[Eyelid reconstruction after removal of tumours, using chondroperichondrial grafts from auricular concha].
The main goal in reconstruction of the full thickness defects of the eyelids after tumour resection is the reconstitution of the tarsal plate as supportive layer of the lid. We report a simple, one stage reconstruction procedure of repairing the eyelid internal lamella. The chondroperichondrial graft from auricular concha was used to reconstruct the tarsoconjunctival layer in nine patients with surgical defects following excision of skin cancer. Local cutaneous flaps were used to reconstruct the external lamella. All grafts appeared completely without reabsorption, healing of the wounds was rapid. Epithelialization on the perichondrium from the surrounding conjunctiva occurred between 2 and 3 weeks. The functional and aesthetic results were judged as very good in seven patients after reconstruction of the lower eyelid. One patient after reconstruction of the upper eyelid has good result too. The last patient needed secondary very extensive operation because of the tumour recurrence. Conchal chondroperichondrial free graft provides simple, one-stage reconstruction of the lower and upper eyelid. Perichondrium substitutes the conjunctiva in early postoperative period and it makes epithelialization possible.


Reflexions about imaging technique and examination protocol 2. MR-examination protocol.
Adequate imaging protocol is crucial for any imaging technique. As MR is a time consuming examination, the physician serves the patient best, when he/she makes the best choice of sequences, which answer the question of the clinician and provide a definite diagnosis. Although any patient requires an individual protocol, some general rules should be known.


Molecular complexes of l-phenylalanine with substituted 1,4-benzoquinones in aqueous medium: spectral and theoretical investigations.
Various spectral techniques such as UV-Vis, FT-IR, and fluorescence have been employed to investigate the charge transfer interaction of L-phenylalanine (LPA) with substituted 1,4-benzoquinones (MQ(1-4)). Kinetic and thermodynamic properties of the complexes were determined in aqueous medium at physiological condition (pH=7). The interaction of MQ(1-4) with L-phenylalanine (LPA) was found to proceed through the formation of donor-acceptor complex, yielding a radical anion. The stoichiometry of the complexes was determined by Jobs continuous variation method and was found to be 1:1 in all the cases. Fluorescence quenching studies showed that the interaction between the donor and the acceptors is spontaneous. The results indicated that the progressive replacement of chlorine atom (-I effect) by methoxy group (+M effect) in the quinone decreased the electron acceptor property of the quinone. The order of the experimentally measured association constant of these complexes was well supported by DFT/B3LYP calculations.


The number of regulatory T cells in transbronchial lung allograft biopsies is related to FoxP3 mRNA levels in bronchoalveolar lavage fluid and to the degree of acute cellular rejection.
The transcription factor Forkhead Box P3 (FoxP3) is a marker of regulatory T cells (Tregs) - a subset of T cells known to suppress a wide range of immune responses. These cells are considered to be pivotal for the induction of tolerance to donor antigens in human allografts. We aimed to correlate the number of lymphocytes expressing FoxP3 in transbronchial biopsies from lung allografts with the FoxP3 expression in bronchoalveolar lavage fluid (BALF). In addition, we aimed to correlate the number of FoxP3+ cells in transbronchial biopsies with the degree of acute cellular rejection in lung allografts. The expression of FoxP3 was evaluated using immunohistochemical staining in 40 lung allograft biopsies obtained from 23 patients. The number of Tregs was related to the FoxP3 mRNA levels as determined using qRT-PCR in corresponding BALF samples from the same patients. Furthermore, the number of Tregs was related to the degree of acute allograft rejection (according to ISHLT criteria, A0-A4). Regression analysis showed a significant concordance between the number of Tregs in lung tissue and the level of FoxP3 mRNA relative to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA levels in BALF (n=40, p=0.0001). In addition, we found a significant increase in the number of Tregs during acute allograft rejections of grades A2 and higher (median: 32.6Tregs/mm(2)) when compared to those of grades A1 and A0 (median: 4.9Tregs/mm(2)) (p=0.0002). The association between the distribution of Tregs in transbronchial biopsies and the level of FoxP3 mRNA in BALF indicates that assessment of FoxP3 mRNA in BALF is a reliable non-invasive method for evaluating the number of Tregs in lung tissue. Furthermore, the association between the number of Tregs in lung tissue and the degree of acute cellular rejection shows that Tregs are recruited to the site of inflammation and may be involved in the regulation of acute rejection. Thus, Tregs may play a role in the cellular processes that affect lung allograft outcome.


Family Intervention: Telephone Tracking (FITT): a pilot stroke outcome study.
The goal of this study was to preliminarily test the efficacy of a telephone intervention, Family Intervention: Telephone Tracking, designed to assist stroke survivors and their primary caregivers during the first 6 months after stroke. Forty-nine stroke survivors and their caregivers were randomly assigned to treatment as usual or treatment as usual plus the telephone intervention. Global outcomes are reported for health care utilization, family functioning, and general functioning. Family and general functioning were positively and significantly changed at 3 and 6 months. Health care utilization was positively and significantly changed at 3 months. Findings suggest that the model has the potential to decrease health care utilization and improve quality of life for stroke survivors and their caregivers. Further study is warranted.


Phototoxicity of phenylenediamine hair dye chemicals in Salmonella typhimurium TA102 and human skin keratinocytes.
Phenylenediamines (PD) are dye precursors used to manufacture hair dyes. The three PDs, 1,2-,1,3-, and 1,4-PD and three chlorinated PDs, 4-chloro-1,2-PD, 4-chloro-1,3-PD, and 4,5-dichloro-1,2-PD were studied for their mutagenic effect in Salmonella typhimurium TA 102, cytotoxicity in human skin keratinocyte cells, and for DNA cleavage. The results show that all six compounds are not toxic/mutagenic in TA 102 bacteria or skin cells, and do not cause DNA cleavage in PhiX 174 phage DNA. If the same tests are carried out by exposing them to light irradiation concurrently, all three chlorinated PDs cause mutation in TA 102 bacteria and single strand cleavage in PhiX174 phage DNA. This indicates that chlorination of the PDs makes these compounds more photochemically active and produces reactive species that cause DNA damage and mutation. For the photocytotoxicity test in skin cells, it appears there is no such structure-activity relationship. Two chlorinated PDs and two non-chlorinated PDs are cytotoxic at a fairly high concentration (1000microM) upon exposure to light irradiation.


The mitochondrial Hsp70 chaperone Ssq1 facilitates Fe/S cluster transfer from Isu1 to Grx5 by complex formation.
The mitochondrial Hsp70 chaperone Ssq1 plays a dedicated role in the maturation of iron-sulfur (Fe/S) proteins, an essential process of mitochondria. Similar to its bacterial orthologue HscA, Ssq1 binds to the scaffold protein Isu1, thereby facilitating dissociation of the newly synthesized Fe/S cluster on Isu1 and its transfer to target apoproteins. Here we use in vivo and in vitro approaches to show that Ssq1 also interacts with the monothiol glutaredoxin 5 (Grx5) at a binding site different from that of Isu1. Grx5 binding does not stimulate the ATPase activity of Ssq1 and is most pronounced for the ADP-bound form of Ssq1, which interacts with Isu1 most tightly. The vicinity of Isu1 and Grx5 on the Hsp70 chaperone facilitates rapid Fe/S cluster transfer from Isu1 to Grx5. Grx5 and its bound Fe/S cluster are required for maturation of all cellular Fe/S proteins, regardless of the type of bound Fe/S cofactor and subcellular localization. Hence Grx5 functions as a late-acting component of the core Fe/S cluster (ISC) assembly machinery linking the Fe/S cluster synthesis reaction on Isu1 with late assembly steps involving Fe/S cluster targeting to dedicated apoproteins.


Episodic autobiographical memory in depression: Specificity, autonoetic consciousness, and self-perspective.
Autobiographical memory (AM) and the self are closely linked. AM retrieval in depression is characterized by a lack of specificity, suggesting an impairment of episodic AM. Autonoetic consciousness and self-perspective, which are critical to episodic AM, have never been addressed in depression. Twenty-one depressed inpatients and 21 matched controls were given an episodic AM task designed to assess positive and negative memories regarding specificity, autonoetic consciousness (remember/know procedure), and self-perspective (field/observer procedure). For specificity, "remember", and "field" responses, ANOVAs revealed a main group effect and a group x valence interaction. Between groups, patients showed lower scores than controls for positive memories. Within groups, patients showed greater scores for negative memories, and controls showed greater scores for positive memories. There is a global episodic AM impairment of positive memories in depression regarding specificity, autonoetic consciousness, and self-perspective. Our results suggest new cognitive interventions to improve the self-relevance of positive memories in depression.


A persistent outbreak of ulcerative enteritis in bobwhite quail (Colinus virginianus).
Ulcerative enteritis is a disease that typically responds well to medication. An outbreak of ulcerative enteritis that was persistent and unresponsive to treatment is described. The outbreak started in semimature birds and progressively spread to younger birds. Confounding factors leading to this persistence were a significant coccidosis problem, a feed mixing error, and suspected antibiotic resistance. Although Clostridium colinum was never isolated, a bacitracin-resistant Clostridium perfringens was cultured from affected birds. Only the combined treatment of the flocks with an anticoccidial and tylosin was effective in controlling clinical disease. Numerous other management and treatment strategies were unsuccessful in lowering the severe mortality.


Surface Architecture Design of LiNi0.8 Co0.15 Al0.05 O2 Cathode with Synergistic Organics Encapsulation to Enhance Electrochemical Stability.
Ni-rich LiNi0.8 Co0.15 Al0.05 O2 (NCA) material attracts extensive attention due to its high discharge specific capacity, but its distinct drawbacks of rapid capacity decline and poor cycle performance at elevated temperatures and high voltage during charge/discharge cycling restricts its widespread application. To solve these problems, a multifunctional coating layer composed of a lithium-ion-conductive lithium polyacrylate (LiPAA) inner layer and a cross-linked polymer outer layer from certain organic substances of silane-coupling agent (KH550) and polyacrylic acid (PAA) is successfully designed on the surface of NCA materials, which is favorable for eliminating residual lithium and improving lithium-ion conductivity, surface stability, and hydrophobicity of NCA materials. In addition, the amount of the coating material is also investigated. A series of characterization methods such as XRD, FTIR, SEM, TEM, and X-ray photoelectron spectroscopy are used to analyze the morphologies and structures for materials of pristine and modified NCA. It is revealed that the co-coating layer plays a vital part in reducing the surface residual alkalis and improving the stability of NCA particles; as a result, the modified NCA exhibits a greatly improved rate capability, cycle performance, and low polarization impedance.


