Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial.
In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients on stable treatment with mycophenolate for at least 6 months before randomisation could participate. The aim of this subgroup analysis was to examine the efficacy and safety of nintedanib by mycophenolate use at baseline. The SENSCIS trial was a randomised, double-blind, placebo-controlled trial, in which patients with SSc-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or placebo for at least 52 weeks. In a prespecified subgroup analysis, we analysed the primary endpoint of rate of decline in FVC over 52 weeks by mycophenolate use at baseline. In a post-hoc analysis, we analysed the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted at week 52 (proposed minimal clinically important difference estimate for worsening of FVC in patients with SSc-ILD) in subgroups by mycophenolate use at baseline. Adverse events were reported in subgroups by mycophenolate use at baseline. Analyses were done in all participants who received at least one dose of study drug. We analysed the annual rate of decline in FVC using a random coefficient regression model (with random slopes and intercepts) including anti-topoisomerase I antibody status, age, height, sex, and baseline FVC as covariates and terms for baseline-by-time, treatment-by-subgroup, and treatment-by-subgroup-by-time interactions. SENSCIS is registered with ClinicalTrials.gov, NCT02597933, and is now complete. Between Nov 30, 2015, and Oct 31, 2017, 819 participants were screened and 576 were enrolled, randomly assigned to, and treated with nintedanib (n=288) or placebo (n=288). 139 (48%) of 288 in the nintedanib group and 140 (49%) of 288 in the placebo group were taking mycophenolate at baseline. In patients taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -40·2 mL per year (SE 19·8) with nintedanib and -66·5 mL per year (19·3) with placebo (difference: 26·3 mL per year [95% CI -27·9 to 80·6]). In patients not taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -63·9 mL per year (SE 19·3) with nintedanib and -119·3 mL per year (19·0) with placebo (difference: 55·4 mL per year [95% CI 2·3 to 108·5]). We found no heterogeneity in the effect of nintedanib versus placebo on the annual rate of decline in FVC between the subgroups by mycophenolate use (p value for interaction=0·45). In a post-hoc analysis, the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted was lower with nintedanib than with placebo in both patients taking mycophenolate (40 [29%] of 138 vs 56 [40%] of 140; odds ratio 0·61 [0·37 to 1·01]) and those not taking mycophenolate (59 [40%] of 149 vs 70 [47%] of 148; 0·73 [0·46 to 1·16]) at baseline. The adverse event profile of nintedanib was similar between the subgroups. Diarrhoea, the most common adverse event, was reported in 106 (76%) of 139 patients in the nintedanib group and 48 (34%) of 140 in the placebo group among those taking mycophenolate at baseline, and in 112 (75%) of 149 in the nintedanib group and 43 (29%) of 148 in the placebo group among those not taking mycophenolate at baseline. Over the entire trial period, 19 patients died (ten in the nintedanib group and nine in the placebo group). One death in the nintedanib group was considered to be related to study drug. Nintedanib reduced the progression of interstitial lung disease both in patients with SSc-ILD who were and were not using mycophenolate at baseline, with no heterogeneity in its treatment effect detected between the subgroups. The adverse event profile of nintedanib was similar in the subgroups by mycophenolate use. Our findings suggest that the combination of mycophenolate and nintedanib offers a safe treatment option for patients with SSc-ILD. More data are needed on the benefits of initial combination therapy versus a sequential approach to treatment of SSc-ILD. Boehringer Ingelheim.


Polymorphic ROS scavenging revealed by CCCP in a lizard.
Ingestion of antioxidants has been argued to scavenge circulating reactive molecules (e.g., free radicals), play a part in mate choice (by mediating access to this important resource), and perhaps increase life span. However, recent work has come to question these relationships. We have shown elsewhere in the polychromatic lizard, Ctenophorus pictus, that diet supplementation of carotenoids as antioxidants does not depress circulating natural reactive oxygen species (ROS) levels and leads to no corresponding improvement of color traits. However, a much stronger test would be to experimentally manipulate the ROS levels themselves and assess carotenoid-induced ROS depression. Here, we achieve this by using carbonyl cyanide 3-chlorophenylhydrazone, which elevates superoxide (SO) formation approximately threefold at 10 microM in this model system. We then look for depressing effects on ROS of the carotenoids in order to assess whether 'super-production' of SO makes carotenoid effects on elevated ROS levels detectable. The rationale for this treatment was that if not even such elevated levels of SO are reduced by carotenoid supplementation, the putative link carotenoids, ROS depression, and mate quality (in terms of antioxidant capacity) is highly questionable. We conclude that there is no significant effect of carotenoids on mean SO levels even at the induced ROS levels. However, our results showed a significant interaction effect between carotenoid treatment and male color, with red males having higher ROS levels than yellow males. We suggest that this may be because different pigments are differently involved in the generation of the integumental colors in the two morphs with concomitant effects on ROS depletion depending on carotenoid uptake or allocation to coloration and antioxidation.


Experimental Realization of Two-Dimensional Buckled Lieb Lattice.
Two-dimensional (2D) materials with a Lieb lattice host exotic electronic band structures. Such a system does not exist in nature, and it is also difficult to obtain in the laboratory due to its structural instability. Here, we experimentally realized a 2D system composed of a tin overlayer on an aluminum substrate by molecular beam epitaxy. The specific arrangement of Sn atoms on the Al(100) surface, which benefits from favorable interface interactions, forms a stabilized buckled Lieb lattice. Theoretical calculations indicate a partially broken nodal line loop and a topologically nontrivial insulating state with a spin-orbital coupling effect in the band structure of this Lieb lattice. The electronic structure of this system is experimentally characterized by angle-resolved photoemission spectroscopy, in which the hybridized states between topmost Al atoms and Sn atoms are revealed. Our work provides an appealing method for constructing 2D quantum materials based on the Lieb lattice.


Cervical headache: an investigation of natural head posture and upper cervical flexor muscle performance.
In this study, 60 female subjects, aged between 25 and 40 years, were divided into two equal groups on the basis of absence or presence of headache. A passive accessory intervertebral mobility (PAIVM) examination was performed to confirm an upper cervical articular cause of the subjects' headache and a questionnaire was used to establish a profile of the headache population. Measurements of cranio-cervical posture and isometric strength and endurance of the upper cervical flexor muscles were compared between the two groups of subjects. The headache group was found to be significantly different from the non-headache group in respect to forward head posture (FHP) (t = -5.98, p < 0.00005), less isometric strength (t = 3.43, p < 0.001) and less endurance (t = 8.71, p < 0.0005) of the upper cervical flexors. A statistically significant relationship was also established between natural head posture and isometric endurance of the upper cervical flexor musculature which demonstrated that FHP corresponded with a low endurance capacity (chi 2 = 13.2; p < 0.01). The outcome of this study highlights the need to screen for cervical etiology in patients who are suspected of suffering from common migraine.


Atypical presentation of anti-N-methyl-D-aspartate receptor encephalitis: two case reports.
Anti-N-methyl-D-aspartate receptor encephalitis is a rare autoimmune disease characterized by severe neurological and psychiatric symptoms and a difficult diagnosis. The disease is often secondary to a neoplastic lesion, seldom diagnosed years later. Psychiatric symptoms are prevalent in adults; neurologic symptoms are more evident in children, who typically present primarily with neurological symptoms. To the best of our knowledge, the association with juvenile idiopathic arthritis has not been described. We report the cases of two caucasian girls with an atypical presentation. The first patient was an 8-year-old girl with normal psychomotor development. Over a 4-month period she developed behavioral problems, speech impairment, and deterioration in academic skills. Within 8 months from the onset of symptoms, choreic movements gradually appeared. Hematological, neuroradiological, and neurophysiological examinations were negative; however, her symptoms worsened and treatment with prednisone was started. Although her choreic movements improved within 1 month, her neuropsychological and behavioral symptoms continued. Anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid and in blood were detected. Therapy with intravenously administered immunoglobulins was administered, without improvement of symptoms. After 2 months of steroid treatment, she suddenly started to pronounce some words with a progressive improvement in language and behavior. The second patient was a 14-year-old girl with classic anti-N-methyl-D-aspartate receptor encephalitis, treated successfully with intravenously administered immunoglobulins and methylprednisolone, followed by orally administered prednisone, who developed chronic arthritis of the hip. The arthritis was confirmed by magnetic resonance imaging and associated to antinuclear antigen antibody positivity. One year after the encephalitis presentation, an ovarian cystic mass was identified as a teratoma. The surgical resection of the mass was followed by the resolution of the psychotic spectrum and arthritis. Anti-N-methyl-D-aspartate receptor encephalitis in pediatric patients can present initially with neuropsychological and behavioral symptoms. In the literature, the association of anti-N-methyl-D-aspartate receptor encephalitis with juvenile idiopathic arthritis is not yet described: to the best of our knowledge, this is the first case reported. The link to a neoplastic lesion can explain the favorable course of encephalitis and arthritis, after the surgical resection of the mass. Early diagnosis and treatment can improve the patient's outcome.


