New insights into the reactivity of aminomethylene derivatives of resorc[4]arene: amine group transfer, conformational analysis, reaction mechanism.
Using the example of aminomethylene derivatives of resorc[4]arene and their Michael reaction with 4-hydroxycoumarin, the possibility of transferring an amine molecule from substrate to product is demonstrated. The conformation of the aminocoumarin derivatives of resorc[4]arene formed is controlled by the polarity of the solvent. For one of the products, conformational analysis was performed by kinetic sampling using metadynamics (MTD). The energies of the final set of conformers were calculated by DFT (r2scan-3c). A reaction mechanism based on multiscale (ONIOM) Nudged Elastic Band (NEB-TS) reaction profile calculations is discussed.


NORMAL TISSUE REACTIONS TO CHRONIC RADIATION EXPOSURE IN MAN.
This paper presents an overview of radiobiological dependences governing the occurrence of tissue (organ) reactions that determine the outcomes of chronic exposure to low-LET ionizing radiation (IR) in humans. The mechanisms involved in the development of tissue reactions (TRs) to long-term exposures to IR and radioadaptation are considered. The overview describes the reactions of the haematopoietic, immune, nervous, reproductive and endocrine systems, lungs, skin and crystalline lens to chronic radiation exposure, which are of fundamental importance in view of radiation protection. It is shown that the individual's physiological tissue (organ) reserve, and also that induced by radiation exposure at low-dose rates are of great significance in the context of TR development.


Reducing exposure to dioxins and related compounds through foods in the next generation.
Dioxins and related compounds are undesirable and unintended contaminants in the food supply, and dietary intake is the major route of exposure. Reducing dietary exposure to dioxins among the most vulnerable segments of the population (i.e., pregnant women, infants, and young girls) is an effective strategy for reducing body burdens in future generations. Exposure to dioxins through foods can be minimized by selecting lower-fat versions of meats, poultry, and dairy products. Consuming all foods, including fatty fish, in recommended amounts is congruent with the goal of reducing dioxin intake exposure and maintaining good health.


Stimulus contrast modulates functional connectivity in visual cortex.
Neurons in visual cortex are linked by an extensive network of lateral connections. To study the effect of these connections on neural responses, we recorded spikes and local field potentials (LFPs) from multi-electrode arrays that were implanted in monkey and cat primary visual cortex. Spikes at each location generated outward traveling LFP waves. When the visual stimulus was absent or had low contrast, these LFP waves had large amplitudes and traveled over long distances. Their effect was strong: LFP traces at any site could be predicted by the superposition of waves that were evoked by spiking in a approximately 1.5-mm radius. As stimulus contrast increased, both the magnitude and the distance traveled by the waves progressively decreased. We conclude that the relative weight of feedforward and lateral inputs in visual cortex is not fixed, but rather depends on stimulus contrast. Lateral connections dominate at low contrast, when spatial integration of signals is perhaps most beneficial.


Beta-thromboglobulin and platelet aggregates in glomerulonephritis.
Circulating platelet aggregate ratios (CPAR) and plasma beta-thromboglobulin (B-TG) concentrations were determined in 53 patients with chronic progressive glomerulonephritis [mesangiocapillary glomerulonephritis (15) and focal and segmental hyalinosis and sclerosis (38)] and compared with those from both normal subjects and patients with no evidence of renal disease. The mean B-TG concentration was higher in patient controls [32.6 +/- 6.2 ng/ml (SEM)] than in normal subjects [19.0 +/- 2.0 ng/ml (SEM)] but this did not reach significance (P < 0.10 > 0.05). Nephritic patients had markedly elevated levels [49.8 +/- 4.0 ng/ml (SEM)], but B-TG was significantly correlated with renal impairment. Elevated B-TG levels in patients with nephritis may thus reflect renal impairment or ill-health. The mean CPAR of the nephritic patients [0.75 +/- 0.02 (SEM)] was lower than that of both normal [0.86 +/- 0.03 (SEM), P < 0.001] and patient controls [0.87 +/- 0.02 (SEM), P < 0.001]. CPAR was not correlated with renal function or platelet concentration. Low CPAR in nephritic subjects provides further evidence for in-vivo activation of platelets in patients with glomerulonephritis.


Electroencephalographic Correlates and Predictors of Treatment Outcome in OCD: A Brief Narrative Review.
Electroencephalography (EEG) measures the brain's electrical activity with high temporal resolution. In comparison to neuroimaging modalities such as MRI or PET, EEG is relatively cheap, non-invasive, portable, and simple to administer, making it an attractive tool for clinical deployment. Despite this, studies utilizing EEG to investigate obsessive-compulsive disorder (OCD) are relatively sparse. This contrasts with a robust literature using other brain imaging methodologies. The present review examines studies that have used EEG to examine predictors and correlates of response in OCD and draws tentative conclusions that may guide much needed future work. Key findings include a limited literature base; few studies have attempted to predict clinical change from EEG signals, and they are confounded by the effects of both pharmacotherapy and psychotherapy. The most robust literature, consisting of several studies, has examined event-related potentials, including the P300, which several studies have reported to be abnormal at baseline in OCD and to normalize with treatment; but even here the literature is quite heterogeneous, and more work is needed. With more robust research, we suggest that the relatively low cost and convenience of EEG, especially in comparison to fMRI and PET, make it well-suited to the development of feasible personalized treatment algorithms.


Effect of Evolocumab on Type and Size of Subsequent Myocardial Infarction: A Prespecified Analysis of the FOURIER Randomized Clinical Trial.
The PCSK9 inhibitor evolocumab reduced major vascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, yet the types and sizes of myocardial outcomes in FOURIER have not been previously explored. To assess the types and sizes of myocardial infarction (MI) and the effect of evolocumab on MI by subtype. A prespecified analysis of a multicenter double-blind randomized clinical trial. Patients were randomized to evolocumab or placebo and followed up for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Clinical end points were evaluated by the Thrombolysis in Myocardial Infarction clinical events committee. Rates presented are 3-year Kaplan-Meier estimates. Data were collected from 2013 to 2016 and analyzed from June 2017 to December 2019. Myocardial infarction was defined based on the third universal MI definition, and further classified according to MI type (universal MI subclass, ST-segment elevation myocardial infarction [STEMI] vs non-STEMI) and by MI size (determined by peak troponin level). A total of 27 564 patients were randomized, with a mean (SD) age of 62.5 (9.0) years, and 20 795 (75%) were male. Of these, 1107 patients experienced a total of 1288 MIs. Most MIs (68%) were atherothrombotic (type 1), with 15% from myocardial oxygen supply-demand mismatch (type 2) and 15% percutaneous coronary intervention-related (type 4). Sudden death (type 3) and coronary artery bypass grafting-related (type 5) accounted for a total of 21 MIs (<2%). Evolocumab significantly reduced the risk of first MI by 27% (4.4% vs 6.3%; hazard ratio [HR], 0.73; 95% CI, 0.65-0.82; P < .001), type 1 by 32% (2.9% vs 4.5%; HR, 0.68; 95% CI, 0.59-0.79; P < .001), and type 4 by 35% (0.8% vs 1.1%; HR, 0.65; 95% CI, 0.48-0.87; P = .004), with no effect on type 2 (0.9% vs 0.8%; HR, 1.09; 95% CI, 0.82-1.45; P = .56). Most MIs (688 [59.8%]) had troponin levels greater than or equal to 10 times the upper limit of normal. The benefit was highly significant and consistent regardless of the size of MI with a 34% reduction in MIs with troponin level greater than or equal to 10 times the upper limit of normal (2.6% vs 3.7%; HR, 0.66; 95% CI, 0.56-0.77; P < .001) and a 36% reduction in the risk of STEMI (1.0% vs 1.5%; HR, 0.64; 95% CI, 0.49-0.84; P < .001). Low-density lipoprotein cholesterol lowering with evolocumab was highly effective in reducing the risk of MI. This reduction with evolocumab included benefit across multiple subtypes of MI related to plaque rupture, smaller and larger MIs, and both STEMI and non-STEMI. These data are consistent with the known benefit of low-density lipoprotein cholesterol lowering and underscore the reduction in clinically meaningful events. ClinicalTrials.gov Identifier: NCT01764633.


Vitamin D kinetics in vivo: effect of 1,25-dihydroxyvitamin D administration.
Administration of 1,25-dihydroxyvitamin D [1,25(OH)2D] can increase the metabolic clearance rate (MCR) of 25-hydroxyvitamin D [25(OH)D]. To determine whether administration of 1,25(OH)2D can also influence the metabolic clearance rates (MCR) of 1,25(OH)2D and 24,25-dihydroxyvitamin D 24,25(OH)2D, we measured metabolic clearance of 1,25(OH)2D, 24,25(OH)2D, and 25(OH)D in rats in which the serum concentration of 1,25(OH)2D was increased by continuous infusion. Infusion of 1,25(OH)2D (12 days at 75 pmol/day) increased serum 1,25(OH)2D from 128 +/- 11 to 244 +/- 14 pg/ml (P less than 0.005) and increased MCR from 169 +/- 13 to 210 +/- 9 microliters.min-1.kg-1 or 24% (P less than 0.025). Increasing serum 1,25(OH)2D to 330-360 pg/ml increased MCR 72%. Infusion of 1,25(OH)2D decreased serum 24,25(OH)2D from 3.5 +/- 0.5 to 2.4 +/- 0.3 ng/ml (P less than 0.05), increased MCR from 25 +/- 2 to 48 +/- 6 microliters.min-1.kg-1 (P less than 0.0025), and increased the production rate (PR) from 70 +/- 11 to 124 +/- 26 pg.min-1.kg-1 (P less than 0.05). Infusion of 1,25(OH)2D decreased serum 25(OH)D from 13.0 +/- 0.5 to 8.0 +/- 0.5 ng/ml (P less than 0.005) and increased MCR from 45 +/- 1 to 75 +/- 7 microliters.min-1.kg-1 (P less than 0.001) but had no effect on PR. The data indicate that increasing serum 1,25(OH)2D by chronic administration can increase the MCR of 1,25(OH)2D and suggest that 1,25(OH)2D can feedback regulate its serum concentration by regulating its MCR. The data also suggest that 1,25(OH)2D administration can increase the MCRs of 24,25(OH)2D and 25(OH)D.


