Neuroscience and learning: implications for teaching practice.
Although neuroscience studies have provided us with an increasingly detailed picture of the basis for learning and memory, very little of this information has been applied within the area of teaching practice. We suggest that a better understanding of neuroscience may offer significant advantages for educators. In this context, we have considered recent studies in the neuroscience of learning and memory, with particular emphasis on working and semantic memory, and also suggest that neuroscience research into self-referential networks may improve our understanding of the learning process. Finally, we propose that advances in understanding the neural basis for metacognition may encourage the development of new perspectives that may help us to motivate students to learn about their own learning processes.


Mitochondrial Structure and Function in the Metabolic Myopathy Accompanying Patients with Critical Limb Ischemia.
Mitochondrial dysfunction has been implicated as a central mechanism in the metabolic myopathy accompanying critical limb ischemia (CLI). However, whether mitochondrial dysfunction is directly related to lower extremity ischemia and the structural and molecular mechanisms underpinning mitochondrial dysfunction in CLI patients is not understood. Here, we aimed to study whether mitochondrial dysfunction is a distinctive characteristic of CLI myopathy by assessing mitochondrial respiration in gastrocnemius muscle from 14 CLI patients (65.3 ± 7.8 y) and 15 matched control patients (CON) with a similar comorbidity risk profile and medication regimen but without peripheral ischemia (67.4 ± 7.4 y). Furthermore, we studied potential structural and molecular mechanisms of mitochondrial dysfunction by measuring total, sub-population, and fiber-type-specific mitochondrial volumetric content and cristae density with transmission electron microscopy and by assessing mitophagy and fission/fusion-related protein expression. Finally, we asked whether commonly used biomarkers of mitochondrial content are valid in patients with cardiovascular disease. CLI patients exhibited inferior mitochondrial respiration compared to CON. This respiratory deficit was not related to lower whole-muscle mitochondrial content or cristae density. However, stratification for fiber types revealed ultrastructural mitochondrial alterations in CLI patients compared to CON. CLI patients exhibited an altered expression of mitophagy-related proteins but not fission/fusion-related proteins compared to CON. Citrate synthase, cytochrome c oxidase subunit IV (COXIV), and 3-hydroxyacyl-CoA dehydrogenase (β-HAD) could not predict mitochondrial content. Mitochondrial dysfunction is a distinctive characteristic of CLI myopathy and is not related to altered organelle content or cristae density. Our results link this intrinsic mitochondrial deficit to dysregulation of the mitochondrial quality control system, which has implications for the development of therapeutic strategies.


The relationship between cesarean delivery and gestational age among US singleton births.
The increasing trend of delivering at earlier gestational ages has raised concerns of the impact on maternal and infant health. The delicate balance of the risks and benefits associated with continuing a pregnancy versus delivering early remains challenging. Among singleton live births in the United States, the proportion of preterm births increased from 9.7% to 10.7% between 1996 and 2004. The increase in singleton preterm births occurred primarily among those delivered by cesarean section, with the largest percentage increase in late preterm births. For all maternal racial/ethnic groups, singleton cesarean section rates increased for each gestational age group. Singleton cesarean section rates for non-Hispanic black women increased at a faster pace among all preterm gestational age groups compared with non-Hispanic white and Hispanic women. Further research is needed to understand the underlying reasons for the increase in cesarean section deliveries resulting in preterm birth.


Serological and structural analysis of HLA class I molecules: beta 2-microglobulin interacts with the two external domains of the HLA class I heavy chain.
The serological reactivities of HLA class I molecules were studied in relation to structural modifications of these molecules, including shuffling of external exons and exchange of human beta 2-microglobulin for beta 2-microglobulin from different species. Two major clusters (I and II) of monomorphic and polymorphic antigenic determinants could be delineated. beta 2-Microglobulin participates in the formation of the two clusters, indicating that the light chain interacts tightly with the two external domains of the HLA class I heavy chain. However, external molecules can modify these interactions and alter the antigenic structure of the overall molecule. Thus, fixation on HLA class I molecules of the Fab fragment of a monoclonal antibody directed at antigenic determinants associated with cluster II resulted in enhanced fixation of a monoclonal antibody (B10.6) related to cluster I. The structural and functional implications of these results are discussed.


A novel B cell-mediated transport of IgE-immune complexes to the follicle of the spleen.
Ag administered i.v. to mice along with specific IgE or IgG2a induces higher Ab- and CD4(+) T cell responses than Ag administered alone. The IgE effect is completely dependent on the low-affinity receptor for IgE, CD23, whereas the IgG2a effect depends on activating FcgammaRs. In vitro studies suggest that IgE/Ag is presented more efficiently than Ag alone to CD4(+) T cells by CD23(+) B cells and that IgG2a/Ag is presented by FcgammaR(+) dendritic cells (DCs). In this study, we investigate in vivo the early events leading to IgE- and IgG2a-mediated enhancement of immune responses. OVA administered i.v. in PBS in combination with specific IgE binds circulating B cells after 5 min and is found in B cell follicles bound to follicular B cells (CD23(high)) after 30 min. This novel B cell-dependent route of entry is specific for IgE because IgG2a-Ag complexes were trapped in the marginal zone. OVA-specific CD4(+) T cells were found at the T-B border in the T cell zones 12 h after immunization both with IgE/OVA or IgG2a/OVA and proliferated vigorously after 3 days. The findings suggest that IgE- and IgG2a-immune complexes are efficient stimulators of early CD4(+) T cell responses and that Ag bound to IgE has a specific route for transportation into follicles.


Small bowel obstruction following perforation of the uterus at induced abortion.
Unsafe abortion is an important contributor to maternal morbidity and mortality. To present a case of small bowel obstruction following perforation of the uterus at induced abortion. A 36-year-old woman, presented at a private hospital, with abdominal pain and weight loss. She had full clinical assessment and laboratory investigations which indicated small bowel obstruction following perforation of the uterus at induced abortion, and was commenced on treatment. She was para 5+0. Her main complaints were abdominal and weight loss following induced abortion of a 12- week pregnancy, four months prior to presentation. At presentation the tools (ultrasound scan, plain abdominal radiograph and barium enema) used for diagnoses only suggested some form of intestinal obstruction and were unremarkable. Correct diagnoses indicating small bowel obstruction was only made at laparotomy. An exploratory laparotomy, adhesiolysis, small bowel resection, end to end anastomosis and bowel decompression was done after bowel preparation. Laparotomy has an enviable place in bowel injuries secondary to uterine perforation especially when there is a diagnostic dilemma. Nigerian female population requires continuous health education on widespread and effective use of contraception. Physicians need training and retraining on abortion techniques and management of abortion complications.


Meningitis caused by Klebsiella spp in two rhesus monkeys.
Two adult, female rhesus monkeys (Macaca mulatta) became depressed, weak, anorectic, and adipsic. Auscultation of the thorax of 1 monkey revealed bilateral harsh rales. Neither monkey responded to therapeutic doses of antibiotics, and both died soon after treatment was started. Meningitis was demonstrated histologically and pure cultures of multiply antibiotic-resistant Klebsiella were isolated from the brains of both monkeys. Of 13 clinically normal rhesus monkeys in the same facility, 5 had multiply antibiotic-resistant Klebsiella spp in their pharynges.


The basal forebrain cholinergic system: efferent and afferent connectivity and long-term effects of lesions.
The first part of this article deals with several aspects of efferents and afferents of the rat basal forebrain cholinergic system (BFChS) studied with anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). PHA-L tracing of the BFChS efferents revealed topographically differentiated axonal trajectories and patterns of presynaptic endings to the neocortex, mesocortex, olfactory nuclei and hippocampus. Combining this method with second immunolabeling, we identified the muscarinic cholinoceptive neurons in the neocortex and the somatostatinergic neurons in the hippocampus as being directly innervated by the magnocellular basal nucleus and the medial septum, respectively. The prefrontal cortex was identified as a source of afferent input to the basal forebrain cholinergic neurons. This projection also exhibits a topographic organization, which shows a reciprocal relationship with the BFChS efferents to the cortex. The second part of this article describes the anatomical changes of cortical cholinergic and some other neurotransmitter systems after long-term cholinergic denervation in the aged rat cortex. The spared cholinergic projection in the largely denervated areas shows abundant malformations, which are similar in appearance to the anatomical alterations of the surviving cholinergic fibers in dementia of the Alzheimer type (AD). Hypertrophic changes also occur in the serotonergic system. The neuropeptide-Y- and somatostatin-containing cortical systems respond with an increment of their axonal densities, in contrast to the decline of these peptides in AD. Although transsynaptic effects are mediated by long-term cholinergic lesions, they do not support the hypothesis that the cholinergic deficiency is a primary event in the pathophysiology of AD.


[Excretion of aldosterone in the urine, renin activity in the plasma and some indices of the metabolism of potassium and sodium in patients with the iodiopathic edema syndrome].
It appeared that urinary aldosterone excretion was increased in 23 of 35 patients with a syndrome of idiopathic edema. The plasma renin activity failed to differ from the norm; consequently it can be supposed that the renin-angiotensin system played no significant role in the mechanism of hyperaldosteronism development in this form of pathology. A negative sodium balance was revealed in some of the patients with an edema syndrome and hyperaldosteronism.


Seroprevalence of hepatitis E in swine abattoir workers.
Hepatitis E (HE) caused by Hepatitis E virus (HEV) is an emerging global public health threat. It has been identified as potentially zoonotic and swine act as main reservoirs. The objective of this study was to determine the seroprevalence and risk factors associated with HEV in swine abattoir workers. This was a cross-sectional study where 45 workers were sampled (N=50), serum collected and tested for presence of anti HEV IgM using ELISA. A seroprevalence of 13.3% was obtained with the highest 50% among slaughterers and the lowest amongst sanitary cleaner, cloth cleaners and inspector. Those in direct contact with live pigs, their carcasses and tissues were at a higher risk compared to those in indirect contact. Seroprevalence was seen to increase with age, with the highest rate among those above 24 years. There is silent HE virus infection in abattoir workers at Wambizi as reflected by presence anti HEV IgM in 13% of the tested serum. However, no single case of HE has ever been reported in swine abattoir workers or general population in Kampala city. This silent maintenance of HEV infection amongst swine abattoir workers is an occupational risk that could challenge public health systems.


