Occult pneumothoraces in patients with penetrating trauma: Does mechanism matter?
Supine anteroposterior (AP) chest radiography is an insensitive test for detecting posttraumatic pneumothoraces (PTXs). Computed tomography (CT) often identifies occult pneumothoraces (OPTXs) not diagnosed by chest radiography. All previous literature describes the epidemiology of OPTX in patients with blunt polytrauma. Our goal was to identify the frequency of OPTXs in patients with penetrating trauma. All patients with penetrating trauma admitted over a 10-year period to Grady Memorial Hospital with a PTX were identified. We reviewed patients' thoracoabdominal CT scans and corresponding chest radiographs. Records for 1121 (20%) patients with a PTX (penetrating mechanism) were audited; CT imaging was available for 146 (13%) patients. Of these, 127 (87%) had undergone upright chest radiography. The remainder (19 patients) had a supine AP chest radiograph. Fifteen (79%) of the PTXs detected on supine AP chest radiographs were occult. Only 10 (8%) were occult when an upright chest radiograph was used (p < 0.001). Posttraumatic PTXs were occult on chest radiographs in 17% (25/146) of patients. Fourteen (56%) patients with OPTXs underwent tube thoracostomy, compared with 95% (115/121) of patients with overt PTXs (p < 0.001). Up to 17% of all PTXs in patients injured by penetrating mechanisms will be missed by standard trauma chest radiographs. This increases to nearly 80% with supine AP chest radiographs. Upright chest radiography detects 92% of all PTXs and is available to most patients without spinal trauma. The frequency of tube thoracostomy use in patients with overt PTXs is significantly higher than for OPTXs in blunt and penetrating trauma.


A subgroup of murine monoclonal anti-deoxyribonucleic acid antibodies traverse the cytoplasm and enter the nucleus in a time-and temperature- dependent manner.
The capacity of lupus autoantibodies to enter living cells and bind to molecules for which they have intrinsic affinity is not well appreciated. In previous studies, we identified a subgroup of three murine monoclonal IgG anti-DNA antibodies, derived from lupus-prone MRL-lpr/lpr mice, that localized within nuclei of cells in multiple organs and induced functional perturbations, in vivo, after passive transfer to normal mice. To examine the mechanisms of this phenomenon, we now extend these observations, using the same monoclonal anti-DNA antibodies and cultured cell lines. Multiple experimental approaches were utilized to track nuclear localization of anti-DNA antibodies, including direct immunofluorescence, confocal microscopy and immunoelectron microscopy. The requirements for nuclear localization were further evaluated quantitatively, in nuclei isolated from co-cultures of cells and 125I-Ig, under varying experimental conditions. Nuclear localization was observed with the same subset of anti-DNA antibodies that localized within nuclei in vivo; it was dependent on the antigen-binding region of the molecule; and it was not found with other anti-DNA antibodies. At progressive intervals, the Ig were observed: at the cell surface, within the cytoplasm, clustered at the nuclear pore, and within the nucleus. Nuclear localization of Ig was found to be a time- and temperature- dependent process, specific for a subset of anti-DNA antibodies and dependent on the antigen binding region of the Ig. This is the first demonstration that monoclonal autoantibodies can traverse both the cell and nuclear membranes to localize within the nuclei of cultured cells. Furthermore, nuclear localization of Ig was regulated in a manner analogous to that of other large cytoplasmic proteins that enter the nucleus. This confirms and extends our results using the same antibodies in whole animals, and it provides the basis to further examine the underlying mechanisms and consequences of this phenomenon.


Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy.
Nitric oxide was proposed as an endogenous inhibitor of myometrial contractility during pregnancy. Carbon monoxide (CO) like nitric oxide increases cGMP and is generated during the degradation of heme to biliverdin IX by hemeoxygenases (HO). Here we report that the expression of both HO-1 (inducible) and HO-2 (constitutive) were > 15-fold higher in pregnant myometrium compared to nonpregnant myometrium (n = 4, P < 0.001, P < 0.005, respectively). Moreover, the activation of the HO-CO pathway by the HO inducer, hemin (10 microM), completely inhibited spontaneous contractility (n = 3). Oxytocin-stimulated contractions (n = 5) were also significantly reduced (P < 0.05) in myometrial strips mounted for isometric recording under 2 g tension in Krebs solution. Reverse transcription-PCR analysis revealed that mRNA encoding HO-1 and HO-2 was undetected in explant cultures of nonlaboring pregnant myometrium under basal conditions, however, exposure to progesterone, but not estradiol-17beta, induced the expression of HO-1 and HO-2 mRNAs. Progesterone also significantly induced HO-1 protein synthesis (n = 4, P < 0.001) while estradiol-17beta had no effect (n = 4). In term (37-42-wk gestation) nonlaboring myometrial explants, CO production was stimulated by progesterone (10(-6) M) (n = 2) and hemin (10 microM) (n = 3) after 2 h of incubation and the effect of hemin was inhibited by 1 h of preincubation with the HO inhibitor tin protoporphyrin IX (20 microM). This study clearly demonstrates the expression of HO in the human myometrium and shows that its induction produces CO that limits uterine contractility in pregnant myometrium indicating a role for the HO-CO-cGMP pathway in the maintenance of the quiescent state of the uterus during pregnancy.


Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers.
Monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters, has an important role in the brain development and function, and MAO inhibitors have a range of potential therapeutic uses. We investigated systematically in vitro effects of pharmacologically different antidepressants and mood stabilizers on MAO activity. Effects of drugs on the activity of MAO were measured in crude mitochondrial fraction isolated from cortex of pig brain, when radiolabeled serotonin (for MAO-A) or phenylethylamine (for MAO-B) was used as substrate. The several antidepressants and mood stabilizers were compared with effects of well known MAO inhibitors such as moclobemide, iproniazid, pargyline, and clorgyline. In general, the effect of tested drugs was found to be inhibitory. The half maximal inhibitory concentration, parameters of enzyme kinetic, and mechanism of inhibition were determined. MAO-A was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > desipramine > amitriptyline > imipramine > citalopram > venlafaxine > reboxetine > olanzapine > mirtazapine > tianeptine > moclobemide, cocaine >> lithium, valproate. MAO-B was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > venlafaxine > amitriptyline > olanzapine > citalopram > desipramine > reboxetine > imipramine > tianeptine > mirtazapine, cocaine >> moclobemide, lithium, valproate. The mechanism of inhibition of MAOs by several antidepressants was found various. It was concluded that MAO activity is acutely affected by pharmacologically different antidepressants at relatively high drug concentrations; this effect is inhibitory. There are differences both in inhibitory potency and in mechanism of inhibition between both several drugs and the two MAO isoforms. While MAO inhibition is not primary biochemical effect related to their therapeutic action, it can be supposed that decrease of MAO activity may be concerned in some effects of these drugs on serotonergic, noradrenergic, and dopaminergic neurotransmission.


The use of photodynamic therapy in dermatology: results of a consensus conference.
Photodynamic therapy (PDT) has significant promise in improving outcomes of patients with a variety of cutaneous conditions. A group of experts met to review the principles, indications, and clinical benefits of PDT with 5-aminolevulinic acid (ALA). They also reviewed PDT with methyl aminolevulinate. The experts established consensus statements for pretreatment, posttreatment, ALA contact time, light sources, and numbers of sessions associated with ALA PDT for actinic keratosis and superficial basal cell carcinoma, photorejuvenation and cosmetic enhancement, acne, sebaceous skin, rosacea, and rhinophyma. They based consensus recommendations on their clinical experience and the medical literature. They also suggested future applications of ALA PDT. Experts concluded that ALA PDT is a safe and effective modality for the treatment of conditions commonly encountered in dermatology. Since downtime is minimal, the technique is suitable for patients of all ages and lifestyles. Appropriate light sources are available in many dermatology offices. The expanding clinical and financial benefits of PDT justify the purchase of an appropriate light source.


Obesity and its Relation With Diabetes and Hypertension: A Cross-Sectional Study Across 4 Geographical Regions.
The implications of rising obesity for cardiovascular health in middle-income countries has generated interest, in part because associations between obesity and cardiovascular health seem to vary across ethnic groups. We assessed general and central obesity in Africa, East Asia, South America, and South Asia. We further investigated whether body mass index (BMI) and waist circumference differentially relate to cardiovascular health; and associations between obesity metrics and adverse cardiovascular health vary by region. Using baseline anthropometric data collected between 2008 and 2012 from 7 cohorts in 9 countries, we estimated the proportion of participants with general and central obesity using BMI and waist circumference classifications, respectively, by study site. We used Poisson regression to examine the associations (prevalence ratios) of continuously measured BMI and waist circumference with prevalent diabetes and hypertension by sex. Pooled estimates across studies were computed by sex and age. This study analyzed data from 31,118 participants aged 20 to 79 years. General obesity was highest in South Asian cities and central obesity was highest in South America. The proportion classified with general obesity (range 11% to 50%) tended to be lower than the proportion classified as centrally obese (range 19% to 79%). Every standard deviation higher of BMI was associated with 1.65 and 1.60 times higher probability of diabetes and 1.42 and 1.28 times higher probability of hypertension, for men and women, respectively, aged 40 to 69 years. Every standard deviation higher of waist circumference was associated with 1.48 and 1.74 times higher probability of diabetes and 1.34 and 1.31 times higher probability of hypertension, for men and women, respectively, aged 40 to 69 years. Associations of obesity measures with diabetes were strongest in South Africa among men and in South America among women. Associations with hypertension were weakest in South Africa among both sexes. BMI and waist circumference were both reasonable predictors of prevalent diabetes and hypertension. Across diverse ethnicities and settings, BMI and waist circumference remain salient metrics of obesity that can identify those with increased cardiovascular risk.