Robotic/virtual reality intervention program individualized to meet the specific sensorimotor impairments of an individual patient: a case study.
A majority of studies examining repetitive task practice facilitated by robots for the treatment of upper extremity paresis utilize standardized protocols applied to large groups. This study will describe a virtually simulated, robot-based intervention customized to match the goals and clinical presentation of a gentleman with upper extremity hemiparesis secondary to stroke. MP, the subject of this case, is an 85-year-old man with left hemiparesis secondary to an intracerebral hemorrhage 5 years prior to examination. Outcomes were measured before and after a 1-month period of home therapy and after a 1-month virtually simulated, robotic intervention. The intervention was designed to address specific impairments identified during his PT examination. When necessary, activities were modified based on MP's response to his first week of treatment. MP's home training program produced a 3-s decline in Wolf Motor Function Test (WMFT) time and a 5-s improvement in Jebsen Test of Hand Function (JTHF) time. He demonstrated an additional 35-s improvement in JTHF and an additional 44-s improvement in WMFT subsequent to the robotic training intervention. A 24-h activity measurement and the Hand and Activities of Daily Living scales of the Stroke Impact Scale improved following the robotic intervention. Based on his responses to training we feel that we have established that a customized program of virtually simulated, robotically facilitated rehabilitation was feasible and resulted in larger improvements than an intensive home training program in several measurements of upper extremity function in our patient with chronic hemiparesis.


Two-dimensional relativistic longitudinal Green's function in the presence of a moving planar dielectric-magnetic discontinuity.
The current contribution is concerned with obtaining the relativistic two-dimensional (three-dimensional in relativity jargon) Green's function of a time-harmonic line current that is embedded in a moving dielectric-magnetic medium with a planar discontinuity. By applying a plane-wave (PW) spectral representation for the relativistic electromagnetic Green's function of a dielectric-magnetic medium that is moving in a uniform velocity, the exact reflected and transmitted (refracted) fields are obtained in the form of a spectral integral over PWs in the so-called laboratory and comoving frames. We investigate these spectral representations, as well as their asymptotic evaluations, and discuss the associated relativistic wave phenomena of direct reflected/transmitted rays and relativistic head waves (lateral waves).


Randomized study of clinical effect of enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer.
Enteral nutrition (EN) is provided for patients with cancer. However, Little is known about the clinical efficacy of EN support during chemotherapy in patients with cancer. Ninety-one patients who received neoadjuvant chemotherapy (5-fluorouracil, cisplatin and adriamycin) for esophageal cancer were enrolled to receive either EN (n = 47) or PN (n = 44) at random. The primary endpoint was the incidence of chemotherapy-related toxicities during chemotherapy. Total and dietary intake calories during chemotherapy were equal in the two groups. There were no significant differences in serum albumin level and body weight change after chemotherapy between the two groups. There was no significant difference in tumor response to chemotherapy between the two groups (EN: 51%, PN: 55%, p = 0.886). Leukopenia and neutropenia of grade 3 or 4, defined according to the Common Toxicities Criteria of the National Cancer Institute, were significantly less frequent in the EN group than PN group (leukopenia: 17% vs 41%, p = 0.011, neutropenia: 36% vs 66%, p = 0.005). Lymphopenia and thrombocytopenia tended to be less frequent in the EN group, albeit insignificantly. Compared with PN support, EN support during neoadjuvant chemotherapy reduced the incidence of chemotherapy-related hematological toxicities in patients with esophageal cancers.


Absence of ras oncogene activation in rat urinary bladder carcinomas induced by N-methyl-N-nitrosourea or N-butyl-N-(4-hydroxybutyl)nitrosamine.
Previously, we demonstrated point mutations of the H-ras gene in N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-induced rat urinary bladder carcinomas. In this study, ras oncogene activation was examined in urinary bladder carcinomas induced by N-(4-hydroxybutyl)nitrosamine (BBN) or N-methyl-N-nitrosourea (MNU) administration followed by uracil treatment. In the first experiment, MNU (20 mg/kg body wt) was i.p. injected into 11 male F344 rats twice a week for 4 weeks, followed by feeding 3% uracil for 20 weeks (MNU/uracil group). Ten rats were given only 3% uracil without MNU pretreatment. In the second experiment, 20 male F344 rats were given 0.05% BBN in the drinking water for 4 weeks, then fed 3% uracil for 20 weeks (BBN/uracil group). Another 20 rats were fed 3% uracil without the BBN pretreatment. Transitional cell carcinomas were induced in the urinary bladder of all rats in the MNU/uracil and BBN/uracil groups. Papillomas and hyperplasias were present in the rats given uracil without prior BBN or MNU. DNA and protein were extracted from the tumors (MNU/uracil or BBN/uracil groups) or from the scraped bladder epithelium (uracil alone groups). Sequences around codons 12, 13 and 61 of H-, K- and N-ras genes were examined by direct sequencing after polymerase chain reaction, and p21 was examined by Western blotting. No mutation was found within the examined sequences and p21 showed no changes in mobility. There was no difference in the level of p21 expression between rats treated with MNU/uracil or BBN/uracil compared to corresponding uracil alone groups. These results indicate that the ras oncogene was not activated in urinary bladder carcinomas induced by BBN or MNU in combination with uracil treatment, in contrast to previous findings with FANFT.


Dietary fat source regulates ob gene expression in white adipose tissue of rats under hyperphagic feeding.
This work was designed to investigate the effect of different lipid sources on ob gene expression and serum leptin levels in rats with two different feeding protocols: (1) free access to food; or (2) energy-controlled feeding. Male Wistar rats were fed diets containing 40 % energy as fat (olive oil, sunflower oil or beef tallow), for 4 weeks. In Expt 1 rats had free access to food, and in Expt 2 rats were fed a controlled amount of food (16 g/d, equivalent to 300 kJ/d). Insulin and leptin were determined by ELISA and ob mRNA by Northern blot. When rats had free access to food, ob mRNA levels were higher in animals fed either olive oil or sunflower oil than in those fed beef tallow. In marked contrast with feeding ad libitum, no differences were found among dietary fat groups in rats fed energy-controlled diets. When both feeding protocols were compared, free access to food induced an increased expression of ob mRNA in perirenal and/or epididymal adipose tissues from rats fed either olive oil or sunflower oil, but not from rats fed beef tallow. Dietary lipid type did not induce modifications in serum leptin concentrations. A tendency to higher serum leptin levels was observed more in rats with free access to food than in rats fed energy-controlled feeding. No differences were found in insulin levels. Dietary fat type importantly affects ob mRNA expression in rat white adipose tissue under hyperphagic conditions. Further study is needed in order to elucidate the mechanism underlying this effect.


Complex pectin metabolism by gut bacteria reveals novel catalytic functions.
The metabolism of carbohydrate polymers drives microbial diversity in the human gut microbiota. It is unclear, however, whether bacterial consortia or single organisms are required to depolymerize highly complex glycans. Here we show that the gut bacterium Bacteroides thetaiotaomicron uses the most structurally complex glycan known: the plant pectic polysaccharide rhamnogalacturonan-II, cleaving all but 1 of its 21 distinct glycosidic linkages. The deconstruction of rhamnogalacturonan-II side chains and backbone are coordinated to overcome steric constraints, and the degradation involves previously undiscovered enzyme families and catalytic activities. The degradation system informs revision of the current structural model of rhamnogalacturonan-II and highlights how individual gut bacteria orchestrate manifold enzymes to metabolize the most challenging glycan in the human diet.


Effects of triclosan and triclocarban, two ubiquitous environmental contaminants, on anatomy, physiology, and behavior of the fathead minnow (Pimephales promelas).
Triclosan (TCS) and triclocarban (TCC) are two common antimicrobial agents found in many personal care products and subsequently are detected ubiquitously in wastewater effluent and receiving waters. Both compounds are of recent regulatory interest due to their omnipresence in the environment, including in humans. Although TCS and TCC have been suggested to be endocrine active, little information exists about their effects on organismal end points in development (growth, escape performance), anatomy (morphological indices, histology), physiology (vitellogenin), and behavior of exposed aquatic organisms. In this study, newly hatched fathead minnows were exposed for 12 days, and mature male and female fathead minnows (Pimephales promelas) were exposed for 21 days to environmentally realistic concentrations (nanograms per liter) of these two compounds singularly and in mixtures. At the end of the exposure, larvae were assessed for growth and predator-avoidance performance, and a subset of mature fish was assessed for plasma vitellogenin induction, expression of secondary sexual characteristics, relative size of liver and gonads, and histopathological changes to both organs. The remaining exposed mature fish were placed in breeding pairs of one male and one female minnow from the same treatment to assess their ability to defend a nest site and reproduce. Exposure to either antimicrobial compound, alone or as a mixture, caused no changes to larval fish, gonad size, or vitellogenin concentrations in mature fathead minnows. In contrast, decreased aggression was seen in adult male fathead minnows exposed to TCC (1.6 μg/l) or a mixture (560 ng/l TCS + 179 ng/l TCC and 1.6 μg/l TCS + 450 ng/l TCC). Decreased aggression would likely decrease their ability to defend and hold a nest site needed for spawning and reproduction. Substantial variability was found in the severity of observed effects within treatments, suggesting that environmentally realistic concentrations of these compounds may only affect particularly sensitive individuals.