Volume of Disease as a Predictor for Clinical Outcomes in Patients With Melanoma Brain Metastases Treated With Stereotactic Radiosurgery and Immune Checkpoint Therapy.
Clinical trials of anti-Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein (CTLA-4) therapies have demonstrated a clinical benefit with low rates of neurologic adverse events in patients with melanoma brain metastases (MBMs). While the combined effect of these immunotherapies (ITs) and stereotactic radiosurgery (SRS) has yielded impressive results with regard to local control (LC) and overall survival (OS), it has also been associated with increased rates of radiation necrosis (RN) compared to historical series of SRS alone. We retrospectively reviewed patients treated with IT in combination with SRS to report on predictors of clinical outcomes. Patients were included if they had MBMs treated with SRS within 1 year of receiving anti-PD-1 and/or CTLA-4 therapy. Clinical outcomes including OS, LC, intracranial death (ID), and RN were correlated with type and timing of IT with SRS, radiation dose, total volume, and size and number of lesions treated. Twenty-nine patients with 171 MBMs were treated between May 2012 and May 2018. Patients had a median of 5 lesions treated (median volume of 6.5 cm3) over a median of 2 courses of SRS. The median dose was 21 Gy. Most patients were treated with ipilimumab (n = 13) or nivolumab-ipilimumab (n = 10). Most patients underwent SRS concurrently or within 3 months of receiving immunotherapy (n = 21). Two-year OS and LC were 54.4% and 85.5%, respectively. In addition, 14% of patients developed RN; however, only 4.7% of the total treated lesions developed RN. The median time to development of RN was 9.5 months. Patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID (p = 0.05) and RN (p = 0.03). There was no difference in OS, ID, or RN with regard to type of IT, timing of SRS and IT, number of SRS courses, SRS dose, or number of cumulative lesions treated. In our series, patients treated with SRS and IT for MBMs had excellent rates of OS and LC; however, patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID and RN. Given the efficacy of combined anti-PD-1/CTLA-4 therapy for MBM management, further study of optimal selection criteria for the addition of SRS is warranted.


[The practical application of marker -2proPSA and health index of prostate phi in diagnostics of prostate cancer].
The article demonstrates that prostate-specific antigen (PSA) has some limitations in detection of cancer of prostate. It was demonstrated that isoform of free PSA - 2proPSA has higher specificity in comparison with total PSA (tPSA) and percentage tPSA and free PSA (%free PSA) in detection of cancer of prostate. The application of Prostate Health Index including such indicators as -2PSA, free PSA and tPSA makes it possible to increase degree of detection of cancer of prostate, to increase specificity and to decrease number of optional biopsies. Besides, correlation was established between value of Prostate Health Index and degree of aggressiveness of forms of cancer of prostate.


Two types of phantom scatter correction factors (Sp) for high-energy photons.
Two types of phantom scatter correction factors (Sp) are introduced for high-energy photons. One is the traditional Sp correction factor. It is produced using the primary absorbed dose under lateral CPE (charged particle equilibrium). It usually takes a non-zero value at zero-area field. The other is produced using the actual primary absorbed dose, which fails in lateral CPE when the field is small. It takes a value of zero at zero-area field. The two types of Sp correction factors can be connected with the laterally spread primary absorbed dose (LSD).


Personal identity, enhancement and neurosurgery: a qualitative study in applied neuroethics.
Recent developments in the field of neurosurgery, specifically those dealing with the modification of mood and affect as part of psychiatric disease, have led some researchers to discuss the ethical implications of surgery to alter personality and personal identity. As knowledge and technology advance, discussions of surgery to alter undesirable traits, or possibly the enhancement of normal traits, will play an increasingly larger role in the ethical literature. So far, identity and enhancement have yet to be explored in a neurosurgical context, despite the fact that 1) neurological disease and treatment both potentially alter identity, and 2) that neurosurgeons will likely be the purveyors of future enhancement implantable technology. Here, we use interviews with neurosurgical patients to shed light on the ethical issues and challenges that surround identity and enhancement in neurosurgery. The results provide insight into how patients approach their identity prior to potentially identity-altering procedures and what future ethical challenges lay ahead for clinicians and researchers in the field of neurotherapeutics.


Discontinuous college enrollment: associations with substance use and mental health.
This study examined the prospective relationship of substance use and mental health problems with risk of discontinuous enrollment in college. Participants were 1,145 students at a large public university who were interviewed annually for four years beginning at college entry in 2004 (year 1). Discontinuous enrollment was defined as a gap in enrollment of one or more semesters during the first two years (early discontinuity) or the second two years (late discontinuity) versus continuous enrollment throughout all four years. Explanatory variables measured in year 1 were scores on the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory, childhood conduct problems, cannabis use, number of illicit drugs used, and alcohol consumption. In years 3 and 4, participants reported lifetime history of clinically diagnosed attention-deficit hyperactivity disorder, depression, and anxiety, including age at diagnosis. Multinomial logistic regression models were developed to evaluate the association between the independent variables and discontinuous enrollment while holding constant background characteristics. Higher BDI scores predicted early discontinuity but not late discontinuity, whereas cannabis and alcohol use predicted only late discontinuity. Receiving a depression diagnosis during college was associated with both early and late discontinuity. Self-reported precollege diagnoses were not related to discontinuous enrollment once background characteristics were taken into account. Students who experience depressive symptoms or seek treatment for depression during college might be at risk of interruptions in their college enrollment. Cannabis use and heavy drinking appear to add to this risk. Students entering college with preexisting psychiatric diagnoses are not necessarily at risk of enrollment interruptions.


Examination of a multi-factorial model of body-related experiences during pregnancy: the relationships among physical symptoms, sleep quality, depression, self-esteem, and negative body attitudes.
The aim of this cross-sectional study was to investigate relationships among women's body attitudes, physical symptoms, self-esteem, depression, and sleep quality during pregnancy. Pregnant women (N=215) at 15-25 weeks gestation completed a questionnaire including four body image subscales assessing self-reported feeling fat, attractiveness, strength/fitness, and salience of weight and shape. Women reported on 29 pregnancy-related physical complaints, and completed the Beck Depression Inventory, Rosenberg Self-esteem Scale, and Pittsburgh Sleep Quality Index. In regressions, controlling for retrospective reports of body image, more frequent and intense physical symptoms were related to viewing the self as less strong/fit, and to poorer sleep quality and more depressive symptoms. In a multi-factorial model extending previous research, paths were found from sleep quality to depressive symptoms to self-esteem; self-esteem was found to be a mediator associated with lower scores on feeling fat and salience of weight and shape, and on higher perceived attractiveness.


Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation.
Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored (GPI-anchored) proteins, resulting from a mutation in the X-linked gene PIGA. Here we report on a set of patients in whom PNH results instead from biallelic mutation of PIGT on chromosome 20. These PIGT-PNH patients have clinically typical PNH, but they have in addition prominent autoinflammatory features, including recurrent attacks of aseptic meningitis. In all these patients we find a germ-line point mutation in one PIGT allele, whereas the other PIGT allele is removed by somatic deletion of a 20q region comprising maternally imprinted genes implicated in myeloproliferative syndromes. Unlike in PIGA-PNH cells, GPI is synthesized in PIGT-PNH cells and, since its attachment to proteins is blocked, free GPI is expressed on the cell surface. From studies of patients' leukocytes and of PIGT-KO THP-1 cells we show that, through increased IL-1β secretion, activation of the lectin pathway of complement and generation of C5b-9 complexes, free GPI is the agent of autoinflammation. Eculizumab treatment abrogates not only intravascular hemolysis, but also autoinflammation. Thus, PIGT-PNH differs from PIGA-PNH both in the mechanism of clonal expansion and in clinical manifestations.


NS3 protease from hepatitis C virus: biophysical studies on an intrinsically disordered protein domain.
The nonstructural protein 3 (NS3) from the hepatitis C virus (HCV) is responsible for processing the non-structural region of the viral precursor polyprotein in infected hepatic cells. NS3 protease activity, located at the N-terminal domain, is a zinc-dependent serine protease. A zinc ion, required for the hydrolytic activity, has been considered as a structural metal ion essential for the structural integrity of the protein. In addition, NS3 interacts with another cofactor, NS4A, an accessory viral protein that induces a conformational change enhancing the hydrolytic activity. Biophysical studies on the isolated protease domain, whose behavior is similar to that of the full-length protein (e.g., catalytic activity, allosteric mechanism and susceptibility to inhibitors), suggest that a considerable global conformational change in the protein is coupled to zinc binding. Zinc binding to NS3 protease can be considered as a folding event, an extreme case of induced-fit binding. Therefore, NS3 protease is an intrinsically (partially) disordered protein with a complex conformational landscape due to its inherent plasticity and to the interaction with its different effectors. Here we summarize the results from a detailed biophysical characterization of this enzyme and present new experimental data.


Pathology in patients with ventricular assist devices: a study of 21 autopsies, 24 ventricular apical core biopsies and 24 explanted hearts.
Ventricular assist devices (VADs) are used as a bridge to cardiac transplantation or as a permanent or sometimes temporary treatment for end stage heart failure. Our autopsy and surgical pathology experience with VADs prior to August 2002 was reviewed. Noted were patient's age, sex, underlying (UCOD) and proximate causes of death (PCOD), duration of VAD implantation, presence of native or prosthetic valvar disease and organ complications. Myocardium from biopsies and explanted hearts were blindly assessed for coagulative necrosis (CN), contraction bands (CB), myocytolysis (MC), increased eosinophilia (IE), myocyte waviness (MW) and fibrosis (F). Each was graded as either mild (score 1), moderate (score 2) or severe (score 3). Autopsy patients: Twenty-one patients, with mean age 55 years (range 10-73), comprised 10 women and 11 men. UCOD was ischemic disease in 16 patients, dilated cardiomyopathy in 4 and aortic valve disease in 1. The mean duration of VAD implantation was 125.7 days (range 1-1095 days, S.D.=253.6). Five patients had biventricular VADs, and 16 had LVAD only. Acquired aortic valve fusion was noted in three patients. PCOD was VAD related in six, donor heart problem in four, cerebrovascular accident in four, miscellaneous in three, pulmonary hypertension in two and aortic disease in two patients. Morbidity: local liver necrosis in seven, acquired aortic valve disease in four, gut infarction in three, abdominal aortic aneurysm in two and host cell assault against VAD porcine aortic valves in one case. Biopsies and explanted hearts: Twenty-four patients had a mean age of 53 years (range 38-68, S.D.=8.6). VADs were implanted for 177.8 days (range 7-593 days, S.D.=151.1). Comparison of histologic scores of biopsies with explanted hearts showed the following: CN 1.33 (S.D.=1.4)/0.21 (S.D.=0.66; P<.001); CB: 2.1 (S.D.=0.93)/0.83 (S.D.=0.28; NS); MC: 0.88 (S.D.=1.19)/0.13 (S.D.=0.34; P<.01); IE: 1.71 (S.D.=1.27)/0.38 (S.D.=0.65; NS); fibrosis: 1.08 (S.D.=1.35)/1.75 (S.D.=1.26; NS); and MW: 1.50 (S.D.=1.22)/0.59 (S.D.=0.73; P<.01). Acquired aortic stenosis developed in six hearts, and one heart showed thrombotic occlusion of the left ventricular outflow tract below an aortic bioprosthesis. VAD significantly reduced the amount of CN, MC and MW in the left ventricle but may lead to acquired aortic stenosis of native aortic valves or total occlusive thrombosis of aortic prosthetic valves. Proximate cause of death was, most often, VAD related.