[Central cervical dissection of lymph nodes in the management of differentiated thyroid carcinoma--our experience].
Total thyroidectomy (TTE) with central compartment lymphonodes (LU) dissection remains a standard procedure in the treatment of differentiated thyroid carcinomas. The retrospective study assessed a group of patients undergoing primary or secondary procedures in our clinic. From 01.01. 2005 to 31. 07. 2007, a total of 50 patients underwent primary procedures, TTE with dissection of central compartment lymphonodes was performed in 18 patients, 58 patients were reoperated for relapses of the disorder. In the primary procedures, the central compartment lymphonodes were affected with increased rate, proportionally to a T-stage of the disorder 28% (T1), 52 (T2), 58% (T3). Multifocal carcinoma was associated with a high risk, where metastatic lymphadenopathy occured in 53% of the cases. In the reoperated subjects, relapses of the disorder were recorded in 78% of the patients in their central compartment lymphonodes and their thyreoglobulin levels decreased. Out of 126 patients, paresis of the nervus laryngeus reccurens was recorded in 4 subjects (3.1%) and postoperative hypoparathyreosis in 14 subjects (11%). Dissection of lymphonodes is a standard part of the surgical management of differentiated carcinomas, providing local control of the disease. 78% of the relapses were located within the central compartment. Risk and complication rates correspond to those reported in total thyroidectomy.


HbA1c AND E-HEALTH: YOUTUBE MIGHT BE GOOD FOR YOU, IF YOU USE IT WISELY.
The purpose of this study is to evaluate YTB content performance on HbA1c and indirectly diabetes, an important pillar of it. The contents in YTB were searched by derivative keywords of HbA1c. The resulting contents were scored using DISCERN and GQS scales. The videos were evaluated by dividing them into four groups: medical doctors, patients, educational channels and other health care professionals, according to the characteristics of producers. The videos included in the study had been watched approximately 25 million times until the article prepared. In examinations, medical doctors have higher scores than the other groups in two scales. The video scores were statistically correlated in DISCERN and GQS (r: 0.874, p<0.05). In the multiple regression analyzes, a statistically significant relationship was found between the DISCERN score and duration of the videos among video features (p<0.05). On the aspect of view counts and view ratios were similar within groups (p>0.05). YTB contents may be useful for diabetes patients with cautious research. Still, consumers must have prior knowledge of their intentions from reliable medical sources and should be meticulous about videos. In conclusion, eHealth literacy is being more crucial than before.


Cannibalism as the cause of an ontogenetic shift in habitat use by fry of the threespine stickleback.
In Crystal Lake, British Columbia, small fry (≤15 mm SL) of the threespine stickleback (Gasterosteus aculeatus) are concentrated in vegetation while larger fry are not. Because fry in all size classes feed primarily on zooplankton, even when in vegetation, we hypothesized that size-limited predation was responsible for the observed shift in habitat use with size. The major predators on fry in Crystal Lake are adult threespine stickleback, the water scorpion, Ranatra sp. (Hemiptera: Nepidae), backswimmers, Notonecta spp. (Hemiptera: Notonectidae), and dragonfly naiads of the genus Aeshna (Odonata: Aeschnidae). On the basis of distribution and hunting behavior we excluded the insects Ranatra sp., and Notonecta sp. as causal agents for this shift in resource by fry in water >0.25 m deep. Ranatra was found almost exclusively near the shoreline in water <0.25 m deep, and both insects hunted primarily as ambush predators within vegetation. Such predators seemed more likely to drive vulnerable fry from vegetation than to restrict them to it. In contrast, Aeshna naiads and adult stickleback frequently hunted outside of vegetation. In prey preference experiments the naiads did not show the decline in predation efficiency on fry >15 mm SL that would be expected if size-limited predation by this insect was responsible for the observed shift in resource use by fry. Adult stickleback only fed on fry <15 mm SL, and in an experimental situation, consumed fry at a rate 10 times greater than that exhibited by any of the insects. Predation experiments demonstrated that small fry (11-15 mm) spent more time in vegetation in the presence of adult conspecifics than they did in control pools, as would be expected if size-limited cannibalism caused small, vulnerable fry to be restricted to vegetation. Fry >15 mm SL were found outside of vegetation more often than in control treatments. The probable cause of this result is that adults become aggressive toward fry at this size, and often could be seen chasing large fry from vegetation during the experiments. Dragonfly naiads (Aeshna spp.) spent most of their time in vegetation in the experimental pools. Both size classes of fry spent less time in vegetation in the presence of dragonfly naiads than they did in control treatments, an apparent reflection of their similar vulnerabilities to these naiads. The presence of vegetation in pools reduced predation rates by adult stickleback on small fry. Because the experiments presented here indicate that fry are capable of rapidly assessing predation risk and of altering their behavior adaptively, we conclude that small fry occupy vegetation as a refuge from cannibalism. Once fry have reached the size-threshold at which they are no longer vulnerable to adult conspecifics they are able to forage farther from vegetation thereby reducing risk of predation by insects in vegetation and possibly acquiring more abundant food resources.


Influence of surgery and endotoxin-induced sepsis combined on natural killer cell activity, oxidative burst of granulocytes and antigen presentation capability of monocytes.
Cell mediated immunity is affected in the course of sepsis and following surgical stress. The natural killer (NK) cells, the granulocytes and the monocytes constitute the immediate unspecific cell mediated immunity. We therefore investigated the effect of surgery- and endotoxin-induced sepsis on NK cells, granulocytes and monocytes in a two-hit model. Three groups of 40 mice. Each group was divided into four groups of 10 mice. All the animals were anesthetized and subjected to either: laparotomy; treatment with Escherichia coli endotoxin i.p.; laparotomy followed 20 min later by endotoxin i.p.; or left untreated as a control group. In the first 40 mice the NK cell activity in the spleen and number of NK cells in the liver were measured, in the second the oxidative burst of granulocytes, and in the third the antigen presentation capacity of monocytes. Endotoxin stimulated the NK cell activity and up-regulated the antigen presentation capability on monocytes. In contrast, surgical stress reduced the NK cell activity, the number of NK cells and down-regulated the antigen presentation capability on monocytes. After surgery, followed by administration of endotoxin, the oxidative burst of granulocytes was stimulated while antigen presentation capability on monocytes was down-regulated. Endotoxin prevented or reverted the postoperative suppression of NK cell activity. Our two-hit model shows that some cell types of the unspecific immune system exhibit an excessive inflammatory response (NK cells, granulocytes) while specific functions of other cell types (monocytes) are simultaneously diminished. This diversity makes a potential therapeutic immunomodulation very complex as some cell types would need to be down-regulated while others need to be stimulated.


Cerebrospinal fluid soluble CD27 is associated with CD8+ T cells, B cells and biomarkers of B cell activity in relapsing-remitting multiple sclerosis.
Cerebrospinal fluid (CSF) soluble CD27 (sCD27) is a sensitive biomarker of intrathecal inflammation. Although generally considered a biomarker of T cell activation, CSF sCD27 has been shown to correlate with biomarkers of B cell activity in multiple sclerosis. We analyzed CSF from 40 patients with relapsing-remitting multiple sclerosis (RRMS) and nine symptomatic controls using flow cytometry and multiplex electrochemiluminescence immunoassays. CSF sCD27 levels were increased in RRMS and correlated with IgG index, soluble B cell maturation antigen, cell count, B cell frequency and CD8+ T cell frequency. We provide new data indicating that CSF sCD27 is associated with CD8+ T cells and B cells in RRMS.


Overcoming crossing barriers between nontuber-bearing and tuber-bearing Solanum species: towards potato germplasm enhancement with a broad spectrum of solanaceous genetic resources.
The first direct sexual hybrids between diploid nontuber-bearing species and diploid potato breeding lines are reported here. Three nontuberous species of Solanum, S. brevidens, S. etuberosum, and S. fernandezianum, were used for sexual crosses, achieved by a combination of rescue pollinations and embryo rescue. Initial hybrid selection was made using an embryo spot marker, followed by the evaluation of morphological and reproductive traits. Putative hybrids were first tested for resistance to potato leaf roll virus derived from the wild species, and then were tested with molecular markers using species-specific DNA probes. Finally, the tuberization of several 2x hybrids was tested for actual potato germplasm enhancement. These hybrids are unique in terms of their potential to enhance recombination between chromosomes of wild species and those of cultivated potatoes in germplasm utilization, and to exploit the genetic nature of tuber formation. The finding that nontuber-bearing Solanum spp. can be directly crossed with tuber-bearing species also has important implications for the regulatory aspects of the use of genetically modified organisms.


Relationship between acid secretion and blood flow in the canine stomach: role of oxygen consumption.
The relationship of acid secretion to blood flow and oxygen consumption was investigated in the isolated canine stomach during intraarterial infusion of pentagastrin. Blood flows above and below control values were achieved by pump perfusion and partial arterial occlusion, respectively. When blood flow was increased from a control value of 38 ml X min-1 X 100 g-1 to 85 ml X min-1 X 100 g-1, both acid secretion and oxygen consumption remained constant at 0.08 mEq X min-1 X 100 g-1 and 2.1 ml X min-1 X 100 g-1, respectively. A reduction in blood flow to 9.0 ml X min-1 X 100 g-1 caused acid secretion and oxygen consumption to decrease to 26% and 44% of control values, respectively. The results indicate that acid secretion is independent of blood flow at flow rates above 38 ml X min-1 X 100 g-1. A model of the interrelationships between blood flow, oxygen consumption, and acid secretion is proposed that may explain much of the conflict in the literature concerning these three parameters.


