The Lipid Status in Patients with Ulcerative Colitis: Sphingolipids are Disease-Dependent Regulated.
The factors that contribute to the development of ulcerative colitis (UC), are still not fully identified. Disruption of the colon barrier is one of the first events leading to invasion of bacteria and activation of the immune system. The colon barrier is strongly influenced by sphingolipids. Sphingolipids impact cell-cell contacts and function as second messengers. We collected blood and colon tissue samples from UC patients and healthy controls and investigated the sphingolipids and other lipids by LC-MS/MS or LC-QTOFMS. The expression of enzymes of the sphingolipid pathway were determined by RT-PCR and immunohistochemistry. In inflamed colon tissue, the de novo-synthesis of sphingolipids is reduced, whereas lactosylceramides are increased. Reduction of dihydroceramides was due to posttranslational inhibition rather than altered serine palmitoyl transferase or ceramide synthase expression in inflamed colon tissue. Furthermore, in human plasma from UC-patients, several sphinglipids change significantly in comparison to healthy controls. Beside sphingolipids free fatty acids, lysophosphatidylcholines and triglycerides changed significantly in the blood of colitis patients dependent on the disease severity. Our data indicate that detraction of the sphingolipid de novo synthesis in colon tissue might be an important trigger for UC. Several lipids changed significantly in the blood, which might be used as biomarkers for disease control; however, diet-related variabilities need to be considered.


Plasma proteomic profiling for detecting and differentiating in situ and invasive carcinomas of the uterine cervix.
The objective of this study was to identify multiple plasma protein markers that might be characteristic of in situ and invasive cervical cancers. Plasma samples obtained from patients with in situ cervical cancer (carcinoma in situ [CIS], n= 32), from patients with early invasive cervical cancer without lymph node metastasis (squamous cell carcinoma [SCC], n= 60), and from age-matched disease-free controls (n= 37) were analyzed by cation-exchange protein chips and surface-enhanced laser desorption and ionization time-of-flight mass spectrometry. A classification tree defined by six protein peaks could discriminate 84 of the 92 cancers (CIS and SCC) and 36 of the 37 controls, with 91% sensitivity and 97% specificity. In comparing the CIS and SCC samples, two protein peaks with Mr values of 6586.41 and 3805.68 were able to classify 55 of the 60 SCC and 31 of the 32 CIS samples, with 92% sensitivity and 97% specificity. This study demonstrates for the first time the feasibility of differentiating in situ and invasive cervical cancers through plasma protein profiling. Identification of the proteins different in invasive and in situ cancer may be of great value in the understanding of cervical cancer invasion and in the development of novel therapeutic intervention.


Intermittent coronary sinus occlusion after coronary arterial ligation results in venous retroperfusion.
Coronary sinus occlusion retards necrosis of ischemic myocardium. To test the hypothesis that coronary sinus occlusion induces retrograde venoarterial flow, the coronary arteriovenous pressure gradient and the coronary arterial oxygen saturation were measured distal to a left anterior descending coronary artery ligature in dogs. In parallel, we constructed a mathematical model of known coronary physiology to characterize pressure and flow patterns during coronary sinus occlusion. In dogs, coronary sinus occlusion produced a systolic pressure gradient between the coronary artery and the coronary sinus of -20 +/- 9 mm Hg (higher venous pressure, p less than 0.0001) and a positive diastolic gradient of 3 +/- 5 mm Hg (lower venous pressure p less than 0.01). An average reduction in the oxygen saturation in the ligated coronary artery of 20 +/- 13% was also observed (p less than 0.005) consequent to admixture of venous (desaturated) blood. By graded inflation of the coronary sinus balloon, it was demonstrated that desaturation of arterial blood typically occurs above a coronary sinus systolic pressure of 40-50 mm Hg. The mathematical model indicates the possibility of venoarterial pressure gradients and reversal of flow at the microcirculatory level during coronary sinus occlusion. These studies provide evidence that retrograde flow into the ischemic zone occurs in association with intermittent coronary sinus occlusion. Thus, alternating flow over the ischemic territory may be the mechanism of myocardial salvage during intermittent coronary sinus occlusion.


The PDQ-Carer: development and validation of a summary index score.
The PDQ-Carer is a 29 item measure of health related quality of life for use with carers of people with Parkinson's disease. The original development of the instrument identified four domains. This study examined the possibility that the four domains could reasonably be summed to provide a single summary index score. The PDQ-Carer was administered in a postal survey of patients and carers registered with local branches of Parkinson's UK. Data from the four domains of the PDQ-Carer was subjected to higher order factor analysis. Reliability and validity of the summary index were assessed. A total of 236 carer questionnaires were returned, a response rate of 61%. The mean age of the sample was 68.2 years (SD 9.49; range 25-89 years); 63.5% females, 21.3% males. Higher order principle components factor analysis produced one factor, accounting for 85.5% of the variance. The newly derived single index was found to be both internally reliable (alpha = 0.94) and valid through correlations with the eight domains of the SF-36 (all p < 0.001). The analyses undertaken here indicate that data from the PDQ-Carer can be presented in summary form. The index will provide an overall indication of the impact of caring. Furthermore, the single index reduces the number of statistical comparisons, and hence the role of chance, when exploring data from the PDQ-Carer.


Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission.
The Shank3 gene encodes a scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse. Previous attempts to delete the Shank3 gene have not resulted in a complete loss of the predominant naturally occurring Shank3 isoforms. We have now characterized a homozygous Shank3 mutation in mice that deletes exon 21, including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major naturally occurring Shank3 protein bands detected by C-terminal and N-terminal antibodies, allowing us to more definitively examine the role of Shank3 in synaptic function and behavior. This loss of Shank3 leads to an increased localization of mGluR5 to both synaptosome and postsynaptic density-enriched fractions in the hippocampus. These mice exhibit a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of the hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. These data suggest that Shank3 isoforms are required for normal synaptic transmission/plasticity in the hippocampus, as well as hippocampus-dependent spatial learning and memory.


Cloning and expression of cDNA encoding protein synthesis elongation factor-2 kinase.
A cDNA from rat skeletal muscle encoding calcium/calmodulin-dependent eukaryotic elongation factor-2 kinase (eEF-2K) has been cloned and sequenced, and the amino acid sequence of the protein has been deduced. The kinase is composed of 724 amino acids and has a predicted molecular mass of 81,499 Da. The cDNA was judged to be full-length, as the protein, expressed in rabbit reticulocyte lysate or wheat germ extract, migrated upon SDS-PAGE with the same apparent molecular weight as the purified kinase and possessed eEF-2K activity. eEF-2K contains all of the 12 catalytic subdomains present in the majority of protein kinases, but they are atypical and display only limited homology with other kinases. A putative calmodulin-binding domain is present C-terminal to the catalytic domain as is a putative pseudosubstrate sequence. Two antipeptide antibodies raised against sequences derived from a partial rabbit cDNA clone, cross-reacted with purified eEF-2K, and one also immunoprecipitated eEF-2K activity from cell extracts. Northern blot analysis demonstrated that eEF-2K mRNA is expressed in a number of different tissues and that it may exist in multiple forms.


Serosurvey of viral infections in free-ranging Namibian cheetahs (Acinonyx jubatus).
Cheetahs (Acinonyx jubatus) in captivity have unusually high morbidity and mortality from infectious diseases, a trait that could be an outcome of population homogeneity or the immunomodulating effects of chronic stress. Free-ranging Namibian cheetahs share ancestry with captive cheetahs, but their susceptibility to infectious diseases has not been investigated. The largest remaining population of free-ranging cheetahs resides on Namibian farmlands, where they share habitat with domestic dogs and cats known to carry viruses that affect cheetah health. To assess the extent to which free-ranging cheetahs are exposed to feline and canine viruses, sera from 81 free-ranging cheetahs sampled between 1992 and 1998 were evaluated for antibodies against canine distemper virus (CDV), feline coronavirus (feline infectious peritonitis virus; FCoV/ FIPV), feline herpesvirus 1 (FHV1), feline panleukopenia virus (FPV), feline immunodeficiency virus (FIV), and feline calicivirus (FCV) and for feline leukemia virus (FeLV) antigens. Antibodies against CDV, FCoV/FIPV, FHV1, FPV, and FCV were detected in 24, 29, 12, 48, and 65% of the free-ranging population, respectively, although no evidence of viral disease was present in any animal at the time of sample collection. Neither FIV antibodies nor FeLV antigens were present in any free-ranging cheetah tested. Temporal variation in FCoV/FIPV seroprevalence during the study period suggested that this virus is not endemic in the free-ranging population. Antibodies against CDV were detected in cheetahs of all ages sampled between 1995 and 1998, suggesting the occurrence of an epidemic in Namibia during the time when CDV swept through other parts of sub-Saharan Africa. This evidence in free-ranging Namibian cheetahs of exposure to viruses that cause severe disease in captive cheetahs should direct future guidelines for translocations, including quarantine of seropositive cheetahs and preventing contact between cheetahs and domestic pets.


Evaluation of cisplatin dose intensity: current status and future prospects.
Cisplatin dose intensity is a potentially important concept in the chemotherapeutic management of several human malignancies. In vitro studies have demonstrated steep dose-response relationships in a variety of tumor types. Although previous clinical trials have also suggested the importance of cisplatin dose, renal insufficiency has limited exploration of more dose-intensive regimens. Recently, therapeutic strategies such as hypertonic saline have allowed dose escalation to the level of 200 mg/m2/28 day cycle, or 50 mg/m2/week as standardized for dose intensity analysis. In this review, we summarize the rationale for investigation of cisplatin dose intensity, pertinent pharmacokinetics, and potential methods of dose escalation. Clinical data are presented regarding both efficacy and newly recognized non-renal toxicities of high-dose cisplatin. We describe the results of a pharmacokinetically designed schedule of high-dose cisplatin in hypertonic saline, administering a divided dose of 100 mg/m2 on days 1 and 8 of each 28-day cycle. This regimen has resulted in high response rates and encouraging survival times in non-small cell lung cancer, and is currently being investigated in several different tumor types. Compared to other dose-intensive regimens, this day 1 and 8 schedule is relatively well-tolerated, with a toxicity pattern not substantially different from standard-dose cisplatin. Since non-renal toxicities such as peripheral neuropathy continue to limit cumulative cisplatin dose, other methods of increasing dose intensity are of considerable interest. We present the rationale and current trials utilizing chemoprotective or "rescue" agents as a means of maximizing cisplatin dose intensity and minimizing the toxicity of this agent.