Interaction of ultraviolet laser light with the cornea.
The effect of pulsed ultraviolet (UV) laser light on the cornea depends on wavelength (photon energy), irradiance (photon flux), and pulse firing rate. At the available excimer laser wavelengths of 193, 249, 308, and 351 nanometers, the authors have varied the irradiance per pulse (10 to 2000 mj/cm2) as well a pulse frequency (1, 10, 25 Hz) and determined the thresholds for coagulation and ablation of the corneal stroma. The latter ablative action creates a groove resembling an incision and was present at all wavelengths studied. The threshold for ablation increased for longer wavelengths and lower pulse frequencies, except for 193-nm exposure, which was characterized by a constant threshold independent of laser pulse rate. The grooves at 193 nm were both biomicroscopically and histologically smooth and no coagulation effects were noted. Some degree of coagulation of adjacent tissues was noted at 249, 308, and 351 nm.


A Fully Reconfigurable Low-Noise Biopotential Sensing Amplifier With 1.96 Noise Efficiency Factor.
A fully reconfigurable biopotential sensing amplifier utilizing floating-gate transistors is presented in this paper. By using the complementary differential pairs along with the current reuse technique, the theoretical limit for the noise efficiency factor of the proposed amplifier is below 1.5. Without consuming any extra power, floating-gate transistors are employed to program the low-frequency cutoff corner of the amplifier and to implement the common-mode feedback. A concept proving prototype chip was designed and fabricated in a 0.35 μm CMOS process occupying 0.17 mm (2) silicon area. With a supply voltage of 2.5 V, the measured midband gain is 40.7 dB and the measured input-referred noise is 2.8 μVrms. The chip was tested under several configurations with the amplifier bandwidth being programmed to 100 Hz, 1 kHz , and 10 kHz. The measured noise efficiency factors in these bandwidth settings are 1.96, 2.01, and 2.25, respectively, which are among the best numbers reported to date. The measured common-mode rejection and the supply rejection are above 70 dB . When the bandwidth is configured to be 10 kHz, the dynamic range measured at 1 kHz is 60 dB with total harmonic distortion less than 0.1%. The proposed amplifier is also demonstrated by recording electromyography (EMG), electrocardiography (ECG), electrooculography (EOG), and electroencephalography (EEG) signals from human bodies.


Altered neural responses to heat pain in drug-naive patients with Parkinson disease.
Pain is a frequent but still neglected nonmotor symptom of Parkinson disease (PD). However, neural mechanisms underlying pain in PD are poorly understood. Here, we explored whether the high prevalence of pain in PD might be related to dysfunctional descending pain control. Using functional magnetic resonance imaging we explored neural responses during the anticipation and processing of heat pain in 21 PD patients (Hoehn and Yahr I-III) and 23 healthy controls (HC). Parkinson disease patients were naive to dopaminergic medication to avoid confounding drug effects. Fifteen heat pain stimuli were applied to the participants' forearm. Intensity and unpleasantness ratings were provided for each stimulus. Subjective pain perception was comparable for PD patients and HC. Neural processing, however, differed between groups: PD patients showed lower activity in several descending pain modulation regions (dorsal anterior cingulate cortex [dACC], subgenual anterior cingulate cortex, and dorsolateral prefrontal cortex [DLPFC]) and lower functional connectivity between dACC and DLPFC during pain anticipation. Parkinson disease symptom severity was negatively correlated with dACC-DLPFC connectivity indicating impaired functional coupling of pain modulatory regions with disease progression. During pain perception PD patients showed higher midcingulate cortex activity compared with HC, which also scaled with PD severity. Interestingly, dACC-DLPFC connectivity during pain anticipation was negatively associated with midcingulate cortex activity during the receipt of pain in PD patients. This study indicates altered neural processing during the anticipation and receipt of experimental pain in drug-naive PD patients. It provides first evidence for a progressive decline in descending pain modulation in PD, which might be related to the high prevalence of pain in later stages of PD.


Blood feeding activates the vitellogenic stage of oogenesis in the mosquito Aedes aegypti through inhibition of glycogen synthase kinase 3 by the insulin and TOR pathways.
Most mosquitoes, including Aedes aegypti, only produce eggs after blood feeding on a vertebrate host. Oogenesis in A. aegypti consists of a pre-vitellogenic stage before blood feeding and a vitellogenic stage after blood feeding. Primary egg chambers remain developmentally arrested during the pre-vitellogenic stage but complete oogenesis to form mature eggs during the vitellogenic stage. In contrast, the signaling factors that maintain primary egg chambers in pre-vitellogenic arrest or that activate vitellogenic growth are largely unclear. Prior studies showed that A. aegypti females release insulin-like peptide 3 (ILP3) and ovary ecdysteroidogenic hormone (OEH) from brain neurosecretory cells after blood feeding. Here, we report that primary egg chambers exit pre-vitellogenic arrest by 8 h post-blood meal as evidenced by proliferation of follicle cells, endoreplication of nurse cells, and formation of cytoophidia. Ex vivo assays showed that ILP3 and OEH stimulate primary egg chambers to exit pre-vitellogenic arrest in the presence of nutrients but not in their absence. Characterization of associated pathways indicated that activation of insulin/insulin growth factor signaling (IIS) by ILP3 or OEH inactivated glycogen synthase kinase 3 (GSK3) via phosphorylation by phosphorylated Akt. GSK3 inactivation correlated with accumulation of the basic helix-loop-helix transcription factor Max and primary egg chambers exiting pre-vitellogenic arrest. Direct inhibition of GSK3 by CHIR-99021 also stimulated Myc/Max accumulation and primary egg chambers exiting pre-vitellogenic arrest. Collectively, our results identify GSK3 as a key factor in regulating the pre- and vitellogenic stages of oogenesis in A. aegypti.


Objective Depression Detection Using EEG and Eye Movement Signals Induced by Oil Paintings.
Depression is a mental disorder characterized by persistent sadness and loss of interest, which has become one of the leading causes of disability worldwide. There are currently no objective diagnostic standards for depression in clinical practice. Previous studies have shown that depression causes both brain abnormalities and behavioral disorders. In this study, both electroencephalography (EEG) and eye movement signals were used to objectively detect depression. By presenting 40 carefully selected oil paintings-20 positive and 20 negative-as stimuli, we were able to successfully evoke emotions in 48 depressed patients (DPs) and 40 healthy controls (HCs) from three centers. We then used Transformer, a deep learning model, to conduct emotion recognition and depression detection. The experimental results demonstrate that: a) Transformer achieves the best accuracies of 89.21% and 92.19% in emotion recognition and depression detection, respectively; b) The HC group has higher accuracies than the DP group in emotion recognition for both subject-dependent and subject-independent experiments; c) The neural pattern differences do exist between DPs and HCs, and we find the consistent asymmetry of the neural patterns in DPs; d) For depression detection, using single oil painting achieves the best accuracies, and using negative oil paintings has higher accuracies than using positive oil paintings. These findings suggest that EEG and eye movement signals induced by oil paintings can be used to objectively identify depression.


The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes.
It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex. Deletion of FKBP51 reduced the mechanical hypersensitivity seen in joint inflammatory and neuropathic pain states in female and male mice. Furthermore, FKBP51 deletion also reduced the hypersensitivity seen in a translational model of chemotherapy-induced pain. Interestingly, these 3 pain states were associated with changes in glucocorticoid signalling, as indicated by the increased expression, at spinal cord level, of the glucocorticoid receptor isoform associated with glucocorticoid resistance, GRβ, and increased levels of plasma corticosterone. These pain states were also accompanied by an upregulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these 3 models of persistent pain with the unique FKBP51 ligand SAFit2. When SAFit2 was combined with a state-of-the-art vesicular phospholipid gel formulation for slow release, a single injection of SAFit2 offered pain relief for at least 7 days. We therefore propose the pharmacological blockade of FKBP51 as a new approach for the treatment of persistent pain across sexes, likely in humans as well as rodents.


2D nanocrystalline ternary selenides Cu2MSe4 (M = Mo/W).
A high-temperature metathesis reaction between CuBr and [Ph4P]2MSe4 (M = Mo or W) gave rise to nanocrystalline Cu2MSe4 with a phase-pure M = Mo compound that was obtained for the first time. After exploring the formation mechanism, we found that the sub-stoichiometric ratios of CuBr to MSe42- resulted in the formation of a linear byproduct impurity, [Ph4P]CuMSe4 (M = Mo or W). However, excess CuBr selectively steered the reaction to the desired Cu2MSe4. As a consequence of the newfound similarity in the reaction conditions for both metals, we have demonstrated the applicability of this method towards a mixed Mo/W quaternary composition.


Probing polar molecules with high harmonic spectroscopy.
We bring the methodology of orienting polar molecules together with the phase sensitivity of high harmonic spectroscopy to experimentally compare the phase difference of attosecond bursts of radiation emitted upon electron recollision from different ends of a polar molecule. This phase difference has an impact on harmonics from aligned polar molecules, suppressing emission from the molecules parallel to the driving laser field while favoring the perpendicular ones. For oriented molecules, we measure the amplitude ratio of even to odd harmonics produced when intense light irradiates CO molecules and determine the degree of orientation and the phase difference of attosecond bursts using molecular frame ionization and recombination amplitudes. The sensitivity of the high harmonic spectrum to subtle phase differences in the emitted radiation makes it a detailed probe of polar molecules and will drive major advances in the theory of high harmonic generation.


