DNA sequence variants in the tyrosinase-related protein 1 (TYRP1) gene are not associated with human pigmentary glaucoma.
Pigmentary glaucoma is a common form of glaucoma affecting young adults. Previous studies have suggested that multiple factors, including multiple genetic factors, may be responsible for this condition. Recently, a form of glaucoma associated with pigment dispersion and iris atrophy was identified in the DBA/2J mouse. Abnormalities in the mouse Tyrp1 gene contribute to this condition. The purpose of this study was to determine if DNA sequence variants in the human TYRP1 gene are associated with pigmentary glaucoma in humans. The protein coding regions and intron/exon boundaries of the human TYRP1 gene were sequenced using genomic DNA samples from probands from pedigrees affected by pigment dispersion syndrome and pigmentary glaucoma. Three novel synonymous single nucleotide polymorphisms (SNPs) were found in two affected individuals. However, these polymorphisms did not define a haplotype that segregated with the disease in the families. DNA sequence variants that altered the amino acid sequence of TYRP1 were not found. Despite the phenotypic similarity between the glaucoma in the DBA/2J mouse and human pigmentary glaucoma, the results of this study suggest that DNA sequence variants in the human TYRP1 gene are not associated with inherited pigmentary glaucoma in humans.


Development of a Polygenic Risk Score to Predict Diverticulitis.
Despite its prevalence and associated morbidity, we remain limited in our ability to predict the course of a patient with diverticular disease. While several clinical and genetic risk factors have been identified, we do not know how these factors relate to one another. To determine if a polygenic risk score could improve risk prediction for diverticulitis and recurrent diverticulitis compared to a model using only clinical factors. An observational study. Study examines the predictive ability of a polygenic risk score for diverticulitis developed using prior genome wide association studies and validated using the MyCode biobank. Patients of European ancestry in the Geisinger Health System who were enrolled in the MyCode Community Health biobanking program. The ability of a polygenic risk score to predict diverticulosis, diverticulitis, and recurrent diverticulitis. A total of 60,861 patients were included, of which 9,912 (16.3%) had diverticulosis or diverticulitis (5,015 with diverticulosis and 4,897 with diverticulitis). When divided into deciles, our polygenic risk score stratified patients by risk of both diverticulosis and diverticulitis with a 2-fold difference in disease risk between the highest and lowest deciles for diverticulitis and a 4.8-fold difference for recurrent complicated diverticulitis. When compared to clinical factors alone, our polygenic risk score was able to improve risk prediction of recurrent diverticulitis. Our population is largely located in a single geographic region and were classified by disease status using international classification of diseases codes. This predictive model stratifies patients based on genetic risk for diverticular disease. The increased frequency of recurrent disease in our high-risk patients suggests that a polygenic risk score, in addition to other factors, may help to guide the discussion regarding surgical intervention.


Glycometabolic adaptation mediates the insensitivity of drug-resistant K562/ADM leukaemia cells to adriamycin via the AKT-mTOR/c-Myc signalling pathway.
In human leukaemia, resistance to chemotherapy leads to treatment ineffectiveness or failure. Previous studies have indicated that cancers with increased levels of aerobic glycolysis are insensitive to numerous forms of chemotherapy and respond poorly to radiotherapy. Whether glycolysis serves a key role in drug resistance of leukaemia cells remains unclear. The present study systematically investigated aerobic glycolytic alterations and regulation in K562/adriamycin (ADM) multidrug‑resistant (MDR) and ADM‑sensitive K562 leukaemia cells in normoxia, and the association between drug resistance and improper glycometabolism. The cell proliferating activity was assessed with an MTT colorimetric assay, glycolysis, including glucose consumption, lactate export and key‑enzyme activity was determined by corresponding commercial testing kits. The expression levels of hexokinase‑II (HK‑II), lactate dehydrogenase A (LDHA), glucose transporter‑4 (GLUT‑4), AKT, p‑AKT473/308, mammalian target of rapamycin (mTOR), p‑mTOR, c‑Myc and hypoxia‑inducible factor‑1α (HIF‑1α) were analyzed by western blot or reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). K562/ADM cells exhibited increased glucose consumption and lactate accumulation, increased lactate dehydrogenase, hexokinase and pyruvate kinase activities, and reduced phosphofructokinase activity. In addition, K562/ADM cells expressed significantly more HK‑II and GLUT‑4. Notably, inhibition of glycolysis effectively killed sensitive and resistant leukaemia cells and potently restored the sensitivity of MDR cells to the anticancer agent ADM. The AKT serine/threonine kinase (AKT)/mechanistic target of rapamycin (mTOR) signalling pathway, a crucial regulator of glycometabolic homeostasis, mediated over‑activation and upregulation of c‑Myc expression levels in K562/ADM cells, which directly stimulated glucose consumption and enhanced glycolysis. In conclusion, the present study demonstrated that MDR leukaemia cells exhibit increased aerobic glycolytic activity and that this may be responsible for resistance to chemotherapeutics in leukaemia MDR cells via activation of the AKT‑mTOR‑c‑Myc signalling pathway. Therefore, inhibition of aerobic glycolysis may be a potential therapeutic strategy to efficiently treat multidrug resistance in relapsed or refractory leukaemia and cancers.


Additive Manufacturing of Advanced Ceramics Using Preceramic Polymers.
Ceramic materials are used in various industrial applications, as they possess exceptional physical, chemical, thermal, mechanical, electrical, magnetic, and optical properties. Ceramic structural components, especially those with highly complex structures and shapes, are difficult to fabricate with conventional methods, such as sintering and hot isostatic pressing (HIP). The use of preceramic polymers has many advantages, such as excellent processibility, easy shape change, and tailorable composition for fabricating high-performance ceramic components. Additive manufacturing (AM) is an evolving manufacturing technique that can be used to construct complex and intricate structural components. Integrating polymer-derived ceramics and AM techniques has drawn significant attention, as it overcomes the limitations and challenges of conventional fabrication approaches. This review discusses the current research that used AM technologies to fabricate ceramic articles from preceramic feedstock materials, and it demonstrates that AM processes are effective and versatile approaches for fabricating ceramic components. The future of producing ceramics using preceramic feedstock materials for AM processes is also discussed at the end.


Mass-induced unilateral hallux valgus.
Various causes of hallux valgus exist. However, mass-induced hallux valgus is a rare phenomenon. To the best of our knowledge, there has been 1 previous report on mass-induced hallux valgus in the English literature; however, that report described giant cell tumor of the extensor digitorum longus tendon sheath. We believe ours to be the first published case of osteochondroma of the second metatarsus-induced hallux valgus. A 19-year-old woman presented with pain and tenderness in the left hallux of 3 months' duration. After a diagnosis of bony mass with hallux valgus, an operative excision was performed through a dorsal approach on the first web space of the left foot. The histopathologic diagnosis was osteochondroma. One-year follow-up radiographs showed a decreased hallux valgus angle and intermetatarsal angle. Unilateral hallux valgus occurs in a mass area. After excision of the mass, hallux valgus angle and intermetatarsal angle decrease. The rotational deformity is not severe. There is little probability of discovering its etiology, but mass-like osteochondroma should be considered.


Academic word coverage and language difficulty of reading passages in College English Test and Test of English for Academic Purposes in China.
The field of English for Specific Purposes (ESP) has gained considerable attention, mainly due to the growing importance of English teaching and the need for preparing international professionals. The primary academic emphasis of this field is largely centered on the study of English for Academic Purposes (EAP). It has become increasingly important for China to provide EAP education to its vast population of college students, who represent a significant proportion of global tertiary-level English learners. By doing so, they can improve their academic literacy and participate more effectively in international academic communication. In 2016, China's College English Test Examination Board issued the National College English Test Syllabus which emphasized the importance of academic English literacy in the test design. This syllabus was released during a contentious debate among Chinese academics about the role of EAP in college English teaching and testing. Despite this heated discussion, there are currently few studies that have analyzed the linguistic nature of academic English tests in a quantitative manner. This paper calculates the academic word coverage of the reading passages in two crucial English proficiency tests designed for college students in China, the College English Test (CET) and the Test of English for Academic Purposes (TEAP). It is found that the academic word coverage of CET is increasing from the year 2013 to 2021 and that the academic word coverage of TEAP is slightly higher than that of CET. In this sense, these English tests can meet the requirements for measuring Chinese college students' academic literacy. It is also found that there is a positive correlation between academic word coverage and language difficulty as is indicated by Flesch-Kincaid Grade Level. These findings provide an empirical reference for the study of academic English tests in China, and other parts of the world, and contribute to EAP teaching and testing reform for the development of students' academic literacy.


The clinical research of Thinprep Cytology Test (TCT) combined with HPV-DNA detection in screening cervical cancer.
Our objective is to explore the clinical value of thinprep cytologic test (TCT) combined with HPV-DNA detection in screening cervical cancer. 420 cervical cancer patients admitted in our hospital between April, 2011-April, 2014 were selected. All patients received TCT and HPV-DNA detection, and cervical tissue biopsy was used to confirm the diagnosis. TCT screening results showed that there were 175 patients were >ASCUS and the positive rate was 41.7%, histopathological screening showed that there were 199 patients were ≥cervical intraepithelial neoplasia (CIN) I and the positive rate was 47.4%. HPV-DNA detection showed 180 patients were positive which was 42.9%, and the positive rate of HPV-DNA detection was increased as the disease severity increased. The sensitivity of TCT combined with HPV-DNA detection was higher than single TCT or HPV-DNA, however the specificity was relatively low, and the positive predictive value and negative predictive value were higher which were similar to pathological results. TCT combined with HPV-DNA detection has high sensitivity and accuracy in screening cervical cancer, which is worthy of clinical application.


Characterization of the major histocompatibility complex class II binding site on LAG-3 protein.
The lymphocyte activation gene-3 (LAG-3), selectively transcribed in human activated T and NK cells, encodes a ligand for major histocompatibility complex (MHC) class II molecules. Like CD4, LAG-3 ectodomain is composed of four Ig-like domains (D1-D4). Nothing is known about the LAG-3 regions or residues required to form a stable MHC class II binding site. In contrast to CD4, soluble LAG-3 molecules stably interact with MHC class II molecules expressed on the cell surface. In addition, the first two N-terminal domains of soluble LAG-3 (D1 and D2) molecules, alone, are capable of binding MHC class II. From a LAG-3 model structure, we designed mutants and tested their ability to bind MHC class II molecules in an intercellular adhesion assay. We found residues on the membrane-distal, CDR1-2-containing top face of D1 that are essential for either binding or repulsing MHC class II proteins. Most of these residues are clustered at the base of a large extra-loop structure that is a hallmark of the LAG-3 D1 Ig-like domain. In addition, as for CD4, oligomerization of LAG-3 on the cell surface may be required to form a stable MHC binding site because mutation of three residues in the ABED beta-strands containing side of D1 results in a dominant negative effect (i.e., binding inhibition of coexpressed wild-type LAG-3).


