Releasing dentate nucleus cells from Purkinje cell inhibition generates output from the cerebrocerebellum.
The cerebellum generates its vast amount of output to the cerebral cortex through the dentate nucleus (DN) that is essential for precise limb movements in primates. Nuclear cells in DN generate burst activity prior to limb movement, and inactivation of DN results in cerebellar ataxia. The question is how DN cells become active under intensive inhibitory drive from Purkinje cells (PCs). There are two excitatory inputs to DN, mossy fiber and climbing fiber collaterals, but neither of them appears to have sufficient strength for generation of burst activity in DN. Therefore, we can assume two possible mechanisms: post-inhibitory rebound excitation and disinhibition. If rebound excitation works, phasic excitation of PCs and a concomitant inhibition of DN cells should precede the excitation of DN cells. On the other hand, if disinhibition plays a primary role, phasic suppression of PCs and activation of DN cells should be observed at the same timing. To examine these two hypotheses, we compared the activity patterns of PCs in the cerebrocerebellum and DN cells during step-tracking wrist movements in three Japanese monkeys. As a result, we found that the majority of wrist-movement-related PCs were suppressed prior to movement onset and the majority of wrist-movement-related DN cells showed concurrent burst activity without prior suppression. In a minority of PCs and DN cells, movement-related increases and decreases in activity, respectively, developed later. These activity patterns suggest that the initial burst activity in DN cells is generated by reduced inhibition from PCs, i.e., by disinhibition. Our results indicate that suppression of PCs, which has been considered secondary to facilitation, plays the primary role in generating outputs from DN. Our findings provide a new perspective on the mechanisms used by PCs to influence limb motor control and on the plastic changes that underlie motor learning in the cerebrocerebellum.


Expression of CRM1 and CDK5 shows high prognostic accuracy for gastric cancer.
To evaluate the predictive value of the expression of chromosomal maintenance (CRM)1 and cyclin-dependent kinase (CDK)5 in gastric cancer (GC) patients after gastrectomy. A total of 240 GC patients who received standard gastrectomy were enrolled in the study. The expression level of CRM1 and CDK5 was detected by immunohistochemistry. The correlations between CRM1 and CDK5 expression and clinicopathological factors were explored. Univariate and multivariate survival analyses were used to identify prognostic factors for GC. Receiver operating characteristic analysis was used to compare the accuracy of the prediction of clinical outcome by the parameters. The expression of CRM1 was significantly related to size of primary tumor (P = 0.005), Borrmann type (P = 0.006), degree of differentiation (P = 0.004), depth of invasion (P = 0.008), lymph node metastasis (P = 0.013), TNM stage (P = 0.002) and distant metastasis (P = 0.015). The expression of CDK5 was significantly related to sex (P = 0.048) and Lauren's classification (P = 0.011). Multivariate Cox regression analysis identified that CRM1 and CDK5 co-expression status was an independent prognostic factor for overall survival (OS) of patients with GC. Integration of CRM1 and CDK5 expression could provide additional prognostic value for OS compared with CRM1 or CDK5 expression alone (P = 0.001). CRM1 and CDK5 co-expression was an independent prognostic factors for GC. Combined CRM1 and CDK5 expression could provide a prognostic model for OS of GC.