Exploring the performance of a functionalized CNT-based sensor array for breathomics through clustering and classification algorithms: from gas sensing of selective biomarkers to discrimination of chronic obstructive pulmonary disease.
An array of carbon nanotube (CNT)-based sensors was produced for sensing selective biomarkers and evaluating breathomics applications with the aid of clustering and classification algorithms. We assessed the sensor array performance in identifying target volatiles and we explored the combination of various classification algorithms to analyse the results obtained from a limited dataset of exhaled breath samples. The sensor array was exposed to ammonia (NH3), nitrogen dioxide (NO2), hydrogen sulphide (H2S), and benzene (C6H6). Among them, ammonia (NH3) and nitrogen dioxide (NO2) are known biomarkers of chronic obstructive pulmonary disease (COPD). Calibration curves for individual sensors in the array were obtained following exposure to the four target molecules. A remarkable response to ammonia (NH3) and nitrogen dioxide (NO2), according to benchmarking with available data in the literature, was observed. Sensor array responses were analyzed through principal component analysis (PCA), thus assessing the array selectivity and its capability to discriminate the four different target volatile molecules. The sensor array was then exposed to exhaled breath samples from patients affected by COPD and healthy control volunteers. A combination of PCA, supported vector machine (SVM), and linear discrimination analysis (LDA) shows that the sensor array can be trained to accurately discriminate healthy from COPD subjects, in spite of the limited dataset.


Patient beliefs and tamoxifen discontinuance in older women with estrogen receptor--positive breast cancer.
To investigate the patterns and predictors of tamoxifen discontinuance throughout a 2-year period in a cohort of women 65 years or older with newly diagnosed, estrogen receptor (ER)-positive breast cancer, focusing on the role of patients' beliefs about the risks and benefits of tamoxifen therapy. We enrolled a convenience sample of women cared for in four geographic regions of the United States with stage 1 (>/= 1 cm), stage II, or stage IIIA disease; no prior history of breast cancer; and no simultaneously diagnosed second primary breast cancer. Data sources included medical records and telephone interviews with patients at 3, 6, 15, and 27 months following definitive surgery. Of the 597 women with ER-positive tumors, 516 women (86%) were prescribed tamoxifen, and of these, 88 (17%) stopped taking tamoxifen during the 2-year follow-up period. Of the women who stopped taking tamoxifen, the majority (68%) took it for less than 1 year. Women with neutral or negative beliefs about the value of tamoxifen (3.0; 95% CI, 1.6 to 5.6) and those with positive nodes (odds ratio = 2.5; 95% CI, 1.0 to 6.3) were more likely to discontinue tamoxifen therapy. How women with early-stage breast cancer perceive the risks and benefits of tamoxifen therapy seems critical for sustaining adherence to adjuvant tamoxifen therapy. Interventions designed to educate women about the benefits and risks of tamoxifen therapy may help to reduce discontinuance.


Evidence for vasopressin activation of adenylate cyclase by subunit dissociation.
Radiation inactivation is used to probe the sequence of subunit interactions involved in the activation of adenylate cyclase by vasopressin in cultured renal epithelial cells (LLC-PK1) based on our previous analysis of the radiation inactivation of multimeric enzymes [Verkman et al., Am. J. Physiol. 250 (Cell Physiol. 19): C103-C114, 1986]. For basal adenylate cyclase activity, a concave downward ln(activity) vs. dose relation was observed with limiting slope corresponding to a molecular weight of (169-196) X 10(3). Similar results were obtained with NaF. In contrast, addition of vasopressin, guanylyl imidodiphosphate, or forskolin resulted in transition to a linear ln(activity) vs. dose relation with a slope corresponding to a molecular weight similar to that observed for basal activity. These findings were incorporated into a cyclic dissociation model for the hormonal activation of adenylate cyclase (graph see text) where H is hormone, R is receptor, C is catalytic unit, alpha and beta are subunits of guanyl nucleotide-regulatory protein (G), GTP is guanosine triphosphate, and GDP is guanosine diphosphate. The addition of H favors the dissociation of G into alpha and beta subunits by providing a rapid pathway for addition of GTP to dissociated alpha subunits. The observed target size of the active enzyme species formed corresponds to the composite molecular weights of alpha GTP with C. This model consolidates the radiation inactivation findings as well as the known biochemical characteristics for adenylate cyclase.


Compressed Sensing 3D-GRASE for faster High-Resolution MRI.
High-resolution three-dimensional (3D) structural MRI is useful for delineating complex or small structures of the body. However, it requires long acquisition times and high SAR, limiting its clinical use. The purpose of this work is to accelerate the acquisition of high-resolution images by combining compressed sensing and parallel imaging (CSPI) on a 3D-GRASE sequence and to compare it with a (CS)PI 3D-FSE sequence. Several sampling patterns were investigated to assess their influence on image quality. The proposed k-space sampling patterns are based on two undersampled k-space grids, variable density (VD) Poisson-disc, and VD pseudo-random Gaussian, and five different trajectories described in the literature. Bloch simulations are performed to obtain the transform point spread function and evaluate the coherence of each sampling pattern. Image resolution was assessed by the full-width at half-maximum (FWHM). Prospective CSPI 3D-GRASE phantom and in vivo experiments in knee and brain are carried out to assess image quality, SNR, SAR, and acquisition time compared to PI 3D-GRASE, PI 3D-FSE, and CSPI 3D-FSE acquisitions. Sampling patterns with VD Poisson-disc obtain the lowest coherence for both PD-weighted and T2 -weighted acquisitions. VD pseudo-random Gaussian obtains lower FWHM, but higher sidelobes than VD Poisson-disc. CSPI 3D-GRASE reduces acquisition time (43% for PD-weighted and 40% for T2 -weighted) and SAR (∼45% for PD-weighted and T2 -weighted) compared to CSPI 3D-FSE. CSPI 3D-GRASE reduces acquisition time compared to a CSPI 3DFSE acquisition, preserving image quality. The design of the sampling pattern is crucial for image quality in CSPI 3D-GRASE image acquisitions.


Australian Bachelor of Midwifery students' mental health literacy: an exploratory study.
Many pregnant and post-partum women experience mental health problems, but midwives are frequently ill-equipped to provide support. The purpose of this study, conducted in Melbourne, Australia, was to examine first-year Bachelor of Midwifery students' mental health literacy about post-partum women with schizophrenia, using the vignette of "Mary". A non-probability sample of 38 commencing students was used. The results showed that the students had a mainly lay person-informed conceptualization of mental health interventions for post-partum women. They acknowledged that Mary had a mental health problem that might have a more favorable outcome with professional support, but this agreement did not extend to their understanding of the consequences of the failure to receive professional help. They believed that negative outcomes were less likely and positive outcomes were just as likely for Mary than for others in the community. The findings highlight the need for mental health theory and clinical subjects to be incorporated in midwifery curricula.


GM-CSF inhibits apoptosis of neural cells via regulating the expression of apoptosis-related proteins.
Recently, we reported that GM-CSF showed therapeutic effects on the spinal cord injury (SCI) in rat model possibly via its anti-apoptotic activity in the nervous system. This study investigated the molecular mechanism of its anti-apoptotic and neuroprotective effects in N2a neuroblastoma cells and in rat SCI model. GM-CSF inhibited staurosporine-induced cytotoxicity and apoptosis of N2a cells. Single administration of GM-CSF either intraperitoneally or locally using a gelfoam, clearly reduced the apoptotic events in the surrounding region of the injury site in rat SCI model. Immunohistochemical analysis showed that apoptosis of cells occurred mainly in the neurons, but not significantly in the astrocytes in the surrounding regions. In both N2a cells and in rat SCI model, GM-CSF actually reduced the expression of pro-apoptotic proteins (p53, p21(WAF1/CIP1) and Bax), while further induced that of an anti-apoptotic protein (Bcl-2). In the Basso-Beattie-Bresnahan (BBB) locomotor test, the single GM-CSF administration showed better behavioral recovery than the untreated control only at early times within 1 week after injury. Overall, GM-CSF was shown to exert its neuroprotective effect on the neural injury by regulating the expression of apoptosis related genes, providing the molecular basis on its anti-apoptotic activity. Longer administration of GM-CSF appeared to be necessary for the sustained functional recovery from SCI.


Sharing the care: the key-working experiences of professionals and the parents of life-limited children.
To explore the lived experience of caring and care planning for a child with a life-limiting condition (LLC). Using van Manen's conceptualisation of hermeneutic phenomenology, three focus groups were conducted with 21 paediatric palliative care professionals, and interviews were conducted with 20 parents of children with LLCs. Parents' expectations for support were raised by the diagnosis, but the reality could disappoint, which put pressures on professionals. Current service designs with respect to key working did not always coincide with family preferences. Both parents and professionals found that the care journey required them to shift personas to respond to different contexts. The findings are limited by the sample characteristics, but they provide insight for current policy and practice initiatives. The key worker needs to be mindful of historical care arrangements and be prepared to step into the family 'team' arrangements.


Evaluation of protective effect of bee pollen against propoxur toxicity in rat.
In this study, 28 Wistar female rats (200-250g) were used and divided into four equal groups. Group 1 was allocated as the control group. Groups 2-4 were administered 100mg/kg/bw/day bee pollen, 20mg/kg/bw/day propoxur, and 100mg/kg/bw/day bee pollen plus 20mg/kg/bw/day propoxur by gavage for 14 days, respectively. At the end of the 14th day, blood and tissues (the liver, kidney, brain, and heart) were collected from all animals. Oxidative stress markers (MDA, CAT, SOD, GSH-Px) and some other biochemical parameters (total protein, albumin, glucose, cholesterol, triglyceride, BUN, creatinine, uric acid, magnesium, sodium, potassium, chloride, total bilirubin, GGT, LDH, AST, ALT, and ALP) were analyzed. According to the data obtained, propoxur was determined to lead to negative changes in most of the biochemical parameters investigated and the administration of bee pollen was determined to alleviate these effects.


Resonant-mass detectors of gravitational radiation.
A network of second-generation low-temperature gravitational radiation detectors is nearing completion. These detectors, sensitive to mechanical strains of order 10(-18), are possible because of a variety of technical innovations hat have been made in cryogenics, low-noise superconducting instrumentation, and vibration isolation techniques. Another five orders of magnitude improvement in energy sensitivity of resonant-mass detectors is possible before the linear amplifier quantum limit is encountered.


