrusor smooth muscle in cases of prostatic hypertrophy.
The light and electron microscopic structure of biopsy samples of trabeculated urinary bladder from patients with proven outlfow obstruction due to prostic hypertrophy has been compared with the morphology of control bladder specimens. In the latter the detrusor muscle bundles were composed of smooth muscle cells closely packed together with very little intervening connective tissue. In contrast, irrespective of age, detrusor muscle from trabeculated bladders contained many muscle bundles in which the constituent cells were of relatively small diameter and were widely separated from each other by dense masses of connective tissue. No morphological evidence for smooth muscle hypertrophy or hyperplasia was obtained in the present study. In the electron microscope the connective tissue between the smooth muscle cells of trabeculated bladders was seen to contain, in addition to collagen fibrils, an extensive meshwork of electron-dense microfibrils apparently in continuity with the basal laminae of the smooth muscle cells. Regions of close approach between smooth muscle cells were seemingly unaffected by trabeculation as was the distrubution and fine structure of autonomic nerve terminals. These observations are intended to form a baseline for comparision with the results of future morphological studies of trabeculation arising in response to different aetiological factors.


Toxicity of combined treatment of adjuvant irradiation and interferon alpha2b in high-risk melanoma patients.
Surgically resected stage III melanoma patients commonly receive adjuvant therapy with interferon (IFN) alpha2b. For those patients with high-risk features of draining node recurrence, radiation therapy can also be considered as a treatment option. The purpose of this retrospective study was to assess the efficacy and radiation-related toxicity of this combined therapy. Eighteen patients receiving adjuvant IFNalpha2b therapy during radiation therapy, or within 1 month of its completion, were reviewed retrospectively and analysed for outcome. Radiation was delivered at 600 cGy dose per fraction, in 16 out of 18 patients, twice a week, and at 200 cGy dose per fraction in two patients five times a week. Total radiation dose and number of fractions were as follows: 30 Gy/5 fr (n=8), 36 Gy/6 fr (n=8) and 50 Gy/25 fr (n=2). The percentage of disease-free patients, with no local recurrence, at 3 years was 88%. In 10 patients, IFNalpha2b was administered concurrently with radiotherapy; in three, within 30 days before or after radiation; and in five, more than 30 days after radiation. All the patients experienced acute skin reactions, grade I on the Radiation Therapy Oncology Group (RTOG) scale. Late radiation-related toxicity was seen in one patient with grade III (RTOG) skin reaction and two with grade IV (RTOG) radiation-induced myelitis. Concurrent use of adjuvant radiotherapy and IFNalpha2b might enhance radiation-induced toxicity, and special care should be taken when the spinal cord is included in the radiation field.


Adverse life events in elderly patients with major depression or dysthymic disorder and in healthy-control subjects.
The authors compared elderly outpatients (> or =60 years) with major depression or dysthymic disorder and healthy-control subjects on the type and subjective impact of adverse life events. The Geriatric Adverse Life Events Scale (GALES) was developed for this purpose. Fifty patients with major depression, 79 patients with dysthymic disorder, and 40 healthy controls completed the GALES. Adverse life events during two time periods were assessed: the year before the evaluation, and the year before onset of the index episode (patients only). During the year before evaluation, patients with major depression reported more life events with greater negative impact, particularly for interpersonal conflicts, and dysthymic patients scored intermediate between patients and controls. Sum scores for perceived stress and negative impact on mood differed significantly among the groups: highest for major depression, intermediate for dysthymic disorder, and lowest for controls. During the year before onset, patients with major depression reported significantly higher sum scores for negative impact on mood than patients with dysthymic disorder. On several measures, patients with major depression perceived greater negative impact of life events than patients with dysthymic disorder and healthy controls, particularly for interpersonal conflicts. The subjective impact of adverse life events may play an important role in the expression of depressive illness in elderly patients, particularly in major depression, and it needs to be considered in clinical management.


Ty3 Retrotransposon Hijacks Mating Yeast RNA Processing Bodies to Infect New Genomes.
Retrotransposition of the budding yeast long terminal repeat retrotransposon Ty3 is activated during mating. In this study, proteins that associate with Ty3 Gag3 capsid protein during virus-like particle (VLP) assembly were identified by mass spectrometry and screened for roles in mating-stimulated retrotransposition. Components of RNA processing bodies including DEAD box helicases Dhh1/DDX6 and Ded1/DDX3, Sm-like protein Lsm1, decapping protein Dcp2, and 5' to 3' exonuclease Xrn1 were among the proteins identified. These proteins associated with Ty3 proteins and RNA, and were required for formation of Ty3 VLP retrosome assembly factories and for retrotransposition. Specifically, Dhh1/DDX6 was required for normal levels of Ty3 genomic RNA, and Lsm1 and Xrn1 were required for association of Ty3 protein and RNA into retrosomes. This role for components of RNA processing bodies in promoting VLP assembly and retrotransposition during mating in a yeast that lacks RNA interference, contrasts with roles proposed for orthologous components in animal germ cell ribonucleoprotein granules in turnover and epigenetic suppression of retrotransposon RNAs.


Topological ring-currents and bond-currents in the altan-[r,s]-coronenes.
π-Electron ring-currents for the altans of the four regular [r,s]-coronenes are calculated by the topological HLPM approach. The bond-current pattern of the parent structure is generally preserved in the core of the corresponding altan. Altan-[10,5]-coronene appears to support an anomalous diamagnetic current in its [4n]-periphery. This invites further investigation.


Prostate-specific Antigen Testing as Part of a Risk-Adapted Early Detection Strategy for Prostate Cancer: European Association of Urology Position and Recommendations for 2021.
Recommendations against prostate-specific antigen (PSA) testing in 2012 have increased advanced-stage diagnosis and prostate cancer-specific mortality rates. To present the position of the European Association of Urology (EAU) in 2021 and provide recommendations for the use of PSA testing as part of a risk-adapted strategy for the early detection of prostate cancer. The authors combined their review of relevant literature, including the EAU prostate cancer guidelines 2021 update, with their own knowledge to provide an expert opinion, representing the EAU's position in 2021. The EAU has developed a risk-adapted early prostate cancer detection strategy for well-informed men based on PSA testing, risk calculators, and multiparametric magnetic resonance imaging, which can differentiate significant from insignificant prostate cancer. This approach largely avoids the overdiagnosis/overtreatment of men unlikely to experience disease-related symptoms during their lifetime and facilitates an early diagnosis of men with significant cancer to receive active treatment. It also reduces advanced-stage diagnosis, thereby potentially reducing prostate cancer-specific mortality and improving quality of life. Education is required among urologists, general practitioners, radiologists, policy makers, and healthy men, including endorsement by the European Commission to adapt the European Council's screening recommendations in its 2022 plan and requests to individual countries for its incorporation into national cancer plans. This risk-adapted approach for the early detection of prostate cancer will reverse current unfavourable trends and ultimately save lives. The European Association of Urology has developed a patient information leaflet and algorithm for the early diagnosis of prostate cancer. It can identify men who do not need magnetic resonance imaging or a biopsy and those who would not show any symptoms versus those with more aggressive disease who require further tests/treatment. We need to raise awareness of this algorithm to ensure that all well-informed men at risk of significant prostate cancer are offered a prostate-specific antigen test.