Action of the diaphragm on the rib cage.
When the diaphragm contracts, pleural pressure falls, exerting a caudal and inward force on the entire rib cage. However, the diaphragm also exerts forces in the cranial and outward direction on the lower ribs. One of these forces, the "insertional force," is applied by the muscle at its attachments to the lower ribs. The second, the "appositional force," is due to the transmission of abdominal pressure to the lower rib cage in the zone of apposition. In the control condition at functional residual capacity, the effects of these two forces on the lower ribs are nearly equal and outweigh the effect of pleural pressure, whereas for the upper ribs, the effect of pleural pressure is greater. The balance between these effects, however, may be altered. When the abdomen is given a mechanical support, the insertional and appositional forces are increased, so that the muscle produces a larger expansion of the lower rib cage and, with it, a smaller retraction of the upper rib cage. In contrast, at higher lung volumes the zone of apposition is decreased, and pleural pressure is the dominant force on the lower ribs as well. Consequently, although the force exerted by the diaphragm on these ribs remains inspiratory, rib displacement is reversed into a caudal-inward displacement. This mechanism likely explains the inspiratory retraction of the lateral walls of the lower rib cage observed in many subjects with chronic obstructive pulmonary disease (Hoover's sign). These observations support the use of a three-compartment, rather than a two-compartment, model to describe chest wall mechanics.


Comparing the similarity of time-series gene expression using signal processing metrics.
Many algorithms have been used to cluster genes measured by microarray across a time series. Instead of clustering, our goal was to compare all pairs of genes to determine whether there was evidence of a phase shift between them. We describe a technique where gene expression is treated as a discrete time-invariant signal, allowing the use of digital signal-processing tools, including power spectral density, coherence, and transfer gain and phase shift. We used these on a public RNA expression set of 2467 genes measured every 7 min for 119 min and found 18 putative associations. Two of these were known in the biomedical literature and may have been missed using correlation coefficients. Digital signal processing tools can be embedded and enhance existing clustering algorithms.


Domain within the helicase subunit Mcm4 integrates multiple kinase signals to control DNA replication initiation and fork progression.
Eukaryotic DNA synthesis initiates from multiple replication origins and progresses through bidirectional replication forks to ensure efficient duplication of the genome. Temporal control of initiation from origins and regulation of replication fork functions are important aspects for maintaining genome stability. Multiple kinase-signaling pathways are involved in these processes. The Dbf4-dependent Cdc7 kinase (DDK), cyclin-dependent kinase (CDK), and Mec1, the yeast Ataxia telangiectasia mutated/Ataxia telangiectasia mutated Rad3-related checkpoint regulator, all target the structurally disordered N-terminal serine/threonine-rich domain (NSD) of mini-chromosome maintenance subunit 4 (Mcm4), a subunit of the mini-chromosome maintenance (MCM) replicative helicase complex. Using whole-genome replication profile analysis and single-molecule DNA fiber analysis, we show that under replication stress the temporal pattern of origin activation and DNA replication fork progression are altered in cells with mutations within two separate segments of the Mcm4 NSD. The proximal segment of the NSD residing next to the DDK-docking domain mediates repression of late-origin firing by checkpoint signals because in its absence late origins become active despite an elevated DNA damage-checkpoint response. In contrast, the distal segment of the NSD at the N terminus plays no role in the temporal pattern of origin firing but has a strong influence on replication fork progression and on checkpoint signaling. Both fork progression and checkpoint response are regulated by the phosphorylation of the canonical CDK sites at the distal NSD. Together, our data suggest that the eukaryotic MCM helicase contains an intrinsic regulatory domain that integrates multiple signals to coordinate origin activation and replication fork progression under stress conditions.


Side effects and toxicities of targeted therapies in stage IV melanoma.
As the incidence of melanoma continues to increase worldwide, the search for new therapies for advanced (stage IV) melanoma brings with it new patterns of toxicity to contend with. This review covers the toxicity profiles of new treatments for advanced melanoma currently in development. Therefore, the latest literature on melanoma treatment was surveyed for data on reported toxicities. The new types of treatments can be roughly divided into targeted tyrosine kinase inhibitors and immunomodulating agents. Each has its own set of toxicities particular to type and to individual drug. Targeted tyrosine kinase inhibitors generally cause fatigue, whereas immunomodulatory agents induce a specific set of adverse events known as immune-related adverse events (irAEs). Despite the incidence of adverse events, these agents hold promise for the treatment of stage IV melanoma. With new treatment opportunities come increased chance of toxic reactions. The key to successful melanoma treatment in the future is likely to be novel combinations of new therapeutic agents.


EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance.
Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histologic response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor. We further show that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a miRNA that targets the EYA3 3'-untranslated region, rather than by binding the EYA3 promoter directly. Importantly, we show that high levels of EYA3 significantly correlate with low levels of miR-708 in Ewing sarcoma samples, suggesting that this miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because EYA proteins are important for cell survival during development, we examine, and show, that loss of EYA3 decreases survival of Ewing sarcoma cells. Most importantly, knockdown of EYA3 in Ewing sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts. These studies identify EYA3 as a novel mediator of chemoresistance in Ewing sarcoma and define the molecular mechanisms of both EYA3 overexpression and of EYA3-mediated chemoresistance.


Permanent Supportive Housing and Specialized Co-Occurring Disorders Wraparound Services for Homeless Individuals.
Among individuals experiencing chronic homelessness, there is a high rate of co-occurring mental health and substance use, which has traditionally been addressed through the delivery of permanent supportive housing along with substance use and mental health services. However, this population often has difficulty engaging in treatment for co-occurring disorders, which can result in exacerbation of symptoms and housing loss. Maintaining Independence and Sobriety Through Systems Integration, Outreach, and Networking (MISSION) is a co-occurring mental health and substance use wraparound approach that was pilot-tested alongside Permanent Supportive Housing (PSH) to improve treatment access and engagement. This pilot was part of a state plan to end homelessness in the Boston metro area. This open pilot study enrolled 136 individuals who were chronically homeless and offered one year of MISSION along with PSH. Program participants also received baseline and 6- and 12-month follow-up assessments. At one-year follow-up, 82.4% of the program participants were housed in PSH. However, due to limited affordable housing in the Boston metro area, it took on average 6.20 months to house the program participants. Furthermore, while MISSION was feasible to implement alongside PSH, fidelity to the MISSION model was lower than expected. This pilot also examined the role of housing status on clinical outcomes and found that the program participants who were housed at the time of discharge displayed a statistically significant improvement in emergency room visits for mental health complaints, the Psychosis subscale of the Behavior and Symptom Identification Scale (BASIS-32), illegal drug use, and pharmacotherapy treatment. This pilot study demonstrated that systematically integrating PSH and MISSION can improve access and engagement in care, housing retention, and mental health outcomes. Despite the preliminary success and while taking into account the limitations of the open single-group pre/post design, this study also identified the lack of affordable housing as a potential barrier to placement as well as the critical role of housing for improved clinical outcomes. Randomized controlled trials are needed to test MISSION with PSH as well as perhaps PSH with and without MISSION to tease apart the effects of integrating both approaches simultaneously.


Effect of increased left ventricle mass on ischemia assessment in electrocardiographic signals: rabbit isolated heart study.
Detailed quantitative analysis of the effect of left ventricle (LV) hypertrophy on myocardial ischemia manifestation in ECG is still missing. The associations between both phenomena can be studied in animal models. In this study, rabbit isolated hearts with spontaneously increased LV mass were used to evaluate the effect of such LV alteration on ischemia detection criteria and performance. Electrophysiological effects of increased LV mass were evaluated on sixteen New Zealand rabbit isolated hearts under non-ischemic and ischemic conditions by analysis of various electrogram (EG) parameters. To reveal hearts with increased LV mass, LV weight/heart weight ratio was proposed. Standard paired and unpaired statistical tests and receiver operating characteristics analysis were used to compare data derived from different groups of animals, monitor EG parameters during global ischemia and evaluate their ability to discriminate between unchanged and increased LV as well as non-ischemic and ischemic state. Successful evaluation of both increased LV mass and ischemia is lead-dependent. Particularly, maximal deviation of QRS and area under QRS associated with anterolateral heart wall respond significantly to even early phase (the 1st-3rd min) of ischemia. Besides ischemia, these parameters reflect increased LV mass as well (with sensitivity reaching approx. 80%). However, the sensitivity of the parameters to both phenomena may lead to misinterpretations, when inappropriate criteria for ischemia detection are selected. Particularly, use of cut-off-based criteria defined from control group for ischemia detection in hearts with increased LV mass may result in dramatic reduction (approx. 15%) of detection specificity due to increased number of false positives. Nevertheless, criteria adjusted to particular experimental group allow achieving ischemia detection sensitivity of 89-100% and specificity of 94-100%, respectively. It was shown that response of the heart to myocardial ischemia can be successfully evaluated only when taking into account heart-related factors (such as LV mass) and other methodological aspects (such as recording electrodes position, selected EG parameters, cut-off criteria, etc.). Results of this study might be helpful for developing new clinical diagnostic strategies in order to improve myocardial ischemia detection in patients with LV hypertrophy.


[Diabetic ketoacidosis in children: review of pathophysiology and treatment with the use of the "two bags system"]
OBJECTIVES: To review diabetic ketoacidosis, including the "two bags system", a method of administering liquids in order to provide a smoother correction of the hyperglycemic and ketotic states. METHODS: Review of recent publications (last 7 years) from a Medline search and chapters published in pediatric textbooks that discuss the etiology, therapy, and complications of diabetic ketoacidosis. The management approach incorporates the findings of these publications as well as the clinical experience at the Childreńs Hospital of Philadelphia and Duke University Medical Center. RESULTS: The pathology of the type 1 Diabetes Mellitus involves the progressive destruction of the ss cells of the pancreas, causing insulin deficiency. Insulin is essential in the metabolism of carbohydrates, protein and fat. Insulin deficiency may lead to diabetic ketoacidosis which has three components: 1) hyperglycemia, which causes glycosuria and consequently dehydration; 2) lipolysis which, causes ketonemia/ketonuria; and 3) acidosis, that is caused by the dehydration and the high serum levels of ketones. Diabetic ketoacidosis is a serious condition and, if not treated appropriately, can cause coma and death. In children cerebral edema is the major complication of the therapy for diabetic ketoacidosis. Careful replacement of insulin, fluids, glucose and electrolytes is essential. CONCLUSIONS: The literature presents different ways to manage DKA in pediatrics, without a consensus on the cause of the most important complication (cerebral edema), and consequently without a consensus on the best approach. The use of the two saline bags in patients in DKA allows fast adjustments in the dextrose concentration of the infusion fluids, simplifying and reducing the costs of the treatment of diabetic ketoacidosis.