Ectopic expression of a Neospora caninum Kazal type inhibitor triggers developmental defects in Toxoplasma and Plasmodium.
Regulated proteolysis is known to control a variety of vital processes in apicomplexan parasites including invasion and egress of host cells. Serine proteases have been proposed as targets for drug development based upon inhibitor studies that show parasite attenuation and transmission blockage. Genetic studies suggest that serine proteases, such as subtilisin and rhomboid proteases, are essential but functional studies have proved challenging as active proteases are difficult to express. Proteinaceous Protease Inhibitors (PPIs) provide an alternative way to address the role of serine proteases in apicomplexan biology. To validate such an approach, a Neospora caninum Kazal inhibitor (NcPI-S) was expressed ectopically in two apicomplexan species, Toxoplasma gondii tachyzoites and Plasmodium berghei ookinetes, with the aim to disrupt proteolytic processes taking place within the secretory pathway. NcPI-S negatively affected proliferation of Toxoplasma tachyzoites, while it had no effect on invasion and egress. Expression of the inhibitor in P. berghei zygotes blocked their development into mature and invasive ookinetes. Moreover, ultra-structural studies indicated that expression of NcPI-S interfered with normal formation of micronemes, which was also confirmed by the lack of expression of the micronemal protein SOAP in these parasites. Our results suggest that NcPI-S could be a useful tool to investigate the function of proteases in processes fundamental for parasite survival, contributing to the effort to identify targets for parasite attenuation and transmission blockage.


The Role of Meibography in the Diagnosis of Meibomian Gland Dysfunction in Ocular Surface Diseases.
To evaluate dysfunction in various ocular surface diseases (OSDs) including primary meibomian gland disease (MGD), perennial allergic conjunctivitis, and primary and secondary Sjögren syndromes. A retrospective analysis of 146 patients (111 women and 35 men) with symptomatic OSDs was performed. Patients were divided into two groups: the non-MGD group (55 patients) and the MGD group (91 patients). All patients had an evaluation of ocular surface symptoms and clinical tests, including tear film breakup time (BUT), the first and the mean noninvasive breakup time (NIKBUTf and NIKBUTavg, respectively). The meibomian gland loss of the lower eyelid was quantified using meibography and the meiboscale. There was no significant difference regarding age or sex ratio between the two groups. The meiboscale in the MGD group was significantly higher than that in the non-MGD group (P = 0.003). The non-MGD patients were more symptomatic than those in the MGD group (P = 0.043). There were no significant differences between MGD and non-MGD groups regarding a Schirmer test (P = 0.195), BUT (P = 0.719), NIKBUTf (P = 0.96), or NIKBUTavg (P = 0.70). In the whole population, there was a negative correlation between meiboscale and NIKBUT (r = -0.21, P = 0.02), but no other correlations were found. Meibomian gland dysfunction was observed among different OSDs. Meibomian gland loss evaluated by meibography might help identify MGD in patients suffering from OSD. Meibography provides a better understanding of MGD in several OSD. It may be useful to integrate this objective analysis to improve treatments of OSD associated to MGD.


Specific isoforms of translation initiation factor 4GI show differences in translational activity.
The eukaryotic initiation factor (eIF) 4GI gene locus (eIF4GI) contains three identified promoters, generating alternately spliced mRNAs, yielding a total of five eIF4GI protein isoforms. Although eIF4GI plays a critical role in mRNA recruitment to the ribosomes, little is known about the functions of the different isoforms, their partner binding capacities, or the role of the homolog, eIF4GII, in translation initiation. To directly address this, we have used short interfering RNAs (siRNAs) expressed from DNA vectors to silence the expression of eIF4GI in HeLa cells. Here we show that reduced levels of specific mRNA and eIF4GI isoforms in HeLa cells promoted aberrant morphology and a partial inhibition of translation. The latter reflected dephosphorylation of 4E-BP1 and decreased eIF4F complex levels, with no change in eIF2alpha phosphorylation. Expression of siRNA-resistant Myc-tagged eIF4GI isoforms has allowed us to show that the different isoforms exhibit significant differences in their ability to restore translation rates. Here we quantify the efficiency of eIF4GI promoter usage in mammalian cells and demonstrate that even though the longest isoform of eIF4GI (eIF4GIf) was relatively poorly expressed when reintroduced, it was more efficient at promoting the translation of cellular mRNAs than the more highly expressed shorter isoforms used in previous functional studies.


Long-term outcome of the surgical treatment of concealed penis.
The term concealed penis describes a spectrum of disorders ranging from penoscrotal webbing to a completely buried penis. A number of surgical procedures have been described to correct this condition but little has been written about long-term results. We report our long-term results of the surgical correction of concealed penis based on a survey of parents. A retrospective review of patients treated from 1995 to 1999 identified 18 males with a minimum of 21 months of followup whose parents were available for evaluation via telephone interview. The parents were questioned about the initial problems that they associated with concealed penis, such as appearance and accessibility of the penis, ease of hygiene, severity of concealment and negative feelings about the appearance of the penis. Parents were also questioned about the results of surgery and how the surgical result improved or failed to improve their concerns. Specifically, they were questioned about whether the surgery helped to alleviate negative concerns, improve hygiene and make the penis more assessable. Of the 18 patients 14 were infants/toddlers (group 1) and 4 were adolescents (group 2). Group 1 patients with a mean age of 2 years were evaluated at a mean of 41.7 (range 21 to 76) months and group 2 patients with a mean age of 12 years were evaluated at a mean of 38.8 (25 to 63) months after surgery. Before surgery 57% of patients in group 1 and 50% in group 2 complained of difficulty with hygiene. Of the parents 64% of group 1 and 75% of group 2 described their child as having a completely hidden penis. On the other hand, only 57% of parents in group 1 expressed negative feelings about the appearance of the penis compared to all parents in group 2. Following surgery group 1 patients fared better reporting improvements in hygiene (87%), accessibility (86%) and improved appearance of the penis (100%). Results from surgical intervention were less successful in group 2, with improved hygiene in 50%, improved penile accessibility in 75% and improved appearance in 50% of patients. Interestingly, all group 2 parents would still recommend the same surgery to a friend with the same problem despite less than perfect results compared to 79% of group 1 parents who would recommend surgery to others. Our long-term outcome survey data demonstrate that surgical correction of concealed penis addresses an array of presenting complaints. According to the parents of patients surgery is almost uniformly successful in toddlers and less often successful in adolescents. However, despite its limited success in older patients, most parents thought that surgery was a positive intervention and would recommend it to a friend with a similar condition.


Population-based Incidence of Pulmonary Nontuberculous Mycobacterial Disease in Oregon 2007 to 2012.
Pulmonary nontuberculous mycobacteria (NTM) disease is a chronic, nonreportable illness, making it difficult to monitor. Although recent studies suggest an increasing prevalence of NTM disease in the United States, the incidence and temporal trends are unknown. To describe incident cases and calculate the incidence and temporal trends of pulmonary NTM disease in Oregon. We contacted all laboratories performing mycobacterial cultures on Oregon residents and collected demographic and specimen information for patients with NTM isolated during 2007 to 2012. We defined a case of pulmonary NTM disease using the 2007 American Thoracic Society/Infectious Disease Society of America microbiologic criteria. We used similar state-wide mycobacterial laboratory data from 2005 to 2006 to exclude prevalent cases from our calculations. We calculated annual pulmonary NTM disease incidence within Oregon during 2007 to 2012, described cases demographically and microbiologically, and evaluated incidence trends over time using a Poisson model. We identified 1,146 incident pulmonary NTM cases in Oregon residents from 2007 to 2012. The median age was 69 years (range, 0.9-97 yr). Cases were more likely female (56%), but among patients less than 60 years old, disease was more common in male subjects (54%). Most (86%) were Mycobacterium avium/intracellulare cases; 68 (6%) were Mycobacterium abscessus/chelonae cases. Although not statistically significant, incidence increased from 4.8/100,000 in 2007 to 5.6/100,000 in 2012 (P for trend, 0.21). Incidence increased with age, to more than 25/100,000 in patients 80 years of age or older. This is the first population-based estimate of pulmonary NTM disease incidence in a region within the United States. In Oregon, disease incidence rose slightly during 2007 to 2012, and although more common in female individuals overall, disease was more common among male individuals less than 60 years of age.


The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia.
Rural Australians have poorer survival for most common cancers, due partially to later diagnosis. Internationally, several initiatives to improve cancer outcomes have focused on earlier presentation to healthcare and timely diagnosis. We aimed to measure the effect of community-based symptom awareness and general practice-based educational interventions on the time to diagnosis in rural patients presenting with breast, prostate, colorectal or lung cancer in Western Australia. 2 × 2 factorial cluster randomised controlled trial. Community Intervention: cancer symptom awareness campaign tailored for rural Australians. GP intervention: resource card with symptom risk assessment charts and local cancer referral pathways implemented through multiple academic detailing visits. Trial Area A received the community symptom awareness and Trial Area B acted as the community campaign control region. Within both Trial Areas general practices were randomised to the GP intervention or control. total diagnostic interval (TDI). 1358 people with incident breast, prostate, colorectal or lung cancer were recruited. There were no significant differences in the median or ln mean TDI at either intervention level (community intervention vs control: median TDI 107.5 vs 92 days; ln mean difference 0.08 95% CI -0.06-0.23 P=0.27; GP intervention vs control: median TDI 97 vs 96.5 days; ln mean difference 0.004 95% CI -0.18-0.19 P=0.99). There were no significant differences in the TDI when analysed by factorial design, tumour group or sub-intervals of the TDI. This is the largest trial to test the effect of community campaign or GP interventions on timeliness of cancer diagnosis. We found no effect of either intervention. This may reflect limited dose of the interventions, or the limited duration of follow-up. Alternatively, these interventions do not have a measurable effect on time to cancer diagnosis.