A linkage map for the Newt Notophthalmus viridescens: Insights in vertebrate genome and chromosome evolution.
Genetic linkage maps are fundamental resources that enable diverse genetic and genomic approaches, including quantitative trait locus (QTL) analyses and comparative studies of genome evolution. It is straightforward to build linkage maps for species that are amenable to laboratory culture and genetic crossing designs, and that have relatively small genomes and few chromosomes. It is more difficult to generate linkage maps for species that do not meet these criteria. Here, we introduce a method to rapidly build linkage maps for salamanders, which are known for their enormous genome sizes. As proof of principle, we developed a linkage map with thousands of molecular markers (N=2349) for the Eastern newt (Notophthalmus viridescens). The map contains 12 linkage groups (152.3-934.7cM), only one more than the number of chromosome pairs. Importantly, this map was generated using RNA isolated from a single wild caught female and her 28 offspring. We used the map to reveal chromosome-scale conservation of synteny among N. viridescens, A. mexicanum (Urodela), and chicken (Amniota), and to identify large conserved segments between N. viridescens and Xenopus tropicalis (Anura). We also show that met1, a major effect QTL that regulates the expression of alternate metamorphic and paedomorphic modes of development in Ambystoma, associates with a chromosomal fusion that is not found in the N. viridescens map. Our results shed new light on the ancestral amphibian karyotype and reveal specific fusion and translocation events that shaped the genomes of three amphibian model taxa. The ability to rapidly build linkage maps for large salamander genomes will enable genetic and genomic analyses within this important vertebrate group, and more generally, empower comparative studies of vertebrate biology and evolution.


Transfection of rhabdomyosarcoma cells with connexin43 induces myogenic differentiation.
Normal cell physiological processes rely heavily on cues from the extracellular environment to coordinate the proper functioning of cellular activities. The intercellular communication that takes place through gap junctions in neighboring cells has been implicated in growth control and embryonic differentiation. Indeed, many tumorigenic cells induced to overexpress gap junction proteins exhibit increased differentiation and decreased cell proliferation. Although absent in mature skeletal muscle, studies have demonstrated that gap junctions are present during the early stages of myogenesis, indicating their possible role in muscle development. In our present study, we have attempted to induce a more differentiated phenotype in communication-deficient rhabdomyosarcoma cells. These tumorigenic human cells were transfected with cDNA encoding the gap junction protein connexin43 (Cx43) such that clones of varying expression were isolated. Intercellular communication as measured with dye passage assays was directly proportional to the level of Cx43 expressed, and in those cells expressing Cx43 at high levels, a marked increase in cell membrane fusion and myosin expression was observed. Furthermore, clones expressing Cx43 at high levels exhibited a significant reduction in growth rate when grown under nonadhesive conditions, an indication that their tumorigenicity had been reduced. This apparent increase in myogenic differentiation lends further evidence to the possible role of gap junctional coupling during developmental processes.


Exploiting transcriptome data for the development and characterization of gene-based SSR markers related to cold tolerance in oil palm (Elaeis guineensis).
The oil palm (Elaeis guineensis, 2n = 32) has the highest oil yield of any crop species, as well as comprising the richest dietary source of provitamin A. For the tropical species, the best mean growth temperature is about 27°C, with a minimal growth temperature of 15°C. Hence, the plantation area is limited into the geographical ranges of 10°N to 10°S. Enhancing cold tolerance capability will increase the total cultivation area and subsequently oil productivity of this tropical species. Developing molecular markers related to cold tolerance would be helpful for molecular breeding of cold tolerant Elaeis guineensis. In total, 5791 gene-based SSRs were identified in 51,452 expressed sequences from Elaeis guineensis transcriptome data: approximately one SSR was detected per 10 expressed sequences. Of these 5791 gene-based SSRs, 916 were derived from expressed sequences up- or down-regulated at least two-fold in response to cold stress. A total of 182 polymorphic markers were developed and characterized from 442 primer pairs flanking these cold-responsive SSR repeats. The polymorphic information content (PIC) of these polymorphic SSR markers across 24 lines of Elaeis guineensis varied from 0.08 to 0.65 (mean = 0.31 ± 0.12). Using in-silico mapping, 137 (75.3%) of the 182 polymorphic SSR markers were located onto the 16 Elaeis guineensis chromosomes. Total coverage of 473 Mbp was achieved, with an average physical distance of 3.4 Mbp between adjacent markers (range 96 bp - 20.8 Mbp). Meanwhile, Comparative analysis of transcriptome under cold stress revealed that one ICE1 putative ortholog, five CBF putative orthologs, 19 NAC transcription factors and four cold-induced orhologs were up-regulated at least two fold in response to cold stress. Interestingly, 5' untranslated region of both Unigene21287 (ICE1) and CL2628.Contig1 (NAC) both contained an SSR markers. In the present study, a series of SSR markers were developed based on sequences differentially expressed in response to cold stress. These EST-SSR markers would be particularly useful for gene mapping and population structure analysis in Elaeis guineensis. Meanwhile, the EST-SSR loci were inducible expressed in response to low temperature, which may have potential application in identifying trait-associated markers in oil palm in the future.


The role of radiation therapy in the treatment of cancer of the prostate.
The review of the literature assessing the value of external radiotherapy in treatment of patients with prostatic cancer is presented. Radiotherapy appears to be the curative treatment since about 55% of 10 years symptoms free survival rate can be achieved in stages A and B and 35% in stage C. The results of radiotherapy in cancer limited to prostate are equal to those obtained with radical prostatectomy. Postoperative irradiation seems to improve survival in patients treated with incomplete surgery. The value of elective irradiation of the pelvic and periaortic lymph nodes has not been established. The impact of TURP on survival is discussed. The factors influencing local control and complications rates like: Treatment volume, dose levels and treatment techniques are analyzed. Several experimental approaches in radiotherapy of prostatic cancer are presented.


[Sample size for the estimation of F-wave parameters in healthy volunteers and amyotrophic lateral sclerosis patients].
Objective: The study aimed to investigate whether sample sizes of F-wave study differed according to different nerves, different F-wave parameters, and amyotrophic lateral sclerosis(ALS) patients or healthy subjects. Methods: The F-waves in the median, ulnar, tibial, and deep peroneal nerves of 55 amyotrophic lateral sclerosis (ALS) patients and 52 healthy subjects were studied to assess the effect of sample size on the accuracy of measurements of the following F-wave parameters: F-wave minimum latency, maximum latency, mean latency, F-wave persistence, F-wave chronodispersion, mean and maximum F-wave amplitude. A hundred stimuli were used in F-wave study. The values obtained from 100 stimuli were considered "true" values and were compared with the corresponding values from smaller samples of 20, 40, 60 and 80 stimuli. F-wave parameters obtained from different sample sizes were compared between the ALS patients and the normal controls. Results: Significant differences were not detected with samples above 60 stimuli for chronodispersion in all four nerves in normal participants. Significant differences were not detected with samples above 40 stimuli for maximum F-wave amplitude in median, ulnar and tibial nerves in normal participants. When comparing ALS patients and normal controls, significant differences were detected in the maximum (median nerve, Z=-3.560, P<0.01; ulnar nerve, t=5.019, P<0.01; tibial nerve, Z=-2.475, P<0.05; peroneal nerve, Z=-2.088, P<0.05)and mean F-wave latency (median nerve, Z=-3.243, P<0.01; ulnar nerve, t=3.876, P<0.01; tibial nerve, Z=-2.206, P<0.05; peroneal nerve, Z=-2.205, P<0.05)in all four nerves, F-wave chronodispersion (Z=-3.152, P<0.01)in the ulnar nerve, F-wave persistence in the median (Z=6.139, P<0.01)and ulnar nerves(Z=5.350, P<0.01), mean F-wave amplitude in the tibial nerve(t=2.981, P<0.01), maximum F-wave amplitude in the ulnar (Z=-2.134, P<0.05)and tibial nerves (t=2.746, P<0.01)with 20 stimuli; for chronodispersion in tibial nerve (t=2.551, P<0.05)100 stimuli, for chronodispersion in peroneal nerve (Z=-2.086, P<0.05)80 stimuli, for F-wave persistence in tibial nerve (Z=2.119, P<0.05) 60 stimuli, for mean F-wave amplitude in ulnar (Z=-2.552, P<0.05)and peroneal nerve (Z=-2.228, P<0.05)40 stimuli, for maximum F-wave amplitude in peroneal nerve (t=2.693, P<0.01)60 stimuli were necessary to detect differences. Conclusions: Sample sizes of F-wave study differed according to different nerves, different F-wave parameters , and ALS patients or healthy subjects.