Effect of Mir-122 on Human Cholangiocarcinoma Proliferation, Invasion, and Apoptosis Through P53 Expression.
BACKGROUND Bile duct carcinoma is a common digestive tract tumor with high morbidity and mortality. As a kind of important non-coding RNA, microRNA (miR) plays an important role in post-transcriptional regulation. MiR-122 is the most abundant miR in the liver. Multiple studies have shown that miR-122 level is reduced in a variety of liver tumors and can be used as a specific marker for liver injury. P53 is a classic tumor suppressor gene that can induce tumor cell apoptosis through various pathways. Whether miR-122 affects p53 in bile duct carcinoma still needs investigation. MATERIAL AND METHODS miR inhibitor or mimics was transfected to bile duct carcinoma cells to evaluate its function on proliferation, invasion, apoptosis, and p53 expression. RESULTS MiR-122 overexpression reduced cell invasion and migration ability, and inhibited cell apoptosis and p53 expression. Inhibiting miR-122 caused the opposite results. CONCLUSIONS Upregulating miR-122 can suppress bile duct carcinoma cell proliferation and induce apoptosis. MiR-122 could be used as a target for bile duct carcinoma treatment, which provides a new strategy for cholangiocarcinoma patients.


A Chemical Biological Approach to Study G Protein-Coupled Receptors: Labeling the Adenosine A1 Receptor Using an Electrophilic Covalent Probe.
G protein-coupled receptors (GPCRs) have been known for decades as attractive drug targets. This has led to the development and approval of many ligands targeting GPCRs. Although ligand binding effects have been studied thoroughly for many GPCRs, there are multiple aspects of GPCR signaling that remain poorly understood. The reasons for this are the difficulties that are encountered upon studying GPCRs, for example, a poor solubility and low expression levels. In this work, we have managed to overcome some of these issues by developing an affinity-based probe for a prototypic GPCR, the adenosine A1 receptor (A1AR). Here, we show the design, synthesis, and biological evaluation of this probe in various biochemical assays, such as SDS-PAGE, confocal microscopy, and chemical proteomics.


Monitoring of cAMP-imprinted polymer by fluorescence spectroscopy.
Conventional functional monomers together with fluorescent monomer, trans-4-[p-(N,N-dimethylamino)styryl]-N-vinylbenzylpyridinium chloride (vb-DMASP), were copolymerised in the presence of a target molecule, nucleotide-cAMP that acted as a molecular template. The polymer was copolymerised in thin-layer films. After removal of the template the functionalised cavities that exist in the fluorescent material are able to specifically bind the template. Subsequent adsorption of the template-cAMP causes quenching of fluorescence of the polymer. The specific photochemical processes accompanying the template adsorption are discussed further. The imprinted polymers monitored by both steady-state and time-resolved fluorescence techniques show specificity and selectivity of binding of the template on the imprinted functionalised cavities.


Analysis of adaptive evolution in Lyssavirus genomes reveals pervasive diversifying selection during species diversification.
Lyssavirus is a diverse genus of viruses that infect a variety of mammalian hosts, typically causing encephalitis. The evolution of this lineage, particularly the rabies virus, has been a focus of research because of the extensive occurrence of cross-species transmission, and the distinctive geographical patterns present throughout the diversification of these viruses. Although numerous studies have examined pattern-related questions concerning Lyssavirus evolution, analyses of the evolutionary processes acting on Lyssavirus diversification are scarce. To clarify the relevance of positive natural selection in Lyssavirus diversification, we conducted a comprehensive scan for episodic diversifying selection across all lineages and codon sites of the five coding regions in lyssavirus genomes. Although the genomes of these viruses are generally conserved, the glycoprotein (G), RNA-dependent RNA polymerase (L) and polymerase (P) genes were frequently targets of adaptive evolution during the diversification of the genus. Adaptive evolution is particularly manifest in the glycoprotein gene, which was inferred to have experienced the highest density of positively selected codon sites along branches. Substitutions in the L gene were found to be associated with the early diversification of phylogroups. A comparison between the number of positively selected sites inferred along the branches of RABV population branches and Lyssavirus intespecies branches suggested that the occurrence of positive selection was similar on the five coding regions of the genome in both groups.


The potential influence of 5-aminosalicylic acid on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients.
To investigate the potential influence of 5-aminosalicylic acid (5-ASA) on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients. (a) The retrospective study included inflammatory bowel disease patients treated with azathioprine (AZA)/6-mercaptopurine (6-MP). Thiopurine methyltransferase (TPMT) activity and 6-thioguanine nucleotide (6-TGN) levels were detected at stable medication points. (b) The prospective study was performed in active disease patients: 4 weeks of AZA 50 mg/day followed by concomitant 5-ASA 3 g/day for another 4 weeks. 6-TGN was analyzed at weeks 4 and 8. (a) Of the 139 retrospective study patients, 45 were on AZA/6-MP+5-ASA and 94 on AZA/6-MP alone. The myelotoxicity rates were 47 and 16%, respectively. Multivariates regression analysis indicated that the administration of concomitant 5-ASA was the only risk factor associated with myelotoxicity (odds ratio=3.45, 95% confidence interval 1.31-9.04, P=0.01). (b) Thiopurine methyltransferase activity was not significantly different between patients on AZA/6-MP+5-ASA and patients on AZA/6-MP alone (P=0.78). (c) 6-TGN levels were significantly higher in samples on AZA/6-MP+5-ASA than those on AZA/6-MP (P=0.003) alone. (d) Sixteen patients completed the prospective study. After 4 weeks on AZA 50 mg/day, 6-TGN levels of 13 patients were less than 230 pmol/8×10 RBC. After another 4 weeks' cotreatment with mesalazine 3 g/day, 12 patients had 6-TGN levels at least 230 pmol/8×10 RBC, five patients had 6-TGN levels at least 420 pmol/8×10 RBC, and two of these five patients developed myelotoxicity. The risk of thiopurine-induced myelotoxicity markedly increases in patients treated with combined 5-ASA and 2 mg/kg/day AZA therapy, which may be correlated to the increase in 6-TGN. 50 mg daily AZA when concomitant 5-ASA might help maintain an effective 6-TGN level without increasing the risk of myelotoxicity.


Human ehrlichioses.
Human ehrlichioses represent one of the best examples of newly emergent infectious diseases in which the classic triad of host, infectious agent, and environment are intertwined closely. These pathogens have existed for eons on the planet, and some were described as veterinary pathogens decades ago. Because of dramatic increases of deer and small mammal populations in certain areas and the subsequent increased populations of particular blood-feeding ticks, the risk of developing these diseases is higher than before. Increasing human populations in suburban areas and increased immunosuppressed populations (transplant patients, human immunodeficiency virus patients, and cancer survivors) also have increased risk of developing severe forms of these diseases.


ED presentation of neutropenic enterocolitis in adult patients with acute leukemia.
The purpose of this study was to investigate the initial clinical features and subsequent outcomes in patients with adult leukemia with typhlitis or neutropenic enterocolitis. A retrospective review of 10 episodes of neutropenic enterocolitis in nine patients (age range, 21-71 years) with acute leukemia from March 1, 1990, through February 28, 2002, was conducted. In clinical presentations, fever appears in all patients, followed by abdominal pain or tenderness (90%) and diarrhea (60%), respectively. In particular, three cases were coincidentally diagnosed as leukemia before any chemotherapy. The most common diagnostic modality used for the diagnosis of neutropenic enterocolitis was computed tomography (CT) scan (seven episodes). Medical treatments, including broad-spectrum antibiotics, bowel rest, and total parenteral nutrition, were applied to seven patients. Laparotomy with bowel resection was performed on two patients with bowel necrosis and severe peritonitis. Of all nine cases, six were fatal as a result of sepsis, a common complication of neutropenic enterocolitis. As the incidence of neutropenic enterocolitis increases in patients with acute leukemia, EPs should be alert and make an early diagnosis of this rapidly deteriorated and life-threatening disease.


Pathological evaluation of Polystichum squarrosum (D. Don) fern in laboratory rats.
Polystichum squarrosum fern fed (30% w/w) rats showed moderate mortality, decrease in body weight, less body fat and splenomegaly. On post-mortem examination, significant gross lesions were not seen in sacrificed animals. Histopathologically, Polystichum fed rats showed dilated Virchow Robin's space in brain, mild to moderate vascular changes likeoedema, engorgement of blood vessels and haemorrhages in most of the visceral organs, interstitial pneumonia in lungs, focal necrosis and generalised vacuolative degenerative changes in liver, more haemosiderin deposition and presence of higher number of megakaryocytes in spleen, shrunken glomeruli, more peri-glomerular space and more number of glomeruli per microscopic field in kidneys, focal hyperplasia of urinary bladder and moderate to marked depletion of germinal epithelium and spermatids in seminiferous tubules of testes. Pathologically, progressive changes were observed only in liver, urinary bladder and testes on 180 days post feeding (DPF). One fern fed rat sacrificed on 135 DPF showed hepatic tumour which was diagnosed as hepatocellular carcinoma. The results showed that P. squarrosum produced almost comparable pathological changes/preneoplastic lesions as reported in bracken fern fed animals. Long term exposure studies (i.e. 2 yrs) are desired.


Prediction for Rational Synthesis Based on Weighted Feature Selection Method.
In this paper, a novel integrated feature selection model is proposed to analyze the relationship between the synthesis factors and the specific resulting structure on the database of AlPO synthesis. Concretely, the proposed model can select the most significant synthesis factors affecting the formation of a (6,12)-ring-containing structure by combining multiple feature selection methods. Firstly, eight feature selection methods are employed to prerank the synthesis factors based on the predictive performance of support vector machine. Then, a weighted fusion mechanism is presented to rerank the results. Finally, sequential forward floating search method is utilized to select the most significant synthesis factors in view of the highest predictive performance. A large number of experimental results show that the proposed model is efficient and feasible. The predictive accuracy can reach 86.47 % with the selected 10 factors among 21 synthesis factors. The selection and ranking results also give a rational understanding for AlPO synthesis. More specifically, a proportional relationship among gel composition parameters is recommended based on the result of feature selection, which has important guiding significance for the rational design and synthesis.


