Angiogenesis vs. response after combined chemoradiotherapy of squamous cell head and neck cancer.
Oxygen/drug supply to cancer cells is an important factor defining response to radiotherapy and chemotherapy. Although tumor angiogenesis is considered an important prognostic marker, its role in the outcome of chemotherapy and radiotherapy is unknown. In the present study we examined the possible correlation of the degree of angiogenesis with response to cytotoxic therapy in locally advanced squamous cell head and neck cancer (HNC). Vascular grade (VG) was assessed immunohistochemically using the JC70 monoclonal antibody (MAb) in tumor specimens from 76 patients treated with platinum/5-fluorouracil (with or without methotrexate) induction chemotherapy (ICT) (n = 37) or concurrent chemoradiotherapy (CCRT) with cisplatin or carboplatin (n = 39). Seventeen of 76 analyzed patients had an overall microvessel score of < 11 (VGI), 25/76 of 11-30 (VG2), 16/76 of 31-50 (VG3) and 18/76 of > 50 (VG4). Complete response rate after ICT or after CCRT was higher in cases with an intermediate vascularization (VG2,3). Both local relapse-free and overall survival were significantly better in the VG2 group. Patients treated with CCRT had a better survival compared to those treated with ICT. This was mainly observed in VG1 tumors. Multivariate analysis showed that VG and treatment modality were independent prognostic factors for local relapse and survival. Intratumoral angiogenesis correlation with the cytotoxic therapy outcome is likely to follow a bell-shaped relation, the response being better in cases with an intermediate VG. This may be the consequence of 2 vasculature-dependent factors, i.e., the drug/oxygen availability and the ability of cancer cells to undergo rapid repopulation in optimally oxygenated conditions. Our pilot study stresses the importance of individualization of therapy according to VG.


TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins.
Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.


Thrombin and its precursor in human cerebrospinal fluid.
The blood coagulation cascade proteolytic enzyme, thrombin, affects many cell types, including neurons and astrocytes, in which it prevents process outgrowth and induces significant morphological degeneration and even cell death. Since thrombin may contribute significantly to pathological conditions in the central nervous system (CNS), where it is synthesized locally, we measured the levels of thrombin and its precursor, prothrombin, in the cerebrospinal fluid (CSF) of 67 individuals from 6 groups: non-neurologic controls (NNC); spinal degenerative disease (SDD); peripheral nerve disease (PND); cerebrovascular, neuroimmune and seizure disorders and tumor (CNSD); traumatic brain injury (TBI) and neurodegenerative disorders (NDD). We employed a sensitive chromogenic assay utilizing the thrombin specific tripeptide substrate, S-2238, to evaluate CSF levels of thrombin and prothrombin. The latter estimated after its conversion to active enzyme by the snake venom prothrombinase, ecarin. No measurable active thrombin was detected in these CSF samples. However, activatable prothrombin was measured in all groups. The mean activatable prothrombin concentrations (in nM) were 7.26 +/- 3.39 (NNC); 8.85 +/- 3.09 (SDD); 6.78 +/- 2.58 (PND); 6.33 +/- 3.87 (CNSD); 5.10 +/- 1.86 (TBI), and 7.80 +/- 3.27 (NDD). Duncan's multiple comparison test showed significant reduction (p <0.05) in prothrombin levels of the TBI group. Our data suggests that the prothrombin zymogen gains access to the CSF, likely across either an intact or compromised blood-brain barrier (BBB), in increased amounts with age. Reduced levels in TBI patients may have diagnostic and/or prognostic value.


Spontaneous Coronary Artery Dissection in the Setting of COVID-19 Pandemic-Related Stressors: A Case Report.
Spontaneous coronary artery dissection (SCAD) is an uncommon but important cause of acute myocardial infarction, particularly in younger women and in patients with underlying fibromuscular dysplasia (FMD). There is increasing literature on patients with SCAD reporting significant emotional stress, particularly stress related to unemployment, in the week prior to their cardiac event, and emotional triggers appear to be associated with worse in-hospital and follow-up cardiac events. Additionally, the COVID-19 pandemic has resulted in significant societal stressors and increased unemployment, which have been associated with increased cardiovascular morbidity. Here, we present a case of a female presenting with an acute MI secondary to SCAD in the setting of recently learning of impending unemployment due to COVID-19 vaccine refusal. This case highlights the importance of considering SCAD in patients with significant recent emotional stress who present with MI. Additionally, in light of the emotional stressors of the COVID-19 pandemic, clinicians must be aware of the consequences significant emotional stress plays on the development of adverse complications of chronic disease.


[Study of the DNA of the causative agent of whooping cough, Bordetella pertussis].
A number of physico-chemical properties of Bordetella pertussis DNA has been studied. The values of its floating density and melting point have been established, which has allowed one to calculate the GC composition of B. pertussis DNA. The average molecular weights of the fragments of B. pertussis DNA, resulting from its hydrolysis with specific endonucleases EcoR, BamH 1, Sal 1, Pst 1, have been determined, and thus the basis has been provided for establishing the number of clones necessary for obtaining the complete lset of B. pertussis genes.


Rejection of retrovirus-infected tumor cells in guinea pigs: effect on bystander tumor cells.
We studied the basis of rejection of retrovirus-infected tumor cells in guinea pigs by evaluating host response to injection of mixtures containing retrovirus-infected tumor cells and, antigenically and biologically distinct, uninfected tumor cells (line 10). After intradermal injection, line 10 grew progressively, metastasized to regional lymph nodes, and led to death of animals; line 107C3 4070A, a murine leukemia virus-infected fibrosarcoma cell line, grew for approximately 1 week and then regressed. Growth of the line 10 hepatoma was suppressed when the hepatoma cells were mixed with viable 107C3 4070A cells before injection into strain 2 guinea pigs. Viable virus-infected 107C3 cells were more effective than irradiated virus-infected cells in suppressing line 10 growth; mixture of line 10 with murine leukemia virus 4070A alone did not inhibit line 10 growth. Suppression of growth of line 10 cells by admixed murine leukemia virus 4070A-infected cells was less effective in animals with established viral immunity. Cyclophosphamide inhibited suppression of line 10 at sites of injection of virus-infected cells. Infection of line 10 with murine leukemia virus in vitro required cocultivation of line 10 cells with murine leukemia virus-infected fibrosarcoma cells; virus alone did not lead to acquisition of murine leukemia virus antigens by line 10 cells.


[Concepts and findings in dentistry in medical dissertations from the 16th, 17th and 18th centuries].
This historical paper deals with medical dissertations from the second half of the 18th century which deal with stomatology. 30 of the 100 consulted dissertations were translated from latin with great differences in scientific content and style, because they dated from the 16th to the 18th century. The views of normal anatomy and physiology of that time are described. Strange views were held on the embryological development. Apart from toothache, dentitio difficilis in children, aphtous stomatitis, cleft palates and the respective therapies were described. The scientific content of those dissertations was way backward when compared to contemporary text book literature.


[Polyneuropathy and fasciitis in eosinophilia-myalgia syndrome].
Eosinophilia-Myalgia-Syndrome (EMS), a newly recognized illness, was described first in October 1989, when it formed an epidemic in the USA and later also in Europe. In the meantime, ingestion of L-tryptophan containing products has been recognized to trigger this syndrome, but the pathophysiological basics are still subject to speculation. Often starting with a flu-like period, the disease is dominated by dermatologic (fasciitis) and neurologic (neuropathy, myopathy) symptoms in the subsequent stages. Reporting on an own case and reviewing the literature, clinicopathological aspects and the problems of treatment are discussed. In contrast with the majority of published cases, which showed predominance of axonal damage, our patient displayed the clinical and electro-physiologic characteristics of demyelinating neuropathy.


Using public health data systems to understand and eliminate cancer disparities.
Identifying and eliminating social disparities in cancer depend upon the availability and ready use of public health surveillance data at the national, state and local levels. As an example of advancing a statewide research agenda in cancer disparities, we present descriptive statistics from major public health surveillance data systems in Massachusetts. Disparities highlighted include higher breast cancer mortality rates among African-American women than women of other racial groups, lower rates of colorectal and cervical cancer screening among Asian-American residents, and striking gradients in cancer risk factor prevalence and screening by income and education. Challenges in utilizing public health surveillance data include lack of information in many domains of social inequity beyond race/ethnicity, uneven quality, and lack of stable, reportable data for smaller populations. Opportunities to maximize the usefulness of cancer registry data include application of geographic information systems and linkage with other data systems tracking information on health services outcomes and clinical trial participation. Analyses of surveillance data can spark advances not only in community-based participatory research but also in programs and policies that may ultimately eliminate disparities along the cancer continuum.


Gonadal Hormone-Dependent Sexual Differentiation of a Female-Biased Sexually Dimorphic Cell Group in the Principal Nucleus of the Bed Nucleus of the Stria Terminalis in Mice.
We recently reported a female-biased sexually dimorphic area in the mouse brain in the boundary region between the preoptic area and the bed nucleus of the stria terminalis (BNST). We reexamined this area and found that it is a ventral part of the principal nucleus of the BNST (BNSTp). The BNSTp is a male-biased sexually dimorphic nucleus, but the ventral part of the BNSTp (BNSTpv) exhibits female-biased sex differences in volume and neuron number. The volume and neuron number of the BNSTpv were increased in males by neonatal orchiectomy and decreased in females by treatment with testosterone, dihydrotestosterone, or estradiol within 5 days after birth. Sex differences in the volume and neuron number of the BNSTpv emerged before puberty. These sex differences became prominent in adulthood with increasing volume in females and loss of neurons in males during the pubertal/adolescent period. Prepubertal orchiectomy did not affect the BNSTpv, although prepubertal ovariectomy reduced the volume increase and induced loss of neurons in the female BNSTpv. In contrast, the volume and neuron number of male-biased sexually dimorphic nuclei that are composed of mainly calbindin neurons and are located in the preoptic area and BNST were decreased by prepubertal orchiectomy but not affected by prepubertal ovariectomy. Testicular testosterone during the postnatal period may defeminize the BNSTpv via binding directly to the androgen receptor and indirectly to the estrogen receptor after aromatization, although defeminization may proceed independently of testicular hormones in the pubertal/adolescent period. Ovarian hormones may act to feminize the BNSTpv during the pubertal/adolescent period.