Virtual scatter modulation for X-ray CT scatter correction using primary modulator.
A new scatter estimation algorithm with a concept of virtual scatter modulation for X-ray scatter correction using primary modulator is proposed to reduce the aliasing errors in the estimated scatter. Virtual scatter modulation can be realized through dividing the measured primary-modulated image by the measured modulation function. After the division, the aggravation of the aliasing of primary due to the non-uniformity of the modulation function is largely transferred to that of scatter. Since scatter in general has less high frequencies than primary does, the aggravation of its aliasing is expected to be weaker, and therefore the overall aliasing can be reduced. A CatPhan©600 phantom and an anthropomorphic thorax phantom are scanned on a tabletop X-ray cone-beam computed tomography system to validate our proposed algorithm. On the Catphan phantom, the oscillations that are clearly observed in the central region of the Catphan scatter profile estimated using the original primary-modulation algorithm, are mostly eliminated with the proposed scatter modulation algorithm, leading to less residual artifacts and better CT number uniformity in the reconstructed image. Compared with 38.9 HU of CT nonuniformity in a selected uniform region when the primary-modulation algorithm is used, the new algorithm significantly reduces it to 4.5 HU, reaching the same level of uniformity as the ground truth reference. On the thorax phantom, overall better CT number uniformity is also achieved.


Tooth Tissue Engineering: The Importance of Blood Products as a Supplement in Tissue Culture Medium for Human Pulp Dental Stem Cells.
One of the goals in using cells for tissue engineering (TE) and cell therapy consists of optimizing the medium for cell culture. The present study compares three different blood product supplements for improved cell proliferation and protection against DNA damage in cultured human dental pulp stem cells for tooth TE applications. Human cells from dental pulp were first characterized as adult stem cells (ectomesenchymal mixed origin) by flow cytometry. Next, four different cell culture conditions were tested: I, supplement-free; II, supplemented with fetal bovine serum; III, allogeneic human serum; and IV, autologous human serum. Cultured cells were then characterized for cell proliferation, mineralized nodule formation, and colony-forming units (CFU) capability. After 28 days in culture, the comet assay was performed to assess possible damage in cellular DNA. Our results revealed that Protocol IV achieved higher cell proliferation than Protocol I (p = 0.0112). Protocols II and III resulted in higher cell proliferation than Protocol I, but no statistical differences were found relative to Protocol IV. The comet assay revealed less cell damage in cells cultured using Protocol IV as compared to Protocols II and III. The damage percentage observed on Protocol II was significantly higher than all other protocols. CFUs capability was highest using Protocol IV (p = 0.0018) and III, respectively, and the highest degree of mineralization was observed using Protocol IV as compared to Protocols II and III. Protocol IV resulted in significantly improved cell proliferation, and no cell damage was observed. These results demonstrate that human blood product supplements can be used as feasible supplements for culturing adult human dental stem cells.


TSG-6 treatment promoted apoptosis in human fibroblasts of pathological scar.
Pathological scars are characterized by excessive fibrosis and extracellular matrix (ECM) deposition and can be functionally and cosmetically problematic; however, there are few satisfactory treatments for controlling pathological scars. The proliferation of fibroblast during wound healing play an important role in pathologic scar formation. Therefore, the promotion of fibroblast apoptosis may be a new point to inhibit scar formation. In this study, pathological scar fibroblasts were treated with TSG-6 in monolayer culture and subjected to examination for cell apoptosis and associated proteins involved in cell apoptosis. We found that TSG-6 significantly promoted cell apoptosis of pathological scar fibroblasts. Meanwhile, expression level of cell apoptosis related cytokine protein Bax increased and cell proliferation related signal transduction pathways are blocked since the expression level of Bcl-2 was decreased.


Triomics Analysis of Imatinib-Treated Myeloma Cells Connects Kinase Inhibition to RNA Processing and Decreased Lipid Biosynthesis.
The combination of metabolomics, lipidomics, and phosphoproteomics that incorporates triple stable isotope labeling by amino acids in cell culture (SILAC) protein labeling, as well as (13)C in vivo metabolite labeling, was demonstrated on BCR-ABL-positive H929 multiple myeloma cells. From 11 880 phosphorylation sites, we confirm that H929 cells are primarily signaling through the BCR-ABL-ERK pathway, and we show that imatinib treatment not only downregulates phosphosites in this pathway but also upregulates phosphosites on proteins involved in RNA expression. Metabolomics analyses reveal that BCR-ABL-ERK signaling in H929 cells drives the pentose phosphate pathway (PPP) and RNA biosynthesis, where pathway inhibition via imatinib results in marked PPP impairment and an accumulation of RNA nucleotides and negative regulation of mRNA. Lipidomics data also show an overall reduction in lipid biosynthesis and fatty acid incorporation with a significant decrease in lysophospholipids. RNA immunoprecipitation studies confirm that RNA degradation is inhibited with short imatinib treatment and transcription is inhibited upon long imatinib treatment, validating the triomics results. These data show the utility of combining mass spectrometry-based "-omics" technologies and reveals that kinase inhibitors may not only downregulate phosphorylation of their targets but also induce metabolic events via increased phosphorylation of other cellular components.


The antioxidative and antilipidemic effects of different molecular weight chitosans in metabolic syndrome model rats.
The effect of high and low molecular weight chitosans (HMC; 1000 kDa, LMC; 30 kDa) on oxidative stress and hypercholesterolemia was investigated using male 6-week-old Wistar Kyoto rats as a normal model (Normal-rats) and spontaneously hypertensive rat/ND mcr-cp (SHP/ND) as a metabolic syndrome model (MS-rats), respectively. In Normal-rats, the ingestion of both chitosans over a 4 week period resulted in a significant decrease in total body weight (BW), glucose (Gl), triglyceride (TG), low density lipoprotein (LDL) and serum creatinine (Cre) levels. The ingestion of both chitosans also resulted in a lowered ratio of oxidized to reduced albumin and an increase in total plasma antioxidant activity. In addition to similar results in Normal-rats, the ingestion of only HMC over a 4 week period resulted in a significant decrease in total cholesterol levels in MS-rats. Further, the ingestion of LMC resulted in a significantly higher antioxidant activity than was observed for HMC in both rat models. In in vitro studies, LMC caused a significantly higher reduction in the levels of two stable radicals, compared to HMC, and the effect was both dose- and time-dependent. The findings also show that LDL showed strong binding in the case of HMC. These results suggest that LMC has a high antioxidant activity as well as antilipidemic effects, while HMC results in a significant reduction in the levels of pro-oxidants such as LDL in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation in metabolic model rats.


Tracheal collapse following esophageal atresia repair.
Expiratory collapse of the trachea was demonstrated radiographically in three infants with esophageal atresia who developed episodes of severe upper respiratory obstruction in the first few weeks of life. The abnormality is most readily seen fluoroscopically in such patients, though tracheal narrowing may be visible on an expiratory lateral chest radiography. An unusually long tracheostomy tube may be required to bypass the site of obstruction.