Treatment Activity, User Satisfaction, and Experienced Usability of Internet-Based Cognitive Behavioral Therapy for Adults With Depression and Anxiety After a Myocardial Infarction: Mixed-Methods Study.
Knowledge about user experiences may lead to insights about how to improve treatment activity in Internet-based cognitive behavioral therapy (iCBT) to reduce symptoms of depression and anxiety among people with a somatic disease. There is a need for studies conducted alongside randomized trials, to explore treatment activity and user experiences related to such interventions, especially among people with older age who are recruited in routine care. The aim of the study was to explore treatment activity, user satisfaction, and usability experiences among patients allocated to treatment in the U-CARE Heart study, a randomized clinical trial of an iCBT intervention for treatment of depression and anxiety following a recent myocardial infarction. This was a mixed methods study where quantitative and qualitative approaches were used. Patients were recruited consecutively from 25 cardiac clinics in Sweden. The study included 117 patients allocated to 14 weeks of an iCBT intervention in the U-CARE Heart study. Quantitative data about treatment activity and therapist communication were collected through logged user patterns, which were analyzed with descriptive statistics. Qualitative data with regard to positive and negative experiences, and suggestions for improvements concerning the intervention, were collected through semistructured interviews with 21 patients in the treatment arm after follow-up. The interviews were analyzed with qualitative manifest content analysis. Treatment activity was low with regard to number of completed modules (mean 0.76, SD 0.93, range 0-5) and completed assignments (mean 3.09, SD 4.05, range 0-29). Most of the participants initiated the introduction module (113/117, 96.6%), and about half (63/117, 53.9%) of all participants completed the introductory module, but only 18 (15.4%, 18/117) continued to work with any of the remaining 10 modules, and each of the remaining modules was completed by 7 or less of the participants. On average, patients sent less than 2 internal messages to their therapist during the intervention (mean 1.42, SD 2.56, range 0-16). Interviews revealed different preferences with regard to the internet-based portal, the content of the treatment program, and the therapist communication. Aspects related to the personal situation and required skills included unpleasant emotions evoked by the intervention, lack of time, and technical difficulties. Patients with a recent myocardial infarction and symptoms of depression and anxiety showed low treatment activity in this guided iCBT intervention with regard to completed modules, completed assignments, and internal messages sent to their therapist. The findings call attention to the need for researchers to carefully consider the preferences, personal situation, and technical skills of the end users during the development of these interventions. The study indicates several challenges that need to be addressed to improve treatment activity, user satisfaction, and usability in internet-based interventions in this population.


Pathogenesis of minimal change nephrotic syndrome: an immunological concept.
Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia. Minimal change nephrotic syndrome (MCNS) is the most common form of INS in children. The pathogenesis of MCNS still remains unclear, however, several hypotheses have been recently proposed. For several decades, MCNS has been considered a T-cell disorder, which causes the impairment of the glomerular filtration barrier with the release of different circulating factors. Increased levels of several cytokines are also suggested. Recently, a "two-hit" theory was proposed that included the induction of CD80 (B7-1) and regulatory T-cell (Treg) dysfunction, with or without impaired autoregulatory functions of the podocyte. In contrast to the well-established involvement of T cells, the role of B cells has not been clearly identified. However, B-cell biology has recently gained more attention, because rituximab (a monoclonal antibody directed against CD20-bearing cells) demonstrated a very good therapeutic response in the treatment of childhood and adult MCNS. Here, we discuss recent insights into the pathogenesis of MCNS in children.


Behavioral and pathological effects in the rat define two groups of neurotoxic nitriles.
Adult male Long-Evans rats (250-350 g) received control vehicles, 3,3'-iminodipropionitrile (IDPN, 400 mg kg(-1) day(-1)), allylnitrile (50 mg kg(-1) day(-1)), cis-crotononitrile (110 mg kg(-1) day(-1)), trans-crotononitrile (250 mg kg(-1) day(-1)), or 2,4-hexadienenitrile (300 mg kg(-1) day(-1)), i.p., for 3 consecutive days. Rats treated with IDPN, allylnitrile, and cis-crotononitrile developed the ECC (excitation with circling and choreiform movements) syndrome, whereas those treated with trans-crotononitrile and hexadienenitrile exhibited a different syndrome, characterized by faltering movements. On quantitative analysis, IDPN, allylnitrile, and cis-crotononitrile induced high scores in a test battery for vestibular dysfunction and hyperactivity in the open field, but they did not significantly decrease stride length. Hexadienenitrile and trans-crotononitrile did not increase the vestibular scores or the locomotor activity, but they caused a marked decrease in stride length; they also decreased holding time on a vertical ladder. In brain and spinal cord tissue from rats exposed to IDPN, allylnitrile, or cis-crotononitrile, Fluoro-Jade B, a selective stain for degenerating neurons, did not reveal any labeling other than that of nerve terminals in the glomeruli of the olfactory bulbs, indicating degeneration of the olfactory mucosa. With the same stain, rats exposed to trans-crotononitrile or hexadienenitrile showed a common pattern of selective neurotoxicity; major targets were the inferior olive and the piriform cortex. Hexadienenitrile did not cause hair cell degeneration in the vestibular and auditory sensory epithelia. Present and previous data indicate that neurotoxic nitriles induce one or the other of two different motor syndromes, through either vestibular hair cell degeneration or neuronal degeneration of the inferior olive.


Whole-Genome Sequencing of Pig Gut Lactobacillus amylovorus CICC 6090.
Lactobacillus amylovorus has been reported to reduce weight and fat content in humans. To identify and understand the mechanism underlying this process, the complete genome of CICC 6090, which was isolated from pig intestines, was sequenced using PromethION and next-generation sequencing.


Control of Hamiltonian chaos as a possible tool to control anomalous transport in fusion plasmas.
It is shown that a relevant control of Hamiltonian chaos is possible through suitable small perturbations whose form can be explicitly computed. In particular, it is possible to control (reduce) the chaotic diffusion in the phase space of a Hamiltonian system with 1.5 degrees of freedom which models the diffusion of charged test particles in a turbulent electric field across the confining magnetic field in controlled thermonuclear fusion devices. Though still far from practical applications, this result suggests that some strategy to control turbulent transport in magnetized plasmas, in particular, tokamaks, is conceivable. The robustness of the control is investigated in terms of a departure from the optimum magnitude, of a varying cutoff at large wave vectors, and of random errors on the phases of the modes. In all three cases, there is a significant region of maximum efficiency in the vicinity of the optimum control term.


Trajectories of fear of progression in nasopharyngeal carcinoma patients receiving proton and heavy ion therapy.
The study examined the growth trajectory of fear of progression(FOP) in nasopharyngeal carcinoma (NPC) patients. In addition, sociodemographic and clinical variables of each trajectory class were analyzed. Two hundred sixteen NPC patients undergoing proton and heavy ion therapy were measured beginning (T0) and end of a 4-week proton and heavy ion therapy (T1), 3 months (T2) and 6 months (T3) after discharge. And data from the final 197 NPC patients were analyzed. NPC patients' FOP was investigated by the Fear of Progression Questionnaire-Short Form (FOP-Q-SF) form T0 to T3. SPSS and Mplus were used for statistical analysis. The LGMM was used to analyze the trajectory of FOP followed up over 6 months after proton and heavy ion therapy. The logistic regression was utilized to compare the differences in sociodemographic and clinical characteristics of patients in different trajectory groups of FOP. One hundred ninety-seven NPC patients were analyzed. LGMM analysis showed that three-group trajectory solution was the best fitting (low-fear decline FOP (14.21%), the moderate-fear stable FOP(43.15%), and high-fear rising FOP (42.64%). Significant positive associations were found between age < 30 years (β = 3.399, p = 0.023), with or without children (β = 3.1, p = 0.002), primary/recurrence (β = -6.196, p < 0.001), diagnosis < 3 months (β = 4.435, p = 0.031), high school education (β = 2.98, p = 0.048), and high fear rising FOP. Patients who had moderate financial stress (β = 2.51, p = 0.041), with or without children (β = 1.564, p = 0.003), primary/recurrence (β = -2.578, p = 0.005), less than 30 radiotherapy times (β = 0.979, p = 0.046) tended to report significant moderate-fear stable FOP over time. 42.64% of the NPC patients showed high-fear rising FOP over the 6 months after treatment. Age 18-30 years, with or without children, relapsed, diagnosis < 3 months, and high school education and reporting being a pessimist predicts higher FOP scores. Early identification of age 18-30 years, with or without children, relapsed, diagnosis < 3 months, and high school education might help to identify populations experiencing long-term FOP. Clinical teams responsible to develop the target interventions for management of FCR in clinical practice.


[Effects of sevoflurane preconditioning on cardiomyocyte apoptosis and myocardial inflammation in rats with sepsis].
To observe the effects of preconditioning with different concentrations of sevoflurane on cariomyocyte apoptosis and myocardial inflammation in rats with sepsis and explore the possible mechanism of sevoflurane for myocardial protection. Forty adult male Sprague-Dawley rats were randomly divided into 4 groups (n=10), namely the control group, LPS group, low-concentration sevoflurane group and high-concentration sevoflurane group. Following sevoflurane pretreatment for 30 min and a washout period for 10 min, all the rats received intraperitoneal injection of LPS or normal saline (NS) and were sacrificed 12 h later to observe the myocardial histopathology. Apoptosis of the ardiomyocytes was detected with TUNEL assay, and enzyme-linked immunosorbent assay was used to detect serum cTnI level and myocardial TNF-α level. Compared with the control group, the rats in the other 3 groups showed significantly increased serum cTnI level, myocardial TNF-α content, and apoptotic index of the cardiomyocytes (P<0.05). Compared with those in LPS group, serum cTnI level, myocardial TNF-α content, and apoptotic index of the cardiomyocytes were significantly decreased in the two sevoflurane preconditioning groups (P<0.05), and the effect was more obvious with a high dose of sevoflurane (P<0.05 CONCLUSION: Sevoflurane preconditioning can concentration-dependently reduce LPS-induced myocardial injury in rats possibly by decreasing cardiomyocyte apoptosis and alleviating myocardial inflammations.


5-Lipoxygenase and cyclooxygenase-1 inhibitory active compounds from Atractylodes lancea.
Lipophilic extracts of Atractylodes lancea rhizomes exhibited potent inhibitory activities in 5-lipoxygenase [IC50 (5-LOX) = 2.9 micrograms/mL (n-hexane extract)] and cyclooxygenase-1 [IC50 (COX-1) = 30.5 micrograms/mL (n-hexane extract)] enzymatic assays. Bioactivity-guided fractionation of the n-hexane extract led to the isolation of a new compound atractylochromene (1), a potent inhibitor in both test systems [IC50 (5-LOX) = 0.6 microM, IC50 (COX-1) = 3.3 microM]. Also obtained was 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2,5-cyclohexadiene-1 ,4-dione (2), which showed a selective inhibitory activity against 5-LOX [IC50 (5-LOX) 0.2 microM, IC50 (COX-1) 64.3 microM]. The sesquiterpene atractylon (3) and the coumarin osthol (4) turned out to be moderate but selective 5-lipoxygenase inhibitors. Atractylenolides I (5), II (6), and III (7) showed no significant inhibitory effects for either enzyme. Structures were established by spectral data interpretation.