Synaptophysin Is a Reliable Marker for Axonal Damage.
Synaptophysin is an abundant membrane protein of synaptic vesicles. The objective of this study was to determine the utility of identifying synaptophysin accumulations (spheroids/ovoids/bulbs) in CNS white matter as an immunohistochemical marker of axonal damage in demyelinating and neuroinflammatory conditions. We studied the cuprizone toxicity and Theiler's murine encephalomyelitis virus (TMEV) infection models of demyelination and analyzed CNS tissue from patients with multiple sclerosis (MS). Synaptophysin colocalized with the amyloid precursor protein (APP), a well-known marker of axonal damage. In the cuprizone model, numerous pathological synaptophysin/APP-positive spheroids/ovoids were identified in the corpus callosum at the onset of demyelination; the extent of synaptophysin/APP-positive vesicle aggregates correlated with identified reactive microglia; during late and chronic demyelination, the majority of synaptophysin/APP-positive spheroids/ovoids resolved but a few remained, indicating persistent axonal damage; in the remyelination phase, scattered large synaptophysin/APP-positive bulbs persisted. In the TMEV model, only a few large- to medium-sized synaptophysin/APP-positive bulbs were found in demyelinated areas. In MS patient tissue samples, the bulbs appeared exclusively at the inflammatory edges of lesions. In conclusion, our data suggest that synaptophysin as a reliable marker of axonal damage in the CNS in inflammatory/demyelinating conditions.


Administrators' perspectives on end-of-life care for cancer patients in Japanese long-term care facilities.
The purpose of this study was to clarify administrators' perspectives on availability of recommended strategies for end-of-life (EOL) care for cancer patients at long-term care (LTC) facilities in Japan. A cross-sectional survey was conducted with administrators at Japanese LTC facilities. Participants were surveyed about their facilities, reasons for hospitalization of cancer patients, and their perspectives on availability of and strategies for EOL care. The 97 responses were divided into medical facility (n = 24) and non-medical facility (n = 73) groups according to physician availability. The most frequent reasons for hospitalization were a sudden change in patient's condition (49.4%), lack of around-the-clock care (43.0%), and inability to palliate symptoms (41.0%). About 50% of administrators believed their facilities could provide EOL care if supported by palliative care experts. There was no significant difference between facility types (P = 0.635). Most administrators (81.2%) regarded unstable cancer patients as difficult to care for. However, many (68.4%) regarded opioids given orally as easy to administer, but regarded continuous subcutaneous infusion/central venous nutrition as difficult. Almost all administrators believed the most useful strategy was transferring patients to hospitals at the request of patients or family members (96.9%), followed by consultation with palliative care experts (88.5%). Although LTC facilities in Japan currently do not provide adequate EOL care for cancer patients, improvement might be possible with support by palliative care teams. Appropriate models are necessary for achieving a good death for cancer patients. Interventions based on these models are necessary for EOL care for cancer patients in LTC facilities.


Length variation of DC-SIGN and L-SIGN neck-region has no impact on tuberculosis susceptibility.
The C-type lectins DC-SIGN and L-SIGN are important pathogen-recognition receptors of the human innate immune system. Both lectins have been shown to interact with a vast range of infectious agents, including Mycobacterium tuberculosis, the etiologic agent of tuberculosis in humans. In addition, DC-SIGN and L-SIGN possess a neck region, made up of a variable number of 23 amino acid tandem repeats, which plays a crucial role in the tetramerization of these proteins and support of the carbohydrate recognition domain. The length of the neck region, which shows variable levels of polymorphism, can critically influence the pathogen binding properties of these two receptors. We therefore investigated the impact of the DC-SIGN and L-SIGN neck-region length variation on the outcome of tuberculosis by screening this polymorphism in a large cohort of Coloured South African origin. The analyses of 711 individuals, including 351 tuberculosis patients and 360 healthy controls, revealed that none of the DC-SIGN and L-SIGN neck-region variants or genotypes seems to influence the individual susceptibility to develop tuberculosis.


Hepatic arterial chemotherapy in metastatic colorectal patients.
Hepatic metastases are a major cause of morbidity and mortality for patients with colorectal cancer (CRC). The rationale for hepatic arterial chemotherapy has both an anatomical and pharmacological basis. Several randomized clinical studies of fluoropyrimidine showed higher response rates in all trials when the drug was given as an hepatic arterial infusion (HAI) versus systemic administration. However, the studies did not accurately define survival for the following reasons: (1) some allowed a crossover; (2) some were too small; and (3) some used inadequate systemic chemotherapy. Patients who have failed to respond to previous systemic chemotherapy have an approximately 50% response rate with HAI treatment. Hepatic toxicity, especially biliary sclerosis, is the dose-limiting toxicity, occurring in 6% to 25% of patients. Adding dexamethasone to HAI fluoropyrimidine decreases the hepatobiliary toxicity. The therapeutic benefit of HAI in one study was also demonstrated by an increased time with normal quality of life. To truly define the role of regional therapy in patients with CRC confined to the liver, the current Cancer and Leukemia Group B (CALGB) study is randomizing patients to HAI versus systemic therapy without a crossover to demonstrate if HAI improves survival and/or quality of life in addition to response rates.


Subacute sepsis impairs vascular smooth muscle contractile machinery and alters vasoconstrictor and dilator mechanisms.
Sepsis results in hyporesponsiveness to alpha-adrenergic stimulation. This is thought to be mediated by the release of vasoactive compounds from the septic endothelium or by the direct effect of sepsis on vascular smooth muscle (VSM) contractile mechanics and machinery. Previous studies have used lethal models of sepsis or endotoxemia to examine this phenomenon. The present study utilizes a clinically relevant, nonlethal model of soft tissue infection to determine the effects of sepsis on alpha-adrenergic mechanisms. We hypothesize that subacute sepsis causes impaired alpha-adrenergic vascular responsiveness by a combination of effects on adrenergic constrictor mechanisms, endogenous dilator tone, and VSM contractile function. Male Sprague-Dawley rats underwent implantation of a 2 x 2-cm2 gauze sponge into a subcutaneous pocket created at the base of the tail. Five days after implantation, sepsis (S) was induced by inoculation of the sponge with 10(9) CFU Escherichia coli and Bacteroides fragilis. Controls (C) were inoculated with saline. Thoracic aortic harvest was performed 24 and 48 h after sponge inoculation for organ bath ring studies. Receptor-mediated (phenylephrine) and nonreceptor-mediated (KCl) maximum force of contraction (Fmax) was measured. Vessel sensitivity (pD2) to phenylephrine, acetylcholine, and KCl was calculated from dose-response curves. At 24 h, sepsis resulted in a lower Fmax to phenylephrine (1.15 for C vs 0.5 for S, P < 0.05 by ANOVA), despite an increase in vessel sensitivity (pD2) to alpha-adrenergic stimulation (6.70 for C vs 6.88 for S, P < 0.05 by ANOVA). Fmax to KCl was lower in septic animals at 24 h (3. 50 for C vs 2.77 for S, P < 0.05 by ANOVA) and sensitivity to acetylcholine (pD2) was markedly increased (6.56 for C vs 7.23 for S, P < 0.05 by ANOVA). At 48 h, the impairment in Fmax to alpha-adrenergic stimulation (2.29 for C vs 1.72 for S, P < 0.05 by ANOVA) and KCl (3.5 for C vs 3.08 for S. P < 0.05 vs 24 h C by ANOVA) persisted without any change in sensitivity to phenylephrine or acetylcholine. Subacute sepsis results in an early suppression of maximum contractile force despite an increase in adrenergic receptor sensitivity (pD2). This may be secondary to an elevation in dilator sensitivity combined with a direct effect of sepsis on VSM contractile mechanisms. Later in the septic process, however, alpha-adrenergic hyporesponsiveness ( downward arrow Fmax) is primarily due to changes in VSM contractile machinery.