In vitro cytotoxicity evaluation of different pulp capping materials: a comparative study.
Direct pulp capping covers the exposed surface of the pulp to maintain its vitality and preserve its functional and biologic activity. The aim of the present study was to compare the biocompatibility effects of seven different pulp-capping materials in vitro: Dycal®, Calcicur®, Calcimol LC®, TheraCal LC®, ProRoot MTA®, MTA-Angelus®, and Biodentine®. Using the Transwell insert methodology by Alamar blue test, we evaluated the cytocompatibility of the above mentioned materials towards murine odontoblasts cells (MDPC-23) at three different times (24, 48, and 72 h). For additional control, the cell viability at 72 hours was also assessed by MTT assay. Morphological analysis of murine odontoblasts was assessed by Confocal Laser Scanning Microscope. The results indicate significantly different biocompatibility among materials with different composition. Biodentine® and mineral trioxide aggregate (MTA)-based products showed lower cytotoxicity, varying from calcium hydroxide-based materials, which exhibited higher cytotoxicity. Although our findings are limited to in vitro conditions, the observation that Biodentine® caused a cytotoxic effect similar to MTA suggests that it may be considered an alternative in pulp-capping treatment, as calcium hydroxide-based materials present higher cytotoxic effects.


Clonidine pretreatment reduces the systemic toxicity of intravenous bupivacaine in rats.
Clonidine prolongs the duration of sensory and motor block induced by bupivacaine, and this association, in constant infusion by the epidural route, is used for postoperative analgesia. After a near-fatal intravenous bolus of bupivacaine in dogs, clonidine improves ventricular electrophysiologic parameters, but probably worsens bupivacaine-induced bradycardia and depression of the myocardial contractility. The current study, using a rodent animal model, evaluated the influence of clonidine pretreatment on the systemic toxic effects of bupivacaine overdose induced by a constant intravenous infusion. Twenty Wistar male rats were anesthetized with thiopental, and controlled ventilation was started with an equal mixture of O2 and N2O. Electrocardiogram (ECG), electroencephalogram (EEG), and invasive arterial blood pressure were continuously recorded. Clonidine (5 micrograms/kg) or saline was injected intravenously in a randomized fashion. After 15 min, an intravenous infusion of bupivacaine was started at 2 mg.kg-1 x min-1. The time of occurrence of the bupivacaine-induced toxic events was recorded and the doses were calculated. Ten (five in each group) additional rats, pretreated according to the same protocol, were killed at the time of the first dysrhythmia, for blood sampling and plasma bupivacaine concentration measurement. Clonidine reduced heart rate and arterial blood pressure before bupivacaine infusion (P < 0.05). The threshold doses at the first QRS modification (11.3 +/- 5.6 vs. 2.1 +/- 0.9 mg/kg) and the first dysrhythmia (40.6 +/- 15.3 vs. 8.48 +/- 3.7 mg/kg), the increase in EEG total spectral power (33.3 +/- 21.9 vs. 8.2 +/- 5.1 mg/kg), the 25 and 50% reduction in baseline mean arterial pressure and heart rate, the isoelectric EEG (58.6 +/- 14 vs. 22 +/- 6.6 mg/kg), and the final systole (99 +/- 16 vs. 51.8 +/- 14.5 mg/kg) were significantly greater in the clonidine group than in the saline group (P < 0.01). The time between the first dysrhythmia and 50% reduction of baseline mean arterial blood pressure was not different between the groups. In the additional series, the first dysrhythmia occurred later (10.9 +/- 4.5 vs. 3.2 +/- 1.0 min, P < 0.01) and plasma bupivacaine levels were greater (18.7 +/- 8.0 vs. 7.8 +/- 3.2 micrograms/ml, P < 0.01) in the clonidine group than in the saline group. In this model, clonidine given prophylactically delays the toxic manifestations of bupivacaine overdose and does not accentuate the subsequent hypotension.


Video-assisted thoracoscopy in single-stage resection of a para-aortic posterior mediastinal dumbbell tumor.
We report the successful single-stage thoracoscopic resection of a neurogenic mediastinal dumbbell tumor close to the aortic arch, using a combined posterior approach. A 63-year-old asymptomatic male was referred to our hospital for evaluation of an abnormal round shadow in the left thoracic cavity on a chest radiograph. He was diagnosed to have an intrathoracic and intraspinal neurogenic dumbbell-shaped tumor close to the aortic arch. Surgery combined both a laminectomy and thoracoscopic tumor resection. The tumor was lysed as deeply as possible via a posterior approach, then with the patient in the right lateral position the pleura around the tumor on the aortic side was clipped and cauterized thorocoscopically, freeing the tumor completely and allowing it to be extracted in toto.


[New salicylic acid derivatives in the treatment of inflammatory intestinal diseases].
Drug therapy for inflammatory bowel disease was limited for many years to sulfasalazine and some corticosteroids. Since the discovery that 5-aminosalicylic acid (5-ASA) is the active moiety of sulphasalazine in the treatment of chronic inflammatory bowel disease, several new drugs have been developed. These consist either of slow- or delayed-release formulations of plaint 5-ASA (mesalazin) or sulpha-free azo-compounds of 5-ASA. The varying bioavailabilities of the different formulations and compounds make it possible to use them alternatively in different clinical situations. A review of the literature is given and suggestions as to how the new drugs can be used in different diseases.


Total hip arthroplasty using TRI-LOCK® DePuy bone preservation femoral stem: our experience.
In this study we report our 3-years experience (from January 2010 to December 2013) of 101 total hip arthroplasties using Tri-Lock® DePuy bone preservation femoral stem, all performed in our clinic. 101 patients (F54-M47; median age around 69 yrs, range 42-84 yrs). 51 arthroplasties were implanted on the right side whereas 50 on the left side. The average follow-up was 27,3 months. All the arthroplasties were coupled with Pinnacle® polyethylene acetabular cup system; 98 prostheses were implanted cementless whereas cement was used in 3 cases. The Tri-Lock® femoral stem allows both soft tissues and bone stock preservation, leading to greater trochanter maintenance, less spongy bone removal and distal cavity bone tissue conservation. In our experience, we were able to implant the Tri-Lock® femoral stem even in osteoporotic and overweight patients using Gription® porous coating. This allowed for commencing an intensive rehabilitation program with stable load from the following day, without observing any early complications or loosening. According to us, this device is solid and safe, providing remarkable sparing of both soft tissues and bone stock.


Directional Kernel Density Estimation for Classification of Breast Tissue Spectra.
In Breast Conserving Therapy, surgeons measure the thickness of healthy tissue surrounding an excised tumor (surgical margin) via post-operative histological or visual assessment tests that, for lack of enough standardization and reliability, have recurrence rates in the order of 33%. Spectroscopic interrogation of these margins is possible during surgery, but algorithms are needed for parametric or dimension reduction processing. One methodology for tumor discrimination based on dimensionality reduction and nonparametric estimation-in particular, Directional Kernel Density Estimation-is proposed and tested on spectral image data from breast samples. Once a hyperspectral image of the tumor has been captured, a surgeon assists by establishing Regions of Interest where tissues are qualitatively differentiable. After proper normalization, Directional KDE is used to estimate the likelihood of every pixel in the image belonging to each specified tissue class. This information is enough to yield, in almost real time and with 98% accuracy, results that coincide with those provided by histological H&E validation performed after the surgery.


The distributions of Chinese yak breeds in response to climate change over the past 50 years.
The effects of prior climate change on yak breed distributions are uncertain. Here, we measured changes in the distributions of 12 yak breeds over the past 50 years in China and examined whether the changes could be attributed to climate change. Long-term records of yak breed distribution, grey relational analysis, fuzzy sets classification techniques and attribution methods were used. Over the past 50 years, the distributions of several yak breeds have changed in multiple directions, mainly shifting northward or westward, and most of these changes are related to the thermal index. Driven by climate change over the past years, the suitable range and the distribution centers of certain yak breeds have changed with fluctuation and have mainly shifted northward, eastward or southward. The consistency of observed versus predicted changes in distribution boundaries or distribution centers is higher for certain yak breeds. Changes in the eastern distribution boundary of two yak breeds over the past 50 years can be attributed to climate change.


Assessing the impact of choline chloride and benzyltrimethylammonium chloride-based deep eutectic solvents on the structure and conformational dynamics of bovine serum albumin: a combined steady-state, time-resolved fluorescence and fluorescence correlation spectroscopic study.
Although deep eutectic solvents (DESs) are regarded as useful substitutes for both ionic liquids and common organic solvents for storage and applications of biomolecules, it is still unclear whether all DESs or only specific types of DESs will be suitable for the said purpose. In view of this, the current study aims to report on the structure and conformational dynamics of BSA in the presence of two DESs, namely ethaline (choline chloride:ethylene glycol) and BMEG (benzyltrimethyl ammonium chloride:ethylene glycol), having the same hydrogen bond donor but with a distinct hydrogen bond acceptor, so that how small changes in one constituent of a DES alter the protein-DES interaction at the molecular level can be understood. The protein-DES interaction is investigated by exploiting both ensemble-averaged measurements like steady-state and time-resolved fluorescence spectroscopy, circular dichroism (CD) spectroscopy, and single-molecule sensitive techniques based on fluorescence correlation spectroscopy (FCS). Interestingly, the results obtained from these studies have demonstrated that while a very small quantity of BMEG completely unfolds the native structure of the protein, it remains in a partially unfolded state even at very high ethaline content. More interestingly, it has been found that at very high concentrations of BMEG, the unfolded protein undergoes enhanced protein-protein interaction resulting in the aggregation of BSA. All of the results obtained from these investigations have essentially suggested that both protein-DES interaction and interspecies interaction among the constituent of DESs play a crucial role in governing the overall stability and conformational dynamics of the protein in DESs.