Long-term outcomes of lung transplant recipients with hepatitis C infection: a retrospective study of the U.S. transplant registry.
Chronic hepatitis C patients in need of a lung transplant are often considered ineligible due to their infection. To assess the association of hepatitis C virus (HCV) infection with long-term outcomes of lung transplants. From the Scientific Registry of Transplant Recipients (1995-2011), we selected all adults with and without HCV infection who underwent lung transplantation. A total of 17 762 lung transplant recipients were included (55.5% bilateral). Of those, 319 (1.83%) had positive HCV serology. The HCV-positive recipients were 1.6 years younger, less Caucasian and more African-American, and had a significantly higher rate of co-infection with hepatitis B virus (all P < 0.001). Post-transplant patients were discharged alive at similar rates regardless of HCV status: 88.4% in HCV+ vs. 90.3% in HCV- (P = 0.25). The mortality rates were also similar at 1 and 2 years after transplantation (20.7% in HCV+ vs. 19.2% in HCV- and 31.6% in HCV+ vs. 28.9% in HCV-, respectively; both P > 0.05), but at post-transplant year 3 year, mortality rate in HCV+ became significantly higher (42.5% vs. 36.4%, P = 0.04) and remained higher for the duration of the follow-up (mean 9.1 years, max 18.4 years). In multivariate survival analysis, after adjustment for confounders, being HCV+ was associated with higher mortality: adjusted hazard ratio 1.24 (1.04-1.46), P = 0.01. No association of HCV infection with time to graft loss was found (P = 0.92). Chronic HCV infection is associated with a moderate increase in post-lung transplant mortality. Treatment of HCV in lung transplant recipients may, therefore, result in improvement of post-transplant outcomes.


MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation.
Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumour Suppressor homologue kinases, are also tumour suppressors. To investigate MOB1A/B's roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium-specific, null mutations of MOB1A/B in mice (SPC-rtTA/(tetO)7-Cre/Mob1aflox/flox/Mob1b-/-; termed luMob1DKO mice). Most mutants (70%) receiving Dox in utero (luMob1DKO (E6.5-18.5) mice) died of hypoxia within 1 h post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome. Intriguingly, mutant mice that received Dox postnatally (luMob1DKO (P21-41) mice) did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumour formation was decreased (rather than increased). Lungs of luMob1DKO (P21-41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche.


A glial cell line-derived neurotrophic factor delivery system enhances nerve regeneration across acellular nerve allografts.
Acellular nerve allografts (ANAs) are used clinically to bridge nerve gaps but these grafts, lacking Schwann cells and therapeutic levels of neurotrophic factors, do not support regeneration to the same extent as autografts. Here we investigated a local drug delivery system (DDS) for glial cell line-derived neurotrophic factor (GDNF) controlled release to implanted ANAs in rats using drug-loaded polymeric microspheres (MSs) embedded in a fibrin gel. In a rat hindlimb nerve gap model, a 10mm ANA was used to bridge a 5mm common peroneal (CP) nerve gap. Experimental groups received DDS treatment at both suture sites of the allografts releasing GDNF for either 2 weeks or 4 weeks. In negative control groups, rats received no DDS treatment or empty DDS. Rats receiving nerve isografts served as the positive control group. The numbers of motor and sensory neurons that regenerated their axons in all the groups with GDNF MS and isograft treatment were indistinguishable and significantly higher as compared to the negative control groups. Nerve histology distal to the nerve graft demonstrated increased axon counts and a shift to larger fiber diameters due to GDNF MS treatment. The sustained delivery of GDNF to the implanted ANA achieved in this study demonstrates the promise of this DDS for the management of severe nerve injuries in which allografts are placed. This work addresses the common clinical situation in which a nerve gap is bridged using acellular nerve allografts. However, these allografts are not as effective in supporting nerve regeneration as the gold standard method of autografting. The novel local drug delivery system used in this study provides sustained and controlled release of glial cell line-derived neurotrophic factor (GDNF), one of the most potent neurotrophic factors, which significantly improves nerve regeneration following severe nerve injuries. Results from this research will provide a mean of improving nerve allografts with locally delivered GDNF. This strategy may lead to a novel "off the shelf" alternative to the current management of severe nerve injuries.


Presence of cells combining features of two different cell types in the colonic crypts and pyloric glands of the mouse.
A small number of epithelial cells which combine features of two cell types were observed in the descending colon and pyloric stomach of the mouse. In the descending colon, where the base of the crypts is mainly composed of poorly differentiated "vacuolated" cells, a few of these cells contain, besides the characteristic "vacuoles," mucous globules identical to those in mucous cells or, less frequently, dense granules such as are found in entero-endocrine cells. Because there is evidence that the poorly differentiated vacuolated cells give rise to the other cells of the epithelium, those which also contain mucous globules or dense granules are likely to be differentiating into mucous cells or entero-endocrine cells respectively. In the pyloric stomach, where the glands are mainly composed of mucous cells, some of which are poorly differentiated, a few of the latter exhibit, besides the mucous globules, entero-endocrine type granules or features of caveolated cells. It is likely that the poorly differentiated mucous cells give rise to the other gland cells; and, therefore, those mucous-containing cells which also display dense granules or caveolated cell features are taken to be differentiating into entero-endocrine or caveolated cells respectively. Most of the cells containing two kinds of secretory materials are believed to be stem cells which initially contain a few vacuoles (colon) or mucous globules (pylorus) but are differentiating into a cell containing a different type of secretion. Rare observations of two kinds of secretory materials in a mature cell suggest that the transitional period may be prolonged, perhaps indefinitely.


[A case of allergic granulomatosis and angiitis without symptoms of asthma].
We present a case of allergic rhinitis in a 68-year-old woman in whom eosinophilia was found when she complained of common cold-like symptoms. The patient noticed a mass lesion on her left neck, which improved with antibiotic treatment, but her coughing continued and edema of both lower extremities appeared. She was admitted to our hospital, because of abnormalities in her electrocardiogram and cardiomegaly seen in a chest radiograph. The discomfort due to the edema in the soles of both feet remained even after steroid therapy. Her chest radiograph revealed ground-glass opacity, and a transbronchial lung biopsy revealed granulation tissue with the infiltration of eosinophils into the interstitium. Allergic granulomatosis angiitis was diagnosed because of granulomatosis vasculitis resulting from sural nerve biopsy. This was a rare case of allergic granulomatosis angiitis because her lung function was normal, she had no history of bronchial asthma, and there were no clear symptoms of bronchial asthma.


Cell swelling and the sensitivity of autophagic proteolysis to inhibition by amino acids in isolated rat hepatocytes.
In the isolated perfused rat liver, autophagic proteolysis is inhibited by hypo-osmotic perfusion media [Häussinger, D., Hallbrucker, C., vom Dahl, S., Lang, F. & Gerok, W. (1990) Biochem. J. 272, 239-242]. Here we report that in isolated hepatocytes, incubated in the absence of amino acids to ensure maximal proteolytic flux, proteolysis was not inhibited by hypo-osmolarity while the synthesis of glycogen from glucose, a process known to be very sensitive to changes in cell volume [Baquet, A., Hue, L., Meijer, A. J., van Woerkom, G. M. & Plomp, P. J. A. M. (1990) J. Biol. Chem. 265, 955-959], was stimulated under identical conditions. However, in isolated hepatocytes, hypo-osmolarity increased the sensitivity of autophagic proteolysis to inhibition by low concentrations of amino acids. The anti-proteolytic effect of hypo-osmolarity in our experiments was not due to stimulation of amino-acid transport into the hepatocytes: neither the consumption of most amino acids, nor the rate of urea synthesis was appreciably affected by hypo-osmotic incubation conditions. In the course of these studies we also found that hypo-osmolarity increased the affinity of protein synthesis for amino acids. In the presence of amino acids the intracellular level of ATP was not much affected. However, because of cell swelling under these conditions the intracellular concentration of ATP decreased. It is proposed that a small part of the inhibition of proteolysis by amino acids may be due to this fall in ATP concentration.