Shared sequence variants of Mus spretus LINE-1 elements tracing dispersal to within the last 1 million years.
LINE-1 repetitive sequences contain a record of an evolving population of transposons within the mammalian genome. Of the 100,000 copies of LINE-1 sequences per genome there are many shared sequence variants representing changes occurring within the propagating LINE-1 elements themselves, rather than changes that occur during retrotransposition or after an element inserts in the genome. These shared sequence variants define families of LINE-1 elements which have spread within specific periods of time. We have been interested in studying events in LINE-1 evolution since the speciation of Mus spretus and Mus domesticus approximately 3 million years (Myr) ago. To do this, we have collected LINE-1 sequences that have shared sequence variants specific to M. spretus. The sampled LINE-1 elements were sequenced at their extreme 3' ends, where the density of sequence variants is highest. The new sequences define six new M. spretus-specific sequence variants. Of these, we have found one that could be used to screen for LINE-1 elements arising in the last 1 Myr, which we argue is a critical sample for understanding the dynamics of LINE-1 propagation.


Spatiotemporal Alignment of Visual Signals on a Special Manifold.
We investigate the problem of spatiotemporal alignment of videos, signals, or feature sequences extracted from them. Specifically, we consider the scenario where the spatiotemporal misalignments can be characterized by parametric transformations. Using a nonlinear analytical structure referred to as an alignment manifold, we formulate the alignment problem as an optimization problem on this nonlinear space. We focus our attention on semantically meaningful videos or signals, e.g., those describing or capturing human motion or activities, and propose a new formalism for temporal alignment accounting for executing rate variations among instances of the same video event. The strategy taken in this effort bridges the family of geometric optimization and the family of stochastic algorithms: We regard the search for optimal alignment parameters as a recursive state estimation problem for a particular dynamic system evolving on the alignment manifold. Subsequently, a Sequential Importance Sampling procedure on the alignment manifold is designed for effective alignment. We further extend the basic Sequential Importance Sampling algorithm into a new version called Stochastic Gradient Sequential Importance Sampling, in which we incorporate a steepest descent structure on the alignment manifold and provide a more efficient particle propagation mechanism. We demonstrate the performance of alignment using manifolds on several types of input data that arise in vision problems.


Dreaming of a learning task is associated with enhanced sleep-dependent memory consolidation.
It is now well established that postlearning sleep is beneficial for human memory performance. Meanwhile, human and animal studies have demonstrated that learning-related neural activity is re-expressed during posttraining nonrapid eye movement (NREM) sleep. NREM sleep processes appear to be particularly beneficial for hippocampus-dependent forms of memory. These observations suggest that learning triggers the reactivation and reorganization of memory traces during sleep, a systems-level process that in turn enhances behavioral performance. Here, we hypothesized that dreaming about a learning experience during NREM sleep would be associated with improved performance on a hippocampus-dependent spatial memory task. Subjects were trained on a virtual navigation task and then retested on the same task 5 hr after initial training. Improved performance at retest was strongly associated with task-related dream imagery during an intervening afternoon nap. Task-related thoughts during wakefulness, in contrast, did not predict improved performance. These observations suggest that sleep-dependent memory consolidation in humans is facilitated by the offline reactivation of recently formed memories, and furthermore that dream experiences reflect this memory processing. That similar effects were not observed during wakefulness suggests that these mnemonic processes are specific to the sleep state.


CD8(+) T cells are not necessary for 1 alpha,25-dihydroxyvitamin D(3) to suppress experimental autoimmune encephalomyelitis in mice.
In addition to its role in calcium and phosphorous homeostasis, 1 alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] appears to be a modulator of the immune system. Administration of 1,25-(OH)(2)D(3) prevents disease in several autoimmune animal models, including experimental autoimmune encephalomyelitis (EAE). The vitamin D receptor is believed to mediate this activity. Among cells of the immune system, CD8(+) T cells have the highest levels of the vitamin D receptor. Because CD8(+) T cells have been implicated as both suppressors and effectors of the inflammation associated with multiple sclerosis and EAE, we examined the question of whether the 1,25-(OH)(2)D(3) suppression of EAE occurs through a CD8(+) T cell-dependent mechanism. To test this hypothesis, mice that are homozygous knockouts for the alpha chain of the CD8 receptor and have been characterized as lacking functional CD8(+) T cells (CD8(+) -/-) were provided 1,25-(OH)(2)D(3) in their diet before EAE induction. Although CD8(+) -/- mice fed the same diet lacking 1,25-(OH)(2)D(3) have a high incidence of EAE, EAE did not occur in CD8(+) -/- mice fed the diet containing 1,25-(OH)(2)D(3). We conclude that CD8(+) T cells neither are needed nor do they play a role in the prevention of EAE by 1,25-(OH)(2)D(3).


Association between autism symptoms and functioning in children with ADHD.
To examine the association between autism spectrum disorder (ASD) symptoms and (a) social functioning, (b) mental health, (c) quality of life and (d) sleep in children with and without attention-deficit hyperactivity disorder (ADHD). Participants were 6-10-year-old children with ADHD (N=164) and without ADHD (N=198). ADHD was assessed via community-based screening (wave 1) and case confirmation using the Diagnostic Interview Schedule for Children IV (DISC-IV) (wave 2). ASD symptoms were identified using the Social Communication Questionnaire (SCQ). Outcome measures were social functioning (Strengths and Difficulties Questionnaire (SDQ)), mental health (DISC-IV, SDQ), quality of life (QoL, Pediatric Quality of Life Inventory 4.0) and sleep problem severity. Greater ASD symptoms were associated with more parent and teacher-reported peer problems and emotional and conduct problems. For every SD increase in SCQ scores, internalising (OR 1.8, 95% CI 1.3 to 2.6, p=0.001) and externalising disorders (OR 1.5, 95% CI 1.1 to 2.1, p=0.02) increased, QoL decreased by 6.7 units (p<0.001), and moderate/severe sleep problems increased (OR 1.5, 95% CI 1.0 to 2.2, p=0.04). Most findings held in analyses adjusting for socio-demographic factors, ADHD symptom severity and comorbidities (when not the outcome), with the exception of externalising disorders and sleep problems. ASD symptoms are associated with poorer functioning in children with ADHD. It is important to identify and potentially manage ASD symptoms in children with ADHD given that they exacerbate functional impairments in this already vulnerable group.


Fracture of the anteromedial facet of the coronoid process. Surgical technique.
Fracture of the anteromedial facet of the coronoid was recently recognized as a distinct type of coronoid fracture resulting from a varus posteromedial rotational injury force. Very few reports are available to help guide the management of these injuries. Eighteen patients with a fracture of the anteromedial facet of the coronoid process were treated over a six-year period. Twelve patients were treated for the acute fracture, and six were managed after initial treatment elsewhere. All but three patients (two with concomitant fracture of the olecranon and one with a second fracture at the base of the coronoid) had avulsion of the origin of the lateral collateral ligament complex from the lateral epicondyle. The initial treatment was operative in fifteen patients and nonoperative in three. The coronoid fracture was secured with a plate applied to the medial surface of the coronoid in nine patients, a screw in one patient, and sutures in one patient. It was not repaired in the remaining seven patients. At the final evaluation, an average of twenty-six months after the injury, six patients had malalignment of the anteromedial facet of the coronoid with varus subluxation of the elbow, which was due to the fact that the fracture had not been specifically treated in four patients and to loss of fracture fixation in two patients. All six had development of arthrosis and a fair or poor result according to the system of Broberg and Morrey. The remaining twelve patients had good or excellent elbow function. Anteromedial fractures of the coronoid are associated with either subluxation or complete dislocation of the elbow in most patients. Secure fixation of the coronoid fracture usually restores good elbow function.


Ethnic variation in drinking, drug use, and sexual behavior among adolescents in Hawaii.
This study examined ethnic differences in substance use and sexual behavior and whether drinking and drug use constitute risk factors for unsafe sexual practices among Native Hawaiian (NH), Caucasian, and Asian/Pacific Islander (API) high school students in Hawaii. A secondary data analysis of the Youth Risk Behavior Survey (1997 and 1999) using a representative sample of 2,657 students in 9-12 grades was performed. Chi-square tests for bivariate associations and multivariate regression analyses were conducted to identify predictors. NHs were more sexually active, initiated sex earlier, and tended to have multiple partners. Alcohol lifetime use was higher in NH, Caucasians, and males. NHs were more likely to initiate drinking by age 12 and engage more in episodic drinking. Non-episodic or episodic drinkers and students who use drugs were at risk to engage in sexual activity, have multiple partners, and use alcohol/drugs during sex. Risk was two times higher for substance use during sex if drinking was initiated at age 10 or younger compared to 15 years or older. Compared to abstainers, the risk doubled for lifetime multiple partners if drinking was initiated at ages 13-14. Overall, females were more sexually active. Because drinking was associated with sexual initiation and risky behavior, adverse effects of alcohol must be addressed in programs targeting underage drinking, thus helping youth delay or minimize sexual activity and prevent other associated problems. Intervention efforts should enhance life skills that endorse abstinence from alcohol and drug use.