Somatosensory evoked cerebral magnetic fields from SI and SII in man.
We have recorded cerebral magnetic fields elicited by electrical stimulation of median and peroneal nerves. Field mapping indicates that the deflections at 30-80 and 150-180 msec are due to activity at SI. Additional activity at 90-125 msec is generated at SII, on the superior bank of the sylvian fissure. At SI, the source locations are in agreement with the known somatotopy. Only contralateral stimuli evoke responses at SI, whereas both ipsi- and contralateral stimuli elicit responses at SII.


A Population-based Model of Local Control and Survival Benefit of Radiotherapy for Lung Cancer.
To estimate the population-based locoregional control and overall survival benefits of radiotherapy for lung cancer if the whole population were treated according to evidence-based guidelines. These estimates were based on a published radiotherapy utilisation (RTU) model that has been used to estimate the demand and planning of radiotherapy services nationally and internationally. The lung cancer RTU model was extended to incorporate an estimate of benefits of radiotherapy alone, and of radiotherapy in conjunction with concurrent chemotherapy (CRT). Benefits were defined as the proportional gains in locoregional control and overall survival from radiotherapy over no radiotherapy for radical indications, and from postoperative radiotherapy over surgery alone for adjuvant indications. A literature review (1990-2015) was conducted to identify benefit estimates of individual radiotherapy indications and summed to estimate the population-based gains for these outcomes. Model robustness was tested through univariate and multivariate sensitivity analyses. If evidence-based radiotherapy recommendations are followed for the whole lung cancer population, the model estimated that radiotherapy alone would result in a gain of 8.3% (95% confidence interval 7.4-9.2%) in 5 year locoregional control, 11.4% (10.8-12.0%) in 2 year overall survival and 4.0% (3.6-4.4%) in 5 year overall survival. For the use of CRT over radiotherapy alone, estimated benefits would be: locoregional control 1.7% (0.8-2.4%), 2 year overall survival 1.7% (0.5-2.8%) and 5 year overall survival 1.2% (0.7-1.9%). The model provided estimates of radiotherapy benefit that could be achieved if treatment guidelines are followed for all cancer patients. These can be used as a benchmark so that the effects of a shortfall in the utilisation of radiotherapy can be better understood and addressed. The model can be adapted to other populations with known epidemiological parameters to ensure the planning of equitable radiotherapy services.


Gender differences in final year medical students' experience of teaching of intimate examinations: a questionnaire study.
To examine final year medical students' experience of being taught to conduct intimate examinations. Prospective questionnaire study. Medical school in the UK. Medical students in the final year cohort 2005/06. Questionnaires were distributed to students in the final week of a final year obstetrics and gynaecology course. Responses to questions about course experience were analysed using frequencies and single-variable analyses. Students' experience of and satisfaction with the teaching of intimate examinations and differences between male and female students. Male and female students performed similar numbers of intimate examinations, but clinical tutors were significantly more likely to introduce female students to patients (76 versus 52%; P = 0.001) and obtain consent on their behalf (75 versus 53%; P = 0.009) when compared with male students. Male students reported a greater degree of embarrassment (mean score 2.41 +/- 1.25 versus 1.69 +/- 0.90; P = 0.002), and a higher number of patients refusing consent to examination (median 2; range 0-12 versus 0; range 0-6; P = 0.0001). Gender discrimination in the behaviour of tutors may impact on students' experience of intimate examinations. It is highly improbable that differences in behaviour are deliberately intended to disadvantage male students, and further research is needed to understand why tutors behave differently with them. In the meantime, tutors need to be aware of potential bias and ensure appropriate support is provided for both male and female students.


Comparisons of δ13C values in leaves of aquatic macrophytes from different habitats in Britain and Finland; some implications for photosynthetic processes in aquatic plants.
The δ13C values of submerged aquatic plants from contrasting but relatively defined habitats, and the δ13C values of emergent, floating and submerged leaves of dimorphic aquatic plants, were measured. In many instances the δ13C values of dissolved inorganic carbon in the water were also measured. Plant δ13C values in the vicinity of-40 to-50‰ were found in rapidly flowing spring waters with carbonate δ13C values of-16 to-21‰, consistent with the notion that species such as Fontinalis antipyretica almost exclusively assimilate free CO2 via RuP2 carboxylase. Plant δ13C values in the vicinity of-10 to-15‰ in sluggish water with carbonate δ13C values of about-5‰ were observed, consistent with the notion that boundary layer diffusion and/or HCO3- uptake may determine the δ13C value of submerged aquatic plants in these circumstances. Comparisons of δ13C values of the same or related species growing in waters of similar carbonate δ13C value but different flow rates confirmed this view; more negative δ13C values were frequently associated with plants in fast moving water. In Britain, but not in Finland, the δ13C values of submerged leaves of dimorphic plants were almost invariably more negative than in aerial leaves. The δ13C value of carbonate from chalk streams and in acid springs indicate substantial inputs of respiratory CO2, as opposed to atmospheric carbon. The contributions of these variations in δ13C of the carbon source, and of isotope fractionation in diffusion, to the δ13C value of submerged parts of dimorphic plants is discussed.


An analysis of diagnostic content in a postgraduate teaching programme.
In this study the diagnoses of consultations collected on videotape for teaching purposes are analysed. The consultations involved genuine patients and Family Medicine Programme trainees during a general practice term. Diagnostic content is demonstrated to reflect the normal work experience of trainee general practitioners.


Dieulafoy lesions of the GI tract: localization and therapeutic outcomes.
Dieulafoy lesions are a rare cause of gastrointestinal hemorrhage with a striking presentation because of rapid blood loss. Endoscopic therapy is usually successful at achieving primary hemostasis, but the best mode of endoscopic intervention is not clear, and outcomes relating to variables such as gender, medication, alcohol, and smoking are not known. We reviewed the clinical experience with Dieulafoy lesions at our institution, focusing on clinico-epidemiological features, management practices, and also survival. A retrospective and prospective cohort of patients with Dieulafoy lesions who underwent endoscopy from January 2004 through April 2009 were studied and detailed clinical data were abstracted and collected. We identified 63 patients with a Dieulafoy lesion. The majority were male with an average age 58 years. Hematemesis and melena were the most common presenting symptoms. Almost half the patients were on anticoagulation medication. Most of the Dieulafoy lesions occurred in the upper GI tract, and mostly in the stomach. Single-modality endoscopic therapy was used as frequently as combination therapy, and both were effective, as primary hemostasis was achieved in 92% of cases. There were 11 deaths overall; death due to Dieulafoy lesion exsanguination was attributed to three patients. Dieulafoy lesions occurred in younger patients than previously reported, and were more frequently diagnosed in males. Most DL lesions occurred in the upper GI tract. Primary hemostasis with endoscopic therapy was highly successful. Overall mortality was 17%, and associated with co-morbidities, and not with medical history, gender, age, or medication.


The synthesis of new adenosine A3 selective ligands containing bioisosteric isoxazoles.
The synthesis and purinergic receptor binding of novel adenosine A3 ligands is described. Many selective A3 receptor agonists e.g. N-(3-iodobenzyl)adenosine-5'-methyluronamide (IB-MECA) contain a 4'-ribosylalkylamide moiety. We found that this amide and other 4'-functional groups could be replaced with an isosteric isoxazole, and the target molecules retained potent binding to the recombinant human A3 receptor.


Endoscopic management of colonic perforations: clips versus suturing closure (with videos).
Perforation during colonoscopy remains the most worrisome adverse event and usually requires urgent surgical rescue. The aim of this study was to evaluate the feasibility and effectiveness of endoscopic closure of full-thickness colonic perforations. We performed a retrospective analysis of all consecutive patients with endoscopically closed colonic perforations over the past 6 years (2009-2014). Colonic perforations were closed by using endoscopic clips or an endoscopic suturing device. Most patients were admitted for treatment with intravenous antibiotics and kept on bowel rest. If their clinical condition deteriorated, urgent surgery was performed. If patients remained stable, oral feeding was resumed, and patients were discharged with subsequent clinical and endoscopic follow-up. Twenty-one patients had iatrogenic colonic perforations closed with an endoscopic suturing device or endoscopic clips during the study period. Primary closure of a colonic perforation was performed with endoscopic clips in 5 patients and sutured with an endoscopic suturing device in 16 patients. All 5 patients after clip closure had worsening of abdominal pain and required laparoscopy (4 patients) or rescue colonoscopy with endoscopic suturing closure (1 patient). Two patients had abdominal pain after endoscopic suturing closure, but diagnostic laparoscopy confirmed complete and adequate endoscopic closure of the perforations. The other 15 patients did not require any rescue surgery or laparoscopy after endoscopic suturing. The main limitation of our study is its retrospective, single-center design and relatively small number of patients. Endoscopic suturing closure of colonic perforations is technically feasible, eliminates the need for rescue surgery, and appears more effective than closure with hemostatic endoscopic clips.


Induction and processing of oxidative clustered DNA lesions in 56Fe-ion-irradiated human monocytes.
Space and cosmic radiation is characterized by energetic heavy ions of high linear energy transfer (LET). Although both low- and high-LET radiations can create oxidative clustered DNA lesions and double-strand breaks (DSBs), the local complexity of oxidative clustered DNA lesions tends to increase with increasing LET. We irradiated 28SC human monocytes with doses from 0-10 Gy of (56)Fe ions (1.046 GeV/ nucleon, LET = 148 keV/microm) and determined the induction and processing of prompt DSBs and oxidative clustered DNA lesions using pulsed-field gel electrophoresis (PFGE) and Number Average Length Analysis (NALA). The (56)Fe ions produced decreased yields of DSBs (10.9 DSB Gy(-1) Gbp(-1)) and clusters (1 DSB: approximately 0.8 Fpg clusters: approximately 0.7 Endo III clusters: approximately 0.5 Endo IV clusters) compared to previous results with (137)Cs gamma rays. The difference in the relative biological effectiveness (RBE) of the measured and predicted DSB yields may be due to the formation of spatially correlated DSBs (regionally multiply damaged sites) which result in small DNA fragments that are difficult to detect with the PFGE assay. The processing data suggest enhanced difficulty compared with gamma rays in the processing of DSBs but not clusters. At the same time, apoptosis is increased compared to that seen with gamma rays. The enhanced levels of apoptosis observed after exposure to (56)Fe ions may be due to the elimination of cells carrying high levels of persistent DNA clusters that are removed only by cell death and/or "splitting" during DNA replication.