The epigenetics of stroke recovery and rehabilitation: from polycomb to histone deacetylases.
Classical de-afferentation studies, as well as experience-dependent visual plasticity paradigms, have confirmed that both the developing and adult nervous system are capable of unexpected levels of plasticity. This capacity is underscored by the significant spontaneous recovery that can occur in patients with mild-to-moderate impairment following stroke. An evolving model is that an interaction of biological and environmental factors during all epochs post-stroke influences the extent and quality of this plasticity. Here, we discuss data that have implicated specific epigenetic proteins as integrators of environmental influences in 3 aspects of stroke recovery: spontaneous impairment reduction in humans; peri-infarct rewiring in animals as a paradigm for developing therapeutically-driven impairment reduction beyond natural spontaneous recovery; and, finally, classical hippocampal learning and memory paradigms that are theoretically important in skill acquisition for both impairment reduction and compensatory strategies in the rehabilitation setting. Our discussion focuses primarily on B lymphoma Mo-MLV1 insertion region proteins of the polycomb repressive complex, alpha thalassemia/mental retardation syndrome X-linked chromatin remodeling factors, and the best known and most dynamic gene repressors, histone deacetylases. We will highlight exciting current data associated with these proteins and provide promising speculation about how they can be manipulated by drugs, biologics, or noninvasive stimulation for stroke recovery.


Antidepressant treatment of juvenile depression.
Although depression is increasingly recognized in children and adolescents, these groups have responded to conventional tricyclic antidepressants less robustly than depressed adults. Emerging research suggests that juvenile depression may respond better to serotonergic and atypical pharmacologic agents, so guidelines for selection and administration of these agents are provided.


Despite misinformation, low trust, and conflict in Somalia, high demand for vaccines and a negative endorsement effect of non-state authorities.
Expanding vaccination coverage in conflict regions is crucial to the prevention of further mutations and outbreaks of COVID-19, as well as of future pandemics, worldwide. However, scholars' suppositions that low levels of trust and control over the flow of misinformation in these regions may necessitate tailored solutions-in particular, that health advice come from trusted non-state authorities-remain largely untested. To better understand the levels and drivers of COVID-19 vaccine receptivity in conflict regions, we partnered with the United Nations and the Somali Ministry of Justice to field a three-wave panel survey ([Formula: see text] = 1672; [Formula: see text] = 880; [Formula: see text] = 908) and vaccine endorsement experiment in South Central Somalia. We observe high overall demand for vaccines (between 90 and 94%), particularly among those who have experienced violence and illness, who perceive high economic disruption due to the pandemic, and who report more favorable views of and exposure to the West and Western-affiliated organizations. The high overall demand is particularly striking given respondents' low interpersonal trust and considerable exposure to vaccine disinformation. Contrary to scholars' and policymakers' expectations, we find that whereas endorsements from government health authorities increase vaccine receptivity, endorsements from non-state customary authorities and extremist militant group Al-Shabaab decrease support for vaccination (- 8 and - 16% points, respectively). Our findings caution against presupposing a need for different approaches to increasing vaccination coverage in conflict regions, and suggest that at least in the short-term, constraints on vaccine supply and access are more likely to bind than those on demand.


Preparation of fluorescent Au-SiO2 core-shell nanoparticles and nanorods with tunable silica shell thickness and surface modification for immunotargeting.
Gold-silica (Au-SiO2) core-shell nanoparticles (NPs) enable multifunctional properties for in vivo biomedical applications. However, scalable synthesis methods are lacking for the preparation of Au-SiO2 core-shell NPs less than 30 nm in overall diameter with a tunable silica shell less than 10 nm in thickness. Therefore, we prepared monodispersed Au-SiO2 core-shell NPs less than 30 nm in overall diameter with a uniform, tunable silica shell ∼1 to 14 nm in thickness using either citrate reduction followed by a modified Stöber method or oleylamine reduction followed by a reverse microemulsion method. Oleylamine reduction enabled up to 80-fold greater concentration yield compared to the citrate reduction method currently used for synthesizing Au core NPs. The formation of a tunable silica shell less than 10 nm in thickness was facilitated by controlling the molecular weight of the priming polymer (modified Stöber) or surfactant (reverse microemulsion) in addition to the concentration of the silane precursor, and was robust for encapsulating non-spherical morphologies such as Au nanorods. The reverse microemulsion method enabled several distinct advantages over the modified Stöber method, including greater control over the silica shell thickness, ∼16-fold greater yield in core-shell NP concentrations for scalable synthesis, and the ability to encapsulate controlled concentrations of a molecular payload (e.g., fluorophores with four different emission profiles) in the silica shell. Au-SiO2 core-shell NPs were also bioconjugated with immunoglobulin-G (IgG) as a model antibody to demonstrate immunotargeting. Bioactivity of Au-SiO2-IgG core-shell NPs was confirmed by agglomeration in the presence of protein A. The presence and proper orientation of IgG on NP surfaces was verified by direct observation in electron microscopy after negative staining. Therefore, the methods in this study for preparing and modifying Au-SiO2 core-shell NPs provide a platform for engineering core-shell NPs with size-dependent functional properties for multispectral/multimodal imaging, drug delivery, and combined theranostics.


[Survival of patients with biopsy-proven idiopathic pulmonary fibrosis: Chilean National Thorax Institute experience].
Idiopathic Pulmonary Fibrosis (IPF) is the most prevalent of all interstitial lung diseases. The usual underlying pathological picture is an interstitial pneumonia (UIP). To describe the evolution of a Chilean cohort of patients with IPF. Patients with the disease were identified at the pathology registry of National Institute of Thoracic Diseases, Santiago, Chile. Patients were included if they had surgical biopsy of UIP and compatible clinical and radiological characteristics. The medical records of included patients were reviewed, recording clinical information and lung function test results. Survival was analyzed obtaining death records from the Chilean National Identification Service. Data from 142 patients with a mean age of 58 years (42% men), were analyzed. Mean initial lung function showed a forced vital capacity (FVC) of 73%, carbon monoxide diffusing capacity (DLCO) of 57% and a distance covered in 6-minute walk (6MWT) of 95% of expected normal values. The median survival was 80 months. Predictors of survival were a DLCO of less than 40% and an oxygen saturation at the end of the 6MWT of less than 89%. Survival in this group of patients was higher than the figures reported elsewhere. DLCO and the fall of oxygen saturation after walking were predictors of mortality, as previously described in other populations.


The two compartment model of the stratum corneum: biochemical aspects and pathophysiological implications.
"La raison d'être" of the epidermis, as beautifully portrayed by Kathy Madison in The Journal of Investigative Dermatology (2003;121:231-41), describes the primary function of the skin: The terminal differentiation of an initially multipotent stem cell produces a protective, semi-permeable SC that permits terrestrial life. The permeability barrier function of the SC is provided by lipid bilayers lamellae surrounding anucleated apoptotic corneocytes. This structure has been described by Peter Elias as the "bricks and mortar" model where the bricks are the cornecytes and the mortar refers to the adjoining lipids. How important is the barrier to the skin? Certain genetic defects are characterized by profound barrier abnormaities due to alterations in either stratum corneum lipid metabolism or protein components of the corneocytes, producing ichthyotic genodermatosis. In this review, the mechanisms that drive barrier formation are summarized and this in the light of our recent scientific findings and publications in the domain of epidermal structure and function.


Genetic basis of strain variation in levels of radiation-induced apoptosis of thymocytes.
Levels of radiation-induced apoptosis of thymocytes were compared in C57BL/6J and C3Hf/Kam mice. For up to 8 h after irradiation, levels of apoptosis were higher in the C57BL/6J strain for all doses assayed. The heritability of the strain difference in the extent of apoptosis resulting from irradiation was investigated using a breeding study. Analysis of the F1 and F2 intercross progeny of these two strains provided strong evidence for a maternal effect but little evidence of sex linkage. The results indicate that in this strain combination the level of apoptosis of thymocytes after irradiation is a heritable trait that is likely to be controlled by few genes. These genes should be detectable in a mapping study.


Metabolomic Profiling of Adults with Congenital Heart Disease.
Metabolomic analysis may provide an integrated assessment in genetically and pathologically heterogeneous populations. We used metabolomic analysis to gain mechanistic insight into the small and diverse population of adults with congenital heart disease (ACHD). Consecutive ACHD patients seen at a single institution were enrolled. Clinical variables and whole blood were collected at regular clinical visits. Stored plasma samples were analyzed for the concentrations of 674 metabolites and metabolic markers using mass spectrometry with internal standards. These samples were compared to 28 simultaneously assessed healthy non-ACHD controls. Principal component analysis and multivariable regression modeling were used to identify metabolites associated with clinical outcomes in ACHD. Plasma from ACHD and healthy control patients differed in the concentrations of multiple metabolites. Differences between control and ACHD were greater in number and in degree than those between ACHD anatomic groups. A metabolite cluster containing amino acids and metabolites of amino acids correlated with negative clinical outcomes across all anatomic groups. Metabolites in the arginine metabolic pathway, betaine, dehydroepiandrosterone, cystine, 1-methylhistidine, serotonin and bile acids were associated with specific clinical outcomes. Metabolic markers of disease may both be useful as biomarkers for disease activity and suggest etiologically related pathways as possible targets for disease-modifying intervention.