Nonhost resistance of Arabidopsis thaliana against Alternaria alternata involves both pre- and postinvasive defenses but is collapsed by AAL-toxin in the absence of LOH2.
The tomato pathotype of Alternaria alternata causes Alternaria stem canker on tomato depending upon the production of the host-specific AAL-toxin. Host defense mechanisms to A. alternata, however, are largely unknown. Here, we elucidate some of the mechanisms of nonhost resistance to A. alternata using Arabidopsis mutants. Wild-type Arabidopsis showed either no symptoms or a hypersensitive reaction (HR) when inoculated with both strains of AAL-toxin-producing and non-producing A. alternata. Yet, when these Arabidopsis penetration (pen) mutants, pen2 and pen3, were challenged with both strains of A. alternata, fungal penetration was possible. However, further fungal development and conidiation were limited on these pen mutants by postinvasion defense with HR-like cell death. Meanwhile, only AAL-toxin-producing A. alternata could invade lag one homologue (loh)2 mutants, which have a defect in the AAL-toxin resistance gene, subsequently allowing the fungus to complete its life cycle. Thus, the nonhost resistance of Arabidopsis thaliana to A. alternata consists of multilayered defense systems that include pre-invasion resistance via PEN2 and PEN3 and postinvasion resistance. However, our study also indicates that the pathogen is able to completely overcome the multilayered nonhost resistance if the plant is sensitive to the AAL-toxin, which is an effector of the toxin-dependent necrotrophic pathogen A. alternata.


Spontaneous tachyarrhythmias after cholinergic suppression in the isolated perfused canine right atrium.
Atrial fibrillation occurs spontaneously after bradycardia induced by acetylcholine infusion or vagal stimulation. To determine the mechanism of initiation of this tachyarrhythmia, we infused acetylcholine (5 ml, 10(-3.5) M) into Krebs-Henseleit-perfused isolated canine right atria (n = 10). Unipolar electrograms were recorded from 250 sites simultaneously during control rhythms, pacing (cycle length = 300 msec) with and without acetylcholine, and recovery of spontaneous activity. Activation sequence maps were constructed from each recording. Stable spontaneous rhythm was present in all preparations during control conditions. Activation sequence maps, recorded during continuous pacing with and without acetylcholine, demonstrated no dromotropic changes due to the acetylcholine. Focal asynchronous recovery of spontaneous activity was initiated from different sites, resulting in bigeminal or trigeminal premature depolarizations in 41 of 73 cases after infusion of acetylcholine. A reentrant tachyarrhythmia was initiated in 24 of 41 cases by the closely coupled recovery beats (A1A2 = 100 +/- 37 msec; A2A3 = 97 +/- 27 msec). The reentry was initiated by interaction of the premature impulse with regions of functional block that were a result of the cholinergically induced dispersion of refractoriness. All the tachyarrhythmias terminated spontaneously, and stable spontaneous control rhythms returned. In conclusion, the data suggest that the premature depolarizations that initiate the reentrant tachyarrhythmia are caused by the asynchronous recovery of multiple right atrial pacemakers accompanied by variable entrance block at the later depolarizing sites.


Colon-targeted oral drug delivery systems: design trends and approaches.
Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.


Autoimmune manifestations of infections.
To provide an update about the interactions between infections and autoimmune diseases (AIDs), from the molecular perspective to the clinical spectrum and the differentiation between infection and disease activity. Any kind of infection may modify the innate and adaptive immune response through the following mechanisms: molecular mimicry, superantigens, epitope spreading and B-cell activation. The consequence is the overproduction of antibodies shared with those found in AIDs. Viral infections, especially HIV and hepatitis C virus, can stimulate the production of antiphospholipid antibodies and confer an increased risk to develop antiphospholipid syndrome. The identification of risk factors to develop infections in patients with AIDs is remarkable to prevent them. These factors are the use of steroids and immunosuppressants, the involvement of a major organ (lungs, brain and kidney) and severe activity. Biomarkers to differentiate infection from disease activity are scarce, but the combination of procalcitonine and C-reactive protein seems to have higher specificity and sensibility to identify infections in patients with AIDs. Finally, the clinical judgment is the hallmark to differentiate between infections and disease activity.