Interleukin-2 receptor beta-chain (p70-75) expressed on leukemic cells from adult T cell leukemia patients.
To determine whether the interleukin-2 receptor (IL-2R) beta-chain (p70-75) is expressed on leukemic cells from patients with adult T cell leukemia (ATL) as well as alpha-chain (p55, Tac), we performed radiolabeled interleukin-2 (IL-2) binding assay, chemical crosslinking of radiolabeled IL-2 and flow cytometric analysis using a newly-developed anti-IL-2R beta-chain antibody. The results showed that leukemic cells from all the 12 ATL patients we examined expressed the IL-2R beta-chain together with the alpha-chain whereas there was no detectable beta-chain expression on unstimulated peripheral blood CD4(+) T cells from healthy volunteers. Southern blot analysis revealed that this abnormal expression was not caused by the structural change of IL-2R beta-chain gene. Though leukemic cells from all ATL patients examined expressed high-affinity IL-2Rs, leukemic cells from only 25% of all ATL patients proliferated in response to IL-2. These results showing abnormal expression of IL-2R beta-chain on leukemic cells from ATL patients (ATL cells) suggest a close association between HTLV-I infection and abnormal beta-chain expression as well as alpha-chain expression.


Determination of the polar drug dimiracetam in human plasma and serum by column-switching high-performance liquid chromatography.
A sensitive and fully automated column-switching HPLC method was developed for the determination of a novel cognition enhancer, dimiracetam, in human plasma and serum. A sample of plasma was ultrafiltered and then directly injected onto a first mu Bondapak C18 column. The sample was eluted with water. The portion of the eluate (heart-cut) from this column containing the drug was selected and loaded on a second mu Bondapak C18 column and eluted with water. During the elution of the second column, the first column was automatically rinsed with water-acetonitrile (50:50, v/v) and then equilibrated for a new injection. The total analysis time for each sample was 35 min. This corresponded to a 30% decrease in analysis time compared with the time that would have been needed with a simple run with two mu Bondapak C18 columns assembled in series. Ultraviolet detection at 200 nm was used to monitor the eluate. The method was fully validated over the quantitation range 27 ng/ml-15 micrograms/ml. The applicability of the method was demonstrated by analysis of serum samples from a study performed in human healthy volunteers.


Separation, characterization and anticancer activities of a sulfated polysaccharide from Undaria pinnatifida.
The purpose of this paper was to investigate separation, characterization and anticancer activities of a sulfated polysaccharide (SPUP) from Undaria pinnatifida. Firstly, polysaccharide from U. pinnatifida was separated by DEAE-52 cellulose and Sephacryl S-400 column chromatography. As results, SPUP was obtained with the yield of 19.42%. Then, SPUP was characterized using chemical analysis, gas chromatography, size-exclusion HPLC chromatography, UV-vis spectra and FT-IR spectrum. The content of total sugar, uronic acid, protein and sulfate radical were 80.48%, 3.21%, 7.12% and 29.14%, respectively. SPUP was a heteropolysaccharide composed of fucose, glucose and galactose in a molar percentage of 27.15:19.34:53.51 with molecular weight of 97.9 kDa. Finally, the strongly against breast cancer activity of SPUP was confirmed by DMBA-induced breast cancer rats model. AS results, SPUP can significantly restrain breast abnormal enlargement, prolong tumor latency and reduced tumor incidence. Immunomodulatory activity and regulating abnormal sex hormones level might contribute to its anticancer activities.


Plasma Levels of microRNA-145 Are Associated with Severity of Coronary Artery Disease.
MicroRNAs (miRNAs) have been shown to be associated with various physiological and pathological conditions, including inflammation and cardiovascular disease, but little is known about their relationship with the presence of coronary artery disease (CAD) and disease severity. A total of 195 consecutive subjects who underwent coronary angiography for chest pain evaluation were enrolled in this study. In CAD patients severity of coronary lesions was assessed by the number of diseased vessels and the Synergy between PCI with Taxus and Cardiac surgery score (SYNTAX score). Plasma levels of miRNA-145 were quantified by real-time quantitative polymerase chain reaction test, and logarithmic transformation of miRNA-145 levels (Ln_miRNA-145) was used for analyses due to its skewed distribution. Of the 195 total subjects 167 patients were diagnosed as having CAD. Ln_miRNA-145 was significantly lower in CAD patients compared with the non-CAD group (-6.11 ± 0.92 vs. -5.06 ± 1.25; p < 0.001). In multivariable linear regression analyses CAD was significantly associated with lower Ln_miRNA-145 (Estimate, -0.50; standard error (SE), 0.11; p < 0.0001). Furthermore, among CAD patients, three-vessel disease, higher SYNTAX scores and STEMI were significantly associated with lower Ln_miRNA-145 ([Estimate, -0.40; SE, 0.07; p < 0.0001]; [Estimate, -0.02, SE, 0.10; p = 0.005] and [Estimate, -0.35, SE, 0.10; p < 0.001] respectively). Lower plasma levels of miRNA-145 were significantly associated with the presence as well as severity of CAD. As a potential biomarker for CAD, plasma miRNA-145 may be useful in predicting CAD and its severity in patients presenting with chest pain.


Perioperative quality assessment of varicose vein surgery : Commission for quality assessment of the German Society for Vascular Surgery.
An estimated 350,000 varicose vein (VV) surgical procedures are performed in Germany each year, with annual treatment costs amounting to about 800 million Euro. To evaluate the outcome quality of this treatment, we examined the intraoperative and postoperative complication rates on record in the VV surgery quality assessment (QA) registry of the German Society for Vascular Surgery (GSVS). Data on 89,647 patients (27,463 men, 62,184 women; average age 52.8 years, range 15-96 years) collected in the GSVS varicose surgery QA registry between 2001 and 2009 were analyzed. In these patients, 95,214 surgical procedures were performed on 105,296 limbs. Complication rates were correlated with the type of VV surgical procedure, with whether surgery was performed on an inpatient or outpatient basis, and with the CEAP classification (C stage) and American Society of Anaesthesiologists' (ASA) stage at the time of surgery. Statistical analyses were performed using a chi-square test, a Cochrane-Armitage test, and an odds ratio calculation. Intraoperative and postoperative complication was low (0.18 and 0.43 %, respectively), being the lowest for radiofrequency ablation (0.25 %) but not differing significantly from those for endovenous laser therapy and high ligation and stripping. General complications occurred in 0.67 % of outpatients and in 0.25 % of inpatients, a highly significant statistical difference (p < 0.0001, chi-square test). With regard to C stage, the higher the stage, the higher the local complication rate. A clear correlation was also found between preoperative ASA stage and postoperative complication rates: for ASA stages I and II, the complication rates were 0.2 and 0.5 %, respectively, increasing for ASA stage III to 1.2 % and for ASA IV to 2.2 %. The differences between the ASA classes were highly statistically significant (p < 0.0001, Cochrane-Armitage test) Outcome quality as reflected in the intraoperative and postoperative complication rates was very good for all patients undergoing inpatient or outpatient VV surgery. Data from the GSVS QA registry shows that VV surgery is performed with very good perioperative results in specialized centers in Germany.


Cellular toxicity and pharmacokinetic study of butachlor by ultra-performance liquid chromatography-tandem mass spectrometry based on tandem mass spectrometry cubed technique.
Butachlor is an aromatic amide compound that plays a role as a herbicide, a xenobiotic, and an environmental contaminant. The aim of this work was to develop a highly selective and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method based on the tandem mass spectrometry cubed technique to determine butachlor in a biological matrix. Butachlor and internal standard acetochlor were separated on a Waters Acquity ultra-performance liquid chromatography BEH C18 column (2.1 × 50 mm, 1.7 μm) with gradient elution using 0.1% formic acid aqueous solution (A) and acetonitrile (B) as mobile phases. The transitions selected for tandem mass spectrometry cubed quantitative analysis in positive ion mode were: for butachlor, mass-to-charge ratio 312.2→238.1→162.1; for acetochlor, mass-to-charge ratio 270.1→224.0→148.1. The total running time for each sample was 5.5 min. The ultra-performance liquid chromatography-tandem mass spectrometry cubed method showed a linear relationship (R2 ≥ 0.995) in the concentration range of 0.5-100 ng/ml. The intra and interday accuracies are within the range of -10.6%-4.3% and precisions are between 4.48% and 13.14%. The novelty of the method is the use of tandem mass spectrometry cubed scanning mode, which improves selectivity and sensitivity. The results indicated that butachlor was cellular toxic. The safety of butachlor should be considered when it is used as a herbicide.


Magnetic resonance imaging of rat brain following kainic acid-induced lesions and fetal striatal tissue transplants.
Use of a small diameter (5.1 cm) radiofrequency coil provided relatively high resolution magnetic resonance (MR) images of rat heads at 0.14 Tesla. On T1-weighted images, the rat brain was clearly visible in the rat head as a region of high signal intensity. No structures were distinguished within the normal rat brain. In contrast, in the brains of rats receiving unilateral kainic acid lesions of the striatum, enlarged lateral ventricles, which are characteristic of the lesion, were clearly visible as dark areas of low signal intensity. Extrastriatal damage on the lesioned side of the brain was also evident in some of the images. Fetal striatal tissue transplants growing within the lesioned striata were also identified in the MR images. The transplanted tissue appeared as areas of high and intermediate signal intensity, similar to the host brain. MR imaging is a useful technique for monitoring excitotoxin lesions of brain and fetal striatal tissue transplants in vivo.


Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis.
Ras is phosphorylated on a conserved tyrosine at position 32 within the switch I region via Src kinase. This phosphorylation inhibits the binding of effector Raf while promoting the engagement of GTPase-activating protein (GAP) and GTP hydrolysis. Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. In comparison to normal astrocytes, SHP2 activity is elevated in astrocytes isolated from glioblastoma multiforme (GBM)-prone H-Ras(12V) knock-in mice as well as in glioma cell lines and patient-derived GBM specimens exhibiting hyperactive Ras. Pharmacologic inhibition of SHP2 activity attenuates cell proliferation, soft-agar colony formation and orthotopic GBM growth in NOD/SCID mice and decelerates the progression of low-grade astrocytoma to GBM in a spontaneous transgenic glioma mouse model. These results identify SHP2 as a direct activator of Ras and a potential therapeutic target for cancers driven by a previously 'undruggable' oncogenic or hyperactive Ras.