Involvement of PUMA in pericyte migration induced by methamphetamine.
Mounting evidence indicates that methamphetamine causes blood-brain barrier damage, with emphasis on endothelial cells. The role of pericytes in methamphetamine-induced BBB damage remains unknown. Our study demonstrated that methamphetamine increased the migration of pericytes from the endothelial basement membrane. However, the detailed mechanisms underlying this process remain poorly understood. Thus, we examined the molecular mechanisms involved in methamphetamine-induced pericyte migration. The results showed that exposure of C3H/10T1/2 cells and HBVPs to methamphetamine increased PUMA expression via activation of the sigma-1 receptor, MAPK and Akt/PI3K pathways. Moreover, methamphetamine treatment resulted in the increased migration of C3H/10T1/2 cells and HBVPs. Knockdown of PUMA in pericytes transduced with PUMA siRNA attenuated the methamphetamine-induced increase in cell migration through attenuation of integrin and tyrosine kinase mechanisms, implicating a role of PUMA in the migration of C3H/10T1/2 cells and HBVPs. This study has demonstrated that methamphetamine-mediated pericytes migration involves PUMA up-regulation. Thus, targeted studies of PUMA could provide insights to facilitate the development of a potential therapeutic approach for alleviation of methamphetamine-induced pericyte migration.


The significance of promitochondrial structures in rat liver for mitochondrial biogenesis.
1. The heavy, light and fluffy mitochondrial fractions obtained by differential centrifugation were further characterized with respect to their protein synthesizing ability in vitro, their nucleic acid content, buoyant density of their DNA and ultrastructure. 2. The light mitochondrial fraction synthesized proteins in vitro at a rate 4-5 times as high as heavy and fluffy mitochondria. The incorporation ability of this fraction was also maximally affected by the thyroid status of the animal. The radioactivity in leucyl-tRNA of the light mitochondrial fraction was about 3-4 times as high as that of the other two fractions. 3. The heavy, light and fluffy mitochondrial fractions contained small but consistent amounts of RNA and DNA. Although the DNA content was the same in all mitochondria fractions, the light mitochondria contained relatively more RNA. The buoyant density of DNA from all the fractions was 1.701g/cm(3). 4. Electron microscopy revealed that the heavy mitochondria have a typical mitochondrial architecture, with densely packed cristae and a well developed double membrane. Light mitochondria were also surrounded by double membranes, but were smaller in size and contained less cristae. The fluffy fraction consisted of a mixture of well formed mitochondria and those in the process of degradation. 5. The significance of these findings in relation to mammalian mitochondrial genesis is discussed.


Association between pet ownership and coronary artery disease in a Chinese population.
A number of studies have suggested the benefits of pet ownership to human health, including cardiovascular disease (CVD). However, there are few findings regarding pet ownership and coronary artery disease (CAD). The objective of this study is to investigate the association between pet ownership and CAD in a Chinese population. From October 2015 to May 2016, a survey consisting of 561 consecutive patients was done in Nanjing, China. Based on the results of coronary arteriography for the first time, participants were divided into 2 groups (non-CAD and CAD groups). Pet ownership information was collected by using a questionnaire. After multivariate adjustments, pet ownership was associated with a decreased CAD risk (odds ratios [OR]: 0.504, 95% confidence intervals [CIs]: 0.310-0.819). There was a reduced CAD risk among dog owners (OR: 0.420, 95% CI: 0.242-0.728) when compared with the cat group (OR: 0.738, 95% CI: 0.240-2.266) and the cat and dog group (OR: 1.052, 95% CI: 0.330-3.355). With the increase of pet ownership duration, there was a decreased tendency of CAD risk, including years of keeping pets (P for trend = 0.008) and time of playing with pets per day (P for trend = 0.001). In addition, similar dose-response relationship was observed for starting age of keeping pets (P for trend = 0.002). Pet ownership, especially dog ownership, can be a protective factor for CAD in Chinese patients.


Electroacupuncture attenuates inflammatory pain via peripheral cannabinoid receptor type 1 signaling pathway in mice.
Pain is strongly associated with neuro-immune activation. Thus, the emerging role of the endocannabinoid system in neuro-inflammation is important. Acupuncture has been used for over 2500 years and is widely accepted for the management of pain. Our study aimed to investigate the effects of electroacupuncture on the regulation of cannabinoid receptor type 1 within the peripheral nervous system. Inflammatory pain was induced by injecting Complete Freund's adjuvant to induce mechanical and thermal hyperalgesia. Electroacupuncture significantly attenuated the mechanical and thermal sensitivities, and AM251, a cannabinoid receptor type 1 antagonist, eliminated these effects. Dual immunofluorescence staining demonstrated that electroacupuncture elevated expression of cannabinoid receptor type 1, co-localized with Nav 1.8. Furthermore, electroacupuncture significantly reduced levels of Nav 1.8 and COX-2 by western blot analysis, but not vice versa as AM251 treatment. Our data indicate that electroacupuncture mediates antinociceptive effects through peripheral endocannabinoid system signaling pathway and provide evidence that electroacupuncture is beneficial for pain treatment.


Drivers of Liking in a Model Retorted Creamy Tomato Soup System with Varying Levels of Sodium, Fat, and Herbs.
Targeting both sodium and fat reduction in processed foods while maintaining consumer acceptance is a challenge in the food industry due to the innate liking by humans toward both ingredients. Canned soup is one of the leading processed food categories containing high quantities of sodium. Efforts to reduce both sodium and fat content in canned soup products have been problematic due to resulting decreased consumer acceptance. The objective of this study was to characterize the changes in the drivers of liking when sodium, fat, and herb levels are varied in a model retorted soup system. A creamy tomato soup system was developed containing four fat levels (free, low, reduced, regular), three sodium levels (low, reduced, regular), and two herb levels (with, without). Ninety-six consumers rated the soups for overall liking on a 9-point hedonic scale. A descriptive analysis panel composed of 10 trained panelists profiled the sensory attributes among the soups. Higher sodium level was found to be a driver of liking when fat content was reduced. Soups were significantly different in saltiness (taste) and tomato (aroma-by-mouth), based on varying fat and sodium levels. Herb content increased overall liking of lower sodium and fat soups and impacted attribute characterization of soups. Future steps would include approaches to increase overall liking of lower fat and sodium soups. Formulation modifications that would decrease intensities of attributes that characterize lower fat and sodium soups, such as sour (taste and aftertaste), grainy (texture), and darkness (appearance), will aid in higher consumer acceptance of these soups. PRACTICAL APPLICATION: With hypertensive individuals requiring reductions of both dietary sodium and fat, food products lower in fat and sodium while maintaining sensory acceptability are needed. Identifying drivers of liking when sodium and fat levels are reduced in processed food systems can assist in product reformulation to increase overall liking. Additionally, understanding the impact of herbs in consumer acceptance of lower sodium and fat food products will also contribute to further advances in product development.


Thermographic analysis of the effect of composite type, layering method, and curing light on the temperature rise of photo-cured composites in tooth cavities.
The purpose of this study was to investigate temperature rise in the composite and dentin of a class I cavity in extracted human molars under different restoration conditions, including the use of different composite types, layering methods, and curing lights. Open occlusal cavities were prepared on 28 extracted human molars. A conventional (Filtek Z250) and a bulk-fill (Filtek Bulk Fill Posterior; BFP) composite were used to restore the preparations. BFP was incrementally layered or bulk-filled. Bulk-filled BFP was cured with two different lights, the Elipar S10 and the BeLite. Each layer was illuminated for 20s, while thermograms of the specimens were recorded for 100s using an infrared thermal camera. Temperature changes on the composite and dentin surfaces were obtained at points of interest (POI) pertaining to successive incremental distances of 0.75mm from the top of the cavity to the pulp. The polymerization kinetics of each composite was determined using photo-differential scanning calorimetry. The greatest temperature rise was observed 0.75mm apical from the top of the cavity. All groups showed over 6°C maximum temperature rise (ΔTmax) at the pulpal side of the dentin. Upon curing, Z250 reached ΔT=5°C faster than BFP; however, ΔTmax of the two composites were comparable at any POI. Bulk filling showed greater ΔTmax than incremental filling at 0.75mm apical from the top and in the middle of the cavity. The Elipar S10 light generated faster temperature changes in the curing composite at all recorded positions throughout the depth of the cavity and greater ΔTmax in all POIs compared to BeLite. Real-time thermographic analysis demonstrated that the composite type and layering method did not influence the temperature rise at the pulpal side of dentin during composite restoration of an occlusal preparation in a tooth. The amount and initial rate of temperature increase was most affected by the radiant exposure of the light curing unit. Within the limitations of this in vitro study, when irradiation time is constant, a curing light with higher radiant power can induce relatively high thermal transfer, thereby increasing the risk of pulpal damage.


In pursuit of individualised margins for prostate cancer patients undergoing image-guided radiotherapy: the effect of body mass index on intrafraction prostate motion.
To analyse the relationship between body mass index (BMI) and intrafraction displacement in patients undergoing prostate cancer image-guided radiotherapy. An analysis was carried out on 151 prostate cancer patients treated with radical dose radiotherapy between January 2007 and March 2009. Patients had their height, weight and daily intrafraction prostate displacement data collected prospectively during fiducial marker image-guided radiotherapy with orthogonal imaging. For each of anterior-posterior, left-right and superior-inferior axes, a univariable linear regression analysis was carried out with the individual patient standard deviation of shift as the response variable and BMI as a continuous explanatory variable. Displacement measurements were recorded from 4764 pre- and post-treatment image sets. Patients were grouped according to BMI as normal weight (24%), overweight (52%), obese (18%), severely obese (3%) or morbidly obese (3%). For intrafraction displacement, a one unit increase in BMI affected the standard deviation of shift by: anterior-posterior -0.02 (95% confidence interval -0.040 to 0.000), left-right -0.006 (95% confidence interval -0.020 to 0.008) and superior-inferior -0.020 (95% confidence interval -0.037 to -0.003). Our data indicate that patients with a higher BMI have less intrafraction displacement of the prostate in the superior-inferior dimension compared with patients with a lower BMI. This has implications for individualised treatment margins for future prostate cancer patients undergoing image-guided radiotherapy. Further study is recommended.