[Characteristics of soil greenhouse gas flux and its driving factors in Horqin sand dune-mea-dow wetland cascade ecosystems.]
Using the static chamber-GC technique, greenhouse gas (CO2, CH4, N2O) fluxes of sand dunes and meadow wetlands were measured in a typical sand dune-meadow cascade ecological zone of Horqin. The dynamics of the greenhouse gas fluxes and driving factors were analyzed. The results showed that soil CH4 flux underwent absorption during the growing season, with average CH4 fluxes of semi-mobile dunes and meadow wetlands were -52.7 μg·m-2·h-1 and -34.7 μg·m-2·h-1, respectively, ranging from -176.1 to 49.8 μg·m-2·h-1. The peak of CH4 absorption in the growing season occurred at August 22nd, 2017. In August and September, the months with heavy rainfall, the CH4 flux in meadow wetlands showed continuous emission, being significantly different from that in semi-mobile dunes. The peak of N2O flux during the growing season was at July 21st. The monthly average N2O flux in semi-mobile dunes was following the order of July > August > September > June > May. Soil temperature and moisture were the key factors affecting CO2 and CH4 fluxes, whereas the N2O flux was mainly affected by soil temperature. The soil temperature sensitivity (Q10) showed the sequence of semi-mobile dune (1.009) < meadow wetland (1.474). The water stress rendered the greenhouse gas fluxes in semi-mobile dunes being less sensitive to soil temperature change than that in meadow wetlands.


Regio- and stereospecificity of filipin hydroxylation sites revealed by crystal structures of cytochrome P450 105P1 and 105D6 from Streptomyces avermitilis.
The polyene macrolide antibiotic filipin is widely used as a probe for cholesterol and a diagnostic tool for type C Niemann-Pick disease. Two position-specific P450 enzymes are involved in the post-polyketide modification of filipin during its biosynthesis, thereby providing molecular diversity to the "filipin complex." CYP105P1 and CYP105D6 from Streptomyces avermitilis, despite their high sequence similarities, catalyze filipin hydroxylation at different positions, C26 and C1', respectively. Here, we determined the crystal structure of the CYP105P1-filipin I complex. The distal pocket of CYP105P1 has the second largest size among P450 hydroxylases that act on macrolide substrates. Compared with previously determined substrate-free structures, the FG helices showed significant closing motion on substrate binding. The long BC loop region adopts a unique extended conformation without a B' helix. The binding site is essentially hydrophobic, but numerous water molecules are involved in recognizing the polyol side of the substrate. Therefore, the distal pocket of CYP105P1 provides a specific environment for the large filipin substrate to bind with its pro-S side of position C26 directed toward the heme iron. The ligand-free CYP105D6 structure was also determined. A small sub-pocket accommodating the long alkyl side chain of filipin I was observed in the CYP105P1 structure but was absent in the CYP105D6 structure, indicating that filipin cannot bind to CYP105D6 with a similar orientation due to steric hindrance. This observation can explain the strict regiospecificity of these enzymes.


Spontaneous intracerebral pseudoaneurysm rupture and meningiomatosis: A case report and review of the literature.
We report the first case of a spontaneous ruptured anterior cerebral artery pseudoaneurysm in a patient affected by meningiomatosis. A 71-year-old female patient was admitted to our emergency department after acute loss of consciousness. An urgent head CT scan showed third ventricle hemorrhage and a giant extra-axial tumor with associated peritumoral bleeding. A second, smaller, and right-sided tumor was detected at the posterior third of the superior sagittal sinus, indicative of meningiomatosis diagnosis. A following CT angiogram showed an hypervascularized lesion at the right frontal convexity and a ruptured A2 pseudoaneurysm. Tumor removal was performed through right frontal craniotomy. After the initial debulking and removal of the peritumoral hemorrhage, the A2 segment associated with the bleeding pseudoaneurysm was surgically coagulated. We report the unique occurrence of two relatively rare neurological entities: meningiomatosis and intracranial pseudoaneurysm. In our experience, their simultaneous and acute presentation is associated to poor prognosis.


A novel nitric oxide-releasing statin derivative exerts an antiplatelet/antithrombotic activity and inhibits tissue factor expression.
NO-releasing statins are new chemical entities, combining HMG-CoA reductase inhibition and slow NO release, that possess stronger anti-inflammatory and antiproliferative activities than the native statins. We evaluated the antithrombotic effects of nitropravastatin (NCX-6550) by assessing its activity on platelet activation and tissue factor (TF) expression by mononuclear cells in vitro and in vivo. In vitro, NCX-6550 inhibited (1) U46619- and collagen-induced platelet aggregation in buffer and plasma; (2) collagen-induced P-selectin expression in whole blood and (3) platelet adhesion to collagen-coated coverslips under high shear stress. These effects were displayed at concentrations of NCX-6550 ranging from 25 to 100 mum, and were totally reverted by the guanylylcyclase inhibitor ODQ (10 microm). Equimolar concentrations of pravastatin had no influence on these parameters of platelet function. LPS- and PMA-induced TF expression by blood mononuclear cells was also inhibited by NCX-6550 (IC50 13 microm), but not by pravastatin, as assessed by functional and immunological assays and by real-time PCR. In a mouse model of platelet pulmonary thromboembolism, induced by the i.v. injection of collagen plus epinephrine, pretreatment with NCX-6550 (24-48 mg kg(-1)) significantly reduced platelet consumption, lung vessel occlusion and mortality. Moreover, nitropravastatin markedly inhibited the generation of procoagulant activity by spleen mononuclear cells and peritoneal macrophages in mice treated with LPS. In these in vivo models too, pravastatin failed to affect platelet activation and monocyte/macrophage procoagulant activity. Our results show that nitropravastatin exerts strong antithrombotic effects in vitro and in vivo, and may represent an interesting antiatherothrombotic agent for testing in acute coronary syndromes.


Electromyographic evaluation of masseter and anterior temporalis muscles in resting position and during maximum tooth clenching of edentulous patients before and after new complete dentures.
The aim of this study was to assess the electrical activity of the masseter and anterior temporal muscles in patients with severe bone resorption, with complete dentures worn for over ten years, and five months after having new dentures put in place. The RDC questionnaire was applied to twelve asymptomatic patients, before and five months after new dentures were put in place. The electrical activity recordings were made in the mandibular position at rest, and during maximum tooth clenching. The electrical activity of the masseter and anterior temporal muscles in the position at rest presented no statistically significant difference after five months of wearing the new complete dentures. Electrical activity during tooth clenching exhibited a statistically significant reduction only in the right temporal muscle. A period longer than five months of wearing the new complete dentures is required for adaptation and the acquisition of functional capacity.