Increased apoptosis in infiltrating mononuclear cells of colorectal cancer: a mechanism for tumor escape.
Disturbance in apoptosis has been proposed as one of the mechanisms involved in the immune response targeting tumor outgrowth. How colorectal cancer cells escape from attack by the immune system is not yet fully understood. To investigate apoptotic molecules associated with colorectal cancer counterattack. Tissue samples of colon from 12 patients with colorectal cancer were collected and analyzed by immunostaining. In addition to tumorous tissues, corresponding nontumorous specimens of colon were obtained as controls. We examined the expression of Bcl-2, Bcl-xl, Bax, caspase-3, and inducible nitric oxide synthase in infiltrating mononuclear cells of colorectal cancer tissues and also in colorectal cancer tissues. The TUNEL assay was used to detect in situ apoptosis. Apoptosis was barely detectable in specimens of colorectal cancer, which was consistent with an increase in Bcl-2 level and a decrease in caspase-3 level. In contrast, infiltrating mononuclear cells of tumorous tissues showed a marked increase in apoptosis compared with those of nontumorous tissues. The increased apoptosis might have resulted from an imbalance of antiapoptotic and proapoptotic molecules, as reflected by reduction of Bcl-2 level and elevation of Bax level. The elevated caspase-3 levels found in this study could be a downstream effector of the Bcl-2 and Bax apoptotic pathways. A significant increase in inducible nitric oxide synthase observed in the infiltrating mononuclear cells might contribute to immunosuppression seen in colorectal cancer. It is tempting to speculate that aberrant expression of apoptotic molecules and inducible nitric oxide synthase in infiltrating mononuclear cells provides the underlying mechanism through which colorectal cancer cells escape attack by the immune system and subsequently grow without control.


A new pencillin with anti-klebsiella activity: 3-(5-tetrazolyl) penam.
The in vitro activity of a new semi-synthetic penicillin, CP-35,587, 3-(5-tetrazolyl) penam, was investigated against 496 clinical isolates of gram-negative bacilli and 113 clinical isolates of gram-positive cocci. All of the gram-positive cocci were sensitive to CP-35,587 except penicillin G resistant isolates of Staphylococcus aureus. This antibiotic inhibited a majority of isolates of Escherichia coli, Klebsiella spp. and Proteus mirabilis at a concentration of 6.25 microgram/ml. Also, approximately half of the isolates of Serratia marcescens and Enterobacter spp. were inhibited at a concentration of 12.5 microgram/ml. CP-35,587 was inactive when high concentrations of organisms were used as inocula. CP-35,587 was more active than mezlocillin, azlocillin, amoxicillin, ticarcillin and carbenicillin against isolates of K. pneumoniae, but other penicillins were more acte than CP-35,587 against other species of gram-negative bacilli.


Trade-Offs in Improving Biofuel Tolerance Using Combinations of Efflux Pumps.
Microbes can be engineered to produce next-generation biofuels; however, the accumulation of toxic biofuels can limit yields. Previous studies have shown that efflux pumps can increase biofuel tolerance and improve production. Here, we asked whether expressing multiple pumps in combination could further increase biofuel tolerance. Pump overexpression inhibits cell growth, suggesting a trade-off between biofuel and pump toxicity. With multiple pumps, it is unclear how the fitness landscape is impacted. To address this, we measured tolerance of Escherichia coli to the biojet fuel precursor α-pinene in one-pump and two-pump strains. To support our experiments, we developed a mathematical model describing toxicity due to biofuel and overexpression of pumps. We found that data from one-pump strains can accurately predict the performance of two-pump strains. This result suggests that it may be possible to dramatically reduce the number of experiments required for characterizing the effects of combined biofuel tolerance mechanisms.


Hydration to Maximize Performance and Recovery: Knowledge, Attitudes, and Behaviors Among Collegiate Track and Field Throwers.
Hydration plays an important role in performance, injury prevention, and recovery for athletes engaged in competitive sports. Therefore, it is important that strength and conditioning coaches understand an athlete's hydration needs to prevent illness and enhance performance. The purpose of this study was to identify hydration knowledge, attitudes, and behaviors of collegiate track and field throwers, as well as identify barriers to hydration and sources of nutritional information. The Rehydration and Refueling in Collegiate Track and Field Throwers Survey was sent to 271 track and field thrower coaches with a request to forward the email to current track and field throwers. Pearson correlation coefficients were calculated regarding knowledge, attitude, and behavior scores among the participants in this sample. Differences among response patterns were assessed via Chi-square analysis. Alpha level was set at p = .05. Results demonstrated that 97.3% (n = 287) of respondents knew that dehydration would decrease performance, but 50.5% (n = 149) erroneously believed thirst was the best indicator of dehydration. Chi-square analysis demonstrated a significant difference in reported values between participants who intended to eat a performance-enhancing diet and those who consumed less fluid than recomended values (207 - 295 m)l in the 2-3 hours prior to competition (χ2 = 10.87, p < .05). Pearson correlation coefficients demonstrated a large association between knowledge and behavior (r = .70, p < .05), a medium association between knowledge and attitude (r = .41, p < .05), and a small association between attitude and behavior (r = .21, p < .05). This suggests that strength and conditioning coaches and health staff need to educate and monitor hydration behaviors among collegiate track and field throwers to optimize performance.


The beta-receptor blocker metoprolol alters detoxification processes in the non-target organism Dreissena polymorpha.
Due to increasing amounts of pharmaceutically active compounds (PhACs) in the aquatic environment, their largely unknown effects to non-target organisms need to be assessed. This study examined physiological changes in the freshwater mussel Dreissena polymorpha exposed to increasing concentrations (0.534, 5.34, 53.4 and 534 microg L(-1)) of the beta-blocker metoprolol in a flow-through system for seven days. The two lower concentrations represent the environmentally relevant range. Surprisingly, metallothionein mRNA was immediately up-regulated in all treatments. For the two higher concentrations mRNA up-regulation in gills was found for P-glycoprotein after one day, and after four days for pi class glutathione S-transferase, demonstrating elimination and biotransformation processes, respectively. Additionally, catalase and superoxide dismutase were up-regulated in the digestive gland indicating oxidative stress. In all treated mussels a significant up-regulation of heat shock protein mRNA was observed in gills after four days, which suggests protein damage and the requirement for repair processes. Metoprolol was 20-fold bioaccumulated for environmentally relevant concentrations.


Iatrogenic Cushing's syndrome due to topical steroid abuse in a child with Psoriasis presenting as septicaemia.
Psoriasis vulgaris is a chronic inflammatory disorder that affects the skin and joints. Mild disease is treated with topical corticosteroids (CS) which forms the first line of treatment for localized disease. While it is well established that prolonged use of oral or parenteral corticosteroids can lead to iatrogenic Cushing's syndrome and suppression of hypothalamic pituitary axis; development of these complications secondary to use of topical CS is rarely described. Since steroids have anti-inflammatory properties, their prolonged use can lead to increased susceptibility to develop bacterial and fungal infections. We hereby report a 11-year-old female with psoriasis who presented with septicaemia and features of iatrogenic Cushing's syndrome due to treatment with topical corticosteroids for 2 years. Presentation of ICS as septicemia due to topical steroid use in this age group or in a psoriatic patient has not been described in the literature so far. Patient also developed hypertension and osteopenia, which are known adverse effects of corticosteroids; but occur rarely due to topical corticosteroids.


Disturbed bovine mitochondrial lipid metabolism: a review.
In mammals, excess energy is stored primarily as triglycerides, which are mobilized when energy demands arise and cannot be covered by feed intake. This review mainly focuses on the role of long chain fatty acids in disturbed energy metabolism of the bovine species. Long chain fatty acids regulate energy metabolism as ligands of peroxisome proliferator-activated receptors. Carnitine acts as a carrier of fatty acyl groups as long-chain acyl-CoA derivatives do not penetrate the mitochondrial inner membrane. There are two different types of disorders in lipid metabolism which can occur in cattle, namely the hypoglycaemic-hypoinsulinaemic and the hyperglycaemic-hyperinsulinaemic type with the latter not always associated with ketosis. There is general agreement that fatty acid β-oxidation capability is limited in the liver of (ketotic) cows. In accord, supplemental L-carnitine decreased liver lipid accumulation in periparturient Holstein cows. Of note, around parturition concurrent oxidation of fatty acids in skeletal muscle is highly activated. Also peroxisomal β-oxidation in liver of dairy cows may be part of the hepatic adaptations to a negative energy balance (NEB) to break down fatty acids. An elevated blood concentration of nonesterified fatty acids is one of the indicators of NEB in cattle among others like increased β-hydroxy butyrate concentration, and decreased concentrations of glucose, insulin, and insulin-like growth factor-I. Assuming that liver carnitine concentrations might limit hepatic fatty acid oxidation capacity in dairy cows, further study of the role of acyl-CoA dehydrogenases and/or riboflavin in bovine ketosis is warranted.


Isolation and identification of Mycobacterium kansasii from pleural fluid of a dog with persistent pleural effusion.
A 3-year-old spayed female Whippet was examined for cough and respiratory distress. Lung lobe torsion with pleural effusion was diagnosed, and lung lobectomy was performed. Pleural effusion recurred during the following 27 months; conventional bacteriologic cultures of pleural effusion did not result in bacterial growth. A second lung lobectomy, pleuroperitoneal shunt placement. and pericardectomy were subsequently performed. Mycobacterium kansasii was eventually isolated from pleural fluid and identified by polymerase chain reaction amplification and DNA sequencing. The dog was euthanatized before therapeutic response could be evaluated. To our knowledge, this is the first report of M. kansasii infection in a dog. Additionally, this is the first report of mycobacterial isolation from pleural fluid, and one of few reports of antemortem mycobacterial isolation from a body fluid, as opposed to identification in specimens during histologic examination. Routine bacteriologic culture methods are insufficient to isolate mycobacterial agents, and special methods are indicated in dogs with persistent pleural effusion.