Study protocol for One Health data collections, analyses and intervention of the Sino-Swedish integrated multisectoral partnership for antibiotic resistance containment (IMPACT).
To effectively minimise the emergence and dissemination of antibiotic resistant bacteria, a holistic One Health approach is called for. The Sino-Swedish Integrated Multisectoral Partnership for Antibiotic Resistance Containment is a cross-sectoral and integrated project on antibiotic resistance, conducted in Shandong Province in China. This paper outlines the overall study protocol for the project. To our knowledge, this is the first research programme aiming to take a true holistic approach across multiple sectors simultaneously in China, and the first to incorporate both antibiotic use and infection prevention and control in addition to antibiotic resistance patterns. The project aims to address gaps in current knowledge and seeks to improve the situation through a system-wide intervention. By using a One Health approach we can address important research questions that individual discipline investigations are unable to. The results obtained should thus more closely reflect the world in which human health, animal health and the environment are inextricably and intimately interlinked. Both quantitative and qualitative studies are included for households from 12 villages, their surrounding environment and a tertiary care hospital in a nearby town. The studies include analyses of antibiotic consumption for humans and pigs; qualitative and quantitative data on perceptions, knowledge and attitudes; faecal carriage of extended spectrum β-lactamase and carbapenemase-producing Enterobacteriaceae from pigs and humans, and occurrence in household drinking water, surface water, waste water and clinical bacterial isolates from the hospital. Carriage of methicillin-resistant Staphylococcus aureus in humans, household pigs and clinical bacterial isolates is also investigated. Furthermore, potential inter-relationships between these sources are analysed. A multifaceted One Health intervention is designed and implemented in 6 of the 12 villages. Repeated and continuous data collections take place over 2 years, where the repeated data collection is performed after 1 year of intervention. Comparisons are made between intervention and control villages, before and after the intervention. Ethics approval was obtained from the first Affiliated Hospital, College of Medicine, Zhejiang University, China, reference number 2015#185 and 2015#283.


Opportunities for multicomponent hybrid hydrogels in biomedical applications.
Hydrogels provide mechanical support and a hydrated environment that offer good cytocompatibility and controlled release of molecules, and myriad hydrogels thus have been studied for biomedical applications. In the past few decades, research in these areas has shifted increasingly to multicomponent hydrogels that better capture the multifunctional nature of native biological environments and that offer opportunities to selectively tailor materials properties. This review summarizes recent approaches aimed at producing multicomponent hydrogels, with descriptions of contemporary chemical and physical approaches for forming networks, and of the use of both synthetic and biologically derived molecules to impart desired properties. Specific multicomponent materials with enhanced mechanical properties are presented, as well as materials in which multiple biological functions are imparted for applications in tissue engineering, cancer treatment, and gene therapies. The progress in the field suggests significant promise for these approaches in the development of biomedically relevant materials.


D-Amino-Acid Oxidase Inhibition Increases D-Serine Plasma Levels in Mouse But not in Monkey or Dog.
D-serine has been shown to improve positive, negative, and cognitive symptoms when used as add-on therapy for the treatment of schizophrenia. However, D-serine has to be administered at high doses to observe clinical effects. This is thought to be due to D-serine undergoing oxidation by D-amino-acid oxidase (DAAO) before it reaches the brain. Consequently, co-administration of D-serine with a DAAO inhibitor could be a way to lower the D-serine dose required to treat schizophrenia. Early studies in rodents to evaluate this hypothesis showed that concomitant administration of structurally distinct DAAO inhibitors with D-serine enhanced plasma and brain D-serine levels in rodents compared with administration of D-serine alone. In the present work we used three potent DAAO inhibitors and confirmed previous results in mice. In a follow-up effort, we evaluated plasma D-serine levels in monkeys after oral administration of D-serine in the presence or absence of these DAAO inhibitors. Even though the compounds reached steady state plasma concentrations exceeding their Ki values by >60-fold, plasma D-serine levels remained the same as those in the absence of DAAO inhibitors. Similar results were obtained with dogs. In summary, in contrast to rodents, DAAO inhibition in monkeys and dogs did not influence the exposure to exogenously administered D-serine. Results could be due to differences in D-serine metabolism and/or clearance mechanisms and suggest that the role of DAAO in the metabolism of D-serine is different across species. These data provide caution regarding the utility of DAAO inhibition for patients with schizophrenia.


Flap technology for reconstructions of urogenital organs.
The purpose of this review is to summarize the different reconstructive options for urogenital indications. The development of various flap techniques to restore congenital and acquired urogenital defects is presented. Various reconstructive techniques have been demonstrated recently. On the basis of the reconstructive requirements, two main techniques can be defined: the standard local or regional flap technique (pedicled flap) and the more sophisticated microvascular free flap technique. Free tissue transplantation (transfer) is a procedure that involves microvascular transplantation of a flap (a fasciocutaneous, muscle or composite flap) in one stage from a donor site in the body to a distant recipient site. The viability of the transplanted flap is maintained by microvascular anastomosis between the flap's vessels (at least one artery and one vein) and recipient vessels. Re-innervation and functioning muscle contraction is achieved by suturing the vessels and a motor nerve in the recipient area to a motor nerve of a free transplanted muscle. After regeneration of the nerve and re-innervation of the transplanted muscle, a functioning free transplanted muscle offers enough contractile capacity and strength to replace the function of the missing muscles at the recipient site. The technique of microvascular free tissue transfer necessitates extensive experience in microvascular technique and this approach could be efficiently applied in cooperation with other specialists. Recent studies show the development and clinical application of these new surgical techniques in urology (e.g. in the treatment of bladder acontractility using innervated free latissimus dorsi muscle and in the use of a free microvascular fillet lower leg flap for the reconstruction of a large pelvic-floor defect). Various reconstructive requirements define the techniques for reconstruction. The main principle is to obtain optimal anatomical and functional reconstruction with minimal donor site morbidity. Depending on the etiology of the defect, different reconstructive options are available to optimize the reconstructive result. Optimal reconstruction might best be achieved by adopting an interdisciplinary approach in which the primary objective is to provide the best possible outcome for each patient. This review presents the main indications for and principles of flap selection according to the reconstructive requirements.


Optimization of the extraction of the p-menthadienol isomers and aristolone contained in the essential oil from Elyonurus hensii using a 23 full factorial design.
The aim of this study was to optimize the extraction of p-menthadienol isomers and aristolone from the essential oil of Elyonurus hensii by hydrodistillation. The study of the seasonal variation in the chemical composition has shown that the plant material has been subject to a natural selection regarding the biosynthesis of the p-menthadienol isomers: during periods of water stress, the extracts are rich in cis and trans-p-mentha-1(7),8-dien-2-ol and poor in cis and trans-p-mentha-2,8-dien-1-ol. Regarding the modeling, eight experiments were carried out by considering three easily interpretable factors (the extraction duration, the residual water content and the state of the division of the plant material). The average yield was 1.33% for the aerial part and 0.74% for the roots. The residual water content is the most important factor, which significantly influences the average yield of the essential oil and the content of the major constituents. Regarding the aerial part, a low residual water content of the plant material varies the essential oil yield (from 0.40% to 2.11%) and the content of cis and trans-p-mentha-2.8-dien-1-ol (from 15.87% to 23.24%). At the root level, the samples that have a very low residual water content provide extracts richer in aristolone. The combined effects of the extraction duration, the state of division, and the residual water content influence greatly the extraction of aristolone (from 36.68% to 54.55%). However, these interactions are more complex and difficult to assess.


[Foreign body granuloma resulting from a lacorhinostomy tube's migration associated with actinomycosis of the lacrimal sac].
Lacorhinostomy is a surgical procedure that establishes a permanent communication between the caruncular region and the nasal fossa using a fixed tube. The main complications involve the biotolerance of this tube. Fifteen years after lacrimal surgery, a patient presented with repeated canthal inflammation associated with epistaxis on the same side. The anterior rhinoscopy showed an occlusion of the inferior meatus by a mucous tumor, bleeding to the contact. A lacrimal sac scan disclosed a local tumor without bone erosion. With an endonasal dacryocystorhinostomy, a lacorhinostomy tube was found hidden in the canthal region associated with actinomycosis of the lacrimal sac. Lacrimal actinomycosis is mostly primitive, although actinomycosis in other locations may be associated with the presence of a foreign body. In that case, the association is probably a coincidence. When a tumor develops after lacrimal surgery, a foreign body reaction must be suspected.


Nutritional evaluation of some potential wild edible plants of North Eastern region of India.
India's north-eastern hill region (NEH) is one of the biodiversity hotspots, inhabited by several tribal communities still maintaining their traditional food habits. Much of their food resources are drawn from wild sources. Fourteen species of wild edible plants of high ethnic importance were collected from remote localities of Nagaland and Meghalaya states of the NEH region of India for nutritional profiling. Nutritional profiling of leaves of six species comprising Gynura cusimbua, Garcinia cowa, Herpetospermum operculatum, Plukenetia corniculata, Trichodesma khasianum, and Elatostemma sessile is conducted first time under present study. Samples were analyzed as per the Official Method of Analysis (AOAC) and standard methods. The range of variation in proximate composition was observed for moisture (72-92%), protein (1.71-6.66%), fat (0.22-1.36%), dietary fibre (5.16-14.58%), sugar (0.30-3.41%), and starch (0.07-2.14%). The highest protein content (6.66%) was recorded in Herpetospermum operculatum, followed by Trichodesma khasianum (5.89%) and Plukenetia corniculata (5.27%). Incidentally, two of these also have high iron (>7.0 mg/100 g) and high zinc (>2.0 mg/100 g) contents, except Trichodesma khasianum, which has low zinc content. High antioxidant activities in terms of gallic acid equivalent (GAE) by the cupric ion reducing antioxidant capacity (CUPRAC) method ranged from 1.10 to 8.40 mg/100 g, and by the Fluorescence recovery after photobleaching (FRAP) method ranged from 0.10 to 1.9 mg/100 g, while phenol content ranged between 0.30 and 6.00 mg/100 g. These wild vegetables have high potential because of their nutritional properties and are fully capable of enhancing sustainability and improving ecosystem services. Efforts were also initiated to mainstream these resources, mainly for widening the food basket of native peoples.


