A comparative molecular docking study of curcumin and methotrexate to dihydrofolate reductase.
Interaction of curcumin (CUR) with the enzyme dihydrofolate reductase (DHFR) was studied by molecular docking using AutoDock 4.2 as the docking software application. AutoDock 4.2 software serves as a valid and acceptable docking application to study the interactions of small compounds with proteins. Interactions of curcumin with DHFR were compared to those of methotrexate (MTX), a known inhibitor of the enzyme. The calculated free energy of binding (ΔG binding) shows that curcumin (ΔG = -9.02 kcal/mol; Ki = 243 nM) binds with affinity comparable to or better than MTX (ΔG = -8.78 kcal/mol; Ki = 363 nM). Binding interactions of curcumin with active site residues of the enzyme are also predicted. Curcumin appears to bind in a bent conformation making extensive VDW contacts in the active site of the enzyme. Hydrogen bonding and pi-pi interaction with key active site residues are also observed. Thus, curcumin can be considered as a good lead compound in the development of new inhibitors of DHFR, which is a potential target of anti-cancer drugs. The results of these studies can serve as a starting point for further computational and experimental studies.


A web-based endodontic case difficulty assessment tool.
To develop a web-based tool to facilitate identification, evaluation and management of teeth requiring endodontic treatment. Following a literature search and thorough analysis of existing case difficulty assessment forms, the web-based tool was developed using an online survey builder (Qualtrics, Qualtrics Lab, UT, USA). Following feedback from a pilot study, it was refined and improved. A study was performed, using the updated version (EndoApp) on a cohort (n = 53) of dental professionals and dental students. The participants were e-mailed instructions detailing the assessment of five test cases using EndoApp, followed by completion of a structured feedback form. Analysis of the EndoApp responses was used to evaluate usage times, whereas the results of the feedback forms were used to assess user experience and relevance, other potential applications and comments on further improvement/s. The average usage time was 2 min 7 s; the average times needed for the last three (Cases 3-5) were significantly less than the preceding two (Cases 1 & 2) test cases. An overwhelming majority of participants expressed favourable views on user experience and relevance of the web-based case difficulty assessment tool. Only two participants (4%) were unlikely or very unlikely to use EndoApp again. The potential application of EndoApp as an 'educational tool' and for 'primary care triage' was deemed the most popular features and of greater importance than the secondary options of 'fee setting' and as a 'dento-legal justification tool'. Within the study limitations, owing to its ability to quantify the level of difficulty and provide guidance, EndoApp was considered user-friendly and helped facilitate endodontic case difficulty assessment. From the feedback, further improvements and the development of a Smartphone App version are in progress. EndoApp may facilitate treatment planning, improve treatment cost-effectiveness and reduce frequency of procedural errors by providing appropriate guidance on endodontic case management.


Spread of an epidemic Pseudomonas aeruginosa strain from a patient with cystic fibrosis (CF) to non-CF relatives.
Colonisation with Pseudomonas aeruginosa is common in adults with cystic fibrosis (CF) and there is increasing evidence that transmissible strains may cross colonise patients. However, transmission of these strains by social contact to healthy non-CF individuals has not been described. A case is presented where an adult CF patient colonised by an epidemic P aeruginosa strain infected her parents with subsequent morbidity.


DNA binding to protein-gold nanocrystal conjugates.
The E. coli DNA binding protein lac repressor (LacI) and a derivative with a designed thiol (T334C) were developed as gold nanocrystal conjugates to assess the effects of conjugation on DNA binding function. The designed derivative was engineered with a solvent-accessible thiol to promote oriented conjugation, avoiding obstruction of the DNA-binding domain by the nanocrystal. Analytical ultracentrifugation (AU) and electrophoretic mobility shift assays (EMSA) were used to evaluate the ability of conjugated repressors to bind the natural operator DNA sequence O(1). The results show that LacI does not retain significant DNA binding function when conjugated to gold nanocrystals, presumably because the basic DNA-binding domain is the site for nonspecific conjugation. T334C, with the potential for both directed and nonspecific conjugation, shows enhanced interaction with O(1) when conjugated. Interestingly, the order of component addition is a key factor in producing functional lac repressor conjugates.


Experimental procedure for the detection of a rare human mRNA with the DIG System.
Newcomers to the DIG System often inquire about the possibility of performing Northern blot hybridizations with nonradioactive techniques. With the following examples, we would like to share our protocol for performing highly sensitive Northern blots. This procedure strictly adheres to the standard procedures detailed in our manuals and pack inserts, and there are no special "tricks" required. As a target, we have used total human skeletal muscle RNA (Clontech). We selected two probes: beta-actin and a probe comprising the cDNA of the transcription factor CTF1, which expresses a low abundant mRNA. We used in vitro transcribed RNAs exclusively as probes because, during the development of the DIG System, we have found that RNA probes exhibit a 10-100-fold higher sensitivity with RNA targets than do DNA probes. They are also less prone to background problems caused by probe concentrations that are too high. For DNA probes, we recommend an optimal probe concentration of 25 ng/ml. Using a probe concentration that is even slightly too high (e.g., 1.5 fold) will dramatically increase the background. For RNA probes, we recommend an optimal probe concentration of 100 ng/ml, which will not lead to background problems. In the following examples, we describe all experimental details, starting from the gel run for the blot.


Phospholipid and nucleic acid gradients in the developing amphibian embryo.
Rana pipiens embryos at the end of the blastula stage were dissociated and the cell suspension was separated into presumptive ectoderm, mesoderm, light endoderm, and heavy endoderm cells by a discontinuous density gradient centrifugation technique. The isolated germ layers were analyzed for total lipid, lipid phosphorus, plasmalogen, RNA, and DNA. Per gram dry weight, DNA showed a threefold decrease from ectoderm to heavy endoderm. On the same basis, the RNA content of the mesoderm was 34 per cent higher than that of ectoderm, and 320 and 570 per cent higher than that of light and heavy endoderm, respectively. In addition to the RNA and DNA gradients, there were at least two superimposed lipid gradients: a neutral lipid gradient decreasing from ectoderm to endoderm, and a total phospholipid gradient increasing from ectoderm to endoderm. In contrast to total phospholipid, a specific phospholipid class, ethanolamine plasmalogen, decreased from ectoderm to endoderm. The total lipid content per gram dry weight was the same in all the germ layers. Total phospholipids were analyzed quantitatively by thin layer chromatography. Phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and inositol phospholipid constituted 34, 13, 12, and 34 per cent, respectively, of the total lipid phosphorus. The phospholipid composition was different in each germ layer. The possible role of specific lipids in embryonic induction and differentiation is discussed.


Organic nanoparticles with ultrahigh stimulated emission depletion efficiency for low-power STED nanoscopy.
Stimulated emission depletion (STED) nanoscopy is a powerful sub-diffraction imaging tool to probe subcellular structures and organelles. Conventional organic dyes require high STED power (PSTED) to obtain sub-diffraction resolution, leading to serious photo-bleaching. Herein, this study demonstrates highly emissive silica-coated core-shell organic nanoparticles (CSONPs) as a new type of photostable probe with ultrahigh stimulated emission depletion efficiency for low-power super-resolution STED nanoscopy. The CSONPs offer (i) efficient red emission with high solid-state fluorescence quantum yields around 0.6, (ii) large Stokes shift of 150 nm and (iii) high photostability owing to silica shell protection. The stimulated emission depletion efficiency (η) of CSONPs was extremely high up to η = 99% (the highest value reported so far) with a saturation intensity as low as Isat = 0.18 MW cm-2. Moreover, this research demonstrates the super-resolution imaging of living HeLa cells stained using CSONPs with a lateral spatial resolution of 63 nm at an extremely low depletion power of ISTED = 0.89 MW cm-2 and a long-term stability >600 s at η = 80% without obvious fatigue. The excellent and comprehensive performances of the CSONPs are promising for super-resolution imaging in biological applications.


Non-monomelic synchronous primary multicentric chondrosarcoma: a case report.
We report a patient with simultaneous presentation of two histologically grade 2 conventional chondrosarcomas non-derived from pre-existing cartilaginous lesions, in the absence of pulmonary or visceral involvement. One tumour was located at the right proximal femur and the other one at the right scapula. There was no evidence of local recurrence or pulmonary or visceral involvement three years and a half after total scapulectomy and resection of the proximal third of the femur. To the best of our knowledge, this is the first report of a patient with two non-monomelic synchronous chondrosarcomas arising in two previously normal bones of the skeleton. Such cases are often difficult to differentiate from metastatic disease.


[Cellular absorption of the active ingredients in different compatibilities of gegenqinlian decoction in human intestinal Caco-2 cells].
To study the intestinal dynamics characteristics of puerarin and other active ingredients in Gegenqinlian decoction. Caco-2 cell monolayer model was used to research the transport of puerarin and baicalin, berberine hydrochloride, liquiritin when they were used in different compatibilities, meanwhile a ultra performance liquid chromato-graphic method was also developed. The concentration of puerarin, haicalin, berberine hydrochloride, liqpiritin in cell culture medium was measured and the apparent permeahility coefficients (Papp) as well as percent absorption (%) from apical side to basolateral side were calculated. The absorption characteristics of the four components were different when they were used in different compatibilities. Furthermore the Papp sequence of puerarin in specific groups were puerarin-baicalin-berberine-liquiritin group > puerarin-baicalin group > puerarin-berberine > puerarin-liquiritin group > single puerarin (P < 0. 05). The intestinal absorption dynamics process of the active ingredients in Gegenqinlian decoction changes as the change of prescription compatibilities. And the intestinal absorption characteristics of puerarin is enhanced by the use of other components.


Retroperitoneal trapdoor endarterectomy for paravisceral "coral-reef" aortic plaque.
A 67-year-old woman presented to the emergency room with progressive claudication, chest pain, and flash-pulmonary edema. Her past medical history was significant for poorly controlled hypertension requiring multiple antihypertensive medications, renal insufficiency, and tobacco abuse. Diagnostic evaluation revealed an extensive exophytic plaque localized to the paravisceral aorta resulting in high-grade stenoses of the proximal aorta as well as the celiac, superior mesenteric, and left renal arteries. She underwent surgical revascularization through a retroperitoneal aortic exposure and trapdoor aortic endarterectomy, the technical conduct of which is described in this manuscript. The patient recovered uneventfully and experienced resolution of her claudication and pulmonary symptoms, improved blood pressure control, and normalization of her creatinine. Review of the medical literature pertaining to management of proximal occlusive disease of the abdominal aorta is discussed.