Interleukin-1 receptor antagonist restores homeostatic function and limits multiorgan damage in heatstroke.
We attempt to investigate whether interleukin-1 receptor antagonist (IL-1ra) therapy improves survival during heatstroke by attenuating multiorgan dysfunction. Anesthetized rabbits, immediately after the onset of heatstroke, are divided into three major groups and given: nothing, normal saline (1 ml/kg, i.v.), or IL-1ra (200-400 microg per 1 ml/kg, i.v.). They are exposed to ambient temperature of 40 degrees C to induce heatstroke. Another group of rabbits is exposed to room temperature (24 degrees C) and used as normothermic controls. Hyperthermia, hypotension, cerebral ischemia and edema, hepatic and renal failure, increased levels of both nitric oxide metabolites (NO ( x ) (-) ) and dihydroxybenzoic acid (DHBA) in plasma, hyperkalemia, respiratory alkalosis, and metabolic acidosis and hypoxia are all observed in vehicle-treated heatstroke animals. When the vehicle-treated animals undergo heat stress, their survival time values are found to be 12-18 min. Resuscitation with IL-1ra dose-dependently improves survival time (duration, 132-303 min). As compared with vehicle-treated heatstroke rabbits, IL-1ra therapy significantly causes attenuation of heatstroke-induced hyperthermia, hypotension, cerebral ischemia and edema, intracranial hypertension, hepatic and renal dysfunction, NO ( x ) (-) and DHBA overproduction, hyperkalemia, hypoxia, respiratory alkalosis, and metabolic acidosis. The results indicate that IL-1ra therapy may restore tissue blood flow and homeostatic function, and limit multiorgan dysfunction and death in heatstroke.


Side effects and quality of life after inadvertent radiation overdosage in brachytherapy of head-and-neck cancer.
By comparing our old (DP5, in use from 1978 to 1994) and new (Plato, Nucletron) dose planning system, we found that the old system underestimated doses by 20-25%. To study the possible consequences for the patients treated between 1978 and 1994, all who were still alive were invited to undergo an examination with respect to side effects and quality of life (QOL). The degree of overdosage was calculated by comparing the isodose distribution generated on the two dose planning systems. Eighty-four patients were then invited to undergo an examination with respect to side effects and QOL. The side effects were scored according to the LENT SOMA system and QOL according to European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), and EORTC Quality of Life Questionnaire-Head & Neck 35 (QLQ-H&N35). The mean overdosage of brachytherapy was 19.3%. No association was found between overdosage and side effects or QOL. For implants in the lateral border of the tongue, we found a statistically significant correlation between osteoradionecrosis and the following parameters: linear activity, total activity, dose rate, and extrapolated response dose. By multivariate analysis, only total implanted activity and the use of lead protection during brachytherapy were found to be of prognostic significance with respect to development of osteoradionecrosis. The incidence of side effects after brachytherapy at the Norwegian Radium Hospital seems to have been somewhat higher in the period under investigation than at other institutions. There may be several explanations, including the use of external beam radiotherapy before brachytherapy and departure from the Paris system among others. However, the side effects were not associated with the overdosage that was the basis for the study. As opposed to the general consensus of opinion, long-term QOL was found to be worse after brachytherapy than after external beam radiotherapy. This calls for increased awareness and a systematic prospective registration of the long-term side effects of brachytherapy.


Complications of subcutaneous low-dose heparin therapy in neurosurgical patients.
Venous thromboembolism is a major cause of postoperative morbidity and mortality in neurosurgery. The use of low-dose unfractionated heparin therapy perioperatively for prophylaxis against deep vein thromboses and pulmonary embolism has been well demonstrated in many other surgical specialties but is less commonly used in neurosurgery because of fears of devastating postoperative hematomas. The safety of such therapy has been analyzed in 950 patients undergoing an inpatient neurosurgical procedure. 872 patients (152 cranial procedures) completed treatment with 5000 U sodium heparin subcutaneously twice a day, commencing before surgery and continuing till patients were ambulatory. There were three minor hemorrhagic complications-two superficial wound hematomas (one requiring treatment) and one gastrointestinal hemorrhage-identified. Three clinically significant major complications developed, two epidural hematomas after spinal surgery requiring evacuation and one intraventricular hemorrhage after brain biopsy. This report, along with an analysis of previously published reports of low-dose perioperative heparin therapy in neurosurgical patients, suggests that such therapy is unlikely to be associated with increased morbidity. Given the known efficacy of low-dose heparin in reducing venous thromboembolism in other surgical patients, such therapy may reduce mortality and morbidity from thromboembolic complications in neurosurgical patients with minimal risk.


Clinical response and autonomic modulation as seen in heart rate variability in mechanical intermittent cervical traction: a pilot study.
To determine the influence of mechanical intermittent cervical traction on the autonomic system. Prospective, cases series study. Sixteen healthy volunteers without contraindications for cervical traction. Subjects received mechanical intermittent cervical traction in a sitting position under two traction forces (10% and 20% of total body weight). Electrocardiographic and neck surface electromyographic signals were recorded and analysed from 3 5-min periods (before, during and after traction). Subjective symptoms, heart rate and heart rate variability parameters, including standard deviation of all normal-to-normal beat intervals, very low-frequency power, low-frequency power, high-frequency power, multiscale entropy, slope of multiscale entropy, and root mean square value of electromyography amplitude were statistically compared. This pilot study showed that using 10% body weight traction force was more comfortable than using 20% body weight. Only subtle perturbation was noted in the autonomic system when using 20% body weight traction force. The response pattern of heart rate variability analysis in this pilot study provides some early information about individual discomfort in cervical traction. The autonomic modulation and the safety of cervical traction with other modality settings or in patients with neck pain require further study.


PtRu/C catalyst slurry preparation for large-scale decal transfer with high performance of proton exchange membrane fuel cells.
The large-area membrane-electrode assembly (MEA) has been fabricated using the decal transfer method with a methanol (MeOH)-based PtRu/C catalyst slurry. The stability of slurry dispersion is important when using a large-area decal transfer method to ensure the integrity of the electrode. In order to prepare stable and well dispersed catalyst slurry, a suitable solvent for the PtRu/C catalyst should be selected. We considered the physical properties of various organic solvents, including ionomer solubility, dielectric constant, and catalyst particle surface physical properties. We found that the MeOH-based PtRu/C slurry dispersion showed the best stability and dispersibility of catalyst-ionomer agglomerates. It was also confirmed that the MeOH-based slurry has the most suitable characteristics for coating the slurry on the substrate film. The decal technique-based MEA using this slurry showed excellent performance when compared with the spray method-based MEA. Furthermore, the large-area PtRu/C MEA with an active area of 51.84 cm2 was fabricated and excellent performance was realized even when a reforming gas was used.


Confocal microscopy study of the distribution, content and activity of mitochondria during Paracentrotus lividus development.
In the present paper we applied confocal microscopy and fluorescence technologies for studying the distribution and the oxidative activity of sea urchin (Paracentrotus lividus) mitochondria during development, by in vivo incubating eggs and embryos with cell-permeant MitoTracker probes. We calculated, by a mathematical model, the intensity values, the variations of intensity, and the variation index of incorporated fluorochromes. Data demonstrate that mitochondrial mass does not change during development, whereas mitochondrial respiration increases. In addition, starting from 16 blastomeres stage, some regions of the embryo contain organelles more active in oxygen consumption.


Synchronous invasive ductal carcinoma of the breast and clear cell renal carcinoma with rare presentation and behaviour: a case report with a literature review.
The presence of two or more primary tumours is a relatively uncommon phenomenon. Recently with the improvement of diagnostic modalities, such cases are increasingly reported in the literature. This paper presents a rare case of synchronous breast and renal tumour with unusual features including RCC metastasis to the duodenum and stomach, rapid recurrence of the tumour at the nephrectomy site, rapid renal cell carcinoma growth rate and the rare presence of syncytial-type giant cells in the renal cell tumour.


Well-defined (N-heterocyclic carbene)-Ag(I) complexes as catalysts for A3 reactions.
The use of well-defined (N-heterocyclic carbene)-Ag(I) complexes for the A(3) reaction allows for the coupling of unactivated aldehydes at room temperature and very short reaction times.


Control of the Metal-Insulator Transition at Complex Oxide Heterointerfaces through Visible Light.
The coupling of the localized surface plasmon resonance of Au nanoparticles is utilized to deliver a visible-light stimulus to control conduction at the LaAlO3 /SrTiO3 interface. A giant photoresponse and the controllable metal-insulator transition are characterized at this heterointerface. This study paves a new route to optical control of the functionality at the heterointerfaces.


Lipid levels in high density lipoprotein subfractions in smokers with peripheral vascular disease.
No significant difference in HDL cholesterol was found between smokers with PVD and corresponding controls. The ratio of HDL cholesterol to the sum of (VLDL + LDL) cholesterol was reduced in patients with PVD. Patients with PVD had significantly highly serum triglyceride levels. A slightly significant difference could be demonstrated for serum cholesterol and serum phospholipids concentrations in smoking patients with PVD.


Mechanism of action of cytochalasin B on actin.
Substoichiometric cytochalasin B (CB) inhibits both the rate of actin polymerization and the interaction of actin filaments in solution. The polymerization rate is reduced by inhibition of actin monomer addition to the "barbed" end of the filaments where monomers normally add more rapidly. 2 microM CB reduces the polymerization rate by up to 90%, but has little effect on the rate of monomer addition at the slow ("pointed") end of the filaments and no effect on the rate of filament annealing. Under most ionic conditions tested, 2 microM CB reduces the steady state high shear viscosity by 10-20% and increases the steady state monomer concentration by a factor of 2.5 or less. In addition to the effects on the polymerization process, 2 microM CB strongly reduces the low shear viscosity of actin filaments alone and actin filaments cross-linked by a variety of macromolecules. This may be due to inhibition of actin filament-filament interactions which normally contribute to network formation. Since the inhibition of monomer addition and of actin filament network formation have approximately the same CB concentration dependence, a common CB binding site, probably the barbed end of the filament, may be responsible for both effects.