Incomplete Refractory Kawasaki Disease in an Infant-A Case Report and a Review of the Literature.
Kawasaki disease (KD) is a febrile vasculitis, which is commonly defined by fever and at least four specific clinical symptoms. Incomplete KD is defined by suggestive echocardiographic findings with an incomplete clinical picture. Refractory KD is diagnosed in patients resistant to intravenous immunoglobulin (IVIG). We report the case of a 6-month-old male infant admitted to our clinic for persistent fever and onset of a generalized polymorphous rash, accompanied by high fever, rhinorrhea, and cough for the past 7 days. The laboratory tests, on the day of admission, revealed leukocytosis with neutrophilia, anemia, thrombocytosis, hypernatremia, hypoalbuminemia, elevated C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Echocardiography showed dilation of the left anterior descending coronary artery (LAD). Based on all these findings, we established the diagnosis of KD, and we initiated IVIG and intravenous pulsed methylprednisolone, with an initial favorable outcome. However, the symptoms reappeared, and we administered a second higher single dose of IVIG, but without any clinical improvement. Moreover, the laboratory parameters and echocardiographic findings worsened. We reinitiated a longer course of intravenous methylprednisolone in a smaller dose, which had a favorable impact on the clinical, laboratory, and echocardiographic parameters. Multiple uncertainties exist related to the management of refractory KD despite the wide spectrum of therapeutic options that have been proposed. Our case demonstrates that in patients refractory to aggressive initial therapy, low or moderate doses of steroid given daily may be helpful.


Endodontic treatment failure consecutive to unsystematic radiographic examination.
This case report describes the endodontic therapy on a three-rooted mandibular first molar. The initial endodontic treatment was carried out after misreading preoperative periapical radiograph. Moreover, the working length was determined only with the apex locator. So, the additional disto-lingual root left unidentified and remained untreated, failing the treatment. A thorough radiographic examination in the initial therapy would have allowed the identification of the supernumerary root and its canal. Although the apex locators determine accurately the working length, it does not inform about the root canal morphology. It can be concluded and remarked that a systematic radiographic examination, including preoperative radiographs, is essential for success in endodontic therapy.


Surgical treatment of infrabony defects with autologous platelet concentrate or bioabsorbable barrier membrane: a prospective case series.
Autologous platelet concentrate (APC) contains concentrated platelet-derived growth factors that promote wound healing and tissue regeneration. The purpose of this prospective case series was to compare the treatment effects of an intralesional graft of APC to guided periodontal regeneration (GPR) using a bioabsorbable barrier membrane (MEM) over a 52-week period. Five patients were recruited for the study from two private periodontal practices. There were four females and one male having a mean age of 33 +/- 10.23 years. The five selected contralateral teeth had similar, but not identical, combinations of 1-, 2-, and 3-wall infrabony defects not involving furcations. Probing depths (PDs) of the defects were > or = 6 mm and had radiographic angular infrabony defects > or = 4 mm in depth. The patients had no local or systemic contraindications to minor oral surgical procedures and had not taken systemic antibiotics for > or = 6 months before the commencement of the study. All patients had completed cause-related periodontal therapy up to 6 months previously and had achieved a satisfactory level of oral hygiene. The selected teeth did not have purulent discharge from the pockets and responded normally to pulp sensibility testing. Patients were excluded if they smoked, were pregnant or lactating, or were allergic to any of the materials to be used in the treatment. At baseline and 8, 26, and 52 weeks after surgery, PDs, recession (REC), presence of plaque, and bleeding on probing were recorded, and standardized periapical radiographs were taken. At the time of surgery, the vertical distance to the deepest point of the infrabony defect was measured from the cemento-enamel junction (CEJ) to the buccal and lingual bone crests. The vertical distance to the base of the defect from the CEJ and defect angles were obtained from radiographs. The paired contralateral infrabony defects were treated with a graft APC or MEM after debridement and EDTA root surface conditioning. Surgical flaps were prepared and closed according to the papilla preservation method. Post-surgical care was provided at 1, 2, 8, 26, and 52 weeks after surgery. A mouthwash of 0.2% chlorhexidine gluconate was used twice daily for the first 3 weeks after surgery. Mean PD, REC, clinical attachment level (CAL), radiographic bone loss, and defect angle were computed and compared for each data collection point. From baseline to 52 weeks, a mean PD reduction of 3 +/- 1.41 mm (APC) and 3.6 +/- 1.67 mm (MEM), mean REC increase of 0.8 +/- 1.01 mm (APC) and 0.6 +/- 1.14 mm (MEM), mean CAL gain of 2.2 +/- 1.79 mm (APC) and 3 +/- 1 mm (MEM), mean radiographic bone fill of 3.24 +/- 2.85 mm (APC) and 2.7 +/- 1.9 mm (MEM), and mean defect-angle increase of 15.25 degrees +/- 18.21 degrees (APC) and 22.4 degrees +/- 27.3 degrees (MEM) were calculated. CAL gain was not related clearly to defect angle at baseline, although radiographic bone fill was slightly greater for defect angles <39.4 degrees +/- 7.88 degrees. This case series of five similar, but not identical, bilateral paired infrabony defects suggests that an APC graft achieves a similar CAL gain and PD reduction to GPR using an MEM over a 52-week period. A larger, controlled clinical trial is needed to evaluate further the efficacy of autologous platelet-rich plasma for the treatment of infrabony defects.


CD44-Targeted Photoactivatable Polymeric Nanosystem with On-Demand Drug Release as a "Photoactivatable Bomb" for Combined Photodynamic Therapy-Chemotherapy of Cancer.
Nowadays, the combined use of chemotherapy and photodynamic therapy (PDT) remains the most popular strategy for cancer treatment with high theraprutic efficacy. However, targeted therapy with the on-demand release of drugs is what most clinical treatments lack, leading to heavy side effects. Herein, a new CD44-targeted and red-light-activatable nanosystem, Ru-HA@DOX nanoparticles (NPs), was developed by conjugating hydrophilic biodegradable hyaluronic acid (HA) and hydrophobic photoresponsive ruthenium (Ru) complexes, which could encapsulate the chemotherapeutic drug doxrubicin (DOX). Ru-HA@DOX NPs can selectively accumulate at the tumor through the enhanced permeability and retention (EPR) effect and CD44-mediated endocytosis, thus avoiding off-target toxicity during circulation. After 660 nm of irradiation at the tumor site, Ru-HA@DOX NPs, as a "photoactivatable bomb", was split via the photocleavable Ru-N coordination bond to fast release DOX and produce singlet oxygen (1O2) for PDT. In general, Ru-HA@DOX NPs retained its integrity before irradiation and possessed minimal cytotoxicity, while under red-light irradiation, Ru-HA@DOX NPs showed significant cytotoxicity due to the release of DOX and production of 1O2 at the tumor. Chemotherapy-PDT of Ru-HA@DOX NPs resulted in a significant inhibition of tumor growth in A549-tumor-bearing mice and reduced the cardiotoxicity of DOX. Therefore, this study offers a novel CD44-targeted drug-delivery system with on-demand drug release for synergistic chemotherapy-PDT.


CIC-DUX4 Sarcoma Involving the Skull Base: A Rare Presentation and Review of the Literature.
Background CIC-DUX4 sarcoma is a rare, aggressive tumor that is difficult to diagnose. Although it is closely related to Ewing's sarcoma, each is a distinct pathologic entity and both have been previously reported in the skin, lymph nodes, and viscera. We report the first description of CIC-DUX4 involving the posterior cranial fossa and review the distinctive symptomatology, morphology, immunoprofile, and genetic signature that differentiate this rare tumor. Case Report A 32-year-old man presented with an enlarging right lateral neck mass, progressive hoarseness, and orofacial pain. Biopsy revealed a high-grade undifferentiated malignant neoplasm. Imaging demonstrated an 8-cm mass in the right neck extending to the skull base and abutting the carotid sheath, in addition to pulmonary nodules and pelvic lymphadenopathy. Despite initial response to chemotherapy, he experienced disease progression and underwent surgical resection, radical neck dissection, and brachytherapy. Definitive pathologic diagnosis was achieved with next-generation sequencing. Within weeks of treatment, he developed symptoms reflecting progression of disease involving the neck, posterior cranial fossa, and lung. Adjuvant chemotherapy was planned, but the patient succumbed to his disease prior to initiation of further therapy. Conclusion CIC-DUX4 sarcomas are uncommon and can progress rapidly. Diagnosis requires either fluorescence in situ hybridization or next-generation sequencing. Due to its rarity, there is no standard-of-care treatment for this tumor and further investigations are needed to understand disease behavior and develop targeted therapeutic modalities.