15N-H-Related Conformational Entropy Changes Entailed By Plexin-B1 RBD Dimerization: Combined Molecular Dynamics/NMR Relaxation Approach.
We report on a new method for determining function-related conformational entropy changes in proteins. Plexin-B1 RBD dimerization serves as example, and internally mobile N-H bonds serve as probes. Sk (entropy in units of kBT) is given by -∫(PeqlnPeq)dΩ, where Peq = exp(-u) is the probability density for probe orientation, and u the local potential. Previous slowly relaxing local structure (SRLS) analyses of 15N-H relaxation in proteins determined linear combinations of D002(Ω) and (D022(Ω) + D0-22(Ω)) (D0KL(Ω) represents a Wigner rotation matrix element in uniaxial local medium) as "best-fit" form of u. SRLS also determined the "best-fit" orientation of the related ordering tensor. On the basis of this information the coefficients (in the linear combination) of the terms specified above are determined with molecular dynamics (MD) simulations. With the explicit expression for u thus in hand, Sk is calculated. We find that in general Sk decreases, i.e., the local order increases, upon plexin-B1 RBD dimerization. The largest decrease in Sk occurs in the helices α1 and α2, followed by the α2/β6 turn. Only the relatively small peripheral β2 strand, β2/α1 turn, and L3 loop become more disordered. That α-helices dominate ΔSk = Sk(dimer) - Sk(monomer), a few peripheral outliers partly counterbalance the overall decrease in Sk, and the probability density function, Peq, has rhombic symmetry given that the underlying potential function, u, has rhombic symmetry, are interesting features. We also derive S2 (the proxy of u in the simple "model-free (MF)" limit of SRLS) with MD. Its conversion into a potential requires assumptions and adopting a simple axial form of u. Ensuing ΔSk(MF) profiles are u-dependent and differ from ΔSk(SRLS). A method that provides consistent, general, and accurate Sk, atomistic/mesoscopic in nature, has been developed. Its ability to provide new insights in protein research has been illustrated.


Methodological Issues in Predicting Pediatric Epilepsy Surgery Candidates Through Natural Language Processing and Machine Learning.
We describe the development and evaluation of a system that uses machine learning and natural language processing techniques to identify potential candidates for surgical intervention for drug-resistant pediatric epilepsy. The data are comprised of free-text clinical notes extracted from the electronic health record (EHR). Both known clinical outcomes from the EHR and manual chart annotations provide gold standards for the patient's status. The following hypotheses are then tested: 1) machine learning methods can identify epilepsy surgery candidates as well as physicians do and 2) machine learning methods can identify candidates earlier than physicians do. These hypotheses are tested by systematically evaluating the effects of the data source, amount of training data, class balance, classification algorithm, and feature set on classifier performance. The results support both hypotheses, with F-measures ranging from 0.71 to 0.82. The feature set, classification algorithm, amount of training data, class balance, and gold standard all significantly affected classification performance. It was further observed that classification performance was better than the highest agreement between two annotators, even at one year before documented surgery referral. The results demonstrate that such machine learning methods can contribute to predicting pediatric epilepsy surgery candidates and reducing lag time to surgery referral.


Cluster synchronization induced by one-node clusters in networks with asymmetric negative couplings.
This paper deals with the problem of cluster synchronization in networks with asymmetric negative couplings. By decomposing the coupling matrix into three matrices, and employing Lyapunov function method, sufficient conditions are derived for cluster synchronization. The conditions show that the couplings of multi-node clusters from one-node clusters have beneficial effects on cluster synchronization. Based on the effects of the one-node clusters, an effective and universal control scheme is put forward for the first time. The obtained results may help us better understand the relation between cluster synchronization and cluster structures of the networks. The validity of the control scheme is confirmed through two numerical simulations, in a network with no cluster structure and in a scale-free network.


Antihypertensive and Antihypertrophic Effects of Acupuncture at PC6 Acupoints in Spontaneously Hypertensive Rats and the Underlying Mechanisms.
The aim of this work is to investigate the effect of electroacupuncture (EA) at PC6 on the hypertension and myocardial hypertrophy in spontaneously hypertensive rats (SHRs). Thirty SHRs were randomized into model, SHR + EA, and SHR + Sham EA group with WKY rats as normal control. EA was applied once a day in 8 consecutive weeks. The blood pressure (BP), cardiac function, and hypertrophy as well as the underlying mechanisms were investigated. After EA treatment, the enhanced BP in SHR + EA group was significantly lower compared to both the period before EA and model group. Echocardiographic, morphological studies showed that the enhanced left ventricular anterior and posterior wall end-diastolic (LVAWd and LVPWd) thickness, diameters and cross-sectional area (CSA) of cardiac myocyte, as well as the ratio of heart weight to body weight (HW/BW), were markedly diminished in SHR + EA group, while the reduced left ventricular ejection fraction, left ventricular short axis fraction shortening, and E/A ratio were significantly ameliorated. The levels of Angiotensin-converting enzyme (ACE) and Angiotensin II Type 1 and 2 receptors (AT1R, AT2R) in SHRs were also significantly attenuated by EA. The results suggest that EA at bilateral PC6 could arrest the hypertension development and ameliorate the cardiac hypertrophy and malfunction in SHRs, which might be mediated by the regulation of ACE, AT1R, and AT2R.


Driving into the sunset: supporting cognitive functioning in older drivers.
The rise in the aging driver population presents society with a significant challenge-how to maintain safety and mobility on the roads. On the one hand, older drivers pose a higher risk of an at-fault accident on a mile-for-mile basis; on the other hand, independent mobility is a significant marker of quality of life in aging. In this paper, we review the respective literatures on cognitive neuropsychology and ergonomics to suggest a previously unexplored synergy between these two fields. We argue that this conceptual overlap can form the basis for future solutions to what has been called "the older driver problem." Such solutions could be found in a range of emerging driver assistance technologies offered by vehicle manufacturers, which have the potential to compensate for the specific cognitive decrements associated with aging that are related to driving.


Striatal dopamine release in sequential learning.
Sequential learning is an important aspect of cognitive processing. Neuropharmacological evidence acquired in laboratory animals suggests that striatal dopaminergic mechanisms may be important for processing of this form of learning. However, because experiments conducted on dopamine deficient patients have reported contradictory evidence, the role of dopamine and the striatum remains unclear in human sequential learning. We used a newly developed dynamic molecular imaging technique to determine whether striatal dopamine is released during performance of a sequential learning task. In this study we localized striatal regions where dopamine receptor ligand (11C-raclopride) was displaced from receptor sites, during performance of a motor sequence learning (serial reaction time) task. The results suggest that the task induces release of endogenous dopamine in the posterior two-third of dorsomedial aspect of left putamen and the anterior part of the body of caudate bilaterally. The activations of the left putamen and the right caudate coincided with the activations observed earlier during performance of a motor planning task. Since these activations are associated with the selection and execution of a response, the activation in the left caudate, which was not observed in motor planning, is probably associated with the detection of a change in the 'context', and in the formulation of a new 'rule'. Thus, the results suggest that sequential learning involves two striatal dopaminergic mechanisms, one for the detection of a change in context, and the other for selection and execution of the response.


Automated machine learning-based model for predicting benign anastomotic strictures in patients with rectal cancer who have received anterior resection.
Benign anastomotic strictures (BAS) significantly impact patients' quality of life and long-term prognosis. However, the current clinical practice lacks accurate tools for predicting BAS. This study aimed to develop a machine-learning model to predict BAS in patients with rectal cancer who have undergone anterior resection. Data from 1973 patients who underwent anterior resection for rectal cancer were collected. Multiple machine learning classification models were integrated to analyze the data and identify the optimal model. Model performance was evaluated using receiver operator characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves. The Shapley Additive exPlanation (SHAP) algorithm was utilized to assess the impact of various clinical characteristics on the optimal model to enhance the interpretability of the model results. A total of 10 clinical features were considered in constructing the machine learning model. The model evaluation results indicated that the random forest (RF)model was optimal, with the area under the test set curve (AUC: 0.888, 95% CI: 0.810-0.965), accuracy: 0.792, sensitivity: 0.846, specificity: 0.791. The SHAP algorithm analysis identified prophylactic ileostomy, operative time, and anastomotic leakage as significant contributing factors influencing the predictions of the RF model. We developed a robust machine-learning model and user-friendly online prediction tool for predicting BAS following anterior resection of rectal cancer. This tool offers a potential foundation for BAS prevention and aids clinical practice by enabling more efficient disease management and precise medical interventions.


Humanization of KC4G3, an anti-human carcinoma antibody.
We have previously constructed a chimeric version of KC4G3, a murine antibody that reacts with several human epithelial cancers and binds to the human breast epithelial mucin. We have now successfully humanized KC4G3 using positional consensus data, previously compiled after examining several other antibody structures, listing residues in the VH and V kappa frameworks that could influence antigen binding. We have previously showed that a fraction of the kappa chains of murine and chimeric KC4G3 migrates abnormally on SDS-PAGE most likely due to N-linked glycosylation in V kappa. The glycosylation signal has now been removed from V kappa, as a consequence of humanization. As expected, the humanized kappa chain migrates normally on SDS-PAGE. We detected no significant differences either in the affinities (1.6 x 10(9) M-1 vs. 1.4 x 10(9) M-1, respectively) or in the ability to compete for antigen binding, between the murine and the humanized antibodies. The humanized version is an IgG1, kappa immunoglobulin produced by mouse myeloma SP2/0-Ag14 cells and is designated HuKC4v2. The HuKC4v2 frameworks conform to the V kappa II and VHIII human consensus in all but six positions in V kappa and three positions in VH.