Virtual Reality in Neurorehabilitation: An Umbrella Review of Meta-Analyses.
Neurological disorders are a leading cause of death and disability worldwide. Can virtual reality (VR) based intervention, a novel technology-driven change of paradigm in rehabilitation, reduce impairments, activity limitations, and participation restrictions? This question is directly addressed here for the first time using an umbrella review that assessed the effectiveness and quality of evidence of VR interventions in the physical and cognitive rehabilitation of patients with stroke, traumatic brain injury and cerebral palsy, identified factors that can enhance rehabilitation outcomes and addressed safety concerns. Forty-one meta-analyses were included. The data synthesis found mostly low- or very low-quality evidence that supports the effectiveness of VR interventions. Only a limited number of comparisons were rated as having moderate and high quality of evidence, but overall, results highlight potential benefits of VR for improving the ambulation function of children with cerebral palsy, mobility, balance, upper limb function, and body structure/function and activity of people with stroke, and upper limb function of people with acquired brain injury. Customization of VR systems is one important factor linked with improved outcomes. Most studies do not address safety concerns, as only nine reviews reported adverse effects. The results provide critical recommendations for the design and implementation of future VR programs, trials and systematic reviews, including the need for high quality randomized controlled trials to test principles and mechanisms, in primary studies and in meta-analyses, in order to formulate evidence-based guidelines for designing VR-based rehabilitation interventions.


Acupuncture for episodic cluster headache: a trigeminal approach.
Following evidence that acupuncture is clinically feasible and cost-effective in the treatment of headache, the UK National Institute for Health and Care Excellence recommends acupuncture as prophylactic treatment for migraine and tension headache. There has thus been expectation that other forms of headache should benefit also. Unfortunately, acupuncture has not generally been successful for cluster headache. This may be due to acupuncturists approaching the problem as one of severe migraine. In fact, cluster headache is classed as a trigeminal autonomic cephalgia. In this case report, episodic cluster headache is treated in the same way as has been shown effective for trigeminal neuralgia. Acupuncture is applied to the contralateral side at points appropriate for stimulating branches of the trigeminal nerve. Thus, ST2 is used for the infraorbital nerve, BL2 and Yuyao for the supratrochlear and supraorbital nerves, and Taiyang for the temporal branch of the zygomatic nerve.


Effect of different freezing rates during cryopreservation of rat mesenchymal stem cells using combinations of hydroxyethyl starch and dimethylsulfoxide.
Mesenchymal stem cells (MSCs) are increasingly used as therapeutic agents as well as research tools in regenerative medicine. Development of technologies which allow storing and banking of MSC with minimal loss of cell viability, differentiation capacity, and function is required for clinical and research applications. Cryopreservation is the most effective way to preserve cells long term, but it involves potentially cytotoxic compounds and processing steps. Here, we investigate the effect of decreasing dimethyl sulfoxide (DMSO) concentrations in cryosolution by substituting with hydroxyethyl starch (HES) of different molecular weights using different freezing rates. Post-thaw viability, phenotype and osteogenic differentiation capacity of MSCs were analysed. The study confirms that, for rat MSC, cryopreservation effects need to be assessed some time after, rather than immediately after thawing. MSCs cryopreserved with HES maintain their characteristic cell surface marker expression as well as the osteogenic, adipogenic and chondrogenic differentiation potential. HES alone does not provide sufficient cryoprotection for rat MSCs, but provides good cryoprotection in combination with DMSO, permitting the DMSO content to be reduced to 5%. There are indications that such a combination would seem useful not just for the clinical disadvantages of DMSO but also based on a tendency for reduced osteogenic differentiation capacity of rat MSC cryopreserved with high DMSO concentration. HES molecular weight appears to play only a minor role in its capacity to act as a cryopreservation solution for MSC. The use of a 'straight freeze' protocol is no less effective in maintaining post-thaw viability of MSC compared to controlled rate freezing methods. A 5% DMSO / 5% HES solution cryopreservation solution using a 'straight freeze' approach can be recommended for rat MSC.


Analysis of macular cone photoreceptors in a case of occult macular dystrophy.
To investigate changes in cone photoreceptors with adaptive optics (AO) fundus imaging and spectral domain optical coherence tomography (SD-OCT) in a case of occult macular dystrophy (OMD). Both eyes of a 42-year-old woman diagnosed with OMD were examined. We used an AO fundus camera to obtain images of cone photoreceptors in the macula of the OMD subject and five healthy control subjects. Correlations between the AO images and the SD-OCT images were examined. Cone photoreceptors in eight areas in the macula of OMD and healthy control subjects were analyzed and compared. SD-OCT showed a loss of the cone outer-segment tips line outside of the fovea in both eyes of the subject with OMD. The left eye with decreased visual acuity showed a discontinuous photoreceptor inner-segment and outer-segment line and cone outer-segment tips line at the fovea in SD-OCT and loss of cone mosaics as a dark spot in the AO image. In panoramic AO images and cone-density maps, less cone density was observed in a ring-like region outside the fovea than in the peripheral retina. In most of the areas examined, the cone densities were lower in the OMD eyes than in the healthy control eyes. Cone densities in the macula of the OMD patient were greatly decreased. AO images were found to be useful to evaluate morphologic changes in cone photoreceptors in patients with OMD.


Results of operative treatment of hypopharyngeal diverticulum.
The so-called hypopharyngeal diverticula may be classified, according to their size, localization, and form, into three stages. Small diverticula (first stage) should not be surgically removed, whereas all other diverticula, that is, those causing symptoms, must be surgically removed as soon after diagnosis as possible. Diverticulectomy performed in one stage is the treatment of choice. A series of patients is reviewed. The risk involved in surgery is found to be of minor degree, and the incidence of complications is low. Radiologically demonstrable recurrence may develop in 10% to 12% of all patients while clinical symptoms of recurrence are seen in only about 2%.


Surveillance and response systems for elimination of tropical diseases: summary of a thematic series in Infectious Diseases of Poverty.
The peer-reviewed journal Infectious Diseases of Poverty provides a new platform to engage with, and disseminate in an open-access format, science outside traditional disciplinary boundaries. The current piece reviews a thematic series on surveillance-response systems for elimination of tropical diseases. Overall, 22 contributions covering a broad array of diseases are featured - i.e. clonorchiasis, dengue, hepatitis, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), H7N9 avian influenza, lymphatic filariasis, malaria, Middle East respiratory syndrome (MERS), rabies, schistosomiasis and tuberculosis (TB). There are five scoping reviews, a commentary, a letter to the editor, an opinion piece and an editorial pertaining to the theme "Elimination of tropical disease through surveillance and response". The remaining 13 articles are original contributions mainly covering (i) drug resistance; (ii) innovation and validation in the field of mathematical modelling; (iii) elimination of infectious diseases; and (iv) social media reports on disease outbreak notifications released by national health authorities. Analysis of the authors' affiliations reveals that scientists from the People's Republic of China (P.R. China) are prominently represented. Possible explanations include the fact that the 2012 and 2014 international conferences pertaining to surveillance-response mechanisms were both hosted by the National Institute of Parasitic Diseases (NIPD) in Shanghai, coupled with P.R. China's growing importance with regard to the control of infectious diseases. Within 4 to 22 months of publication, three of the 22 contributions were viewed more than 10 000 times each. With sustained efforts focusing on relevant and strategic information towards control and elimination of infectious diseases, Infectious Diseases of Poverty has become a leading journal in the field of surveillance and response systems in infectious diseases and beyond.


On the inability to ignore touch when responding to vision in the crossmodal congruency task.
We investigated the extent to which people can selectively ignore distracting vibrotactile information when performing a visual task. In Experiment 1, participants made speeded elevation discrimination responses (up vs. down) to a series of visual targets presented from one of two eccentricities on either side of central fixation, while simultaneously trying to ignore task-irrelevant vibrotactile distractors presented independently to the finger (up) vs. thumb (down) of either hand. Participants responded significantly more slowly, and somewhat less accurately, when the elevation of the vibrotactile distractor was incongruent with that of the visual target than when they were presented from the same (i.e., congruent) elevation. This crossmodal congruency effect was significantly larger when the visual and tactile stimuli appeared on the same side of space than when they appeared on different sides, although the relative eccentricity of the two stimuli within the hemifield (i.e., same vs. different) had little effect on performance. In Experiment 2, participants who crossed their hands over the midline showed a very different pattern of crossmodal congruency effects to participants who adopted an uncrossed hands posture. Our results suggest that both the relative external location and the initial hemispheric projection of the target and distractor stimuli contribute jointly to determining the magnitude of the crossmodal congruency effect when participants have to respond to vision and ignore touch.


Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.
Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.


HIV infection is associated with a lower incidence of constriction in presumed tuberculous pericarditis: a prospective observational study.
Pericardial constriction is a serious complication of tuberculous pericardial effusion that occurs in up to a quarter of patients despite anti-tuberculosis chemotherapy. The impact of human immunodeficiency virus (HIV) infection on the incidence of constrictive pericarditis following tuberculous pericardial effusion is unknown. We conducted a prospective observational study to determine the association between HIV infection and the incidence of constrictive pericarditis among 185 patients (median age 33 years) with suspected tuberculous pericardial effusion. These patients were recruited consecutively between March and October 2004 on commencement of anti-tuberculosis treatment, from 15 hospitals in Cameroon, Nigeria and South Africa. Surviving patients (N = 119) were assessed for clinical evidence of constrictive pericarditis at 3 and 6 months of follow-up. Clinical features of HIV infection were present in 42 (35.2%) of the 119 patients at enrolment into the study. 66 of the 119 (56.9%) patients consented to HIV testing at enrolment. During the 6 months of follow-up, a clinical diagnosis of constrictive pericarditis was made in 13 of the 119 patients (10.9 %, 95% confidence interval [CI] 5.9-18%). Patients with clinical features of HIV infection appear less likely to develop constriction than those without (4.8% versus 14.3%; P = 0.08). None of the 33 HIV seropositive patients developed constriction, but 8 (24.2%, 95%CI 11.1-42.3%) of the 33 HIV seronegative patients did (P = 0.005). In a multivariate logistic regression model adjusting simultaneously for several baseline characteristics, only clinical signs of HIV infection were significantly associated with a lower risk of constriction (odd ratio 0.14, 95% CI 0.02-0.87, P = 0.035). These data suggest that HIV infection is associated with a lower incidence of pericardial constriction in patients with presumed tuberculous pericarditis.