The prevalence of dentin hypersensitivity in general dental practices in the northwest United States.
The prevalence of dentin hypersensitivity is uncertain, yet appropriate diagnosis and treatment of dentin hypersensitivity require accurate knowledge regarding its prevalence. The authors conducted a study to estimate the prevalence of dentin hypersensitivity in general dental practices and to investigate associated risk factors. The authors conducted a cross-sectional survey of 787 adult patients from 37 general dental practices within Northwest Practice-based Research Collaborative in Evidence-based DENTistry (PRECEDENT). Dentin hypersensitivity was diagnosed by means of participants' responses to a question regarding pain in their teeth and gingivae, and practitioner-investigators conducted a clinical examination to rule out alternative causes of pain. Participants recorded their pain level on a visual analog scale and the Seattle Scales in response to a one-second air blast. The authors used generalized estimating equation log-linear models to estimate the prevalence and the prevalence ratios. The prevalence of dentin hypersensitivity was 12.3 percent; patients with hypersensitivity had, on average, 3.5 hypersensitive teeth. The prevalence of dentin hypersensitivity was higher among 18- to 44-year olds than among participants 65 years or older; it also was higher in women than in men, in participants with gingival recession than in those without gingival recession and in participants who underwent at-home tooth whitening than in those who did not. Hypersensitivity was not associated with obvious occlusal trauma, noncarious cervical lesions or aggressive toothbrushing habits. One in eight participants from general practices had dentin hypersensitivity, which was a chronic condition causing intermittent, low-level pain. Patients with hypersensitivity were more likely to be younger, to be female and to have a high prevalence of gingival recession and at-home tooth whitening. Given dentin hypersensitivity's prevalence, clinicians should diagnose it only after investigating all other possible sources of pain.


Structural organization of str 246C and str 246N, plant defense-related genes from Nicotiana tabacum.
We have previously identified a cDNA clone, pNt246, whose corresponding transcripts accumulate in leaves in response to inoculation by compatible and incompatible isolates of the phytopathogenic bacterium Pseudomonas solanacearum [19]. We now describe the nucleotide sequence of a genomic clone, str 246C, corresponding to this cDNA species, and of a related genomic clone, str 246N, which appears to be a pseudogene with a 5'-end deletion. The nucleotide sequence of the str 246C gene was found to be identical to that of the parA gene, previously shown to be regulated by auxin [28, 29]. Upstream of the str 246N gene, sequences homologous to a Bam HI repetitive element described in Vicia faba [15] are present within an ORF showing significant homologies to an integrase-encoding gene of several retroviruses. This observation indicates that this highly repetitive DNA originates from sequences present in transposable mobile elements.


Inflammatory vulnerability associated with the rh5-HTTLPR genotype in juvenile rhesus monkeys.
Individual variation in serotonergic function is associated with reactivity, risk for affective disorders, as well as an altered response to disease. Our study used a nonhuman primate model to further investigate whether a functional polymorphism in the promoter region for the serotonin transporter gene helps to explain differences in proinflammatory responses. Homology between the human and rhesus monkey polymorphisms provided the opportunity to determine how this genetic variation influences the relationship between a psychosocial stressor and immune responsiveness. Leukocyte numbers in blood and interleukin-6 (IL-6) responses are sensitive to stressful challenges and are indicative of immune status. The neutrophil-to-lymphocyte ratio and cellular IL-6 responses to in vitro lipopolysaccharide stimulation were assessed in 27 juvenile male rhesus monkeys while housed in stable social groups (NLL = 16, NS = 11) and also in 18 animals after relocation to novel housing (NLL = 13, NS = 5). Short allele monkeys had significantly higher neutrophil-to-lymphocyte ratios than homozygous Long allele carriers at baseline [t(25) = 2.18, P = 0.02], indicative of an aroused state even in the absence of disturbance. In addition, following the housing manipulation, IL-6 responses were more inhibited in short allele carriers (F1,16 = 8.59, P = 0.01). The findings confirm that the serotonin transporter gene-linked polymorphism is a distinctive marker of reactivity and inflammatory bias, perhaps in a more consistent manner in monkeys than found in many human studies.


Heterogeneous degradation of amoxicillin in the presence of synthesized alginate-Fe beads catalyst by the electro-Fenton process using a graphite cathode recovered from used batteries.
Iron alginate beads (Fe-Alg) were prepared, characterized and implemented for the degradation of amoxicillin (AMX) by the heterogeneous electro-Fenton process using a graphite cathode recovered from used batteries. Scanning electron microscopy (SEM) showed that (Fe-Alg) beads have a spherical shape and the results of energy dispersive spectrometric (EDS) revealed the presence of iron in (Fe-Alg). Optimization of the operating parameters showed that a complete degradation of AMX was achieved within 90 min of heterogeneous electro-Fenton treatment by operating under these conditions: initial AMX concentration: 0.0136 mM, I = 600 mA, [Na2SO4] = 50 mM, pH = 3, T = 25 °C, ω = 360 rpm. The corresponding chemical oxygen demand (COD) abatement was 50%. Increasing the contact time increased the COD abatement to 85.71%, after 150 min of heterogeneous electro-Fenton treatment. The results of the kinetic study by using nonlinear methods demonstrated that the reaction of AMX degradation obeyed to a pseudo-second-order kinetic. Iron content of 4.63% w/w was determined by the acid digestion method. After 5 cycles of use, the Alg-Fe catalyst depletion was only 8%. Biodegradability was remarkably improved after electro-Fenton pretreatment, since it increased from 0.07 initially to 0.36. The heterogeneous electro-Fenton process had efficiently eliminated AMX and it increased the biodegradability of the treated solution.


Injury burden during an insurgency: the untold trauma of infrastructure breakdown in Baghdad, Iraq.
Injuries as a result of the ongoing violence in Iraq have been a topic of both lay and academic interest. However, to date, attempts to quantify injuries in the country have focused primarily on direct mortality, which represents only a small portion of overall injury burden and ignores those injuries indirectly resulting from the conflict-induced breakdown of Iraqi infrastructure. We performed a cross-sectional household survey from October to November, 2009, within the Baghdad Governorate of central Iraq. Using two-stage cluster-sampling with a proportional-to-size methodology, we randomized a total of 60 clusters to Baghdad's five governmental districts. Within each cluster, we interviewed heads of households regarding all injuries during the last 3 months. We surveyed 1,172 households, gathering information regarding 7,396 individuals. Only 8.4% of injuries were intentional, and fatalities represented only a small fraction (1.7%) of overall injury burden. The well-publicized intentional explosions in Baghdad, although accounting for close to half (44%) of all intentional injuries, made up only 4% of the total. Other injuries at least partially attributable to the conflict-induced breakdown of Iraqi infrastructure proved a much larger burden, for example, those from electric shock, unintentional explosions, unintentional gunshot wounds, and falls. Past and current fighting in Baghdad continues to adversely affect the Iraqi populace, where the indirect effects of infrastructure breakdown are likely the primary source of injury. When measuring the burden of large-scale violence, health researchers should account for the full injury burden, including both injury morbidity and indirect injuries.


Vestibular Nucleus Involvement in Patients With Acute Vertigo Due to Herpes Zoster Oticus or Vestibular Neuritis.
Herpes zoster oticus (HZO) typically provokes vestibular symptoms and is traditionally viewed as a cranial nerve equivalent of shingles, but in contrast to vestibular neuritis (VN), it is unclear whether the pathology of HZO is limited to the vestibular nerve (neuritis) or can also involve the brainstem (nucleitis). We retrospectively compared brain MRIs of patients with HZO with those of patients with VN to study radiologic changes in the brainstem. Five of 10 patients with HZO showed signal abnormalities in the vestibular nuclei, which lie in multiple vascular territories, whereas no patients with VN exhibited such findings. HZO may at least in part reflect vestibular nucleitis, as opposed to a pure neuritis.


N, N' (p-Xylylidene)-bis-aminoguanidine (2HCI) resistant mutants in Saccharomyces cerevisiae and their relation to the amino acid transport system.
N,N'-(p-Xylylidene)-bis-aminoguanidine 2HCl proved to be an efficient inducer of non-chromosomal petite mutation in Saccharomyces cerevisiae in either growing or non-growing conditions. A mutant Agr-7 resistant to this compound was obtained. Resistance proved to dominate over its XBAG-sensitive allele in the diploid formed in cross. Mutant Agr-7 is characterized by slow growth rate on YEPG or minimal medium and small colony size. Studies on uptake of amino acids and sugars indicate that the phenomenon of resistance is involved in alteration of the general amino acid permease activity.


Exercise training and glycemic control in adolescents with poorly controlled type 1 diabetes mellitus.
This study sought to establish whether the glycemic control achieved in exercise-trained adolescents with type 1 diabetes mellitus (DM) is dependent on the quality of glycemic control prior to the initiation of exercise training. Adolescents with type 1 DM were randomly assigned to groups with either lower or higher than 9% glycosylated hemoglobin (HbA1c), and submitted to 12 weeks of supervised training followed by 12 weeks of unsupervised training (n = 12 per group). Supervised training caused a 17% rise in the patients' aerobic capacity which during the ensuing period of unsupervised training decreased to pre-training levels, thus suggesting a poor compliance with unsupervised training. The average levels of HbA1c in poorly and well controlled diabetic patients were not affected by training, a finding indicating that irrespective of the quality of glycemia prior to exercise training, glycemic control in adolescents with type 1 DM does not improve in response to exercise training alone.


Dose-dependent reversal of KCC2 hypofunction and phenobarbital-resistant neonatal seizures by ANA12.
Neonatal seizures have an incidence of 3.5 per 1000 newborns; while hypoxic-ischemic encephalopathy (HIE) accounts for 50-60% of cases, half are resistant to 1st-line anti-seizure drugs such as phenobarbital (PB). Tyrosine receptor kinase B (TrkB) activation following ischemic injury is known to increase neuronal excitability by downregulation of K-Cl co-transporter 2 (KCC2); a neuronal chloride (Cl-) co-transporter. In this study, three graded doses of ANA12, a small-molecule selective TrkB antagonist, were tested in CD1 mice at P7 and P10 following induction of neonatal ischemia by a unilateral carotid ligation. The PB loading dose remained the same in all treatment groups at both ages. Evaluation criteria for the anti-seizure efficacy of ANA12 were: (1) quantitative electroencephalographic (EEG) seizure burden and power, (2) rescue of post-ischemic KCC2 and pKCC2-S940 downregulation and (3) reversal of TrkB pathway activation following ischemia. ANA12 significantly rescued PB resistant seizures in a dose-dependent manner at P7 and improved PB efficacy at P10. Additionally, female pups responded better to lower doses of ANA12 compared to males. ANA12 significantly reversed post-ischemic KCC2 downregulation and TrkB pathway activation at P7 when PB alone was inefficacious. Rescuing KCC2 hypofunction may be critical for preventing emergence of refractory seizures.