Blood pressure and clinical outcomes in the International Stroke Trial.
Among patients with acute stroke, high blood pressure is often associated with poor outcome, although the reason is unclear. We analyzed data from the International Stroke Trial (IST) to explore the relationship between systolic blood pressure (SBP), subsequent clinical events over the next 2 weeks, and functional outcome at 6 months in patients with acute stroke. We included in the analysis 17 398 patients from IST with confirmed ischemic stroke. A single measurement of SBP was made immediately before randomization. Clinical events within 14 days of randomization were recorded: recurrent ischemic stroke, symptomatic intracranial hemorrhage, death resulting from presumed cerebral edema, fatal coronary heart disease, and death. Survival and dependency were assessed at 6 months. Outcomes were adjusted for age, sex, clinical stroke syndrome, time to randomization, consciousness level, atrial fibrillation, and treatment allocation (aspirin, unfractionated heparin, both, or neither). A U-shaped relationship was found between baseline SBP and both early death and late death or dependency: early death increased by 17.9% for every 10 mm Hg below 150 mm Hg (P<0.0001) and by 3.8% for every 10 mm Hg above 150 mm Hg (P=0.016). The rate of recurrent ischemic stroke within 14 days increased by 4.2% for every 10-mm Hg increase in SBP (P=0.023); this association was present in both fatal and nonfatal recurrence. Death resulting from presumed cerebral edema was independently associated with high SBP (P=0.004). No relationship between symptomatic intracranial hemorrhage and SBP was seen. Low SBP was associated with a severe clinical stroke (total anterior circulation syndrome) and an excess of deaths from coronary heart disease (P=0.002). Both high blood pressure and low blood pressure were independent prognostic factors for poor outcome, relationships that appear to be mediated in part by increased rates of early recurrence and death resulting from presumed cerebral edema in patients with high blood pressure and increased coronary heart disease events in those with low blood pressure. The occurrence of symptomatic intracranial hemorrhage within 14 days was independent of SBP.


Electrocardiographic changes in young patients with spontaneous pneumothorax: A retrospective study.
Primary spontaneous pneumothorax (PSP) commonly occurs in adolescents. PSP symptoms can mimic cardiac event. We aimed to examine electrocardiography (ECG) changes that accompanied PSP in relation to side and size of pneumothorax.A retrospectively reviewed 57 adolescents presented with PSP and underwent a cardiac evaluation.Overall, 49 patients (86%) were male, median age of 16 years. Of these, 1 patient had a known mitral valve prolapse. In 56 patients the initial episode of PSP was unilateral (16 left sided and 40 right sided), and 1 was bilateral. The main initial symptom was chest pain or dyspnea and chest pain 66.6% and 33.3% respectively. Small pneumothorax was right and left sided in 1and 8 patients respectively, medium right (n = 8) medium left (n = 22), large right (n = 7) and large left (n = 10). One additional patient had medium bilateral pneumothorax. ECG findings were abnormal in 12 patients (21%) and included ST elevation in 5 patients, inverted T wave in 2 patients, incomplete right bundle branch block in 2 patients, poor R wave progression, left axis deviation and low QRS voltage in 1 patient each. Only 2 patients had abnormal echocardiography findings, MPV (n = 1) and minimal mitral and tricuspid regurgitation (n = 1). Serum troponin-T levels were normal in all patients.ECG changes were found in 21% among pediatric patients with PSP. No correlation was observed between ECG changes and side/size of pneumothorax. It is important to rule out pneumothorax among children presented with chest pain, dyspnea and ECG changes.


Consistently Modest Antidepressant Effects in Clinical Trials: the Role of Regulatory Requirements.
Despite being widely heralded following their discovery, the effectiveness and clinical utility of antidepressants has been questioned, in part due to the release of several decades of regulatory trial data. Upon investigation, contemporary regulatory trials of antidepressants have demonstrated a nearly identical effect size (0.3) for the past 40 years, regardless of placebo response or attempts to improve trial design. In this review, we examine the historical methods of antidepressant trials and re-evaluate regulatory trial data over time and according to drug class (SSRIs, SNRIs, and atypicals) with the addition of two classes of antidepressants not previously analyzed: tricyclics used as active comparators and the recently-approved NMDA receptor antagonist, esketamine. We show that among these five classes of antidepressants there were no significant differences between effect sizes or percent symptom reduction. We suggest that within the context of a regulatory trial of antidepressants, effect sizes will remain modest (~0.3) regardless of class or novel drug mechanism, possibly due to regulatory changes to trial design and conduct following the Kefauver-Harris Act of 1962. We comment that the regulatory double-blind, parallel, placebo-controlled trial model is an artificial creation for a narrow purpose-designed to demonstrate simple superiority over placebo and to determine basic safety. We should be cautious of stretching trial results beyond their limited capacity to inform clinical practice as trials are not representative of real-world patients or medication management practices. There is a substantial need to develop more realistic models to evaluate the clinical utility of antidepressants.


Synthesis of (+)-Turmeronol A, an Inhibitor of Soybean Lipoxygenase, and (+)-ar-Turmerone.
Syntheses of optically pure turmeronol A and turmerone were achieved in a simple manner starting from ethyl (R)-3-hydroxybutanoate (4) of 100% e.e. The key step was the displacement of the chiral tosylate (6) with an organocopper reagent.


Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects.
Darier disease (DD) is a rare genodermatosis caused by heterozygous mutations in the ATP2A2 gene. It has been associated with neuropsychiatric manifestations. To investigate the genetic basis of Israeli patients with DD, and its association with the neuropsychiatric phenotype. A cohort of 32 families comprising 74 affected individuals and 13 unaffected family members was recruited from the Haemek Dermatology Department and other dermatology clinics in Israel. The individuals were evaluated by detailed questionnaires, physical examination and genetic analysis. The main outcome measures were genetic mutations, psychiatric profile and their association. Twenty-three mutations in ATP2A2 were scattered over the entire gene, 14 of them novel. Two families shared the same mutation. Twenty-one patients (28%) had a history of psychiatric disorders, most of them mood disorders. Another seven patients (9%) were highly suspected of having a psychiatric disorder; 21 (28%) reported suicidal thoughts and five (7%) had attempted suicide. The psychiatric phenotype demonstrated inter- and intrafamilial variability, and was not associated with disease severity, family history of psychiatric disease or mutation location. The cohort demonstrated genetic heterogeneity with no mutation cluster along the gene, and a high prevalence of psychiatric disorders. Although no clear genotype-phenotype correlation was found, the results point to a major effect of genetic background on psychiatric phenotype, together with other modifiers.


Antimicrobial Resistance Profiles of Non-typhoidal Salmonella From Retail Meat Products in California, 2018.
Non-typhoidal Salmonella remains a leading cause of foodborne illness in the United States, with food animal products serving as a key conduit for transmission. The emergence of antimicrobial resistance (AMR) poses an additional public health concern warranting better understanding of its epidemiology. In this study, 958 retail meat samples collected from January to December 2018 in California were tested for Salmonella. From multivariable logistic regression, there was a 6.47 (90% CI 2.29-18.27), 3.81 (90% CI 1.29-11.27), and 3.12 (90% CI 1.03-9.45) higher odds of contamination in samples purchased in the fall, spring, and summer than in winter months, respectively, and a 3.70 (90% CI 1.05-13.07) higher odds in ground turkey compared to pork samples. Fourteen distinct serotypes and 17 multilocus sequence types were identified among the 43 isolates recovered, with S. Kentucky (25.58%), S. Reading (18.60%), S. Infantis (11.63%), and S. Typhimurium (9.30%) comprising the top serotypes. High prevalence of resistance was observed in retail chicken isolates for streptomycin (12/23, 52.17%) and tetracycline (12/23, 52.17%), in ground turkey isolates for ampicillin (8/15, 53.34%), and in ground beef isolates for nalidixic acid (2/3, 66.67%). Fourteen (32.56%) were susceptible to all antimicrobials tested, 11 (25.58%) were resistant to one drug, and 12 (27.91%) were resistant to two drugs. The remaining six isolates (13.95%) were multidrug-resistant (MDR, ≥3 drug classes) S. Infantis (n = 4), S. Reading (n = 1), and S. Kentucky (n = 1). Whole-genome sequencing (WGS) identified 16 AMR genes and 17 plasmid replicons, including bla CTX-M-65 encoding ceftriaxone resistance and a D87Y mutation in gyrA conferring resistance to nalidixic acid and reduced susceptibility to ciprofloxacin. The IncFIB(pN55391) replicon previously identified in connection to the worldwide dissemination of pESI-like mega plasmid carriage in an emerged S. Infantis clone was detected in four of the six MDR isolates. Genotypes from WGS showed high concordance with phenotype with overall sensitivity and specificity of 95.31% and 100%, respectively. This study provides insight into the AMR profiles of a diversity of Salmonella serotypes isolated from retail meat products in California and highlights the value of routine retail food surveillance for the detection and characterization of AMR in foodborne pathogens.


Occurrence of two newly named oral treponemes - Treponema parvum and Treponema putidum - in primary endodontic infections.
Recent evidence from molecular genetic studies has revealed that oral Treponema species are involved in infections of endodontic origin. This study assessed the occurrence of two newly named oral treponemes - Treponema parvum and Treponema putidum - in primary endodontic infections using a culture-independent identification technique. Genomic DNA was isolated directly from clinical samples, and a 16S rRNA gene-based nested polymerase chain reaction (PCR) assay was used to determine the presence of T. parvum and T. putidum. Species-specific primer pairs were developed by aligning closely related 16S rRNA gene sequences. The specificity for each primer pair was validated by running PCR against a panel of oral bacteria and by sequence analysis of PCR products from positive clinical samples. T. parvum was detected in 52% of the root canals associated with chronic apical periodontitis, in 20% of the cases diagnosed as acute apical periodontitis, and in no abscessed case. In general, T. parvum was detected in 26% of the samples from primary endodontic infections. T. putidum was found in only one case of acute apical periodontitis (2% of the total number of cases investigated). The devised nested PCR protocol was able to identify both T. parvum and T. putidum directly in clinical samples and demonstrated that these two treponemes can take part in endodontic infections.