Caspase-9 inhibition triggers Hsp90-based chemotherapy-mediated tumor intrinsic innate sensing and enhances antitumor immunity.
Antineoplastic chemotherapies are dramatically efficient when they provoke immunogenic cell death (ICD), thus inducing an antitumor immune response and even tumor elimination. However, activated caspases, the hallmark of most cancer chemotherapeutic agents, render apoptosis immunologically silent. Whether they are dispensable for chemotherapy-induced cell death and the apoptotic clearance of cells in vivo is still elusive. A rational cell-based anticancer drug library screening was performed to explore the immunogenic apoptosis pathway and therapeutic targets under apoptotic caspase inhibition. Based on this screening, the potential of caspase inhibition in enhancing chemotherapy-induced antitumor immunity and the mechanism of actions was investigated by various cells and mouse models. Heat shock protein 90 (Hsp90) inhibition activates caspases in tumor cells to produce abundant genomic and mitochondrial DNA fragments and results in cell apoptosis. Meanwhile, it hijacks Caspase-9 signaling to suppress intrinsic DNA sensing. Pharmacological blockade or genetic deletion of Caspase-9 causes tumor cells to secrete interferon (IFN)-β via tumor intrinsic mitochondrial DNA/the second messenger cyclic GMP-AMP (cGAS) /stimulator of interferon genes (STING) pathway without impairing Hsp90 inhibition-induced cell death. Importantly, both Caspase-9 and Hsp90 inhibition triggers an ICD, leading to the release of numerous damage-associated molecular patterns such as high-mobility group box protein 1, ATP and type I IFNs in vitro and remarkable antitumor effects in vivo. Moreover, the combination treatment also induces adaptive resistance by upregulating programmed death-ligand 1 (PD-L1). Additional PD-L1 blockade can further overcome this acquired immune resistance and achieve complete tumor regression. Blockade of Caspase-9 signaling selectively provokes Hsp90-based chemotherapy-mediated tumor innate sensing, leading to CD8+ T cell-dependent tumor control. Our findings implicate that pharmacological modulation of caspase pathway increases the tumor-intrinsic innate sensing and immunogenicity of chemotherapy-induced apoptosis, and synergizes with immunotherapy to overcome adaptive resistance.


The association between edentulism and progress of multimorbidity over 12 years among older American adults.
To examine the relationship between edentulism and the progress of multimorbidity, and the role of nutritional intake and behaviours among older Americans. We used 7 waves (2006-2018) of the Health and Retirement Study, a longitudinal survey of older Americans (number included in analysis 2,224). Edentulism was assessed in 2006 and 2012. Multimorbidity was indicated by 5 self-reported conditions: diabetes, heart conditions, lung diseases, cancer, and stroke. Behavioural factors were smoking, excessive alcohol consumption, physical activity, and body mass index. Nutritional intake was calculated by summing 10 nutrients (Protein, Vitamins C, D, B12, E, Calcium, Zinc, Polyunsaturated fatty acids, Folate and ß- carotene). Multilevel models for analysis of longitudinal data were used to assess the association between change in repeated measures of multimorbidity (between 2006 and 2018) and edentulism (2006) adjusting for nutritional intake, behavioural and socioeconomic factors. Participants who were edentate in 2006 and 2012 had higher rate-ratios (RR) for change in multimorbidity between 2006 to 2018 (RR: 1.29 and 1.28, respectively). After adjusting for socioeconomic factors, total nutrients and behavioural factors, these RR attenuated to 1.12 (95%CI: 1.06, 1.18) and 1.10 (95%CI: 1.05, 1.16), respectively. Total nutrition was negatively associated with progress of multimorbidity, but after adjusting for socioeconomic and behavioural factors the association became insignificant. Total nutrients rates in 2013 were significantly lower among those who were edentate in 2006 and 2012. There was a longitudinal association between edentulism and progress of multimorbidity. The relationship appeared to be mediated be behaviours and nutrition.


I-BAR protein antagonism of endocytosis mediates directional sensing during guided cell migration.
Although directed cellular migration facilitates the coordinated movement of cells during development and repair, the mechanisms regulating such migration remain poorly understood. Missing-in-metastasis (MIM) is a defining member of the inverse Bin/Amphiphysin/Rvs domain (I-BAR) subfamily of lipid binding, cytoskeletal regulators whose levels are altered in a number of cancers. Here, we provide the first genetic evidence that an I-BAR protein regulates directed cell migration in vivo. Drosophila MIM (dmim) is involved in Drosophila border cell migration, with loss of dmim function resulting in a lack of directional movement by the border cell cluster. In vivo endocytosis assays combined with genetic analyses demonstrate that the dmim product regulates directed cell movement by inhibiting endocytosis and antagonizing the activities of the CD2-associated protein/cortactin complex in these cells. These studies demonstrate that DMIM antagonizes pro-endocytic components to facilitate polarity and localized guidance cue sensing during directional cell migration.


Sympathetic nerve activity and peripheral vasodilator capacity in young and older men.
Interindividual variability in sympathetic nerve activity (SNA) has provided insight into integrative mechanisms contributing to blood pressure (BP) regulation in humans. In young people, the influence of high SNA on BP is balanced by lower cardiac output and less adrenergic vasoconstrictor responsiveness. Older people have higher SNA and higher BP. We hypothesized that SNA has a restraining effect on peripheral vasodilator responsiveness in young and older men, such that individuals with higher tonic SNA would show less forearm vasodilatation to exogenous vasodilators. We measured muscle SNA (MSNA; microneurography) and forearm vasodilator responses to intra-arterial infusions of acetylcholine (ACh; endothelium dependent) and sodium nitroprusside (SNP; endothelium independent) in 13 young (age; 27 ± 1 yr) and 16 older (61 ± 2 yr) men. Forearm vascular conductance (FVC) responses to ACh were lower in the older men at the two highest doses (2 and 4 μg·100 ml(-1)·min(-1); Δ395 ± 81 vs. 592 ± 87% and 412 ± 87 vs. 616 ± 132%, P < 0.05), and MSNA was higher (64 ± 4 vs. 41 ± 2 bursts/100 hb; P < 0.05). There was no difference in the FVC response to SNP between young and older men (P > 0.05). In young men, there was an inverse relationship between resting MSNA and FVC responses (%change) to both ACh and SNP (r = -0.83 and r = -0.83, respectively; P < 0.05). In older men, however, this relationship was not observed. Tonic SNA may act to restrain vasodilator responses in young men, whereas in older men a lack of such restraint may be protective against the pressor effects of higher SNA.


Association of chronic kidney disease with clinical outcomes after coronary revascularization: the Arterial Revascularization Therapies Study (ARTS).
Chronic kidney disease (CKD) is associated with adverse outcomes after coronary artery bypass graft surgery (CABG) and percutaneous coronary interventions (PCI), but it is unclear which of these revascularization strategies is associated with lower risk for morbidity and mortality in this population. In the Arterial Revascularization Therapies Study (ARTS), we compared long-term clinical outcomes after CABG or PCI with multivessel stenting in patients with CKD. The ARTS randomly assigned 1205 participants with and without CKD to CABG or PCI with multivessel stenting. We defined CKD as creatinine clearance < or =60 mL/min, estimated by the Cockroft-Gault equation. The primary outcome was the composite of death, myocardial infarction (MI), or stroke; and, a secondary outcome was repeat revascularization. Participants were followed for a mean of 3 years after their intervention. We evaluated whether randomization to CABG or PCI was associated with different outcomes among participants with CKD. Two hundred ninety participants (25%) had CKD at entry into ARTS. One hundred fifty-one received PCI, and 139 received CABG. No difference was observed in the primary endpoint with CABG or PCI among CKD participants (adjusted Hazard Ratio [HR] CABG vs PCI = 0.93; 95% CI 0.54-1.60; P = .97). However, CABG was associated with a reduced risk for repeat revascularization (HR = 0.28; 95% CI 0.14-0.54; P < .01). Compared with participants with normal renal function, CKD was associated with a nearly 2-fold risk for the primary outcome (unadjusted HR = 1.9; 95% CI 1.4-2.7; P < .01). After multivariate adjustment, this association remained significant (HR 1.6; 95% CI 1.1-2.4). In patients with multivessel CAD and CKD, treatment with CABG or PCI with multivessel stenting led to similar outcomes of death, MI, or stroke, but CABG was associated with decreased repeat revascularizations. When compared with ARTS participants with normal renal function, those with CKD had substantially elevated risk of adverse clinical outcomes after coronary revascularization.


Haemodynamic effects of intracoronary neuropeptide Y in dogs: resistance to alpha adrenergic blockade.
Neuropeptide Y is a peptide isolated from brain and neural tissue around human coronary arteries. It has been shown to produce coronary vasoconstriction and myocardial ischaemia. The purposes of this study were (a) to determine whether the vasoconstriction induced by neuropeptide Y was mediated by alpha adrenergic receptors in vivo, and (b) to determine the time course of the effect and whether it was reproducible with a second administration. Neuropeptide Y (200 micrograms over 2 min) was given by intracoronary injection on two occasions 1 h apart to group I dogs (control). In group II the second dose was preceded by treatment with the alpha blocker phenoxybenzamine (4-10 mg.kg-1). The time course and magnitude of the effect was studied in the two groups to determine the effects of alpha blockade and of repeated neuropeptide Y dosage. 14 mongrel dogs (n = 7 per group) were anaesthetised with chloralose for a left thoracotomy to measure coronary blood flow, aortic pressure, left ventricular pressure, and heart rate. Reproducible prolonged increases in coronary vascular resistance occurred after the first [33(SD 18)%] and second [34(17)%] doses of neuropeptide Y. At this infusion rate mean aortic pressure increased with each dose by 21% and coronary blood flow decreased by 7%. In group II dogs, phenoxybenzamine given intravenously 20 min after the first dose of neuropeptide Y reduced mean aortic pressure by 15-20 mm Hg. In this group neuropeptide Y also caused reproducible increases in coronary vascular resistance before (36%) and after (46%) alpha blockade. Neuropeptide Y constricts coronary arteries in vivo by mechanisms that do not require intact alpha adrenergic receptors, and the coronary vasoconstriction was prolonged and reproducible.


Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes.
Impaired lymphangiogenesis is a complication of chronic complex diseases, including diabetes. VEGF-C/VEGFR3 signaling promotes lymphangiogenesis, but how this pathway is affected in diabetes remains poorly understood. We previously demonstrated that loss of epsins 1 and 2 in lymphatic endothelial cells (LECs) prevented VEGF-C-induced VEGFR3 from endocytosis and degradation. Here, we report that diabetes attenuated VEGF-C-induced lymphangiogenesis in corneal micropocket and Matrigel plug assays in WT mice but not in mice with inducible lymphatic-specific deficiency of epsins 1 and 2 (LEC-iDKO). Consistently, LECs isolated from diabetic LEC-iDKO mice elevated in vitro proliferation, migration, and tube formation in response to VEGF-C over diabetic WT mice. Mechanistically, ROS produced in diabetes induced c-Src-dependent but VEGF-C-independent VEGFR3 phosphorylation, and upregulated epsins through the activation of transcription factor AP-1. Augmented epsins bound to and promoted degradation of newly synthesized VEGFR3 in the Golgi, resulting in reduced availability of VEGFR3 at the cell surface. Preclinically, the loss of lymphatic-specific epsins alleviated insufficient lymphangiogenesis and accelerated the resolution of tail edema in diabetic mice. Collectively, our studies indicate that inhibiting expression of epsins in diabetes protects VEGFR3 against degradation and ameliorates diabetes-triggered inhibition of lymphangiogenesis, thereby providing a novel potential therapeutic strategy to treat diabetic complications.


Copolythiophene-based water-gated organic field-effect transistors for biosensing.
This paper reports on the sensing of proteins using water-gated organic field-effect transistors. As a proof-of-concept, streptavidin and avidin were used, with a biotinylated polymer as the active sensing material. The latter is a copolythiophene modified to graft biotin by peptidic coupling. After characterization of its structure, it was integrated as the channel material into transistors and its interactions with several proteins were investigated. Non-specific interactions were reduced when the polymer surface was pretreated with 1-octanol. In this case, human serum albumin had no effect on the transistor characteristics whereas avidin and streptavidin led to a decrease of the drain current.


Multicentre validation of a computer-based tool for differentiation of acute Kawasaki disease from clinically similar febrile illnesses.
The clinical features of Kawasaki disease (KD) overlap with those of other paediatric febrile illnesses. A missed or delayed diagnosis increases the risk of coronary artery damage. Our computer algorithm for KD and febrile illness differentiation had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 94.8%, 70.8%, 93.7% and 98.3%, respectively, in a single-centre validation study. We sought to determine the performance of this algorithm with febrile children from multiple institutions across the USA. We used our previously published 18-variable panel that includes illness day, the five KD clinical criteria and readily available laboratory values. We applied this two-step algorithm using a linear discriminant analysis-based clinical model followed by a random forest-based algorithm to a cohort of 1059 acute KD and 282 febrile control patients from five children's hospitals across the USA. The algorithm correctly classified 970 of 1059 patients with KD and 163 of 282 febrile controls resulting in a sensitivity of 91.6%, specificity of 57.8% and PPV and NPV of 95.4% and 93.1%, respectively. The algorithm also correctly identified 218 of the 232 KD patients (94.0%) with abnormal echocardiograms. The expectation is that the predictive accuracy of the algorithm will be reduced in a real-world setting in which patients with KD are rare and febrile controls are common. However, the results of the current analysis suggest that this algorithm warrants a prospective, multicentre study to evaluate its potential utility as a physician support tool.


Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo.
The role of T helper type 1 (Th1) and Th2 cells in tumor immunity was investigated using Th cells induced from ovalbumin (OVA)-specific T cell receptor transgenic mice. Although Th1 cells exhibited stronger cytotoxicity than Th2 cells, both cell types completely eradicated tumors when transferred into mice bearing A20 tumor cells transfected with the OVA gene (A20-OVA). Th1 cells eradicated the tumor mass by inducing cellular immunity, whereas Th2 cells destroyed the tumor by inducing tumor necrosis. Both Th1 and Th2 cells required CD8(+) T cells to eliminate tumors, and neither of these cells were able to completely eliminate A20-OVA tumors from T and B cell-deficient RAG2(-/-) mice. Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8(+) cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy. Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1-dependent cell-cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy. These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.


Back to the basic sciences: an innovative approach to teaching senior medical students how best to integrate basic science and clinical medicine.
Abraham Flexner persuaded the medical establishment of his time that teaching the sciences, from basic to clinical, should be a critical component of the medical student curriculum, thus giving rise to the "preclinical curriculum." However, students' retention of basic science material after the preclinical years is generally poor. The authors believe that revisiting the basic sciences in the fourth year can enhance understanding of clinical medicine and further students' understanding of how the two fields integrate. With this in mind, a return to the basic sciences during the fourth year of medical school may be highly beneficial. The purpose of this article is to (1) discuss efforts to integrate basic science into the clinical years of medical student education throughout the United States and Canada, and (2) describe the highly developed fourth-year basic science integration program at the University of Pittsburgh School of Medicine. In their critical review of medical school curricula of 126 U.S. and 17 Canadian medical schools, the authors found that only 19% of U.S. medical schools and 24% of Canadian medical schools require basic science courses or experiences during the clinical years, a minor increase compared with 1985. Curricular methods ranged from simple lectures to integrated case studies with hands-on laboratory experience. The authors hope to advance the national discussion about the need to more fully integrate basic science teaching throughout all four years of the medical student curriculum by placing a curricular innovation in the context of similar efforts by other U.S. and Canadian medical schools.


[Transparent solid nutrient medium for studying the lytic spectrum of bacteriophages of microbes of the genus Bordetella].
A solid, transparent culture medium for the study of the lytic spectrum of the phages, active against B. pertussis and B. bronchiseptica, in respect to homologous and heterologous bacteria of the genus Bordetella has been developed. The Cohen-Wheeler liquid medium with nicotinic acid and nicotinamide added, solidified with agar, is nicotinamide added, solidified with agar, is used as the base of the new medium. This base ensures the growth of B. parapertussis and B. bronchiseptica. To stimulate the growth of B. pertussis, the tissue stimulant of B. pertussis growth (a transparent substrate obtained from the tissue of the large intestine of a rabbit) has been used. With 10% of this stimulant added, B. pertussis cells have been found to preserve their typical morphological and immunobiological properties.


Arginase I induction in macrophages, triggered by Th2-type cytokines, supports the growth of intracellular Leishmania parasites.
Leishmania spp. are intracellular protozoan parasites that invade and replicate within macrophages. In a previous report, we have demonstrated that the growth of intracellular amastigotes could be controlled by inhibition of arginase. This enzyme, induced in host cells by Th2 cytokines, synthesizes L-ornithine which can be used by parasites to generate polyamines and proliferate. In this study, we have designed experiments to better analyse the dependence of parasite proliferation on arginase induction in infected macrophages. Treatment of Leishmania major-infected BALB/c macrophages with interleukin (IL)-4, IL-10 or transforming growth factor-beta, which are all inducers of arginase I in murine macrophages, led to a proportional increase in the number of intracellular amastigotes. Moreover, parasite proliferation and arginase activity levels in macrophages from the susceptible BALB/c mice were significantly higher than those from infected C57BL/6 cells when treated with identical doses of these cytokines, indicating that a strong correlation exist between the permissibility of host cells to L. major infection and the induction of arginase I in macrophages. Specific inhibition of arginase by N(omega)-hydroxy-nor-L-arginine (nor-LOHA) reverted growth, while L-ornithine and putrescine promoted parasite proliferation, indicating that the parasite cell division depends critically on the level of L-ornithine available in the host. Therefore, arginase induction in the context of a Th2 predominant response might be a contributor to susceptibility in leishmaniasis.


A depth estimation algorithm with a single image.
This paper explains the use of a sharpening filter to calculate the depth of an object from a blurred image of it. It presents a technique which is independent of edge orientation. The technique is based on the assumption that a defocused image of an object is the convolution of a sharp image of the same object with a two-dimensional Gaussian function whose spread parameter (SP) is related to the object depth. A sharp image of an object is obtained from a defocused image of the same object by applying sharpening filters. The defocused and sharp images of the object are used to calculate the SP which is then related to the object depth. The paper gives experimental results which show the feasibility of employing sharpening filters for depth computation.


Broadband Photodetector Based on FePS3/WS2 van der Waals Type II Heterostructure.
In order to understand broadband photodetectors from ultraviolet-visible (UV-vis) to the near-infrared range, one needs to find novel two-dimensional (2D) van der Waals (vdW) materials with broadband optoelectronic performance. Transition metal phosphorus sulfides (TMPSs) have been reported as a new type of vdW material with generally broadband and p-type conductivity. Here, we report a high-performance and broadband photodetector consist of p-type FePS3 and n-type WS2 with a working range of 405-785 nm. The maximum values of responsivity and specific detectivity are 32.5 mA/W and 1.73 × 1012 jones at 405 nm and 2 V bias, which are better than those of its individual constituents and many other 2D vdW heterostructures. The high performance of the FePS3/WS2 photodetector is attributed to the built-in electric field in the FePS3/WS2 p-n heterostructure and type II band alignment. Present study demonstrates that the material family of TMPSs could be a promising platform for broadband photodetector applications.


Integration of Geriatric Assessment in the Care of Patients with Gastrointestinal Malignancies.
The majority of patients with gastrointestinal (GI) malignancies are older. Recently, it has become evident that elements from a geriatric assessment (GA) are powerful predictors of outcomes such as postoperative morbidity and mortality, length of stay, type of treatment received, and survival across several GI tumor types in older adults. A GA is a systematic evaluation of functional status, comorbidities, polypharmacy, cognition, nutritional status, emotional status, and social support. A PubMed search was performed in order to identify clinical studies investigating the association between GA and outcomes in patients with GI malignancies. A total of 31 studies were included in this review. For colorectal cancer, the evidence linking GA variables and frailty to negative outcomes is substantial and consistent. The data regarding other GI malignancies is more limited, but generally shows the same findings. Increasing data shows that elements from a GA and frailty are consistently associated with negative short- and long-term treatment outcomes in older patients with GI malignancies. Future studies should investigate the impact of geriatric interventions on outcomes.


Multi-Layered Triboelectric Nanogenerators with Controllable Multiple Spikes for Low-Power Artificial Synaptic Devices.
In the domains of wearable electronics, robotics, and the Internet of Things, there is a demand for devices with low power consumption and the capability of multiplex sensing, memory, and learning. Triboelectric nanogenerators (TENGs) offer remarkable versatility in this regard, particularly when integrated with synaptic transistors that mimic biological synapses. However, conventional TENGs, generating only two spikes per cycle, have limitations when used in synaptic devices requiring repetitive high-frequency gating signals to perform various synaptic plasticity functions. Herein, a multi-layered micropatterned TENG (M-TENG) consisting of a polydimethylsiloxane (PDMS) film and a composite film that includes 1H,1H,2H,2H-perfluorooctyltrichlorosilane/BaTiO3 /PDMS are proposed. The M-TENG generates multiple spikes from a single touch by utilizing separate triboelectric charges at the multiple friction layers, along with a contact/separation delay achieved by distinct spacers between layers. This configuration allows the maximum triboelectric output charge of M-TENG to reach up to 7.52 nC, compared to 3.69 nC for a single-layered TENG. Furthermore, by integrating M-TENGs with an organic electrochemical transistor, the spike number multiplication property of M-TENGs is leveraged to demonstrate an artificial synaptic device with low energy consumption. As a proof-of-concept application, a robotic hand is operated through continuous memory training under repeated stimulations, successfully emulating long-term plasticity.