The willingness and actual situation of Chinese cancer patients and their family members participating in medical decision-making.
In China, not only patients and physicians are involved in medical decision-making (MDM) but also the patients' family members. The objective is to investigate the willingness and actual situation of cancer patients and their family members participating in the MDM process. In this cross-sectional study, questionnaires were administered to 247 pairs of cancer inpatients and their relatives. Information regarding participants' willingness and actual experience during the decision-making process was documented. Eligible participants were cancer inpatients or their relatives, 18 years of age or older, and informed of the cancer diagnosis. All the patients should have received chemotherapy. The effective response rate was 72.9% (180/247). Over half of the patients (53.3%) and family members (57.8%) were willing to be part of the MDM process. In contrast, only 35.0% of patients and 46.1% of family members actually experienced this process (p = 0.001 and p = 0.011, respectively). Fewer family members (42.2%) than patients (53.3%) believed that patients should be involved in the MDM process (p < 0.001). Patients who were the head of their family (odds ratio 2.577, 95% CI 1.198-5.556, p = 0.015) experienced more involvement in MDM. Although more than half of Chinese cancer patients and family members wanted to be part of MDM, the actual participation was below their expectation. Majority of family members do not want the patients to be involved in the process of MDM.


Excellent outcomes of cardiac surgery in patients infected with HIV in the current era.
Over the past decade, significant advances have been made in the medical treatment of patients with human immunodeficiency virus type 1 infection, leading to a steady increase in referrals for cardiac surgery. We report the outcome of cardiac surgery recently performed in patients with documented human immunodeficiency virus type 1 infection.


Calibrating Vision: Concepts and Questions.
The idea that visual coding and perception are shaped by experience and adjust to changes in the environment or the observer is universally recognized as a cornerstone of visual processing, yet the functions and processes mediating these calibrations remain in many ways poorly understood. In this article we review a number of facets and issues surrounding the general notion of calibration, with a focus on plasticity within the encoding and representational stages of visual processing. These include how many types of calibrations there are - and how we decide; how plasticity for encoding is intertwined with other principles of sensory coding; how it is instantiated at the level of the dynamic networks mediating vision; how it varies with development or between individuals; and the factors that may limit the form or degree of the adjustments. Our goal is to give a small glimpse of an enormous and fundamental dimension of vision, and to point to some of the unresolved questions in our understanding of how and why ongoing calibrations are a pervasive and essential element of vision.


Uveitis, glaucoma, and cataract with mevalonate kinase deficiency.
We report 7 years of follow-up data on ocular findings in a 2-month-old boy who presented with early-onset bilateral granulomatous panuveitis with subsequent development of secondary glaucoma and total cataract, along with multisystem involvement. He was diagnosed with mevalonate kinase deficiency (MKD), with a homozygous missense variant in exon-6 of the mevalonate kinase (MVK) gene on chromosome-12 that resulted in the substitution of aspartic acid for asparagine at codon 205 (p.Asn205Asp). Despite being managed with topical/systemic steroids and immunosuppression therapy with methotrexate and a short course of adalimumab, the patient continued to develop recurrent episodes of uveitis along with multisystem manifestations. The occurrence of early-onset uveitis is rare, as is the diagnosis of MKD.


Neurons associated with behavioral context errors in the primary and higher-order gustatory cortices in the monkey.
Cue responses of neurons in the taste-related cortex of Japanese macaque monkeys were studied during a NaCl-water discrimination GO-NOGO task, to compare the correct and incorrect responses. Most neurons produced a steady pattern of discharges in response to a given cue at both correct and incorrect responses, presumably responding to the physicochemical nature of the cue. Some neurons showed the discharge pattern for a certain cue changing to that for another cue at task error, presumably representing the subsequent behavioral reaction or behavioral context. These neurons were mainly located in the precentral operculum and orbitofrontal cortex, and rarely in the primary gustatory area, area G.


Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers.
To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes (T2DM) on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microalbuminuria or macroalbuminuria at baseline. Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12-week reductions in albuminuria compared with placebo: -33.2% [95% confidence interval (CI) -45.4, -18.2]. The reduction in albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: -23.5% (95% CI -37.6, -6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal-related adverse events were observed in any group. Dapagliflozin was effective in lowering albuminuria in patients with T2DM and hypertension using renin-angiotensin system blockade therapy. Reductions in albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin-induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long-term renal and cardiovascular risk.


Screening of mental health and substance users in frequent users of a general Swiss emergency department.
The objectives of this study were to determine the proportions of psychiatric and substance use disorders suffered by emergency departments' (EDs') frequent users compared to the mainstream ED population, to evaluate how effectively these disorders were diagnosed in both groups of patients by ED physicians, and to determine if these disorders were predictive of a frequent use of ED services. This study is a cross-sectional study with concurrent and retrospective data collection. Between November 2009 and June 2010, patients' mental health and substance use disorders were identified prospectively in face-to-face research interviews using a screening questionnaire (i.e. researcher screening). These data were compared to the data obtained from a retrospective medical chart review performed in August 2011, searching for mental health and substance use disorders diagnosed by ED physicians and recorded in the patients' ED medical files (i.e. ED physician diagnosis). The sample consisted of 399 eligible adult patients (≥18 years old) admitted to the urban, general ED of a University Hospital. Among them, 389 patients completed the researcher screening. Two hundred and twenty frequent users defined by >4 ED visits in the previous twelve months were included and compared to 169 patients with ≤4 ED visits in the same period (control group). Researcher screening showed that ED frequent users were more likely than members of the control group to have an anxiety, depressive disorder, post-traumatic stress disorder (PTSD), or suffer from alcohol, illicit drug abuse/addiction. Reviewing the ED physician diagnosis, we found that the proportions of mental health and substance use disorders diagnosed by ED physicians were low both among ED frequent users and in the control group. Using multiple logistic regression analyses to predict frequent ED use, we found that ED patients who screened positive for psychiatric disorders only and those who screened positive for both psychiatric and substance use disorders were more likely to be ED frequent users compared to ED patients with no disorder. This study found high proportions of screened mental health and/or substance use disorders in ED frequent users, but it showed low rates of detection of such disorders in day-to-day ED activities which can be a cause for concern. Active screening for these disorders in this population, followed by an intervention and/or a referral for treatment by a case-management team may constitute a relevant intervention for integration into a general ED setting.


Analysis of hTERT expression in exfoliated cells from patients with bladder transitional cell carcinomas using SYBR green real-time fluorescence quantitative PCR.
To investigate whether hTERT mRNA expression could be used as a diagnostic and prognostic marker of bladder transitional cell carcinoma. SYBR green I real-time fluorescence quantitative PCR method was used to quantify hTERT mRNA expression in exfoliated cells from patients with bladder transitional cell carcinomas. A significant correlation was observed between the level of hTERT mRNA expression in exfoliated cells collected in urine with pathological grade and clinical stage. Our results show that SYBR green real-time fluorescence quantitative evaluation of hTERT mRNA could be a useful marker of tumor progression for the early diagnosis and prognosis of bladder cancers.


High-performance thermoelectric nanocomposites from nanocrystal building blocks.
The efficient conversion between thermal and electrical energy by means of durable, silent and scalable solid-state thermoelectric devices has been a long standing goal. While nanocrystalline materials have already led to substantially higher thermoelectric efficiencies, further improvements are expected to arise from precise chemical engineering of nanoscale building blocks and interfaces. Here we present a simple and versatile bottom-up strategy based on the assembly of colloidal nanocrystals to produce consolidated yet nanostructured thermoelectric materials. In the case study on the PbS-Ag system, Ag nanodomains not only contribute to block phonon propagation, but also provide electrons to the PbS host semiconductor and reduce the PbS intergrain energy barriers for charge transport. Thus, PbS-Ag nanocomposites exhibit reduced thermal conductivities and higher charge carrier concentrations and mobilities than PbS nanomaterial. Such improvements of the material transport properties provide thermoelectric figures of merit up to 1.7 at 850 K.


Understanding the UK Psychoactive Substances Act.
This review paper is based on a talk given at the British Pharmaceutical Society Winter Meeting in 2018 derived from the Home Office Report on the workings of the UK Psychoactive Substances Act (PSA) published in November 2018. The review deals with the context in which the PSA 2016 arose and how this piece of legislation differs from other UK drug regulations. It attempts to put the PSA in context with other control schemes being instituted around the world and to assess the success of the Act in its first 2 years of implementation. For more details the reader is referred to Review of the Psychoactive Substances Act 2016, Home Office, November 2018.


Electrophysiologic studies of perphenazine and protriptyline in a patient with psychotropic drug-induced ventricular fibrillation.
A 51 year old woman sustained ventricular fibrillation while receiving perphenazine and protriptyline. After successful resuscitation and clinical stabilization, cardiac electrophysiologic studies were performed before and after the administration of each of these medications. Perphenazine widened the ventricular echo zone and facilitated induction of short salvoes of ventricular tachycardia (repetitive ventricular response). Protriptyline also widened the ventricular echo zone and allowed easy induction of long runs of ventricular tachycardia. Both psychotropic agents increased the incidence of ventricular dysrhythmias in this patient. The electrophysiologic study is a useful technique in determining the interaction between psychotropic drugs and life-threatening arrhythmias; it may provide a means of identifying the patients with cardiac disease in whom administration of these agents may be fatal.


[Trends of doctoral dissertations in nursing science: focused on studies submitted since 2000].
The purpose of this study was to identify the characteristics of doctoral dissertations in nursing science submitted since 2000. Three-hundred and five dissertations of six schools of nursing published from 2000 to 2006 in Korea were analyzed with the categories of philosophy, method, body of knowledge, research design, and nursing domain. In philosophy, 82% of all dissertations were identified as scientific realism, 15% were relativism, and 3% were practicism. Two-hundred and fifty dissertations (82%) were divided into a quantitative methodology and 55 dissertations (18%) were qualitative methodology. Specifically, 45% were experimental, 23% methodological, 13% survey and 17% qualitative designed researches. Prescriptive knowledge was created in 47% of dissertations, explanatory knowledge in 29%, and descriptive knowledge in 24%. Over 50% of all research was studied with a community-based population. In the nursing domain, dissertations of the practice domain were highest (48.2%). Dissertations since 2000 were markedly different from the characteristics of the previous studies (1982-1999) in the increase of situation-related, prescriptive and community-based population studies. A picture of current nursing science identified in this study may provide a future guideline for the doctoral education for nursing.