Burnout and engagement in relation with job demands and resources among dental staff in Northern Ireland.
To investigate the psychological health--in particular, levels of burnout and engagement, job demands, job resources, and general psychological distress--among dental staff in Northern Ireland. Three hundred questionnaires were administered to all dental offices in the western part of Northern Ireland. The questionnaire consisted of 'Maslach Burnout Inventory (MBI)', 'Job Demands in Dentistry measure', 'Utrecht Work Engagement Scale (UWES)', 'Job Resources in dentistry measure', and 'General Health Questionnaire (GHQ)'. Overall response rate among all staff members was 45% (for general dental practitioners: 65%). Burnout mean scores were unfavourable when compared with MBI manual norm scores, 26% had scores in the 'high' categories of both emotional exhaustion (EE) and depersonalization (DP). This is an indication of severe burnout risk. Time pressure, financial worries, and difficult patients appeared to be the most prominent work demands (mean scores >3). All job demands' scales correlated significantly (P < 0.01) and positively with both EE and DP: 0.30 > r < 0.62. Mean scores for UWES, and all job resources' subscales were all well above each subscale's range midpoint. Treatment results appeared the most prominent work resource. GHQ mean score for all was 1.05 (SD = 0.51). No difference in mean score was found between dentists and other staff (F(1,123) = 1.08, NS). With 'case level' set at a score >3 as a cut-off point, 25% of the subjects have to be considered cases. Burnout is a serious threat for the dental team in this region of Northern Ireland, especially among general dental practitioners. One-quarter of the dentists were categorized as having a serious burnout risk. Dentists appeared to have most trouble with the work environment aspects: time pressure and financial worries. Furthermore, the proportion of those suffering from psychological distress was unusually high. In contrast to these findings, encouraging levels of engagement were identified. It is recommended that attention for burnout risk is given priority by dental associations.


fMRI Language Activation-If You See It Don't Resect It….
fMRI Prediction of Naming Change After Adult Temporal Lobe Epilepsy Surgery: Activation Matters. You X, Zachery AN, Fanto EJ, et al. Epilepsia. 2019. doi:10.1111/epi.14656. [Epub ahead of print] PMID: 30740666 . We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability. Thirty-five adults (mean age: 37.5 ± 10.9 years, 13 males) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative magnetic resonance imaging tissue map comparison. This mask provided the following: (a) resection volume, (b) overlap between resection and preoperative activation, and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance. Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjusted r2 = 0.28, P = .012). The percentage of top 10% fMRI activation resected (P = .017) was the most significant contributor. Other factors in the model included WA LI, ASO, volume of WA resected, and WA LI absolute value (extent of laterality). Resection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection.


High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: A drug repurposing strategy for advanced cancer.
Targeting exosome biogenesis and release may have potential clinical implications for cancer therapy. Herein, we have optimized a quantitative high throughput screen (qHTS) assay to identify compounds that modulate exosome biogenesis and/or release by aggressive prostate cancer (PCa) CD63-GFP-expressing C4-2B cells. A total of 4,580 compounds were screened from the LOPAC library (a collection of 1,280 pharmacologically active compounds) and the NPC library (NCGC collection of 3,300 compounds approved for clinical use). Twenty-two compounds were found to be either potent activators or inhibitors of intracellular GFP signal in the CD63-GFP-expressing C4-2B cells. The activity of lead compounds in modulating the secretion of exosomes was validated by a tunable resistive pulse sensing (TRPS) system (qNano-IZON) and flow cytometry. The mechanism of action of the lead compounds in modulating exosome biogenesis and/or secretion were delineated by immunoblot analysis of protein markers of the endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways. The lead compounds tipifarnib, neticonazole, climbazole, ketoconazole, and triademenol were validated as potent inhibitors and sitafloxacin, forskolin, SB218795, fenoterol, nitrefazole and pentetrazol as activators of exosome biogenesis and/or secretion in PC cells. Our findings implicate the potential utility of drug-repurposing as novel adjunct therapeutic strategies in advanced cancer.


Common Genetic Variant of insig2 Gene rs7566605 Polymorphism Is Associated with Severe Obesity in North India
Obesity is a very common disorder resulting from an imbalance between food intake and energy expenditure, and it has a substantial impact on the development of chronic diseases. The aim of this study was to examine the association of INSIG2 (rs7566605) gene polymorphism with obesity and obesity associated phenotypes in North Indian subjects. The variants were investigated for association in 642 obese and non-obese individuals. The genotyping of INSIG2 (rs7566605) single nucleotide polymorphism was analyzed by the TaqMan allelic discrimination protocol. A significant association was observed for INSIG2 (rs7566605) single nucleotide polymorphism with obesity and obesity-related phenotypes. Furthermore, a significant relationship was found between the rs7566605 and insulin, homeostasis model of assessment-insulin resistance, the percentage of body fat, fat mass, leptin, and adiponectin. The present study observed significant association between INSIG2 (rs7566605) single nucleotide polymorphism and obesity, as well as obesity-associated phenotypes in North Indian population.


Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.


Selective alteration of brush-border hydrolases in intestinal diseases in childhood.
1. Biochemical estimates of lactase, sucrase and maltase activities, carried out on intestinal biopsies appearing histologically normal, were compared with those obtained from children suffering from coeliac disease, cow's milk protein intolerance/postenteritis syndrome and the intractable diarrhoea syndrome of infancy. Lactase deficiency in these children was found to be more pronounced than sucrase or maltase deficiencies. 2. Quantitative cytochemical investigations showed characteristic disease-induced changes in the ability of enterocytes to express alpha- and beta-glucosidases, but not alkaline phosphatase activities, during migration along stunted villi. 3. Separate estimates of the time course describing hydrolase development in normal and coeliac tissue showed the initial rate of lactase appearance to be halved in coeliac patients, while that for alpha-glucosidases remained constant and that for alkaline phosphatase increased by a factor of four. Enteroblastic replacement of mature enterocytes cannot provide a general explanation for hydrolase deficiency in diseased intestine.


Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus.
A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.


Mutation-induced loss of APP function causes GABAergic depletion in recessive familial Alzheimer's disease: analysis of Osaka mutation-knockin mice.
The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.


Two-stage resection of a bilateral pheochromocytoma and pancreatic neuroendocrine tumor in a patient with von Hippel-Lindau disease: A case report.
von Hippel-Lindau disease (vHL disease) is a hereditary disease in which tumors and cysts develop in many organs, in association with central nervous system hemangioblastomas, pheochromocytomas, and pancreatic tumors. We herein report a case of vHL disease (type 2A) associated with bilateral pheochromocytomas, pancreatic neuroendocrine tumors (PNET), and cerebellar hemangioblastomas treated via pancreatectomy after adrenalectomy. A 51-year-old woman presented with a cerebellar tumor, bilateral hypernephroma, and pancreatic tumor detected during a medical checkup. 18F-fluorodeoxyglucose positron emission tomography-computed tomography revealed a bilateral adrenal gland tumor and a tumor in the head of the pancreas, while an abdominal computed tomography examination revealed a 30-mm tumor with strong enhancement in the head of the pancreas. Cranial magnetic resonance imaging showed a hemangioblastoma in the cerebellum. Therefore, a diagnosis of vHL disease (type 2A) was made. Her family medical history included renal cell carcinoma in her father and bilateral adrenal pheochromocytoma and spinal hemangioblastoma in her brother. A detailed examination of endocrine function showed that the adrenal mass was capable of producing catecholamine. Treatment of the pheochromocytoma was prioritized, and therefore, laparoscopic left adrenalectomy and subtotal resection of the right adrenal gland were performed. Once the postoperative steroid levels were replenished, subtotal stomach-preserving pancreatoduodenectomy was performed for the PNET. After a good postoperative course, the patient was discharged in remission on the 11th day following surgery. Histopathological examination findings indicated NET G2 (MIB-1 index 10-15%) pT3N0M0 Stage II A and microcystic serous cystadenoma throughout the resected specimen. The patient is scheduled to undergo treatment for the cerebellar hemangioblastoma. A two-staged resection is a safe and effective treatment option for bilateral pheochromocytoma and PNET associated with vHL disease.


Asthma control in Europe: a real-world evaluation based on an international population-based study.
Epidemiologic evidence related to asthma control in patients from the general population is scanty. We sought to assess asthma control in several European centers according to the Global Initiative for Asthma (GINA) guidelines and to investigate its determinants. In the European Community Respiratory Health Survey II (1999-2002), 1241 adults with asthma were identified and classified into inhaled corticosteroid (ICS) users and non-ICS users in the last year. Control was assessed in both groups by using the GINA proposal (controlled, partly controlled, and uncontrolled asthma), and it was related to potential determinants. Only 15% (95% CI, 12% to 19%) of subjects who had used ICSs in the last year and 45% (95% CI, 41% to 50%) of non-ICS users had their asthma under control; individuals with uncontrolled asthma accounted for 49% (95% CI, 44% to 53%) and 18% (95% CI, 15% to 21%), respectively. Among ICS users, the prevalence of uncontrolled asthma showed great variability across Europe, ranging from 20% (95% CI, 7% to 41%; Iceland) to 67% (95% CI, 35% to 90%; Italy). Overweight status, chronic cough and phlegm, and sensitization to Cladosporium species were associated with poor control in ICS users. About 65% and 87% of ICS users with uncontrolled and partly controlled asthma, respectively, were on a medication regimen that was less than recommended by the GINA guidelines. Six of 7 European asthmatic adults using ICSs in the last year did not achieve good disease control. The large majority of subjects with poorly controlled asthma were using antiasthma drugs in a suboptimal way. A wide variability in asthma control emerged across Europe. Greater attention should be paid to asthma management and to the implementation of the GINA guidelines.