Effectiveness of robust optimization in volumetric modulated arc therapy using 6 and 10 MV flattening filter-free beam therapy planning for lung stereotactic body radiation therapy with a breath-hold technique.
We investigated the feasibility of a robust optimization with 6 MV X-ray (6X) and 10 MV X-ray (10X) flattening filter-free (FFF) beams in a volumetric modulated arc therapy (VMAT) plan for lung stereotactic body radiation therapy (SBRT) using a breath-holding technique. Ten lung cancer patients were selected. Four VMAT plans were generated for each patient; namely, an optimized plan based on the planning target volume (PTV) margin and a second plan based on a robust optimization of the internal target volume (ITV) with setup uncertainties, each for the 6X- and 10X-FFF beams. Both optimized plans were normalized by the percentage of the prescription dose covering 95% of the target volume (D95%) to the PTV (1050 cGy × 4 fractions). All optimized plans were evaluated using perturbed doses by specifying user-defined shifted values from the isocentre. The average perturbed D99% doses to the ITV, compared to the nominal plan, decreased by 369.1 (6X-FFF) and 301.0 cGy (10X-FFF) for the PTV-based optimized plan, and 346.0 (6X-FFF) and 271.6 cGy (10X-FFF) for the robust optimized plan, respectively. The standard deviation of the D99% dose to the ITV were 163.6 (6X-FFF) and 158.9 cGy (10X-FFF) for the PTV-based plan, and 138.9 (6X-FFF) and 128.5 cGy (10X-FFF) for the robust optimized plan, respectively. Robust optimized plans with 10X-FFF beams is a feasible method to achieve dose certainty for the ITV for lung SBRT using a breath-holding technique.


Histamine release test in comparison to standard tests in diagnosis of childhood allergic asthma.
An allergen-specific histamine release test (HR) was investigated in 93 children with a history of extrinsic asthma and suspected allergy to house dust mite or fungi. For both allergy groups the correlations between HR and the bronchial provocation test were better than those between the inhalation test and prick test or RAST. It is concluded that, especially in childhood where performance of a bronchial provocation should be avoided because of its potential risk and required hospitalization, the HR test can represent a significant diagnostic aid.


The Research Society on Alcoholism.
Until the 1960s, the small amount of federal funding available in the alcohol field in the USA was provided by a division of the Alcohol, Drug and Mental Health Administration. In the late 1960s, the National Council on Alcoholism (NCA) joined the American Medical Society on Alcoholism (AMSA, which accepted only physicians). A group of physicians at NCA-AMSA felt that progress in our field needed the concerted effort of both physicians and nonphysician scientists, creating the Research Society on Alcoholism (RSA) in 1977. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) had been created a few years earlier. From 250 members in 1978, the RSA has grown to 1500 in 2001, with a ratio of about three PhDs (with specialities that range from gene therapy to social policy) to each MD. The society holds yearly meetings-visitors can find more information on the web page (http://www.RSoA.org). The society publishes the journal Alcoholism: Clinical and Experimental Research. RSA committees are active in presenting the most recent findings to the public and to elected representatives, and in making recommendations on areas of research that need funding.


Hereditary diabetes in the KK mouse: an overview.
Table III compares metabolic and morphologic characteristics of different species of control and KK mice. The C57BL/6J demonstrates no significant metabolic, clinical or histologic abnormalities. Our two highly inbred Swiss albino groups I and II also do not show significant glomerular lesions, although we found striking intolerance to glucose, hyperinsulinism, and obesity among them. Thus a genetic predisposition may be necessary in addition to various environmental factors to produce microangiopathy in KK mice. The yellow AY mouse is included in this table, since it is strikingly hyperinsulinemic and obese without concomitant vasculopathy such as the other mentioned control strains have. In conclusion, the KK mice develop chemical diabetes preceded by a stage of prediabetes and also demonstrate renal, retinal and neurologic complications similar to those seen in human diabetes. Of particular interest is the development of mild to moderate glomerulosclerosis in the prediabetic stage; with progression to severe glomerulosclerosis and attendant proteinuria later in life. With proper back-crossing, both hyperglycemia and glomerulosclerosis can be transmitted to normal control mice, suggesting that a specific genetic background is necessary for the development of diabetes and diabetic-like microangiopathy. We therefore suggest that the KK mouse serves as an ideal genetic animal for the study of non-insulin-dependent diabetes mellitus and its complications for rational prevention and therapy.


Indications for omega-3 fatty acid supplementation in prevention of cardiovascular disease: From fish to pharmaceuticals.
To explore the evidence for omega-3 fatty acid (O3FA) supplementation in primary and secondary prevention of cardiovascular disease (CVD). PubMed, Cochrane reviews, and Google Scholar were searched for meta-analyses and reviews related to O3FAs and CVD. Salient, recent randomized controlled trials referenced in these reviews were retrieved. Current lipid guidelines were reviewed. Most O3FAs are derived from marine or aquatic microalgae, which are consumed by fish. The essential fatty acids eicosapentaenoic acid and docosahexaenoic acid are mainly sourced from fish, with a small fraction coming from plants. Omega-3 fatty acids modestly lower triglyceride levels, but the major impact on CVD is through a variety of other mechanisms related to cell membrane function, antioxidant properties, and reduction of atherogenic small low-density lipoprotein cholesterol particles. Guidelines continue to recommend eating 2 servings of fish per week. There is little evidence of benefit of O3FAs in primary prevention of CVD. Given that 40% of Canadians have insufficient levels and that these low levels may be associated with other chronic diseases over time, supplementation with O3FAs could be considered, particularly in those with hypertriglyceridemia, in those who eat no fish, or for vegetarians or vegans. Doses up to 1 g daily are considered safe. For secondary prevention after statin optimization, if triglyceride levels are between 1.5 and 5.6 mmol/L, guidelines recommend with level 1A evidence taking 2 g of icosapent ethyl twice a day. This is also recommended in primary prevention for patients with diabetes and hypertriglyceridemia and additional CVD risk factors. As fish stocks dwindle over time, preserving fisheries for developing countries and obtaining O3FA from microalgal or genetically modified plant sources may become important. All guidelines recommend at least 2 servings of oily fish per week, although benefit from O3FAs is mostly seen in secondary prevention. Fish oil and combination preparations of eicosapentaenoic acid and docosahexaenoic acid have failed to show benefit at any dose at any level of prevention in patients who are appropriately prescribed statins. High-dose eicosapentaenoic acid shows substantial benefit in selected patients taking statins who have high triglyceride levels.


