The laterodorsal tegmentum contributes to behavioral sensitization to amphetamine.
A critical event in the development of behavioral sensitization is a transient increase in excitatory drive to dopamine neurons of the ventral tegmental area (VTA). This is likely to be due, in part, to the ability of drugs of abuse to produce long-term potentiation, expressed as increased AMPA receptor transmission, at excitatory synapses onto VTA dopamine neurons. We investigated the role of the laterodorsal tegmentum (LDT) in behavioral sensitization because LDT neurons provide an important source of excitatory drive to VTA dopamine neurons, through mixed glutamate and cholinergic inputs. To test the role of the LDT in amphetamine sensitization, ibotenic acid or sham lesions of the LDT were performed 1 week before the first of six daily amphetamine injections. When challenged with amphetamine 13 days after the last injection, sham rats expressed sensitization of stereotypy and post-stereotypy locomotor hyperactivity, whereas the latter was attenuated by ibotenic acid lesions of the LDT. To determine whether plasticity occurs in the LDT during amphetamine sensitization, we used a previously developed microdialysis assay in which increased ability of AMPA to activate a pathway serves as a marker for long-term potentiation. Two days after discontinuing repeated saline or amphetamine injections, the responsiveness of LDT-VTA neurons to AMPA was determined by microinjecting AMPA (0.4 nmol) into the LDT and measuring glutamate efflux in the ipsilateral VTA. Glutamate efflux was transiently increased in both groups but a delayed group difference was apparent with relatively higher glutamate efflux in amphetamine rats 30-60 min after AMPA injection. In parallel experiments, dopamine efflux in the nucleus accumbens (NAc) following intra-LDT AMPA declined in saline rats but remained relatively stable in amphetamine rats. Both results suggest relatively greater excitability of the LDT-VTA-NAc pathway after repeated amphetamine treatment. Our results provide the first evidence that neuronal plasticity in the LDT contributes to behavioral sensitization.


[The implementation of a hospital's fall management protocol: results of a four-year follow-up].
Inpatient falls are common occurrences with negative effects for patients and institutions. The objective of this descriptive study was to present the results of a fall management protocol used in a private hospital located in São Paulo, Brazil. Follow-up consisted of reviewing the fall rates and performing a descriptive analysis of the data. Subjects were the patients admitted between 2005 and 2008, accounting for 284 falls in 207,067 patient-days. The rates showed a monthly variability, with reductions following the implementation of interventions and rises in rates after management actions and training. In 2008, falls were more frequent among patients in clinical units of greater complexity - the elderly - using drugs that affected the central nervous system or having an impaired gait. The performed actions caused a reduction in fall rates, and the characterization of the events permitted staff to redirect interventions focusing on patients who were more susceptible to falls, as well as strengthen educational actions.


Deep Brain Stimulation, Authenticity and Value.
In this article, we engage in dialogue with Jonathan Pugh, Hannah Maslen, and Julian Savulescu about how to best interpret the potential impacts of deep brain stimulation on the self. We consider whether ordinary peoples' convictions about the true self should be interpreted in essentialist or existentialist ways. Like Pugh, Maslen, and Savulescu, we argue that it is useful to understand the notion of the true self as having both essentialist and existentialist components. We also consider two ideas from existentialist philosophy-Jean-Paul Sartre and Simone de Beauvoir's ideas about "bad faith" and "ambiguity"-to argue that there can be value to patients in regarding themselves as having a certain amount of freedom to choose what aspects of themselves should be considered representative of their true selves. Lastly, we consider the case of an anorexia nervosa patient who shifts between conflicting mind-sets. We argue that mind-sets in which it is easier for the patient and his or her family to share values can plausibly be considered to be more representative of the patient's true self, if this promotes a well-functioning relationship between the patient and the family. However, we also argue that families are well advised to give patients room to determine what such shared values mean to them, as it can be alienating for patients if they feel that others try to impose values on them from the outside.


Medical education, cost and policy: what are the drivers for change? Commentary.
Medical education is expensive. Its expense has led many stakeholders to speculate on how costs could be reduced. In an ideal world such decisions would be made on sound evidence; however this is impossible in the absence of evidence. Sometimes practice will be informed by policy, but policy will not always be evidence based. So how is policy in the field of cost and value in medical education actually developed? The foremost influence on policy in cost and value should be evidence-based knowledge. Unfortunately policy is sometimes influenced by what might at best be termed tradition and at worst inertia. Another influence on policy will be people--but some individuals may have more influence than others. A further influence on policy in this field is events, and mainly events that have gone wrong. One final influence on emerging policy in medical education cost analysis is that of the media.


Cognitive Deficits in Mood Disorders: Role and Contradictions in Psychiatry.
The principal aim of this work is to reflect about the assessment and management of cognitive deficits in psychiatric disorders, and, particularly, in mood disorders (MDD and BD). The current trend of research and clinical practice is to give more importance to cognitive dysfunctions in psychiatric disorders. There are numerous studies that highlighted the cognitive alterations as the core deficit in MDD and BD, observed across several domains (e.g., executive function, working memory, attention). There are also numerous tools that allow the identification of these cognitive deficits, as well as assessment tools. But are these, really, effective and usable in daily clinical practice? Are they accepted by patients? Could relying only these tools run the risk of forgetting the good clinical practice? Can the doctor-patient (or HCW-patient) relationship and deepening of psychopathological aspects to be marginalized? These and other considerations are carried out in this work.


Multivariate analyses to assess treatment effectiveness in advanced head and neck cancer.
To assess relative benefit of combined radiotherapy and surgery over single-modality treatment for advanced-stage squamous cell carcinoma of the aerodigestive tract by means of several multivariable analyses to control for patient variables. Medical chart review. University medical center. The study included 532 patients receiving initial therapy between January 1, 1980, and December 31, 1989. Three multivariate techniques (multiple logistic regression, propensity score stratification, and conjunctive consolidation) were used to compare outcomes for treatment groups. Five-year survival. Survival for radiation, surgery, and combined treatment groups were 24%, 40%, and 46%, respectively. With the use of multiple logistic regression to control patient variables, the radiation group had a significantly lower survival than the combined therapy group (risk ratio, 2.24; 95% confidence interval, 1.32-3.80), while there was no statistical difference for the surgery group compared with the combined therapy group (risk ratio, 1.26; 95% confidence interval, 0.78-2.03). When analyzed by propensity score, 5-year survival was higher in each quintile for the combined therapy group than for the group who received radiation alone (P =.002). There was no significant difference in survival between the surgery and combined treatment groups (P =.25). Conjunctive consolidation was used to create a clinical staging system to compare outcomes across treatment groups. In each clinical severity stage, radiation alone had a lower survival than combined therapy (P =.001), while no statistical difference was noted between surgery and combined therapy (P =.50). All 3 statistical techniques showed a significantly lower survival for patients treated with radiation alone vs combined therapy. No significant difference was noted between surgery and combined therapy. Propensity score analysis and conjunctive consolidation are useful techniques to control prognostic variables in cancer database studies and should be used in future outcome studies that address more current treatment dilemmas in head and neck oncology.


The relationship between stroke mortality and red blood cell parameters.
Several factors influence on the outcome of ischemic stroke. The aim of this study was determination the relationship between stroke mortality and red blood cell parameters. This cross-sectional study was conducted from 2011 July to June 2012. For all patients with ischemic stroke in middle cerebral artery (MCA) territory, the cell blood count test was performed. We recorded their mortality on the 1(st) week and the 1(st) month after ischemic stroke. Data analysis was performed using t-test, χ(2), Mann-Whitney U-test, logistic regression and receiver operating characteristic curve in SPSS for Windows 19.0. A total of 98 subjects (45.9% men and 54.1% women) with the mean age of 71.0 ± 13.9 years were assessed, while 67.3% of them were anemic. The prevalence of 1(st) week mortality among anemic and non-anemic patients was 40.9% and 34.4% (P = 0.534). The prevalence of mortality after 1(st) week till 1(st) month was 19.6% and 21.0% respectively (P = 0.636). In univariant analysis, only 1(st) month mortality had a significant relationship with red blood cell (RBC) count (P = 0.022). However, the result of logistic regression model showed that RBC (P = 0.012) and mean corpuscular volume (MCV) (P = 0.021) remained as predictors of the 1(st) week and the 1(st) month mortality (P = 0.011 and P = 0.090 respectively). The best cutoff point of RBC for the prediction of the 1(st) week mortality with 44.7% specificity and 69.5% sensitivity was estimated 4.07 million/μl and for the 1(st) month mortality with 46.6% specificity and 72.2% sensitivity was estimated 4.16 million/μl. The RBC count and MCV are independent predictors of ischemic stroke short-term mortality.


Efficacy and Adverse Reactions of Arthroscopic Half-Moon Plate Invasive Surgery in Patients with Acute Knee Pain (AKP): Systematic Review and Meta-Analysis.
To evaluate the efficacy and adverse reactions of arthroscopic half-moon plate invasive surgery (DEB) in patients with knee pain (AKP) using meta-analysis techniques. The computer retrieves from the English databases PubMed, EMBASE, Cochrane Library, and Web of Science and the Chinese databases China Knowledge Network, Wanfang Database, VIP Database, and China Biomedical Literature Database to collect information about DEB therapeutic AKP randomized controlled trial. Develop criteria for documentation inclusion and exclusion, evaluate the quality and bias risk of literature, and compare differences in efficacy and adverse responses before and after DEB treatment and other conservative treatments. A total of 14 randomized controlled trials and 1464 AKP patients were included in the study, with follow-up duration of 1-12 months. The total knee scores for DEB at 1, 3, 6, and 12 months after treatment were significantly better than baseline levels (1 month: WMD = 34.56, P = 0.02; 3 months: WMD = 27.73, P = 0.0001; 6 months: SMD = 2.38, P = 0.0001; 12 months: SMD = 1.69, P = 0.001). At 6 months of follow-up, DEB improved knee function better than HA (SMD = 0.47, P = 0.003), and during follow-up for 12 months, DEB relieved knee pain (SMD = 0.55, P = 0.0007) and improved knee function (SMD = 0.88, P = 0.0001) which is significantly better than HA. DEB was less effective at improving knee function in 1, 3, and 12 months than DEB joint HA injections (1 month P = 004; 3 months P = 0.01; 12 months P = 0.03). At 6 and 12 months of follow-up, DEB was better at pain relief and improved function than ozone (P > 0.05). DEB and glucocorticosteroids have similar effects in pain relief and improved function at various follow-up times. In terms of adverse reactions, DEB does not increase the risk of adverse events compared to HA (OR = 0.96, P = 0.85). Compared to HA and ozone, DEB is a more effective treatment for AKP joints, while DEB is combined with HA. The clinical efficacy of injection therapy AKP is better than that of DEB alone.