The effect of morphology on spelling and reading accuracy: a study on Italian children.
In opaque orthographies knowledge of morphological information helps in achieving reading and spelling accuracy. In transparent orthographies with regular print-to-sound correspondences, such as Italian, the mappings of orthography onto phonology and phonology onto orthography are in principle sufficient to read and spell most words. The present study aimed to investigate the role of morphology in the reading and spelling accuracy of Italian children as a function of school experience to determine whether morphological facilitation was present in children learning a transparent orthography. The reading and spelling performances of 15 third-grade and 15 fifth-grade typically developing children were analyzed. Children read aloud and spelled both low-frequency words and pseudowords. Low-frequency words were manipulated for the presence of morphological structure (morphemic words vs. non-derived words). Morphemic words could also vary for the frequency (high vs. low) of roots and suffixes. Pseudo-words were made up of either a real root and a real derivational suffix in a combination that does not exist in the Italian language or had no morphological constituents. Results showed that, in Italian, morphological information is a useful resource for both reading and spelling. Typically developing children benefitted from the presence of morphological structure when they read and spelled pseudowords; however, in processing low-frequency words, morphology facilitated reading but not spelling. These findings are discussed in terms of morpho-lexical access and successful cooperation between lexical and sublexical processes in reading and spelling.


Time delays in diagnosis of pulmonary tuberculosis: a systematic review of literature.
Delay in diagnosis of pulmonary tuberculosis results in increasing severity, mortality and transmission. Various investigators have reported about delays in diagnosis of tuberculosis. We aimed at summarizing the data on these delays in diagnosis of tuberculosis. A systematic review of literature was carried out. Literature search was done in Medline and EMBASE from 1990 to 2008. We used the following search terms: delay, tuberculosis, diagnosis, and help-seeking/health-seeking behavior without language restrictions. In addition, indices of four major tuberculosis journals were hand-searched. Subject experts in tuberculosis and authors of primary studies were contacted. Reference lists, review articles and text book chapters were also searched. All the studies were assessed for methodological quality. Only studies carried out on smear/culture-positive tuberculosis patients and reporting about total, patient and health-care system delays were included. A total of 419 potential studies were identified by the search. Fifty two studies qualified for the review. The reported ranges of average (median or mean) total delay, patient delay, health system delay were 25-185 days, 4.9-162 days and 2-87 days respectively for both low and high income countries. Average patient delay was similar to health system delay (28.7 versus 25 days). Both patient delay and health system delay in low income countries (31.7 days and 28.5 days) were similar to those reported in high income countries (25.8 days and 21.5 days). The results of this review suggest that there is a need for revising case-finding strategies. The reported high treatment success rate of directly observed treatment may be supplemented by measures to shorten the delay in diagnosis. This may result in reduction of infectious cases and better tuberculosis control.


The role of dietary methionine concentrations on growth, metabolism and N-retention in cobia (Rachycentron canadum) at elevated water temperatures.
This study determined impacts of dietary methionine concentrations at two temperatures on growth, feeding efficiency and N-metabolites in juvenile cobia. Methionine concentrations of the experimental diets were deficient (M9; 9 g/kg), sufficient (M12; 12 g/kg) and surplus (M16, 16 g/kg). Water temperature was normal (30°C) or elevated (34°C). Twenty cobia in triplicate tanks were fed the experimental diets for 6 weeks. Both methionine and temperature affected cobia's growth and feeding efficiency. Cobia fed M9 performed lower than the fish fed M12 and M16 diets. Additionally, cobia reared at 34°C performed poorer than at 30°C, probably due to lower voluntary feed intake in the fish reared at 34°C. Protein efficiency ratio and protein productive value in cobia fed M9 diet were less than M12 or M16 diets. This was confirmed with the improved retentions of indispensable amino acids (AAs). No interactions between methionine and temperature were observed in growth and protein accretion. At 30°C, CF improved, while HSI and VSI declined upon methionine supplementation levels. Of which an interaction between temperature and methionine was present. Plasma, muscle and liver free AA and N-metabolites were affected by methionine and temperature. Furthermore, temperature affected cobia's lipid class composition, resulting in increased phospholipids and cholesterol at 34°C.


Galanin-like peptide as a link in the integration of metabolism and reproduction.
The arcuate nucleus is a hypothalamic center that couples energetics and reproduction. Peptide-releasing neurons in the arcuate nucleus receive and process humoral signals from the periphery and relay this information to other nuclei in the hypothalamus and preoptic area. Galanin-like peptide (GALP) is expressed in the arcuate nucleus, and GALP-containing neurons are targets for the action of leptin. GALP-containing neurons are closely apposed to gonadotropin-releasing hormone (GnRH) neurons in the preoptic area, and CNS injections of GALP stimulate GnRH-mediated secretion of luteinizing hormone. These observations indicate that GALP is a molecular signal that couples circulating indices of metabolism to the neuroendocrine reproductive system and, thus, regulates reproductive activity as a function of the energy state. In this article, we describe the involvement of GALP in metabolism and reproduction, and in the coupling between these two processes.


Locus of control and regional differences in sickness absence in Sweden.
The aim of this study was to investigate if there are differences in locus of control (LOC), at a societal level, between two residential areas in Sweden with substantial differences in sickness absence. A postal questionnaire was sent to 1500 randomly selected men and women aged 20 - 64 years. Five hundred questionnaires were sent to people living in Stromsund (a sparsely populated municipality in northern Sweden with high rates of sickness absence) and 1000 questionnaires to people in the Swedish capital of Stockholm, which has a low rate of sickness absence. A comparison of LOC in the two study areas supported our hypothesis to a certain extent, external locus being more prominent in Stromsund. When physical and mental health and income were considered, however, the differences disappeared. Consequently, this study did not support the opinion that differences in sickness absence can be explained by LOC at a societal level.


Alternative splice variants of AID are not stoichiometrically present at the protein level in chronic lymphocytic leukemia.
Activation-induced deaminase (AID) is a DNA-mutating enzyme that mediates class-switch recombination as well as somatic hypermutation of antibody genes in B cells. Due to off-target activity, AID is implicated in lymphoma development by introducing genome-wide DNA damage and initiating chromosomal translocations such as c-myc/IgH. Several alternative splice transcripts of AID have been reported in activated B cells as well as malignant B cells such as chronic lymphocytic leukemia (CLL). As most commercially available antibodies fail to recognize alternative splice variants, their abundance in vivo, and hence their biological significance, has not been determined. In this study, we assessed the protein levels of AID splice isoforms by introducing an AID splice reporter construct into cell lines and primary CLL cells from patients as well as from WT and TCL1(tg) C57BL/6 mice (where TCL1 is T-cell leukemia/lymphoma 1). The splice construct is 5'-fused to a GFP-tag, which is preserved in all splice isoforms and allows detection of translated protein. Summarizing, we show a thorough quantification of alternatively spliced AID transcripts and demonstrate that the corresponding protein abundances, especially those of splice variants AID-ivs3 and AID-ΔE4, are not stoichiometrically equivalent. Our data suggest that enhanced proteasomal degradation of low-abundance proteins might be causative for this discrepancy.


Bidirectional 60-GHz radio-over-fiber systems with downstream OFDMA and wavelength reuse upstream SC-FDMA.
We have proposed and experimentally demonstrated a 60-GHz bidirectional radio-over-fiber system with downstream orthogonal frequency division multiplexing address (OFDMA) and wavelength reuse upstream single-carrier frequency division multiple address (SC-FDMA). In the downstream, a 3-dB optical coupler is used for two-carrier injection-locking a distributed feedback (DFB) laser in order to realize the single-sideband modulation. In the upstream, the weakly modulated one of the two downstream carriers is filtered out for wavelength reuse. Transmission of 9.65-Gb/s 16-QAM downstream OFDMA on 60-GHz carrier and 5-Gb/s QPSK upstream SC-FDMA (2.5 Gb/s for each user) are both successfully demonstrated over 53-km standard single mode fiber without chromatic dispersion compensation. The crosstalk between the downstream OFDMA and the upstream SC-FDMA can be neglected.


Oxidative DNA damage stalls the human mitochondrial replisome.
Oxidative stress is capable of causing damage to various cellular constituents, including DNA. There is however limited knowledge on how oxidative stress influences mitochondrial DNA and its replication. Here, we have used purified mtDNA replication proteins, i.e. DNA polymerase γ holoenzyme, the mitochondrial single-stranded DNA binding protein mtSSB, the replicative helicase Twinkle and the proposed mitochondrial translesion synthesis polymerase PrimPol to study lesion bypass synthesis on oxidative damage-containing DNA templates. Our studies were carried out at dNTP levels representative of those prevailing either in cycling or in non-dividing cells. At dNTP concentrations that mimic those in cycling cells, the replication machinery showed substantial stalling at sites of damage, and these problems were further exacerbated at the lower dNTP concentrations present in resting cells. PrimPol, the translesion synthesis polymerase identified inside mammalian mitochondria, did not promote mtDNA replication fork bypass of the damage. This argues against a conventional role for PrimPol as a mitochondrial translesion synthesis DNA polymerase for oxidative DNA damage; however, we show that Twinkle, the mtDNA replicative helicase, is able to stimulate PrimPol DNA synthesis in vitro, suggestive of an as yet unidentified role of PrimPol in mtDNA metabolism.


Targeted therapy for non-small cell lung cancer: current standards and the promise of the future.
In recent years, there has been a major paradigm shift in the management of non-small cell lung cancer (NSCLC). NSCLC should now be further sub-classified by histology and driver mutation if one is known or present. Translational research advances now allow such mutations to be inhibited by either receptor monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKI). Whilst empirical chemotherapy with a platinum-doublet remains the gold standard for advanced NSCLC without a known driver mutation, targeted therapy is pushing the boundary to significantly improve patient outcomes and quality of life. In this review, we will examine the major subtypes of oncogenic drivers behind NSCLC as well as the development of targeted agents available to treat them both now and in the foreseeable future.


Stretching-induced ion complexation in physical polyampholyte hydrogels.
Recently, we have developed a series of charge balanced polyampholyte (PA) physical hydrogels by random copolymerization in water, which show extraordinarily high toughness, self-healing ability and viscoelasticity. The excellent performance of PA hydrogels is ascribed to dynamic ionic bond formation through inter- and intra-chain interactions. The randomness results in ionic bonds of wide strength distribution, the strong bonds, which serve as permanent crosslinking, imparting the elasticity, while the weak bonds reversibly break and re-form, dissipating energy. In this work, we developed a simple physical method, called a pre-stretching method, to promote the performance of PA hydrogels. By imposing a pre-stretching on the sample in the as-prepared state, ion complexation during dialysis is prominently accelerated and the final performance is largely promoted. Further analysis suggests that the strong bond formation induced by pre-stretching is responsible for the change in final performance. Pre-stretching decreases the entropy of the system and increases the chain alignment, resulting in an increased possibility for strong bond formation.