Platelets at the crossroads of thrombosis, inflammation and haemolysis.
Platelets play a critical role at the interphase of thrombosis and inflammation, key features in haemolysis-associated disorders. Exercising this role requires expression of pattern recognition receptors by platelets, including toll-like receptor 4 (TLR4) and nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3), the latter forming intraplatelet multiprotein inflammasome complexes. Platelets are a potential target of various damage-associated molecular pattern (DAMP) molecules, such as free haem, a degradation by-product of haemoglobin oxidation during haemolysis, and high-mobility group box 1 (HMGB1), a DNA-binding protein released by dying or stressed cells and activated platelets. We have recently identified platelet TLR4, NLRP3, and Bruton tyrosine kinase (BTK) as critical regulators of platelet aggregation and thrombus formation, suggesting that the BTK inhibitor ibrutinib is a potential therapeutic target. Increasing evidence suggests that these and other DAMP-driven signalling mechanisms employed by platelets might be key in mediating inflammation and thrombosis encountered in haemolytic disorders. However, the precise regulatory triggers and their clinical relevance are poorly understood. We provide new insights into these less-well characterised platelet mechanisms, which are potentially targetable in haemolytic disorders.


MHCPEP: a database of MHC-binding peptides.
MHCPEP is a curated database comprising over 4000 peptide sequences known to bind MHC molecules. Entries are compiled from published reports as well as from direct submissions of experimental data. Each entry contains the source protein (when known), an estimate of binding affinity and critical anchor residues (if identified), and is fully referenced. The present format of the database allows test string matching searches. The database can be accessed via Internet using gopher.


[Prognostic value of aquaporin-4 antibody in patients of inflammatory demyelinating diseases in central nervous system].
To determine the prognostic value of AQP4 antibody in the cohort of Chinese patients with neuromyelitis optical (NMO), HR-NMO (high-risk NMO)and classic multiple sclerosis (MS). Sera of patients with NMO, HR-NMO and MS were all investigated for the presence of AQP4 antibody by indirect immunofluorescence in human AQP4-transfected cells. The diagnostic and prognostic values of anti-AQP4 antibody were evaluated in 352 patients with NMO (n=106), HR-NMO (n=84) including optico-spinal MS (OSMS), longitudinally extensive transverse myelitis (LETM), recurrent optic neuritis (RON) and optic neuritis (ON) or transverse myelitis (TM) with other autoimmune disease and classic MS (n=162). All patients were followed up at outpatient clinics or by telephone. In our study, the anti-AQP4 antibody's seropositivity in all demyelinating cases (n=352) was 31.3%. And 72 (65.5%) seropositive patients presented with severe ON, 82 (74.5%) with TM, 60 (54.4%) with spinal-cord lesion more than 3 segments, 16 (14.5%) had relapses of ON and 38 (34.5%) relapses of TM during a follow-up period of 24 months. Significant differences existed between anti-AQP4 antibody seropositivity and seronegative in terms of concurrent severe ON, TM, spinal-cord lesion more than 3 segments and relapses of ON and TM (P<0.05). Also, in NMO patient seropositive for anti-AQP4 antibody (n=78), 28 (35.9%) developed relapses of TM. However, in HR-NMO patient with seropositivity (n=28), 4 (14.3%) developed relapses of ON and 10 (35.7%) relapses of TM. The relapse of ON or TM occurred in 57/110 seropositive patients versus 17/242 seronegative ones (P<0.05). As compared with anti-AQP4 antibody-negative ones, anti-AQP4 antibody-positive patients show significantly higher frequencies of severe ON, TM, longitudinal spinal-cord segments and they are more predisposed to ON or TM relapse. And seropositive NMO and HR-NMO patients are more likely to develop relapses of ON or TM. Anti-AQP4 antibody may play some roles in the diagnosis and prognostic predication of demyelinating diseases in central nervous system.


Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies.
Aromatase inhibitors (AIs) as effective candidates have been used in the treatment of hormone-dependent breast cancer. In this study, we have proposed 300 structures as potential AIs and filtered them by Lipinski's rule of five using DrugLito software. Subsequently, they were subjected to docking simulation studies to select the top 20 compounds based on their Gibbs free energy changes and also to perform more studies on the protein-ligand interaction fingerprint by AuposSOM software. In this stage, anastrozole and letrozole were used as positive control to compare their interaction fingerprint patterns with our proposed structures. Finally, based on the binding energy values, one active structure (ligand 15) was selected for molecular dynamic simulation in order to get information for the binding mode of these ligands within the enzyme cavity. The triazole of ligand 15 pointed to HEM group in aromatase active site and coordinated to Fe of HEM through its N4 atom. In addition, two π-cation interactions was also observed, one interaction between triazole and porphyrin of HEM group, and the other was 4-chloro phenyl moiety of this ligand with Arg115 residue.


Ionic Exchange of Metal-Organic Frameworks for Constructing Unsaturated Copper Single-Atom Catalysts for Boosting Oxygen Reduction Reaction.
Regulating the coordination environment of atomically dispersed catalysts is vital for catalytic reaction but still remains a challenge. Herein, an ionic exchange strategy is developed to fabricate atomically dispersed copper (Cu) catalysts with controllable coordination structure. In this process, the adsorbed Cu ions exchange with Zn nodes in ZIF-8 under high temperature, resulting in the trapping of Cu atoms within the cavities of the metal-organic framework, and thus forming Cu single-atom catalysts. More importantly, altering pyrolysis temperature can effectively control the structure of active metal center at atomic level. Specifically, higher treatment temperature (900 °C) leads to unsaturated Cu-nitrogen architecture (CuN3 moieties) in atomically dispersed Cu catalysts. Electrochemical test indicates atomically dispersed Cu catalysts with CuN3 moieties possess superior oxygen reduction reaction performance than that with higher Cu-nitrogen coordination number (CuN4 moieties), with a higher half-wave potential of 180 mV and the 10 times turnover frequency than that of CuN4 . Density functional theory calculation analysis further shows that the low N coordination number of Cu single-atom catalysts (CuN3 ) is favorable for the formation of O2 * intermediate, and thus boosts the oxygen reduction reaction.


[Fiberoptic endoscopic evaluation of swallowing--the Tel Aviv Voice and Swallowing Disorders Clinic].
Fiberoptic endoscopic evaluation of swallowing (FEES) involves passing a fiberoptic laryngoscope transnasally to visualize the hypopharynx, larynx, and proximal trachea in order to assess swallowing disorders. FEES has been compared with the modified barium swallow (MBS) (the presumed "gold standard"). To date, reports have demonstrated that FEES is as sensitive as, or even more sensitive, for use as a tool in swallowing assessment compared with the MBS. FEES provides the clinician with a safe, portable, effective, and valid means of evaluating individuals with swallowing disturbances. FEES allows the examiner to identify swallowing physiology, determine the safest and least restrictive level of oral intake, implement appropriate compensatory techniques, and identify a dysphagia rehabilitation plan. In this article we present the Tel-Aviv Voice and Swallowing Disorders Center experience. Out of 100 patients that were referred to our center for swallowing evaluation 97 patients underwent 102 FEES examinations. Three patients couldn't tolerate the examination. In 63% of the patients swallowing pathology was found. FEES were performed by teamwork involving a speech-language pathologist and otolaryngologist collaborating together thus optimally managing the individual with dysphagia safely and efficiently.


Prediction of treatment response in head and neck cancer by magnetic resonance spectroscopy.
Poor treatment outcome remains high in patients with squamous cell carcinoma (SCC) of the head and neck region. Treatment of head and neck cancer could be improved and perhaps standardized if reliable markers for tumor progression and poor prognosis could be developed. MR spectroscopy has been used previously to differentiate between malignant and adjacent normal specimen in these cancers. This study explores the capability of MR spectroscopy in providing an indication of the aggressiveness of a tumor and its response to treatment. Thirty-six SCC patients with treatment failure, and 22 other patients who were treated concurrently at the same center but with no indication of failure for a period of 3 years, were selected for the study. Tumor specimens were kept frozen at -70 degrees C, and later subjected to 1H-MR spectroscopy at 25 degrees C. The resonance areas for 6 spectral regions were determined, and their ratio calculated. The mean values of the ratios were then compared between the 2 groups by using the Student t test. The choline-to-creatine (3.2/3.0 parts per million [ppm]) and the 1.3/0.9 ppm spectral intensity ratios (signal due to lipid or lactic acid) were the 2 most notable ones to be significantly elevated in the group with poor response. Using these ratios, a sensitivity of 83% and a specificity of 82% were obtained in predicting which head and neck cancer patients would fail treatment. These preliminary results suggest that MR spectroscopy has the potential to contribute to an accurate and early prediction of tumor behavior and response to treatment in squamous cell carcinoma of the head and neck region.


Spatial patterning of bone stiffness in the anterior mandibular corpus of Macaca fascicularis: Implications for models of bone adaptation.
Elastic modulus of bone from the anterior mandibular corpus was determined via microindentation in a mixed-sex ontogenetic sample (N = 14) of Macaca fascicularis. This investigation focused on the hypothesis that material heterogeneity in the macaque mandibular symphysis-provided an accounting of age and sex variation-is explicable as a means to homogenize strains in this region. Experimental data and theoretical models of masticatory loading indicate that in the absence of material compensation, large strain gradients exist in the anterior mandibular corpus of macaques, particularly between lingual and labial cortical plates owing to the effects of lateral transverse bending. Microindentation data indicate that juvenile macaques possess less stiff bone than their subadult and adult counterparts; however, sex differences in elastic modulus are not apparent. Anisotropy variation is idiosyncratic; that is, there is not a common pattern of variation in stiffness sampled among orthogonal planes across individuals. Similarly, differences in stiffness between lingual and labial cortical plates, as well as differences among alveolar, midcorpus, and basal regions are inconsistently observed. Consequently, we find little evidence in support of the hypothesis that spatial variation in bone stiffness functions to homogenize strains in the anterior corpus; in fact, in some individuals, this spatial variation serves to exacerbate, rather than to minimize, strain gradients. The mechanical benefit of elastic modulus variation in the macaque mandibular symphysis is unclear; this variation may not confer adaptive benefit in terms of structural integrity despite the fact that such variation has discernible functional consequences.