Ionic mechanisms of phototransduction in photoreceptor cells from the epistellar body of the octopus eledone cirrhosa
Intracellular recordings were made from extraocular photoreceptor cells within isolated epistellar bodies of the lesser or northern octopus Eledone cirrhosa. The cells had resting potentials around -41+/-5 mV (mean +/- s.d., N=60) and showed light-flash-induced membrane depolarisation. The evoked response to a brief light flash consisted of a transient peak depolarisation, followed by a plateau component. The magnitude of the light-induced peak depolarisation response was decreased by bathing the epistellar body in artificial sea water (ASW) low in Na+, where choline+ replaced Na+, or by passing steady depolarising current. Replacement of external Na+ by Li+ had no effect on the light-stimulated response. The external application of the Na+ channel blocker tetrodotoxin (3 micromol l-1) increased the light-evoked response, but this was accompanied by a loss of action potential activity. The amplitude and duration of the response to a light flash was increased by bathing the epistellar body in ASW low in Ca2+, or in ASW containing 10 mmol l-1 Co2+, and after intracellular microinjection of the Ca2+ buffer EGTA. Intracellular microinjection of Ca2+ or inositol 1,4,5-trisphosphate, or external application of the phospholipase C inhibitor U-73122, had no apparent effect on the light-evoked response. These results are consistent with the interpretation that (1) the majority of the light-induced inward current is carried by Na+, probably via a non-selective cation channel, and (2) an increase in the intracellular free Ca2+ concentration, mediated by the phototransduction process, is involved in regulating the light-induced inward photocurrent and thus, in effect, determines the amplitude, time course and sensitivity of the receptor potential.


Correlates of benzodiazepine abuse in methadone maintenance treatment. A 1 year prospective study in an Israeli clinic.
This study addressed the following questions for patients after 1 year of methadone maintenance treatment (MMT); (1) What are the demographic features and past history of drug use of benzodiazepine (BZD) abusers? (2) Do BZD abusers abuse more heroin, cocaine and/or cannabis and do they receive a higher methadone dosage level? (3) Do BZD abusers suffer more from hepatitis C (HCV) and do they have more HIV/HCV risk-taking behaviors than non-abusers? (4) Do BZD abusers have more psychopathology and more emotional distress than non-abusers? All 148 patients who completed 1 year of MMT underwent random and twice-weekly observed urine analysis for various drugs of abuse, responded to self-report questionnaires (SCL-90-R; POMS; HIV/HCV risk-taking behaviors), interviews (ASI) and underwent testing for hepatitis C. Abuse in this study is defined as any use during the 12th month of treatment. After 1 year of MMT, more BZD abusers (n = 63) were single, had spent time in prison, were unemployed and had at least one parent with an addiction problem or mental illness in comparison to non-abusers (n = 85). They had started using heroin and cocaine earlier and currently abused more cocaine, heroin and cannabis. They had significantly more psychopathology and negative mood. They had significantly more HCV and reported more HIV/HCV risk-taking behavior. We suggest that this group of patients is in need of more intensive pharmacological and psychological treatment.


The anti-inflammatory mechanism of sulfasalazine is related to adenosine release at inflamed sites.
The anti-inflammatory mechanism of sulfasalazine is not well understood. It has recently been shown that sulfasalazine inhibits 5-aminoimidazole-4-carboxamidoribonucleotide (AICAR) transformylase, an enzyme involved in de novo purine biosynthesis. We recently demonstrated that methotrexate promotes intracellular AICAR accumulation, thereby increasing adenosine release and diminishing inflammation, so we tested the hypothesis that sulfasalazine similarly promotes intracellular AICAR accumulation. We studied adenosine release and the state of inflammation in in vitro and in vivo models of the inflammatory process. The adhesion of stimulated neutrophils (FMLP) to endothelial cells preincubated with sulfasalazine was inhibited in a dose-dependent manner. Elimination of extracellular adenosine by addition of adenosine deaminase or inhibition of adenosine by the adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) completely reversed the anti-inflammatory effect of sulfasalazine (at concentrations <1 microM in this in vitro model. To determine whether this phenomenon was relevant to inhibition of inflammation in vivo, we studied the effect of sulfasalazine (100 mg/kg/day by gastric gavage for 3 days) on leukocyte accumulation in the murine air pouch model of inflammation. Treatment with sulfasalazine markedly decreased the number of leukocytes that accumulated in the inflamed (carrageenan, 2 mg/ml) air pouch. Injection of either adenosine deaminase or DMPX, but not the A1 receptor antagonist 8-cyclopentyl-dipropylxanthine, significantly reversed the anti-inflammatory effects of sulfasalazine treatment. Sulfasalazine increased the exudate adenosine concentration from 127 +/- 64 nM to 869 +/- 47 nM. Moreover, sulfasalazine treatment promoted a marked increase in splenocyte AICAR concentration from 35 +/- 6 to 96 +/- 3 pmols/10(6) splenocytes, which is consistent with the in vitro observation that sulfasalazine inhibits AICAR transformylase. These results indicate that sulfasalazine, like methotrexate, enhances adenosine release at an inflamed site and that adenosine diminishes inflammation via occupancy of A2 receptors on inflammatory cells. Our studies provide evidence that sulfasalazine and methotrexate may be described as a newly recognized family of anti-inflammatory agents that share the property of using adenosine as an antagonist of inflammation.


[EEG in patients with infantile cerebral palsy before and after the treatment by the method of functional biofeedback].
The paper is concerned with a study into the mechanisms of central restructures in formation of a new motor stereotype using functional biomonitoring (FBM) after different pharmacological exposures. There were 117 patients aged 5 to 14 years with spastic forms of infantile cerebral paralysis. Biomonitoring sessions were carried out with the aid of portable indicators. Pharmacological correction was performed by midocalm or galanthamine or by combining the latter one with ganglerone++. The treatment course consisted of 15 training sessions. To study the EEG structure, use was made of the method of computing conditional probabilities of one wave of the EEG, provided it was preceded by any other one. Analysis of the dynamics of the biorhythmical structure of the EEG revealed the common mechanism of restructuring the central components of movements regulation for all the patients' groups using FBM. That mechanism lay in a highly significant increase of interrelated correlations of the main components of the EEG to the alpha-component together with formation or gain of the "alpha-nucleus". The patients' group who underwent biomonitoring sessions after galanthamine and gangleron administration manifested, as compared to the other groups, a highly significant transformation of teta- and delta-components to the alpha-frequency range and enhancement of interrelation of teta-components in the "working" hemisphere. This was coupled with the most beneficial data on the patients' status.


Offspring born to ewes fed high salt during pregnancy have altered responses to oral salt loads.
Prenatal growth is sensitive to the direct and indirect effects of maternal dietary intake; manipulation can lead to behavioural and physiological changes of the offspring later in life. Here, we report on three aspects of how a high-salt diet during pregnancy (conception to parturition) may affect the offspring's response to high oral salt loads: (i) dietary preferences for salt; (ii) response to salt and water balance and aldosterone and arginine vasopressin (AVP) concentrations after an oral salt challenge; (iii) concentrations of insulin and leptin after an oral salt challenge. We used two groups of lambs born to ewes fed either a high-salt (13% NaCl) diet during pregnancy (S lambs; n = 12) or control animals born to ewes fed a conventional (0.5% NaCl) diet during pregnancy (C lambs; n = 12). Lambs were subjected to short- (5 min) and long-term (24 h) preference tests for a high-salt (13% NaCl) or control diet, and the response to an oral challenge with either water or 25% NaCl solution were also carried out. Weaned lambs born to ewes fed high salt during pregnancy did not differ in their preference for dietary salt, but they did differ in their physiological responses to an oral salt challenge. Results indicate that these differences reflect an alteration in the regulation of water and salt balance as the metabolic hormones, insulin and leptin, were not affected. During the first 2 h after a single salt dose, S lambs had a 25% lower water intake compared to the C lambs. S lambs had, on average, a 13% lower AVP concentration than the C lambs (P = 0.014). The plasma concentration of aldosterone was higher in the S lambs than in the C lambs (P = 0.013). Results suggest that lambs born to ewes that ingest high amounts of salt during pregnancy are programmed to have an altered thirst threshold, and blunted response in aldosterone to oral salt loads.


Environmental Risk Factors in Bipolar Disorder and Psychotic Depression: A Systematic Review and Meta-Analysis of Prospective Studies.
The aim of this systematic review and meta-analysis was to study the association between specific environmental risk factors (ERF) and later development of Bipolar disorder and Psychotic depression. A systematic search of prospective studies was conducted in MEDLINE, EMBASE and PsycINFO databases, and supplemented by hand searching, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (registration number: CRD42018092253). Selected ERF included: pre-/peri-natal factors-paternal age at birth, maternal infection, obstetric complications, perinatal stress; early childhood factors-urbanicity at birth, childhood infection, childhood adversity; later life factors-substance misuse, ethnic minority and migration, urbanicity later in life, stressful life events, and traumatic head injury. Pooled effect sizes of the association between these ERF and affective psychoses were calculated from systematically selected studies. When studies examining each ERF were insufficient for meta-analysis, results were presented narratively. Forty-six studies were included for quantitative analyses among selected ERF for affective psychosis, with significant association found for paternal age >40 years (OR 1.17, 95%CI 1.12-1.23), early (OR 1.52, 95%CI 1.07-2.17) and late (OR 1.32, 95%CI 1.05-1.67) gestational age, childhood adversity (OR 1.33, 95%CI 1.18-1.50), substance misuse (OR 2.87, 95%CI 1.63-5.50), and being from an ethnic minority (OR 1.99, 95%CI 1.39-2.84). These results suggest some shared environmental load between non-affective and affective psychosis, implying generalized risks for psychosis rather than for specific diagnostic categories. Nonetheless, published studies for some ERF in the affective psychoses are scarce, and further longitudinal studies are needed.