Perspectives from Employers, Insurers, Lawyers and Healthcare Providers on Factors that Influence Workers' Return-to-Work Following Surgery for Non-Traumatic Upper Extremity Conditions.
Return-to-work (RTW) stakeholders have varied roles and may therefore hold their own perspectives regarding factors that may influence outcomes. This study aimed to determine stakeholders' perspectives on factors influencing RTW following surgery for non-traumatic upper extremity conditions. A questionnaire was distributed to RTW stakeholders via gatekeeper organizations. Stakeholders rated 50 potential prognostic factors from 'not' to 'extremely' influential. Data were dichotomized to establish stakeholders' level of agreement. Disagreements between stakeholder groups were analyzed using χ 2. The relationship between stakeholder demographic variables and rating of a factor was determined via regression analysis. One thousand and eleven stakeholders completed the survey: healthcare providers (77.8 %); employer representatives (12.2 %); insurer representatives (6.8 %); and lawyers (3.2 %). Factors with the highest stakeholder agreement for influencing RTW were: self-efficacy (92.2 %); post-operative psychological status (91.8 %); supportive employer/supervisor (91.4 %); employer's willingness to accommodate job modifications (90.7 %); worker's recovery expectations (88.3 %); mood disorder diagnosis (86.6 %); post-operative pain level (86.4 %); and whether the job can be modified (86.3 %). Disagreements between stakeholder groups were found for 19 (36 %) factors. The strongest disagreements were for: age; gender; obesity; doctor's RTW recommendation; and presence of a RTW coordinator. Respondents' characteristics (e.g., age, workers' compensation jurisdiction, work experience, stakeholder group) were associated with factor rating. The factors stakeholders rated as having the greatest influence on RTW were predominately psychosocial and modifiable. These variables should be the focus of future research to determine prognostic factors for RTW for workers with upper extremity conditions, and to develop effective RTW interventions.


Thiamine diphosphate in whole blood, thiamine and thiamine monophosphate in breast-milk in a refugee population.
The provision of high doses of thiamine may prevent thiamine deficiency in the post-partum period of displaced persons. The study aimed to evaluate a supplementation regimen of thiamine mononitrate (100 mg daily) at the antenatal clinics in Maela refugee camp. Women were enrolled during antenatal care and followed after delivery. Samples were collected at 12 weeks post partum. Thiamine diphosphate (TDP) in whole blood and thiamine in breast-milk of 636 lactating women were measured. Thiamine in breast-milk consisted of thiamine monophosphate (TMP) in addition to thiamine, with a mean TMP to total thiamine ratio of 63%. Mean whole blood TDP (130 nmol/L) and total thiamine in breast-milk (755 nmol/L) were within the upper range reported for well-nourished women. The prevalence of women with low whole blood TDP (<65 nmol/L) was 5% and with deficient breast-milk total thiamine (<300 nmol/L) was 4%. Whole blood TDP predicted both breast-milk thiamine and TMP (R(2) = 0.36 and 0.10, p<0.001). A ratio of TMP to total thiamine ≥63% was associated with a 7.5 and 4-fold higher risk of low whole blood TDP and deficient total breast-milk thiamine, respectively. Routine provision of daily 100 mg of thiamine mononitrate post-partum compared to the previous weekly 10 mg of thiamine hydrochloride resulted in significantly higher total thiamine in breast-milk. Thiamine supplementation for lactating women in Maela refugee camp is effective and should be continued. TMP and its ratio to total thiamine in breast-milk, reported for the first time in this study, provided useful information on thiamine status and should be included in future studies of breast-milk thiamine.


Congenic mapping of the type 1 diabetes locus, Idd3, to a 780-kb region of mouse chromosome 3: identification of a candidate segment of ancestral DNA by haplotype mapping.
Type 1 diabetes in the nonobese diabetic (NOD) mouse arises as a consequence of T cell-mediated destruction of the insulin-producing beta cells of the pancreas. Although little is known of the events that initiate and subsequently drive beta-cell destruction it is clear that the entire process is under complex genetic control. At present 19 loci have been mapped that influence the development of diabetes either at the level of initiation of insulitis or at the level of progression from insulitis to overt diabetes, or both. Previously, we have mapped one of these loci, Idd3, to a 0.35-cM interval on proximal mouse chromosome 3. In the present study we have narrowed the map position of this locus to an interval of 0.15 cM by a combination of novel congenic strains and an ancestral haplotype analysis approach. We have constructed a physical contig in bacterial artificial chromosome (BAC) clones across the minimal interval. Restriction mapping of the BAC contig placed the maximum size of the Idd3 interval at 780 kb between the markers D3Nds36 and D3Nds76. To refine further the Idd3 interval we developed a series of novel single nucleotide polymorphisms (SNPs) and carried out haplotype analysis on DNA from mouse strains known to carry either Idd3 susceptibility or protective alleles. This haplotype analysis identified a 145-kb segment of ancestral DNA between the microsatellite marker D3Nds6 and the SNP 81.3. One haplotype of this ancestral segment of DNA is found in mouse strains carrying an Idd3 susceptibility allele and another is found in mouse strains carrying an Idd3 protective allelle. Within the 780-kb congenically defined interval this 145-kb segment represents the most likely location for Idd3. The Il2 gene, which encodes the cytokine interleukin 2 (IL2), maps to this interval and is a strong candidate for Idd3. To investigate whether sequence variation exists in the promoter region of the Il2 gene, which might alter its expression, we sequenced the promoter region of the Il2 gene from mouse strains carrying either an Idd3 susceptibility or resistance allele. Two sequence variants were identified, neither of which fell in known regulatory elements within the Il2 promoter. In agreement with this observation steady-state Il2 mRNA levels showed no variation between susceptible and resistant mouse strains. These data suggest that the profound protection from diabetes seen in congenic mice carrying an Idd3 protective allele is unlikely to be due to differences in the level of expression of the Il2 gene. Instead, all of the current data support our hypothesis that Idd3 corresponds to amino acid variation at the amino terminus of Il2.


Molar macrowear reveals Neanderthal eco-geographic dietary variation.
Neanderthal diets are reported to be based mainly on the consumption of large and medium sized herbivores, while the exploitation of other food types including plants has also been demonstrated. Though some studies conclude that early Homo sapiens were active hunters, the analyses of faunal assemblages, stone tool technologies and stable isotopic studies indicate that they exploited broader dietary resources than Neanderthals. Whereas previous studies assume taxon-specific dietary specializations, we suggest here that the diet of both Neanderthals and early Homo sapiens is determined by ecological conditions. We analyzed molar wear patterns using occlusal fingerprint analysis derived from optical 3D topometry. Molar macrowear accumulates during the lifespan of an individual and thus reflects diet over long periods. Neanderthal and early Homo sapiens maxillary molar macrowear indicates strong eco-geographic dietary variation independent of taxonomic affinities. Based on comparisons with modern hunter-gatherer populations with known diets, Neanderthals as well as early Homo sapiens show high dietary variability in Mediterranean evergreen habitats but a more restricted diet in upper latitude steppe/coniferous forest environments, suggesting a significant consumption of high protein meat resources.


Effects of omega-3 polyunsaturated fatty acids on psychophysiological symptoms of post-traumatic stress disorder in accident survivors: A randomized, double-blind, placebo-controlled trial.
Psychophysiological symptoms (e.g., pounding heart) are known to be a prominent feature of post-traumatic stress disorder (PTSD). Although omega-3 polyunsaturated fatty acids (PUFAs) have a beneficial potential pharmacological effect of preventing these psychophysiological symptoms, no clinical data is yet available. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of Japanese accident survivors. A total of 83 participants received either omega-3 PUFAs (1470mg docosahexaenoic acid and 147mg eicosapentaenoic acid per day) or placebo within 10 days of the accidental injury. After 12-week supplementation, participants performed script-driven imagery of their traumatic event during monitoring of their heart rate and skin conductance. Analysis revealed that heart rate during both rest and script-driven imagery was significantly lower in the omega-3 group than the placebo group, whereas baseline heart rate was comparable between the two groups. The present trial was conducted at a single-center in Japan and psychophysiological symptoms of PTSD in most participants were not serious. These findings suggest that post-trauma supplementation of omega-3 PUFAs might be effective for the secondary prevention of psychophysiological symptoms of PTSD.


Ice-Age Climate Adaptations Trap the Alpine Marmot in a State of Low Genetic Diversity.
Some species responded successfully to prehistoric changes in climate [1, 2], while others failed to adapt and became extinct [3]. The factors that determine successful climate adaptation remain poorly understood. We constructed a reference genome and studied physiological adaptations in the Alpine marmot (Marmota marmota), a large ground-dwelling squirrel exquisitely adapted to the "ice-age" climate of the Pleistocene steppe [4, 5]. Since the disappearance of this habitat, the rodent persists in large numbers in the high-altitude Alpine meadow [6, 7]. Genome and metabolome showed evidence of adaptation consistent with cold climate, affecting white adipose tissue. Conversely, however, we found that the Alpine marmot has levels of genetic variation that are among the lowest for mammals, such that deleterious mutations are less effectively purged. Our data rule out typical explanations for low diversity, such as high levels of consanguineous mating, or a very recent bottleneck. Instead, ancient demographic reconstruction revealed that genetic diversity was lost during the climate shifts of the Pleistocene and has not recovered, despite the current high population size. We attribute this slow recovery to the marmot's adaptive life history. The case of the Alpine marmot reveals a complicated relationship between climatic changes, genetic diversity, and conservation status. It shows that species of extremely low genetic diversity can be very successful and persist over thousands of years, but also that climate-adapted life history can trap a species in a persistent state of low genetic diversity.