A Rare Case of Typhoid Fever in the United States Associated With Travel to Mexico.
Typhoid fever is an infectious febrile illness caused by Salmonella typhi that is rare in the United States but is endemic in regions of South Asia and Africa. Typhoid fever initially presents with nonspecific symptoms such as fever, malaise, and abdominal pain. We describe a case of typhoid fever in an adult in the United States with recent travel to Mexico. After a nonspecific presentation, the patient developed Faget sign and computed tomography (CT) of the abdomen revealed mesenteric adenitis, which prompted additional workup. Diagnosis of typhoid fever was established by blood culture and the patient was treated with ciprofloxacin.


Late coronary BVS malapposition and aneurysm: A Time for Appraisal.
Late strut malapposition of currently available stents is a major issue, associated with an increased risk of stent thrombosis. To this day, biovascular scaffolds showed an increased immediate risk of struts malapposition, that however resulted reduced after a few months. Little is known about late acquired struts malapposition of biovascular scaffolds. We here describe two cases that recently occurred in our patients, and we speculate on possible mechanisms for this unexpected and potentially lethal complication.


[Isolation of maize genes related to aluminum tolerance].
To investigate gene expression profile in response to aluminum stress and to cloning the key genes related to aluminum tolerance, are crucial to genetic improvement of plant aluminum tolerance. In this study, suppression subtractive hybridization method was adopted to construct SSH-cDNA libraries at seedling stage of two maize inbred lines (Fig. 1), of which Mo17 is sensitive to aluminum toxicity and TL94B is tolerant. As a result, a forward SSH-cDNA library including 762 clones and a reverse SSH-cDNA library including 382 clones were constructed for Mo17. In the same way, a forward SSH-cDNA library including 760 clones and a reverse SSH-cDNA library including 380 clones were constructed for TL94B. Identification of these SSH-cDNA libraries shows that the length of inserted fragments ranges from 250 bp to 1.0 kb (Fig. 2), of which nearly 18% are positive clones. Through differential hybridization screening (Fig. 3), 124 and 47 positive clones were screened from forward and reverse SSH-cDNA libraries of Mo17 respectively; 103 and 64 positive clones from forward and reverse SSH-cDNA libraries of TL94B respectively. Total 338 positive clones from four SSH-cDNA libraries were sequenced, and all of the sequences of inserted fragments were analyzed using bioinformatical methods. A total of 232 kinds of EST sequences were obtained. Among these ESTs, 70.2% had significant homology with known genes, and the remaining 29.8% were function-unknown including 21 kinds of newly found ESTs (Table 1). An aluminum tolerant gene, GDP dissociation inhibitor gene, was detected its expression character by Northern hybridization (Fig. 4). These results indicate that the responses of maize to aluminum stress involve the interactions among different signal/metabolism pathways, such as signal transduction of stress-related factors, transcription and regulation of responsive genes, synthesis and transport of substances, changes in cell structures and functions.


Efficacy of dexmedetomidine for the control of junctional ectopic tachycardia after repair of tetralogy of Fallot.
Junctional ectopic tachycardia occurs frequently after congenital cardiac surgery and can be a cause of increased morbidity and mortality. Dexmedetomidine (DEX) is an α2 adrenoreceptor agonist, has properties of controlling tachyarrhythmia by regulating the sympatho-adrenal system. To evaluate the efficacy of DEX for control of junctional ectopic tachycardia after repair of Tetralogy of Fallot (TOF). Two hundred and twenty pediatric cardiac patients with TOFs were enrolled in a prospective randomized control study. Patients underwent correction surgery. They were divided into two groups, i.e., Group 1 (DEX) and Group 2 (control). Heart rate, rhythm, mean arterial pressure (MAP) were recorded after the anesthetic induction (T1), after termination of bypass (T2), after 04 hours (T3), and 08 hours after transferring the patient to intensive care unit (ICU; T4). Heart rate was comparable between two groups before starting the drug but statistically significant after bypass until 08 hours after transferring the patient to ICU. Junctional ectopic tachycardia occurred more in Group-2 (20%) as compared to Group-1 (9.09%; P = 0.022). Junctional ectopic tachycardia occurs early in Group-2 (0.14 ± 0.527 hours) as compared to Group 1 (0.31 ± 1.29 hours; P = 0.042). The duration of junctional ectopic tachycardia was more prolonged in Group-2 (1.63 ± 3.64 hours) as compared to Group-1 (0.382 ± 1.60 hours; P = 0.012). The time to withdraw from mechanical ventilation and ICU stay of Group 1 patient was less than of Group 2 patients (P = <0.001). DEX had a therapeutic role in the prevention of junctional ectopic tachycardia in patients undergoing repair for TOF.


Arts on prescription: a qualitative outcomes study.
In recent years, participatory community-based arts activities have become a recognized and regarded method for promoting mental health. In the UK, Arts on Prescription services have emerged as a prominent form of such social prescribing. This follow-up study reports on the findings from interviews conducted with participants in an Arts on Prescription programme two years after previous interviews to assess levels of 'distance travelled'. This follow-up study used a qualitative interview method amongst participants of an Arts on Prescription programme of work. Ten qualitative one-to-one interviews were conducted in community-based arts venues. Each participant was currently using or had used mental health services, and had been interviewed two years earlier. Interviews were digitally recorded, transcribed and analysed. For each of the 10 participants, a lengthy attendance of Arts on Prescription had acted as a catalyst for positive change. Participants reported increased self-confidence, improved social and communication skills, and increased motivation and aspiration. An analysis of each of the claims made by participants enabled them to be grouped according to emerging themes: education: practical and aspirational achievements; broadened horizons: accessing new worlds; assuming and sustaining new identities; and social and relational perceptions. Both hard and soft outcomes were identifiable, but most were soft outcomes. Follow-up data indicating progress varied between respondents. Whilst hard outcomes could be identified in individual cases, the unifying factors across the sample were found predominately in the realm of soft outcomes. These soft outcomes, such as raised confidence and self-esteem, facilitated the hard outcomes such as educational achievement and voluntary work.


A comprehensively characterized large panel of head and neck cancer patient-derived xenografts identifies the mTOR inhibitor everolimus as potential new treatment option.
Patient-derived xenograft (PDX) models have shown to reflect original patient tumors better than any other preclinical model. We embarked in a study establishing a large panel of head and neck squamous cell carcinomas PDX for biomarker analysis and evaluation of established and novel compounds. Out of 115 transplanted specimens 52 models were established of which 29 were characterized for response to docetaxel, cetuximab, methotrexate, carboplatin, 5-fluorouracil and everolimus. Further, tumors were subjected to sequencing analysis and gene expression profiling of selected mTOR pathway members. Most frequent response was observed for docetaxel and cetuximab. Responses to carboplatin, 5-fluorouracil and methotrexate were moderate. Everolimus revealed activity in the majority of PDX. Mutational profiling and gene expression analysis did not reveal a predictive biomarker for everolimus even though by trend RPS6KB1 mRNA expression was associated with response. In conclusion we demonstrate a comprehensively characterized panel of head and neck cancer PDX models, which represent a valuable and renewable tissue resource for evaluation of novel compounds and associated biomarkers.


Establishment and characterization of a tumor cell line derived from a mouse infected with murine gammaherpesvirus 78.
A tumor cell line, NB-78, was derived from a lymphoma from a BALB/c mouse infected with Murine gammaherpesvirus 78 (MHV-78). Cultures of the cells of this line underwent till now more than 100 passages, displaying an epitheloid transformed morphology and a diploid complement of 40 chromosomes. Viral antigen was detected in 12% of cells by immunofluorescence (IF) test. Reactivation of latent MHV-78 was proved by detecting infectious virus in culture medium only at passages 4345. The presence of viral M1, M2, M3, and M4 gene sequences in the genome of the cells was demonstrated by PCR. NB-78 is the first continuous cell line, which originates from a tumor of a MHV-78-infected host, harbors viral genome or at least its several genes, and produces infectious virus only rarely upon reactivation. It can be assumed that this cell line is primarily associated with MHV-78 and will serve as an invaluable tool for studying the MHV-78 latency.


Pain management in the critically.
The treatment of pain continues to be a major concern in the critically ill patient. Despite advances in pain management, a greater understanding of the mechanisms of pain and advanced methods of analgesic delivery, the treatment of pain is not always a priority on the intensive care unit. Difficulties with pain assessment, in the critically ill ventilated, sedated patient compound the problems of pain management. Physiological signs are difficult to interpret and psychological factors must be considered.


Cytotoxic T-lymphocyte-associated antigen-4.
Previously, the development of immune-based therapies has primarily focused on vaccines and cytokines, yielding benefit in a small percentage of patients. Recent advances in our understanding of the function of costimulatory molecules have revitalized enthusiasm in the development of immune therapies for cancer. This family of proteins possesses properties involved in both lymphocyte activation and immune-inhibitory functions. The costimulatory molecule with the greatest translation into the clinic thus far is CTL-associated antigen-4 (CTLA-4). CTLA-4 engagement leads to T-cell inhibition by two principle mechanisms. The first involves competitive binding with CD28 for B7 on the antigen-presenting cell. The second is direct intracellular inhibitory signals mediated by the CTLA-4 cytoplasmic tail. Numerous clinical trials testing the blockade of CTLA-4 signaling with fully human monoclonal antibodies have treated a variety of cancers, with the most experience in the treatment of metastatic melanoma. Significant antitumor activity as well as potential autoimmune-related toxicities have been observed. Further clinical investigation with CTLA-4 blockade, planned clinical trials testing manipulation of other costimulatory molecules, and continued improvement in understanding of costimulatory pathways present a new era of immune therapies for cancer patients.