Growth inhibitory activity of extracts and compounds from Cimicifuga species on human breast cancer cells.
The purpose of this report is to explore the growth inhibitory effect of extracts and compounds from black cohosh and related Cimicifuga species on human breast cancer cells and to determine the nature of the active components. Black cohosh fractions enriched for triterpene glycosides and purified components from black cohosh and related Asian species were tested for growth inhibition of the ER(-) Her2 overexpressing human breast cancer cell line MDA-MB-453. Growth inhibitory activity was assayed using the Coulter Counter, MTT and colony formation assays. Results suggested that the growth inhibitory activity of black cohosh extracts appears to be related to their triterpene glycoside composition. The most potent Cimicifuga component tested was 25-acetyl-7,8-didehydrocimigenol 3-O-beta-d-xylopyranoside, which has an acetyl group at position C-25. It had an IC(50) of 3.2microg/ml (5microM) compared to 7.2microg/ml (12.1microM) for the parent compound 7,8-didehydrocimigenol 3-O-beta-d-xylopyranoside. Thus, the acetyl group at position C-25 enhances growth inhibitory activity. The purified triterpene glycoside actein (beta-d-xylopyranoside), with an IC(50) equal to 5.7microg/ml (8.4microM), exhibited activity comparable to cimigenol 3-O-beta-d-xyloside. MCF7 (ER(+)Her2 low) cells transfected for Her2 are more sensitive than the parental MCF7 cells to the growth inhibitory effects of actein from black cohosh, indicating that Her2 plays a role in the action of actein. The effect of actein on Her2 overexpressing MDA-MB-453 and MCF7 (ER(+)Her2 low) human breast cancer cells was examined by fluorescent microscopy. Treatment with actein altered the distribution of actin filaments and induced apoptosis in these cells. These findings, coupled with our previous evidence that treatment with the triterpene glycoside actein induced a stress response and apoptosis in human breast cancer cells, suggest that compounds from Cimicifuga species may be useful in the prevention and treatment of human breast cancer.


Strategic planning: the basics and benefits.
Strategic planning can help a medical practice take an honest look at itself in light of the changes taking place in its environment and within the practice itself. The objective is for the group to design a plan, or road map, to its envisioned future. For medical practices, strategic planning is a four part process: 1) gaining buy-in for the process itself from the leadership and physicians; 2) gathering pertinent data about the group's environment through external resources, and about the group itself through interviews and surveys of physicians; 3) conducting a facilitated off-site retreat of key physicians and leaders in order to review data, discuss issues and develop a one to two year action plan; and, 4) carrying out the action plan developed at the retreat and measuring its outcomes. A follow-up mini-retreat about six months after the first retreat is highly recommended, as is instituting a process of sharing of the results and outcomes of the plan with all members of the organization.


Characteristics of premenopausal and postmenopausal women with acquired, generalized hypoactive sexual desire disorder: the Hypoactive Sexual Desire Disorder Registry for women.
Little is known about the natural history of hypoactive sexual desire disorder (HSDD). We examined the sociodemographic, relationship, help seeking, sexual function, and medical characteristics of women with a clinical diagnosis of generalized, acquired HSDD by menopause status. This study was a cross-sectional baseline data analysis from the HSDD Registry for Women (N = 1,574, from 33 US clinical sites). HSDD was clinically diagnosed and confirmed. Validated measures of sexual function, relationship factors, and health, as well as newly developed questions on help seeking were assessed using the questionnaire. Participants were predominantly married or living with a partner (81.7%) and represented a range of race/ethnic backgrounds and ages (mean ± SD, 42.9 ± 11.9 y). Most (56.8%) described their HSDD severity as "moderate to severe," with 26.5% rating the problem severe. Nonetheless, most women (69.8%) reported being happy in their relationship, and 61.8% were satisfied with their partner communication. Postmenopausal women had lower Female Sexual Function Index total scores, indicating worse sexual function (14.0 ± 7.5) than premenopausal women (16.7 ± 6.8, P < 0.001), although both groups had similarly low scores on the sexual desire domain (3.4 ± 1.3 vs 3.3 ± 1.4). Less than half of the overall sample had sought professional help, among whom hormonal treatments had been used by 23.7% of postmenopausal women and by 7.6% of premenopausal women. Most women with HSDD were in long-term partner relationships with high levels of overall relationship satisfaction. Postmenopausal women were more likely to seek help for their disorder, despite similarly high levels of distress associated with HSDD. Further research is needed to examine treatment outcomes.


Counterclockwise or clockwise reciprocating motion for oval root canal preparation: a micro-CT analysis.
To evaluate oval root canal preparation using one or two instruments in counterclockwise or clockwise reciprocating motion. The radiographic diameter of mandibular human incisors was evaluated, and oval canals were selected (2 ≤ Diameter Ratio ≤ 4). Fifty-seven teeth were assigned to root canal preparation (n = 19): Reciproc 40 (R40) in a counterclockwise reciprocating motion; Mtwo size 40, .06 taper (M 40.06) in a clockwise reciprocating motion or Mtwo size 20, .06 taper and size 40, .06 taper (M 20/40.06) in a clockwise reciprocating motion. Mtwo instruments were coupled to an ENDO DUAL motor, turning 150° clockwise and 30° counterclockwise. Scanning was performed before and after root canal preparation using a SkyScan 1176 micro-computed tomography. Volume, percentage of debris and percentage of uninstrumented surface were analysed in the entire root canal and in each third of the canal. Data were compared using anova and Tukey's tests or Kruskal-Wallis and Dunn tests. The Reciproc and Mtwo systems using different kinematics were associated with a similar increase in root canal volume. Additionally, both system had similar percentage of uninstrumented surface (P > 0.05). Mtwo size 20, .06 taper and size 40, .06 taper was associated with significantly lower debris (P < 0.05) in the middle third (0.56%) when compared to R40 (1.31%) and M size 40, .06 taper (1.54%). The conventional reciprocation motion for R40 and the clockwise reciprocation motion for Mtwo resulted in similar root canal preparations. Less remaining debris was present in the middle third when two instruments with different diameters were used.


Male meiotic spindle features that efficiently segregate paired and lagging chromosomes.
Chromosome segregation during male meiosis is tailored to rapidly generate multitudes of sperm. Little is known about mechanisms that efficiently partition chromosomes to produce sperm. Using live imaging and tomographic reconstructions of spermatocyte meiotic spindles in Caenorhabditis elegans, we find the lagging X chromosome, a distinctive feature of anaphase I in C. elegans males, is due to lack of chromosome pairing. The unpaired chromosome remains tethered to centrosomes by lengthening kinetochore microtubules, which are under tension, suggesting that a 'tug of war' reliably resolves lagging. We find spermatocytes exhibit simultaneous pole-to-chromosome shortening (anaphase A) and pole-to-pole elongation (anaphase B). Electron tomography unexpectedly revealed spermatocyte anaphase A does not stem solely from kinetochore microtubule shortening. Instead, movement of autosomes is largely driven by distance change between chromosomes, microtubules, and centrosomes upon tension release during anaphase. Overall, we define novel features that segregate both lagging and paired chromosomes for optimal sperm production.


Attenuation of vibrotactile spatial summation.
Masked and quiet thresholds at several frequencies of vibratory stimuli were measured as a function of contactor area. The test site was the left index finger; the masking site was the left little finger. The quiet threshold data were consistent with previous investigations: Low-frequency stimuli showed no spatial summation, whereas high-frequency stimuli did. In the presence of a masker, spatial summation was reduced or eliminated for high-frequency stimuli, i.e., the masked threshold was, under some conditions, independent of contactor area. Low-frequency stimuli continued to show no spatial summation in the presence of a masker. The attenuation of spatial summation appears to be a direct function of the intensity of the masking stimulus. Additional measurements with the left thenar eminence as the test site showed that spatial summation could be attenuated by a masker placed on a contralateral body site. The implications of the results for quantifying the effectiveness of a masking stimulus, for the duplex mechanoreceptor hypothesis, and for the nature of spatial summation on the skin are discussed.


Multiplication of Spodoptera littoralis granulosis virus in a cell line established from Phthorimaea operculella.
A complete replication of the Spodoptera littoralis granulosis virus (SpliGV) was obtained, in vitro by both virus infection and DNA transfection in the ORS-Pop-95 (Pop-95) cell line established from embryonic cells of the potato tuber moth, Phthorimaea operculella. SpliGV multiplied significantly during several passages in Pop-95 cells at 19 degrees C. When the cells were infected and kept at 19 degrees C for the first 4 hrs and then at 27 degrees C for the rest of the experiment (20 days), the viral multiplication proceeded at the same rate. Comparison of SpliGV progenies, multiplied either in vivo or in vitro, using electron microscopy and restriction profile analysis, showed their identity.


Lipid anchoring of Arabidopsis phototropin 1 to assess the functional significance of receptor internalization: should I stay or should I go?
The phototropin 1 (phot1) blue light receptor mediates a number of adaptive responses, including phototropism, that generally serve to optimize photosynthetic capacity. Phot1 is a plasma membrane-associated protein, but upon irradiation, a fraction is internalized into the cytoplasm. Although this phenomenon has been reported for more than a decade, its biological significance remains elusive. Here, we use a genetic approach to revisit the prevalent hypotheses regarding the functional importance of receptor internalization. Transgenic plants expressing lipidated versions of phot1 that are permanently anchored to the plasma membrane were used to analyse the effect of internalization on receptor turnover, phototropism and other phot1-mediated responses. Myristoylation and farnesylation effectively prevented phot1 internalization. Both modified photoreceptors were found to be fully functional in Arabidopsis, rescuing phototropism and all other phot1-mediated responses tested. Light-mediated phot1 turnover occurred as in the native receptor. Furthermore, our work does not provide any evidence of a role of phot1 internalization in the attenuation of receptor signalling during phototropism. Our results demonstrate that phot1 signalling is initiated at the plasma membrane. They furthermore indicate that release of phot1 into the cytosol is not linked to receptor turnover or desensitization.