Site-Specific Labelling of Native Mammalian Proteins for Single-Molecule FRET Measurements.
Human cells are complex entities in which molecular recognition and selection are critical for cellular processes often driven by structural changes and dynamic interactions. Biomolecules appear in different chemical states, and modifications, such as phosphorylation, affect their function. Hence, using proteins in their chemically native state in biochemical and biophysical assays is essential. Single-molecule FRET measurements allow exploration of the structure, function and dynamics of biomolecules but cannot be fully exploited for the human proteome, as a method for the site-specific coupling of organic dyes into native, non-recombinant mammalian proteins is lacking. We address this issue showing the site-specific engineering of fluorescent dyes into human proteins on the basis of bioorthogonal reactions. We show the applicability of the method to study functional and post-translationally modified proteins on the single-molecule level, among them the hitherto inaccessible human Argonaute 2.


Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models.
This article reviews the mechanism of dopamine delivery in the CNS in order to determine the optimal set of genes for effective gene therapy in Parkinson's disease (PD). Systematic neurobiological investigation of the biochemical steps has revealed that tyrosine hydroxylase (TH), which has been used in earlier studies, functions only when the essential cofactor, tetrahydrobiopterin (BH1) is present. Transduction of the gene for GTP cyclohydrolase I, the first and rate-limiting step in BH1 synthesis, along with the TH gene, generated cells that are capable of producing L-DOPA spontaneously both in vitro and in vivo. When the aromatic L-amino acid decarboxylase (AADC) gene was added as a third gene, in an attempt to increase the conversion of L-DOPA to dopamine, feedback inhibition by the end product, dopamine, on TH activity resulted. To circumvent this problem, we employed a complementary strategy. Gene transfer of the vesicular monoamine transporter was combined with AADC and produced genetically modified cells that can convert L-DOPA to dopamine and store it for gradual release. This approach provided a means to regulate final dopamine delivery by controlling precursor doses and to achieve more sustained delivery of dopamine. Our investigation into determining the genes necessary for optimal dopamine delivery has been facilitated by in vivo biochemical assays using microdialysis. This technique has provided us with a clear and quantitative tool to compare the effects of various genes involved in dopamine synthesis and processing.


Dietary and pharmacological treatment of abdominal pain in IBS.
This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron), non-absorbed antibiotic (rifaximin), secretagogues (lubiprostone, linaclotide), μ-opioid receptor (OR) and κ-OR agonist, δ-OR antagonist (eluxadoline), histamine H1 receptor antagonist (ebastine), neurokinin-2 receptor antagonist (ibodutant) and GABAergic agents (gabapentin and pregabalin). Efficacy and safety are discussed based on pivotal trials or published systematic reviews and meta-analysis, expressing ORs or relative risks and their 95% CIs. Potential new approaches may be based on recent insights on mucosal expression of genes, and microRNA and epigenetic markers in human biopsies and in animal models of visceral hypersensitivity.The objectives of this review are to appraise the physiology and anatomy of gut sensation and the efficacy in the relief of visceral pain (typically in IBS) of several classes of therapies. These include fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and different classes of medications (box 1). Box 1Classes of pharmacological agents for visceral painAntidepressants (tricyclic agents, selective serotonin reuptake inhibitors)Peppermint oil5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron)Non-absorbed antibiotic (rifaximin)Secretagogues (lubiprostone, linaclotide)μ-Opioid receptor (OR) and κ-OR agonist and δ-OR antagonist (eluxadoline)Histamine H1 receptor antagonist (ebastine)Neurokinin-2 receptor antagonist (ibodutant)GABAergic agents (gabapentin and pregabalin).


Modulation of crystalline Proteus mirabilis biofilm development on urinary catheters.
The crystalline biofilms formed by Proteus mirabilis can seriously complicate the care of patients undergoing long-term bladder catheterization. The generation of alkaline urine by the bacterial urease causes calcium and magnesium phosphates to precipitate from urine and accumulate in the catheter biofilm, blocking the flow of urine from the bladder. The pH at which these salts crystallize from a urine sample, the nucleation pH (pH(n)), can be elevated by diluting the urine and by increasing its citrate content. The aim of this study was to examine whether manipulation of pH(n) in these ways modulated the rate at which crystalline biofilm developed. Experiments in laboratory models of the catheterized bladder infected with P. mirabilis showed that when the bladder was supplied with a concentrated urine (pH(n) 6.7) at a low fluid output (720 ml per 24 h), catheters blocked at 19-31 h. Diluting this urine 1:4 increased the pH(n) to 7.5 and models supplied with this urine at 2880 ml per 24 h took 110-137 h to block. When models were supplied with urine containing citrate at 1.5 mg ml(-1) or above (pH(n) 8.3-9.1), the catheters drained freely for the full 7 day experimental period. Scanning electron microscopy revealed that the catheter biofilms that developed in urine with high pH(n) values were devoid of crystalline formations. These observations should encourage a clinical trial to examine the effect of increasing a patient's fluid intake with citrate-containing drinks on the encrustation and blockage of catheters.


Psychophysiological effects of slow-paced breathing at six cycles per minute with or without heart rate variability biofeedback.
Heart rate variability (HRV) biofeedback, referring to slow-paced breathing (SPB) realized while visualizing a heart rate, HRV, and/or respiratory signal, has become an adjunct treatment for a large range of psychologic and medical conditions. However, the underlying mechanisms explaining the effectiveness of HRV biofeedback still need to be uncovered. This study aimed to disentangle the specific effects of HRV biofeedback from the effects of SPB realized alone. In total, 112 participants took part in the study. The parameters assessed were emotional (valence, arousal, and control) and perceived stress intensity as self-report variables and the root mean square of the successive differences (RMSSD) as a physiologic variable. A main effect of condition was found for emotional valence only, valence being more positive overall in the SPB-HRVB condition. A main effect of time was observed for all dependent variables. However, no main effects for the condition or time x condition interaction effects were observed. Results showed that for PRE and POST comparisons (referring, respectively, to before and after SPB), both SPB-HRVB and SPB-NoHRVB conditions resulted in a more negative emotional valence, lower emotional arousal, higher emotional control, and higher RMSSD. Future research might investigate psychophysiological differences between SPB-HRVB and SPB-NoHRVB across different time periods (e.g., long-term interventions), and in response to diverse psychophysiological stressors.


Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations.
The great therapeutic achievements of antibiotics have been dramatically undercut by the evolution of bacterial strategies that overcome antibiotic stress. These strategies fall into two classes. 'Resistance' makes it possible for a microorganism to grow in the constant presence of the antibiotic, provided that the concentration of the antibiotic is not too high. 'Tolerance' allows a microorganism to survive antibiotic treatment, even at high antibiotic concentrations, as long as the duration of the treatment is limited. Although both resistance and tolerance are important reasons for the failure of antibiotic treatments, the evolution of resistance is much better understood than that of tolerance. Here we followed the evolution of bacterial populations under intermittent exposure to the high concentrations of antibiotics used in the clinic and characterized the evolved strains in terms of both resistance and tolerance. We found that all strains adapted by specific genetic mutations, which became fixed in the evolved populations. By monitoring the phenotypic changes at the population and single-cell levels, we found that the first adaptive change to antibiotic stress was the development of tolerance through a major adjustment in the single-cell lag-time distribution, without a change in resistance. Strikingly, we found that the lag time of bacteria before regrowth was optimized to match the duration of the antibiotic-exposure interval. Whole genome sequencing of the evolved strains and restoration of the wild-type alleles allowed us to identify target genes involved in this antibiotic-driven phenotype: 'tolerance by lag' (tbl). Better understanding of lag-time evolution as a key determinant of the survival of bacterial populations under high antibiotic concentrations could lead to new approaches to impeding the evolution of antibiotic resistance.


Rubisco activities, properties, and regulation in three different C4 grasses under drought.
In C4 plants, water deficit may decrease photosynthetic CO2 assimilation independently of changes in stomatal conductance, suggesting decreased turnover by ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). The activity and biochemistry of Rubisco was studied in three different C4 grasses: Paspalum dilatatum, Cynodon dactylon, and Zoysia japonica. The objectives were to characterize the C4 Rubisco in these species and to identify factors associated with decreased photosynthetic rates caused by drought. Rubisco isolated from each of the three C4 grasses was characterized by smaller specificity factors (SC/O), larger Michaelis-Menten constants for CO2 (Kc) and O2 (Ko), and larger maximum carboxylation velocities (Vc) than Rubisco from wheat, which can be rationalized in terms of the CO2-rich environment of C4 Rubisco in the bundle sheath. During leaf dehydration the quantity and maximum activity of Rubisco remained unchanged but the initial and total activities declined slightly, possibly due to increased inhibition. Tight-binding inhibitors were present in the light but were more abundant in the dark, especially in Z. japonica, and increased in quantity with drought stress. The inhibitor from darkened leaves of Z. japonica was identified as 2-carboxyarabinitol-1-phosphate (CA1P). Consistent with the presence of CA1P, the total activity of Rubisco was decreased after 12 h darkness in Z. japonica. Ribulose-1,5-bisphosphate (RuBP) in the leaves decreased with drought stress, to quantities approximating those of Rubisco catalytic sites. The magnitude of the decrease in RuBP suggested that, at least in C. dactylon and Z. japonica, it could contribute to the drought-induced decrease in photosynthesis.