Contribution of Calpain and Caspases to Cell Death in Cultured Monkey RPE Cells.
AMD is the leading cause of human vision loss after 65 years of age. Several mechanisms have been proposed: (1) age-related failure of the choroidal vasculature leads to loss of RPE; (2) RPE dysfunctions due to accumulation of phagocytized, but unreleased A2E (N-retinylidene-N-retinylethanolamine); (3) zinc deficiency activation of calpain and caspase proteases, leading to cell death. The purpose of the present study is to compare activation of calpain and caspase in monkey RPE cells cultured under hypoxia or with A2E. Monkey primary RPE cells were cultured under hypoxic conditions in a Gaspak pouch or cultured with synthetic A2E. Immunoblotting was used to detect activation of calpain and caspase. Calpain inhibitor, SNJ-1945, and pan-caspase inhibitor, z-VAD-fmk, were used to confirm activation of the proteases. (1) Hypoxia and A2E each decreased viability of RPE cells in a time-dependent manner. (2) Incubation under hypoxia alone induced activation of calpain, but not caspases. SNJ-1945 inhibited calpain activation, but z-VAD-fmk did not. (3) Incubation with A2E alone induced activation of calpain, caspase-9, and caspase-3. SNJ-1945 inhibited calpain activation. z-VAD-fmk inhibited caspase activation, suggesting no interaction between calpain and caspases. Hypoxia activated the calpain pathway, while A2E activated both calpain and caspase pathways in monkey RPE cells. Such knowledge may be utilized in the treatment of AMD if inhibitor drugs against calpain and/or caspase are used to prevent RPE dysfunction caused by hypoxia or A2E.


Expression of toll-like receptor 4 and 2 in horse lungs.
Toll-like receptor (TLR) is a key component in launching innate immune response to microbial challenge. TLR4 and TLR2 are recognized as specific receptors for components of Gram-negative and Gram-positive bacteria, respectively. Horses are extremely sensitive to endotoxin-induced cardiopulmonary distress and mortality which causes significant economic losses. To date, there are no data on the expression of TLR4 and TLR2 in horse lungs. Therefore, we examined the expression of TLR4 and TLR2 in lungs from normal or Escherichia coli lipopolysaccharide (E. coli LPS; 50 ng/kg; iv) treated horses. We also studied the impact of the depletion of pulmonary intravascular macrophages (PIM) on TLR4 and TLR2 expression in normal or LPS-treated horses. RT-PCR showed TLR4 mRNA but not TLR2, in normal horse lungs. PIM depletion reduced TLR4 mRNA expression without affecting TLR2. The LPS treatment increased the expression of TLR4 and TLR2 mRNA in normal and PIM-depleted horses compared to normal saline-treated horses. Light and electron microscopic immunocytochemistry showed TLR4 protein in PIM, alveolar macrophages and septal endothelium in lungs from normal or LPS-treated horses. Immuno-gold electron microscopy showed TLR4 in PIM and dual-label immuno-electron microscopy co-localized TLR4 and LPS in the cytoplasm and nucleus of PIM of LPS-treated horses. The present manuscript is the first report on the expression of TLR4 and TLR2 in normal and LPS-treated horses and direct co-localization of TLR4 with LPS molecules in PIM. These data provide evidence that PIM are equipped with TLR4 to handle and rapidly respond to circulating endotoxins.


The role of disease characteristics in the ethical debate on personal genome testing.
Companies are currently marketing personal genome tests directly-to-consumer that provide genetic susceptibility testing for a range of multifactorial diseases simultaneously. As these tests comprise multiple risk analyses for multiple diseases, they may be difficult to evaluate. Insight into morally relevant differences between diseases will assist researchers, healthcare professionals, policy-makers and other stakeholders in the ethical evaluation of personal genome tests. In this paper, we identify and discuss four disease characteristics--severity, actionability, age of onset, and the somatic/psychiatric nature of disease--and show how these lead to specific ethical issues. By way of illustration, we apply this framework to genetic susceptibility testing for three diseases: type 2 diabetes, age-related macular degeneration and clinical depression. For these three diseases, we point out the ethical issues that are relevant to the question whether it is morally justifiable to offer genetic susceptibility testing to adults or to children or minors, and on what conditions. We conclude that the ethical evaluation of personal genome tests is challenging, for the ethical issues differ with the diseases tested for. An understanding of the ethical significance of disease characteristics will improve the ethical, legal and societal debate on personal genome testing.


A randomized study of the efficacy and safety of intravenous acetaminophen compared to oral acetaminophen for the treatment of fever.
The purpose of this study was to assess the safety and dynamics of the onset of antipyretic efficacy of intravenous (IV) acetaminophen versus oral (PO) acetaminophen in the treatment of endotoxin-induced fever. This randomized, double-blind, double-dummy, single-dose study was conducted at a single center in the United States in healthy volunteer adult males with an endotoxin-induced fever to assess the antipyretic efficacy and safety of IV acetaminophen 1 g versus PO acetaminophen 1 g over 6 hours. Subjects who achieved a sufficient fever response to a test dose of reference standard endotoxin were randomly assigned to receive either IV acetaminophen and PO placebo (n = 54) or PO acetaminophen and IV placebo (n = 51). The primary efficacy outcome was the weighted sum of temperature differences from baseline at time T0 through T120 minutes. Safety evaluations included adverse event (AE), physical exam, and laboratory assessments. Of 105 subjects receiving study medication, 24 vomited within 2 hours postdose (PO acetaminophen, n = 15; and IV acetaminophen, n = 9) and were excluded from the modified intent-to-treat population that consisted of 36 and 45 subjects treated with PO and IV acetaminophen, respectively. While this was done to not confer an advantage to the IV formulation, a sensitivity analysis including these subjects did not change the overall efficacy results. Statistically significant results favoring IV acetaminophen were observed for the primary endpoint (weighted sum of temperature differences over 120 minutes, p = 0.0039) and also at each time point from T30 to T90 minutes, although the maximum mean observed temperature difference was only 0.3°C. The study drugs were well tolerated. The AE frequency was comparable between the IV and PO groups. A single dose of IV acetaminophen is as safe and effective in reducing endotoxin-induced fever as PO acetaminophen. IV acetaminophen may be useful where patients are unable to tolerate PO intake or when an earlier onset of action is desirable.


A CYP2D6 phenotype-genotype mismatch in Japanese psychiatric patients.
The aim of the present study was to seek a CYP2D6 genotypic-phenotypic discordance possibility in Japanese patients under psychotropic drug treatment where the CYP2D6 status and pharmacodynamic responses differ from those in Caucasian psychiatric patients. Ninety drug-free, healthy volunteers and 14 patients undergoing psychotropic drug treatment were phenotyped for their individual CYP2D6 activity using dextromethorphan as a probe, and then the metabolic ratio (MR) was calculated. For the genotyping, eight mutant alleles of the CYP2D6 genes were identified. Serum concentrations of two frequently co-medicated psychotropic drugs, biperiden and levomepromazine, were determined by GC/MS. Genotyping revealed no poor metabolizers (PMs) enrolled in our study. Healthy volunteers exhibited an identical phenotype-genotype concordance, whereas 7 of the 14 patients had significantly high (p < 0.05) MRs compared with genotype-matched volunteers. Three of the patients who had the extensive metabolizer (EM) genotype had extremely high MRs and were classified as phenotypic PMs. Five patients plus all of the seven high MR patients were treated with levomepromazine and/or biperiden, respectively. Their mean serum steady-state concentrations were 27.4 and 7.6 ng/ml, respectively. A CYP2D6 phenotype-genotype mismatch (phenocopying) can occur in Japanese psychiatric patients receiving clinical doses of some psychotropic drugs where the prevalence of PMs is low and the pharmacodynamic responses to those drugs are enhanced compared to Caucasian patients.


Evaluating an interactive acceptance and commitment therapy (ACT) workshop delivered to trained therapists working with cancer patients in the United Kingdom: a mixed methods approach.
SURECAN (SUrvivors' Rehabilitation Evaluation after CANcer) is a multi-phase study developing and evaluating an Acceptance and Commitment Therapy (ACT) intervention integrated with exercise and work when highly valued (thus we called the intervention ACT+), for people who have completed treatment for cancer but who have low quality of life. We developed a training programme for therapists working in different psychological services to be delivered over 2-3 days. Our aim was to evaluate the extent to which the training could improve therapists' knowledge and confidence to deliver ACT+ to cancer patients in a trial setting. Three interactive workshops were delivered to 29 therapists from three clinical settings in London and in Sheffield. A mixed-methods approach was used. Questionnaires were designed to assess knowledge and confidence in using ACT+ with people who have low quality of life after cancer treatment. They were self-administered immediately prior to and after each workshop. Open text-based questions were used to elicit feedback about the workshops alongside a satisfaction scale. Semi-structured interviews were conducted with a purposive sample of therapists (n = 12) to explore their views about the training more deeply, and how it might be optimised. Quantitative analysis showed that knowledge of ACT, as well as confidence in using the ACT+ intervention in this setting increased significantly after training (28.6 and 33.5% increase in the median score respectively). Qualitative analysis indicated that most therapists were satisfied with the content and structure of the programme, valued the rich resources provided and enjoyed the practice-based approach. Potential barriers/facilitators to participation in the trial and to the successful implementation of ACT+ were identified. For some therapists, delivering a manualised intervention, as well as supporting exercise- and work-related goals as non-specialists was seen as challenging. At the same time, therapists valued the opportunity to be involved in research, whilst training in a new therapy model. Training can effectively improve the knowledge and confidence of therapists from different clinical backgrounds to deliver a modified ACT intervention to cancer patients in a trial setting.