Maintenance of retinal stem cells by Abcg2 is regulated by notch signaling.
ABCG2 belongs to the ATP-binding cassette superfamily of transmembrane proteins and is ubiquitously expressed in stem cells including those in the developing nervous system. The ability of ABCG2 to preferentially exclude DNA-intercalating dyes is regarded to be the basis for the enrichment of stem cells or progenitors as dye(low) side population (SP) cells. However, the role of ABCG2 in neural stem cells remains speculative and poorly understood. Here, we demonstrate using retinal stem cells, that ABCG2 is the molecular determinant of SP cell phenotype of neural stem cells and plays an important role in their maintenance. Overexpression of ABCG2 prevents the SP cell phenotype and adversely affects the lineage commitment of retinal stem cells. By contrast, targeted attenuation of ABCG2 depletes retinal SP cells and promotes their differentiation along pan neural and retinal lineages. In addition, we demonstrate for the first time that ABCG2 is a target of Notch signaling, and as such, constitutes one of the genes in the regulatory network of Notch signaling, involved in the maintenance of stem cells.


Methacholine inhalation challenge: a shorter, cheaper and safe approach.
Increased nonspecific bronchial hyperresponsiveness to pharmacological agents such as histamine or methacholine (MCh) is a hallmark of asthma. The measurement of airway reactivity is quite sensitive but testing is tedious, and time and money consuming. The present aim was, therefore, to design the shortest possible, yet safe inhalation challenge protocol applicable for a lung function referral centre. All records of studies performed in our institution during 1996 were analyzed retrospectively with a baseline ratio (bl) of forced expiratory volume in one second/forced vital capacity (FEV1/FVC) > or = 0.7 (n=449). It was questioned what the initial dose should be, and whether some inhalation steps could have been skipped without losing pertinent information and/or causing an adverse response (a fall in FEV1 >40%). When unavailable, provocative dose causing a 20% fall in FEV1 (PD20) values were obtained by linear inter- or extrapolation of the existing data. The present study showed that three-fold concentration steps could have been employed with minimal change in outcome. Only 151449 patients (3.3%) would have experienced a severe response. Five subjects (of 169, 3.0%) with FEV1/FVCbl 0.7-0.8 reacted to inhalation up to 0.073 micromol. Four subjects (of 280, 1.4%) with FEV1/ FVCbl> or =0.8 reacted to inhalation up to 0.219 micromol. The authors suggest that: 1) an initial dose of 0.219 micromol (initial concentration= 0.21 mg.mL(-1)) may be used when the baseline ratio of forced expiratory volume in one second to forced vital capacity > or =0.8 and 0.073 micromol (initial concentration=0.07 mg.mL(-1)) when the baseline ratio is <0.8; 2) a tripling dose protocol is easier to perform, cheaper and 30.2%, faster, yet just as safe; and 3) other abbreviated protocols used in epidemiologic settings may not be applicable in a referral centre setting.


Ultrashort pulse propagation through a strongly scattering medium: simulation and experiments.
Forward light scattering of femtosecond pulses through strongly scattering media is investigated experimentally and numerically. Computations are based on a semi-Monte Carlo method including polarization effects when experiments depend on a Ti:sapphire regenerative amplifier (100 fs, 1 kHz, 1 mJ@ 800 nm). The temporal separation between ballistic light and scattered light is exhibited and used to perform optical depth measurements up to 22 (transmission factor of approximately 10(-10)). Quantitative comparisons between experiments and Monte Carlo simulations show a good agreement. Temporal forward scattered light evolutions with concentration and particle size are presented. Numerical results show that the early scattered light contains information on particle size, opening the way to particle sizing in strongly scattering media.


Population requirements for capitation planning in pediatric cardiac surgery.
To determine the population number necessary to generate a sufficient volume of pediatric cardiac surgeries to allow accurate prediction of resource utilization. All pediatric cardiac surgical patients receive care in our institution by means of only four clinical pathways that are based on acuity, not diagnosis or procedure. This allows accurate tracking of resource utilization. Based on available information, 750 consecutive surgically treated patients were retrospectively assigned to a pathway. They were subsequently subdivided into study groups of decreasing sizes from 150 to 35. Variability of pathway distribution from group to group was examined as a measure of the ability to predict resource utilization based on group size. Pediatric cardiac statistics from the state of Ohio were then used to extrapolate to the population base necessary to generate each group size. A regional pediatric cardiac referral center. All sequential patients who underwent pediatric cardiac surgery between July 1991 and January 1994. Statewide statistics showed that a population base of 1 million people generates 100 pediatric cardiac operations. Groups of 100 patients or greater had minimal variation in pathway distribution from group to group, allowing accurate prediction of hospital charges. This was not true for groups of 50 patients or less. Resource utilization for pediatric cardiac surgery can be accurately predicted in a capitated setting for populations of 1 million covered lives (100 procedures) or greater. For populations of 500 000 covered lives or less, variability of case mix is great enough to suggest the need for a more individualized payment mechanism.


Longitudinal random effects models for genetic analysis of binary data with application to mastitis in dairy cattle.
A Bayesian analysis of longitudinal mastitis records obtained in the course of lactation was undertaken. Data were 3341 test-day binary records from 329 first lactation Holstein cows scored for mastitis at 14 and 30 days of lactation and every 30 days thereafter. First, the conditional probability of a sequence for a given cow was the product of the probabilities at each test-day. The probability of infection at time t for a cow was a normal integral, with its argument being a function of "fixed" and "random" effects and of time. Models for the latent normal variable included effects of: (1) year-month of test + a five-parameter linear regression function ("fixed", within age-season of calving) + genetic value of the cow + environmental effect peculiar to all records of the same cow + residual. (2) As in (1), but with five parameter random genetic regressions for each cow. (3) A hierarchical structure, where each of three parameters of the regression function for each cow followed a mixed effects linear model. Model 1 posterior mean of heritability was 0.05. Model 2 heritabilities were: 0.27, 0.05, 0.03 and 0.07 at days 14, 60, 120 and 305, respectively. Model 3 heritabilities were 0.57, 0.16, 0.06 and 0.18 at days 14, 60, 120 and 305, respectively. Bayes factors were: 0.011 (Model 1/Model 2), 0.017 (Model 1/Model 3) and 1.535 (Model 2/Model 3). The probability of mastitis for an "average" cow, using Model 2, was: 0.06, 0.05, 0.06 and 0.07 at days 14, 60, 120 and 305, respectively. Relaxing the conditional independence assumption via an autoregressive process (Model 2) improved the results slightly.


Differences in plasma proteomes for active tuberculosis, latent tuberculosis and non-tuberculosis mycobacterial lung disease patients with and without ESAT-6/CFP10 stimulation.
Tuberculosis (TB) is one of the world's most problematic infectious diseases. The pathogen Mycobacterium tuberculosis (Mtb) is contained by the immune system in people with latent TB infection (LTBI). No overt disease symptoms occur. The environmental and internal triggers leading to reactivation of TB are not well understood. Non-tuberculosis Mycobacteria (NTM) can also cause TB-like lung disease. Comparative analysis of blood plasma proteomes from subjects afflicted by these pathologies in an endemic setting may yield new differentiating biomarkers and insights into inflammatory and immunological responses to Mtb and NTM. Blood samples from 40 human subjects in a pastoral region of Ethiopia were treated with the ESAT-6/CFP-10 antigen cocktail to stimulate anti-Mtb and anti-NTM immune responses. In addition to those of active TB, LTBI, and NTM cohorts, samples from matched healthy control (HC) subjects were available. Following the generation of sample pools, proteomes were analyzed via LC-MS/MS. These experiments were also performed without antigen stimulation steps. Statistically significant differences using the Z-score method were determined and interpreted in the context of the proteins' functions and their contributions to biological pathways. More than 200 proteins were identified from unstimulated and stimulated plasma samples (UPSs and SPSs, respectively). Thirty-four and 64 proteins were differentially abundant with statistical significance (P < 0.05; Benjamini-Hochberg correction with an FDR < 0.05) comparing UPS and SPS proteomic data of four groups, respectively. Bioinformatics analysis of such proteins via the Gene Ontology Resource was indicative of changes in cellular and metabolic processes, responses to stimuli, and biological regulations. The m7GpppN-mRNA hydrolase was increased in abundance in the LTBI group compared to HC subjects. Charged multivesicular body protein 4a and platelet factor-4 were increased in abundance in NTM as compared to HC and decreased in abundance in NTM as compared to active TB. C-reactive protein, α-1-acid glycoprotein 1, sialic acid-binding Ig-like lectin 16, and vitamin K-dependent protein S were also increased (P < 0.05; fold changes≥2) in SPSs and UPSs comparing active TB with LTBI and NTM cases. These three proteins, connected in a STRING functional network, contribute to the acute phase response and influence blood coagulation. Plasma proteomes are different comparing LTBI, TB, NTM and HC cohorts. The changes are augmented following prior blood immune cell stimulation with the ESAT-6/CFP-10 antigen cocktail. The results encourage larger-cohort studies to identify specific biomarkers to diagnose NTM infection, LTBI, and to predict the risk of TB reactivation.


Impulsive aggression, delay discounting, and adolescent suicide attempts: effects of current psychotropic medication use and family history of suicidal behavior.
Impulsive-aggressive behaviors have been consistently implicated in the phenomenology, neurobiology, and familial aggregation of suicidal behavior. The purpose of this study was to extend previous work by examining laboratory behavioral measures of delayed reward impulsivity and impulsive aggression in adolescent suicide attempters and never-suicidal comparison subjects. Using the Point Subtraction Aggression Paradigm (PSAP) and the Delay Discounting Task (DDQ), the authors examined delay discounting and impulsive aggression in 40 adolescent suicide attempters, ages 13-18, and 40 never-suicidal, demographically matched psychiatric comparison subjects. Overall, suicide attempters and comparison subjects performed similarly on the PSAP and DDQ. There was a significant group by current psychotropic medication use interaction (p=0.013) for mean aggressive responses on the PSAP. Group comparisons revealed that attempters emitted more aggressive responses per provocation than comparison subjects, only in those not on psychotropic medication (p=0.049), whereas for those currently treated with psychotropic medication, there were no group differences (p>0.05). This interaction effect was specific to current antidepressant use. Among all subjects, family history of suicidal behavior (suicide or suicide attempt) in first degree relatives was significantly correlated with both delay discounting (r=-0.22, p=0.049), and aggressive responding (r=0.27, p=0.015). Family history of suicidal behavior was associated with delay discounting, but not with aggressive responding on the PSAP, after controlling for relevant covariates. In this study, impulsive-aggressive responding was associated with suicide attempt only in those not being treated with antidepressants. Future work to replicate and extend these findings could have important therapeutic implications for the treatment of depressed suicide attempters, many of whom are affected by impulsive aggression.