Factors Associated With Continuous Improvement by Local Boards of Health.
The continuous improvement function, 1 of the 6 public health governance functions, can be usefully applied in the context of local boards of health (LBoHs) operations to target self-improvements. The purpose of this study was to determine the engagement level of LBoHs in continuous improvement efforts and to identify factors associated with this function. Negative binomial regression was performed to analyze data from the 2015 Local Board of Health National Profile. The LBoH taxonomy was used as the guiding model. The taxonomy includes 6 governance functions as structural domains and LBoHs' characteristics and strengths as the central or seventh domain. For the 17 items that comprise the continuous improvement domain, the mean of the dichotomous responses was 4.97 (SD = 3.41). The negative binomial regression analysis showed that the overall summary scale for the other 5 governance domains and the LBoHs' other strengths domain had a significant positive association with the governance domain continuous improvement domain (incidence rate ratio [IRR] = 1.05, P < .001). The 5 individual scales for the governance domains also had significant positive associations with the continuous improvement domain, which included the governance functions of policy development (IRR = 1.13, P < .001), resource stewardship (IRR = 1.18, P < .001), legal authorization (IRR = 1.09, P < .001, partnership engagement (IRR = 1.12, P < .001), and oversight (IRR = 1.29, P < .001). The scale for other characteristics and strengths also showed positive association with continuous improvement (IRR = 1.14, P < .001). The findings of this study revealed that there was room for improvement in LBoHs' engagement in the continuous improvement governance function. The results also identified other governance functions and LBoHs' characteristics as factors associated with their continuous improvement.


Differences in Noradrenaline Receptor Expression Across Different Neuronal Subtypes in Macaque Frontal Eye Field.
Cognitive functions such as attention and working memory are modulated by noradrenaline receptors in the prefrontal cortex (PFC). The frontal eye field (FEF) has been shown to play an important role in visual spatial attention. However, little is known about the underlying circuitry. The aim of this study was to characterize the expression of noradrenaline receptors on different pyramidal neuron and inhibitory interneuron subtypes in macaque FEF. Using immunofluorescence, we found broad expression of noradrenaline receptors across all layers of the FEF. Differences in the expression of different noradrenaline receptors were observed across different inhibitory interneuron subtypes. No significant differences were observed in the expression of noradrenaline receptors across different pyramidal neuron subtypes. However, we found that putative long-range projecting pyramidal neurons expressed all noradrenaline receptor subtypes at a much higher proportion than any of the other neuronal subtypes. Nearly all long-range projecting pyramidal neurons expressed all types of noradrenaline receptor, suggesting that there is no receptor-specific machinery acting on these long-range projecting pyramidal neurons. This pattern of expression among long-range projecting pyramidal neurons suggests a mechanism by which noradrenergic modulation of FEF activity influences attention and working memory.


Manifold learning for fMRI time-varying functional connectivity.
Whole-brain functional connectivity (FC) measured with functional MRI (fMRI) evolves over time in meaningful ways at temporal scales going from years (e.g., development) to seconds [e.g., within-scan time-varying FC (tvFC)]. Yet, our ability to explore tvFC is severely constrained by its large dimensionality (several thousands). To overcome this difficulty, researchers often seek to generate low dimensional representations (e.g., 2D and 3D scatter plots) hoping those will retain important aspects of the data (e.g., relationships to behavior and disease progression). Limited prior empirical work suggests that manifold learning techniques (MLTs)-namely those seeking to infer a low dimensional non-linear surface (i.e., the manifold) where most of the data lies-are good candidates for accomplishing this task. Here we explore this possibility in detail. First, we discuss why one should expect tvFC data to lie on a low dimensional manifold. Second, we estimate what is the intrinsic dimension (ID; i.e., minimum number of latent dimensions) of tvFC data manifolds. Third, we describe the inner workings of three state-of-the-art MLTs: Laplacian Eigenmaps (LEs), T-distributed Stochastic Neighbor Embedding (T-SNE), and Uniform Manifold Approximation and Projection (UMAP). For each method, we empirically evaluate its ability to generate neuro-biologically meaningful representations of tvFC data, as well as their robustness against hyper-parameter selection. Our results show that tvFC data has an ID that ranges between 4 and 26, and that ID varies significantly between rest and task states. We also show how all three methods can effectively capture subject identity and task being performed: UMAP and T-SNE can capture these two levels of detail concurrently, but LE could only capture one at a time. We observed substantial variability in embedding quality across MLTs, and within-MLT as a function of hyper-parameter selection. To help alleviate this issue, we provide heuristics that can inform future studies. Finally, we also demonstrate the importance of feature normalization when combining data across subjects and the role that temporal autocorrelation plays in the application of MLTs to tvFC data. Overall, we conclude that while MLTs can be useful to generate summary views of labeled tvFC data, their application to unlabeled data such as resting-state remains challenging.


Physiological and comparative genomic analysis of Acidithiobacillus ferrivorans PQ33 provides psychrotolerant fitness evidence for oxidation at low temperature.
Friendly environmental hydrometallurgy at low temperatures is principally promoted by Acidithiobacillus ferrivorans. Until recently, the synergy between cold tolerance and the molecular mechanism of ferrous iron (Fe2+) oxidation was unknown. In the present paper, we conducted a physiological and comparative genomics analysis of the new strain A. ferrivorans PQ33 to elucidate the oxidation mechanism at low temperatures, with emphasis placed on trehalose and the Rus operon. PQ33 exhibited a doubling time of 66.6 h in Fe2+ at pH 1.6 and 63.6 h in CuS at 5 °C. Genomic island (GI) identification and comparative genome analysis were performed with four available genomes of Acidithiobacillus sp. The genome comprised 3,298,172 bp and 56.55% GC content. In contrast to ATCC Acidithiobacillus ferrooxidans strains, the genome of A. ferrivorans PQ33 harbors one GI, which contains a RusB gene. Moreover, five genes of peptidyl-prolyl cis-trans isomerase (PPIases) were observed. Furthermore, comparative analysis of the trehalose operon suggested the presence of a horizontal transfer event. In addition, comparison of rusticyanin proteins revealed that RusB has better intrinsic flexibility than RusA. This comparison suggests psychrotolerant fitness and supports the genetic canalization of A. ferrivorans PQ33 for oxidation at low temperature.


Relation between coagulation/fibrinolysis and lactate in the course of human septic shock.
The pathogenic role of disseminated intravascular coagulation (DIC) during septic shock is incompletely understood. To study the relation between indicators of DIC and lactate concentrations over time to evaluate whether a coagulation/fibrinolysis imbalance could directly contribute to tissue hypoxygenation. 14 consecutive septic shock patients with a pulmonary artery catheter in place were prospectively studied. For 3 days after admission, haemodynamic variables and plasma concentrations of lactate, thrombin-antithrombin complexes, tissue plasminogen activator, plasminogen activator inhibitor (PAI), plasmin-α2-antiplasmin complexes, fibrinogen, and the inflammatory mediators tumour necrosis factor-α and interleukin-6, as well as activated partial thromboplastin time (aPTT), prothrombin time (PT) and platelet counts were serially measured. Eight of the 14 patients died in the intensive care unit. All patients had a hyperdynamic circulation with an increased cardiac index and mild hyperlactataemia. They had prolonged PT, thrombocytopenia and raised inflammatory, coagulation and fibrinolysis variables. The time course of PAI best predicted the time course of lactate, independently of haemodynamics, inflammatory mediators, PT, fibrinogen and platelet counts. High lactate, PAI and PT concentrations persisted in non-survivors compared with survivors. The course of human septic shock, particularly inhibition of activated fibrinolysis during DIC, may be independently associated with hyperlactataemia; therefore a coagulation/fibrinolysis imbalance may contribute to tissue hypoxygenation and ultimately thereby to demise.


Relationship between Plasma Homocysteine Level and Glaucomatous Retinal Nerve Fiber Layer Defect.
To investigate the association between plasma homocysteine levels and glaucomatous retinal nerve fiber layer (RNFL) defect in South Korean population. This retrospective cross-sectional study included subjects who underwent screening at Kangbuk Samsung Hospital Health Screening Center between August 2012 and July 2013. Subjects underwent physical examination and provided samples for laboratory analysis of homocysteine. Subjects were divided equally into four quartiles (Qs) based on plasma homocysteine level. Digital fundus photographs of both eyes were obtained. Determination of glaucomatous disc appearance was based on criteria set forth by the International Society of Geographical and Epidemiological Ophthalmology and based on the appearance of the RNFL and optic disc. Multivariate logistic regression models were used to define elevated glaucoma risk with P < 0.2 on univariate analysis. A total of 78,049 subjects were included; 76,093 subjects were male, and 1956 subjects were female. When analyzed by gender, the mean homocysteine level in the male group with glaucomatous RNFL defects (11.05 ± 3.80 µmol/L) was higher than those without RNFL defects (10.81 ± 4.12 µmol/L (P = 0.000, χ2 test). Upon multifactorial logistic regression analysis adjusted for age, gender, creatinine, diabetes mellitus, hypertension, and hyperlipidemia, glaucomatous RNFL defects had a significant correlation with plasma homocysteine level. Based on the Q2 level, the odds ratio (OR) of Q3 was 1.267, while the OR of Q4 was 1.285 (95% CI = 1.067-1.505, 1.081-1.529, respectively, P for trend = 0.001). Our results suggest that homocysteine level is associated with the presence of glaucomatous RNFL defects.


The role of the GluR-A (GluR1) AMPA receptor subunit in learning and memory.
It is widely believed that synaptic plasticity may provide the neural mechanism that underlies certain kinds of learning and memory in the mammalian brain. The expression of long-term potentiation (LTP) in the hippocampus, an experimental model of synaptic plasticity, requires the GluR-A subunit of the AMPA subtype of glutamate receptor. Genetically modified mice lacking the GluR-A subunit show normal acquisition of the standard, fixed-location, hidden-platform watermaze task, a spatial reference memory task that requires the hippocampus. In contrast, these mice are dramatically impaired on hippocampus-dependent, spatial working memory tasks, in which the spatial response of the animal is dependent on information in short-term memory. Taken together, these results argue for two distinct and independent spatial information processing mechanisms: (i) a GluR-A-independent associative learning mechanism through which a particular spatial response is gradually or incrementally strengthened, and which presumably underlies the acquisition of the classic watermaze paradigm and (ii) a GluR-A-dependent, non-associative, short-term memory trace which determines performance on spatial working memory tasks. These results are discussed in terms of Wagner's SOP model (1981).