Visible-light-induced addition of carboxymethanide to styrene from monochloroacetic acid.
Where monochloroacetic acid is widely used as a starting material for the synthesis of relevant groups of compounds, many of these synthetic procedures are based on nucleophilic substitution of the carbon chlorine bond. Oxidative or reductive activation of monochloroacetic acid results in radical intermediates, leading to reactivity different from the traditional reactivity of this compound. Here, we investigated the possibility of applying monochloroacetic acid as a substrate for photoredox catalysis with styrene to directly produce γ-phenyl-γ-butyrolactone. Instead of using nucleophilic substitution, we cleaved the carbon chlorine bond by single-electron reduction, creating a radical species. We observed that the reaction works best in nonpolar solvents. The reaction does not go to full conversion, but selectively forms γ-phenyl-γ-butyrolactone and 4-chloro-4-phenylbutanoic acid. Over time the catalyst precipitates from solution (perhaps in a decomposed form in case of fac-[Ir(ppy)3]), which was proven by mass spectrometry and EPR spectroscopy for one of the catalysts (N,N-5,10-di(2-naphthalene)-5,10-dihydrophenazine) used in this work. The generation of HCl resulting from lactone formation could be an additional problem for organometallic photoredox catalysts used in this reaction. In an attempt to trap one of the radical intermediates with TEMPO, we observed a compound indicating the generation of a chloromethyl radical.


An automaton for preclinical pain testing.
In this issue of Cell Reports Methods, Dedek et al. present RAMalgo-an AI-powered, automated platform for quantifying nociceptive behaviors in mice. With integrated video tracking and mechanical, thermal, and optogenetic stimulation, RAMalgo has the potential to increase standardization and throughput of pain behavior measurement in rodents.


Multi-Task Learning U-Net for Functional Shoulder Sub-Task Segmentation.
The assessment of a frozen shoulder (FS) is critical for evaluating outcomes and medical treatment. Analysis of functional shoulder sub-tasks provides more crucial information, but current manual labeling methods are time-consuming and prone to errors. To address this challenge, we propose a deep multi-task learning (MTL) U-Net to provide an automatic and reliable functional shoulder sub-task segmentation (STS) tool for clinical evaluation in FS. The proposed approach contains the main task of STS and the auxiliary task of transition point detection (TPD). For the main STS task, a U-Net architecture including an encoder-decoder with skip connection is presented to perform shoulder sub-task classification for each time point. The auxiliary TPD task uses lightweight convolutional neural networks architecture to detect the boundary between shoulder sub-tasks. A shared structure is implemented between two tasks and their objective functions of them are optimized jointly. The fine-grained transition-related information from the auxiliary TPD task is expected to help the main STS task better detect boundaries between functional shoulder sub-tasks. We conduct the experiments using wearable inertial measurement units to record 815 shoulder task sequences collected from 20 healthy subjects and 43 patients with FS. The experimental results present that the deep MTL U-Net can achieve superior performance compared to using single-task models. It shows the effectiveness of the proposed method for functional shoulder STS. The code has been made publicly available at https://github.com/RobinChu9890/MTL-U-Net-for-Functional-Shoulder-STS.Clinical Relevance- This work provides an automatic and reliable functional shoulder sub-task segmentation tool for clinical evaluation in frozen shoulder.


Design and evaluation of voluntary opening and voluntary closing prosthetic terminal device.
Body-powered prostheses use a cable-operated system to generate forces and move prosthetic joints. However, this control system can only generate forces in one direction, so current body-powered prehensor designs allow the user either to voluntarily open or voluntarily close the tongs. Both voluntary opening (VO) and voluntary closing (VC) modes of operation have advantages for certain tasks, and many end-users desire a terminal device that can switch between the two modes. However, such a terminal device must maintain the same thumb position (i.e., point of Bowden cable attachment) and movement direction in both modes in order to avoid the need to readjust the harness after every mode switch. In this study, we demonstrate a simple design that fulfills these requirements while allowing the user to switch easily between modes. We describe the design concept, describe a rugged split-hook prototype, provide specifications (size, weight, efficiency, etc.), and present a pilot study in which five subjects with intact arms and two subjects with amputation used the VO and VC split-hook prehensor to perform the Southampton Hand Assessment Procedure. Subjects performed an average of 4 to 7 (+/- 0.2) points better when they could choose to switch between modes on a task-by-task basis than when they were constrained to using only VO or VC modes.


A novel structure for double negative NIMs towards UV spectrum with high FOM.
A novel ring structure is proposed for double negative NIMs at visible light spectrum with high FOM (e.g. about 11 at a wavelength of 583 nm) and low loss. Besides the effective medium theory, an equivalent circuit model is also given to explain physically why our novel structure can give double negative behavior with low loss. Adapted from the original ring structure, two other types of structures, namely, disk and nanowire structures, are also given to further push double negative NIMs toward ultraviolet (UV) spectrum.


Influence of prevertebral soft tissue swelling on dysphagia after anterior cervical discectomy and fusion using a rectangular titanium stand-alone cage.
Postoperative oropharyngeal complications such as dysphagia after anterior cervical spine surgery are some of the least discussed surgery-related complications. The purpose of this retrospective study is to investigate the incidence and possible risk factors for 30-day postoperative dysphagia after anterior cervical discectomy and fusion (ACDF). This study included 152 consecutive patients who underwent 1- or 2-level ACDF using a rectangular titanium stand-alone cage in our institutes. Surgery-related dysphagia early after surgery was analyzed based on hospital charts. Radiological evaluation of prevertebral soft tissue swelling (PSTS) was performed by comparing plain lateral radiographs of the cervical spine before surgery with those after surgery. The percentage of PSTS (%PSTS) was defined by retropharyngeal soft tissue diameter divided by vertebral diameter. Positive %PSTS was determined when %PSTS exceeded its mean + 2 standard deviations. Twelve patients (7.9%) demonstrated prolonged symptoms of dysphagia within 30-day postoperatively. All patients eventually demonstrated satisfactory or acceptable recovery late after surgery, except one case of hypoglossal nerve palsy. %PSTS was significantly highest early after surgery and returned to presurgical levels within 30 days after surgery. Statistical analysis suggested that the positive %PSTS at C3 or C4 level early after surgery was significantly associated with the occurrence of postoperative dysphagia. Although the possible reasons for postoperative dysphagia may not only be multifactorial but also be highly surgeon-dependent, such a complication is still underestimated and needs to be carefully resolved. %PSTS appeared to be easy and reliable index to judge the possible risk of postoperative dysphagia.


Mechanical Micronization of Lipoaspirates: Squeeze and Emulsification Techniques.
Condensation of grafted fat has been considered a key for achieving better outcomes after fat grafting. The authors investigated the therapeutic potential of two mechanical tissue micronizing procedures: squeeze and emulsification. Human aspirated fat was centrifuged (centrifuged fat) and fragmented with an automated slicer (squeezed fat). Alternatively, centrifuged fat was emulsified by repeated transfer between two syringes through a small-hole connecter and then separated by mesh filtration into two portions: residual tissue of emulsified fat and filtrated fluid of emulsified fat. The four products were examined for cellular components. Histologic and electron microscopic analyses revealed that squeezed fat and residual tissue of emulsified fat contained broken adipocytes and fragmented capillaries. Compared with centrifuged fat, the squeezed fat and residual fat products exhibited increased specific gravity and increased numbers of adipose-derived stem/stromal cells and endothelial cells per volume, suggesting successful cell/tissue condensation in both squeezed fat and residual tissue of emulsified fat. Although cell number and viability in the stromal vascular fraction were well maintained in both squeezed fat and residual fat, stromal vascular fraction culture assay showed that adipose-derived stromal cells were relatively damaged in residual tissue of emulsified fat but not in squeezed fat. By contrast, no adipose-derived stromal cells were cultured from filtrated fluid of emulsified fat. The authors' results demonstrated that mechanical micronization is easily conducted as a minimal manipulation procedure, which can condense the tissue by selectively removing adipocytes without damaging key components, such as adipose-derived stromal cells and endothelial cells. Depending on the extent of adipocyte removal, the product may be a useful therapeutic tool for efficient tissue volumization or therapeutic revitalization/fertilization. Therapeutic, V.


Versatile use of microliths as a technological advantage in the miniaturization of Late Pleistocene toolkits: The case study of Neve David, Israel.
The miniaturization of stone tools, as reflected through the systematic production of bladelets and bladelet tools (microliths), characterized many industries of the Late Pleistocene, with the Levantine Epipalaeolithic serving as a well-studied example. It is commonly held that microliths were used as modular inserts in composite projectiles, while their incorporation in other tools for different tasks is generally overlooked, the latter aspect being the main focus of this paper. We present here a more inclusive approach through a case study of the Geometric Kebaran (Middle Epipalaeolithic, ca. 18,500-15,000 cal BP) site of Neve David, Mount Carmel, Israel. Recent excavations at the site exposed a variety of features, and one well-preserved shallow pit provided a large lithic assemblage with ca. 90 microliths. We studied this assemblage using both the low- and high- magnification use-wear protocols, accompanied by a range of experiments. Our results show that a) the fragmentation rate is very high in this assemblage (ca. 90%), b) most of the microliths have identifiable use-wear, c) the microliths were commonly used as inserts in composite projectiles, d) many microliths were used for functions not related to weaponry and hunting, such as wood-working, weed harvesting and meat processing. These findings strongly support the suggestion that the small insets, regardless of their specific type (trapeze, rectangle, backed/retouched bladelet), were used in a wide variety of composite tools. We argue that such a versatile approach and flexibility in the use of microliths reflect a technological advantage where a minimal set of microlithic types, produced in large numbers, could provide the required elements for weapons, as well as for a variety of cutting, processing and harvesting tools needed for mundane tasks at a large Middle Epipalaeolithic camp.