Cord blood lipids in infants born to HIV-1-infected women treated with combination antiretroviral therapy.
To investigate the effect of exposure to protease inhibitor (PI) therapy in utero on cord blood lipids in infants born to mothers enrolled in AIDS Clinical Trials Group protocol 5084, a prospective, multicentre, observational study of antiretroviral therapy (ART) during pregnancy. Clinical outcome was determined in 80 infants born to women treated with PIs and 73 infants born to women treated with other antiretrovirals during pregnancy. Cord blood serum from 117 of these infants was assayed for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein A1 (apoA1), apolipoprotein B100 (apoB) and lipoprotein (a). Covariates considered in the analysis included race/ethnicity, gestational age, infant gender, infant birth weight, mode of delivery, maternal tobacco and alcohol use, post-partum body mass index, and ART duration. Cord blood total and HDL cholesterol, triglyceride, apoA1, apoB, lipoprotein (a) and apoB/apoA1 ratio were not different between the two groups. Cord blood lipid levels in these HIV-exposed infants were similar to those reported in other neonatal cohorts. Controlling for race/ethnicity, infants born to women treated with PIs had higher LDL cholesterol than those born to women not treated with PIs (29 mg/dl versus 27 mg/dl, P = 0.006). Only LDL cholesterol was significantly higher in the cord blood of PI-exposed infants versus those not exposed to PIs in utero. As the difference between the two groups was small, the clinical relevance of the effect of maternal PI treatment on infant LDL cholesterol levels at birth is not clear.


Multiple subfailures characterize blunt aortic injury.
Blunt aortic injuries result from rapid deceleration of the thorax as may occur during automotive impacts and falls from extreme heights. Pathological findings can range from failure of specific vessel layers to immediate vessel wall rupture. The purpose of this investigation was to determine the sequence of local structural events that may lead to aortic wall disruption. Fourteen porcine aorta specimens were opened to expose the intima and longitudinally distracted until rupture. Longitudinal mechanics were quantified and subfailures were identified. Histology was used to examine internal layer subfailure. Videography demonstrated that subfailures propagated into complete vessel wall rupture. Subfailures occurred before complete vessel rupture in 93% of specimens. Intimal and medial subfailures were present at 74% of the stress and 82% of the strain to rupture. Multiple subfailures were evident in 79% of specimens. Present results supported the clinical theory that nonimmediate death as a result of blunt aortic injury is commonly caused by propagation of lesser lesions, initiating on the intimal layer, into complete vessel rupture including the adventitial layer. This finding, along with histologic evidence of subfailure pathological findings, confirms the presence of an acute window during which recognition and initiation of permissive hypotension may be lifesaving.


Acoustic competition in the gulf toadfish Opsanus beta: acoustic tagging.
Nesting male gulf toadfish Opsanus beta produce a boatwhistle advertisement call used in male-male competition and to attract females and an agonistic grunt call. The grunt is a short-duration pulsatile call, and the boatwhistle is a complex call typically consisting of zero to three introductory grunts, a long tonal boop note, and zero to three shorter boops. The beginning of the boop note is also gruntlike. Anomalous boatwhistles contain a short-duration grunt embedded in the tonal portion of the boop or between an introductory grunt and the boop. Embedded grunts have sound-pressure levels and frequency spectra that correspond with those of recognized neighbors, suggesting that one fish is grunting during another's call, a phenomenon here termed acoustic tagging. Snaps of nearby pistol shrimp may also be tagged, and chains of tags involving more than two fish occur. The stimulus to tag is a relatively intense sound with a rapid rise time, and tags are generally produced within 100 ms of a trigger stimulus. Time between the trigger and the tag decreases with increased trigger amplitude. Tagging is distinct from increased calling in response to natural calls or stimulatory playbacks since calls rarely overlap other calls or playbacks. Tagging is not generally reciprocal between fish, suggesting parallels to dominance displays.


"Small size" in the Philippine human fossil record: is it meaningful for a better understanding of the evolutionary history of the negritos?
"Pygmy populations" are recognized in several places over the world, especially in Western Africa and in Southeast Asia (Philippine "negritos," for instance). Broadly defined as "small-bodied Homo sapiens" (compared with neighboring populations), their origins and the nature of the processes involved in the maintenance of their phenotype over time are highly debated. Major results have been recently obtained from population genetics on present-day negrito populations, but their evolutionary history remains largely unresolved. We present and discuss the Upper Pleistocene human remains recovered from Tabon Cave and Callao Cave in the Philippines, which are potentially highly relevant to these research questions. Human fossils have been recovered in large numbers from Tabon Cave (Palawan Island) but mainly from reworked and mixed sediments from several archaeological layers. We review and synthesize the long and meticulous collaborative work done on the archives left from the 1960s excavations and on the field. The results demonstrate the long history of human occupations in the cave, since at least ~30,000 BP. The examination of the Tabon human remains shows a large variability: large and robust for one part of the sample, and small and gracile for the other part. The latter would fit quite comfortably within the range of variation of Philippine negritos. Farther north, on Luzon Island, the human third metatarsal recently recovered from Callao Cave and dated to ~66,000 BP is now the oldest direct evidence of human presence in the Philippines. Previous data show that, compared with H. sapiens (including Philippine negritos), this bone presents a very small size and several unusual morphological characteristics. We present a new analytical approach using three-dimensional geometric morphometrics for comparing the Callao fossil to a wide array of extant Asian mammals, including nonhuman primates and H. sapiens. The results demonstrate that the shape of the Callao metatarsal is definitely closer to humans than to any other groups. The fossil clearly belongs to the genus Homo; however, it remains at the margin of the variation range of H. sapiens. Because of its great antiquity and the presence of another diminutive species of the genus Homo in the Wallace area during this time period (H. floresiensis), we discuss here in detail the affinities and potential relatedness of the Callao fossil with negritos that are found today on Luzon Island.


Can urethral retroresistance pressures predict midurethral sling outcomes?
To determine whether preoperative urethral resistance pressure (URP) measurements could predict success or failure of a tension-free vaginal tape (TVT) sling. Subjects came from a previously published study comparing URP measurements to a validated urinary incontinence symptom survey (UISS). We contacted patients from that study to determine whether they had subsequently undergone TVT surgery. Within that cohort, we determined the "current" (i.e., postoperative) UISS and Sandvik urinary incontinence severity score. Success of a TVT sling in this group was defined in 4 ways: (1) postoperative UISS score <3, (2) postoperative UISS score < 75% of the preoperative score, (3) postoperative Sandvik score <6, and (4) postoperative Sandvik score <2. These definitions of "success" were compared across demographic and treatment variables using the Student's t test, ANOVA, chi2 and ROC curves. We contacted 69 women who had in fact received a TVT sling after their participation in the previously published study mentioned above. Among these 69 women, mean preoperative urethral retroresistance pressure values were not predictive of surgical success. Preoperative urethral retroresistance pressure measurements did not reliably predict surgical success or failure; therefore, this urodynamic test is of little value to the clinician.


Results of an online questionnaire to survey calf management practices on dairy cattle breeding farms in Austria and to estimate differences in disease incidences depending on farm structure and management practices.
Calf disease may result in great economic losses. To implement prevention strategies it is important to gain information on management and to point out risk factors. The objective of this internet based survey was to describe calf management practices on registered dairy breeding farms in Austria and to estimate differences in calf disease incidences depending on farm structure and management practices. A total of 1287 questionnaires were finally analysed (response rate 12.2 %). Herd characteristics and regional distribution of farms indicated that this survey gives a good overview on calf management practices on registered dairy farms in Austria. The median number of cows per farm was 20 (interquartile range 13-30). Significant differences regarding farm characteristics and calf management between small and large farms (≤20 vs >20 cows) were present. Only 2.8 % of farmers tested first colostrum quality by use of a hydrometer. Storing frozen colostrum was more prevalent on large farms (80.8 vs 64.2 %). On 85.1 % of the farms, whole milk, including waste milk, was fed to the calves. Milk replacer and waste milk were more often used on large farms. In accordance with similar studies from other countries, calf diarrhoea was indicated as the most prevalent disease. Multivariable logistic regression analysis revealed that herd size was associated with calf diarrhoea and calf respiratory tract disease, with higher risk of disease on large farms. Furthermore, feeding waste milk to the calves was associated with increasing calf diarrhoea incidence on farm. In the final model with calf respiratory tract disease as outcome, respondents from organic farms reported less often a respiratory tract disease incidence of over 10 % compared with conventional farms [odds ratio (OR) 0.40, 95 % confidence interval (CI) 0.21-0.75] and farmers that housed calves individually or in groups after birth significantly reported more often to have an incidence of respiratory tract disease >10 % compared with farms where all calves were housed individually (OR 2.28, 95 % CI 1.16-4.48). The results obtained in this study provide an overview on calf management on dairy breeding farms in Austria and may help to further point out areas to be improved on farm.