Cannabis and joints: scientific evidence for the alleviation of osteoarthritis pain by cannabinoids.
Cannabis has been used for millennia to treat a multitude of medical conditions including chronic pain. Osteoarthritis (OA) pain is one of the most common types of pain and patients often turn to medical cannabis to manage their symptoms. While the majority of these reports are anecdotal, there is a growing body of scientific evidence which supports the analgesic potential of cannabinoids to treat OA pain. OA pain manifests as a combination of inflammatory, nociceptive, and neuropathic pain, each requiring modality-specific analgesics. The body's innate endocannabinoid system (ECS) has been shown to ameliorate all of these pain subtypes. This review summarizes the components of the ECS and details the latest research pertaining to plant-based and man-made cannabinoids for the treatment of OA pain. Recent pre-clinical evidence supporting a role for the ECS to control OA pain is described as well as current clinical evidence of the efficacy of cannabinoids for treating OA pain in mixed patient populations.


Does Cervical Screening in Young Women Aged 20-25 Years Lead to Unnecessary and Harmful Interventions?
Cervical human papillomavirus (HPV) infection among young women (20-25 years of age) is common and normally transient. There are growing concerns that referral to a colposcopy clinic may lead to unnecessary treatment with an increased risk of obstetric complications. Therefore, the purpose of this study was to determine the level of intervention for cervical abnormalities in this age group of the Northern Ireland population. A review of all serial new patients under 25 years of age, who were referred to colposcopy clinics in Northern Ireland between January 1, 2009 to June 30, 2009 formed the basis of this study. During the study period, a total of 4,767 women under 25 years of age were screened. Two-hundred-and- thirty-four (4.9%) cases were referred to the colposcopy clinics. The cervical cytology results were: high-grade abnormality in 35%, and low-grade abnormality in 31% of these cases. One-hundred-and-seventy-eight (76%) of the referred women received at least one treatment. One-hundred-and-twenty-one of 234 (51.5%) women underwent an excisional treatment with histology showing the presence of high-grade abnormalities (CIN2-3) in 52%, CIN1 in 28%, and Koilocytosis or normal tissue in 20% of this sub-group of cases. Screening women under the age of 25 years cause unnecessary referral for colposcopy. This may also result in considerable anxiety and psychosexual morbidity. It leads to an over-treatment with a potential of negative impact on the future pregnancy outcomes (including pre-term delivery, low birth weight, and pre-term premature rupture of membranes).


Effects of Beet necrotic yellow vein virus in Spinach Cultivars.
Beet necrotic yellow vein virus (BNYVV) causes one of the most economically destructive diseases of sugar beet (Beta vulgaris), rhizomania, which may reduce sugar yield by 80%. This field investigation was conducted to evaluate the interactions between spinach genotypes and different BNYVV strains, and to determine whether BNYVV is transmitted through spinach seeds. Eight commercial spinach cultivars were planted in two BNYVV-infested fields and two control fields in Salinas, CA in 2009. Spinach plants in the BNYVV-infested fields showed disease symptoms of yellow-green or light-green vein clearing, mottling, or yellow-green chlorotic lesions on younger leaves as early as 28 days after planting (four- to six-true leaf stage). Leaves may also become stiff, more crinkled, and necrotic. There was an increase of lateral roots and leaf number but a decrease in leaf weight compared to healthy plants. Infected plants often became stunted, deformed, wilted, and dead. Symptomatic leaves and roots from plants with or without leaf symptoms in BNYVV-infested fields all tested positive for BNYVV by enzyme-linked immunosorbent assay. A more aggressive (resistance-breaking) strain of BNYVV led to higher disease incidence in spinach than in the wild type. BNYVV was not transmitted through spinach seeds. There were significant differences in disease development among cultivars, with disease incidence ranging from 8 to 44%, suggesting that genetic improvement of BNYVV resistance through spinach breeding should be feasible.


Morphological, Physiological and Proteomic Analyses Provide Insights into the Improvement of Castor Bean Productivity of a Dwarf Variety in Comparing with a High-Stalk Variety.
Ricinus communis displays a broad range of phenotypic diversity in size, with dwarf, common, and large-sized varieties. To better understand the differences in plant productivity between a high-stalk variety and a dwarf variety under normal growth conditions, we carried out a comparative proteomic study between Zhebi 100 (a high stalk variety) and Zhebi 26 (a dwarf variety) combined with agronomic and physiological analyses. Over 1000 proteins were detected, 38 of which differed significantly between the two varieties and were identified by mass spectrometry. Compared with Zhebi 100, we found that photosynthesis, energy, and protein biosynthesis related proteins decreased in abundance in Zhebi 26. The lower yield of the dwarf castor is likely related to its lower photosynthetic rate, therefore we hypothesize that the lower yield of the dwarf castor, in comparing to high stalk castor, could be increased by increasing planting density. Consequently, we demonstrated that at the higher planting density in Zhebi 26 (36,000 seedlings/hm2) can achieve a higher yield than that of Zhebi 100 (12,000 seedlings/hm2). Proteomic and physiological studies showed that for developing dwarf R. communis cultivar that is suitable for large scale-production (i.e., mechanical harvesting), it is imperative to identify the optimum planting density that will contribute to higher leaf area index, higher photosynthesis, and eventually higher productivity.


Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain.
In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM. We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method. In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08). Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.


Propolis from the Stingless Bee Trigona incisa from East Kalimantan, Indonesia, Induces In Vitro Cytotoxicity and Apoptosis in Cancer Cell lines.
Previously, stingless bee (Trigona spp.) products from East Kalimantan, Indonesia, were successfully screened for in vitro antiproliferative activity against human cancer derived cell lines. It was established that propolis from T. incisa presented the highest in vitro cytotoxicity against the SW620 colon cancer cell line (6% cell survival in 20 μg/mL). Propolis from T. incisa was extracted with methanol and further partitioned with n-hexane, ethyl acetate and methanol. The in vitro cytotoxicity of the extracts was assessed by the MTT assay against human colon (SW620), liver (Hep-G2), gastric (KATO-III), lung (Chago) and breast (BT474) cancer derived cell lines. The active fractions were further enriched by silica gel quick column, absorption and size exclusion chromatography. The purity of each fraction was checked by thin layer chromatography. Cytotoxicity in BT-474 cells induced by cardanol compared to doxorubicin were evaluated by MTT assay, induction of cell cycle arrest and cell death by flow cytometric analysis of propidium iodide and annexin-V stained cells. A cardol isomer was found to be the major compound in one active fraction (F45) of T. incisa propolis, with a cytotoxicity against the SW620 (IC50 of 4.51±0.76 μg/mL), KATO-III (IC50 of 6.06±0.39 μg/mL), Hep-G2 (IC50 of 0.71±0.22 μg/mL), Chago I (IC50 of 0.81±0.18 μg/mL) and BT474 (IC50 of 4.28±0.14 μg/mL) cell lines. Early apoptosis (programmed cell death) of SW620 cells was induced by the cardol containing F45 fraction at the IC50 and IC80 concentrations, respectively, within 2-6 h of incubation. In addition, the F45 fraction induced cell cycle arrest at the G1 subphase. Indonesian stingless bee (T. incisa) propolis had moderately potent in vitro anticancer activity on human cancer derived cell lines. Cardol or 5-pentadecyl resorcinol was identified as a major active compound and induced apoptosis in SW620 cells in an early period (≤6 h) and cell cycle arrest at the G1 subphase. Thus, cardol is a potential candidate for cancer chemotherapy.


The role of magnetic resonance imaging in the diagnostic evaluation of malignant peripheral nerve sheath tumors.
Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of mortality in patients with neurofibromatosis type-1 (NF1)); however, they may also arise sporadically. Differences in magnetic resonance imaging (MRI) features between MPNSTs arising in NF1 subjects versus non-NF1 subjects have not been studied before. The accuracy of MRI in distinguishing MPNSTs from benign peripheral nerve sheath tumors (BPNSTs) has also been debated. The objective of this study was to determine the potential differentiating MRI features between (a) NF1-related and non-NF1-related MPNSTs and (b) MPNSTs and BPNSTs. We retrospectively evaluated the MRI studies of 21 patients (12 NF1 subjects and nine non-NF1 subjects) with MPNSTs and 35 patients with BPNSTs. In all studies, the lesions were assessed in terms of size, margins, T1 and T2 signal characteristics, internal architecture, pattern of contrast enhancement, invasion of adjacent structures and necrosis/cystic degeneration as well as for the presence of tail-, target- and split-fat signs. MPNSTs of NF1 subjects occurred at an earlier age and displayed a higher incidence of necrosis/cystic degeneration compared with MPNSTs of non-NF1 subjects. Compared with BPNSTs, MPNSTs were significantly larger at the time of diagnosis and demonstrated a higher incidence of ill-defined margins (specificity 91%, sensitivity 52%) and invasion of adjacent structures (specificity 100%, sensitivity 43%). Differences exist between NF1-related and non-NF1-related MPNSTs regarding the age of occurrence and MRI appearance. In the MRI evaluation of peripheral nerve sheath tumors, the presence of ill-defined tumor margins and/or invasion of adjacent structures are highly specific for malignancy.


Kinetics of azoreductase and assessment of toxicity of metabolic products from azo dyes by Pseudomonas luteola.
This is a continuous study on a decolorization strain, Pseudomonas luteola, which involves treating seven azo dyes with different structures. This study focuses mainly on determining both the mechanism of decolorization by P. luteola and the activity of azoreductase from P. luteola as well as identifying and assessing the toxicity of metabolic products of azo dyes. The growth of P. luteola reached the stationary phase after shaking incubation for 24 hours. Then, while being kept static, the color of seven tested azo dyes (100 mg/l) could be removed. The proportion of color removal was between 59-99%, which figure is related to the structure of the dye. Monoazo dyes (RP2B, V2RP and Red 22) showed the fastest rate of decolorization, i.e. from 0.23-0.44 mg dye-mg cell-1 hr-1. P. luteola could remove the color of V2RP and a leather dye at a concentration of 200 mg/l, and as to the rest of the azo dyes, it could remove at a concentration of up to 100 mg/l. Decolorization of RP2B and Red 22 required activation energy of 7.00 J/mol and 6.63 J/mole, respectively, indicating that it was easier for azoreductase to decolorize structurally simple dyes. The kinetics of azoreductase towards seven azo dyes suggested a competitive inhibition model be applied. Microtox was used to analyze the toxicity of the metabolic products of azo dyes. EC50 showed differences in toxicity before and after the azo dyes had been metabolized. Analysis revealed significant differences between the results obtained by EC50 with Blue 15 and those obtained with the leather dye, indicating that the toxicities of the metabolic products were increased. The differences obtained by EC50 with Red 22, RP2P and V2RP were small, and Black 22 showed no such difference. Sulfanic acid and orthanilic acid may be the intermediate products of Violet 9 and RP2B, respectively. However, according to FT-IR analysis, aromatic amines were present in the metabolic product.