Optics in liechtenstein.
In the late nineteen forties, a company was founded in the Principality of Liechtenstein, a tiny country located on the right bank of the upper Rhine. The development of this Balzers Company, which took its name from the village where it was and still is located, is briefly reviewed, and its uniqueness is discussed.


Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors.
The neuropeptides oxytocin (OT) and vasopressin (AVP) have been shown to play a central role in social behaviors; as a consequence, they have been recognized as potential drugs to treat neurodevelopmental and psychiatric disorders characterized by impaired social interactions. However, despite the basic and preclinical relevance of mouse strains carrying genetic alterations in the OT/AVP systems to basic and preclinical translational neuroscience, the pharmacological profile of mouse OT/AVP receptor subtypes has not been fully characterized. To fill in this gap, we have characterized a number of OT and AVP agonists and antagonists at three murine OT/AVP receptors expressed in the nervous system as follows: the oxytocin (mOTR) and vasopressin V1a (mV1aR) and V1b (mV1bR) subtypes. These three receptors were transiently expressed in vitro for binding and intracellular signaling assays, and then a homology model of the mOTR structure was constructed to investigate how its molecular features compare with human and rat OTR orthologs. Our data indicate that the selectivity profile of the natural ligands, OT and AVP, is conserved in humans, rats, and mice. Furthermore, we found that the synthetic peptide [Thr(4)Gly(7)]OT (TGOT) is remarkably selective for the mOTR and, like the endogenous OT ligand, activates Gq and Gi and recruits β-arrestins. Finally, we report three antagonists that exhibit remarkably high affinities and selectivities at mOTRs. These highly selective pharmacological tools will contribute to the investigation of the specific physiologic and pathologic roles of mOTR for the development of selective OT-based therapeutics.


Quality of life and its determinants among hemodialysis patients: A single-center study.
The purpose of this study was to investigate the relation between selected demographic and clinical characteristics and quality of life (QOL) scores in patients with end-stage renal disease who receive dialysis. We conducted the study at one hemodialysis (HD) unit in Bahrain from May 2018 to July 2018. We used standard QOL Index (QOLI) score instrument in Arabic form. This study included 100 patients (66 men and 34 women), aged 22 to 80 years on treatment with maintenance HD for four to 190 months. Inclusion criteria were as follows: those aged >18 years with no severe morbidities or psychological diseases and were on dialysis for at least three months. The following QOL scores were recorded: the health and functioning domain (64.8 ± 15.3), the social and economic domain (65.6 ± 14.1), the psychological/spiritual domain (74.9 ± 14.3), and the family subscale domain (75.9 ± 14.5). Male patients had reduced QOL though not statistically significant and younger patients had better QOL scores. The QOL scores revealed a decreasing trend with decreasing level of education, and they were higher among those who were not working and stayed at home. In addition, the family subclass scores were significantly higher among the married patients. Correlations between the demographic characteristics and QOL scores showed that there was a significant negative correlation between family domain and educational level and marital status, while there was a significant positive correlation between residence and psychological domain. Age, gender, marital status, residence, ethnicity, education level, employment status, income, and duration on HD nonsignificantly affected one or more domains of QOLI scores in such patients. Adequate management of these factors could influence patient outcomes.


17q12 Deletion in a patient with Williams syndrome: Case report and review of the literature.
Williams syndrome (WS) is a complex genomic disorder entailing distinctive facial dysmorphism, cardiovascular abnormalities, intellectual disabilities, unusual behavioral features, and a specific cognitive profile with considerable variability. Additional symptoms include endocrine abnormalities, renal anomalies and connective tissue disorders. We report a monozygotic twin patient with WS who presented with multicystic kidneys in the newborn period, and, in addition to the typical WS deletion at 7q11.23, was found to have a de novo 1.7 Mb deletion in the 17q12 region on microarray comparative genomic hybridization. The co-twin was selectively terminated at 23 wk of gestation after being diagnosed with bilateral multicystic dysplastic kidneys and anhydramnios. Review of the literature shows that deletion of chromosome 17q12, encompassing hepatocyte nuclear factor 1beta gene, is associated with cystic renal disease and is the first recurrent genomic deletion associated with maturity onset diabetes of the young. In addition, reports of female reproductive tract malformations and patients with neurocognitive or psychiatric phenotypes have recently been described. This review of the literature summarizes 47 other cases involving 17q12 deletions with wide variability in phenotype, possibly suggesting a contiguous gene syndrome. It is likely that the additional 17q12 deletion has played a role in modifying the phenotype in our patient. This case highlights the importance of using array comparative genomic hybridization in the clinical setting to uncover the etiology of atypical findings in individuals with known microdeletion syndromes.


Antigenic diversity in Eimeria maxima and the influence of host genetics and immunization schedule on cross-protective immunity.
Eimeria spp. are a group of highly successful intracellular protozoan parasites that develop within enterocytes. Eimeria maxima from the chicken is characterized by high immunogenicity (a small priming infection gives complete immunity to subsequent homologous challenge) and naturally occurring antigenically variant populations that do not completely cross-protect. In this study we examined the expression of antigenic diversity in E. maxima, as manifested by cross-strain protection in a series of inbred chicken lines. The IAH line of Light Sussex chickens and all lines of inbred White Leghorns were susceptible to primary infections with either of two strains (H and W) of E. maxima and were protected completely against challenge with the homologous strain of parasite. The extent of cross-protection against the heterologous parasite strain varied from 0 to almost 100% depending on host genetics. Interestingly, in one inbred line of chickens (line 15I) the cross-protective phenotype was directional and intensely influenced by the infection history of the host. The basis for the observed variation in cross-protection is not known, but our results suggest that the major histocompatibility complex is not a major genetic component of the phenotype. These results are discussed in relation to the number of protective antigens presented by complex pathogens and the development of immunoprotective responses in hosts of different genetic backgrounds.


Assessment of logistical support for road maintenance to manage road accidents in Vhembe district municipalities.
This article discusses the problems of logistical support for road maintenance to manage road accidents in Vhembe district municipalities. A budget deficit model was used to explain the level of inadequate logistics support to manage operations and maintenance of municipal roads as a preventative measure against road accident and disaster risks. A hypothetical road maintenance deficit model informed by current literature on road maintenance was used to explain how cost of road maintenance increases exponentially if initial maintenance was not undertaken when the facility was newly constructed to draw the link between road maintenance and the risk of road accidents. Inadequate logistical support to address road maintenance backlogs in Vhembe district municipalities has been on the increase over the last 10 years. Current studies show that inadequate road maintenance can lead to the development of potholes - a major cause of road accidents and damages to motor vehicles. Literature on logistics support emphasises a comprehensive approach to road maintenance to provide a balance between funding, routine maintenance, quality of materials used for maintenance, use of stipulated specifications, the required maintenance technology, innovations and employment of qualified service providers to ensure quality roads and reduction of accidents on municipal roads.


Liver transplantation in cancer--a review.
Whilst liver transplantation is an accepted therapeutic modality for end stage cirrhosis, its application for hepatic malignancy has remained a controversial issue. This is due to the early experience in several centres of tumour recurrence within the first year. More recently, stringent patient selection criteria have been established to decrease the risk of tumour recurrence. Pre-operative assessment including liver biopsy, computerised axial tomography (CT) of both the thorax and abdomen, bone scans and pre-transplant laparotomy are routinely performed to exclude extrahepatic spread. Of the primary tumours, the most common groups are the hepatocellular carcinomas (HCC) and cholangiocarcinomas. A hierarchy of tumours favourable for transplantation exists, with HCC giving the best results, followed by central bile duct carcinoma, cholangiocellular carcinoma (peripheral), and secondaries, in descending order of suitability. With better patient selection based on adequate staging, and the confinement of liver grafting to lymph node negative stages, there has been a marked improvement in survival in otherwise unresectable and mainly untreatable tumours. The improved results support the application of liver grafting for malignancy, and suggest that the often discussed danger of tumour growth enhancement because of immunosuppression may not significantly be present. Despite the risk of tumour recurrence, liver transplantation gives worthwhile survival with the chance of cure for some and in others, considerable palliation with prolonged survival.


Evidence of blood-brain barrier dysfunction in human cerebral malaria.
Patients infected with the malaria parasite Plasmodium falciparum may develop a diffuse reversible encephalopathy, termed cerebral malaria. It is unclear how the intraerythrocytic parasite, which sequesters in the cerebral microvasculature but does not enter the brain parenchyma, induces this neurological syndrome. Adhesion of parasitized red blood cells in the brain microvasculature is mediated by specific receptors on the host endothelium, including intercellular adhesion molecule (ICAM)-1, CD36 and CD31. Leucocyte binding to cerebral endothelial cells in culture induces intracellular signalling via ICAM-1. The hypothesis that parasitized red blood cells binding to receptors on cerebral endothelial cells causes changes in the integrity of the blood-brain barrier was tested. Immunohistochemistry was used to examine the blood-brain barrier in human cerebral malaria, with antibodies to macrophage and endothelial activation markers, intercellular junction proteins, and plasma proteins. The distribution of the cell junction proteins occludin, vinculin and ZO-1 were altered in cerebral malaria cases compared to controls. While fibrinogen was the only plasma protein detected in the perivascular space, there was widespread perivascular macrophage activation, suggesting that these cells had been exposed to plasma proteins. It was concluded that functional changes to the blood-brain barrier occur in cerebral malaria, possibly as a result of the binding of parasitized red blood cells to cerebral endothelial cells. These changes require further examination in vitro.