[Treatment outcome of patients with cranial base lesions of unknown etiology: focusing on infectious cases with multiple cranial nerve disorders].
Involvement of cranial nerves caused by cranial base lesions manifests diverse symptoms according to the localization of lesions. These localization-related symptoms are classified into syndromes such as orbital apex syndrome, cavernous sinus syndrome, and jugular foramen syndrome. Since the lesions may have various etiologies including infection, inflammation and tumor, etiological diagnosis should be performed simultaneously if possible. However, previous reports have described poor and/or fatal outcome following inappropriate treatment mainly due to difficulties in making a definitive pathological diagnosis. Nineteen patients with multiple cranial nerve involvement caused by skull base lesions were enrolled over the past 12 years. The patients were divided into an "infectious" group (n=11) and a "noninfectious" group (n=8) based on the final diagnosis. Chi-square analysis was conducted to examine the sensitivity and specificity of various factors including patient characteristics, clinical course and treatment response in infectious and noninfectious groups. Consequently, we identified some patients with good outcome irrespective of infectious or noninfectious etiology, even though a pathological diagnosis was not reached before the initial treatment. These patients with good outcome consistently received antifungal therapy in the early stage if infectious etiologies were suspected. We recommend conducting diagnostic therapy with antifungal drugs in patients with skull base lesions of unknown origin although infection cannot be excluded, when a pathological diagnosis is difficult due to various patient conditions.


Hantavirus GnT elements mediate TRAF3 binding and inhibit RIG-I/TBK1-directed beta interferon transcription by blocking IRF3 phosphorylation.
Hantaviruses successfully replicate in primary human endothelial cells by restricting the early induction of beta interferon (IFN-β) and interferon-stimulated genes (ISGs). Gn proteins from NY-1V, ANDV, and TULV, but not PHV, harbor elements in their 142-residue cytoplasmic tails (GnTs) that inhibit RIG-I/MAVS/TBK1-TRAF3-directed IFN-β induction. Here, we define GnT interactions and residues required to inhibit TRAF3-TBK1-directed IFN-β induction and IRF3 phosphorylation. We observed that GnTs bind TRAF3 via residues within the TRAF-N domain (residues 392 to 415) and that binding is independent of the MAVS-interactive TRAF-C domain (residues 415 to 568). We determined that GnT binding to TRAF3 is mediated by C-terminal degrons within NY-1V or ANDV GnTs and that mutations that add degrons to TULV or PHV GnTs confer TRAF3 binding. Further analysis of GnT domains revealed that TRAF3 binding is a discrete GnT function, independent of IFN regulation, and that residues 15 to 42 from the NY-1V GnT C terminus are required for inhibiting TBK1-directed IFN-β transcription. Mutagenesis of the NY-1V GnT revealed that altering tyrosine 627 (Y627A/S/F) abolished GnT regulation of RIG-I/TBK1-directed IRF3 phosphorylation and transcriptional responses of ISRE, κB, and IFN-β promoters. Moreover, GnTs from NY-1V, ANDV, and TULV, but not PHV, inhibited RIG-I-directed IRF3 phosphorylation. Collectively, these findings suggest a novel role for GnTs in regulating RIG-I/TBK1 pathway-directed IRF3 phosphorylation and IFN-β induction and define virulence determinants within GnTs that may permit the attenuation of pathogenic hantaviruses. IMPORTANCE These findings provide a mechanism for selected hantavirus GnT interactions to regulate RIG-I/TBK1 signaling responses required for IFN-β induction by inhibiting TBK1 phosphorylation of IRF3. These studies culminate in showing that a single GnT residue, Y627, is required for the NY-1V GnT to inhibit RIG-I/TBK1-directed IRF3 phosphorylation and IFN-β induction. These findings define a potential virulence determinant within the NY-1V GnT that may permit hantavirus attenuation.


Fluoroscopy time is not accurate as a surrogate for radiation exposure.
Objective The Food and Drug Administration and the Vascular Quality Initiative still utilize fluoroscopy time as a surrogate marker for procedural radiation exposure. This study demonstrates that fluoroscopy time does not accurately represent radiation exposure and that dose area product and air kerma are more appropriate measures. Methods Lower extremity endovascular interventions ( N = 145) between 2013 and 2015 performed at an academic medical center on a Siemens Artis-Zee floor mounted c-arm were identified. Data was collected from the summary sheet after every case. Scatter plots with Pearson correlation coefficients were created. A strong correlation was indicated by an r value approaching 1. Results Overall mean AK and DAP was 380.27 mGy and 4919.2 µGym2. There was a poor correlation between fluoroscopy time and total AK or DAP ( r = 0.27 and 0.32). Total DAP was strongly correlated to cine DAP and fluoroscopy DAP ( r = 0.92 vs. 0.84). The number of DSA runs and average frame rate did not affect AK or DAP levels. Mean magnification level was significantly correlated with total AK ( r = 0.53). Conclusions Fluoroscopy time shows minimal correlation with radiation delivered and therefore is a poor surrogate for radiation exposure during fluoroscopy procedures. DAP and AK are more suitable markers to accurately gauge radiation exposure.


[Spontaneous rupture of mediastinal cystic teratoma (case report)].
Teratomas are rare tumors in the mediastinum. Benign cystic teratomas of anterior mediastinum are rarely complicated by rupture into an adjacent body cavity. Such rupture, however, is usually associated with life-threatening complications. We present a case with spontaneous rupture of mediastinal cystic teratoma. The patient was evaluated with chest radiograph, computed tomography (CT) and magnetic resonance imaging (MRI). A complex mass including predominantly cystic components was detected in the left anterior mediastinum. After surgery, pathologic diagnosis was reported as mature cystic teratoma. High levels of amylase and lipase were detected in both the cystic fluid and serum. This finding supported the hypothesis of autolysis for the explanation of rupture. In addition, carbohydrate antigen (CA) 19-9, CA 125 and carcinoembryonic antigen (CEA) levels were high in the cystic fluid.


Zanthoxylum piperitum (DC), a potential feeding deterrent for mammals: studies with Microtus ochrogaster (Wagner).
Total extract from the fruit of Szechuan pepper (Zanthoxylum piperitum DC), the volatile components of the extract and a non-volatile fraction containing alkylamides (NVA fraction) are feeding deterrents for rats. The present study investigated the effectiveness of these natural repellents in prairie voles (Microtus ochrogaster Wagner). Two-choice feeding trials were conducted during which food-deprived voles were offered choices between oat-bran wafers. In Experiment 1, 10 voles were given three sets of feeding trials, each 2 h long. Baseline consumption was established during the first set of two trials by offering a choice between two oat-bran wafers dipped in ethanol, the control solvent. During the second set of two trials the voles were given a choice between an oat-bran wafer dipped in ethanol and a wafer dipped in Zanthoxylum extract. During the third set the voles were given a choice between a wafer served on top of a screened dish containing a sample of ethanol and a wafer served on top of a dish containing a sample of extract. In this manner the voles were exposed to volatile compounds emanating from the extract but could not contact it. Wafers dipped in extract were almost completely avoided. The volatile components of extract also significantly reduced food intake. In Experiment 2, habituation to the volatile constituents of extract was examined in 16 Zanthoxylum-naïve voles. Baseline consumption was established by offering two wafers served on top of screened dishes containing ethanol. This was followed by twelve tests during which a choice between a wafer served above a sample of ethanol and a wafer served above a sample of extract was given. The voles failed to habituate to the volatile components of extract, consistently consuming less of the wafers served above extract. In Experiment 3 a dose-response curve to Zanthoxylum extract was established, using 12 stimulus-naive voles. After baseline consumption was established, the animals were given two tests each, presenting a choice between a control wafer and a wafer dipped in a dilution of extract (0.001-100 g liter(-1)). Only concentrations of 10 and 100 g liter(-1) reduced food intake. In Experiment 4 the effects of the non-volatile fraction of extract were compared to those of whole extract. Vegetable oil was used as solvent. Eight stimulus-naïve voles were given two tests with a choice between an oil-dipped and an extract-dipped wafer. A second group of eight voles received two tests with a choice between an oil-dipped and NVA-dipped wafer. Extract-dipped wafers were avoided, but the NVA fraction had no effect on food consumption.


Platelet concentrates: Balancing between efficacy and safety?
Platelet transfusions continue to be the mainstay to treat patients with quantitative and qualitative platelet disorders. Each year, about 10 millions of platelet transfusions are administered to patients worldwide with marked differences in usage between regions depending on socioeconomic development of the countries. Unfortunately, its use is associated to immune and non-immune side effects. Among the non-immune, bacterial contamination is still the major infectious risk. When bacterial culture methods are introduced for preventing bacterial septic reactions it has been found that this strategy reduce to one half the septic reactions, but do not eliminate completely that risk. To remove completely the risk, a new bacteria detection test at the time of issuance in the case of platelets stored for four or five days would be needed. Pathogen inactivation (PI) methods already in the market (based in the addition of amotosalen (A-L) or riboflavin (R-L) and the illumination with ultraviolet light) or under development (ultraviolet light C and agitation) have shown to be efficacious in the inactivation of bacteria and no cases of septic reactions associated to a pathogen-reduced product has been identified. However, it has been shown that PI technologies have measurable effects on platelet in vitro parameters and reduce the recovery and survival of treated platelets in vivo. Although these effects do not hamper the hemostatic capacity of treated platelets, an increased usage associated with PI technologies has been reported. This increase in utilization seems to be the toll to be paid if we want to completely eliminate the risk of bacterial sepsis in the recipients of platelet transfusion.


An ontological view of the human embryo. A paradigm.
In the present paper I analyze the existing paradigms explaining the ontological status of the organisms originating during a given developmental process and the potentiality these paradigms offer. These paradigms give us a hint of the ontological and ethical status of these organisms. It is described that during the history of human thought two theories have been developed to explain the origin of living organisms. One theory placed the world's origin and the origin of living organisms in a transcendent reality while the second stated that the growing complexity of these organisms was rooted in an internal 'dynamis' (the internal potential of a thing, generally a living thing, to acquire new properties) that is present in each one of them. These paradigms are analysed concluding that at the time they were formulated there was no formal understanding of the process of development because the emergence of novelties through evolution was not included in them. At that time growth and development were two aspects of the same thing. A critical turning point in biological and philosophical thinking was provided by the founders of the DNA paradigm as the program directing development. Due to new insights, a paradigm is presented here which includes the epigenesic information as an essential element of the program of development together with the DNA. The consequence of this paradigm is that the program of development is time- and space-dependent and that the biological elements which originate during the process are not preformed but adopt specific values. This way of thinking introduces new approaches to the analysis of the value of the human embryo with repercussions in the ethical discussions on research programs using embryonic stem cells.


[Oral medicine in Israel: Current status and future directions].
The oral cavity-body relationships are bi-directional: oral diseases affect the welfare and health of the individual, while diseases and conditions of organs and tissues in the human body affect oral health. The global policy of the World Health Organization is to improve oral health in the 21st century as an integral part of promoting our general health. During the recent years the knowledge of the dental profession has grown exponentially and widened its fields of interest and this has led to impressive advances at both clinical and research levels. Oral medicine, which is a recognized, licensed specialty in Israel, is a definite example that reflects this process. In the last decade residency programs in oral medicine are in the process of constant increased demand. The authors discuss this trend and comment on the need to maintain excellence in this specialty.