New production techniques for alberta oil sands.
Low world oil prices represent a serious threat to expanded commercial development of the Canadian oil sands in the near term, as they do to all of the higher cost alternatives to crude oil such as oil shales and coal liquefaction. Nonetheless, research and field testing of new technology for production of oil from oil sands are being pursued by industry and government in Alberta. New production technology is being developed in Canada to produce synthetic oil from the vast resources of bitumen trapped in the oil sands and bituminous carbonates of northern Alberta. This technology includes improved methods of mining, extraction, and upgrading of bitumen from near-surface deposits as well as new drilling and production techniques for thermal production of bitumen from the more deeply buried reservoirs. Of particular interest are the cluster drilling methods designed to reduce surface disturbance and the techniques for horizontal drilling of wells from underground tunnels to increase the contact of injection fluids with the reservoir.


PG545, an angiogenesis and heparanase inhibitor, reduces primary tumor growth and metastasis in experimental pancreatic cancer.
Aggressive tumor progression, metastasis, and resistance to conventional therapies lead to an extremely poor prognosis for pancreatic ductal adenocarcinoma (PDAC). Heparanase, an enzyme expressed by multiple cell types, including tumor cells in the tumor microenvironment, has been implicated in angiogenesis and metastasis, and its expression correlates with decreased overall survival in PDAC. We evaluated the therapeutic potential of PG545, an angiogenesis and heparanase inhibitor, in experimental PDAC. PG545 inhibited the proliferation, migration, and colony formation of pancreatic cancer cells in vitro at pharmacologically relevant concentrations. Heparanase inhibition also reduced the proliferation of fibroblasts but had only modest effects on endothelial cells in vitro. Furthermore, PG545 significantly prolonged animal survival in intraperitoneal and genetic models (mPDAC: LSL-Kras(G12D); Cdkn2a(lox/lox); p48(Cre)) of PDAC. PG545 also inhibited primary tumor growth and metastasis in orthotopic and genetic endpoint studies. Analysis of tumor tissue revealed that PG545 significantly decreased cell proliferation, increased apoptosis, reduced microvessel density, disrupted vascular function, and elevated intratumoral hypoxia. Elevated hypoxia is a known driver of collagen deposition and tumor progression; however, tumors from PG545-treated animals displayed reduced collagen deposition and a greater degree of differentiation compared with control or gemcitabine-treated tumors. These results highlight the potent antitumor activity of PG545 and support the further exploration of heparanase inhibitors as a potential clinical strategy for the treatment of PDAC.


Equating quantitative emphysema measurements on different CT image reconstructions.
To mathematically model the relationship between CT measurements of emphysema obtained from images reconstructed using different section thicknesses and kernels and to evaluate the accuracy of the models for converting measurements to those of a reference reconstruction. CT raw data from the lung cancer screening examinations of 138 heavy smokers were reconstructed at 15 different combinations of section thickness and kernel. An emphysema index was quantified as the percentage of the lung with attenuation below -950 HU (EI950). Linear, quadratic, and power functions were used to model the relationship between EI950 values obtained with a reference 1 mm, medium smooth kernel reconstruction and values from each of the other 14 reconstructions. Preferred models were selected using the corrected Akaike information criterion (AICc), coefficients of determination (R2), and residuals (conversion errors), and cross-validated by a jackknife approach using the leave-one-out method. The preferred models were power functions, with model R2 values ranging from 0.949 to 0.998. The errors in converting EI950 measurements from other reconstructions to the 1 mm, medium smooth kernel reconstruction in leave-one-out testing were less than 3.0 index percentage points for all reconstructions, and less than 1.0 index percentage point for five reconstructions. Conversion errors were related in part to image noise, emphysema distribution, and attenuation histogram parameters. Conversion inaccuracy related to increased kernel sharpness tended to be reduced by increased section thickness. Image reconstruction-related differences in quantitative emphysema measurements were successfully modeled using power functions.


Effect of injectable alginate implant on cardiac remodeling and function after recent and old infarcts in rat.
Adverse cardiac remodeling and progression of heart failure after myocardial infarction are associated with excessive and continuous damage to the extracellular matrix. We hypothesized that injection of in situ-forming alginate hydrogel into recent and old infarcts would provide a temporary scaffold and attenuate adverse cardiac remodeling and dysfunction. We developed a novel absorbable biomaterial composed of calcium-crosslinked alginate solution, which displays low viscosity and, after injection into the infarct, undergoes phase transition into hydrogel. To determine the outcome of the biomaterial after injection, calcium-crosslinked biotin-labeled alginate was injected into the infarct 7 days after anterior myocardial infarction in rat. Serial histology studies showed in situ formation of alginate hydrogel implant, which occupied up to 50% of the scar area. The biomaterial was replaced by connective tissue within 6 weeks. Serial echocardiography studies before and 60 days after injection showed that injection of alginate biomaterial into recent (7 days) infarct increased scar thickness and attenuated left ventricular systolic and diastolic dilatation and dysfunction. These beneficial effects were comparable and sometimes superior to those achieved by neonatal cardiomyocyte transplantation. Moreover, injection of alginate biomaterial into old myocardial infarction (60 days) increased scar thickness and improved systolic and diastolic dysfunction. We show for the first time that injection of in situ-forming, bioabsorbable alginate hydrogel is an effective acellular strategy that prevents adverse cardiac remodeling and dysfunction in recent and old myocardial infarctions in rat.


Factors associated with wearing inadequate outdoor footwear in populations at risk of foot ulceration: A cross-sectional study.
Few studies have investigated if people at risk of foot ulceration actually wear the footwear recommended by best practice guidelines to prevent foot ulceration. This study aimed to investigate the prevalence of, and factors associated with, wearing inadequate outdoor footwear in those with diabetes or peripheral neuropathy in an inpatient population. This was a secondary analysis of a multi-site cross-sectional study investigating foot conditions in a large representative inpatient population admitted into hospital for any medical reason on one day. A range of explanatory variables were collected from all participants including sociodemographic, medical and foot condition factors. The outcome variable for this study was the self-reported outdoor footwear type worn most by participants outside the house in the year prior to hospitalisation. The self-reported footwear type was then categorised into adequate and inadequate according to footwear features recommended in guidelines for populations at risk of foot ulceration. Logistic regression identified factors independently associated with inadequate footwear in all inpatient participants, and diabetes and neuropathy subgroups. Overall, 47% of a total of 726 inpatients wore inadequate outdoor footwear; 49% of the 171 in the diabetes subgroup and 43% of 159 in the neuropathy subgroup. Wearing inadequate outdoor footwear was independently associated (Odds Ratio (95% Confidence Interval)) with being female in the diabetes (2.7 (1.4-5.2)) and neuropathy subgroups (3.7 (1.8-7.9)) and being female (5.1 (3.7-7.1)), having critical peripheral arterial disease (2.5 (1.1-5.9)) and an amputation (0.3 (0.1-0.7)) in all inpatients (all, p<0.05). Almost half of all inpatients at risk of foot ulceration reported wearing outdoor footwear most of the time that did not meet recommendations for prevention. We found women were much more likely to wear inadequate footwear. More work needs to be done to increase the uptake of footwear recommendations in these populations to prevent foot ulceration.


Reversal of diuretic-induced hepatic encephalopathy with infusion of albumin but not colloid.
In patients with cirrhosis, dehydration induced by diuretics is a common precipitant of hepatic encephalopathy (HE), which may respond to volume expansion. The mechanism of HE in this situation is not fully understood. The present study evaluates the effect of plasma volume expansion on the severity of HE, plasma and urinary ammonia in patients with diuretic-induced HE. Fifteen patients with alcoholic cirrhosis and diuretic-induced HE of Grade 2 or more were enrolled. In eight patients, 4.5% human albumin solution (HAS) was used for volume expansion and in seven patients colloid (Gelofusine) was used. Significant improvement of HE Grade was observed at 24 h and was sustained at 72 h ( P <0.05) only in the group treated with HAS. There were similar and statistically significant reductions in plasma ammonia concentration, plasma renin activity and angiotensin II and an increase in mean arterial pressure, renal plasma flow and urinary ammonia excretion in both groups. Plasma malondialdehyde was elevated in both groups, but was reduced significantly only in the group treated with HAS. The findings of the present study show that plasma volume expansion results in significant reduction in plasma ammonia concentration, possibly through an increase in urinary ammonia excretion. This reduction in ammonia concentration translates into an improvement in mental state only in those patients treated with HAS in whom concomitant reduction in oxidative stress was observed. These data support the notion that other factors, such as oxidative stress, act as adjuncts to ammonia in the pathogenesis of diuretic-induced HE and suggest a possible role for albumin infusion in its treatment.


Attention/memory complaint is correlated with motor speech disorder in Parkinson's disease.
The mechanisms underlying the online modulation of motor speech in Parkinson's disease (PD) have not been determined. Moreover, medical and rehabilitation interventions for PD-associated motor speech disorder (MSD) have a poor long-term prognosis. To compare risk factors in PD patients with MSD to those without MSD (non-MSD) and determine predictive independent risk factors correlated with the MSD phenotype, we enrolled 314 PD patients, including 250 with and 64 without MSD. We compared demographic, characteristic data, as well as PD-associated evaluations between the MSD group and non-MSD group. Univariate analysis showed that demographic characteristics, including occupation, educational level, monthly income and speaking background; clinical characteristics, including lesions in the frontal and temporal lobes, and concurrent dysphagia; and PD-associated evaluations, including the activity of daily living (ADL) score, non-motor symptoms scale (NMSS) domain 4 score (perceptual problem), and NMSS domain 5 score (attention/memory) were all significantly different between the MSD and non-MSD group (all P < 0.05). Multivariate logistic regression analysis showed that educational level, frontal lesions, and NMSS domain 5 score (attention/memory) were independent risk factors for PD-associated MSD (all P < 0.005). We determined an association between MSD phenotype and cognitive impairment, reflected by low-level education and related clinical profiles. Moreover, attention and memory dysfunction may play key roles in the progression of MSD in PD patients. Further studies are required to detail the mechanism underlying abnormal speech motor modulation in PD patients. Early cognitive intervention may enhance rehabilitation management and motor speech function in patients with PD-associated MSD.