Direct medical costs and their predictors in patients with rheumatoid arthritis: a three-year study of 7,527 patients.
To estimate total direct medical costs in persons with rheumatoid arthritis (RA) and to characterize predictors of these costs. Patients (n = 7,527) participating in a longitudinal study of outcome in RA completed 25,050 semiannual questionnaires from January 1999 through December 2001. From these we determined direct medical care costs converted to 2001 US dollars using the consumer price index. We used generalized estimating equations to examine potential predictors of the costs. Monte Carlo simulations and sensitivity analyses were performed to evaluate the varying prevalence and cost of biologic therapy. The mean total annual direct medical care cost in 2001 for a patient with RA was 9,519 US dollars. Drug costs were 6,324 US dollars (66% of the total), while hospitalization costs were only 1,573 US dollars (17%). Approximately 25% of patients received biologic therapy. The mean total annual direct cost for patients receiving biologic agents was 19,016 US dollars per year, while the cost for those not receiving biologic therapy was 6,164 US dollars. RA patients who were in the worst quartile of functional status, as measured by the Health Assessment Questionnaire, experienced direct medical costs for the subsequent year that were 5,022 US dollars more than the costs incurred by those in the best quartile. Physical status as determined by the Short Form 36 physical component scale had a similar large effect on RA costs, as did comorbidity. Medical insurance type played a more limited role. However, those without insurance had substantially lower service utilization and costs, and health maintenance organization patients had lower drug costs and total medical costs. Increased years of education, increased income, and majority ethnic status were all associated with increased drug costs but not hospitalization costs. Costs in all categories decreased after age 65 years. Estimates of direct medical costs for patients with RA are substantially higher than cost estimates before the biologic therapy era, and costs are now driven predominantly by the cost of drugs, primarily biologic agents. RA patients with poor function continue to incur substantially higher costs, as do those with comorbid conditions, and sociodemographic characteristics also play an important role in determination of costs.


Leukemoid reaction in extremely low-birth-weight infants.
The objective of this paper was to determine the incidence of leukemoid reaction and to evaluate its relationship with maternal and neonatal factors in extremely low-birth-weight (ELBW) infants. The design a case-controlled retrospective study of all live-born ELBW infants (<1000 g) over a period of 2 years, from July 1994 to June 1996. A total of 60 preterm infants were born during the study period, and are included in this report. The infants who demonstrated leukemoid reaction formed the study group, while the remainder formed the control group. Leukemoid reaction was defined as a white blood cell (WBC) count > or = 50,000/mm3. The relationship between maternal and neonatal variables and WBC counts was studied. Nine of the 60 infants studied demonstrated counts >50,000/mm3, with an incidence of 15%. There was no significant association demonstrated between maternal or neonatal variables and leukemoid reaction. Patients with leukemoid reaction had a better overall survival. Leukemoid reaction in ELBW infants is a rare and recently documented phenomenon. In our study the incidence was 15%. Although many factors have been postulated as a cause of this phenomenon, we could not demonstrate any relationship between these factors and high WBC counts, including sepsis and the use of antenatal steroids, the two most likely variables. It was interesting to note that the infants who were able to mount a leukemoid response had a better chance of survival than those who did not.


Polycomb associates genome-wide with a specific RNA polymerase II variant, and regulates metabolic genes in ESCs.
Polycomb repressor complexes (PRCs) are important chromatin modifiers fundamentally implicated in pluripotency and cancer. Polycomb silencing in embryonic stem cells (ESCs) can be accompanied by active chromatin and primed RNA polymerase II (RNAPII), but the relationship between PRCs and RNAPII remains unclear genome-wide. We mapped PRC repression markers and four RNAPII states in ESCs using ChIP-seq, and found that PRC targets exhibit a range of RNAPII variants. First, developmental PRC targets are bound by unproductive RNAPII (S5p(+)S7p(-)S2p(-)) genome-wide. Sequential ChIP, Ring1B depletion, and genome-wide correlations show that PRCs and RNAPII-S5p physically bind to the same chromatin and functionally synergize. Second, we identify a cohort of genes marked by PRC and elongating RNAPII (S5p(+)S7p(+)S2p(+)); they produce mRNA and protein, and their expression increases upon PRC1 knockdown. We show that this group of PRC targets switches between active and PRC-repressed states within the ESC population, and that many have roles in metabolism.


Semantic Memory and the Hippocampus: Revisiting, Reaffirming, and Extending the Reach of Their Critical Relationship.
Since Tulving proposed a distinction in memory between semantic and episodic memory, considerable effort has been directed towards understanding their similar and unique features. Of particular interest has been the extent to which semantic and episodic memory have a shared dependence on the hippocampus. In contrast to the definitive evidence for the link between hippocampus and episodic memory, the role of the hippocampus in semantic memory has been a topic of considerable debate. This debate stems, in part, from highly variable reports of new semantic memory learning in amnesia ranging from profound impairment to full preservation, and various degrees of deficit and ability in between. More recently, a number of significant advances in experimental methods have occurred, alongside new provocative data on the role of the hippocampus in semantic memory, making this an ideal moment to revisit this debate, to re-evaluate data, methods, and theories, and to synthesize new findings. In line with these advances, this review has two primary goals. First, we provide a historical lens with which to reevaluate and contextualize the literature on semantic memory and the hippocampus. The second goal of this review is to provide a synthesis of new findings on the role of the hippocampus and semantic memory. With the perspective of time and this critical review, we arrive at the interpretation that the hippocampus does indeed make necessary contributions to semantic memory. We argue that semantic memory, like episodic memory, is a highly flexible, (re)constructive, relational and multimodal system, and that there is value in developing methods and materials that fully capture this depth and richness to facilitate comparisons to episodic memory. Such efforts will be critical in addressing questions regarding the cognitive and neural (inter)dependencies among forms of memory, and the role that these forms of memory play in support of cognition more broadly. Such efforts also promise to advance our understanding of how words, concepts, and meaning, as well as episodes and events, are instantiated and maintained in memory and will yield new insights into our two most quintessentially human abilities: memory and language.


A Feasibility Study of Restorative Yoga Versus Vigorous Yoga Intervention for Sedentary Breast and Ovarian Cancer Survivors.
Yoga has been shown to improve cancer survivors' quality of life, yet regular yoga practice is a challenge for those who are sedentary. We conducted a pilot randomized controlled study to assess feasibility and adherence of two types of yoga intervention among sedentary cancer survivors. Sedentary breast and ovarian cancer survivors were randomized to practice either restorative yoga (minimal physical exertion, Group R) or vigorous yoga (considerable physical exertion, Group V) in three 60-minute supervised sessions a week for 12 weeks, followed by 12 weeks of home practice. Accrual, adherence, and attendance rates were assessed. Of the 226 eligible patients, 175 (77%) declined to participate in the study, citing time commitment and travel as the most common barriers. Forty-two subjects consented to participate in the study. Of the 35 participants who began the intervention (20 in Group R and 15 in Group V), adherence rate (percentage remaining in the study at week 12) was 100% and 87%, respectively. Rate of adequate attendance (more than 66% of the scheduled supervised sessions) was 85% and 73%, respectively. Rate of completion of the home practice period was 85% and 77%, respectively. In this study, sedentary cancer survivors were able to adhere to a long-term, regular yoga regimen. The rate of adequate attendance was higher for restorative yoga. Future studies for sedentary patients should focus on reducing time commitment and travel requirements to improve recruitment, and on using restorative yoga as a more feasible intervention for this population.


Structural processing in biological motion perception.
To investigate the basis for biological motion perception, structural and motion information were manipulated independently in a dynamic display using a novel stimulus with multiple apertures. Performance was compared in discrimination of global motion (translation and rotation) and biological motion. When structural information in the display was eliminated but motion information was intact, human observers were able to perceive global motion yet were at chance in discriminating walking direction of biological movement. In contrast, when the display provided even noisy and impoverished structural information, walking direction became identifiable. The present findings thus provide direct psychophysical evidence that motion information is insufficient and structural information is necessary for the identification of walking direction in biological movement. These findings imply that computational models must utilize a structural representation of the human body to account for perception of biological movements.


Vorinostat in solid and hematologic malignancies.
Vorinostat (Zolinza), a histone deacetylase inhibitor, was approved by the US Food and Drug Administration in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. This review summarizes evidence on the use of vorinostat in solid and hematologic malignancies and collated tolerability data from the vorinostat clinical trial program. Pooled vorinostat clinical trial data from 498 patients with solid or hematologic malignancies show that vorinostat was well tolerated as monotherapy or combination therapy. The most commonly reported drug-related adverse events (AEs) associated with monotherapy (n = 341) were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%), and Grade 3/4 drug-related AEs included fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.3%), and decreased platelet count (5.3%). The most common drug-related AEs observed with vorinostat in combination therapy (n = 157, most of whom received vorinostat 400 mg qd for 14 days) were nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), vomiting (31.2%), and anorexia (20.4%), with the majority of AEs being Grade 2 or less. In Phase I trials, combinations with vorinostat were generally well tolerated and preliminary evidence of anticancer activity as monotherapy or in combination with other systemic therapies has been observed across a range of malignancies. Ongoing and planned studies will further evaluate the potential of vorinostat in combination therapy, including combinations with radiation, in patients with diverse malignancy types, including non-small-cell lung cancer, glioblastoma multiforme, multiple myeloma, and myelodysplastic syndrome.