Vocal Cord Melanosis: To Worry or Not to Worry?
Laryngeal Melanosis is a rare entity with unclear significance: whether it is a premalignant lesion for squamous cell carcinoma of the larynx or a sign of mucosal melanoma. In the few reported cases in the literature, it is descried as localised/diffused brownish discoloration of the mucosal surface of the involved subsite of the larynx. We hereby report a raised localised laryngeal melanosis of the vocal cord with an initial histopathology report of dysplasia.


Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42.
Efficient chemotaxis requires directional sensing and cell polarization. We describe a signaling mechanism involving G beta gamma, PAK-associated guanine nucleotide exchange factor (PIX alpha), Cdc42, and p21-activated kinase (PAK) 1. This pathway is utilized by chemoattractants to regulate directional sensing and directional migration of myeloid cells. Our results suggest that G beta gamma binds PAK1 and, via PAK-associated PIX alpha, activates Cdc42, which in turn activates PAK1. Thus, in this pathway, PAK1 is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. This G beta gamma-PAK1/PIX alpha/Cdc42 pathway is essential for the localization of F-actin formation to the leading edge, the exclusion of PTEN from the leading edge, directional sensing, and the persistent directional migration of chemotactic leukocytes. Although ligand-induced production of PIP(3) is not required for activation of this pathway, PIP(3) appears to localize the activation of Cdc42 by the pathway.


The accurate measurement of second virial coefficients using self-interaction chromatography: experimental considerations.
Measurement of B22, the second virial coefficient, is an important technique for describing the solution behaviour of proteins, especially as it relates to precipitation, aggregation and crystallisation phenomena. This paper describes the best practise for calculating B22 values from self-interaction chromatograms (SIC) for aqueous protein solutions. Detailed analysis of SIC peak shapes for lysozyme shows that non-Gaussian peaks are commonly encountered for SIC, with typical peak asymmetries of 10%. This asymmetry reflects a non-linear chromatographic retention process, in this case heterogeneity of the protein-protein interactions. Therefore, it is important to use the centre of mass calculations for determining accurate retention volumes and thus B22 values. Empirical peak maximum chromatogram analysis, often reported in the literature, can result in errors of up to 50% in B22 values. A methodology is reported here for determining both the mean and the variance in B22 from SIC experiments, includes a correction for normal longitudinal peak broadening. The variance in B22 due to chemical effects is quantified statistically and is a measure of the heterogeneity of protein-protein interactions in solution. In the case of lysozyme, a wide range of B22 values are measured which can vary significantly from the average B22 values.


Evaluation of the Safety, Tolerability, and Pharmacokinetics of Gammaplex® 10% Versus Gammaplex® 5% in Subjects with Primary Immunodeficiency.
This phase 3, multicenter, open-label, randomized, two-period, crossover bioequivalence trial evaluated the safety, tolerability, and pharmacokinetics of intravenous immunoglobulins (IVIGs) Gammaplex 5% and Gammaplex 10% in 33 adults and 15 children with primary immunodeficiency diseases (PIDs). Eligible adults received five Gammaplex 5% infusions followed by five Gammaplex 10% infusions, or vice versa, stratified by a 21- or 28-day dosing regimen. Pediatric subjects received five Gammaplex 10% infusions only. The primary objective, to demonstrate the bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval, was met based on the Gammaplex 10%/Gammaplex 5% ratio of area under the concentration versus time curve (AUC0-28) values. Throughout the study, total immunoglobulin G trough levels were well maintained, with total values generally ≥600 mg/dL (minimum level for study inclusion). At the dosing schedules and infusion rates used in this study, safety and tolerability were comparable and acceptable in adult and pediatric PID subjects treated with Gammaplex 10% and 5%. In this study, the first direct comparison of 5% IVIG and 10% IVIG products in PID subjects, the pharmacokinetic analysis demonstrated bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval. The Gammaplex 10% formulation was safe and well tolerated in pediatric and adult PID subjects. Based on the results from this bridging study in PID subjects, Gammaplex 10% could be expected to have a therapeutic effect similar to the licensed Gammaplex 5%, which has demonstrated efficacy and tolerability in patients with PID and idiopathic thrombocytopenic purpura.


Potential future application with therapeutic agents.
Several new approaches to radiation therapy with radionuclides have been discussed. Iron 55 is selectively utilized in the red cell developmental cycle and in therapeutic doses, can lower marrow and circulating erythrocyte levels with much smaller degrees of effect on other cell lines. A serious complication, noted in animal studies, is the induction of neoplasma, especially osteosarcoma. Selective irradiation of the cell nucleus is possible with 125IUdR. This results in highly efficient cell killing due to the highly concentrated region of ionization. High concentrations of densely ionizing radiation in the malignant cell may also be accomplished with 211At. The use of labeled liposomes is an additional approach to the delivery of intracellular irradiation. None of these approaches is applicable for the practical treatment of human malignancy at the present time. The importance of these approaches is their value as models for future development of methods that can provide highly selective radiation to target sites.


Regorafenib (BAY 73-4506): stromal and oncogenic multikinase inhibitor with potential activity in renal cell carcinoma.
The introduction of targeted therapies, specifically those that target the VEGF receptor (VEGFR), PDGF receptor (PDGFR) and the mTOR pathways, has significantly changed the approach to patients with unresectable renal cell cancer (RCC). However, drug resistance develops through bypassing of targeted pathways. Regorafenib (BAY 73-4506) is a novel bi-aryl urea compound that has potential anti-tumour activity in RCC, as along with targeting VEGF and PDGF receptors, it targets additional kinases associated with alternative pathways of angiogenesis and resistance to VEGF-targeted drugs. Based on a phase II clinical trial, the efficacy outcome of regorafenib in the first-line setting of unresectable RCC appears comparable that of other targeted first-line drugs. However, testing regorafenib in standard phase III trials seems inappropriate in view of its toxic effects. Further assessment of regorafenib should exploit the drug's ability to inhibit mechanisms of escape from anti-angiogenic treatment through biomarker-driven clinical trials.


Radiofrequency Ablation for Treatment of Leiomyomas: Review of the Manufacturer and User Facility Device Experience (MAUDE) Database.
Radiofrequency ablation (RFA) is a relatively novel, increasingly popular treatment option for leiomyomas. We studied medical device-related reports of leiomyoma RFA devices to determine whether there are emerging device-related issues. The Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database was queried from 2012 through November 2022. Sixty unique reports, including adverse events and device malfunctions, were analyzed for both laparoscopic and transcervical RFA devices. Forty-three injury reports were reviewed. The most common adverse event was infection. Of the injury cases, 34.9% required additional surgical intervention. Although the details of each event are limited, these reports highlight the importance of postmarket surveillance of new technologies and the necessity of improving the current system of implementation and monitoring.


Identification of a region of the Arabidopsis AtAOX1a promoter necessary for mitochondrial retrograde regulation of expression.
Chemical inhibition of the mitochondrial electron transport chain (mtETC) by antimycin A (AA) or the TCA cycle by monofluoroacetate (MFA) causes increased expression of nucleus-encoded alternative oxidase (AOX) genes in plants. In order to better understand the mechanisms of this mitochondrial retrograde regulation (MRR) of gene expression, constructs containing deleted and mutated versions of a promoter region of the Arabidopsis thaliana AOX1a gene (AtAOX1a) controlling expression of the coding region of the enhanced firefly luciferase gene were employed to identify regions of the AtAOX1a promoter important for induction in response to mtETC or TCA cycle inhibition. Transient transformation coupled with in vitro and in vivo assays as well as plants containing transgenes with truncated promoter regions were used to identify a 93 base pair portion of the promoter, termed the MRR region, that was necessary for induction. Further mutational analyses showed that most of the 93 bp MRR region is important for both AA and MFA induction. Sub-regions within the MRR region that are especially important for strong induction by both AA or MFA were identified. Specific mutations in a W-box and Dof motifs in the MRR region indicate that these specific motifs are not important for induction. Recent evidence suggests that MRR of AOX genes following inhibition of the mtETC is via a separate signaling pathway from MRR resulting from metabolic shifts, such as those that result from MFA treatment. Our data suggest that these signaling pathways share regulatory regions in the AtAOX1a promoter. Arabidopsis proteins interacted specifically with a probe containing the MRR region, as shown by electrophoretic mobility shift assays and Southwestern blotting. These interactions were eliminated under reducing conditions.


pH-Promoted Release of a Novel Anti-Tumour Peptide by "Stealth" Liposomes: Effect of Nanocarriers on the Drug Activity in Cis-Platinum Resistant Cancer Cells.
To evaluate the potential effects of PEGylated pH-sensitive liposomes on the intracellular activity of a new peptide recently characterized as a novel inhibitor of the human thymidylate synthase (hTS) over-expressed in many drug-resistant human cancer cell lines. Peptide-loaded pH-sensitive PEGylated (PpHL) and non-PEGylated liposomes (nPpHL) were carefully characterized and delivered to cis-platinum resistant ovarian cancer C13* cells; the influence of the PpHL on the drug intracellular activity was investigated by the Western Blot analysis of proteins involved in the pathway affected by hTS inhibition. Although PpHL and nPpHL showed different sizes, surface hydrophilicities and serum stabilities, both carriers entrapped the drug efficiently and stably demonstrating a pH dependent release; moreover, the different behavior against J774 macrophage cells confirmed the ability of PEGylation in protecting liposomes from the reticuloendothelial system. Comparable effects were instead observed against C13* cells and biochemical data by immunoblot analysis indicated that PEGylated pH-sensitive liposomes do not modify the proteomic profile of the cells, fully preserving the activity of the biomolecule. PpHL can be considered as efficient delivery systems for the new promising anti-cancer peptide.