Comparing telehealth-based and clinic-based group cognitive behavioral therapy for adults with depression and anxiety: a pilot study.
The primary objective of this pilot study was to demonstrate reliable adherence to a group cognitive behavioral (CBT) therapy protocol when delivered using on-line video conferencing as compared with face-to-face delivery of group CBT. A secondary aim was to show comparability of changes in subject depression inventory scores between on-line and face-to-face delivery of group CBT. We screened 31 individuals, 18 of whom met the criteria for a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) diagnosis of mood and/or anxiety disorder. All qualifying participants had the necessary equipment (computer, webcam, Internet) for participation in the study, but could exercise their preference for either the on-line or face-to-face format. Eighteen completed the 13 weekly session intervention program (ten face-to-face; eight video conferencing). We coded adherence to protocol in both intervention formats and generated pre-post changes in scores on the Beck Depression Inventory Second Edition (BDI-II) for each participant. Application of the CBT protocol coding system showed reliable adherence to the group CBT intervention protocol in both delivery formats. Similarly, qualitative analysis of the themes in group discussion indicated that both groups addressed similar issues. Pre-post intervention scores for the BDI-II were comparable across the two delivery formats, with 60% of participants in each group showing a positive change in BDI-II severity classification (eg, from moderate to low symptoms). This pilot study demonstrates that group CBT could be delivered in a technology-supported environment (on-line video conferencing) and can meet the same professional practice standards and outcomes as face-to-face delivery of the intervention program.


Between the modern and the postmodern. The possibility of self and progressive understanding in psychology.
Psychology assumes defensible notions of human subjectivity and understanding. Yet, some versions of postmodernism, including some of those currently influential within psychology, eschew the possibility of the kind of understanding-capable personhood on which modern psychology has depended. The authors argue for a skeptical, middle-ground position that might allow psychologists to resist a forced choice between modernism and postmodernism in their subject matter and understanding. The authors set up their argument with 2 stories of human development and change. These stories assume no fixed, essentialist foundations of the sort favored in classically modern psychologies, yet they maintain the possibility of both self and understanding within a real but contingent physical, biological, and sociocultural world. The authors then articulate a middle-ground position as one that avoids the fixed foundationalism, essentialism, and absolute certitude of modernity, without endorsing the radical arbitrariness, antisubjectivism, and anarchistic relativism of some versions of postmodernity.


Measurement of serum lipase activity with the oxygen electrode.
We describe the measurement of lipase (triacylglycerol lipase; EC 126.96.36.199) in serum by continuous monitoring of relative rates of oxygen consumption with a polarographic oxygen electrode. The reactions described by Proelss and Wright (Clin. Chem. 23: 522-531, 1977) are used: trilinolein, with lipase catalysis, yields linoleic acid, which reacts with oxygen in the presence of lipoxygenase. Lipase activity is measured by comparing the zero order reaction rate of the specimen with that obtained with linoleic acid standards. Results for lipase (y) correlated well with those by the copper-soap method of Myrtle and Zell (x) (Clin. Chem. 21: 1469-1473, 1975); y = 0.33x - 11; r = 0.98; n = 34. Results are unaffected by specimen dilution, and the standard curve is linear to 520 U/L. Day-to-day precision (CV) is 10.4% for normal activities, 6.1% for above-normal activities. We believe the method offers a precise, practical approach to lipase analysis.


Does enhancement of specific immune responses predispose laying hens for feather pecking?
To mimic airborne immune challenges, layer hens were intratracheally and concurrently challenged with various doses of the protein antigen human serum albumin (HuSA) and the pathogen-associated molecular pattern lipopolysaccharide (LPS) at 7 and 13 wk of age. All groups received 1 similar dose of HuSA plus LPS at 11 mo of age. Evaluation of plumage and body condition at 12 mo of age revealed that birds that had undergone intratracheal immunization with a high dosage of HuSA, irrespective of the concurrent dose of LPS, had significantly more feather damage but less wounds to the vent region, as opposed to birds not receiving HuSA. On the other hand, a high dosage of LPS was related to comb damage. These results suggest that stimulation of specific (humoral) immune responses (to HuSA) rather than innate responses (to LPS) at a young age may predispose layers for feather pecking (FP) behavior at later ages. Involvement of immune mechanisms in FP or vent damage may differ. Predisposal for FP behavior by specific immunity can have consequences for health and vaccine management.


Regulation of synaptic position, size, and strength in anuran skeletal muscle.
An analysis of the physiology, morphology, and position of endplates on identified fibers in the Xenopus laevis pectoralis muscle has revealed the following. 1. The percentage of fibers with one endplate is lower in large muscles, and within the same muscle, singly innervated fibers are smaller than dually innervated fibers. 2. Single junctions tend to be stronger than junctions on dually innervated fibers. 3. Single junctions typically are located near the middle of their fibers, while the endplates on dually innervated fibers are located toward either end and usually are separated by at least 20% of the total fiber length. A significant proportion of dually innervated fibers appears to be innervated by the same axon at both junctions. 4. Junctions on the same dually innervated fiber tend to be more similar in length than do junctions on different fibers of the same input resistance. This observation is the same whether both junctions on a given fiber are formed by the same or different axons. There is no corresponding tendency for greater similarity in physiological strength of paired junctions, which frequently show large differences in endplate potential amplitude. 5. The total terminal length on dually innervated fibers of equivalent input resistance is inversely correlated with the mean release per unit length and total release of both junctions. There is no apparent correlation between the distance separating endplates and their strength or length. The data support a model of synaptic regulation in which nerve terminals are attracted, grow, and are maintained in proportion to the amount of a substance supplied by muscle fibers. Our findings suggest that such a substance is produced or distributed uniformly throughout each fiber in amounts proportional to the fiber size and inversely proportional to the total transmitter output of all junctions innervating the fiber. A form of competitive interaction between the terminals which helps to determine synaptic spacing may involve local depletion or inactivation of this substance.


Medical management of human immunodeficiency virus infection.
The human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome (AIDS) pandemic has pervasive effects on culture, economics, policy, and human development. All organs can be affected by complications of HIV/AIDS, including the eye. When sufficient resources are available and widespread antiretroviral resistance does not exist, the four available classes of antiretroviral agents - nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors - can be combined to provide highly active antiretroviral therapy (HAART). For many (not all) patients, HAART converts an inexorably fatal disease into a chronic disease with a fairly good prognosis. Use of HAART often induces partial immune recovery, which has predominantly beneficial effects on ocular complications of AIDS. However, HAART-induced immune recovery sometimes results in immune recovery inflammatory syndromes, such as immune recovery uveitis. Use of HAART is the single most useful intervention for most patients with ocular complications of AIDS. However, specific ocular therapy is also critical to avoid blindness in the early months before immune recovery can occur, or if HAART is unavailable. Increasing availability of HAART worldwide shows great promise to alleviate one of the world's greatest plagues. However, predictable secular trends in the AIDS epidemic make it likely that the number of cases of ocular complications of AIDS will increase substantially before they decrease. Ophthalmologists worldwide should be familiar with the diagnosis and management of cytomegalovirus retinitis - the most common ocular complication of AIDS - and should establish partnerships with physicians who are able to provide HAART. Research is needed to determine the optimal approach for managing cytomegalovirus retinitis in resource-constrained settings.


Determination of plasma fibronectin and serum C-reactive protein in patients with cerebrovascular events.
The relationship between the levels of C-reactive protein (CRP) and fibronectin (FN) and atherosclerotic diseases such as coronary heart disease has already been studied, but their relationship with cerebrovascular events has not. The aim of this study was to determine the levels of plasma FN and serum CRP in cerebrovascular events, and their relationship with the outcome of the disease. CRP and FN levels were analysed in 133 patients with acute cerebrovascular disease, together with 66 healthy controls. Cerebrovascular event patients were divided into subgroups according to disease severity. FN and CRP levels in patients with cerebrovascular disease were found to be significantly elevated compared with the control group (p<0.001). CRP levels correlated with disease severity, in contrast to FN levels. We conclude that FN is not a clinically useful marker in patients with acute differentiative cerebrovascular events, in contrast to CRP which may be useful in such cases.


The genetics of mental illness: implications for practice.
Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neural substrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history and treatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born of early pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explain the pathogenesis of depression or schizophrenia. Gone is the notion that there is a single gene that causes any mental disorder or determines any behavioural variant. The concept of the causative gene has been replaced by that of genetic complexity, in which multiple genes act in concert with non-genetic factors to produce a risk of mental disorder. Discoveries in genetics and neuroscience can be expected to lead to better models that provide improved representation of the complexity of the brain and behaviour and the development of both. There are likely to be profound implications for clinical practice. The complex genetics of risk should reinvigorate research on the epidemiology and classification of mental disorders and explain the complex patterns of disease transmission within families. Knowledge of the timing of the expression of risk genes during brain development and of their function should not only contribute to an understanding of gene action and the pathophysiology of disease but should also help to direct the search for modifiable environmental risk factors that convert risk into illness. The function of risk genes can only become comprehensible in the context of advances at the molecular, cellular and systems levels in neuroscience and the behavioural sciences. Genetics should yield new therapies aimed not just at symptoms but also at pathogenic processes, thus permitting the targeting of specific therapies to individual patients.