Whole-island carbon stocks in the tropical Pacific: implications for mangrove conservation and upland restoration.
Management of forest carbon (C) stocks is an increasingly prominent land-use issue. Knowledge of carbon storage in tropical forests is improving, but regional variations are still poorly understood, and this constrains forest management and conservation efforts associated with carbon valuation mechanisms (e.g., carbon markets). This deficiency is especially pronounced in tropical islands and low-lying coastal areas where climate change impacts are expected to be among the most severe. This study presents the first field estimate of island-wide carbon storage in ecosystems of Oceania, with special attention to the regional role of coastal mangroves, which occur on islands and coastal zones throughout the tropics. On two island groups of Micronesia (Yap and Palau), we sampled all above- and belowground C pools, including soil and vegetation, in 24 sites distributed evenly among the three major vegetation structural types: mangroves, upland forests, and open savannas (generally on degraded lands formerly forested). Total C stocks were estimated to be 3.9 and 15.2 Tg C on Yap and Palau, respectively. Mangroves contained by far the largest per-hectare C pools (830-1218 Mg C ha(-1)), with deep organic-rich soils alone storing more C (631-754 Mg C ha(-1)) than all pools combined in upland systems. Despite covering just 12-13% of land area, mangroves accounted for 24-34% of total island C stocks. Savannas (156-203 Mg C ha(-1)) contained significantly lower C stocks than upland forests (375-437 Mg C ha(-1)), suggesting that reforesting savannas where appropriate has high potential for carbon-based funding to aid restoration objectives. For mangroves, these results demonstrate the key role of these systems within the broader context of C storage in island and coastal landscapes. Sustainable management of mangrove forests and their large C stocks is of high importance at the regional scale, and climate change mitigation programs such as REDD+ could play a large role in avoiding deforestation of mangroves where this is a management objective.


The osteocyte--a novel endocrine regulator of body phosphate homeostasis.
Although osteocytes are the most abundant cell type in bone, much of their biology remains enigmatic. They are known to transduce mechanical stress into signals that initiate local bone remodeling, and are targets for systemic and local endocrine signals that affect bone architecture and mineral homeostasis. However, recent data reveal that osteocytes themselves act as endocrine cells that synthesize fibroblast growth factor 23 (FGF23) and several other phosphatonins, shown to underpin the systemic regulation of phosphate homeostasis. This review will synthesize the emerging discoveries concerning the osteocytic endocrine role in phosphate homeostasis through the biology and pathophysiology of these phosphatonins. We also suggest future research paths that might resolve existing uncertainties, and look ahead at how greater understanding might improve the management of clinical disorders of phosphate homeostasis.


Central hypotensive effects of the alpha2a-adrenergic receptor subtype.
alpha2-Adrenergic receptors (alpha2ARs) present in the brainstem decrease blood pressure and are targets for clinically effective antihypertensive drugs. The existence of three alpha2AR subtypes, the lack of subtype-specific ligands, and the cross-reactivity of alpha2AR agonists with imidazoline receptors has precluded an understanding of the role of individual alpha2AR subtypes in the hypotensive response. Gene targeting was used to introduce a point mutation into the alpha2aAR subtype in the mouse genome. The hypotensive response to alpha2AR agonists was lost in the mutant mice, demonstrating that the alpha2aAR subtype plays a principal role in this response.


Lrig1 is a haploinsufficient tumor suppressor gene in malignant glioma.
Recently, a genome-wide association study showed that a single nucleotide polymorphism (SNP) -rs11706832-in intron 2 of the human LRIG1 (Leucine-rich repeats and immunoglobulin-like domains 1) gene is associated with susceptibility to glioma. However, the mechanism by which rs11706832 affects glioma risk remains unknown; additionally, it is unknown whether the expression levels of LRIG1 are a relevant determinant of gliomagenesis. Here, we investigated the role of Lrig1 in platelet-derived growth factor (PDGF)-induced experimental glioma in mice by introducing mono-allelic and bi-allelic deletions of Lrig1 followed by inducing gliomagenesis via intracranial retroviral transduction of PDGFB in neural progenitor cells. Lrig1 was expressed in PDGFB-induced gliomas in wild-type mice as assessed using in situ hybridization. Intriguingly, Lrig1-heterozygous mice developed higher grade gliomas than did wild-type mice (grade IV vs. grade II/III, p = 0.002). Reciprocally, the ectopic expression of LRIG1 in the TB107 high-grade human glioma (glioblastoma, grade IV) cell line decreased the invasion of orthotopic tumors in immunocompromised mice in vivo and reduced cell migration in vitro. Concomitantly, the activity of the receptor tyrosine kinase MET was downregulated, which partially explained the reduction in cell migration. In summary, Lrig1 is a haploinsufficient suppressor of PDGFB-driven glioma, possibly in part via negative regulation of MET-driven cell migration and invasion. Thus, for the first time, changes in physiological Lrig1 expression have been linked to gliomagenesis, whereby the SNP rs11706832 may affect glioma risk by regulating LRIG1 expression.


Prefrontal cortex lesions differentially disrupt cocaine-reinforced conditioned place preference but not conditioned taste aversion.
The reinforcing efficacy of cocaine is thought to involve, at least in part, mesocortical dopaminergic (DA) neurons. Rats will self-administer cocaine applied directly into the medial prefrontal cortex but not into nucleus accumbens or the ventral tegmental area (Goeders & Smith, 1983). The present experiments were conducted to assess whether lesions of prefrontal cortex (mesocortical DA target regions) attenuate the reinforcing properties of systemically administered cocaine. Male Sprague-Dawley rats were anesthetized, and one of three subfields (medial, orbital, or precentral) of the prefrontal cortex was removed by aspiration or no brain injury was done (sham operates). In four experiments the rats were tested on conditioned place preference (CPP), conditioned taste aversion (saccharin conditioned stimulus, cocaine unconditioned stimulus), general activity in the running wheel and open field, and food-reinforced spatial alternation in the T-maze. Sham operates demonstrated a cocaine-induced place preference, rats with medial frontal lesions showed a cocaine-induced place aversion, and other operates showed neither a conditioned place preference nor an aversion. The results of this experiment suggest that lesions of the DA projection fields of the prefrontal cortex in the rat reduce the positive reinforcing properties of systemically injected cocaine. In the second experiment, all subjects showed a conditioned taste aversion of equal magnitude. This suggests that whereas the positive reinforcing properties were affected differentially by prefrontal cortex lesions, the aversive properties were not affected. In Experiment 3 there were no lesion-induced differences in activity in either the running wheel or the open field. Therefore, changes in motor activity cannot account for the CPP data. In the final experiment, the medial frontal operates were impaired relative to the precentral and sham operates on learning to alternate choices in the T-maze, but the orbital frontal operates' performance was not different from that of any other group. This suggests that a general disruption of all reinforcement mechanisms did not occur following these lesions. Instead, these results indicate that mesocortical DA projection regions are involved with mediating the reinforcing properties of cocaine and that there is a separate system mediating the aversive properties of cocaine.


Inadequate clearance of translocated bacterial products in HIV-infected humanized mice.
Bacterial translocation from the gut and subsequent immune activation are hallmarks of HIV infection and are thought to determine disease progression. Intestinal barrier integrity is impaired early in acute retroviral infection, but levels of plasma lipopolysaccharide (LPS), a marker of bacterial translocation, increase only later. We examined humanized mice infected with HIV to determine if disruption of the intestinal barrier alone is responsible for elevated levels of LPS and if bacterial translocation increases immune activation. Treating uninfected mice with dextran sodium sulfate (DSS) induced bacterial translocation, but did not result in elevated plasma LPS levels. DSS-induced translocation provoked LPS elevation only when phagocytic cells were depleted with clodronate liposomes (clodrolip). Macrophages of DSS-treated, HIV-negative mice phagocytosed more LPS ex vivo than those of control mice. In HIV-infected mice, however, LPS phagocytosis was insufficient to clear the translocated LPS. These conditions allowed higher levels of plasma LPS and CD8+ cell activation, which were associated with lower CD4+/CD8+ cell ratios and higher viral loads. LPS levels reflect both intestinal barrier and LPS clearance. Macrophages are essential in controlling systemic bacterial translocation, and this function might be hindered in chronic HIV infection.


Deep learning of orthographic representations in baboons.
What is the origin of our ability to learn orthographic knowledge? We use deep convolutional networks to emulate the primate's ventral visual stream and explore the recent finding that baboons can be trained to discriminate English words from nonwords. The networks were exposed to the exact same sequence of stimuli and reinforcement signals as the baboons in the experiment, and learned to map real visual inputs (pixels) of letter strings onto binary word/nonword responses. We show that the networks' highest levels of representations were indeed sensitive to letter combinations as postulated in our previous research. The model also captured the key empirical findings, such as generalization to novel words, along with some intriguing inter-individual differences. The present work shows the merits of deep learning networks that can simulate the whole processing chain all the way from the visual input to the response while allowing researchers to analyze the complex representations that emerge during the learning process.


Surface-functionalized ionic liquid crystal-supported ionic liquid phase materials: ionic liquid crystals in mesopores.
The influence of confinement on the ionic liquid crystal (ILC) [C(18)C(1)Im][OTf] is studied using differential scanning calorimetry (DSC), polarized optical microscopy (POM), and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). The ILC studied is supported on Si-based powders and glasses with pore sizes ranging from 11 to 50 nm. The temperature of the solid-to-liquid-crystalline phase transition seems mostly unaffected by the confinement, whereas the temperature of the liquid-crystalline-to-liquid phase transition is depressed for smaller pore sizes. A contact layer with a thickness in the order of 2 nm is identified. The contact layer exhibits a phase transition at a temperature 30 K lower than the solid-to-liquid-crystalline phase transition observed for the neat ILC. For applications within the "supported ionic liquid phase (SILP)" concept, the experiments show that in pores of diameter 50 nm a pore filling of α>0.4 is sufficient to reproduce the phase transitions of the neat ILC.


Development of starch-gelatin complex microspheres as sustained release delivery system.
The starch was isolated from jackfruit seeds and evaluated for its preformulation properties, like tapped density, bulk density, and particle size. The fourier transform infrared (FTIR) analysis was done and compared with that of the commercially available starch which confirmed the properties. Using the various concentrations of jackfruit seed starch, the microspheres were prepared, combining with gelatin by ionotropic gelation technique. The developed microspheres were subjected to analysis of particle size, drug content, entrapment efficiency, and percentage yield. The spectral analysis confirmed the presence of drug and absence of interactions. Scanning electron microscope image showed that the particles were in spherical shape with a rough surface. The in vitro drug release in water for 12 hours proved to be in the range of 89 to 100%. The various kinetic models were applied using release data to confirm the mechanism of drug. It was concluded that the jackfruit starch-gelatin microspheres gave satisfactory results and met pharmacopieal limits.