Proposed Methods for Real-Time Measurement of Posterior Condylar Angle during TKA.
Conventional instruments are known to result in high numbers of outliers in restoring femoral component rotation primarily due to fixed degree of external rotation resection relative to the posterior condylar line (PCL). Outliers can be reduced by determining the patient specific posterior condylar angle (PCA) preoperatively or intraoperatively. There is a paucity of methods that can be used during surgery for determining the PCA. We propose two simple, real-time methods to determine the PCA and hence to measure the axial anatomical variation during surgery. The study was conducted using axial computed tomography (CT) scans of the knees of 26 patients. The commercial software K-PACS and our proposed two methods (trigonometric and protractor) were used to measure the angle between the transepicondylar axis and PCL, i.e., PCA. Statistical comparison between the mean angles obtained by K-PACS and our methods were done. The three methods resulted in similar PCAs. The mean PCA measured by the three methods were similar. The mean PCA value measured by the K-PACS, trigonometric method and protractor method was 6.27° (range, 0° to 12°), 6.23° (range, 0° to 11.11°) and 6.31° (range, 0° to 12°), respectively. There were significant correlations between the K-PACS measured PCA and trigonometrically or protractor measured PCA. Our novel, simple, easily reproducible, real-time and radiation-free PCA measurement methods obviate the need for preoperative CT scan for identification of patient specific PCA.


Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers.
A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, PFDR<0.05, kE=2198, x=-30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, PFDR<0.05, kE=6094, x=-28, y=-36, z=-2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.


Particle size and magnetic field-induced optical properties of magnetic fluid nanoparticles.
Magnetite nanoparticles with diameters of 7, 9, and 12 nm have been prepared by a chemical coprecipitation method. The transmission of light through magnetic fluid containing these nanoparticles has been investigated as a function of film thickness with wavelength between 400 and 750 nm, and applied magnetic fields up to 275 Oe. The transmission threshold shifts to the lower wavelength side with decreasing magnetic fluid film thickness as well as the particle size. For a given film thickness, the transmittance increases with increasing magnetic field for films with a particle size of 7 and 9 nm, but decreases in the 12-nm film. This is attributed to the competition between the van der Waals and dipole-dipole interaction.


Porous Material (Titanium Gas Diffusion Layer) in Proton Exchange Membrane Fuel Cell/Electrolyzer: Fabrication Methods & GeoDict: A Critical Review.
Proton exchange membrane fuel cell (PEMFC) is a renewable energy source rapidly approaching commercial viability. The performance is significantly affected by the transfer of fluid, charges, and heat; gas diffusion layer (GDL) is primarily concerned with the consistent transfer of these components, which are heavily influenced by the material and design. High-efficiency GDL must have excellent thermal conductivity, electrical conductivity, permeability, corrosion resistance, and high mechanical characteristics. The first step in creating a high-performance GDL is selecting the appropriate material. Therefore, titanium is a suitable substitute for steel or carbon due to its high strength-to-weight and superior corrosion resistance. The second crucial parameter is the fabrication method that governs all the properties. This review seeks to comprehend numerous fabrication methods such as tape casting, 3D printing, freeze casting, phase separation technique, and lithography, along with the porosity controller in each process such as partial sintering, input design, ice structure, pore agent, etching time, and mask width. Moreover, other GDL properties are being studied, including microstructure and morphology. In the future, GeoDict simulation is highly recommended for optimizing various GDL properties, as it is frequently used for other porous materials. The approach can save time and energy compared to intensive experimental work.


Leukocytes of humans exposed to lysergic acid diethylamide: lack of chromosomal damage.
Leukocyte cultures from eight human subjects who had had recent exposure to large doses of lysergic acid diethylamide were examined for chromosome abnormalities. The number of abnormalities was not significantly greater than that in control cultures.


[Development of a hybrid bio-artificial liver].
Despite recent advances in medical management, fulminant hepatic failure (FHF) is still associated with high mortality. Liver transplantation is currently the only effective therapy for patients with FHF in many countries, but not yet in Japan. Thus, it is needed to introduce a bioartificial liver (BAL) support system using hepatocytes that substitutes for insufficient metabolism until the liver can recover. To function as a surrogate liver, BAL must meet two metabolic criteria: the first criterion requires highly differentiated liver cells; the second requires a mass sufficient to support the needs of the patients. Cell-extracellular matrix interaction is biologically relevant to regulating gene expression and maintaining cell differentiation of hepatocyte through activating liver-enriched transcriptional factors, including hepatocyte nuclear factor-1 (HNF-1) and HNF-4. With the advance of biotechnology, clinical trials of BAL using porcine primary hepatocytes or human hepatoblastoma cell lines have been successfully performed in the United States. In the near future, a hybrid liver support system is expected to be widely used for treating patients with FHF.


Location of motor pools innervating chick wing.
Intramuscular injections of HRP were used to map the spinal cord location of motoneurons innervating wing and shoulder girdle muscles in newly hatched chicks. Motor pools are grouped in the lateral motor column in relationship to embryonic origin of the muscles: muscles derived from the ventral muscle mass are innervated by medially lying motor pools, while muscles derived from the dorsal mass are innervated by lateral pools. Motor pool position is also well correlated with nerve supply. Muscles innervated by nerves diverging from common nerve trunks are innervated by neighboring motor pools. The rostro-caudal organization of the motor pools reflects both proximo-distal and antero-posterior axes of the limb with proximal and anterior muscles innervated from rostral motor pools.


Regional variations and time trends of hantavirus pulmonary syndrome in Brazil.
Hantavirus pulmonary syndrome (HPS) is a zoonosis and a public health concern in the Americas due to its high fatality rate. Since the first cases were identified in USA in 1993, HPS has been observed over a wide area of the American continents. Over 1600 HPS cases have been confirmed in Brazil since 1993, and different genotypes of hantavirus have been identified in several biomes in this country of continental dimensions. We performed a retrospective study of data from 2001 to 2011 that encompassed all notified cases of HPS in the National Disease Notification System (SINAN) of Brazil to determine the regional differences and temporal trends of the disease. During the study period, 1486 cases were reported, and analyses of the temporal trends of the disease revealed that the number of cases in Brazil increased over this period (P < 0·01). The frequency distributions of the cases stratified by region revealed different patterns of seasonality; however, these patterns were not statistically significant with the exception of the South region (P < 0·05). We found regional differences in the occurrence of the disease throughout the year and a trend towards an increasing number of cases. These findings reinforce the necessity of adjusting surveillance tools and control policies to respond effectively to this public health problem.


Impact of implementing a vancomycin protocol to reduce kidney toxicity: A comparative study.
Introduction: Vancomycin is a frequently used antibiotic for treating severe infections caused by multidrug-resistant, Gram-positive pathogens. To ensure its effectiveness and minimize the risk of nephrotoxicity, safe administration and dose monitoring are crucial. Understanding the impact of vancomycin serum levels on clinical outcomes is of paramount importance, necessitating improved knowledge on its use, dose monitoring, nephrotoxicity, and safe administration. Objective: This study aimed to evaluate the incidence of acute kidney injury (AKI) in patients receiving vancomycin before and after the implementation of an institutional protocol for vancomycin administration in a public tertiary hospital in southern Brazil. Materials and methods: A cross-sectional study design was employed, analyzing data from the electronic medical records of 422 patients who received vancomycin. The patient population was divided into two independent cohorts: those treated in 2016 (pre-protocol) and those treated in 2018 (post-protocol), following the implementation of the institutional vancomycin administration protocol. Results: The study included 211 patients in each year of assessment. Patients from both cohorts had a Charlson Comorbidity Index (CCI) score of 4. The post-protocol cohort consisted of older individuals, with a mean age of 62.8 years. In addition, patients in the post-protocol year had higher baseline creatinine levels, higher rates of intensive care unit (ICU) hospitalization, and increased use of vasopressors. In the pre-protocol year, patients received vancomycin therapy for a longer duration. When comparing the incidence of AKI between the two groups, an intervention study revealed rates of 38.4% in group 1 and 20.9% in group 2, indicating a significant reduction (p < 0.001) in the post-protocol group. A logistic regression model was developed to predict AKI, incorporating variables that demonstrated significance (p ≤ 0.250) in bivariate analysis and those recognized in the literature as important factors for AKI, such as the duration of therapy, vancomycin serum level, and ICU hospitalization. The logistic regression classification performance was assessed using a receiver operating characteristic (ROC) curve, yielding an area under the curve of 0.764, signifying acceptable discrimination of the regression model. Conclusion: Implementation of the institutional protocol for vancomycin administration resulted in a significant and cost-effective impact, ensuring appropriate therapeutic dosing, reducing adverse events (e.g., nephrotoxicity), and improving clinical outcomes for patients in the study population.


Phenotypic concordance in familial inflammatory bowel disease (IBD). Results of a nationwide IBD Spanish database.
Disease outcome has been found to be poorer in familial inflammatory bowel disease (IBD) than in sporadic forms, but assessment of phenotypic concordance in familial IBD provided controversial results. We assessed the concordance for disease type and phenotypic features in IBD families. Patients with familial IBD were identified from the IBD Spanish database ENEIDA. Families in whom at least two members were in the database were selected for concordance analysis (κ index). Concordance for type of IBD [Crohn's disease (CD) vs. ulcerative colitis (UC)], as well as for disease extent, localization and behaviour, perianal disease, extraintestinal manifestations, and indicators of severe disease (i.e., need for immunosuppressors, biological agents, and surgery) for those pairs concordant for IBD type, were analyzed. 798 out of 11,905 IBD patients (7%) in ENEIDA had familial history of IBD. Complete data of 107 families (231 patients and 144 consanguineous pairs) were available for concordance analyses. The youngest members of the pairs were diagnosed with IBD at a significantly younger age (p<0.001) than the oldest ones. Seventy-six percent of pairs matched up for the IBD type (κ=0.58; 95%CI: 0.42-0.73, moderate concordance). There was no relevant concordance for any of the phenotypic items assessed in both diseases. Familial IBD is associated with diagnostic anticipation in younger individuals. Familial history does not allow predicting any phenotypic feature other than IBD type.


Understanding the diagnosis of pre-diabetes in patients aged over 85 in English primary care: a qualitative study.
The benefit of a "diagnosis" of pre-diabetes in very elderly patients is debated. How clinicians manage pre-diabetic blood results in these patients is unknown. This study aims to understand how clinicians are "diagnosing" older patients with pre-diabetic blood parameters. Semi-structured interviews and focus groups with health care staff (24 total participants) were conducted in the north of England. Interviews and focus groups were recorded, transcribed and analysed thematically. A grounded theory approach was taken with the theory of candidacy being used as a sensitising concept through which questions were framed and results interpreted. There is a complex system of competing pressures that influence a clinician in deciding whether, and in what way, to inform a very elderly patient that they have pre-diabetes. The majority of clinicians adjust their management of pre-diabetes to the age and perceived risk/benefit for the patient. Whilst some clinicians choose not to inform certain patients of their blood results, many clinicians maintain, what could be seen as a somewhat paradoxical approach of labeling all older patients with pre-diabetes but downplaying the significance to the patient. The policy, organisational context, workload and professional constraints under which clinicians work, play a significant role in shaping how they deal with pre-diabetic blood results in the very elderly. There has been recent acknowledgement of how policy and organisational context frames decision-making, but there is a lack of evidence on how this influences uncertainty and dilemmas in decision-making in practice. These findings add further weight for the argument that treatment burden should be included in clinical guidelines.