Effects of long-term oral administration of arachidonic acid and docosahexaenoic acid on the immune functions of young rats.
Natural killer (NK) cells have many functional activities, including cytotoxicity and the capacity to produce cytokines and chemokines. NK cell activity is regulated partly by eicosanoids, which are produced from arachidonic acid (ARA) and eicosapentaenoic (EPA) acid. In this study, we investigated the effects of long-term therapy with ARA or docosahexaenoic acid (DHA) on the cytotoxic effects of the NK cells of young rats, which were fed on a nonfish oil diet for two generations. Control oil, ARA (240 mg/kg BW/day) or DHA (240 mg/kg BW/day) were orally administrated to the rats for 13 weeks before determining the cytotoxic activity of NK cells from the spleen against YAC-1 mouse lymphoma cell line, as well as the plasma levels of docosanoids or eicosanoids and inflammatory cytokines. Long-term ARA administration significantly suppressed the cytotoxic activity of NK cells. Moreover, ARA administration significantly increased the plasma levels of ARA, prostaglandin (PG) E2, and PGD2. However, DHA administration did not produce any different effects compared with those in the control rats. Furthermore, the inflammatory cytokine levels were not affected by the administration of ARA or DHA. These results suggest that long-term ARA administration has an inhibitory effect on the tumor cytotoxicity of NK cells in rat spleen lymphocytes owing to the enhanced synthesis of PGE2 and PGD2 from ARA because of the elevated plasma ARA levels in young rats.


Brain organization for music processing.
Research on how the brain processes music is emerging as a rich and stimulating area of investigation of perception, memory, emotion, and performance. Results emanating from both lesion studies and neuroimaging techniques are reviewed and integrated for each of these musical functions. We focus our attention on the common core of musical abilities shared by musicians and nonmusicians alike. Hence, the effect of musical training on brain plasticity is examined in a separate section, after a review of the available data regarding music playing and reading skills that are typically cultivated by musicians. Finally, we address a currently debated issue regarding the putative existence of music-specific neural networks. Unfortunately, due to scarcity of research on the macrostructure of music organization and on cultural differences, the musical material under focus is at the level of the musical phrase, as typically used in Western popular music.


Insulin implants prevent the temporal development of mechanical allodynia and opioid hyposensitivity for 24-wks in streptozotocin (STZ)-diabetic Wistar rats.
As the diabetes control and complications trial showed that intensive glycemic control in patients with Type 1 diabetes decreased the risk of development of long-term microvascular complications including painful diabetic neuropathy by approximately 60%, hyperglycemia was implicated as a causal factor in the etiology of this condition. Hence, the present study was designed as a 24-week longitudinal investigation of the extent to which the level of glycemic control in the streptozotocin (STZ)-diabetic rat model of Type 1 diabetes affects the development of mechanical allodynia and opioid hyposensitivity in these animals. Diabetes was fully developed (blood glucose levels ≥ 15 mM) in adult male Wistar rats by 7 days after intravenous STZ (75 mg/kg) administration. Mechanical allodynia developed in a temporal manner in the rat hindpaws, such that it was fully developed by 6 weeks and persisted for at least 24 weeks post-STZ administration. Morphine hyposensitivity also developed in a temporal manner in the same animals. By contrast, restoration and maintenance of euglycemia using insulin implants commencing at diabetes diagnosis on Day 7 post-streptozotocin administration, prevented development of both mechanical allodynia and opioid hyposensitivity in STZ-diabetic rats for the 24-week study duration. This study shows that long-term restoration of euglycemia over a 6-month period in STZ-diabetic rats prevents the hallmark symptoms of PDN including morphine hyposensitivity. Our findings are consistent with epidemiological data showing that tight glycemic control in patients with Type 1 diabetes markedly reduces the prevalence of PDN, further implicating persistent hyperglycemia as a pathogenic factor.


Identification of genetic variation in the 5' and 3' non-coding regions of the protamine genes in patients with protamine deregulation.
Deregulation of sperm nuclear protamine ratio (P1/P2) has been shown to correlate with male factor infertility in humans, but the cause of this abnormal protein expression has yet to be identified. Recent studies have shown that there is little genetic variability in the coding regions of either of the protamine gene sequences. However, these studies did not investigate the 5' or 3' non-coding regions of these genes for mutations that might account for changes in the transcriptional or translational regulation of the protamines. In an effort to determine if genetic variation in these non-coding regions may account for aberrant protamine expression, we have sequenced the 5' and 3' untranslated regions (UTRs) of both protamine 1 (P1) and protamine 2 (P2) genes in a population of infertile men with protamine deregulation, men presenting for infertility work-up with normal protamine ratios, and a population of unrelated, fertile men from the Utah Genetic Reference Project (UGRP). This analysis has identified 14 single nucleotide polymorphisms (SNPs), of which 13 were novel SNPs in the UTRs of P1 and P2, and verified the existence of a variable length repeat (VLR), GAn, in the P2 5' region. The SNP frequencies and VLR allelic frequencies did not achieve statistical significance between the populations, however, one of the SNPs identified in the 3' UTR of protamine 2 was found at a low frequency in the abnormal protamine patients, but was completely absent in men with verified normal protamine ratio and donors of known fertility. In conclusion, a number of SNPs have been reported in the protamine genes and the untranslated regions, however, these gene variants do not appear to be responsible for protamine deficiency. Hence, the underlying cause for aberrant protamine expression may possibly be due to abnormalities in candidate spermatogenic transcriptional/translational regulators, post-translational modifiers, or as-of-yet unidentified factors affecting the testicular environment.


Functional effects of the ABO locus polymorphism on plasma levels of von Willebrand factor, factor VIII, and activated partial thromboplastin time.
Lower levels of factor VIII and von Willebrand factor (vWF) have been reported in individuals with blood type O compared with individuals with other ABO blood types. However, this relationship has been demonstrated only by association studies and not by linkage studies. Also, it is not clear whether the ABO locus exerts a functional effect directly on these plasma factors or whether the ABO locus is in linkage disequilibrium with another locus that controls these factors. To distinguish between these 2 possibilities, we applied new statistical methods combining linkage and association tests in a pedigree-based sample. In contrast to most previous studies that used the ABO phenotypes, our study used the ABO genotypes, permitting us to distinguish AO from AA and BO from BB. Our results clearly showed significant linkage between the ABO locus and vWF antigen (P=0.00075). In addition, factor VIII coagulant activity and activated partial thromboplastin time showed suggestive linkage with the ABO locus (P=0.10 and P=0.13). All 3 plasma phenotypes showed significant differences between OO and non-OO genotypes. In addition, vWF antigen exhibited significant differences between O heterozygotes and non-OO homozygotes. This study is unique because it used a combined linkage and association test, which indicated that the ABO locus itself has a functional effect on these plasma phenotypes.


Changes in the aerobic faecal flora of patients treated with antibiotics for acute intra-abdominal infection.
An open observational study was performed to investigate changes in the rectal flora and antibiotic susceptibility among faecal bacteria in patients treated with antibiotics for acute intra-abdominal infection. One hundred and forty patients with acute intra-abdominal infection requiring antibiotic treatment and hospitalization were included. Eight surgical units from the southern part of Sweden participated, between January 2006 and November 2007. Antibiotic treatments were according to local guidelines. Rectal swabs were obtained on admission (sample 1) and 2-14 days after the end of antibiotic treatment (sample 2). Aerobic bacteria and yeasts were analysed. The material was divided into 2 groups: 1 group with Enterobacteriaceae and 1 group with non-fermentative Gram-negative bacteria. The susceptibility to antibiotics in each group was compared between samples 1 and 2. The main finding of this study on patients with severe intra-abdominal infections was a shift in the aerobic faecal flora following antibiotic treatment, from Escherichia coli to other more resistant Enterobacteriaceae, Enterococcus faecium, and yeasts. The susceptibility to cephalosporins and piperacillin-tazobactam decreased in Enterobacteriaceae. Following antibiotic treatment, a shift in the aerobic rectal flora to species with intrinsic antibiotic resistance was observed. This indicates that the emergence of resistance is not due to new mutations, but rather to selection of more resistant species. This should be taken into account when designing treatments for secondary intra-abdominal infections.


The peripheral zone of increase density in cranial computed tomography.
The band of increased attenuation seen on in vivo CCT images of adults, frequently designated as the cerebral cortex, has been proved clinically and experimentally to be an artifact in the reconstructed image. Recognition of this artifact may be of help in identifying intracranial lesions, such as shallow subdural hematomas. Attenuation values of isolated cortex and white matter were also studied and do not account for the band of high attenuation.


An unusual case of leptomeningeal carcinomatosis in a patient with primary adenocarcinoma of the lung.
A 72-year-old man was brought to the emergency department with acute onset confusion and haemoptysis. Chest X-ray showed a possible lung mass, while CT head showed a fluid-filled, space-occupying lesion (SOL) in the right frontal lobe of the brain. MRI head indicated that this SOL had spilt its contents into the subarachnoid and intraventricular spaces. Due to a fluctuating Glasgow Coma Scale (GCS), the patient underwent emergency debulking. Macroscopically, a frail-walled cystic tumour filled with straw-coloured fluid was noted; histology confirmed metastasis from a primary lung adenocarcinoma. Whole brain radiotherapy was given, with a view to commence systemic therapy. The patient, however, deteriorated and unfortunately passed away a few weeks after completing radiotherapy. This patient presented with leptomeningeal metastasis as the first presentation of a lung adenocarcinoma, and had a highly unusual mechanism by which leptomeningeal spread had occurred, with metastatic brain tumour spilling its contents into the meningeal spaces.


Small-scale variation of ammonia oxidisers within intertidal sediments dominated by ammonia-oxidising bacteria Nitrosomonas sp. amoA genes and transcripts.
While numerous studies have investigated the abundance of ammonia oxidising bacteria and archaea (AOB/AOA) via the ammonia monooxygenase gene amoA, less is known about their small-scale variation and if amoA gene abundance equates to activity. Here we present a spatial and temporal study of ammonia oxidation in two small intertidal bays, Rusheen and Clew bay, Ireland. Potential Nitrification Rate (PNR) was ten-fold higher in Rusheen bay (Clew: 0.27 ± SD 0.55; Rusheen: 2.46 ± SD 3.4 NO2- µg-1 g-1 day-1, P < 0.001) than in Clew bay but amoA gene abundances were similar between bays, and comparable to those in other coastal ecosystems. Within bays AOB genes increased towards the muddy sediments and were positively correlated with PNR and pH. Less spatial variation was observed in AOA abundances which nevertheless positively correlated with pH and temperature and negatively with salinity and ammonia. Transcriptionally active AOB and AOA were quantified from all sites in Rusheen bay, February 2014, following the general trends observed at DNA level. AOB phylotypes predominantly from the known Nitrosomonas group were distributed across the bay, while Nitrosomonas group B phylotypes were absent from low salinity sites. AOA genes and transcripts were primarily affiliated with Thaumarchaeota group I.1a.