Compromised maturation of GABAergic inhibition underlies abnormal network activity in the hippocampus of epileptic Ca2+ channel mutant mice, tottering.
Cholinergically induced network activity is a useful analogue of theta rhythms involved in memory processing or epileptiform activity in the hippocampus, providing a powerful tool to elucidate the mechanisms of synchrony in neuronal networks. In absence epilepsy, although its association with cognitive impairments has been reported, the mechanisms underlying hippocampal synchrony remain poorly investigated. Here we simultaneously recorded electrical activities from 64 sites in hippocampal slices of CaV2.1 Ca(2+) channel mutant tottering (tg) mice, a well-established mouse model of spontaneous absence epilepsy, to analyze the spatiotemporal pattern of cholinergically induced hippocampal network activity. The cholinergic agonist carbachol induced oscillatory discharges originating from the CA3 region. In tg/tg mice, this hippocampal network activity was characterized by enhanced occupancy of discharges of relatively high frequency (6-10 Hz) compared to the wild type. Pharmacological analyses of slices, patch clamp electrophysiological characterization of isolated neurons, and altered patterns of hippocampal GABAA receptor subunit and Cl(-) transporter messenger RNA (mRNA) transcript levels revealed that this abnormality is attributable to a developmental retardation of GABAergic inhibition caused by immature intracellular Cl(-) regulation. These results suggest that the inherited CaV2.1 Ca(2+) channel mutation leads to developmental abnormalities in Cl(-) transporter expression and GABAA receptor compositions in hippocampal neurons and that compromised maturation of GABAergic inhibition contributes to the abnormal synchrony in the hippocampus of tg absence epileptic mice.


Gut Microbiota in the First 2 Years of Life and the Association with Body Mass Index at Age 12 in a Norwegian Birth Cohort.
Childhood obesity is a growing problem worldwide. Recent research suggests that the gut microbiota may play an important and potentially causal role in the development of obesity and may be one mechanism that explains the transgenerational transmission of obesity risk. Here we examine the early-life gut microbiota at days 4, 10, 30, 120, 365, and 730 and the association with body mass index (BMI) z-scores at age 12 in a Norwegian prospective cohort (n = 165), and evaluate how these BMI-associated taxa relate to maternal overweight/obesity (Ow/Ob) and excessive gestational weight gain (GWG). We performed 16S rRNA gene sequencing on the gut microbiota samples. Taxonomic phylogeny at days 10 and 730 was significantly associated with childhood BMI, and the gut microbiota taxa at two years of age explained over 50% of the variation in childhood BMI in this cohort. The subset of the early-life taxa within the gut microbiota that best predicted later childhood BMI showed substantial overlap with the maternal taxa most strongly associated with maternal Ow/Ob and excessive GWG. Our results show an association between the infant gut microbiota and later BMI, and they offer preliminary evidence that the infant gut microbiota, particularly at 2 years of age, may have potential to help identify children at risk for obesity.IMPORTANCE Understanding the role of the early-life gut microbiota in obesity is important because there may be opportunities for preventive strategies. We examined the relationships between infant gut microbiota at six times during the first two years of life and BMI at age 12 in a birth cohort of 165 children and their mothers. We found that the gut microbiota from early life to two years shows an increasingly strong association with childhood BMI. This study provides preliminary evidence that the gut microbiome at 2 years of age may offer useful information to help to identify youth who are at risk for obesity, which could facilitate more-targeted early prevention efforts.


Primary obturator internus and obturator externus pyomyositis.
Pyomyositis is a rare condition in immune competent patients and is usually seen in tropical countries. Pyomyositis of obturator muscles in particular is an extremely rare condition, which causes hip pain and mimics septic arthritis. This is a case report of a 9-year-old boy without an underlying disease or a compromised immune system, who presented with knee pain that progressed to hip pain and inability to bear weight. He was diagnosed initially with septic arthritis of the hip and underwent unnecessary hip exploration surgery. Magnetic resonance imaging scan was performed postoperatively and showed pyomyositis of obturator internus and obturator externus muscles. He was managed medically and had a good outcome. A greater awareness of this emergency condition is necessary to prevent misdiagnosis, unnecessary surgical intervention, and to avoid the devastating possible complications of delayed diagnosis.


The effectiveness of lumbar interlaminar epidural injections in managing chronic low back and lower extremity pain.
Intervertebral disc herniation, spinal stenosis, intervertebral disc degeneration without disc herniation, and post lumbar surgery syndrome are the most common diagnoses of chronic persistent low back and lower extremity symptoms, resulting in significant economic, societal, and health care impact. Epidural injections are one of the most commonly performed interventions in the United States in managing chronic low back pain. However the evidence is highly variable among different techniques utilized - namely interlaminar, caudal, and transforaminal - and for various conditions, namely - intervertebral disc herniation, spinal stenosis, and discogenic pain without disc herniation or radiculitis. Multiple systematic reviews conducted in the evaluation of the effectiveness of interlaminar epidural injections have been marred with controversy. Consequently, the debate continues with regards to the effectiveness, indications, and medical necessity of interlaminar epidural injections. A systematic review of lumbar interlaminar epidural injections with or without steroids. To evaluate the effect of lumbar interlaminar epidural injections with or without steroids in managing various types of chronic low back and lower extremity pain emanating as a result of disc herniation or radiculitis, spinal stenosis, and chronic discogenic pain. The available literature on lumbar interlaminar epidural injections with or without steroids in managing various types of chronic low back pain with or without lower extremity pain was reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria as utilized for interventional techniques for randomized trials and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, or limited based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to December 2011, and manual searches of the bibliographies of known primary and review articles. The primary outcome measure was pain relief (short-term relief = up to 6 months and long-term > 6 months). Secondary outcome measures were improvement in functional status, psychological status, return to work, and reduction in opioid intake. Overall, 82 lumbar interlaminar trials were identified. All non-randomized studies without fluoroscopy and randomized trials not meeting the inclusion criteria were excluded. Overall, 15 randomized trials and 11 non-randomized studies were included in the analysis. Analysis was derived mainly from fluoroscopically-guided randomized trials and non-randomized studies. The evidence is good for radiculitis secondary to disc herniation with local anesthetics and steroids, fair with local anesthetic only; whereas it is fair for radiculitis secondary to spinal stenosis with local anesthetic and steroids, and fair for axial pain without disc herniation with local anesthetic with or without steroids, with fluoroscopically-guided epidural injections. The limitations of this study include that we were unable to perform meta-analysis for disc herniation, and the paucity of evidence for discogenic pain and spinal stenosis. Further, methodological criteria have been highly variable along with sample sizes. The studies were heterogenous. The evidence based on this systematic review is good for lumbar epidural injections under fluoroscopy for radiculitis secondary to disc herniation with local anesthetic and steroids, fair with local anesthetic only; whereas it is fair for radiculitis secondary to spinal stenosis with local anesthetic and steroids, and fair for axial pain without disc herniation with local anesthetic with or without steroids.


Prevalence of multidrug-resistant organisms in refugee patients, medical tourists and domestic patients admitted to a German university hospital.
Patients with contact to healthcare-system in high-prevalence countries (HPC) and refugee patients in hospital settings (REF) have previously been identified to be at risk of carrying multidrug-resistant organisms (MDRO). Comparative studies addressing the epidemiology of MDRO in patients transferred from hospitals abroad (ABROAD) and REF are lacking but are necessary to introduce refined infection control measures. From December 2015 to June 2016, 117 REF, 84 ABROAD and 495 patients admitted to intensive care unit, with no refugee history or pre-treatment abroad (ICU), at University Hospital Frankfurt, Germany (UHF) were screened for MDRO on day of admittance. Data within these groups were compared and set in an epidemiological context. 52.1% (95% confidence interval = 42.7-61.5) of REF and 41.6% (31.0-52.9) of ABROAD, were positive for at least one MDRGN, respectively. In contrast, 7.9% (5.6-10.6) of ICU were positive for MDRGN. Thereof, 0.9% (0.0-4.7) of REF, 15.5% (8.5-25.0) of ABROAD and 0% (0.0-0.7) of ICU were positive for at least one MDRGN with carbapenem resistance (CR). In total, 19 MDRGN with CR were detected in ABROAD, with the most frequent species with CR being A. baumannii with 42.1% (20.3-66.5). Regarding MRSA, 10.3% (5.4-17.2) of REF, 5.9% (1.9-13.3) of ABROAD and a significantly lower proportion 1.4% (0.6-2.9) of ICU, respectively, were tested positive. Both REF and ABROAD pose a relevant hospital hygiene risk. High prevalence of MDRGN with CR in ABROAD was observed. Concise screening and infection control guidelines are needed in patient cohorts with increased risk for MDRO carriage.


Delayed luminescence induced by complex domains in water and in TEOS aqueous solutions.
Many recent studies on water have conjectured a complex structure composed of hydrogen bonded low- and high-density domains. In this work the structure of pure water and aqueous solutions of silica gel (TEOS) has been investigated by using delayed luminescence, which has previously shown a significant increase in aqueous salt solutions where low-density domain formation is expected. Photon emission shows an Arrhenius trend with an activation energy in water-TEOS solutions larger than in pure water and salt-water solutions. Moreover, delayed photon emission decay shows an intrinsic lifetime of about 5 μs both in solutions and in pure water that, along with secondary lifetimes induced by the presence of TEOS, could be related to the formation of different domains.