Curcumin inhibits lipoxygenase by binding to its central cavity: theoretical and X-ray evidence.
Many lipoxygenase inhibitors including curcumin are currently being studied for their anti-carcinogenic properties. Curcumin is a naturally occurring polyphenolic phytochemical isolated from the powdered rhizome of the plant Curcuma longa that possesses anti-inflammatory properties and inhibits cancer formation in mice. Recently it was shown that the soybean lipoxygenase L1 catalyzed the oxygenation of curcumin and that curcumin can act as a lipoxygenase substrate. In the current study, we investigated the fate of curcumin when used as a soybean lipoxygenase L3 substrate. By use of X-ray diffraction and mass spectrometry, we found an unoccupied electron mass that appears to be an unusual degradation product of curcumin (4-hydroxyperoxy-2-methoxyphenol) located near the soybean L3 catalytic site. Understanding how curcumin inhibits lipoxygenase may help in the development of novel anti-cancer drugs used for treatment where lipoxygenases are involved.


Background characteristics of basic health examination participants: the JPHC Study Baseline Survey.
Although epidemiologic studies including the Japan Public Health Center-based Prospective Study on Cancer and Cardiovascular Disease (JPHC study) have frequently used the basic health examination participants as study subjects, their background characteristics have rarely been investigated. The aim of this study is to clarify the background characteristics of participants and to discuss their impact on epidemiologic studies. Subjects were 43,140 (Cohort I) and 34,892 (Cohort II) respondents aged 40-59 years who completed a self-administered questionnaire in 1990 or 1993-94 by the JPHC Study. Respondents whose data of the basic health examination were also available were defined as participants. We compared their sociodemographic factors, personal medical history, and lifestyle-related factors with those of non-participants. Participants tended to be older and less educated. They were more likely to engage in agriculture, forestry and fisheries or to be self-employed persons, or homemakers. Male participants smoked less and were more likely to drink alcohol beverage moderately. Female participants smoked and drank less but tended to participate more in sports and physical exercise in their leisure time. Both male and female participants tended to eat fruits and green vegetables more often than non-participants. In short, participants had a different socioeconomic status from non-participants and a favorable lifestyle profile, especially among women. These findings were principally consistent between the two cohorts. These differences between participants and non-participants in the basic health examination might cause a selection bias that limits the application of the results to only participants in the basic health examination.


GEI-8, a homologue of vertebrate nuclear receptor corepressor NCoR/SMRT, regulates gonad development and neuronal functions in Caenorhabditis elegans.
NCoR and SMRT are two paralogous vertebrate proteins that function as corepressors with unliganded nuclear receptors. Although C. elegans has a large number of nuclear receptors, orthologues of the corepressors NCoR and SMRT have not unambiguously been identified in Drosophila or C. elegans. Here, we identify GEI-8 as the closest homologue of NCoR and SMRT in C. elegans and demonstrate that GEI-8 is expressed as at least two isoforms throughout development in multiple tissues, including neurons, muscle and intestinal cells. We demonstrate that a homozygous deletion within the gei-8 coding region, which is predicted to encode a truncated protein lacking the predicted NR domain, results in severe mutant phenotypes with developmental defects, slow movement and growth, arrested gonadogenesis and defects in cholinergic neurotransmission. Whole genome expression analysis by microarrays identified sets of de-regulated genes consistent with both the observed mutant phenotypes and a role of GEI-8 in regulating transcription. Interestingly, the upregulated transcripts included a predicted mitochondrial sulfide:quinine reductase encoded by Y9C9A.16. This locus also contains non-coding, 21-U RNAs of the piRNA class. Inhibition of the expression of the region coding for 21-U RNAs leads to irregular gonadogenesis in the homozygous gei-8 mutants, but not in an otherwise wild-type background, suggesting that GEI-8 may function in concert with the 21-U RNAs to regulate gonadogenesis. Our results confirm that GEI-8 is the orthologue of the vertebrate NCoR/SMRT corepressors and demonstrate important roles for this putative transcriptional corepressor in development and neuronal function.


Multi-radionuclide digital autoradiography of the intra-aortic atherosclerotic plaques using a monoclonal antibody targeting oxidized low-density lipoprotein.
The aim of this study was to use multi-radionuclide autoradiography to compare the different distributions of three radiolabelled tracers in an atherosclerotic mouse model. This method, along with immunohistochemistry, was applied to investigate the intra-aortic distribution of 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG), (131)I/(125)I labeled anti-oxidized Low Density Lipoprotein (oxLDL), and non-binding control antibodies. Aortas were isolated from a total of 12 apoB-100/LDL receptor deficient mice 73 h post injection of radioiodine-labeled anti-oxLDL and control antibody and 1 h post injection of (18)F-FDG. A solid-state real-time digital autoradiography system was used to image the slide mounted aortas. Contributions from each radionuclide were separated by half-life and emission energy and the aortas were subsequently stained with Oil Red O for plaque to aorta contrast ratios. Immunohistochemical staining was performed to detect anti-oxLDL and control antibody localization. Radiolabeled anti-oxLDL showed increased total activity uptake in the aorta over control antibody and immunohistochemical analysis of plaques indicated increased binding of the specific antibody compared to control. The intra-aortic activity distribution of the anti-oxLDL antibody was however very similar to that of the control antibody although both had higher atherosclerotic plaques to aorta wall ratios than (18)F-FDG. Given the right choice of radionuclides, multi-radionuclide digital autoradiography can be employed to compare several tracers ex vivo in the same animal. The distribution of anti-oxLDL antibodies did not significantly differ from the control antibody but it did appear to have a better plaque to aorta contrast at 73 h post injection than (18)F-FDG at 1 h post injection.


Hydatid Cyst of the Parotid Gland: A Rare Location.
Hydatid disease of the parotid gland is a very rare entity and may be easily overlooked in the diagnosis of parotid masses. Although Turkey remains an endemic area for echinococcosis, involvement of the parotid gland is extremely rare. A 26-year-old man presented with primary parotid gland mass without any other organ involvement. During the first surgery, the cyst was perforated accidentally and in a short time recurrence was occurred. Maximum attention was given for the second surgery for total removal without damaging the cyst with medical treatment. The clinicians should take hydatid disease of parotid gland into consideration and great care must be given for not damaging the capsule of the cystic tumors in order to prevent recurrences.


Inhibition of monoamine oxidase-B by selegiline reduces cigarette smoke-induced oxidative stress and inflammation in airway epithelial cells.
Chronic obstructive pulmonary disease (COPD) is caused by the build-up of oxidative stress-induced damages due to cigarette smoking, but how monoamine oxidase (MAO)-B signaling is involved remains unclear. This study aims to establish the involvement of MAO-B signaling pathways in cigarette smoke medium (CSM)-induced oxidative stress and inflammation in human airway epithelial cells (AECs). CSM treatment increased MAO-B activity, ROS levels and IL-8 release in AECs. Pretreatment with MAO-B selective inhibitor selegiline reversed the CSM-induced changes in MAO-B activity, ROS levels and IL-8 release in a dose-dependent manner. Selegiline also reversed CSM-induced changes of anti-oxidant enzymes superoxide dismutase (SOD) and catalase (CAT) activities, GSH/GSSG ratio, as well expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). The effects of selegiline are partially driven through the nuclear factor erythroid 2 related factor 2 (Nrf2) and cytosol translocation of its negative regulator, BTB and CNC homolog 1 (Bach1). Nevertheless, selegiline fully reversed the CSM-induced effects on IKK, cytoplasmic IκB expression, and nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit. Our study demonstrated that in AECs, inhibition of MAO-B using selegiline reversed the CSM-induced oxidative stress and inflammation. These data may provide a novel strategy for therapy in COPD.


The genomic map of breast cancer: which roads lead to better targeted therapies?
Recent advances in whole-genome technologies have supplied the field of cancer research with an overwhelming amount of molecular data. Improvements in massively parallel sequencing approaches have led to logarithmic decreases in costs, and so these methods are becoming almost commonplace in the analysis of clinical trials and other cohorts of interest. Furthermore, whole-transcriptome quantification by RNA sequencing is quickly replacing microarrays. However, older chip-based methodologies such as comparative genomic hybridization and single-nucleotide polymorphism arrays have benefited from this technological explosion and are now so accessible that they can be employed in increasingly larger cohorts of patients. The study of breast cancer lends itself particularly well to these technologies. It is the most commonly diagnosed neoplasm in women, giving rise to nearly 230,000 new cases each year. Many patients are given a diagnosis of early-stage disease, for which surgery is the standard of care. These attributes result in excellent availability of tissues for whole-genome/transcriptome analysis. The Cancer Genome Atlas project has generated comprehensive catalogs of publically available genomic breast cancer data. In addition, other studies employing the power of genomic technologies in medium to large cohorts were recently published. These data are now publically available for the generation of novel hypotheses. However, these studies differed in the methods, patient cohorts, and analytical techniques employed and represent complementary snapshots of the molecular underpinnings of breast cancer. Here, we will discuss the convergences and divergences of these reports as well as the scientific and clinical implications of their findings.


The dynamic envelope of a fusion class II virus. E3 domain of glycoprotein E2 precursor in Semliki Forest virus provides a unique contact with the fusion protein E1.
In alphaviruses, here represented by Semliki Forest virus, infection requires an acid-responsive spike configuration to facilitate membrane fusion. The creation of this relies on the chaperone function of glycoprotein E2 precursor (p62) and its maturation cleavage into the small external E3 and the membrane-anchored E2 glycoproteins. To reveal how the E3 domain of p62 exerts its control of spike functions, we determine the structure of a p62 cleavage-impaired mutant virus particle (SQL) by electron cryomicroscopy. A comparison with the earlier solved wild type virus structure reveals that the E3 domain of p62(SQL) forms a bulky side protrusion in the spike head region. This establishes a gripper over part of domain II of the fusion protein, with a cotter-like connection downward to a hydrophobic cluster in its central beta-sheet. This finding reevaluates the role of the precursor from being only a provider of a shield over the fusion loop to a structural playmate in formation of the fusogenic architecture.


Mechanical phase inversion of Pickering emulsions via metastable wetting of rough colloids.
The possibility to invert emulsions from oil-in-water to water-in-oil (or vice versa) in a closed system, i.e. without any formulation change, remains an open fundamental challenge with many opportunities for industrial applications. Here, we propose a mechanism that exploits particle surface roughness to induce metastable wetting and obtain mechanically-responsive Pickering emulsions. We postulate that the phase inversion is driven by an in situ switch of the particle wettability from metastable positions at the interface following the input of controlled mechanical energy. Oil-in-water emulsions can be prepared at low energy using mildly hydrophobic rough colloids, which are dispersed in water and weakly pinned at the interface, and switched to water-in-oil emulsions by a second emulsification at higher energy, which triggers the relaxation of the particle contact angle. The same principle is demonstrated for the complementary emulsions using mildly hydrophilic colloids initially dispersed in oil. Our experiments and simulations support that the delicate interplay between particle surface design during synthesis and the energy of the emulsification process can encode a kinetic pathway for the phase inversion. Both organic and inorganic nanoparticles can be used, allowing for the future implementation of our strategy in a broad range of smart industrial formulations.