Anisakiasis.
Anisakiasis is a zoonotic disease caused by the ingestion of larval nematodes in raw seafood dishes such as sushi, sashimi, ceviche, and pickled herring. Symptoms of anisakiasis include abdominal pain, nausea, vomiting, and diarrhea. Because symptoms are vague, this disease is often misdiagnosed as appendicitis, acute abdomen, stomach ulcers, or ileitis. Endoscopic examination with biopsy forceps has facilitated the diagnosis of gastric anisakiasis. Worms can be removed and identified, and a definitive diagnosis can be made. Patients generally recover with no further evidence of disease. Worms can become invasive, however, and migrate beyond the stomach, penetrating the intestine, omentum, liver, pancreas, and probably the lungs. Surgery is often necessary for treatment of invasive anisakiasis. With the increase in popularity of eating lightly cooked or raw fish dishes, the number of cases of anisakiasis may be expected to increase.


[Morphologic and functional characterization of human aortic endothelium. III. Growth in culture and colony formation at low seeding density].
In human aortic endothelial cell (HAEC) cultures, obtained separately from aortic zones of low (LP) and high (HP) probability of atherosclerosis, proliferative characteristics of cells and HAEC ability to form colonies at clonal seeding density were studied. It has been found that the population doubling time is significantly higher in endothelial cell (EC) cultures from HP-zones, compared to that in cultures from LP-zones of the same vessels. In cultures from both LP- and HP-zones only a few percent of EC had a proliferative potential enough to form cell colonies. The number of formed colonies was always lower in EC cultures from HP-zones, and decreased depending on atherosclerotic lesions and cell donor age. The obtained data suggest that the decline of EC proliferative potential, mostly in HP-zones (even without visible signs of atherosclerotic lesions) is due to a decrease in the number of cells with a high mitotic activity, i.e. "cambial" cells.


The fate of the pregnant diabetic in the developing country: Kenya.
A six-year survey of pregnancies complicated by diabetes has been performed at the Kenyatta National Hospital, Nairobi. Fifty-five babies were delivered with 14 perinatal deaths-a perinatal mortality rate of 254/1000, which was five times that of the nondiabetic population. There was one maternal death. Diabetes tended to be of short duration compared with similar series reported from developed countries. There were no perinatal deaths within a small sub-group managed according to a simple plan based on early referral for antenatal care, monitoring of diabetic control by blood glucose, and timing of delivery by use of the "shake test".


Using n-alkanes to estimate diet composition of herbivores: a novel mathematical approach.
N-alkanes are long-chain saturated hydrocarbons occurring in plant cuticles that can be used as chemical markers for estimating the diet composition of herbivores. An important constraint of using n-alkanes to estimate diet composition with currently employed mathematical procedures is that the number of markers must be equal or larger than the number of diet components. This is a considerable limitation when dealing with free-ranging herbivores feeding on complex plant communities. We present a novel approach for the estimation of diet composition using n-alkanes which applies equally to cases where the number of markers is lower, equal or greater than the number of plant species in the diet. The model uses linear programming to estimate the minimum and maximum proportions of each plant in the diet, and avoids the need for grouping species in order to reduce the number of estimated dietary components. We illustrate the model with two data sets of n-alkane content of plants and faeces obtained from a sheep grazing experiment conducted in Australia and a red deer study in Portugal. Our results are consistent with previous studies on those data sets and provide additional information on the proportions of individual species in the diet. Results show that sheep included in the diet high proportions of white clover (from 0.25 to 0.37), and relatively high proportions of grasses (e.g. brome from 0.14 to 0.26) but tended to avoid Lotus spp. (always less than 0.04 of the diet). For red deer we found high proportions of legumes (e.g. Trifolium angustifolium and Vicia sativa reaching maximum proportions of 0.42 and 0.30 of the diet, respectively) with grasses being less important and Cistus ladanifer, a browse, also having relevance (from 0.21 to 0.42 of the diet).


Axisymmetric polydimethysiloxane microchannels for in vitro hemodynamic studies.
The current microdevices used for biomedical research are often manufactured using microelectromechanical systems (MEMS) technology. Although it is possible to fabricate precise and reproducible rectangular microchannels using soft lithography techniques, this kind of geometry may not reflect the actual physiology of the microcirculation. Here, we present a simple method to fabricate circular polydimethysiloxane (PDMS) microchannels aiming to mimic an in vivo microvascular environment and suitable for state-of-the-art microscale flow visualization techniques, such as confocal microPIV/PTV. By using a confocal microPTV system individual red blood cells (RBCs) were successfully tracked trough a 75 microm circular PDMS microchannel. The results show that RBC lateral dispersion increases with the volume fraction of RBCs in the solution, i.e. with the hematocrit.


Individualised prediction of progression of solitary sub-solid pulmonary nodules based on CT semantic and clinical features: a 3-year follow-up study.
To develop and validate a progressive prediction model for estimating the time to progression (TTP) of sub-solid pulmonary nodules (SSNs). A total of 126 cases who met inclusion and exclusion criteria were included in the study. The primary endpoint of the study was TTP of SSNs. Baseline characteristics were assessed in terms of clinical and CT semantic features. Kaplan-Meier analysis and Cox regression analysis were performed to determine the relationship between SSNs TTP and factors from the entire data set. The nomogram was constructed based on the result of multivariate analysis and internal validation was performed using the bootstrapping. The nomogram's performance was assessed with the C-index, calibration curves, and decision curve analysis. The median follow-up time of the population was 42.5 (21.5) months. On Kaplan-Meier analysis, patients with higher or positive values of the indices had higher cumulative progression rates (p<0.05). Multivariate Cox regression models identified diameter, consolidation tumour ratio (CTR), morphology, and vasodilation sign (VDS) as independent risk factors of TTP. These predictors were included in the final model to estimate individual probabilities of progression in the 3 years, which performed well in the discrimination (the C-index was 0.901 [95%CI: 0.830-0.981] and 0.875 [95%CI: 0.805-0.942] in the training and internally validation sets). The radiological semantic features nomogram is a promising and favourable prognostic biomarker for predicting progression and may aid in clinical risk stratification and decision-making for SSNs.


Performance of medical students on a virtual reality simulator for knee arthroscopy: an analysis of learning curves and predictors of performance.
Ethical concerns for surgical training on patients, limited working hours with fewer cases per trainee and the potential to better select talented persons for arthroscopic surgery raise the interest in simulator training for arthroscopic surgery. It was the purpose of this study to analyze learning curves of novices using a knee arthroscopy simulator and to correlate their performance with potentially predictive factors. Twenty medical students completed visuospatial tests and were then subjected to a simulator training program of eight 30 min sessions. Their test results were quantitatively correlated with their simulator performance at initiation, during and at the end of the program. The mean arthroscopic performance score (z-score in points) at the eight test sessions were 1. -35 (range, -126 to -5) points, 2. -16 (range, -30 to -2), 3. -11 (range, -35 to 4), 4. -3 (range, -16 to 5), 5. -2 (range, -28 to 7), 6. 1 (range, -18 to 8), 7. 2 (range, -9 to 8), 8. 2 (range, -4 to 7). Scores improved significantly from sessions 1 to 2 (p = 0.001), 2 to 3 (p = 0.052) and 3 to 4 (p = 0.001) but not thereafter. None of the investigated parameters predicted performance or development of arthroscopic performance. Novices improve significantly within four 30 min test virtual arthroscopy knee simulator training but not thereafter within the setting studied. No factors, predicting talent or speed and magnitude of improvement of skills could be identified.


[Morphological and physiological differences of wheat genotypes at seedling stage under water stress].
Taking thirty six wheat cultivars bred in different era and ecological regions as test materials, their seedlings growth under water stress was investigated, and their drought resistance was evaluated by gray correlation grade analysis. Significant difference was observed in the drought resistance among the cultivars. The weighted drought resistance index ranged from 0.6580 to 0.2434. Among the test seventeen morphological and physiological traits, shoot dry mass had the greatest correlation degree (0.9473) with drought resistance, while SPAD had the smallest one (0.5356). The test cultivars were clustered into three groups, among which, eight cultivars belonged to strong drought resistance group, twenty three cultivars belonged to medium drought resistance group, and five cultivars belonged to drought-sensitive group. The shoot dry mass, root dry mass, plant dry mass, plant height, root nitrogen accumulation, leaf area, and tiller number per plant differed significantly among the three groups, which could be used for evaluating the drought resistance of wheat cultivars at seedling stage.


Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified.
The capacity of DNA damaging agents to induce apoptosis is regulated by target gene induction by p53. We found that p53 targeted MDM2 in cells in which DNA repair was occurring, but persistent DNA damage induced by chemotherapy led p53 to selectively target PTEN. High dose chemotherapy induced the phosphorylation of p53 on serine 46, whereas low dose chemotherapy did not. A nonphosphorylatable serine 46 to alanine p53 mutant (S46A) targeted the MDM2 promoter in preference to that for PTEN. A serine 46 to aspartate mutant (S46D, a phosphorylation mimic) targeted PTEN in preference to MDM2. These observations show that phosphorylation of serine 46 in p53 is sufficient for it to induce the PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor protein in preference to MDM2. S46A induced significantly less cell death than the S46D in cells. The phosphorylation-induced change of p53 promoter targeting suppresses the induction of MDM2 and the formation of the autoregulatory feedback loop. Induction of PTEN by p53 followed by expression of PTEN inhibits AKT-induced translocation of MDM2 into the nucleus and sustains p53 function. The protection of p53 from MDM2 by PTEN and the damage-induced activation of PTEN by phosphorylated p53 leads to the formation of an apoptotic amplification cycle in which p53 and PTEN coordinately increase cellular apoptosis.