Evaluation of ERBB2 gene status and chromosome 17 anomalies in male breast cancer.
Male breast cancer (MBC) is an uncommon neoplasm that shares several biologic characteristics with its female counterpart. In the latter, abnormalities in the expression and/or copy number of the ERBB2 gene are present in 10% to 30% of invasive carcinoma and behave as poor prognostic markers. ERBB2 abnormalities have also been reported in MBC, yet at lower frequency, but their prognostic significance remains controversial. Furthermore, no study has addressed the impact of chromosome 17 abnormalities in MBC survival. In this study, the ERBB2-gene status (overexpression and amplification) and chromosome 17 numerical abnormalities were investigated in a series of 50 archival cases of MBC. The results, together with patient's age, histologic grade, pathologic stage, and estrogen receptor status were correlated with overall survival. ERBB2-protein overexpression was present in 7 cases (14%), ERBB2-gene amplification in 4 (8%), and aneuploidy of chromosome 17 in 12 cases (33.3%). The pathologic stage, ERBB2 overexpression and ERBB2 amplification were significantly correlated with overall survival (P=0.002, 0.016, and 0.009, respectively). No correlation was observed between chromosome 17 aneuploidy and overall survival. Therefore, despite their low incidence in MBC, expression abnormalities of ERBB2 behave, together with the pathologic stage of the tumor, as predictors of overall survival, akin to what has been reported for its female counterpart.


Influence of diffusion on the kinetics of excited-state association--dissociation reactions: comparison of theory and simulation.
Several recent theories of the kinetics of diffusion influenced excited-state association--dissociation reactions are tested against accurate Brownian dynamics simulation results for a wide range of parameters. The theories include the relaxation time approximation (RTA), multiparticle kernel decoupling approximations and the so-called kinetic theory. In the irreversible limit, none of these theories reduce to the Smoluchowski result. For the pseudo-first-order target problem, we show how the RTA can be modified so that the resulting formalism does reduce correctly in the irreversible limit. We call this the unified Smoluchowski approximation, because it unites modern theories of reversible reactions with Smoluchowski's theory of irreversible reactions.


Collagenase injections for Dupuytren's disease: prospective cohort study assessing 2-year treatment effect durability.
To assess 2-year durability of joint contracture correction following collagenase injections for Dupuytren's disease. Prospective cohort study. Orthopaedic Department in Sweden. Patients with palpable Dupuytren's cord and active extension deficit (AED) ≥30° in the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joint. A surgeon injected 0.80 mg collagenase into multiple cord parts and performed finger manipulation under local anaesthesia after 24-48 hours. A hand therapist measured joint contracture before and 5 weeks after injection in all treated patients. Of 57 consecutive patients (59 hands), 48 patients (50 hands) were examined by a hand therapist 24-35 months (mean 26) after injection. Five of the patients had received a second injection in the same finger within 6 months of the first injection. Primary outcome was proportion of treated joints with ≥20° worsening in AED from 5 weeks to 2 years. Between the 5-week and the 2-year measurements, AED had worsened by ≥20° in seven MCP and seven PIP joints (28% of the treated hands; all had received a single injection). Mean AED for the MCP joints was 54° before injection, 6° at 5 weeks and 9° at 2 years and for the PIP joints 30°, 13° and 16°, respectively. For joints with ≥10° contracture at baseline, mean (95 % CI) baseline to 2 years AED improvement was for MCP 49° (41-54) and for PIP 25° (17-32). No treatment-related adverse events were observed at the 2-year follow-up evaluation. Two years after collagenase injections for Dupuytren's disease, improvement was maintained in 72% of the treated hands. Complete contracture correction was seen in more than 80% of the MCP but in less than half of the PIP joints.


Evaluation of oral aclarubicin treatment for tumors of the gastrointestinal track.
Aclarubicin (ACR), a drug useful for the treatment not only of tumors of the hematopoietic system but also of those of the gastrointestinal tract, has been administered invariably by the intravenous route. We attempted oral administration of ACR to increase its specificity in the treatment of gastrointestinal tumors. Oral administration resulted in a much higher intratumor concentration but lower peripheral blood cell or bone marrow cell concentration of the drug as compared with intravenous administration. The reduced peripheral cell inhibition and bone marrow suppression permits the administration of the drug in higher doses, and the absence of the drug in the plasma suggests a reduced likelihood of myocardial cell injury and hepatocyte impairment. These favorable findings are considered to warrant early clinical trial of the treatment.


Glutamate dehydrogenase from Mycoplasma laidlawii.
Mycoplasma laidlawii possesses a single glutamate dehydrogenase (GDH) with dual coenzyme specificity [specificity for nicotinamide adenine dinucleotide (H) and nicotinamide adenine dinucleotide phosphate (H)]. A purification procedure is reported which results in an enzyme preparation with a specific activity of 79.5 units/mg and which displays only one significant protein band after gel electrophoresis. This one band was determined, by activity staining, to have all of the GDH nucleotide specificities. The molecular weight of the enzyme is 250,000 +/- 10%, and it has a subunit size of about 48,000. The enzyme exhibits measurable activity with aspartate and pyruvate but is inactive with eight other possible substrates. Purine nucleotides do not affect the activity. The K(m) for reduced nicotinamide adenine dinucleotide was 1.8 x 10(-4)m. The optimal substrate concentrations and pH optimum for each of the respective GDH activities are also reported.


The dynamics of laser droplet generation.
We propose an experimental setup allowing for the characterization of laser droplet generation in terms of the underlying dynamics, primarily showing that the latter is deterministically chaotic by means of nonlinear time series analysis methods. In particular, we use a laser pulse to melt the end of a properly fed vertically placed metal wire. Due to the interplay of surface tension, gravity force, and light-metal interaction, undulating pendant droplets are formed at the molten end, which eventually completely detach from the wire as a consequence of their increasing mass. We capture the dynamics of this process by employing a high-speed infrared camera, thereby indirectly measuring the temperature of the wire end and the pendant droplets. The time series is subsequently generated as the mean value over the pixel intensity of every infrared snapshot. Finally, we employ methods of nonlinear time series analysis to reconstruct the phase space from the observed variable and test it against determinism and stationarity. After establishing that the observed laser droplet generation is a deterministic and dynamically stationary process, we calculate the spectra of Lyapunov exponents. We obtain a positive largest Lyapunov exponent and a negative divergence, i.e., sum of all the exponents, thus indicating that the observed dynamics is deterministically chaotic with an attractor as solution in the phase space. In addition to characterizing the dynamics of laser droplet generation, we outline industrial applications of the process and point out the significance of our findings for future attempts at mathematical modeling.


Cap-Based Transcranial Optical Tomography in an Awake Infant.
Although Blood Oxygenation Level Dependent (BOLD) functional MRI (fMRI) is widely used to examine brain function in adults, the need for general anesthesia limits its practical utility in infants and small children. Functional Near-Infrared Spectroscopy - Diffuse Optical Tomography (fNIRS-DOT) imaging promises to be an alternative brain network imaging technique. Yet current versions of continuous-wave fNIRS-DOT systems are restricted to the cortical surface measurements and do not probe deep structures that are frequently injured especially in premature infants. Herein we report a transcranial near infrared optical imaging system, called Cap-based Transcranial Optical Tomography (CTOT) able to image whole brain hemodynamic activity with 3 seconds of data acquisition time. We show the system is capable of whole brain oxygenation mapping in an awake child, and that tomographically reconstructed static CTOT-derived oxy- and deoxygenated blood volumes are spatially correlated with the time-averaged BOLD fMRI volumes. By removing time bottlenecks in the current system, dynamic CTOT mapping should be possible, which would then enable evaluation of functional connectivity in awake infants.


Elements of analytic style: Bion's clinical seminars.
The author finds that the idea of analytic style better describes significant aspects of the way he practices psychoanalysis than does the notion of analytic technique. The latter is comprised to a large extent of principles of practice developed by previous generations of analysts. By contrast, the concept of analytic style, though it presupposes the analyst's thorough knowledge of analytic theory and technique, emphasizes (1) the analyst's use of his unique personality as reflected in his individual ways of thinking, listening, and speaking, his own particular use of metaphor, humor, irony, and so on; (2) the analyst's drawing on his personal experience, for example, as an analyst, an analysand, a parent, a child, a spouse, a teacher, and a student; (3) the analyst's capacity to think in a way that draws on, but is independent of, the ideas of his colleagues, his teachers, his analyst, and his analytic ancestors; and (4) the responsibility of the analyst to invent psychoanalysis freshly for each patient. Close readings of three of Bion's 'Clinical seminars' are presented in order to articulate some of the elements of Bion's analytic style. Bion's style is not presented as a model for others to emulate or, worse yet, imitate; rather, it is described in an effort to help the reader consider from a different vantage point (provided by the concept of analytic style) the way in which he, the reader, practices psychoanalysis.


Surgical anatomy of the ophthalmic artery: its origin and proximal course.
We examined the surgical anatomy of the ophthalmic artery (OA) by dissection of cadaver heads, evaluating the anatomic relationships between the origin of the OA and both its proximal course and surrounding structures. In addition, we demonstrated the surgical application of these anatomic features for safe surgical exploration of this region. Through anatomic dissection, the origin of the OA was examined in both sides of 25 formalin-fixed and 10 fresh cadaver specimens. The following parameters were evaluated: the location of the origin of the OA in relation to the dural rings, the topographic relationship of the paraclinoid region, and the location of the dural penetrating point of the OA in the optic canal. The OA originated from the internal carotid artery within the intradural space in 49% of cases, just above the upper dural ring in 37%, at the clinoid segment in 7%, and within the cavernous sinus in 6%. The dural penetrating point of the OA was anterior to the falciform ligament, and thereby in the optic canal, in 74% of cases, ventral to the falciform ligament in 19%, and posterior to the falciform ligament in 7%. The anterior circumference point of the upper dural ring, the point at which the upper dural ring intersects the anterior edge of the internal carotid artery, was more anterior to the falciform ligament in 40% of cases and ventral and posterior to the falciform ligament in 16.4% and 43.6%, respectively. Our anatomic findings demonstrate anatomic variation of the OA in terms of its region of origin. Several anatomic points that were noteworthy during surgical exploration of this region are discussed.