Aggregates of Defined Stereochemical Scaffolds: A Study in Solution of a Zinc(II) Schiff Base Complex Derived from the Enantiopure trans-1,2-Cyclopentanediamine.
Molecular aggregation of bis(salicylaldiminato) ZnII Schiff base, ZnL, complexes is a topic of current interest. In this paper, we report a novel complex derived from the enantiopure trans-1,2-cyclopentanediamine, (R)-1, in order to probe the effect of the defined stereochemistry on its coordination geometry and aggregation properties, through detailed 1H NMR, DOSY NMR, UV/vis, and circular dichroism spectroscopic studies and accurate DFT calculations. This complex shows several peculiarities in solution, behaving very differently from ZnL complexes and more importantly from the related trans-1,2-diaminocyclohexane derivative. Unexpectedly, experimental data suggest the existence in DMSO of two species in equilibrium, the classical monomeric adduct and a dimer, indicating that the DMSO is not sufficiently strong Lewis basic to completely deaggregate the complex. Also, in chloroform an unusual behavior is observed with the existence of a single defined dimeric species characterized as a dinuclear double helicate Zn2L2 structure which does not deaggregate even with the addition of pyridine in large stoichiometric excess. The formation of mononuclear adducts occurs only when dissolving the complex in the stronger Lewis base pyridine. All these data indicate the helicate (R)-1-h complex has a higher thermodynamic stability than that of the cyclohexane analogue, leading to its unique aggregation properties.


Educational impact of a Family Practice Clinic Patient Medical Advisor Booklet.
The present study was conducted to test the efficacy of a new "Family Practice Clinic Patient Medical Advisor Booklet" developed by the author for patient education. Experimental group patients were given the booklet with a prepared 25-minute talk describing it. Two to four weeks later they were seen again to answer a health knowledge questionnaire. Control group patients were seen only once. At that time, the questionnaire was given without the preceding presentation. The interviewer then discussed incorrect answers with control group patients and distributed the booklet. Both groups were asked to evaluate the booklet by mail approximately one month after administration of the health knowledge questionnaire. The experimental group showed a statistically significant higher mean score on the health knowledge questionnaire. The experimental group answered 96.8% correctly, compared to 71.6% for the control group. In their responses to the mailed evaluation forms, both experimental and control groups thought the booklet was well written and useful in understanding and treating the illnesses described.


Influences on human papillomavirus vaccination status among female college students.
In 2006, the Food and Drug Administration (FDA) approved the human papillomavirus (HPV) vaccine Gardasil® (Merck) for girls and women aged 9-26 years. Although the vaccine is ideally administered to 11 and 12 year olds, college-aged women may be uniquely at risk for HPV due to high rates of sexual activity and, thus, serve as an important catch-up population for the HPV vaccine. The purpose of this study is to examine factors associated with HPV vaccination status among college women. In fall 2008, a convenience sample of 256 undergraduate women enrolled in an introductory social science course at a large, public, urban university in the southeastern United States was surveyed. The 30-item paper-and-pencil questionnaire asked for demographic information, HPV knowledge, HPV vaccine beliefs, and HPV vaccination status. The overall survey response rate was 89.6%. Most women were unmarried/single (91.7%), with a mean age of 18.9 years (range 17-42). Race/ethnicity status included 73.0% white, 17.5% Hispanic, and 7.7% black/African American. One hundred eleven (40.5%) women reported receiving the vaccine. Nonvaccinated women were less likely to have heard of the vaccine through a healthcare provider (odds ratio [OR] 0.12, 95% confidence interval [CI] 0.04-0.35) or from a family member (OR 0.33, 95% CI 0.16-0.68) and more likely to consider a healthcare provider recommendation as being only somewhat important (OR 2.91, 95% CI 1.32-6.41) or not important at all (OR 5.61, 95% CI 0.44-71.87) vs. very important. Findings suggest that healthcare providers have an important role in encouraging HPV vaccination. Continuing education for providers who see preadolescent girls in conjunction with a parent or who treat women of college age may be a worthwhile endeavor.


Single-molecule imaging of NGF axonal transport in microfluidic devices.
Nerve growth factor (NGF) signaling begins at the nerve terminal, where it binds and activates membrane receptors and subsequently carries the cell-survival signal to the cell body through the axon. A recent study revealed that the majority of endosomes contain a single NGF molecule, which makes single-molecule imaging an essential tool for NGF studies. Despite being an increasingly popular technique, single-molecule imaging in live cells is often limited by background fluorescence. Here, we employed a microfluidic culture platform to achieve background reduction for single-molecule imaging in live neurons. Microfluidic devices guide the growth of neurons and allow separately controlled microenvironment for cell bodies or axon termini. Designs of microfluidic devices were optimized and a three-compartment device successfully achieved direct observation of axonal transport of single NGF when quantum dot labeled NGF (Qdot-NGF) was applied only to the distal-axon compartment while imaging was carried out exclusively in the cell-body compartment. Qdot-NGF was shown to move exclusively toward the cell body with a characteristic stop-and-go pattern of movements. Measurements at various temperatures show that the rate of NGF retrograde transport decreased exponentially over the range of 36-14 degrees C. A 10 degrees C decrease in temperature resulted in a threefold decrease in the rate of NGF retrograde transport. Our successful measurements of NGF transport suggest that the microfluidic device can serve as a unique platform for single-molecule imaging of molecular processes in neurons.


Electrostatic interactions and the folding of the four-way DNA junction: analysis by selective methyl phosphonate substitution.
The structure and dynamics of the four-way (Holliday) junction are strongly dependent on the presence of metal ions. In this study, the importance of phosphate charge in and around the point of strand exchange has been explored by selective replacement with electrically neutral methyl phosphonate groups, guided by crystal structures of the junction in the folded, stacked X conformation. Junction conformation has been analysed by comparative gel electrophoresis and fluorescence resonance energy transfer (FRET). Three of sets of phosphate groups on the exchanging strands have been analysed; those at the point of strand exchange and those to their 3' and 5' sides. The exchanging and 3' phosphate groups form a box of negatively charged groups on the minor groove face of the junction, while the 5' phosphate groups face each other on the major groove side, with their proR oxygen atoms directed at one another. The largest effects are observed on substitution of the exchanging phosphate groups; replacement of both groups leads to the loss of the requirement for addition of metal ions to allow junction folding. When the equivalent phosphate groups on the continuous strands were substituted, a proportion of the junction folded into the alternative conformer so as to bring these phosphate groups onto the exchanging strands. These species did not interconvert, and thus this is likely to result from the alternative diasteromeric forms of the methyl phosphonate group. This shows that some of the conformational effects result from more than purely electrostatic interactions. Smaller but significant effects were observed on substitution of the flanking phosphate groups. All methyl phosphonate substitutions at these positions allowed folding to proceed at a reduced concentration of magnesium ions, with double substitutions more effective than single substitutions. Substitution of 5' phosphates resulted in a greater degree of folding at a given ionic concentration compared to the corresponding 3' phosphate substitutions. These results show that the phosphate groups at the point of strand exchange exert the largest electrostatic effect on junction folding, but a number of phosphate groups in the vicinity of the exchange region contribute to the overall effects.


Incorporating pleiotropic quantitative trait loci in dissection of complex traits: seed yield in rapeseed as an example.
A comprehensive linkage atlas for seed yield in rapeseed. Most agronomic traits of interest for crop improvement (including seed yield) are highly complex quantitative traits controlled by numerous genetic loci, which brings challenges for comprehensively capturing associated markers/genes. We propose that multiple trait interactions underlie complex traits such as seed yield, and that considering these component traits and their interactions can dissect individual quantitative trait loci (QTL) effects more effectively and improve yield predictions. Using a segregating rapeseed (Brassica napus) population, we analyzed a large set of trait data generated in 19 independent experiments to investigate correlations between seed yield and other complex traits, and further identified QTL in this population with a SNP-based genetic bin map. A total of 1904 consensus QTL accounting for 22 traits, including 80 QTL directly affecting seed yield, were anchored to the B. napus reference sequence. Through trait association analysis and QTL meta-analysis, we identified a total of 525 indivisible QTL that either directly or indirectly contributed to seed yield, of which 295 QTL were detected across multiple environments. A majority (81.5%) of the 525 QTL were pleiotropic. By considering associations between traits, we identified 25 yield-related QTL previously ignored due to contrasting genetic effects, as well as 31 QTL with minor complementary effects. Implementation of the 525 QTL in genomic prediction models improved seed yield prediction accuracy. Dissecting the genetic and phenotypic interrelationships underlying complex quantitative traits using this method will provide valuable insights for genomics-based crop improvement.


T lymphocytes sense antigens within seconds and make a decision within one minute.
Adaptive immune responses are triggered by the rapid and sensitive detection of MHC-bound peptides by TCRs. The kinetics of early TCR/APC contacts are incompletely known. In this study, we used total internal reflection fluorescence microscopy to image human T cell membranes near model surfaces: contact was mediated by mobile protrusions of <0.4 μm diameter. The mean lifetime of contacts with a neutral surface was 8.6 s. Adhesive interactions increased mean contact time to 27.6 s. Additional presence of TCR ligands dramatically decreased contact to 13.7 s, thus evidencing TCR-mediated triggering of a pulling motion within seconds after ligand encounter. After an interaction typically involving 30-40 contacts formed during a 1-min observation period, TCR stimulation triggered a rapid and active cell spreading. Pulling events and cell spreading were mimicked by pharmacological phospholipase Cγ1 activation, and they were prevented by phospholipase Cγ1 inhibition. These results provide a quantitative basis for elucidating the earliest cell response to the detection of foreign Ags.