The isolation and characterization of Stenotrophomonas maltophilia T4-like bacteriophage DLP6.
Increasing isolation of the extremely antibiotic resistant bacterium Stenotrophomonas maltophilia has caused alarm worldwide due to the limited treatment options available. A potential treatment option for fighting this bacterium is 'phage therapy', the clinical application of bacteriophages to selectively kill bacteria. Bacteriophage DLP6 (vB_SmoM-DLP6) was isolated from a soil sample using clinical isolate S. maltophilia strain D1571 as host. Host range analysis of phage DLP6 against 27 clinical S. maltophilia isolates shows successful infection and lysis in 13 of the 27 isolates tested. Transmission electron microscopy of DLP6 indicates that it is a member of the Myoviridae family. Complete genome sequencing and analysis of DLP6 reveals its richly recombined evolutionary history, featuring a core of both T4-like and cyanophage genes, which suggests that it is a member of the T4-superfamily. Unlike other T4-superfamily phages however, DLP6 features a transposase and ends with 229 bp direct terminal repeats. The isolation of this bacteriophage is an exciting discovery due to the divergent nature of DLP6 in relation to the T4-superfamily of phages.


Runx transcription factors repress human and murine c-Myc expression in a DNA-binding and C-terminally dependent manner.
The transcription factors Runx1 and c-Myc have individually been shown to regulate important gene targets as well as to collaborate in oncogenesis. However, it is unknown whether there is a regulatory relationship between the two genes. In this study, we investigated the transcriptional regulation of endogenous c-Myc by Runx1 in the human T cell line Jurkat and murine primary hematopoietic cells. Endogenous Runx1 binds to multiple sites in the c-Myc locus upstream of the c-Myc transcriptional start site. Cells transduced with a C-terminally truncated Runx1 (Runx1.d190), which lacks important cofactor interaction sites and can block C-terminal-dependent functions of all Runx transcription factors, showed increased transcription of c-Myc. In order to monitor c-Myc expression in response to early and transiently-acting Runx1.d190, we generated a cell membrane-permeable TAT-Runx1.d190 fusion protein. Murine splenocytes treated with TAT-Runx1.d190 showed an increase in the transcription of c-Myc within 2 hours, peaking at 4 hours post-treatment and declining thereafter. This effect is dependent on the ability of Runx1.d190 to bind to DNA. The increase in c-Myc transcripts is correlated with increased c-Myc protein levels. Collectively, these data show that Runx1 directly regulates c-Myc transcription in a C-terminal- and DNA-binding-dependent manner.


Effectiveness of lifestyle-based weight loss interventions for adults with type 2 diabetes: a systematic review and meta-analysis.
To provide a systematic review and meta-analysis of recent evidence on the effectiveness of lifestyle-based weight loss interventions for adults with type 2 diabetes. A search of the literature from January 2003 to July 2013 was conducted (PubMed, Embase, CINAHL and Web of Science). The studies considered eligible were randomized controlled trials evaluating weight loss interventions (diet and physical activity, with or without behavioural strategies) of ≥12 weeks duration, compared with usual care or another comparison intervention. Ten studies were included for review. Some heterogeneity was present in the sample, therefore, random-effects models were used to calculate pooled effects. Intervention duration ranged from 16 weeks to 9 years, with all but one delivered via individual or group face-to-face sessions. From six studies comparing lifestyle intervention with usual care the pooled effect on weight (n = 5795) was -3.33 kg [95% confidence interval (CI) -5.06, -1.60 kg], and on glycated haemoglobin (HbA1c; n = 5784) was -0.29% (95% CI -0.61, 0.03%), with both attenuated in sensitivity analyses. The pooled within-group effect on weight (n = 3063) from all 10 lifestyle intervention groups was -5.33 kg (95% CI -7.33, -3.34 kg), also attenuated in sensitivity analyses. None of the participant or intervention characteristics examined explained the heterogeneity. Only one study assessed whether intervention effects were maintained after the end of the intervention. Lifestyle-based weight loss intervention trials in type 2 diabetes achieve, on average, modest reductions in weight and HbA1c levels, but results were heavily influenced by one trial. Evidence-based approaches for improving the effectiveness of lifestyle-based interventions in type 2 diabetes are needed, along with future studies reporting on maintenance and cost-effectiveness.


[Retention of a complete denture by the enclave method. Convergent enclaves].
The authors propose a technical variant of the method of enclaves for the retention of the full denture, this in the inferior maxilla because it is there that the problem of retention is posed with the greatest acuity and frequency. But whereas in the processes described the enclaves, 2 in number, corresponding with the zone of implantation of the canines, are perpendicular to the mandible in the frontal and sagittal planes, in the technique explained here each of the enclaves makes with the mandible, in the frontal plane, an angle of 10 degrees with respect to the median axis, thus leading to a convergence and hence an increased retention of the prosthesis with which they are connected.


Tubulation with dental pulp cells promotes facial nerve regeneration in rats.
Dental pulp is an easily obtainable source of viable cells for potential use in peripheral nerve regeneration. We prepared artificial conditions for nerve regeneration using a silicone tube containing a collagen gel embedded with rat dental pulp cells, and we examined its effectiveness for repairing a gap in the rat facial nerve. Twelve days after transplantation, defective facial nerves connected with silicone tubes containing dental pulp cells were repaired more rapidly than control tubes containing the collagen gel alone. When a tube containing green fluorescent protein (GFP)-positive dental pulp cells was transplanted into a facial nerve gap in a GFP-negative rat, we observed regenerated nerves with GFP-positive cells at 2 weeks posttransplantation. The regenerated nerves included Tuj1-positive axons, RECA1 and GFP double-positive blood vessels, and S100 and GFP double-positive Schwann-like supportive cells. Osmium-toluidine blue staining revealed that the regenerated nerves contained myelinated fibers. Moreover, fluorescent retrograde tracing analysis by application of Fluoro-Gold into the regenerated nerves demonstrated the presence of Fluoro-Gold-positive motor neurons in the facial nucleus of the rat brain. These results suggest that the transplanted dental pulp cells formed blood vessels and myelinating tissue and contributed to the promotion of normal nerve regeneration.


Selective inactivation of parvulin-like peptidyl-prolyl cis/trans isomerases by juglone.
In contrast to FK506 binding proteins and cyclophilins, the parvulin family of peptidyl-prolyl cis/trans isomerases (PPIases; E.C. 220.127.116.11) cannot be inhibited by either FK506 or cyclosporin A. We have found that juglone, 5-hydroxy-1,4-naphthoquinone, irreversibly inhibits the enzymatic activity of several parvulins, like the E. coli parvulin, the yeast Ess1/Ptf1, and human Pin1, in a specific manner, thus allowing selective inactivation of these enzymes in the presence of other PPIases. The mode of action was studied by analyzing the inactivation kinetics and the nature of products of the reaction of E. coli parvulin and its Cys69Ala variant with juglone. For all parvulins investigated, complete inactivation was obtained by a slow process that is characterized by pseudo-first-order rate constants in the range of 5.3 x 10(-)4 to 4. 5 x 10(-)3 s-1. The inactivated parvulin contains two juglone molecules that are covalently bound to the side chains of Cys41 and Cys69 because of a Michael addition of the thiol groups to juglone. Redox reactions did not contribute to the inactivation process. Because thiol group modification was shown to proceed 5-fold faster than the rate of enzyme inactivation, it was considered as a necessary but not sufficient condition for inactivation. When measured by far-UV circular dichroism (CD), the rate of structural alterations following thiol group modification parallels exactly the rate of inactivation. Thus, partial unfolding of the active site of the parvulins was thought to be the cause of the deterioration of PPIase activity.


Hepatitis B viral markers in patients with primary hepatocellular carcinoma in Taiwan.
The presence of hepatitis B viral markers in patients with primary hepatocellular carcinoma (PHC) was studied retrospectively at the Taiwan Veterans General Hospital in Taipei, Taiwan. Serum samples from 102 PHC patients and from 100 control individuals were tested for hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), antibody to hepatitis B core antigen (anti-HBc), hepatitis Be antigen (HBeAg), and antibody to HBeAg (anti-HBe). Of the 102 PHC patients, 72 (71%) were positive for HBsAg. Nine (9%) additional patients were positive for anti-HBc alone in high titer, 19 (19%) had both anti-HBc and anti-HBs, and 9 (9%) had HBsAg, anti-HBc, and anti-HBs. In the 100 controls, 12 (12%) were HBsAg-positive, whereas 22 (22%) had anti-HBc alone and 50 (50%) had both anti-HBc and anti-HBs. Only 4 (4%) controls and no PHC patients had anti-HBs alone. Of the HBsAg-positive patients with PHC, 17 (29%) had HBeAg and 36 (61%) had anti-HBe. The alpha-fetoprotein (AFP) levels above 400 ng/ml were found in 44% of the PHC patients. Values of AFP above 1 x 10(5) ng/ml were more frequently detected in PHC patients who were HBsAg-positive. Categorization of the geographic origins of the families whose members had PHC revealed that most families had originated from southern China. This study confirms that hepatitis B viral markers are frequently present in Chinese patients with PHC.