Primary gastrointestinal non-Hodgkin's lymphoma: treatment outcome.
Primary gastrointestinal lymphoma is the most common extranodal presentation of non-Hodgkin's lymphoma. In this retrospective study, all cases of primary gastrointestinal lymphoma registered at Kuwait Cancer Control Center between January 1992 and December 2001 were reviewed. Patients were diagnosed through an endoscopic biopsy or exploratory laparotomy. Staging procedures included computed axial tomography scan, bone marrow biopsy, barium and follow-through study, as well as routine chemistry (including lactate dehydrogenase) and hemography. There were 46 patients (30 men and 16 women); ages ranged from 16 to 82 years (median age, 43.6 years). The most common site of involvement was the stomach (70%), and the most common histology was large B cell. At least 50% of cases underwent primary radical surgery, and the majority of patients received subsequent chemotherapy and/or local radiation therapy. Chemotherapy consisted of the CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) regimen for large B-cell histology and CVP (cyclophosphamide/vincristine/prednisone) or oral alkylating agents for low-grade histology. Of this cohort, only 12 cases (26%) have had local or distant relapse. Disease-free survival rates for low-grade and high-grade non-Hodgkin's lymphoma were 64% and 81%, respectively. Primary gastrointestinal lymphoma is a potentially curable malignancy.


Genomic, regulatory and epigenetic mechanisms underlying duplicated gene evolution in the natural allotetraploid Oryza minuta.
Polyploid species contribute to Oryza diversity. However, the mechanisms underlying gene and genome evolution in Oryza polyploids remain largely unknown. The allotetraploid Oryza minuta, which is estimated to have formed less than one million years ago, along with its putative diploid progenitors (O. punctata and O. officinalis), are quite suitable for the study of polyploid genome evolution using a comparative genomics approach. Here, we performed a comparative study of a large genomic region surrounding the Shattering4 locus in O. minuta, as well as in O. punctata and O. officinalis. Duplicated genomes in O. minuta have maintained the diploid genome organization, except for several structural variations mediated by transposon movement. Tandem duplicated gene clusters are prevalent in the Sh4 region, and segmental duplication followed by random deletion is illustrated to explain the gene gain-and-loss process. Both copies of most duplicated genes still persist in O. minuta. Molecular evolution analysis suggested that these duplicated genes are equally evolved and mostly manipulated by purifying selection. However, cDNA-SSCP analysis revealed that the expression patterns were dramatically altered between duplicated genes: nine of 29 duplicated genes exhibited expression divergence in O. minuta. We further detected one gene silencing event that was attributed to gene structural variation, but most gene silencing could not be related to sequence changes. We identified one case in which DNA methylation differences within promoter regions that were associated with the insertion of one hAT element were probably responsible for gene silencing, suggesting a potential epigenetic gene silencing pathway triggered by TE movement. Our study revealed both genetic and epigenetic mechanisms involved in duplicated gene silencing in the allotetraploid O. minuta.


A new spiroindene pigment from the medicinal fungus Phellinus ribis.
A new spiroindene pigment, phelliribsin A, was isolated from the medicinal fungus Phellinus ribis, and its structure was determined by two dimensional (2D)-NMR methods. Phelliribsin A is an unprecedented spiroindene compound, and was found to have cytotoxic activity against PC12 cells at a concentration of 30 µM.


Building complexity in O2-binding copper complexes. Site-selective metalation and intermolecular O2-binding at dicopper and heterometallic complexes derived from an unsymmetric ligand.
A novel unsymmetric dinucleating ligand (L(N3N4)) combining a tridentate and a tetradentate binding sites linked through a m-xylyl spacer was synthesized as ligand scaffold for preparing homo- and dimetallic complexes, where the two metal ions are bound in two different coordination environments. Site-selective binding of different metal ions is demonstrated. L(N3N4) is able to discriminate between Cu(I) and a complementary metal (M' = Cu(I), Zn(II), Fe(II), Cu(II), or Ga(III)) so that pure heterodimetallic complexes with a general formula [Cu(I)M'(L(N3N4))](n+) are synthesized. Reaction of the dicopper(I) complex [Cu(I)2(L(N3N4))](2+) with O2 leads to the formation of two different copper-dioxygen (Cu2O2) intermolecular species (O and (T)P) between two copper atoms located in the same site from different complex molecules. Taking advantage of this feature, reaction of the heterodimetallic complexes [CuM'(L(N3N4))](n+) with O2 at low temperature is used as a tool to determine the final position of the Cu(I) center in the system because only one of the two Cu2O2 species is formed.


Microaneurysms segmentation with a U-Net based on recurrent residual convolutional neural network.
Microaneurysms (MAs) play an important role in the diagnosis of clinical diabetic retinopathy at the early stage. Annotation of MAs manually by experts is laborious and so it is essential to develop automatic segmentation methods. Automatic MA segmentation remains a challenging task mainly due to the low local contrast of the image and the small size of MAs. A deep learning-based method called U-Net has become one of the most popular methods for the medical image segmentation task. We propose an architecture for U-Net, named deep recurrent U-Net (DRU-Net), obtained by combining the deep residual model and recurrent convolutional operations into U-Net. In the MA segmentation task, DRU-Net can accumulate effective features much better than the typical U-Net. The proposed method is evaluated on two publicly available datasets: E-Ophtha and IDRiD. Our results show that the proposed DRU-Net achieves the best performance with 0.9999 accuracy value and 0.9943 area under curve (AUC) value on the E-Ophtha dataset. And on the IDRiD dataset, it has achieved 0.987 AUC value (to our knowledge, this is the first result of segmenting MAs on this dataset). Compared with other methods, such as U-Net, FCNN, and ResU-Net, our architecture (DRU-Net) achieves state-of-the-art performance.


Meta-Analysis of Children's Acute Psychological Stress and Action Stress on Immune Function under Microscope Images.
The immune system is a complex system, mainly including immune cells and immune organs. When the human body is invaded by foreign substances, the immune system will play a role in resisting the attack of harmful substances and pure necrotic cells, which is the defense structure of the body. The purpose of this study was to analyze children's acute psychological stress and action stress, and judge the adverse effects on immune function. Through the stress experiment of rats, three experimental groups were set up, which were placebo control group, placebo stress group, and drug stress group. The experiments include material-level test, sugar preference test, body weight test, and lymphocyte test. The experimental data show that stress reaction not only causes negative emotions, but also reduces weight gain by about 5%, and sugar preference decreases by about 40% compared with the normal group. There was no significant difference in the number of granulocytes and intermediate cells in the blood, but the number of lymphocytes increased from 2.49 × 109/L to 5.03 × 109/L. It shows that acute psychological stress has an inhibitory effect on the immune function of the body; not only suitable load exercise can improve the immune function of the body but also the mechanism may be that moderate load exercise makes the rat axis has better adaptability, and improves hormones, cytokines, and cytokines. The secretion of neurotransmitters can maintain the stability of the body's immune function.


Multiple mini-interviews: same concept, different approaches.
Increasing numbers of educational institutions in the medical field choose to replace their conventional admissions interviews with a multiple mini-interview (MMI) format because the latter has superior reliability values and reduces interviewer bias. As the MMI format can be adapted to the conditions of each institution, the question of under which circumstances an MMI is most expedient remains unresolved. This article systematically reviews the existing MMI literature to identify the aspects of MMI design that have impact on the reliability, validity and cost-efficiency of the format. Three electronic databases (OVID, PubMed, Web of Science) were searched for any publications in which MMIs and related approaches were discussed. Sixty-six publications were included in the analysis. Forty studies reported reliability values. Generally, raising the number of stations has more impact on reliability than raising the number of raters per station. Other factors with positive influence include the exclusion of stations that are too easy, and the use of normative anchored rating scales or skills-based rater training. Data on criterion-related validities and analyses of dimensionality were found in 31 studies. Irrespective of design differences, the relationship between MMI results and academic measures is small to zero. The McMaster University MMI predicts in-programme and licensing examination performance. Construct validity analyses are mostly exploratory and their results are inconclusive. Seven publications gave information on required resources or provided suggestions on how to save costs. The most relevant cost factors that are additional to those of conventional interviews are the costs of station development and actor payments. The MMI literature provides useful recommendations for reliable and cost-efficient MMI designs, but some important aspects have not yet been fully explored. More theory-driven research is needed concerning dimensionality and construct validity, the predictive validity of MMIs other than those of McMaster University, the comparison of station types, and a cost-efficient station development process.


Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Nutrition and health". Nutritional therapies to improve health: lessons from companion animals.
Companion animals represent an under-utilised resource. The present paper is designed to encourage collaborative studies. Dogs and cats are out-bred animals that are willing to consume a consistent diet for long periods, so are ideal candidates for prospective studies of naturally-occurring disease. In some studies the effect of diet on survival has been substantial. Food restriction, for example, slows the development of osteoarthritis and increases the lifespan of Labrador retrievers by 2 years, protein and P restriction more than doubles the median survival time of dogs and cats with chronic kidney disease and adding n-3 fats and arginine to the diet of dogs with stage 3 lymphoma improves median survival time by one-quarter. Obesity is also very common in both dogs and cats and is also associated with disease as in human subjects. When interpreting these results, however, it is essential to take into account pathophysiological differences among species. Dogs and cats do not display all the characteristics of metabolic disease in human subjects, they metabolise fat well and atherosclerosis and cardiac infarction are uncommon. Such differences should not, however, preclude further study because differences among species often clarify knowledge. Monitoring of disease in companion animals may also provide a surveillance system for the safety of the food supply, as illustrated by recent outbreaks of acute renal failure and liver failure in cats and dogs in the USA caused respectively by melamine and mycotoxin contamination of pet foods.