Women of valor: post-traumatic stress disorder in the dental practice.
Dental professionals can intervene in head, neck and facial pain found in female patients who suffer from post-traumatic stress disorder (PTSD). There are three theories for why women are predisposed to pain: hormonal differences, nervous system rewiring and sympathetic issues. This article includes case studies of three patients who are representative of these theories. A rapid, nonintrusive intervention will also be described.


[Effects of cell malignant transformation induced by benzo[a]pyrene on DNA methylation transferases].
To investigate the expression level and enzymatic activity of DNA methylation transferases (dnmts) in mouse embryonic fibroblast malignant transformed cells induced by benzopyrene (B[a]P). Two kinds of cell lines, pol beta wild-type cells (pol beta +/+) and malignant transformation cells induced by BaP (pol beta-T) were applied as cellular models. Pol beta +/+ cells were served as controls, RT-PCR and Western blot were used to measure the change of dnmts expression level in malignant transformation cells induced by BaP. The enzymatic activity of DNMTs was also detected with DNA methyltransferase (DNMT) activity/inhibition assay kit. The mRNA and protein expression levels of dnmt1 and dnmt3b in pol beta-T cells (0.940 +/- 0.033 and 0.905 +/- 0.062) were much higher than that in pol beta +/+ cells (0.560 +/- 0.031 and 0.666 +/- 0.041), however the expression level of dnmt3a had no difference between these two cell lines. On the contrary, the enzymatic activity level of DNMTs in pol beta-T cells ((329.48 +/- 52.11) OD x h(-1) x mg(-1)) was much lower than that in pol beta +/+ cells ((253.70 +/- 20.56) OD x h(-1) x mg(-1)). The over expression of dnmt1 and dnmt3b and the change of DNMTs activity may be contribute to the cell malignant transformation process induced by BaP.


Phenolics and Terpenoids; the Promising New Search for Anthelmintics: A Critical Review.
Ailments caused by helminth parasites are global causing different types of clinical complications with permanent and long term morbidity in humans. Although huge advances have been made in medical sciences the effectiveness of available anthelmintics are still quite limited. Starting from the 50's, most importance was given to synthetic compounds for developing remedies from them, however, the traditional knowledge of medicine of different countries continued to provide us clues against this widespread health problem. Natural products or structural analogs with diverse structures are always been the major sources for discovering new therapeutics and in recent past different active compounds have also been identified form these plant sources having anthelmintic properties. Although compounds of diverse chemical nature and classes were identified most active ones belong to either phenol or terpene in broad chemical nature. The mechanism of action of these phytotherapeutics is usually multi-targeted and can act against the helminth parasites through diverse spectrum of activities. In this reviewwe summarized the effective anthelmintics belong to either phenolics or terpenoids and highlighted the major way of their effectiveness. This also highlights the recent development of new therapeutic strategies against helminth parasites in the light of recent advances of knowledge. In addition, developing efficient strategies to promote apoptosis and disturbing redox status in them by natural products can provide us a clue in antifilarial drug developmental research and crucial unmet medical need.


Bacterial classification of fish-pathogenic Mycobacterium species by multigene phylogenetic analyses and MALDI Biotyper identification system.
Mycobacterium marinum is difficult to distinguish from other species of Mycobacterium isolated from fish using biochemical methods. Here, we used genetic and proteomic analyses to distinguish three Mycobacterium strains: M. marinum strains MB2 and Europe were isolated from tropical and marine fish in Thailand and Europe, and Mycobacterium sp. 012931 strain was isolated from yellowtail in Japan. In phylogenetic trees based on gyrB, rpoB, and Ag85B genes, Mycobacterium sp. 012931 clustered with M. marinum strains MB2 and Europe, but in trees based on 16S rRNA, hsp65, and Ag85A genes Mycobacterium sp. 012931 did not cluster with the other strains. In proteomic analyses using a Bruker matrix-assisted laser desorption ionization Biotyper, the mass profile of Mycobacterium sp. 012931 differed from the mass profiles of the other two fish M. marinum strains. Therefore, Mycobacterium sp. 012931 is similar to M. marinum but is not the same, suggesting that it could be a subspecies of M. marinum.


Spatial-temporal survey and occupancy-abundance modeling to predict bacterial community dynamics in the drinking water microbiome.
Bacterial communities migrate continuously from the drinking water treatment plant through the drinking water distribution system and into our built environment. Understanding bacterial dynamics in the distribution system is critical to ensuring that safe drinking water is being supplied to customers. We present a 15-month survey of bacterial community dynamics in the drinking water system of Ann Arbor, MI. By sampling the water leaving the treatment plant and at nine points in the distribution system, we show that the bacterial community spatial dynamics of distance decay and dispersivity conform to the layout of the drinking water distribution system. However, the patterns in spatial dynamics were weaker than those for the temporal trends, which exhibited seasonal cycling correlating with temperature and source water use patterns and also demonstrated reproducibility on an annual time scale. The temporal trends were driven by two seasonal bacterial clusters consisting of multiple taxa with different networks of association within the larger drinking water bacterial community. Finally, we show that the Ann Arbor data set robustly conforms to previously described interspecific occupancy abundance models that link the relative abundance of a taxon to the frequency of its detection. Relying on these insights, we propose a predictive framework for microbial management in drinking water systems. Further, we recommend that long-term microbial observatories that collect high-resolution, spatially distributed, multiyear time series of community composition and environmental variables be established to enable the development and testing of the predictive framework. Safe and regulation-compliant drinking water may contain up to millions of microorganisms per liter, representing phylogenetically diverse groups of bacteria, archaea, and eukarya that affect public health, water infrastructure, and the aesthetic quality of water. The ability to predict the dynamics of the drinking water microbiome will ensure that microbial contamination risks can be better managed. Through a spatial-temporal survey of drinking water bacterial communities, we present novel insights into their spatial and temporal community dynamics and recommend steps to link these insights in a predictive framework for microbial management of drinking water systems. Such a predictive framework will not only help to eliminate microbial risks but also help to modify existing water quality monitoring efforts and make them more resource efficient. Further, a predictive framework for microbial management will be critical if we are to fully anticipate the risks and benefits of the beneficial manipulation of the drinking water microbiome.


Gonadotropin modulation of interleukin-1 secretion.
To determine the influence of pituitary gonadotropins, which increase dramatically in concentration at ovulation and in the early years of the postmenopausal transition, on inflammatory cytokine production. Cross-sectional population sampling, in vitro experimentation. Healthy subjects, including six men, five women between the ages of 18 and 35 years, and four women who were four to 20 years past menopause. Isolated peripheral blood mononuclear cells were incubated with physiological concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The concentrations of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) secreted into the supernatants were measured by enzyme-linked immunosorbent assays. Under basal conditions, FSH stimulated IL-1 beta secretion by cells isolated from women in the follicular phase. Under conditions of cellular activation with bacterial lipopolysaccharide, FSH and LH interacted to inhibit IL-1 beta secretion by cells isolated from all groups. The gonadotropins had no significant influence on IL-6 secretion regardless of donor group or cellular activation state. The results of this study support the concept that gonadotropins may contribute to the changes in IL-1 beta secretion that occur at the periovulatory and postmenopausal periods.


[Changes of parameters of the central hemodynamics during general surgeries in patients with continuous electrocardiostimulation].
Investigations of the central-hemodynamics parameters made in 23 patients with constant pace making showed a hypokinetic blood circulation type in 17 of them. It was during a narcosis-assisted laparoscopic cholecystectomy, that a general trend was pointed out towards essentially changing parameters of the central hemodynamics for the worse; that was more pronounced, when carboxyperitomium was applied, when the patients was positioned in Fovler's posture or when he (or she) was turned to the left side. In herniotomy and in plasty of the anterior abdominal wall, made with epidural anesthesia, changes occurred mostly in the on-side posture and in introduction of naropin test-doses as well as in 30 minutes after anesthesia was over. There was a need, in a number of cases, to reprogram the pacemaker and to get the inotropic support in order to correct the hemodynamic shifts.


Specificity study of kits for detection of group A streptococci directly from throat swabs.
A total of 78 Streptococcus strains, 15 Staphylococcus strains, and 2 Stomatococcus strains were used to test the specificity of 18 different antigen detection systems for group A streptococci and five products that detect a specific enzyme associated with group A streptococci. All streptococcal strains possessing the group A antigen were correctly identified with 31 different lots of reagents in the 18 antigen detection systems. The specificities of the 31 different lots of reagents ranged between 88.5 and 100%. A limited number of nonspecific reactions were observed with Enterococcus gallinarium, group C Streptococcus strain C23, and Staphylococcus aureus F49 and Cowan 1. The antigen detection kits that used enzymes as the extraction reagent gave slightly more specific results than did the kits that used chemical extraction reagents. The reagents in the five kits designed to detect the enzyme pyroglutamic acid arylamidase in Streptococcus pyogenes reacted positively with S. pyogenes (group A streptococcus); however, the reagents also reacted positively with all group D enterococcal streptococci and with about half of the staphylococcal strains treated. The nonspecificity of tests based on pyroglutamic acid arylamidase detection would seem to limit the usefulness of these kits with mixed cultures.


Nanofluids research: key issues.
Nanofluids are a new class of fluids engineered by dispersing nanometer-size structures (particles, fibers, tubes, droplets) in base fluids. The very essence of nanofluids research and development is to enhance fluid macroscopic and megascale properties such as thermal conductivity through manipulating microscopic physics (structures, properties and activities). Therefore, the success of nanofluid technology depends very much on how well we can address issues like effective means of microscale manipulation, interplays among physics at different scales and optimization of microscale physics for the optimal megascale properties. In this work, we take heat-conduction nanofluids as examples to review methodologies available to effectively tackle these key but difficult problems and identify the future research needs as well. The reviewed techniques include nanofluids synthesis through liquid-phase chemical reactions in continuous-flow microfluidic microreactors, scaling-up by the volume averaging and constructal design with the constructal theory. The identified areas of future research contain microfluidic nanofluids, thermal waves and constructal nanofluids.