Inoculation with the plant-growth-promoting rhizobacterium Azospirillum brasilense causes little disturbance in the rhizosphere and rhizoplane of maize (Zea mays).
Inoculation with Azospirillum brasilense exerts beneficial effects on plant growth and crop yields. In this study, a comparative analysis of maize (Zea mays) root inoculated or not inoculated with A. brasilense strains was performed in two soils. Colonization dynamics of the rhizobacteria were tracked in various root compartments using 16S rRNA-targeted probes and 4',6'diamidino-2-phenylindole staining, and the structure of bacterial populations in the same samples was analyzed by denaturing gradient gel electrophoresis (DGGE) of polymerase chain reaction products of the 16S rRNA gene. Based on whole cell hybridization, a large fraction of the bacterial community was found to be active in both the rhizoplane-endorhizosphere and rhizosphere soil compartments, in both soil types. A DGGE fingerprint analysis revealed that plant inoculation with A. brasilense had no effect on the structural composition of the bacterial communities, which were also found to be very similar at the root tip and at zones of root branching. However, rhizobacterial populations were strongly influenced by plant age, and their complexity decreased in the rhizoplane-endorhizosphere in comparison to rhizosphere soil. A clone library generated from rhizosphere DNA revealed a highly diverse community of soil and rhizosphere bacteria, including an indigenous Azospirillum-like organism. A large proportion of these clones was only distantly related to known species.


Parkinsonian syndrome and ataxia as a presenting finding of acquired hepatocerebral degeneration.
The term "acquired hepatocerebral degeneration" (AHD) was coined to describe clinical entity distinct from genetically defined Wilson's disease. AHD is chronic neurological disorder, characterized by extrapyramidal and neuropsychiatric symptoms accompanied with advanced liver disease with portosystemic shunts. In majority of AHD cases, extrapyramidal symptoms appear in the presence of known liver disease. Here we present a patient with subacute onset of bilateral, asymmetric, hypokinetic-rigid syndrome and ataxia as initial presentation of liver cirrhosis. Manganese toxicity have major role in AHD pathogenesis. Failure of liver detoxification and presence of portosystemic shunting enables neurotoxic substance of manganese to avoid hepatic metabolism and to enter and accumulate in central nervous system. Predilection brain regions for manganese deposits are globus pallidum (GP) and substantia nigra (SN). Characteristic MRI findings of bilateral, symmetrical hyperintensities of GP and SN on T1-weighted sequences supported the diagnosis of AHD in our patient. In addition, increased T2 signal in dendate nuclei seen in our patient is rare radiological finding. So far, no consensus guidelines regarding medical treatment of AHD exist. We initiated low-dose levodopa treatment, but failed to provide beneficial effect. In conclusion, AHD is distinct clinical entity that should be included in differential diagnosis of both typical and atypical parkinsonian syndromes. Furthermore, our case highlights the importance of performing MRI in patients with atypical parkinsonism.


Topical cyproterone acetate treatment in women with acne: a placebo-controlled trial.
To evaluate the clinical and hormonal response of topically applied cyproterone acetate, oral cyproterone acetate, and placebo lotion in women with acne. Placebo-controlled, randomized study. Patients were recruited from the Institute of Endocrine Cosmetics, Vienna, Austria. Forty women with acne. Treatment with oral medication consisting of 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate (n=12), 20 mg of topical cyproterone acetate lotion (n=12), and placebo lotion (n=16) was offered. Patients were assessed monthly for 3 months. Clinical grading according to acne severity and lesion counts as well as determinations of serum cyproterone acetate concentrations. After 3 months of therapy with topical cyproterone acetate, the decrease of mean facial acne grade from 1.57 to 0.67 was significantly better (P<.05) compared with placebo (which showed a change from 1.57 to 1.25), but not compared with oral medication (1.56 to 0.75) (P>.05). Lesion counts also decreased from 35.9 to 9.1 in the topical cyproterone acetate group compared with oral medication (45.4 to 15.5) (P>.05) and placebo (38.2 to 23.1) (P<.05). After topical cyproterone acetate treatment, serum cyproterone acetate concentrations were 10 times lower than those found after oral cyproterone acetate intake. The therapeutic effect of topically applied cyproterone acetate for acne treatment was clearly demonstrated. Topically applied sexual steroids in combination with liposomes are as effective as oral antiandrogen medication in acne treatment, while reducing the risk of adverse effects and avoiding high serum cyproterone acetate concentrations.


Identification and characterization of capsule depolymerase Dpo48 from Acinetobacter baumannii phage IME200.
The emergence of multidrug- or extensively drug-resistant Acinetobacter baumannii has made it difficult to treat and control infections caused by this bacterium. It is urgently necessary to search for alternatives to conventional antibiotics for control of severe A. baumannii infections. In recent years, bacteriophages and their derivatives, such as depolymerases, showed great potential as antibacterial or antivirulence agents against bacterial infections. Nonetheless, unlike broad-spectrum bactericidal antibiotics, phage-encoded depolymerase targets only a limited number of bacterial strains. Therefore, identification of novel depolymerases and evaluation of their ability to control A. baumannii infections is important. A bacteriophage was isolated from hospital sewage using an extensively drug-resistant A. baumannii strain as the host bacterium, and the phage's plaque morphology and genomic composition were studied. A polysaccharide depolymerase (Dpo48) was expressed and identified, and the effects of pH and temperature on its activity were determined. Besides, a serum killing assay was conducted, and amino acid sequences homologous to those of putative polysaccharide depolymerases were compared. Phage IME200 yielded clear plaques surrounded by enlarged halos, with polysaccharide depolymerase activity against the host bacterium. A tail fiber protein with a Pectate_lyase_3 domain was identified as Dpo48 and characterized . Dpo48 was found to degrade the capsule polysaccharide of the bacterial surface, as revealed by Alcian blue staining. Dpo48 manifested stable activity over a broad range of pH (5.0-9.0) and temperatures (20-70 °C). Results from in vitro serum killing assays indicated that 50% serum was sufficient to cause a five log reduction of overnight enzyme-treated bacteria, with serum complement playing an important role in these killing assays. Moreover, Dpo48 had a spectrum of activity exactly the same as its parental phage IME200, which was active against 10 out of 41 A. baumannii strains. Amino acid sequence alignment showed that the putative tail fiber proteins had a relatively short, highly conserved domain in their N-terminal sequences, but their amino acid sequences containing pectate lyase domains, found in the C-terminal regions, were highly diverse. Phage-encoded capsule depolymerases may become promising antivirulence agents for preventing and controlling A. baumannii infections.


Tumor and metastasis suppression by the human RNASET2 gene.
The region 6q27 from human chromosome 6 has been reported to contain one or more tumor suppressor genes on the basis of cytogenetic, molecular and functional studies. We have recently carried out a detailed analysis of a candidate gene from 6q27 to evaluate its putative role as a tumor suppressor gene involved in ovarian cancer pathogenesis. The RNASET2 gene was shown to behave as a class II tumor suppressor and abolish the tumorigenic potential of an ovarian cancer-derived cell line. In this study, we have started the cellular and biochemical characterization of RNASET2 and showed that it is a secreted glycoprotein. Moreover, we have extended our previous studies by evaluating the effect of RNASET2 on the metastatic behavior of the highly-invasive ovarian cancer cell line HEY3MET2. From such analysis, RNASET2 was found to significantly decrease the metastatic potential of this cell line in vivo. Moreover, RNASET2-mediated suppression of tumorigenesis and metastasis was not affected by a double point mutation targeted to the putative ribonuclease catalytic sites, suggesting that tumor suppression by RNASET2 is not mediated by its ribonuclease activity. The potential biological implications of this unexpected finding are discussed in relation to the current evolutionary models.


A novel approach for rapidly measuring volatile fatty acids in anaerobic process.
Volatile fatty acids (VFAs), the intermediate of the anaerobic process, are considered to be the critical, high-sensitive and reliable indicators of the process stability. Close monitoring and control of VFAs are paramount for the efficient operation of the anaerobic reactors. In this study, a buffer intensity-based mathematical model was developed, and the least square method was integrated into the model to solve the issue of non-linear fitting of the titration curve. An automatic analyzer embedded with the developed model was designed and implemented for measuring VFAs and alkalinity. Through model optimization, the pH range of 3.5-5.6 was found to be suitable for VFAs analysis. The developed approach was validated by different VFAs (up to 500 mg/L as acetic acid) and carbonate alkalinity concentrations (up to 1500 mg/L as CaCO3) with high recovery rates (>0.9). Optimal ratios of carbonate alkalinity to VFAs are identified in the range of 2.4-7.5 for accuracy. Owing to the non-linear fitting of the titration curve, the impact of other weak acid subsystems (e.g., phosphate, ammonium and sulfide) can be negligible. The one-year real-time monitoring of environmental samples by using the automatic analyzer indicates a high consistency and stability compared with the 5 pH point titration. This approach proves to be rapid (<3 min/sample), accurate, reliable and can be applied for real-time automatic monitoring of the anaerobic process.


A comparison of skeletal maturity and growth.
Somatic and bone development have each been studied in detail, but rarely in conjunction. The aim of this study was to determine what somatic and bone development have in common and how they differ. A second aim was to check for a pubertal spurt in bone age (BA) and to quantify it in a similar way as has been done for height. The Preece-Baines model is used to fit longitudinal data for BA. The data analysed are from the 1st Zurich Longitudinal Growth Study comprising 120 boys and 112 girls with almost complete data from birth to adulthood. Variability of somatic milestones was reduced in terms of BA and there was an aftergrowth after reaching adult RUS score 1000. A strong increase in the RUS score was seen at a late stage of the pubertal spurt (PS). Somatic milestones correlated with the RUS score attained at these ages and more so at an early stage of the PS. A PS for BA was clearly identified with a location at 14.2 years for boys and 12.2 years for girls. Age of peak bone development correlated highly with age of peak velocity of somatic variables. BA can be successfully modelled as a semi-quantitative entity. Bone development shows marked associations with somatic development, despite the fact that the latter reflects changes in size, while the former is essentially a maturity index and reflects changes in biochemical composition of tissues.