Transfer RNA gene redundancy and translational selection in Saccharomyces cerevisiae.
A total of 274 transfer RNA genes, representing the entire tRNA gene set of the yeast Saccharomyces cerevisiae, has been extracted from the whole genome sequence of this organism using a dedicated search algorithm (Pol3scan). All tRNA genes were assigned to 42 classes of distinct codon specificity. Accordingly, four deviations from previously proposed rules for third position wobble pairing in yeast, three G:U and one A:I codon-anticodon pairings, were found to be required to account for the reading of 61 coding triplets. The gene copy number for individual tRNA species, which ranges from one to 16, correlates well with both the frequency of codon occurrence in a sample of 1756 distinct protein coding sequences (r = 0.82) and the previously measured intracellular content of 21 tRNA species. A close link between tRNA gene redundancy and the overall amino acid composition of yeast proteins was also observed. Regression analysis values for individual protein coding sequences proved to be effective descriptions of the translational selective pressure operating on a particular gene. A significantly stronger co-adaptation between codon choice and tRNA gene copy number was observed in highly expressed genes. These observations strongly support the notion that intracellular tRNA levels in normally growing yeast cells are mainly determined by gene copy number, which, along with codon choice, is the key parameter acted upon by translational selection.


[The extent of the atypical squamous epithelium of the cervix uteri (author's transl)].
210 cone biopsies were examined. In 27 cases a dysplasia of low degree and in 30 cases a dysplasia of higher degree was found to be the maximal epithelial lesion; a carcinoma in situ was found in 87 cases and an early stromal invasion in 66 cases. The examinations were performed in sagittal sections of the central areas of cone specimens. In each section the lengths of all atypical epithelial extensions were measured. In cases with different atypical epithelial in the same section, e.g. different dysplasias or carcinomata in situ, the extent of the atypical epithelium was defined as the total sum of all respective epithelial lengths. Moreove,the sum of these lengths is considered as a parameter of the surface area of an atypial field and is expressed as a percentage of the total epithelial cone surface. It was observed that in any given lesion, the higher the maximal epithelial atypia, the more frequent the coincidence of different types of atypia. The coincidence was most frequent in early stromal invasion. These results are in conflict with the present theory that carcinoma in situ orginates from dysplasia: under that assumption the dysplasias would have to become less frequent with the occurence of a carcinoma in situ. The average surface area of an atypical epithelium is greatest in cases of early stromal invasion; it is significantly greater in cases of carcinomata in situ than in dysplasias. The extent of the atypical epithelial fields can be attributed to two factors: On the one hand, the coincidence of different types of atypical epithelium is directly proportional of the degree at atypia; on the other hand, areas of carcinomata in situ were in themselves more extensive than areas of dysplasias. Expansion variations were also shown in different types of dysplasias. However, no differences in expansion could be observed in carcinomata in situ with and without stromal invasion. In early stromal invasion the significant increase in surface-area was almost exclusively due to the coincidence of carcinomata in situ with dysplasias. It is evident that a positive correlation exists between the tendency toward invasive growth and the extent of the atypical epithelium. Finally, the degree of the epithelial atypia appears to be a function of the extent of the atypical epithelium on the surface of the cervix.


Pharmacist-provided rapid HIV testing in two community pharmacies.
To evaluate the acceptability and feasibility of pharmacist-provided rapid testing for human immunodeficiency virus (HIV) infection in community pharmacies. A pharmacist-provided HIV testing model-including rapid HIV testing, counseling, and linkage to confirmatory HIV testing services-was developed and implemented. Two independent pharmacies located in Michigan cities of different size and with different prevalence of HIV infection. Number of HIV tests performed, time required for HIV testing services, description of participants who received an HIV test, and pharmacist and participant perception of the HIV testing experience. From October 2011 to March 2013, pharmacists provided HIV tests to 69 participants. One (1.5%) participant had a reactive HIV test and was immediately referred to an appropriate health care provider for confirmatory testing. HIV testing services required a median time of 30 (range, 20-90) minutes. Participants had a median age of 23 (range, 18-61) years and were diverse by gender (59.4% women) and race (46.4% black; 39.1% white). This was the first HIV test for 42% of participants, many of whom reported high-risk behaviors in the prior 6 months. Participants and pharmacists reported favorable perceptions of the HIV testing experience. This project demonstrates the acceptability and feasibility of pharmacist-provided rapid HIV testing in two community pharmacies with distinct characteristics. Further development of HIV testing services in this practice setting is warranted.


Complexity of persistent type II endoleak associated with sac expansion after endovascular abdominal aortic aneurysm repair.
Type II endoleak after endovascular aortic aneurysm repair still remains the Achilles' heel of the treatment, the source of which regularly is difficult to identify and treat. We present a patient with a persistent type II endoleak associated with a continuous aneurysm sac expansion after endovascular aortic aneurysm repair for which many diagnostic modalities were used during his follow-up such as duplex scan, computed tomography angiography and magnetic resonance angiography. Attempts were undertaken to treat the source of endoleak including coil micro-embolisation of lumbar arteries and subsequent open ligation of the inferior mesenteric artery, but they failed to eliminate the endoleak. Finally, a middle sacral artery was identified as the source of the endoleak. At that time, the patient was subjected to surgery for sigmoid carcinoma, and simultaneously, a ligation of the sacral artery was undertaken which eventually eliminated the endoleak completely. This case highlights that type II endoleak may be evoked by various sources and there can be a great difficulty to identify these feeding vessels; thus, careful planning for its management is mandatory.


Results of the 2014 Survey of the Association of Directors of Radiation Oncology Programs (ADROP).
In 2014, the Association of Directors of Radiation Oncology Programs (ADROP) conducted an in-depth survey of program directors along several axes. We report the results of this survey and compare the major findings with those of the 2007 ADROP survey. The survey was written and approved by ADROP leadership in 2012, announced online through broadcasts throughout 2013 and early 2014, and closed in mid-2014. The results based on question groups related to (1) hours spent in activities, (2) budget and nonprogram resources, (3) physics/biology didactics, (4) mock exams/didactics/research, (5) electives, (6) students, and (7) resources/challenges were tabulated. Descriptive comparisons with the 2007 survey were performed. There was 26% participation (23/88 programs). Major areas of time commitment were faculty and site organization, maintenance, and corrections (70 hours/year) and didactics/conferences and rounds (200 hours/year). The median program director protected time was 23% (range 0%-50%). All responding programs (100%) had biology and physics courses and assigned directors, but only approximately 20% of respondents had a threshold grade in these courses for graduation. Major resources desired were templates of goals/objectives by disease site, competency evaluations by level, journal club repository, and software for contouring, oral examination preparation, grant writing, publication writing, oral presentation, and effective teaching. Major activity challenges were Accreditation Council for Graduate Medical Education external review and time commitment. Overall, the 2014 results are similar to those of the 2007 survey. The average time commitment remains considerably higher than the 10% minimum required in the current ACGME program requirements. The survey results may guide ADROP membership in centralizing some of the identified resources needed.


Common features of low-temperature spin-charge separation and superlattice formation in multiferroic manganites and antiferromagnetic cuprates.
The paper reports on new results obtained for tetragonal quasi-2D antiferromagnetic Eu2CuO4 at temperatures below 30-40 K. A set of ferromagnetic resonance lines similar to ones obtained earlier for a number of multiferroic manganites (Sanina et al 2012 J. Phys.: Condens. Matter 24 346002), with similar electric polarization and local conductivity, were measured, i.e., a multiferroic behavior was revealed in Eu2CuO4 at low temperatures. We attribute these observations to the 1D superlattices that are formed due to phase separation and self-organization of charge carriers and occupy a small crystal volume, as in the multiferroic manganites studied earlier. Characteristic features of these superlattices include a spin-charge separation and conductivity in their ferromagnetic layers. It is supposed that superlattices are domain walls separating the volume antiferromagnetic domains. A similarity between the superlattices in a number of crystals having different symmetries and bulk properties suggests that a topological order similar to that of the topological insulator exists in them at low temperatures.


Facilitators and inhibitors of the emergency nurse practitioner role.
Factors that facilitate or inhibit implementation of the Emergency Nurse Practitioner (ENP) role were studied. ENPs were surveyed by questionnaire. Sixty-eight (64.7 percent) responded, providing data about motivating factors influencing the decision to seek ENP education and subsequent job acceptance; current employment status; role concept; performance and autonomy; and barriers to practice. Nearly all program graduates had practiced as ENPs, but only 43 percent were doing so at the time of survey. Of the rest, a third were nurse practitioners in a nonemergency room setting (NPs), and 22 percent were practicing in other nursing roles (NNPs). Respondents were motivated to enter an ENP program by greater role credibility, autonomy, job advancement, learning new skills, and dissatisfaction with their jobs. Similarly, ENPs accepted their jobs because of the opportunity to use their new skills, available medical backup, and the location of employment. NPs and NNPs reported leaving ENP practice because of resistance from other health care providers. ENPs experienced resistance in their practice, although they believed the role was accepted by consumers and health care colleagues. They tended to perform tasks they believed appropriate to the role and not to perform tasks inappropriate to the role. Most ENPs reported role autonomy and a collaborative or independent practice. While 42 percent reported no barrier to practice, the majority of ENPs reported greater than one barrier. Resistance and legal status were the most frequently reported barriers. The need for further onsite and nationwide research on the ENP is suggested.


AHK5 histidine kinase regulates root elongation through an ETR1-dependent abscisic acid and ethylene signaling pathway in Arabidopsis thaliana.
The Arabidopsis thaliana genome encodes a small family of histidine (His) protein kinases, some of which have redundant functions as ethylene receptors, whereas others serve as cytokinin receptors. The most poorly characterized of these is authentic histidine kinase 5 (AHK5; also known as cytokinin-independent 2, CKI2). Here we characterize three independent ahk5 mutants, and show that they have a common phenotype. Our results suggest that AHK5 His-kinase acts as a negative regulator in the signaling pathway in which ethylene and ABA inhibit the root elongation through ETR1 (an ethylene receptor).