Vocal tract function in birdsong production: experimental manipulation of beak movements.
Kinematic analyses have demonstrated that the extent to which a songbird's beak is open when singing correlates with the acoustic frequencies of the sounds produced, suggesting that beak movements function to modulate the acoustic properties of the vocal tract during song production. If motions of the beak are necessary for normal song production, then disrupting the ability of a bird to perform these movements should alter the acoustic properties of its song. We tested this prediction by comparing songs produced normally by white-throated sparrows and swamp sparrows with songs produced when the beak was temporarily immobilized. We also observed how temporarily loading the beak of canaries with extra mass affected vocal tract movements and song production. Disruption of vocal tract movements resulted in the predicted frequency-dependent amplitude changes in the songs of both white-throated sparrows and swamp sparrows. Canaries with mass added to their beak sang with their beak open more widely than normal and produced notes with greater harmonic content than those without weights. Both manipulations resulted in acoustic changes consistent with a model in which beak motions affect vocal tract resonances, thus supporting the hypothesis that dynamic vocal tract motions and post-production modulation of sound are necessary features of normal song production.


GNC and CGA1 modulate chlorophyll biosynthesis and glutamate synthase (GLU1/Fd-GOGAT) expression in Arabidopsis.
Chloroplast development is an important determinant of plant productivity and is controlled by environmental factors including amounts of light and nitrogen as well as internal phytohormones including cytokinins and gibberellins (GA). The paralog GATA transcription factors GNC and CGA1/GNL up-regulated by light, nitrogen and cytokinin while also being repressed by GA signaling. Modifying the expression of these genes has previously been shown to influence chlorophyll content in Arabidopsis while also altering aspects of germination, elongation growth and flowering time. In this work, we also use transgenic lines to demonstrate that GNC and CGA1 exhibit a partially redundant control over chlorophyll biosynthesis. We provide novel evidence that GNC and CGA1 influence both chloroplast number and leaf starch in proportion to their transcript level. GNC and CGA1 were found to modify the expression of chloroplast localized GLUTAMATE SYNTHASE (GLU1/Fd-GOGAT), which is the primary factor controlling nitrogen assimilation in green tissue. Altering GNC and CGA1 expression was also found to modulate the expression of important chlorophyll biosynthesis genes (GUN4, HEMA1, PORB, and PORC). As previously demonstrated, the CGA1 transgenic plants demonstrated significantly altered timing to a number of developmental events including germination, leaf production, flowering time and senescence. In contrast, the GNC transgenic lines we analyzed maintain relatively normal growth phenotypes outside of differences in chloroplast development. Despite some evidence for partial divergence, results indicate that regulation of both GNC and CGA1 by light, nitrogen, cytokinin, and GA acts to modulate nitrogen assimilation, chloroplast development and starch production. Understanding the mechanisms controlling these processes is important for agricultural biotechnology.


The Impact of Parental Detention on the Psychological Wellbeing of Palestinian Children.
Since 1967, the Palestinian Occupied Territories are marked by a political conflict between Palestinians and Israel. During this conflict, about one fifth of the Palestinian population has been detained; about one quarter of these are parents. Although we know that father's incarceration might impact their children's psychological wellbeing, little is known about the impact of father's imprisonment on young children (under 11 years old), and when the incarceration is framed in contexts of political conflict. Therefore, this study aimed at gaining insight into the impact of parental detention on young children's psychological wellbeing, and the impact of witnessing the detention process itself. Based on the list of imprisoned Palestinian men with children living in the West Bank, a group of 79 (3- to 10-years old) children was randomly composed. Above, through schools and health centers, a comparison sample of 99 children who didn't experience imprisonment of a family member was selected. Mothers of these children completed two cross-culturally validated questionnaires on their children's psychological wellbeing, the UCLA-PTSD-Index and the Strength and Difficulties Questionnaire (SDQ). Results showed higher levels of PTSD and general mental health problems associated with father's capturing. Above, when the children watched the arrest process of their fathers, scores still increased further. Younger children tended to show higher SDQ scores, and children living in villages reported higher posttraumatic stress scores compared to children living in urban areas or refugee camps. Little gender differences were found. This study shows the important impact of parental detention on the psychological wellbeing for young children and urges for more psychological care and support for family members--in particular children--of detainees.


Epitope mapping of the major allergen from Atlantic cod in Spanish population reveals different IgE-binding patterns.
IgE-epitope mapping of allergens reveal important information about antigen components involved in allergic reactions. The peptide-based microarray immunoassay has been used to map epitopes of some food allergens. We developed a peptide microarray immunoassay to map allergenic epitopes in parvalbumin from Atlantic cod (Gad m 1), the most consumed cod species in Spain. Sera from 13 fish-allergic patients with specific IgE to cod parvalbumin were used. A library of overlapping peptides was synthesized, representing the primary sequence of Gad m 1. Peptides were used to analyze allergen-specific IgE antibodies in patient sera. 100% of the patients recognized one antigenic region of 15 amino acids in length in Gad m 1. This region only partially correlated with one of the three antigenic determinants of Gad c 1 (Allergen M), parvalbumin from Baltic cod (Gadus callarias). In the 3D model of the protein, this region was located on the surface of the protein. We have identified a relevant antigenic region in Gad m 1. This epitope could be considered as a severity marker and provides additional information to improve fish allergy diagnosis and the design of safe immunotherapeutic tools.


Tailoring graphene oxide assemblies by pinning on the contact line of a dissolving microdroplet.
The controlled dissolution of microdroplets on a supporting substrate is an effective approach that can be used to tune the assembled microstructure of basic units suspended within the droplet. In this work, we studied the self-assembly of two-dimensional graphene oxide (GO) nanosheets driven by the dissolution of a microdroplet situated at the interface between a solid substrate and the surrounding liquid phase. We found that although uniform microstructures form at the liquid-liquid interface of the droplets, the contact between the droplet and the substrate can give rise to a variety of different morphologies near the base of the droplet. In particular, pinning effects at the boundary of the dissolving droplet on the substrate lead to non-spherical GO assemblies. The results in this work demonstrate the possibility that tailored three-dimensional architectures of nanosheets assembled in a dissolving droplet may be achieved through control of the wetting properties of the droplet on the supporting substrate.


Tumor angiogenesis. From bench to bedside.
Starting with the hypothesis of Judah Folkman that tumor growth is angiogenesis dependent, this area of research has a solid scientific foundation. More than 30 years ago, Folkman found a revolutionary new way to think about cancer. He postulated that in order to survive and grow, tumors require blood vessels and that by cutting off the blood supply a cancer could be starved into remission. Several clinical studies have shown a positive correlation between the number of vessels in the tumor, metastasis formation and prognosis. The genetic instability of tumor cells permits the occurrence of multiple genetic alterations that facilitate tumor progression and metastasis, and cell clones with diverse biological aggressiveness may coexist within the same tumor. These two properties allow tumors to acquire resistance to cytotoxic agents. Inhibiting angiogenesis is a major area of therapeutic development for the treatment of cancer. Whereas conventional chemotherapy, radiotherapy and immunotherapy are directed against tumor cells, anti-angiogenic therapy is aimed at the vasculature of a tumor and will either cause total tumor regression or keep tumors in a state of dormancy. Even though numerous compounds inhibit angiogenesis, few of them have proved effective in vivo, and only a couple of agents have been able to induce tumor regression. Bevacizumab is considered to be the first specific angiogenesis inhibitor for clinical oncology.


Addition of mushroom powder to pasta enhances the antioxidant content and modulates the predictive glycaemic response of pasta.
This study reports the effects of addition of mushroom powder on the nutritional properties, predictive in vitro glycaemic response and antioxidant potential of durum wheat pasta. Addition of the mushroom powder enriched the pasta as a source of protein, and soluble and insoluble dietary fibre compared with durum wheat semolina. Incorporation of mushroom powder significantly decreased the extent of starch degradation and the area under the curve (AUC) of reducing sugars released during digestion, while the total phenolic content and antioxidant capacities of samples increased. A mutual inhibition system between the degree of starch gelatinisation and antioxidant capacity of the pasta samples was observed. These results suggest that mushroom powder could be incorporated into fresh semolina pasta, conferring healthier characteristics, namely lowering the potential glycaemic response and improving antioxidant capacity of the pasta.


Limits of adaptation: the evolution of selective neutrality.
Many enzymes in intermediary metabolism manifest saturation kinetics in which flux is a concave function of enzyme activity and often of the Michaelis-Menten form. The result is that, when natural selection favors increased enzyme activity so as to maximize flux, a point of diminishing returns will be attained in which any increase in flux results in a disproportionately small increase in fitness. Enzyme activity ultimately will reach a level at which the favorable effect of an increase in activity is of the order 1/(4Ne) or smaller, where Ne is the effective population number. At this point, many mutations that result in small changes in activity will result in negligible changes in fitness and will be selectively nearly neutral. We propose that this process is a mechanism whereby conditions for the occurrence of nearly neutral mutations and gene substitutions can be brought about by the long-continued action of natural selection. Evidence for the hypothesis derives from metabolic theory, direct studies of flux, studies of null and other types of alleles in Drosophila melanogaster and chemostat studies in Escherichia coli. Limitations and complications of the theory include changes in environment or genetic background, enzymes with sharply defined optima of activity, overdominance, pleiotropy, multifunctional enzymes and branched metabolic pathways. We conclude that the theory is a useful synthesis that unites many seemingly unrelated observations. The principal theoretical conclusion is that the conditions for the occurrence of neutral evolution can be brought about as an indirect result of the action of natural selection.