Effect of conjugated linoleic acids, vitamin E and their combination on the clinical outcome of Iranian adults with active rheumatoid arthritis.
Despite beneficial effects of conjugated linoleic acids (CLAs) in animal studies, there is little information on their effects on human inflammatory and autoimmune diseases. To investigate the effects of CLAs as an adjuvant therapy on the clinical manifestations of rheumatoid arthritis (RA) in adults with an active disease. In a randomized, double-blind placebo-controlled trial, 87 patients with active RA were divided into four groups receiving one of the following daily supplements for 3 months: group C: CLAs 2.5 g equivalent to 2 g mixture of cis 9-trans 11 and trans 10-cis12 CLAs at a rate of 50/50; group E: vitamin E: 400 mg; group CE: CLAs and vitamin E at above doses; group P: placebo. Serum alpha-tocopherol was determined by high-performance liquid chromatography. Clinical data was determined by physician examination and filling the questionnaire by interview. Complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-Reactive protein (CRP) and rheumatoid factor (RF) were measured in each patient. DAS28 (diseases activity score) was also determined. A 3-month supplementation resulted significant reduction in DAS28, pain and morning stiffness in the groups C and CE compared with group P (P < 0.05). Compared with the baseline, ESR levels decreased significantly in the groups C (P < or = 0.05), E (P < or = 0.05) and CE (P < or = 0.001). Group CE had significantly lower ESR levels than group P (P v 0.05). CRP dropped non-significantly in all four groups (P > 0.1). The reduction of white blood cell count was significant in group CE compared with other groups (P < 0.05). Decrease in platelet count was non-significant in groups CE, C, and E. Changes in RF, body mass index, red blood cell count and hemoglobin were not significant in four groups, while RF decreased non-significantly in groups CE and E. In comparison with the baseline, alpha-tocopherol increased significantly in groups C (P < or = 0.05), E (P < or = 0.01) and CE (P < or = 0.001) and in groups E and CE compared with group P. CLA supplementation resulted in significant improvement in clinical manifestation among RA patients and may be useful in their treatments.


A comparison of algorithms for calculating glaucoma change probability confidence intervals.
To evaluate the ability to detect change in standard automated perimetry data using 4 different methods for calculating the glaucoma change probability (GCP). A database of stable visual fields, collected within 1 week from 35 glaucoma patients and within 6 months from 15 normal patients, was used to determine confidence intervals for GCP using 4 different methods. The methods classified visual field locations on the basis of either defect or mean threshold, and used test-retest data or baseline-less-follow-up data to determine values for the confidence intervals. The specificity of the 4 methods was measured using 3700 locations artificially generated to simulate stable visual field data. The sensitivity of the methods was measured using 3330 artificially generated locations that decreased in either a linear, curvilinear, or bi-linear fashion by 2, 3, or 4 dB per year on average. Using GCP with confidence intervals built using the methods described in the literature (on the basis of defect and test-retest differences) resulted in a higher specificity than techniques based on mean threshold. However, the mean-based methods were more sensitive at detecting a decrease in a location. Building confidence intervals using the difference between a baseline and the current measurement (baseline-less-follow-up), rather than test-retest differences, also improved the detection of visual field progression. Stratifying baseline visual field measurements based on defect and eccentricity as described in the literature results in an unusually high specificity: 98% accuracy in classifying the same stable data that generated the 95% confidence intervals, rather than the expected 95% accuracy. By stratifying measurements based on mean threshold, and using baseline-less-follow-up rather than test-retest differences to build 95% confidence intervals, sensitivity is increased by 14.1%. This increase in sensitivity comes with a corresponding 2.2% decrease in specificity.


Structure-anti-leukemic activity relationship study of B- and D-ring modified and non-modified steroidal esters of chlorambucil's active metabolite.
We have studied the effect of modification of the B-steroidal ring to lactamic on the anti-leukemic potency of D-modified and D-non-modified steroidal esters of chlorambucil's active metabolite. The compounds synthesized were studied against leukemias P388 and L1210 after the subsequent estimation of their toxicity in vivo, and for their ability to induce sister chromatid exchanges (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro. The in vitro results correlated well, on a molar basis, with the results obtained from the study of the anti-leukemic potency. In a comparative study, the B-lactamic steroidal derivatives proved less active than the 7-oxidized ones against both leukemias. The presence of the -NHCO- group in the B-steroidal ring did not have the same positive effect on the biological action of chlorambucil's active metabolite esters as in the D-lactamic ring. However, this new modification of the B-ring rendered the final esteric derivatives much more toxic, compared with to the corresponding esters with a simple B-ring. This loss of the anti-leukemic specificity, which occurs from the modification of the B-ring, is additional evidence for the role of the steroidal part on the mechanism of action of these promising compounds. This provides support for the notion that the steroidal part of these molecules is not just a simple biological carrier, as has been speculated for many years.


Impaired disengagement of attention in young children with autism.
The present study examined the disengage and shift operations of visual attention in young children with autism. For this purpose, we used a simple visual orienting task that is thought to engage attention automatically. Once attention was first engaged on a central fixation stimulus, a second stimulus was presented on either side, either simultaneously or successively. Latency to begin an eye movement to the peripheral stimulus served as the main dependent measure. The two stimulus conditions (simultaneous and successive) provided independent measures of disengaging and shifting attention, respectively. Performance of children with autism was compared to that of children with Down syndrome and a normal group. The main finding was that relative to both comparison groups, children with autism had marked difficulty in disengaging attention. Indeed, on 20% of trials they remained fixated on the first of two competing stimuli for the entire 8-second trial duration. Evidence is also provided for a more subtle problem in executing rapid shifts of attention. Our findings on disengagement in autism parallel those reported in normal 2-month-olds, in whom attention has been described as 'obligatory'. Discussion focuses on the potential role of general versus domain-specific processes in producing some of the core features of autism.


Republished: The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis.
To examine the association of serum inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and serum lipid measures (low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol) with risk of myocardial infarction (MI) and ischaemic stroke (IS) among rheumatoid arthritis (RA) patients. We conducted a retrospective cohort study using 2005-2010 data from a US commercial health plan. Eligible patients had two or more physician diagnoses of RA during a baseline period of at least 180 days with continuous medical and pharmacy coverage. We computed age-adjusted incidence rates of MI and IS, and used spline regression to assess non-linear associations and Cox-regression to quantify the independent association between the laboratory values and the outcomes. We identified 44 418 eligible RA patients (mean age 49 years; 76% women). CRP>10 mg/L compared with <1 mg/L was associated with increased MI risk (HR 2.12; 95% CI 1.02 to 4.38). ESR>42 mm/h compared with <14 mm/h was associated with increased risk of MI (HR 2.53; 95% CI 1.48 to 4.31) and IS (HR 2.51; 95% CI 1.33 to 4.75) risk. HDL-cholesterol ≥60 mg/dL (1.6 mmol/L) compared with <40 mg/dL (1.0 mmol/L) was associated with reduced MI risk (HR 0.37; 0.21 to 0.66). The association between LDL and MI was not linear; the lowest risk was observed among patients with LDL between 70 mg/L (1.8 mmol/L) and 100 mg/L (2.6 mmol/L). We did not observe a significant association between LDL and IS. This study provides evidence supporting the hypothesis that RA-related systemic inflammation plays a role in determining cardiovascular risk and a complex relationship between LDL and cardiovascular risk.


[Iatrogenic disease and self-injury: significant factors in hospital admission?].
The frequency of adverse effects caused by doctors may serve as a quality control. We therefore assessed the number of adverse effects leading to a hospital admission and occurring during a six-month period in the medical department of a district hospital. We compared these figures with the number of admissions caused by substance-abuse by the patient himself. At admission to hospital 35 patients (6.4%) suffered from adverse effects. In 89% of these, the adverse effect was the leading factor to admit the patient; in the remaining 4 patients (11%) the adverse effect was detected by routine-screening upon admission. Further 8.6% developed adverse effects in the hospital which in 12.5% had consequences upon course and duration of the hospitalization. Self-afflicted hospital-admissions (substance-abuse, suicide-attempts) were found in 13%. Iatrogenic adverse effects brought 3.5% of the patients to the hospital. Adverse effects caused by diagnostic and therapeutic activities of doctors considerably contribute to hospital-admissions and course of hospital-stay, but even more often the patient himself is responsible by his self-damaging behavior.


Investigation of sensory profiles and hedonic drivers of emerging aquaculture fish species.
The aquaculture sector needs to increase the diversity fish species and their processed products to cover rising consumer demands. Candidates for this diversification have been identified to be meagre, greater amberjack, pikeperch and wreckfish. Yet scientific knowledge on their sensory profiles and consumer hedonic responses is scarce. The aim of the current study was to investigate these aspects, since they are essential for product development and market targeting. Species exhibited different sensory profiles with the exception of the odor/flavor profiles of meagre and greater amberjack, which were similar. Texture was more important than odor/flavor in explaining interspecies differences. Yet the hedonic responses were equally related to texture and odor/flavor. None of the species received negative hedonic scores. Both positive and negative hedonic drivers were identified within the odor/flavor and texture modalities. The distinct profiles of meagre, greater amberjack, pikeperch and wreckfish make these fish species valuable first materials for new product development and for covering markets with different sensory preferences. Differences in fish texture are more easily perceivable, yet small variations in fish odor/flavor can have a great impact on consumers' hedonic responses. © 2017 Society of Chemical Industry.


[Telepsychiatry, the potential to live up to its promise].
Telepsychiatry, or videoconferencing in psychiatry has existed for around forty years in a number of countries. Factors contributing to its development include difficulties in physically accessing specialists or in mobilising certain categories of patients (children, elderly or disabled people). Still not widely developed in France, certain technological and demographic evolutions nevertheless make it increasingly necessary.


The impact of prior tonsillitis and treatment modality on the recurrence of peritonsillar abscess: a nationwide cohort study.
Studies suggest an increased risk of peritonsillar abscess (PTA) recurrence in patients with prior tonsillitis. However, this association is inconsistent and could be confounded by different treatment modalities. This study aimed to assess the risk of recurrence among PTA patients with different degrees of prior tonsillitis and treatment modalities, and the role of tonsillectomy in current practice. All in-patients with peritonsillar abscess between January 2001 and December 2009 were identified in a nationwide, retrospective cohort study. Recurrence was defined as the first occurrence of PTA ≧30 days from the initial PTA. Factors independently associated with recurrence were analyzed using Cox proportional hazard model after adjusting for demographic and clinical data. There were 28,837 patients, with a 5.15% recurrence rate and 4.74 years of follow-up. The recurrence rates were significantly higher among subjects with more than five prior tonsillitis or 1-4 prior tonsillitis compared to those without prior tonsillitis (adjusted hazard ratio, 2.82 [95% confidence interval, 2.39-3.33] and 1.59 [95% CI: 1.38-1.82]). The adjusted HR in patients treated with needle aspiration was 1.08 compared to those treated with incision & drainage (95% CI: 0.85-1.38). After age stratification, the adjusted HRs of more than five prior tonsillitis increased to 2.92 and 3.50 in patients aged ≦18 and 19-29 years respectively. The adjusted HR of needle aspiration only increased in patients ≦18 years old (aHR: 1.98 [95% CI: 0.99-3.97]). The overall tonsillectomy rate was 1.48% during our study period. The risk of PTA recurrence increases with higher degrees of prior tonsillitis in all age groups and management by needle aspiration only in the pediatric population. Patients younger than 30 years old with PTA and more than five prior tonsillitis have the greatest risk of recurrence.