Side effects of Ricinus lectin (RCA 120) on nucleic acid synthesis in chick embryo fibroblasts.
When fibroblasts from chick embryos were treated with Ricinus lectin, the effects observed depended on the stage of development of the embryo from which the cells were prepared. Thus, in 16-day fibroblasts, which have a weak proliferative capacity, nucleic acid synthesis was less sensitive to the effect of this lectin than that in 8-day fibroblasts, whose proliferative capacity is high.


Stage distribution utilizing magnetic resonance imaging in an unselected population of primary rectal cancers.
Pre-operative radiotherapy (RT) or chemo-radiotherapy (CRT) are sometimes recommended prior to rectal cancer surgery, but guideline recommendations vary. The aim was to describe stage distribution and other important characteristics required for the treatment decision of patients with primary rectal cancers utilizing magnetic resonance imaging (MRI) in an unselected population. All 796 histopathologically verified rectal adenocarcinomas diagnosed 2010-2015 in two counties in Sweden (population 630,000 in 2015) were identified. Staging with pelvic MRI unless contraindications were present, treatment and pathology followed Swedish guidelines. Twenty-three % of cases (n = 186) had distant metastases at diagnosis, demonstrating more advanced tumor and nodal stages when compared with non-metastatic patients (p < 0.001), and they more often displayed MRI-identified mucinous features and extramural vascular invasion (EMVI) than non-metastatic tumors (p < 0.001 for both). In non-metastatic patients, 8% displayed clinical stage T1 (cT1), 21% cT2, and 53% cT3; one-third of the latter threatened or involved the mesorectal fascia (MRF+). Almost 20% had stage cT4 (4% cT4a, 14% cT4b) of which 50% were considered "non-resectable". EMVI was seen in 33% of cT3M0 tumors and in 48% of cT4M0 tumors. In an unselected population, approximately 80% of primary rectal cancers are referred to as "locally advanced" (stage II-III, or cT3-4 or N+), meaning that they, according to many international guidelines, are recommended neo-adjuvant treatment. This study provides a detailed description of the clinical stages and presence of characteristics identifiable on MRI which are of importance when assessing the needs for RT/CRT, when using different guidelines.


Design, synthesis, and structure-activity relationship of a bicyclic HBV capsid assembly modulator chemotype leading to the identification of clinical candidate AB-506.
Disruption of the HBV capsid assembly process through small-molecule interaction with HBV core protein is a validated target for the suppression of hepatitis B viral replication and the development of new antivirals. Through combination of key structural features associated with two distinct series of capsid assembly modulators, a novel aminochroman-based chemotype was identified. Optimization of anti-HBV potency through generation of SAR in addition to further core modifications provided a series of related functionalized aminoindanes. Key compounds demonstrated excellent cellular potency in addition to favorable ADME and pharmacokinetic profiles and were shown to be highly efficacious in a mouse model of HBV replication. Aminoindane derivative AB-506 was subsequently advanced into clinical development.


Comparison of protein force fields for molecular dynamics simulations.
In the context of molecular dynamics simulations of proteins, the term "force field" refers to the combination of a mathematical formula and associated parameters that are used to describe the energy of the protein as a function of its atomic coordinates. In this review, we describe the functional forms and parameterization protocols of the widely used biomolecular force fields Amber, CHARMM, GROMOS, and OPLS-AA. We also summarize the ability of various readily available noncommercial molecular dynamics packages to perform simulations using these force fields, as well as to use modern methods for the generation of constant-temperature, constant-pressure ensembles and to treat long-range interactions. Finally, we finish with a discussion of the ability of these force fields to support the modeling of proteins in conjunction with nucleic acids, lipids, carbohydrates, and/or small molecules.


Effects of restricted feeding on the activity of hypothalamic Orexin (OX)-A containing neurons and OX2 receptor mRNA level in the paraventricular nucleus of rats.
We have examined the effects of 3 weeks of food restriction on both the activity of neurons containing hypothalamic orexin (OX)-A and the level of OX receptor type 2 (OX2R) mRNA in the paraventricular nucleus (PVN) of rats. Double immunohistochemistry was used to examine the expression of OX-A and Fos in the lateral hypothalamic area (LHA), and in situ hybridization histochemistry was used to measure levels of OX2R mRNA in the PVN. After the period of restricted feeding, 20-30% of OX-A-containing neurons exhibited Fos-like immunoreactivity (LI). The distribution of OX-A-LI/Fos-LI cells in the food-restricted rats was similar to that observed in glucose-deprived rats after intracerebroventricular (icv) administration of 2-deoxy-D-glucose (2-DG). In addition, 3 weeks of food restriction caused a significant decrease in the expression of the OX2R gene in the parvocellular division of the PVN. These results suggest that the activation of OX-A-containing neurons induced by restricted feeding may be involved in neuroendocrine responses to food restriction.


Expression of a putative alfalfa helicase increases tolerance to abiotic stress in Arabidopsis by enhancing the capacities for ROS scavenging and osmotic adjustment.
Plant helicases are known to be involved in salinity and low-temperature tolerance. However, a functional involvement of helicases in the antioxidative response of plants has not been described. We have isolated a DEAD-box-containing cDNA sequence from Medicago sativa (alfalfa) that is a homolog of the pea DNA helicase 45 (PDH45) and named it M. sativa helicase 1 (MH1). Transient transfection of 35S::MH1-GFP to onion epidermis revealed that MH1 was localized in the nucleus. Expression of MH1 was detected in roots, stems and leaves of alfalfa. Furthermore, real-time PCR analysis revealed that mannitol, NaCl, methyl viologen and abscisic acid induced the expression of MH1. The ectopic expression of MH1 in Arabidopsis improved seed germination and plant growth under drought, salt and oxidative stress. The capacity for osmotic adjustment, superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities and proline content were also elevated in the transgenic Arabidopsis plants. Our results suggest that MH1 responds to reactive oxygen species (ROS) and functions in drought and salt stress tolerance by enhancing the capacities for ROS scavenging and osmotic adjustment.


Discrimination of SARS-CoV-2 omicron variant and its lineages by rapid detection of immune-escape mutations in spike protein RBD using asymmetric PCR-based melting curve analysis.
The SARS-CoV-2 Omicron strain has multiple immune-escape mutations in the spike protein receptor-binding domain (RBD). Rapid detection of these mutations to identify Omicron and its lineages is essential for guiding public health strategies and patient treatments. We developed a two-tube, four-color assay employing asymmetric polymerase chain reaction (PCR)-based melting curve analysis to detect Omicron mutations and discriminate the BA.1, BA.2, BA.4/5, and BA.2.75 lineages. The presented technique involves combinatory analysis of the detection of six fluorescent probes targeting the immune-escape mutations L452R, N460K, E484A, F486V, Q493R, Q498R, and Y505H within one amplicon in the spike RBD and probes targeting the ORF1ab and N genes. After protocol optimization, the analytical performance of the technique was evaluated using plasmid templates. Sensitivity was assessed based on the limit of detection (LOD), and reliability was assessed by calculating the intra- and inter-run precision of melting temperatures (Tms). Specificity was assessed using pseudotyped lentivirus of common human respiratory pathogens and human genomic DNA. The assay was used to analyze 40 SARS-CoV-2-positive clinical samples (including 36 BA.2 and 4 BA.4/5 samples) and pseudotyped lentiviruses of wild-type and BA.1 viral RNA control materials, as well as 20 SARS-CoV-2-negative clinical samples, and its accuracy was evaluated by comparing the results with those of sequencing. All genotypes were sensitively identified using the developed method with a LOD of 39.1 copies per reaction. The intra- and inter-run coefficients of variation for the Tms were ≤ 0.69% and ≤ 0.84%, with standard deviations ≤ 0.38 °C and ≤ 0.41 °C, respectively. Validation of the assay using known SARS-CoV-2-positive samples demonstrated its ability to correctly identify the targeted mutations and preliminarily characterize the Omicron lineages. The developed assay can provide accurate, reliable, rapid, simple and low-cost detection of the immune-escape mutations located in the spike RBD to detect the Omicron variant and discriminate its lineages, and its use can be easily generalized in clinical laboratories with a fluorescent PCR platform.


Dural arteriovenous fistula of the transverse-sigmoid sinus causing trigeminal neuralgia.
The authors analysed an unusual case of dural arteriovenous fistula (DAVF) of the transverse-sigmoid sinus causing trigeminal neuralgia is presented. Although progression to almost continuous facial pain has been reported, symptoms may be indistinguishable from typical trigeminal neuralgia. The patient had a 6-year history of right-sided trigeminal neuralgia initially well controlled by medical management. He was referred for surgical management after 10 months of progressively worsening of symptoms. At the time of consultation, the patient complained of pulsatile tinnitus in the right ear. Computed tomography imaging and angiography demonstrated a DAVF involving the right transverse-sigmoid sinus junction with retrograde venous drainage. Surgical resection of the DAVF provided both angiographic cure and complete relief of all symptoms. The authors discuss the pathophysiology of trigeminal neuralgia in patients with a DAVF.


PANENE: A Progressive Algorithm for Indexing and Querying Approximate k-Nearest Neighbors.
We present PANENE, a progressive algorithm for approximate nearest neighbor indexing and querying. Although the use of k-nearest neighbor (KNN) libraries is common in many data analysis methods, most KNN algorithms can only be queried when the whole dataset has been indexed, i.e., they are not online. Even the few online implementations are not progressive in the sense that the time to index incoming data is not bounded and cannot satisfy the latency requirements of progressive systems. This long latency has significantly limited the use of many machine learning methods, such as t-SNE, in interactive visual analytics. PANENE is a novel algorithm for Progressive Approximate k-NEarest NEighbors, enabling fast KNN queries while continuously indexing new batches of data. Following the progressive computation paradigm, PANENE operations can be bounded in time, allowing analysts to access running results within an interactive latency. PANENE can also incrementally build and maintain a cache data structure, a KNN lookup table, to enable constant-time lookups for KNN queries. Finally, we present three progressive applications of PANENE, such as regression, density estimation, and responsive t-SNE, opening up new opportunities to use complex algorithms in interactive systems.