Clostridium perfringens challenge and dietary fat type affect broiler chicken performance and fermentation in the gastrointestinal tract.
The aim of the present work was to examine how different fats commonly used in the feed industry affect broiler performance, nutrient digestibility and microbial fermentation in the gastrointestinal tract of broiler chickens challenged with virulent Clostridium perfringens strains. Two experiments were carried out, each including 480-day-old male broilers (Ross 308), which were randomly distributed to eight experimental groups using six replicate pens per treatment and 10 birds per pen. In Experiment 1, birds were fed diets containing soybean oil, palm kernel fatty acid distillers, rendered pork fat and lard. In Experiment 2, birds were fed diets containing rapeseed oil, coconut oil, beef tallow and palm oil. In both experiments, the birds were either not challenged or challenged with a mixture of three C. perfringens type A strains. Irrespective of the fat type present in the diet, C. perfringens did not affect broiler chicken body weight gain (BWG) and mortality in either of the two experiments. The BWG was affected by dietary fat type in both experiments, indicating that the fatty acid composition of the fat source affects broiler growth performance. In particular, the inclusion of animal fats tended to improve final BW to a greater extent compared with the inclusion of unsaturated vegetable oils. In Experiment 2, irrespective of the dietary fat type present in the diet, C. perfringens challenge significantly impaired feed conversion ratio in the period from 14 to 28 days (1.63 v. 1.69) and at 42 days (1.65 v. 1.68). In both experiments apparent metabolizable energy values were affected by dietary fat type. Irrespective of the fat type present in the diet, C. perfringens challenge decreased the digesta pH in the crop and ileum, but had no effect in cecal contents. Moreover, in Experiment 1, total organic acid concentration in the ileum was two to three times lower on soybean oil diets as compared with other treatments, indicating that C. perfringens as well as dietary fat type significantly affects microbiota activity in the broiler chicken gastrointestinal tract.


Annual Research Review: Quality of life and childhood mental and behavioural disorders - a critical review of the research.
An individual's subjective perception of well-being is increasingly recognized as an essential complement to clinical symptomatology and functional impairment in children's mental health. Measurement of quality of life (QoL) has the potential to give due weight to the child's perspective. Our aim was to critically review the current evidence on how childhood mental disorders affect QoL. First, the major challenges in this research field are outlined. Then we present a systematic review of QoL in children and adolescents aged 0-18 years formally diagnosed with a mental and behavioural disorder, as compared to healthy or typically developing children or children with other health conditions. Finally, we discuss limitations of the current evidence base and future directions based on the results of the systematic review and other relevant literature. The systematic review identified 41 eligible studies. All were published after the year 2000 and 21 originated in Europe. The majority examined QoL in neurodevelopmental disorders, including attention-deficit hyperactivity disorder (k = 17), autism spectrum disorder (k = 6), motor disorders (k = 5) and intellectual disability (k = 4). Despite substantial heterogeneity, studies demonstrate that self-reported global QoL is significantly reduced compared to typical/healthy controls across several disorders and QoL dimensions. Parents' ratings were on average substantially lower, casting doubt on the validity of proxy-report. Studies for large diagnostic groups such as depressive disorders, anxiety disorders, (early onset) schizophrenia and eating disorders are largely lacking. We conclude that representative, well-characterized normative and clinical samples as well as longitudinal and qualitative designs are needed to further clarify the construct of QoL, to derive measures of high ecological validity, and to examine how QoL fluctuates over time and is attributable to specific conditions or contextual factors.


Learning in normal and mutant Drosophila larvae.
Adult Drosophila melanogaster have previously been conditioned with shock to avoid various odors. In these experiments, larvae also sensed airborne odorants, responded to electric shock, and learned. Larval behavior paralleled adult behavior for (i) a mutant, smellblind, which failed to respond to odorants; (ii) three mutants, dunce, turnip, and cabbage, which were deficient in olfactory learning ability; and (iii) a mutant heterozygote, turnip/+, which learned but also forgot rapidly.


The mesolimbic dopaminergic response to novel palatable food consumption increases dopamine-D1 receptor-mediated signalling with complex modifications of the DARPP-32 phosphorylation pattern.
Acute cocaine administration increases extraneuronal dopamine and Thr34 phosphorylation of dopamine- and cAMP-regulated phosphoprotein (M(r) 32 kDa; DARPP-32) in striatal and cortical areas. Novel palatable food consumption increases extraneuronal dopamine in the same areas. We examined the DARPP-32 phosphorylation pattern in food non-deprived rats at different times after vanilla sugar consumption. The phosphorylation state of DARPP-32 and two cAMP-dependent protein kinase (PKA) substrates, GluR1 and NR1, were detected by immunoblotting. Thirty to 45 min after vanilla sugar consumption, phospho-Thr34 DARPP-32, GluR1 and NR1 levels increased in the nucleus accumbens, and phospho-Thr75 DARPP-32 levels decreased. At 60 min, all parameters returned to baseline values. However, 2 and 3 h after vanilla sugar consumption, phospho-Thr34 DARPP-32 levels decreased, while phospho-Thr75 DARPP-32 levels increased. In contrast to the pattern observed in the NAcS, no delayed changes in DARPP-32 phosphorylation were observed in the mPFC. Both early and delayed DARPP-32, GluR1 and NR1 phosphorylation changes were prevented by a dopamine D1 receptor antagonist administration. The delayed modifications in nucleus accumbens DARPP-32 phosphorylation were prevented by an mGluR5 antagonist administration. The mesolimbic dopaminergic response to an unfamiliar taste is correlated to a gustatory memory trace development, and the observed changes in DARPP-32 phosphorylation may be part of this process.


Cardiomyogenic potential of mesenchymal progenitors derived from human circulating CD14+ monocytes.
Previously, we reported a unique CD14+CD45+CD34+type I collagen+ cell fraction derived from human circulating CD14+ monocytes, named monocyte-derived mesenchymal progenitors (MOMPs). These primitive cells differentiate along mesenchymal lineages, including bone, cartilage, fat, and skeletal muscle. Here, we demonstrate that CD14+ monocytes generate MOMPs that differentiate into cardiomyocytes. MOMPs labeled with a fluorescent marker and co-cultivated with rat cardiomyocytes for 4 weeks expressed the cardiomyocyte-specific transcription factors Nkx2.5, GATA-4, eHAND, and MEF2 and the hematopoietic/monocytic markers CD45 and CD14 within 10 days and retained their proliferative capacity for up to 16 days. A subpopulation of MOMPs subsequently expressed the cardiomyocyte-specific markers micro-sarcomeric actinin, troponin I, and atrial natriuretic peptide on day 21. Furthermore, fluorescence-labeled, spontaneously beating cells that formed gap junctions with adjacent rat cardiomyocytes appeared in these cultures and these cells exhibited electrophysiological properties typical of ventricular myocytes. The co-cultivation of human MOMPs with rat GFP-tagged cardiomyocytes resulted in the generation of human cardiomyocytes lacking green fluorescent protein (GFP) staining, suggesting that our observations could not solely be explained by cell fusion. Our results demonstrate for the first time that human circulating CD14+ monocytes include progenitors capable of proliferating and differentiating along the cardiomyogenic lineage via their differentiation into MOMPs.


Trigger Tool-Based Automated Adverse Event Detection in Electronic Health Records: Systematic Review.
Adverse events in health care entail substantial burdens to health care systems, institutions, and patients. Retrospective trigger tools are often manually applied to detect AEs, although automated approaches using electronic health records may offer real-time adverse event detection, allowing timely corrective interventions. The aim of this systematic review was to describe current study methods and challenges regarding the use of automatic trigger tool-based adverse event detection methods in electronic health records. In addition, we aimed to appraise the applied studies' designs and to synthesize estimates of adverse event prevalence and diagnostic test accuracy of automatic detection methods using manual trigger tool as a reference standard. PubMed, EMBASE, CINAHL, and the Cochrane Library were queried. We included observational studies, applying trigger tools in acute care settings, and excluded studies using nonhospital and outpatient settings. Eligible articles were divided into diagnostic test accuracy studies and prevalence studies. We derived the study prevalence and estimates for the positive predictive value. We assessed bias risks and applicability concerns using Quality Assessment tool for Diagnostic Accuracy Studies-2 (QUADAS-2) for diagnostic test accuracy studies and an in-house developed tool for prevalence studies. A total of 11 studies met all criteria: 2 concerned diagnostic test accuracy and 9 prevalence. We judged several studies to be at high bias risks for their automated detection method, definition of outcomes, and type of statistical analyses. Across all the 11 studies, adverse event prevalence ranged from 0% to 17.9%, with a median of 0.8%. The positive predictive value of all triggers to detect adverse events ranged from 0% to 100% across studies, with a median of 40%. Some triggers had wide ranging positive predictive value values: (1) in 6 studies, hypoglycemia had a positive predictive value ranging from 15.8% to 60%; (2) in 5 studies, naloxone had a positive predictive value ranging from 20% to 91%; (3) in 4 studies, flumazenil had a positive predictive value ranging from 38.9% to 83.3%; and (4) in 4 studies, protamine had a positive predictive value ranging from 0% to 60%. We were unable to determine the adverse event prevalence, positive predictive value, preventability, and severity in 40.4%, 10.5%, 71.1%, and 68.4% of the studies, respectively. These studies did not report the overall number of records analyzed, triggers, or adverse events; or the studies did not conduct the analysis. We observed broad interstudy variation in reported adverse event prevalence and positive predictive value. The lack of sufficiently described methods led to difficulties regarding interpretation. To improve quality, we see the need for a set of recommendations to endorse optimal use of research designs and adequate reporting of future adverse event detection studies.