Biomechanical effect of ankle ligament injury in AO 44B2.1 lateral malleolus fractures after lateral plate fixation: A finite element analysis.
Distal fibula fractures at the ankle level are common and are usually accompanied by ligament injuries. This study aims to evaluate the effects of ankle ligament ruptures on ankle joints, fracture instability, and plate stress after distal fibula fracture fixed with plate created by finite element analysis (FEA) modeling and loading applied to ligament rupture models that may accompany this fracture. A finite element model consisting of 3-D (3D) fibula, tibia, foot bones, and ankle ligaments was designed to investigate the effects of ligament injuries accompanying plate-detected Arbeitsgemeinschaft für Osteosynthesefragen (AO 44B2.1)-type fractures on fracture detection, fixation material, and ankle joints. Then, the results were evaluated by modeling ligament rupture in 6 different ways. In the modeling where the deltoid and the talofibular ligament are broken together, instability is the highest in the ankle (2.31 mm) and fracture line (0.15 mm). In our study, the rupture of the tibiofibular anterior and posterior ligaments associated with syndesmosis caused less instability in the fracture and ankle than the single rupture models of both the deltoid and the talofibular ligament. In the finite element modeling of AO 44B2.1-type fractures detected with plate, the importance and potential effects of often overlooked ankle ligaments are pointed out shown. It is important to keep in mind that when treating ankle injuries, the ankle should be treated as a whole, with both bone and soft tissue. In some cases, the fracture may represent the visible tip of the iceberg.


#HowNotToDoPatientEngagement: the engaging with purpose patient engagement framework based on a twitter analysis of community perspectives on patient engagement.
Evaluation of patient engagement practices are frequently researcher-driven, researcher-funded, and asymmetric in power dynamics. Little to no literature on patient experiences in patient engagement exist that is are not framed by institutionally-driven research inquiries (i.e., from the lens of a research team lead, or healthcare administrative setting). Understanding these perspectives can help us understand: (i)what matters to patients when they are engaged in research; (ii)why it matters to them, and(iii) how to improve patient engagement practices, so that the needs and priorities of patients are consistently met. This is a patient partner-initiated study. Study authors (including patient partners) conducted a conventional and summative content analysis of textual data retrieved from a highly engaged conversation on Twitter regarding the hashtags #HowNotToDoPatientEngagement and #HowToDoPatientEngagement posted between February 2018 to June 2021. Twitter is a microblogging platform that allows for free-flowing discussions between users not pre-bound by specific community groupings (like within that of Facebook). A total of 276 tweets were retrieved from 178 separate contributors across seven geographical locations. Four stakeholder groups were identified. We generated 24 codes, nine subthemes and five overarching themes: respect, support, collaboration, inclusivity and impact. Four of these themes are closely aligned with the Strategy for Patient Oriented (SPOR) Patient Engagement framework. We identify impact as a separate and new theme. Based on our findings we offer the Engaging with Purpose Patient Engagement Framework that defines and describes respect, support, collaboration, inclusivity and impact as five key pillars of meaningful patient engagement.


Predicting couple therapy outcomes based on speech acoustic features.
Automated assessment and prediction of marital outcome in couples therapy is a challenging task but promises to be a potentially useful tool for clinical psychologists. Computational approaches for inferring therapy outcomes using observable behavioral information obtained from conversations between spouses offer objective means for understanding relationship dynamics. In this work, we explore whether the acoustics of the spoken interactions of clinically distressed spouses provide information towards assessment of therapy outcomes. The therapy outcome prediction task in this work includes detecting whether there was a relationship improvement or not (posed as a binary classification) as well as discerning varying levels of improvement or decline in the relationship status (posed as a multiclass recognition task). We use each interlocutor's acoustic speech signal characteristics such as vocal intonation and intensity, both independently and in relation to one another, as cues for predicting the therapy outcome. We also compare prediction performance with one obtained via standardized behavioral codes characterizing the relationship dynamics provided by human experts as features for automated classification. Our experiments, using data from a longitudinal clinical study of couples in distressed relations, showed that predictions of relationship outcomes obtained directly from vocal acoustics are comparable or superior to those obtained using human-rated behavioral codes as prediction features. In addition, combining direct signal-derived features with manually coded behavioral features improved the prediction performance in most cases, indicating the complementarity of relevant information captured by humans and machine algorithms. Additionally, considering the vocal properties of the interlocutors in relation to one another, rather than in isolation, showed to be important for improving the automatic prediction. This finding supports the notion that behavioral outcome, like many other behavioral aspects, is closely related to the dynamics and mutual influence of the interlocutors during their interaction and their resulting behavioral patterns.


Association between behavioral and psychological symptoms and psychotropic drug use among old people with cognitive impairment living in geriatric care settings.
Behavioral and psychological symptoms are common among cognitively impaired individuals and psychotropic drugs are widely used for their treatment. The aim of this study was to describe the prevalence and associated factors of psychotropic and anti-dementia drug use among old people with cognitive impairment living in geriatric care settings. The study comprised 2,019 cognitively impaired people living in geriatric care units in the county of Västerbotten, Sweden. Data concerning psychotropic and anti-dementia drug use, function in activities of daily living, cognitive function, and prevalence of behavioral and psychological symptoms were collected, using the Multi-Dimensional Dementia Assessment Scale. Of the study population, 1,442 individuals (71%) were prescribed at least one psychotropic drug (antidepressants (49%), anxiolytics, hypnotics, and sedatives (36%), antipsychotics (25%)). Furthermore, 363 individuals (18%) received anti-dementia drugs. Associations between various behavioral and psychological symptoms were found for all psychotropic drug classes and anti-dementia drugs. Verbally disruptive/attention-seeking behavior was associated with all psychotropic drugs. Use of antipsychotics was associated with several behavioral and psychological symptoms, including aggressive behavior. The associations between behavioral and psychological symptoms and psychotropic drug use found in this study indicate that these drugs are prescribed to treat behavioral and psychological symptoms among cognitively impaired individuals despite limited evidence of their efficacy. Given the significant risk of adverse effects among old people with cognitive impairment, it is important to ensure that any medication used is both appropriate and safe.


Gesture and metaphor comprehension: electrophysiological evidence of cross-modal coordination by audiovisual stimulation.
In recent years, studies have suggested that gestures influence comprehension of linguistic expressions, for example, eliciting an N400 component in response to a speech/gesture mismatch. In this paper, we investigate the role of gestural information in the understanding of metaphors. Event related potentials (ERPs) were recorded while participants viewed video clips of an actor uttering metaphorical expressions and producing bodily gestures that were congruent or incongruent with the metaphorical meaning of such expressions. This modality of stimuli presentation allows a more ecological approach to meaning integration. When ERPs were calculated using gesture stroke as time-lock event, gesture incongruity with metaphorical expression modulated the amplitude of the N400 and of the late positive complex (LPC). This suggests that gestural and speech information are combined online to make sense of the interlocutor's linguistic production in an early stage of metaphor comprehension. Our data favor the idea that meaning construction is globally integrative and highly context-sensitive.


Estrogen regulation of gene expression in the brain: a possible mechanism altering the response to psychostimulants in female rats.
Acute behavioral responses to cocaine are more pronounced in female than in male rats. We have shown that 3 weeks of treatment with 17beta-estradiol (E(2)) implants significantly enhanced the hyperactivity induced by cocaine in ovariectomized (OVX) rats. The ligand-bound estrogen receptor (ER) functions as a transcription factor to regulate the expression of E-responsive genes. Thus, we hypothesized that estrogen (E) modulates the behavioral response to cocaine via regulation of expression of components of dopamine (DA) and serotonin (5-HT) systems in mesolimbic nuclei important in the response to cocaine as well as the hypothalamus, a brain area known to be E-responsive. Adult female Sprague-Dawley rats were OVX; half of them then received E(2) implant (OVX+E) (n=8/group, two groups). Twenty-seven days later, brain tissue was collected to study E(2) effects on mRNA expression for DA D(1)-like (D(1)) and D(2)-like (D(2S), D(2L), D(3)) receptors, DA transporter (DAT), 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(2C) receptors, and 5-HT transporter (SERT) as well as ERalpha and ERbeta in amygdala, hypothalamus, nucleus accumbens, midbrain, and ventral tegmental area (VTA). We found that E(2) implants in OVX rats increased mRNA levels for D(1) receptor in hypothalamus, D(2L) receptor in midbrain, and D(3) receptor in VTA, and decreased D(3) receptor mRNA levels in midbrain relative to OVX controls. E(2) also increased 5-HT(2C) receptor mRNA levels in midbrain and hypothalamus. In addition, E(2) decreased mRNA levels for ERalpha in amygdala and hypothalamus and ERbeta in amygdala. The present study demonstrates that E can regulate mRNA expression for specific DA and 5-HT receptors in a region-specific manner and suggests that such modifications may contribute to the behavioral response to cocaine.


The importance of life-time changes in fluorescence depolarization.
The rotational relaxation time, rho, calculated from measurements of fluorescence depolarization, is clearly dependent on the assumed mean life-time, tau, of the excited state. However, variations in tau with experimental conditions (temperature and solvent composition) occur and the effect of such alterations in tau is demonstrated. In particular it should be noted that, unless life-time changes can be excluded, the occurrence of linear plots of reciprocal degree of polarization against the temperature/viscosity ratio does not necessarily indicate the absence of intramolecular freedoms. An attempt to correct for such life-time changes by measurement of the fluorescence intensity is made for the bovine serum albumin-1-dimethyl-aminonaphthalene-5-sulphonyl chloride system. The value of rho/3tau thus obtained for this system at 20 degrees is approx. 4.7, as against approx. 3.4 obtained by several workers in the absence of life-time corrections.