A PTEN-Regulated Checkpoint Controls Surface Delivery of δ Opioid Receptors.
The δ opioid receptor (δR) is a promising alternate target for pain management because δR agonists show decreased abuse potential compared with current opioid analgesics that target the μ opioid receptor. A critical limitation in developing δR as an analgesic target, however, is that δR agonists show relatively low efficacy in vivo, requiring the use of high doses that often cause adverse effects, such as convulsions. Here we tested whether intracellular retention of δR in sensory neurons contributes to this low δR agonist efficacy in vivo by limiting surface δR expression. Using direct visualization of δR trafficking and localization, we define a phosphatase and tensin homolog (PTEN)-regulated checkpoint that retains δR in the Golgi and decreases surface delivery in rat and mice sensory neurons. PTEN inhibition releases δR from this checkpoint and stimulates delivery of exogenous and endogenous δR to the neuronal surface both in vitro and in vivo PTEN inhibition in vivo increases the percentage of TG neurons expressing δR on the surface and allows efficient δR-mediated antihyperalgesia in mice. Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the δR, explain the low efficacy of δR agonists in vivo, and provide evidence that active δR relocation is a viable strategy to increase δR antinociception.SIGNIFICANCE STATEMENT Opioid analgesics, such as morphine, which target the μ opioid receptor (μR), have been the mainstay of pain management, but their use is highly limited by adverse effects and their variable efficacy in chronic pain. Identifying alternate analgesic targets is therefore of great significance. Although the δ opioid receptor (δR) is an attractive option, a critical limiting factor in developing δR as a target has been the low efficacy of δR agonists. Why δR agonists show low efficacy is still under debate. This study provides mechanistic and functional data that intracellular localization of δR in neurons is a key factor that contributes to low agonist efficacy, and presents a proof of mechanism that relocating δR improves efficacy.


Amniotic sac, fetal heart area, fetal curvature, and other morphometrics using first trimester vaginal ultrasonography and color Doppler imaging.
Ultrasonographic morphometric measurements were obtained with transvaginal ultrasonography from 121 patients with first trimester singleton pregnancies. Amniotic and gestational sac diameters, fetal heart area, and fetal length increased in a linear rate relative to crown-rump length, whereas the amniotic and gestational sac volumes increased at an exponential rate. The yolk sac exhibited a biphasic growth pattern with a peak at a crown-rump length of 3.5 cm. The ratio of crown-rump length to anteroposterior dimension increased over the first trimester, suggesting less curvature in older fetuses. In conclusion, vaginal ultrasonography permits accurate measurement of many new morphometric parameters.


Mre11-Rad50-Nbs1-dependent processing of DNA breaks generates oligonucleotides that stimulate ATM activity.
DNA double-strand breaks (DSBs) can be processed by the Mre11-Rad50-Nbs1 (MRN) complex, which is essential to promote ataxia telangiectasia-mutated (ATM) activation. However, the molecular mechanisms linking MRN activity to ATM are not fully understood. Here, using Xenopus laevis egg extract we show that MRN-dependent processing of DSBs leads to the accumulation of short single-stranded DNA oligonucleotides (ssDNA oligos). The MRN complex isolated from the extract containing DSBs is bound to ssDNA oligos and stimulates ATM activity. Elimination of ssDNA oligos results in rapid extinction of ATM activity. Significantly, ssDNA oligos can be isolated from human cells damaged with ionizing radiation and injection of small synthetic ssDNA oligos into undamaged cells also induces ATM activation. These results suggest that MRN-dependent generation of ssDNA oligos, which constitute a unique signal of ongoing DSB repair not encountered in normal DNA metabolism, stimulates ATM activity.


Association of plasma iron with the risk of incident cancer in Chinese adults with hypertension: a nested case-control study.
Iron is an essential element for organismal health but excessive iron is potentially toxic. However, few observational studies link plasma iron (PI) concentrations and cancer risk, and the results are inconsistent. This study aimed to explore the associations of PI concentrations with cancer risk in Chinese adults with hypertension. We conducted a nested, case-control study, including 223 pairs of incident cancer cases and matched controls from the China Stroke Primary Prevention Trial. The median time between blood sample collection and subsequent cancer event occurrence was 2.13 years. The odds ratio (OR) and 95% confidence interval (CI) for the risk of cancer by PI were estimated from multivariable conditional logistic regression models. There was a nonlinear association between PI concentrations and total cancer risk. When compared with participants in tertile 2 of PI, the ORs of total cancer were 2.17 (95%CI: 1.25-3.85) and 1.29 (95%CI: 0.77-2.19) in participants in PI tertiles 3 and 1, respectively. Furthermore, higher PI was associated with increased digestive system cancer risk (OR=3.25, 95%CI:1.29-8.90), while lower PI was associated with increased risk of non-digestive system cancer (OR=3.32, 95%CI: 1.39-8.71). In a sensitivity analysis, the increases in total cancer risk or digestive system cancer risk were still observed with higher PI after excluding cancer cases occurring within the first year. Our results showed an increased risk of cancer related to higher PI or lower PI in Chinese adults with hypertension. Higher iron levels were linked to an increased risk of digestive system cancers, whereas lower iron levels were linked to an increased risk of non-digestive system cancers.


Self-incompatibility in Petunia inflata: the relationship between a self-incompatibility locus F-box protein and its non-self S-RNases.
The highly polymorphic S (for self-incompatibility) locus regulates self-incompatibility in Petunia inflata; the S-RNase regulates pistil specificity, and multiple S-locus F-box (SLF) genes regulate pollen specificity. The collaborative non-self recognition model predicts that, for any S-haplotype, an unknown number of SLFs collectively recognize all non-self S-RNases to mediate their ubiquitination and degradation. Using a gain-of-function assay, we examined the relationships between S2-SLF1 (for S2-allelic product of Type-1 SLF) and four S-RNases. The results suggest that S2-SLF1 interacts with S7- and S13-RNases, and the previously identified S1- and S3-RNases, but not with S5- or S11-RNase. An artificial microRNA expressed by the S2-SLF1 promoter, but not by the vegetative cell-specific promoter, Late Anther Tomato 52, suppressed expression of S2-SLF1 in S2 pollen, suggesting that SLF1 is specific to the generative cell. The S2 pollen with S2-SLF1 suppressed was compatible with S3-, S5-, S7-, S11-, and S13-carrying pistils, confirming that other SLF proteins are responsible for detoxifying S5- and S11-RNases and suggesting that S2-SLF1 is not the only SLF in S2 pollen that interacts with S3-, S7-, and S13-RNases. Petunia may have evolved at least two types of SLF proteins to detoxify any non-self S-RNase to minimize the deleterious effects of mutation in any SLF.


Emerging role of calcium-activated potassium channel in the regulation of cell viability following potassium ions challenge in HEK293 cells and pharmacological modulation.
Emerging evidences suggest that Ca(2+)activated-K(+)-(BK) channel is involved in the regulation of cell viability. The changes of the cell viability observed under hyperkalemia (15 mEq/L) or hypokalemia (0.55 mEq/L) conditions were investigated in HEK293 cells expressing the hslo subunit (hslo-HEK293) in the presence or absence of BK channel modulators. The BK channel openers(10(-11)-10(-3)M) were: acetazolamide(ACTZ), Dichlorphenamide(DCP), methazolamide(MTZ), bendroflumethiazide(BFT), ethoxzolamide(ETX), hydrochlorthiazide(HCT), quercetin(QUERC), resveratrol(RESV) and NS1619; and the BK channel blockers(2 x 10(-7)M-5 x 10(-3)M) were: tetraethylammonium(TEA), iberiotoxin(IbTx) and charybdotoxin(ChTX). Experiments on cell viability and channel currents were performed using cell counting kit-8 and patch-clamp techniques, respectively. Hslo whole-cell current was potentiated by BK channel openers with different potency and efficacy in hslo-HEK293. The efficacy ranking of the openers at -60 mV(Vm) was BFT> ACTZ >DCP ≥RESV≥ ETX> NS1619> MTZ≥ QUERC; HCT was not effective. Cell viability after 24 h of incubation under hyperkalemia was enhanced by 82+6% and 33+7% in hslo-HEK293 cells and HEK293 cells, respectively. IbTx, ChTX and TEA enhanced cell viability in hslo-HEK293. BK openers prevented the enhancement of the cell viability induced by hyperkalemia or IbTx in hslo-HEK293 showing an efficacy which was comparable with that observed as BK openers. BK channel modulators failed to affect cell currents and viability under hyperkalemia conditions in the absence of hslo subunit. In contrast, under hypokalemia cell viability was reduced by -22+4% and -23+6% in hslo-HEK293 and HEK293 cells, respectively; the BK channel modulators failed to affect this parameter in these cells. In conclusion, BK channel regulates cell viability under hyperkalemia but not hypokalemia conditions. BFT and ACTZ were the most potent drugs either in activating the BK current and in preventing the cell proliferation induced by hyperkalemia. These findings may have relevance in disorders associated with abnormal K(+) ion homeostasis including periodic paralysis and myotonia.


Consensus opinion for the selection and use of therapeutic products for the treatment of haemophilia in Spain.
The period between isolation of HIV in the early 1980s and the development of effective viral inactivation procedures able to eradicate the virus from the blood supply was long and unfortunately many recipients of blood-derived products became infected; this translated into a devastating impact on their quality of life, quality of care as well as on their life expectancy. Some years later, hepatitis C virus infection was identified as another known blood-borne disease complicating the treatment of haemophilia. Nowadays, the potential threat of emerging new pathogens has stressed the need to provide effective but primarily safe products with regard to infectious agents, as well as to regularly update therapeutic guidelines for haemophilia. The aim of the present publication was to review some of the crucial aspects related to the choice of haemostatic concentrates for the treatment of haemophilia and other inherited bleeding disorders, to analyse the current situation in the United States, Canada and European Union countries and to report the most relevant aspects of the Spanish consensus opinion of haemophilia-treating doctors for the use of therapeutic products for haemophilia recently issued. Essentially, it suggests that a gradual switch to recombinant concentrates may be a beneficial decision for patients with haemophilia and for the National Health Service.