Complications associated with use of levamisole-contaminated cocaine: an emerging public health challenge.
Levamisole is an immunomodulatory agent that was used to treat various cancers before being withdrawn from the United States market in 2000 because of adverse effects. Levamisole is currently approved as an antihelminthic agent in veterinary medicine, but is also being used illicitly as a cocaine adulterant. Potential complications associated with use of levamisole-laced cocaine include neutropenia, agranulocytosis, arthralgias, retiform purpura, and skin necrosis. Treatment is primarily supportive, and skin lesions typically resolve with cessation of cocaine use. The incidence of hospitalizations related to use of levamisole-contaminated cocaine continues to increase and clinicians should be aware of the more common clinical manifestations.


Lung transplantation triggered "jackhammer esophagus": a case report and review of literature.
A 19-years-old girl was referred for lung transplant due to end stage lung disease secondary to idiopathic bilateral bronchiectasis. Her routine pre lung transplant evaluation showed normal esophageal high-resolution manometry (HRM) and 24-hours impedance pH monitoring. Four weeks after the bilateral sequential lung transplantation (LTx), she developed dysphagia, chest pain and regurgitation, complicated by aspiration pneumonia. Repeated HRM showed Jackhammer esophagus, delayed gastric emptying and abnormal 24-hour pH impedance monitoring consistent with the diagnosis of gastroesophageal reflux disease. Twelve weeks after LTx, she was symptom free, HRM and 24-hour impedance pH monitoring returned to normal. To the best of our knowledge, this rare transient esophageal hypercontractility episode occurred after LTx and recovered without any specific treatment was never reported in literature. The etiopathogenesis of Jackhammer esophagus in general and LTx induced dysmotility in particular is discussed and reviewed.


Induction of detoxication enzymes in insects.
Most of the known enzyme systems involved in the degradation of insecticides, other xenobiotics, and hormones of insects, appear to be inducible by various dietary chemicals, both plant-based and man-made. Although the understanding of the mechanism of this phenomenon comes almost entirely from studies of higher animals, there are good reasons to believe that the insect system is similar in most respects. If so, it involves a recognition system wherein exogenous chemicals in the insect's environment can stimulate the production of the enzymes that degrade them. Evidence is presented that some plant species and some plant allelochemicals are capable of such enhancement and that this is sufficient to increase the tolerance of an insect to various insecticides. It is also suggested that induction by plant chemicals may be involved in the insect's adaptation to its plant diet. Further understanding of the phenomenon, especially in regard to the cyclic nature of the process in plants and insects, may be of value in organizing pest management programs.


Bronchopulmonary arteriovenous malformation presenting as cryptogenic hemoptysis in a patient with bicuspid aortic valve.
We report the case of a 44-year-old male patient with bicuspid aortic valve, presenting with hemoptysis. Catheter angiography revealed an abnormal communication between bronchial and pulmonary artery, which remained undetected on computed tomography angiography. Angioembolization was done using polyvinyl alcohol and gelfoam particles. This is the first case in literature describing bronchial arteriovenous malformation associated with bicuspid aortic valve.


Evaluation of the clinical benefit of an electromagnetic navigation system for CT-guided interventional radiology procedures in the thoraco-abdominal region compared with conventional CT guidance (CTNAV II): study protocol for a randomised controlled trial.
Interventional radiology includes a range of minimally invasive image-guided diagnostic and therapeutic procedures that have become routine clinical practice. Each procedure involves a percutaneous needle insertion, often guided using computed tomography (CT) because of its availability and usability. However, procedures remain complicated, in particular when an obstacle must be avoided, meaning that an oblique trajectory is required. Navigation systems track the operator's instruments, meaning the position and progression of the instruments are visualised in real time on the patient's images. A novel electromagnetic navigation system for CT-guided interventional procedures (IMACTIS-CT®) has been developed, and a previous clinical trial demonstrated improved needle placement accuracy in navigation-assisted procedures. In the present trial, we are evaluating the clinical benefit of the navigation system during the needle insertion step of CT-guided procedures in the thoraco-abdominal region. This study is designed as an open, multicentre, prospective, randomised, controlled interventional clinical trial and is structured as a standard two-arm, parallel-design, individually randomised trial. A maximum of 500 patients will be enrolled. In the experimental arm (navigation system), the procedures are carried out using navigation assistance, and in the active comparator arm (CT), the procedures are carried out with conventional CT guidance. The randomisation is stratified by centre and by the expected difficulty of the procedure. The primary outcome of the trial is a combined criterion to assess the safety (number of serious adverse events), efficacy (number of targets reached) and performance (number of control scans acquired) of navigation-assisted, CT-guided procedures as evaluated by a blinded radiologist and confirmed by an expert committee in case of discordance. The secondary outcomes are (1) the duration of the procedure, (2) the satisfaction of the operator and (3) the irradiation dose delivered, with (4) subgroup analysis according to the expected difficulty of the procedure, as well as an evaluation of (5) the usability of the device. This trial addresses the lack of published high-level evidence studies in which navigation-assisted CT-guided interventional procedures are evaluated. This trial is important because it addresses the problems associated with conventional CT guidance and is particularly relevant because the number of interventional radiology procedures carried out in routine clinical practice is increasing. ClinicalTrials.gov identifier: NCT01896219 . Registered on 5 July 2013.


X-ray tomography of a crumpled plastoelastic thin sheet.
Three-dimensional x-ray tomography is performed to investigate the internal structure and its evolution of a crumpled aluminum foil ball. The upper and lower bounds of the internal geometric fractal dimension are determined, which increase with the compression. Contrary to the simulation results, we find that the mass distribution changes from being inhomogeneous to uniform. Corroborated with the evidence from previous experiments, these findings support the physical picture that the elastic property precedes the plastic one at dominating the deformation and mechanical response for all crumpled structures. We show that the interior of a crumpled ball at the plastic regime can be mapped to the compact packing of a granular system.


Selective apoptosis of natural killer-cell tumours by l-asparaginase.
We examined the effectiveness of various anti-tumour agents to natural killer (NK)-cell tumour cell lines and samples, which are generally resistant to chemotherapy, using flow cytometric terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling (TUNEL) assay. Although NK-YS and NK-92 were highly resistant to various anti-tumour agents, l-asparaginase induced apoptosis in these two NK-cell lines. NK-cell leukaemia/lymphoma and acute lymphoblastic leukaemia (ALL) samples were selectively sensitive to l-asparaginase and to doxorubicin (DXR) respectively. Samples of chronic NK lymphocytosis, an NK-cell disorder with an indolent clinical course, were resistant to both drugs. Our study clearly separated two major categories of NK-cell disorders and ALL according to the sensitivity to DXR and l-asparaginase. We examined asparagine synthetase levels by real-time quantitative polymerase chain reaction (RQ-PCR) and immunostaining in these samples. At least in nasal-type NK-cell lymphoma, there was a good correlation among asparagine synthetase expression, in vitro sensitivity and clinical response to l-asparaginase. In aggressive NK-cell leukaemia, although asparagine synthetase expression was high at both mRNA and protein levels, l-asparaginase induced considerable apoptosis. Furthermore, samples of each disease entity occupied a distinct area in two-dimensional plotting with asparagine synthetase mRNA level (RQ-PCR) and in vitrol-asparaginase sensitivity (TUNEL assay). We confirmed rather specific anti-tumour activity of l-asparaginase against NK-cell tumours in vitro, which provides an experimental background to the clinical use of l-asparaginase for NK-cell tumours.


Corticostriatal covariance patterns of 6-[18F]fluoro-L-dopa and [18F]fluorodeoxyglucose PET in Parkinson's disease.
6-[18F]fluoro-L-dopa (FDOPA) is a common presynaptic dopaminergic tracer used in examinations by positron emission tomography (PET) for patients with Parkinson's disease (PD). The distinct metabolic covariance pattern in the uptake of [18F]fluorodeoxyglucose (FDG) can also be used to investigate PD pathology. Although the two tracers are widely used in PD research and clinical assessment, no thorough comparative studies of the tracers have been made. In this study, 25 PD patients were examined with FDOPA and FDG to investigate relationships and clinical correlates of metabolic and monoaminergic function in the Parkinsonian brain. A VOI (volume-of-interest) analysis was achieved by 3D spatial normalisation and fixed VOI-sets. The hemisphere ipsi- and contralateral to the predominant symptoms of PD was identified in each data set, and data across subjects were related using that laterality, rather than body side. Regional covariance patterns for FDOPA and FDG were derived from principal component analysis (PCA). The results demonstrated hemispheric asymmetries and sex-differences in the striatal FDOPA uptake, which were not seen with FDG. In addition, the PCA analysis identified a positive relationship between a major component in FDOPA uptake (associated with the striatal uptake) and an FDG component, which had positive loadings in the thalamus and the cerebellum. The subject scores for these components correlated positively, and both had a negative association with the clinical severity of the disease. The specific extrastriatal FDG covariance pattern contained the thalamus and the cerebellum, components of the previously reported PD related pattern, but not the striatum. The network correlated with both the severity of clinical symptoms of PD and the severity of nigrostriatal dopaminergic hypofunction. The results indicate that FDG PET, when combined with multivariate network analysis at group-level, can be used as an indicator of PD severity.


Profile of tobacco users identified in primary care practice and predictors of readiness to quit: a cross-sectional survey.
The aim of this study was to document the prevalence of tobacco use and describe the characteristics of tobacco users identified in primary care practices. We conducted a cross-sectional survey in 49 primary care practices in the province of Ontario. Consecutive patients were screened for smoking status at the time of their clinic appointment. Patients reporting current tobacco use completed a survey, which documented sociodemographic and smoking-related characteristics. Multilevel modelling was used to examine predictors of readiness to quit smoking and the presence of anxiety and/or depression. A total of 56 592 patients were screened, and 5245 tobacco users participated in the survey. Prevalence of tobacco use was 18.2% and varied significantly across practices (range 12.4%-36.1%). Of the respondents, 46.3% reported current anxiety and/or depression, and 61.3% reported smoking within the first 30 minutes of waking. A total of 41.1% of respondents reported they were ready to quit smoking in the next 6 months, and 30.1% reported readiness to quit in the next 30 days. Readiness to quit was positively associated with higher self-efficacy, male sex, presence of chronic obstructive pulmonary disease and more years of tobacco use. The presence of anxiety and/or depression was associated with lower cessation self-efficacy and time to first cigarette within 30 minutes of waking, but did not predict readiness to quit. Tobacco users identified in primary care practices reported high rates of nicotine dependence and anxiety and/or depression, but also high rates of readiness to quit. Study findings support the need to tailor interventions to address the needs of tobacco users identified in primary care settings.