Cytochrome p450 gene variants, race, and mortality among clopidogrel-treated patients after acute myocardial infarction.
Clopidogrel is recommended after acute myocardial infarction but has variable efficacy and safety, in part related to the effect of cytochrome P450 (CYP) polymorphisms on its metabolism. The effect of CYP polymorphisms on cardiovascular events among clopidogrel-treated patients after acute myocardial infarction remains controversial, and no studies to date have investigated the association of CYP variants with outcomes in black patients. Subjects (2732: 2062 whites; 670 blacks) hospitalized with acute myocardial infarction enrolled in the prospective, multicenter TRIUMPH study were genotyped for CYP polymorphisms. The majority of whites (79%) and blacks (64.4%) were discharged on clopidogrel. Among whites, carriers of the loss-of-function CYP2C19*2 allele had significantly increased 1-year mortality (adjusted hazards ratio [HR]: 1.70; confidence interval [CI]: 1.01-2.86; P=0.046) and a trend toward increased rate of recurrent MI (adjusted HR: 2.10; CI: 0.95-4.63; P=0.066). Among blacks, increased 1-year mortality was associated with the gain-of-function CYP2C19*17 allele (adjusted HR for *1/*17 versus *1/*1: 2.02; CI: 0.92-4.44; *17/*17 versus *1/*1: 8.97; CI: 3.34-24.10; P<0.0001) and the CYP1A2*1C allele (adjusted HR for *1/*1C versus *1/*1: 1.89; CI: 0.85-4.22; *1C/*1C versus *1/*1: 4.96; CI: 1.69-14.56; P=0.014). Bleeding events were significantly more common among black carriers of CYP2C19*17 or CYP1A2*1C. Both loss-of-function and gain-of-function CYP polymorphisms affecting clopidogrel metabolism are associated with increased mortality among clopidogrel-treated patients after acute myocardial infarction; the specific polymorphism and the putative mechanism vary according to race.


Microsurgical keyhole approach for middle fossa arachnoid cyst fenestration.
The optimal surgical treatment for symptomatic temporal arachnoid cysts is controversial. Therapeutic options include cyst shunting, endoscopic fenestration, and craniotomy for fenestration. We reviewed the results for patients who were treated primarily with craniotomy and fenestration at our institution, to provide a baseline for comparisons of the efficacies of other treatment modalities. A retrospective review of data for 50 children who underwent keyhole craniotomy for fenestration of temporal arachnoid cysts between 1994 and 2001 was performed after institutional review board approval. During that period, the first-line treatment for all symptomatic middle fossa arachnoid cysts was microcraniotomy for fenestration. Microsurgical dissection to create communications between the cyst cavity and basal cisterns was the goal. All patient records were reviewed and numerous variables related to presentation, cyst size and classification, treatment, cyst resolution, symptom resolution, follow-up periods, and cyst outcomes were recorded. Fifty temporal arachnoid cysts in 50 treated patients were identified. The average age at the time of surgery was 68 +/- 57.2 months. The follow-up periods averaged 36 months. There were 34 male and 16 female patients in the series. Twenty-six cysts were on the left side. Indications for surgery included intractable headaches (45%), increasing cyst size (21%), seizures (25%), and hemiparesis (8%). The symptoms most likely to improve were hemiparesis (100%) and abducens nerve palsies. Headaches (67%) and seizure disorders (50%) were less likely to improve. Nine patients exhibited progressive increases in cyst size in serial imaging studies. Those patients were monitored for a mean of 40 +/- 23 months before intervention. In the entire series, 82% of patients demonstrated decreases in cyst size in serial imaging studies. Of those patients, 18% demonstrated complete cyst effacement. Overall, 83% of patients with Grade II cysts and 75% of patients with Grade III cysts exhibited evidence of decreases in cyst size in long-term monitoring. Two patients required shunting after craniotomy (4%). Hospital stays averaged 3.4 days. Total surgical times averaged 115 minutes. No significant blood loss occurred (5-50 ml). Complications included spontaneously resolving pseudomeningocele (10%), transient Cranial Nerve III palsy (6%), cerebrospinal fluid leak (6%), subdural hematoma (4%), and wound infection (2%). A microsurgical keyhole approach to arachnoid cyst fenestration is a safe effective method for treating middle fossa cysts. This procedure can be performed with minimal morbidity via a minicraniotomy. Compared with an endoscopic approach, better control of hemostasis can be obtained, because of the ability to use bipolar forceps and other standard instruments. The operative time and length of hospital stay were not excessively increased.


First principles study on spin and orbital magnetism of 3d transition metal monatomic nanowires (Mn, Fe and Co).
We have demonstrated the electronic structure and magnetic properties of 3d transition metal nanowires (Mn, Fe and Co) in the framework of relativistic density functional theory. The equilibrium bond lengths were optimized using the generalized gradient approximation. In a full relativistic regime individual spin and orbital moments induced from spin polarization via spin-orbit coupling were calculated. In order to get an upper estimate for orbital moments, we used an orbital polarization correction to our exchange-correlation functional. We found that the orbital magnetic moments of Fe and Co linear chains are strongly enhanced in the presence of an orbital polarization correction. We have calculated the exchange coupling parameters between two nearest-neighbor magnetic atoms according to a Heisenberg-like model in the presence of the orbital polarization correction. We found that the Co and Fe nanowires behave like a ferromagnetic linear chain whereas a Mn monatomic nanowire remains antiferromagnetic.


Construction and Characterization of a Gradient Strength Promoter Library for Fine-Tuned Gene Expression in Bacillus licheniformis.
Bacillus licheniformis DW2 is an important industrial strain for bacitracin production, and it is also used for biochemical production, however, the lack of effective toolkit for precise regulation of gene expression hindered its application seriously. Here, a gradient strength promoter library was constructed based on bacitracin synthetase gene cluster promoter PbacA. First, different PbacA promoter variants were constructed via coupling PbacA with various 5'-UTRs, and expression ranges of 32.6-741.8% were attained among these promoters. Then, three promoters, PUbay (strong), PbacA (middle), and PUndh (weakest), were applied for red fluorescent protein (RFP) and keratinase expression assays, and these promoters were proven to have good universality for different proteins. Second, the promoter of bacitracin synthetase gene cluster was replaced by these three promoters, and bacitraicn titer was enhanced by 14.62% when PUbay was applied, which was decreased by 98.05% under the mediation of PUndh compared with that of the original strain DW2. Third, promoters PUbay, PUyvgO, and PUndh were selected to regulate the expression levels of critical genes that are responsible for pucheriminic acid synthesis, and pucheriminic acid yield was increased by 194.1% via manipulating synthetic and competitive pathways. Finally, promoters PUbay, PbacA, and PUndh were applied for green fluorescent protein (GFP) and RFP expression in Escherichia coli, and consistent effects were attained based on our results. Taken together, a gradient strength promoter library was constructed in this research, which provided an effective toolkit for fine-tuning gene expression and reprogramming metabolite metabolic flux in B. licheniformis.


Narrow- versus Broad-Spectrum Antibiotics for Simple Acute Appendicitis Treated by Appendectomy: A Post Hoc Analysis of EAST MUSTANG Study.
We sought to compare the effectiveness of narrow- versus broad-spectrum antibiotics (abx) in preventing infectious complications in adults with acute appendicitis treated with appendectomy. In this post hoc analysis of a prospective multicenter observational study of appendicitis in adults (≥18 y) conducted from January 2017 to June 2018, we included only patients with simple appendicitis. Subjects were grouped based on receipt of broad-spectrum or narrow-spectrum abx before and/or after appendectomy. Outcomes compared were surgical site infection, intra-abdominal abscess, secondary interventions (percutaneous drainage or operation), emergency department (ED) visits, 30-d readmission, and hospital length of stay. A total of 2336 subjects were analyzed. In comparing narrow (n = 778) versus broad (n = 1558) groups, there were no differences in male sex (53% versus 54%, P = 0.704), white blood cell (13.0 ± 3.9 versus 13.4 ± 4.5, P = 0.05), Alvarado score (6 [5-7] versus 6 [5-7], P = 0.25), or Charlson comorbidity index (0 [0-1] versus 0 [0-1], P = 0.09). A total of 688 (29%) received postoperative abx, [184 (24%) narrow and 504 (32%) broad, P < 0.001] for a median 5 [2-7] d [42 (23%) narrow and 235 (47%) broad, P < 0.001]. There were no significant differences between narrow and broad groups in surgical site infection, intra-abdominal abscess, secondary interventions, ED visits, or hospital readmissions. Significant practice variation in duration and spectrum of antibiotic adjunct for surgical treatment of simple acute appendicitis treatment is evident, and broad-spectrum abx did not offer clinical advantages over narrow-spectrum abx. Restriction of antibiotic spectrum should be considered, although randomized trials are required to overcome selection bias.


Fc receptor(s) induced by human cytomegalovirus bind differentially with human immunoglobulin G subclasses.
The IgG subclass specificity of Fc receptor(s) induced on cells by infection with human cytomegalovirus (HCMV) was studied in a binding assay by using infected cells and purified iodinated IgG of various subclasses from HCMV seronegative healthy adult donors. All four human IgG subclasses bound to HCMV-infected cells, with the following relative magnitudes: IgG1 greater than or equal to IgG4 greater than IgG2 greater than IgG3. The IgG subclass specificity of the Fc receptor was further analysed in an inhibition assay by using fragments prepared from purified human IgG by papain digestion, and using unlabelled subclass proteins. Fc but not Fab fragments inhibited the binding of 125I-labelled human IgG to HCMV-infected cells. The biological role of the Fc receptor in HCMV infection is discussed.