Will Septal Correction Surgery for Deviated Nasal Septum Improve the Sense of Smell? A Prospective Study.
Background and Objectives. Nasal obstruction due to deviated nasal septum is a common problem bringing a patient to an otorhinolaryngologist. Occasionally, these patients may also complain of olfactory impairment. We proposed to study the effect of septal deviation on the lateralised olfactory function and the change in olfaction after surgery of the septum (septoplasty). Methods. Forty-one patients with deviated nasal septum were evaluated for nasal airflow, olfactory score, and nasal symptomatology. Septoplasty was done under local anesthesia. Pre- and postoperative olfactory scores, airflow and olfactory scores, and nasal symptomatology and olfactory scores were compared and correlated. Results. The range of preoperative composite olfactory score (COS) on the side of septal deviation was 4-14 (mean 7.90 ± 2.234) and on the nonobstructed side was 9-18 (mean 14.49 ± 2.378). Severity of deviated nasal septum and preoperative COS of diseased side were correlated and the correlation was found to be significant (rho = -0.690, p = 0.000 (<0.001)). The preoperative mean COS (7.90 ± 2.234) was compared with the postoperative mean COS (12.39 ± 3.687) and the improvement was found to be statistically significant (p = 0.000 (<0.001)). Conclusion. We found improvement in olfactory function in 70.6% patients after surgery, no change in 20.1%, and reduced function in 7.6%. With the limitation of a small sample size and a potential repeat testing bias, we would conclude that correction of nasal septal deviation may lead to improvement in sense of smell.


Covalent attachment of the heme prosthetic group in the CYP4F cytochrome P450 family.
We demonstrated earlier that the heme in cytochrome P450 enzymes of the CYP4A family is covalently attached to the protein through an I-helix glutamic acid residue [Hoch, U., and Ortiz de Montellano, P. R. (2001) J. Biol. Chem. 276, 11339-11346]. As the critical glutamic acid residue is conserved in many members of the CYP4F class of cytochrome P450 enzymes, we investigated covalent heme binding in this family of enzymes. Chromatographic analysis indicates that the heme is covalently bound in CYP4F1 and CYP4F4, which have the required glutamic acid residue, but not in CYP4F5 and CYP4F6, which do not. Catalytic turnover of CYP4F4 with NADPH-cytochrome P450 reductase shows that the heme is covalently bound through an autocatalytic process. Analysis of the prosthetic group in the CYP4F5 G330E mutant, into which the glutamic acid has been reintroduced, shows that the heme is partially covalently bound and partially converted to noncovalently bound 5-hydroxymethylheme. The modified heme presumably arises by trapping of a 5-methyl carbocation intermediate by a water molecule. CYP4F proteins thus autocatalytically bind their heme groups covalently in a process that requires a glutamic acid both to generate a reactive (cationic) form of the heme methyl and to trap it to give the ester bond.


[Translational frameshift may be occur in p11, an interaction protein of Cx31, in yeast].
Connexin 31 is a member of connexin family. The carboxy-terminal cytosolic domain of connexin 31 contains several potential phosphorylation sites. In this work, a yeast two-hybrid protein interaction screen have been used to identify proteins that bind to the carboxy-terminus of connexin 31, and the p11 protein, an unique member of S100 protein family, and one of the two subunits of the annexin II tetramer was isolated. Interestingly, from yeast two-hybrid AD's coding sequence, three different reading frames of p11 DNA sequence were found,which come from different AD plasmids. By constructing AD plasmids using p11 ORF or 5' UTR, the protein coding by p11 ORF bind to connexin 31, while polypeptides coding by three kinds of 5 UTR did not bind to connexin 31, suggesting a translational frameshift of p11 fusion protein. To construct baits by dividing connexin 31 C-terminus into two domain, the p11 binding domain of connexin 31 was found located between 206-237 codons. The plasmid Cx31CT-pGEX-4T-2 was constructed for expression and purification of GST-Cx31CT; and p11-pQE30 for expression and purification of 6xHis-p11. In vitro binding assay showed that recombinant Cx31 interacted with recombinant p11.


Cognitive dysfunction in multiple sclerosis: methods and prevalence from the GEDMA Study.
Cognitive dysfunction is a major handicap in multiple sclerosis (MS). Its prevalence varies due to disease heterogeneity and methodological issues. A neuropsychological battery of intermediate size was designed for and explored in the screening of cognitive dysfunction in MS patients. The battery was administered to a hospital-based sample of 191 MS patients and 50 matched controls. Eleven test scores measuring verbal fluency, verbal learning, attention, calculation and visuoperceptual ability were selected on the basis of sensitivity and lack of redundancy. Two alternative approaches were compared for diagnosis of cognitive dysfunction based, firstly, on the number of failed tasks, and secondly, on a single standardized global score. The approach based on the number of failed tasks discriminated better than did the global approach between patients and controls. Using a cutoff of two altered scores, a cognitive dysfunction prevalence of 34% was obtained. The score yielded after summing errors in all tests was the most frequently altered and proved particularly useful for detecting minimally impaired patients. The purpose-designed battery was adequate for the screening of cognitive dysfunction in MS patients. The better accuracy of the single-task approach might reflect MS heterogeneity.


Variability of the closing volume measurement in normal subjects.
The repeatablilty of the measurement of closing volume (nitrogen method) in healthy, normal subjects was investigated. At least 7 consecutive measurements at 5-min intervals were made in each of 22 subjects. The mean coefficient of variation for the absolute volume of phase IV was 36.1 per cent and for the percentage ratio of phase IV to vital capacity, 36.1 per cent. Repeated measurements by the same observer of the same records on various days did not differ significantly (P greater than 0.5). There was a significant difference (P less than 0.05) between 2 observers measuring the same records, but there was no significant difference between the two observers in the variance of the closing variability in the same subject, it may be necessary to perform several closing volume maneuvers in each subject to establish his or her range before changes in the closing volume can be interpreted.


Cerebral hemodynamic and metabolic profiles in fulminant hepatic failure: relationship to outcome.
The purpose of this retrospective study was to examine the potential role of cerebral hemodynamic and metabolic factors in the outcome of patients with fulminant hepatic failure (FHF). Based on the literature, a hypothetical model was proposed in which physiologic changes progress sequentially in five phases, as defined by intracranial pressure (ICP) and cerebral blood flow (CBF) measurements. Seventy-six cerebral physiologic profiles were obtained in 26 patients (2 to 5 studies each) within 6 days of FHF diagnosis. ICP was continuously measured by an extradural fiber optic monitor. Global CBF estimates were obtained by xenon clearance techniques. Jugular venous and peripheral artery catheters permitted calculation of cerebral arteriovenous oxygen differences (AVDO2), from which cerebral metabolic rate for oxygen (CMRO2) was derived. A depressed CMRO2 was found in all patients. There was no evidence of cerebral ischemia as indicated by elevated AVDO2s. Instead, over 65% of the patients revealed cerebral hyperemia. Eight of the 26 patients underwent orthotopic liver transplantation-all recovered neurologically, including 6 with elevated ICPs. Of the 18 patients receiving medical treatment only, all 7 with increased ICP died in contrast to 9 survivors whose ICP remained normal (P < 0.004). Hyperemia, per se, was not related to outcome, although it occurred more frequently at the time of ICP elevations. Six patients were studied during brain death. All 6 revealed malignant intracranial hypertension, preceded by hyperemia. In conclusion, the above findings are consistent with the hypothetical model proposed. Prospective longitudinal studies are recommended to determine the precise evolution of the pathophysiologic changes.


A call for total nursing role reformation: Perceptions of Ghanaian nurses.
Nurses in Ghana believe that training, practise, practitioner and policy reforms are required for total nursing profession reform to be effective. Their views for role reformation in the nursing profession, which is currently needed, are not only academic but also clinically relevant in the pursuit of health equity and quality nursing care. We explored and described nurses' views on their roles in the profession using data collected from 24 professional nurses in three regional hospitals in Ghana. Using an inductive descriptive qualitative design, data were gathered and analysed using a qualitative content analysis to describe the views of the nurses. Four major themes, namely practise reforms, practitioner reforms, training reforms and policy reforms have emerged in relation to role reformation in the nursing profession. Three strategic areas, practitioner attitudes, new training modalities and policy realignment, must be reviewed and remodelled for better positioning of the nursing profession before its entire role reformation.