Preserved protein synthesis in the heart in response to acute fasting and chronic food restriction despite reductions in liver and skeletal muscle.
Whole body protein synthesis is reduced during the fed-to-fasted transition and in cases of chronic dietary restriction; however, less is known about tissue-specific alterations. We have assessed the extent to which protein synthesis in cardiac muscle responds to dietary perturbations compared with liver and skeletal muscle by applying a novel (2)H(2)O tracer method to quantify tissue-specific responses of protein synthesis in vivo. We hypothesized that protein synthesis in cardiac muscle would be unaffected by acute fasting or food restriction, whereas protein synthesis in the liver and gastrocnemius muscle would be reduced when there is a protein-energy deficit. We found that, although protein synthesis in liver and gastrocnemius muscle was significantly reduced by acute fasting, there were no changes in protein synthesis in the left ventricle of the heart for either the total protein pool or in isolated mitochondrial or cytosolic compartments. Likewise, a chronic reduction in calorie intake, induced by food restriction, did not affect protein synthesis in the heart, whereas protein synthesis in skeletal muscle and liver was decreased. The later observations are supported by changes in the phosphorylation state of two critical mediators of protein synthesis (4E-BP1 and eIF2alpha) in the respective tissues. We conclude that cardiac protein synthesis is maintained in cases of nutritional perturbations, in strong contrast to liver and gastrocnemius muscle, where protein synthesis is decreased by acute fasting or chronic food restriction.


[Conservation status of Goodeidae familiy fishes (Cyprinodontiformes) from the Mexican Central Plateau].
Conservation status of Goodeidae familiy fishes (Cyprinodontiformes) from the Mexican Central Plateau. To establish the conservation status and threats for Goodeidae fishes in the high plateau of Mexico, I assessed limnological descriptions, and the reduction in range and in number of localities where they are found, in 53 localities (58.8% of historically reported localities). This assessment included the comparison of current collections with historical records. A principal component analysis of limnological variables showed that most remnant Goodeid species inhabit localities characterised by low environmental degradation: few appear to have a high tolerance to environmental degradation. Overall, 65% of species suffered a reduction in number of localities where they are found. Almost all species face some conservation threat, considering the criteria and categories established by the International Union for the Conservation of Nature (IUCN). Data suggest that one species is extinct (Allotoca catarinae), one more is extinct in the wild (Skiffia francesae), eight are critically endangered (Allodontichthys hubbsi, Allotoca goslinei, Allotoca regalis, Allotoca zacapuensi, Ameca splendens, Characodon audax, Hubbsina turneri, and Zoogoneticus tequila), eleven are endangered, eight can be regarded as vulnerable, four are "near threatened" and only two appear to under "least concern". Habitat loss, introduction of exotic fish, and being species with restricted physiographic range or ecologically specialised, are the main factors leading to the threat of extinction of the Goodeidae family. Recovery actions are needed for the conservation of this fish group.


Clonal structure of Shiga toxin (Stx)-producing and beta-D-glucuronidase-positive Escherichia coli O157:H7 strains isolated from outbreaks and sporadic cases in Hokkaido, Japan.
A total of 22 clonal phenotypic variants of Shiga toxin (Stx)-producing Escherichia coli (STEC) O157:H7 was isolated from six different locations in Hokkaido, Japan. These isolates were negative for sorbitol fermentation but positive for beta-D-glucuronidase (GUD+). They carried eaeA, EHEC-hlyA, pas and etpD genes like typical E. coli O157:H7 and, in addition, st1 and stx2 genes. However, they were shown to lack katP and espP genes that are present in typical STEC O157:H7. All these atypical GUD+ STEC O157:H7 isolates had very similar antimicrobial susceptibilities. Pulsed-field gel electrophoresis analysis with XbaI, SfiI, SwaI, SpeI and NotI indicated that they were identical or closely related to one another. From their phenotypic and genotypic features, these GUD+ STEC O157:H7 isolates may represent a distinct clone among STEC O157.


[Acute/subacute disseminated paracoccidioidomycoses. First case in Rio Grande do Sul].
The first autochthonous case of acute/subacute disseminated paracoccidioidomycosis observed in a child in Rio Grande do Sul (Brazil) is reported. The disease started with widespread superficial lymphadenopathy six months before the patient was admitted to the hospital. The diagnosis was made through a cervical lymph node biopsy. The spectrum of the clinical forms of the mycosis observed in this State is commented upon.


Subunit composition of AMPD varies in response to changes in AMPD1 and AMPD3 gene expression in skeletal muscle.
Adenosine monophosphate deaminase (AMPD), a central enzyme in energy metabolism in skeletal muscle, is encoded by a multigene family in higher eukaryotes. Denervation was used as a stimulus to induce a change in fiber type composition of rat gastrocnemius muscle and, consequently, gene expression. Specific antisera and nucleic acid probes were used to assess changes in expression of the AMPD1 and AMPD3 genes. Total AMPD activity in denervated skeletal muscle increased by 34%. The composition of the AMPD tetrameric holoenzyme was altered in two ways: The percentage of AMPD holoenzyme molecules consisting of one or more AMPD3 subunits increased three-fold, and the percentage of AMPD1 mRNA that excludes exon 2-encoded sequences doubled. These results suggest that expression of the AMPD1 and AMPD3 genes may be coordinated in myocytes to effect production of an AMPD holoenzyme of varying subunit composition.


Colonization of rock holes by Aedes albopictus in the southeastern United States.
Aedes albopictus was collected from water-holding rock holes along 3 streams in Georgia and 1 in South Carolina. To compare the occurrence of Ae. albopictus and Aedes atropalpus, rock holes were sampled for immature Aedes at 2 sites where there were numerous rock holes harboring mosquitoes. At 1 of these sites, tree holes and various types of artificial containers were also sampled for immature Aedes. At both sites, immature Ae. albopictus occurred in rock holes much less frequently than the rock-pool specialist, Aedes atropalpus. Moreover, the distribution of Ae. albopictus was limited to rock holes in less flood prone locations, whereas Ae. atropalpus was often a common mosquito even in rock holes that were among the most susceptible to flooding by rising stream levels. By contrast. Ae. albopictus was frequently found in the samples from tree holes and artificial containers. Thus, it appears that riverine rock holes that are flooded frequently may be, at best, marginal habitats for Ae. albopictus.


Pericentrin deficiency in smooth muscle cells augments atherosclerosis through HSF1-driven cholesterol biosynthesis and PERK activation.
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is caused by biallelic loss-of-function variants in pericentrin (PCNT), and premature coronary artery disease (CAD) is a complication of the syndrome. Histopathology of coronary arteries from patients with MOPDII who died of CAD in their 20s showed extensive atherosclerosis. Hyperlipidemic mice with smooth muscle cell-specific (SMC-specific) Pcnt deficiency (PcntSMC-/-) exhibited significantly greater atherosclerotic plaque burden compared with similarly treated littermate controls despite similar serum lipid levels. Loss of PCNT in SMCs induced activation of heat shock factor 1 (HSF1) and consequently upregulated the expression and activity of HMG-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis. The increased cholesterol biosynthesis in PcntSMC-/- SMCs augmented PERK signaling and phenotypic modulation compared with control SMCs. Treatment with the HMGCR inhibitor, pravastatin, blocked the augmented SMC modulation and reduced plaque burden in hyperlipidemic PcntSMC-/- mice to that of control mice. These data support the notion that Pcnt deficiency activates cellular stress to increase SMC modulation and plaque burden, and targeting this pathway with statins in patients with MOPDII has the potential to reduce CAD in these individuals. The molecular mechanism uncovered further emphasizes SMC cytosolic stress and HSF1 activation as a pathway driving atherosclerotic plaque formation independently of cholesterol levels.


Measurement of intracellular chloride ion concentration in ICC in situ and in explant culture.
Chloride channels are proposed to play a central role in the electrical pacemaking mechanism of interstitial cells of Cajal (ICC). A key unknown factor in the consideration of this role is the chloride equilibrium potential (E(Cl)), as determined by the relative concentrations of intra- ([Cl(-)](i)) and extracellular ([Cl(-)](o)) chloride ions. To calculate the E(Cl) of ICC, [Cl(-)](i) was measured with the fluorescent chloride indicator N-(6-methoxyquinolyl) acetoethyl ester (MQAE). Pacemaker ICC in explant cultures or in situ, i.e. ICC associated with the myenteric plexus of the small intestine, were loaded with MQAE and fluorescence was measured by laser scanning confocal microscopy. The dye fluorescence was then calibrated against known [Cl(-)](i) by treating the explants or in situ preparations with chloride ionophore and varying bath chloride concentrations. In explants, ICC [Cl(-)](i) was measured as 13 mmol L(-1) with [Cl(-)](o) of 100 mmol L(-1), giving an E(Cl) of -52 mV [corrected]. With [Cl(-)](o) at 166 mmol L(-1), [Cl(-)](i) was 26 mmol L(-1), giving an E(Cl) of -47 mV[corrected]. In situ, ICC [Cl(-)](i) was measured as 26 mmol L(-1) with [Cl(-)](o) of 130 mmol L(-1), giving an E(Cl) of -41 mV [corrected]. Importantly ICC compensate for changes in extracellular chloride by changing [Cl(-)](i) and thus maintain E(Cl). In ICC explant clusters, [Cl(-)](i) was seen to fluctuate, possibly evoked by rhythmic changes in intracellular calcium. The intracellular chloride concentration in ICC fluctuates to keep its equilibrium potential constant. The identification of E(Cl) as positive to the resting membrane potential of ICC indicates that opening of chloride channels will depolarize ICC.


Tuning of the antiferromagnetic-type interaction in photo-excited single-decker porphyrin-lanthanide complexes with different crown capping ligands.
The magnetic interaction between the total angular momentum (J) of the 4f electrons in a lanthanide ion and the orbital angular momentum (L) of a porphyrin in the photo-excited states of 5,10,15,20-tetraphenylporphyrinato Dy(III) complexes capped with a crown ether with one of two different symmetries, 12-crown-4 or 1-aza-12-crown-4, was investigated by temperature- and magnetic dependent magnetic circular dichroism (VT-VH MCD). The analysis was conducted on the complexes with different non-aromatic ligands to investigate how different symmetries of the non-aromatic ligands have an impact on the electronic interaction causing an anti-parallel orientation of J and L. The magnitude of the J-L interaction was determined from simulation-based fitting to experimental ratios. While in both cases an antiferromagnetic-type interaction between J and L was identified, an asymmetric non-aromatic ligand resulted in an increased magnitude of the J-L interaction.