Difficulties with the conceptualization and assessment of Criterion A in the DSM-5 alternative model of personality disorder: A reply to Morey (2019).
The DSM-5 introduced an alternative model of personality disorders that is predicated on the presence of personality dysfunction (Criterion A) and pathological personality traits (Criterion B). Recently, a member of the DSM-5 Personality and Personality Disorder Work Group-Morey-published a measure of Criterion A. Our study (Sleep, Lynam, Widiger, Crowe, & Miller, 2019, this issue) examined the performance of Morey's (2017) Levels of Personality Functioning Scale-Self-Report (LFPS-SR) by testing its factor structure, relations with Axis I and II symptoms, and its incremental validity in predicting traditional personality disorders in comparison to Criterion B traits. In his response, Morey raised a number of issues regarding our examination of the LPFS-SR in relation to its factor structure, discriminant validity, and incremental validity. Moreover, he suggested our approach (i.e., pitting Criterion A vs. B) is emblematic of problems in the field that contributed to the relegating of the AMPD to Section III (on emerging measures and models). In our response, we answer his criticisms. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Delusions and Hallucinations Are Associated With Greater Severity of Delirium.
The 3 core domains of delirium (cognitive, higher level thinking, circadian) do not include the less common noncore psychotic symptoms. However, psychosis might inform about perturbations of neural circuitry, outcomes, or suggest tailored clinical management. We assessed relationships between psychosis and other characteristics of delirium in patients without dementia or antipsychotics treatment. Cross-sectional analysis of 366 adults with delirium per the Delirium Rating Scale Revised-98, whose items distinguish hallucinations and delusions from other types of misperceptions and abnormal thought content, assessed during the preceding 24 hours to capture symptom severity fluctuation. The relationship of psychosis with other delirium characteristics was assessed using bivariate comparisons and analysis of variance as appropriate for groups with no psychosis and any psychosis (hallucinations and/or delusions), and subgroups with only hallucinations, only delusions, or both. A discriminant logistic model assessed variables associated with presence of any psychotic features versus none. Delirium with any psychotic features occurred in 44.5% (163 of 366). Of the 366, 119 (32.5%) had only hallucinations (Hall), 14 (3.8%) had only delusions (Del), and 30 (8.2%) had both (Both). In the psychotic group (n = 163), 73.0% were Hall, 8.6% Del, and 18.4% Both. All psychotic patient groupings had significantly greater delirium severity on the Delirium Rating Scale Revised-98. Delusions and hallucinations were discordant for occurring together. The discriminant model found increased odds of having psychosis as 3 symptom severities increased (visuospatial ability, thought process, and sleep-wake cycle) where these each represented a delirium core domain. The noncore symptom of lability of affect had high odds ratio for psychosis, while motor retardation reduced odds of psychosis in this model. Consistent with prior reports, psychosis occurred in less than half of delirious patients with delusions being infrequent, and an association with affective lability was found. Given that previous functional magnetic resonance imaging research found a correlation between neural network dysconnectivity with greater severity of delirium, psychotic symptoms might be a clinical marker for greater underlying cerebral cortical neural circuitry dysfunction.


New developments and opportunities in oral mucosal drug delivery for local and systemic disease.
The oral mucosa's accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.


Aligning incentives in supply chains.
Most companies don't worry about the behavior of their supply chain partners. Instead, they expect the supply chain to work efficiently without interference, as if guided by Adam Smith's famed invisible hand. In their study of more than 50 supply networks, V.G. Narayanan and Ananth Raman found that companies often looked out for their own interests and ignored those of their network partners. Consequently, supply chains performed poorly. Those results aren't shocking when you consider that supply chains extend across several functions and many companies, each with its own priorities and goals. Yet all those functions and firms must pull in the same direction for a chain to deliver goods and services to consumers quickly and cost-effectively. According to the authors, a supply chain works well only if the risks, costs, and rewards of doing business are distributed fairly across the network. In fact, misaligned incentives are often the cause of excess inventory, stock-outs, incorrect forecasts, inadequate sales efforts, and even poor customer service. The fates of all supply chain partners are interlinked: If the firms work together to serve consumers, they will all win. However, they can do that only if incentives are aligned. Companies must acknowledge that the problem of incentive misalignment exists and then determine its root cause and align or redesign incentives. They can improve alignment by, for instance, adopting revenue-sharing contracts, using technology to track previously hidden information, or working with intermediaries to build trust among network partners. It's also important to periodically reassess incentives, because even top-performing networks find that changes in technology or business conditions alter the alignment of incentives.


Influence of the hippocampus on interneurons of the rat prefrontal cortex.
The hippocampus and prefrontal cortex (PFC), two structures implicated in learning and memory processes, are linked by a direct hippocampo-prefrontal pathway. It has been shown that PFC pyramidal cells receive monosynaptic excitatory inputs from the hippocampus and, in this study, we sought to determine the influence of the hippocampus on PFC interneurons in anesthetized rats. Extracellular recordings were coupled to juxtacellular injections of neurobiotin or biotinylated dextran amine to morphologically differentiate interneurons from pyramidal cells. In all cases, the action potentials of labeled interneurons were of shorter duration (< 0.70 ms) than those of identified pyramidal cells (> 0.70 ms). Single pulse stimulation of the hippocampal CA1/subiculum region induced an excitatory response in 70% of recorded interneurons in the prelimbic and medial-orbital areas of the PFC. In contrast to the one to two action potentials generated by pyramidal cells, an important group of interneurons fired a burst of action potentials in response to hippocampal stimulation. A large proportion of these excitatory responses was probably monosynaptic as their latency is consistent with the conduction time of the hippocampo-prefrontal pathway. In addition, when both a pyramidal cell and an interneuron were simultaneously recorded and both responded to stimulation, the interneuron consistently fired before the pyramidal cell. In conclusion, the hippocampus exerts a direct excitatory influence on PFC interneurons and is thus capable of feedforward inhibition of pyramidal cells. Hippocampal output is spatially and temporally focalized via this inhibitory process and consequently could facilitate the synchronization of a specific subset of PFC neurons with hippocampal activity.


High-Performance Oxide-Based p-n Heterojunctions Integrating p-SnOx and n-InGaZnO.
The fabrication of oxide-based p-n heterojunctions that exhibit high rectification performance has been difficult to realize using standard manufacturing techniques that feature mild vacuum requirements, low thermal budget processing, and scalability. Critical bottlenecks in the fabrication of these heterojunctions include the narrow processing window of p-type oxides and the charge-blocking performance across the metallurgical junction required for achieving low reverse current and hence high rectification behavior. The overarching goal of the present study is to demonstrate a simple processing route to fabricate oxide-based p-n heterojunctions that demonstrate high on/off rectification behavior, a low saturation current, and a small turn-on voltage. For this study, room-temperature sputter-deposited p-SnOx and n-InGaZnO (IGZO) films were chosen. SnOx is a promising p-type oxide material due to its monocationic system that limits complexities related to processing and properties, compared to other multicationic oxide materials. For the n-type oxide, IGZO is selected due to the knowledge that postprocessing annealing critically reduces the defect and trap densities in IGZO to ensure minimal interfacial recombination and high charge-blocking performance in the heterojunctions. The resulting oxide p-n heterojunction exhibits a high rectification ratio greater than 103 at ±3 V, a low saturation current of ∼2 × 10-10 A, and a small turn-on voltage of ∼0.5 V. In addition, the demonstrated oxide p-n heterojunctions exhibit excellent stability over time in air due to the p-SnOx with completed reaction annealing in air and the reduced trap density in n-IGZO.


CNS putative L-prolyl-L-leucyl-glycinamide (PLG) receptors, brain and lymphocyte dopamine receptors.
1. In view of previously demonstrated modulatory effects of PLG on the sensitivity of central dopamine receptors, we developed a radioligand binding assay to identify specific binding sites of PLG in rat and normal human brain. 2. 3H-PLG binds specifically to rat striatum exhibiting high affinity (KD = 4.69 +/- 0.50 nM) saturability (Bmax = 9.20 +/- 0.30 fmoles/mg protein) and reversibility; the highest density of specific PLG binding sites occurring in the striatum, followed by the hypothalamus and cerebral cortex. 3. Saturable, high-affinity binding sites of PLG were identified in human striatum. The substantia nigra was enriched with the highest level of specific PLG binding sites. 4. Dopamine receptors were identified in human lymphocytes. 5. The results are compatible with the hypothesis that differential modulation of CNS dopamine receptors by PLG is functionally associated with interacting with specific PLG binding sites in the rat and human brain, and pose implications for Parkinson's disease and tardive dyskinesia.


Atenolol exposure and risk for development of adverse metabolic effects: a pilot study.
To evaluate whether the level of systemic exposure to atenolol explains observed interindividual differences in adverse metabolic responses. Open-label, prospective, pharmacokinetic pilot substudy of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. General clinical research center. Fifteen hypertensive adults (mean age 46 +/- 8.9 yrs) who were enrolled in the PEAR study. Patients received atenolol therapy for at least 8 weeks, with 5 of those weeks at a dosage of 100 mg/day, and then underwent a 2-hour oral glucose tolerance test during a pharmacokinetic study visit. Twenty-hour plasma atenolol concentrations were measured during the pharmacokinetic visit. Glucose and insulin levels were measured during the 2-hour oral glucose tolerance test, and fasting plasma lipid, glucose, and insulin levels were measured at baseline and after 8 weeks of atenolol treatment. A significant association was noted between atenolol area under the concentration-time curve (AUC) and change in fasting glucose level when adjusted for covariates (p=0.0025); the effect was strongest in women. No significant relationship was noted between plasma atenolol concentration and glucose AUC during oral glucose tolerance testing (r=0.08, p=0.78), nor between atenolol AUC and change in triglyceride levels (r=0.13, p=0.63). Higher plasma atenolol exposure may be a risk factor for an increase in fasting plasma glucose level during atenolol treatment. These findings require confirmation in a larger sample.


The effect of biosynthetic human proinsulin on the hepatic response to glucagon in insulin-deficient diabetes.
The relative tissue specificities of biosynthetic human proinsulin and porcine insulin were compared in eight insulin-deficient diabetic patients. Variable proinsulin and insulin infusions were administered iv for at least 18 h on separate occasions to achieve euglycemia. Once equivalence with respect to this end point was established, the paired infusions were made constant and compared with respect to their effect on plasma glucose, hepatic glucose output (Ra), glucose utilization, glucose clearance, and blood beta-hydroxybutyrate, alanine, and glycerol in response to a glucagon infusion (3 ng/kg X min). Basal Ra did not differ between euglycemia established using proinsulin vs. insulin [1.92 +/- 0.12 vs. 1.65 +/- 0.07 mg/kg X min] when data were analyzed by multivariate analysis of variance; likewise, the increment in Ra in response to glucagon infusion did not differ between the two treatments (1.26 +/- 0.22 vs. 1.17 +/- 0.24 mg/kg X min). Blood beta OHB, alanine, and glycerol also did not differ between the insulin and proinsulin treatments. Under these conditions of prolonged infusion in which the differences in clearance properties between proinsulin and insulin do not play a role and which maintain basal euglycemia, the two compounds equally limit the response to a stimulus to hepatic glucose production. Under nonsteady state conditions, when the differences in clearance rates are operative, proinsulin may have relatively greater effects on Ra than do doses of insulin that are biologically equivalent after prolonged infusions.