Molecular construction, characterization, and photophysical properties of supramolecular lanthanide-calix[4]arene covalently bonded hybrid systems.
Hydroxyl groups of the macrocyclic compound p-tert-butylcalix[4]arene have been converted into urethanesil (-NH(C=O)O-)-grafted bridges through a hydrogen transfer nucleophilic addition reaction. Subsequently, the modified macrocyclic derivative can coordinate to lanthanide ions (Tb, Eu) effectively and form a hybrid framework after the cohydrolysis and copolycondensation process through the triethoxysilane components. The above sol-gel-derived inorganic-organic supramolecular hybrids are analyzed under infrared spectroscopy, ultraviolet absorption, and luminescence spectroscopy for interpretation of their photophysical properties. Spectroscopic data point out that the modified calix[4]arene could sensitize diverse lanthanide ions to exhibit attractive green and red luminescence. It is noted that the triplet energy level of this particular macrocyclic bridged ligand is more suitable for the emissive energy level of Tb(3+) ions than the Eu(3+) ions. The luminescent lifetimes and quantum yields of europium hybrids are discussed, and the number of water molecules coordinated to Eu(3+) is estimated.


Fibrotic changes in high-resolution computed tomography in patients with sarcoidosis.
The aim of the study is presenting the typical findings of fibrotic changes in high-resolution computed tomography in patients with sarcoidosis. Material comprises a group of 18 patients with sarcoidosis, in whom HRCT examination was performed. The scanning was performed from lung apices to the level of diaphragm, at full inspiration with patients in supine position. The presence and character of HRCT findings were noted and analyzed. Additional expiratory scans were performed to diagnose air-trapping, and in case of subpleural densities in posterior, dependent lung areas additional scans were obtaining in prone patients positions. Fibrotic changes were found in the area of confluent nodular lesions in five patients. In these fibrotic areas the bronchiectasis, as well as parenchymal bands and fibrotic masses were seen. In six patients the reticular pattern was the predominant pathology. Thickened lobular septa did not resolve during the remission of the diseases, suggesting the presence of irreversible, reticular fibrotic changes. Intensive fibrosis led towards destruction of the lung parenchyma, with honeycombing involving large lung areas. In the areas of active disease fibrotic changes with traction bronchiectasis were accompanied by the confluent nodular changes and presence of consolidation. After resolving of active reversible changes the intensive fibrosis with large bronchiectasis forming the honeycombing pattern with reticular changes were seen in five patients. In three cases the most intensive changes both fibrotic and productive (granuloma) changes were localized in the lower lobe, mimicking the idiopathic pulmonary fibrosis. The classical HRCT findings in sarcoidosis are well known. But most of them, nodules, ground glass opacities, peribronchovascular thickening or hilar adenopathy are reversible. The irreversible fibrotic changes develop in about 25% of patients. In the early stage they are subtle and invisible on plain radiographs or even on normal CT sections. So the HRCT is necessary to reveal fibrotic changes in patients with sarcoidosis and to monitor the progression of the diseases. Therefore, the good knowledge of HRCT signs of fibrosis is essential.


Social and psychological problems of adolescence and their relevance to dental care.
Troublesome behaviours of adolescent patients are explained using the cognitive-developmental framework of Elkind (1978). Self-contradictory and seemingly irrational behaviours reflect the limited experience of adolescents with newly acquired thinking and reasoning processes. The most important task of adolescence is establishing the adult identity. Just as physiological factors are producing a new adult body, cognitive processes are producing a new adult mind with new behaviour patterns. The erratic behaviours of adolescents are 'symptoms' of the cognitive-developmental process. Four such symptoms are described. 'Pseudostupidity' is the adolescent's tendency to overlook the obvious and inability to make appropriate choices. It results from the lack of experience with newly attained abilities to perceive many possibilities simultaneously. The 'imaginary audience' is the adolescent's self-conscious belief that everyone is watching and evaluating him or her. It reflects the new ability to think about the thoughts of others and the inability to distinguish them from personal thoughts. The 'personal fable' refers to a strong feeling of invulnerability and uniqueness, which reflects an incomplete understanding of the self. 'Apparent hypocrisy' comes from the new ability to conceive ideals and the inability to relate ideals to behaviours. These constructs are applied to situations in the dental setting that reflect difficulties in communication between dentists and adolescent patients and the aesthetic concerns of adolescents. Dentists are advised to remember that adolescent behaviour patterns are not fixed. Of primary importance is the willingness of dentists to listen to young patients and to work towards trusting relationships with them. By serving as a stable adult role model the dentist can facilitate the adolescent's personal growth, as well as positively influencing dental health.


Short communication: Phenotypic and genetic effects of the polled haplotype on yield, longevity, and fertility in US Brown Swiss, Holstein, and Jersey cattle.
Phenotypes from the December 2018 US national genetic evaluations were used to compute effects of the polled haplotype in US Brown Swiss (BS), Holstein (HO), and Jersey (JE) cattle on milk, fat, and protein yields, somatic cell score, single-trait productive life, daughter pregnancy rate, heifer conception rate, and cow conception rate. Lactation records pre-adjusted for nongenetic factors and direct genomic values were used to estimate phenotypic and genetic effects of the polled haplotype, respectively. No phenotypic or direct genomic values effects were different from zero for any trait in any breed. Genomic PTA (gPTA) for the lifetime net merit (NM$) selection index of bulls born since January 1, 2012, that received a marketing code from the National Association of Animal Breeders (Madison, WI), and cows born on or after January 1, 2015, were compared to determine whether there was a systematic benefit to polled or horned genetics. Horned bulls had the highest average gPTA for NM$ in all 3 breeds, but that difference was significant only in HO and JE (HO: 615.4 ± 1.9, JE: 402.3 ± 3.4). Homozygous polled BS cows had significantly higher average gPTA for NM$ than their heterozygous polled or horned contemporaries (PP = 261.4 ± 43.5, Pp = 166.1 ± 13.7, pp = 174.1 ± 1.8), but the sample size was very small (n = 9). In HO and JE, horned cows had higher gPTA for NM$ (HO = 378.3 ± 0.2, JE = 283.3 ± 0.3). Selection for polled cattle should not have a detrimental effect on yield, fertility, or longevity, but these differences show that, in the short term, selection for polled over horned cattle will result in lower rates of genetic gain.


Cytotoxic principles of a Bangladeshi crude drug, akond mul (roots of Calotropis gigantea L.).
Three cardenolide glycosides, calotropin (1), frugoside (2), and 4'-O-beta-D-glucopyranosylfrugoside (3), were obtained as the cytotoxic principles of "akond mul" (roots of Calotropis gigantea L.). The cytotoxicity of these compounds against various cell lines of human and mouse origin was tested. They showed similar cell line selectivity to those of cardiac glycosides such as digoxin and ouabain: they are toxic to cell lines of human origin, but not to those from mouse at 2 micrograms/ml.


Rapid MR imaging.
During the past few years major improvements have been made in MR systems resulting in increased S/N, which is now being traded for more rapid imaging times. As discussed, there are three general strategies to decrease acquisition time and more will likely surface. Gradient-echo imaging, which has provided the most clinical experience to date, can be used for rapid imaging, functional studies and unique contrast mechanisms such as susceptibility imaging. While the contrast mechanisms and ultimate clinical utility require further study, it seems likely that gradient-echo imaging will become a routine part of clinical MR imaging.


Temporal expression of estrogen receptor alpha in the hypothalamus and medulla oblongata during fasting: a role of noradrenergic neurons.
Fasting-induced LH suppression is augmented by estrogen in female rats. We investigated the temporal changes in the number of estrogen receptor alpha (ERalpha)-immunoreactive (ir) cells in various brain regions in ovariectomized rats fasted for 6, 24, 30, and 48 h, commencing at 1300 h. We also determined the anatomical relationship of ERalpha immunoreactivity and dopamine-beta-hydroxylase (DBH) neurons in the A2 region of the nucleus of the solitary tract (NTS) and the paraventricular nucleus (PVN). The number of ERalpha-ir cells significantly increased after 30 h from the onset of fasting in the PVN and NTS compared with the unfasted controls and was sustained until 48 h. In the A2 region of 48-h fasted rats, 46.75% DBH-ir cells expressed ERalpha, and this was significantly higher than in unfasted controls (8.16% DBH-ir cells expressed ERalpha). In the PVN, most ERalpha-ir neurons were juxtaposed with DBH-ir varicosities. These results suggest that ERalpha is expressed in specific brain regions at a defined time from the onset of fasting. In addition, the anatomical relationship of noradrenergic and ERalpha-ir neurons in the A2 region and PVN may suggest a role for estrogen in increasing the activity of noradrenergic neurons in the A2 region and enhancing sensitivity of the PVN to noradrenergic input arising from the lower brainstem and thereby augmenting the suppression of LH secretion during fasting.


The clinical potential of inotuzumab ozogamicin in relapsed and refractory acute lymphocytic leukemia.
Antibody-drug conjugates (ADCs) are likely to make a significant contribution in the treatment of acute lymphoblastic leukemia (ALL) by combining the cytotoxicity of chemotherapy with the specificity of monoclonal antibodies. CD22, an endocytic receptor expressed by the majority of B cells, is an excellent target for ADCs. Inotuzumab ozogamicin (INO) is an ADC that consists of a cytotoxic moiety (derivative of calicheamicin) attached to a humanized monoclonal anti-CD22 antibody. As a single agent, INO, was shown to be effective with an objective response rate of 50% in the treatment of relapsed and refractory CD22 positive ALL patients. Clinical trials investigating the combination of INO with the conventional chemotherapies are ongoing. This review summarizes the clinical potential of INO in treatment of relapsed and refractory ALL, based on currently available data in the literature.