[Space-time distribution of individual cat EEG theta-oscillations in biologically different situations].
A study was made of statistical properties of temporal sequences of single oscillations in theta-range arising on EEG of different areas of the cat brain in two experimental situations: indifferent to the animal or biologically significant for it. EEG of eight structures in the left hemisphere were analysed in six cats: the caudate nucleus, the ventral and dorsal hippocampus, the mediodorsal nucleus of the thalamus, the lateral hypothalamus, the occipital, temporal and frontal cortical areas. It was found that the acquisition of biological significance by the acoustic stimulus is reflected in the distribution of single EEG-oscillations of the theta-range in the studied brain structures both directly before the acoustic stimulus (background) and in the process of the animal's performance of the experimental task. The temporal distribution of the above oscillations in each brain area separately also undergoes changes.


[Cannabidiol: its use in refractory epilepsies].
Some epileptic syndromes are characterised by seizures that are difficult to control and are associated to delayed neuropsychomotor development, which results in a deterioration in the patient's quality of life as well as in that of his or her family. To evaluate the use of cannabidiol as adjuvant therapy in patients with refractory epilepsies. An observational study was conducted by means of a survey addressed to the patient's caregiver. Data collected included information about the patient and the caregiver, changes observed in the seizures, neuropsychological effects, side effects and the family's overall perception following the use of cannabidiol. The evaluation examined 15 patients with refractory epilepsies, who received cannabidiol over a period ranging from one month to one year. The frequency of seizures decreased in 40% of the patients, 60% of the patients were seen to have control over 50% of their seizures and in 27% of them the seizures disappeared completely. Neurocognitive changes were also reported: behaviour improved in 73%; 60% reported an improvement in language; in 50% sleep improved; 43% reported improvements in eating habits; and 100% said their mood had improved. The overall perception of the illness was that there had been improvements in 73% of respondents. The most common side effects were drowsiness and fatigue. These results suggest a possible beneficial effect of cannabidiol on the control of seizures and on the improvement of certain neurocognitive aspects in patients with refractory epilepsies.


Comparison of early versus standard timing for silicone stent removal following External Dacrocystorhinostomy under local anaesthesia.
The first line treatment for nasolacrimal duct obstruction (NLDO) is external dacrocystorhinostomy (DCR). Following DCR, patients are required to return to Tilganga Institute of Ophthalmology (TIO) six weeks postoperatively for the removal of a silicone stent. As the majority of patients travel large distances at significant cost to reach TIO, most often patients remain within Kathmandu during this six weeks interval. This places a large financial burden on patients. A randomized controlled trial was designed to compare patient outcomes after early (two weeks postoperatively) versus standard (six weeks postoperatively) removal of silicone stents. 50 selected patients were randomized into two equal groups. At the time of publication, 31 patients (14 in group A and 17 in group B) had completed three months follow up. A success rate of 92.9% was noted in Group A and a success rate of 94.1% observed in group B. No significant difference was found between the two groups for success rate and rate of complications. Early tube removal post DCR appears to cause no significant difference in outcome or complication rates compared to standard tube removal.


Understanding and treating hoarding: a biopsychosocial perspective.
This article offers a practice-friendly review of conceptualizing and treating hoarding based on biological and psychological research. Although hoarding has commonly been conceptualized as a variant of obsessive-compulsive disorder, research suggests a more complex pattern of overlap with attention deficit-hyperactivity disorder, organic brain disease, depression, anxiety, personality disorders, and impulsivity. The phenomenon of hoarding is discussed in terms of familial and environmental vulnerabilities, maladaptive cognitive process, maladaptive cognitive content, and maladaptive behavioral patterns. The article concludes with a summary of treatment efficacy and 10 promising clinical practices.


Isolation and characterization of a full-length expressible cDNA for human hypoxanthine phosphoribosyl transferase.
We have cloned a full-length 1.6-kilobase cDNA of a human mRNA coding for hypoxanthine phosphoribosyltransferase (HPRT; IMP:pyrophosphate phosphoribosyltransferase, EC 22.214.171.124) into a simian virus 40-based expression vector and have determined its full nucleotide sequence. The inferred amino acid sequence agrees with a partial amino acid sequence determined for authentic human HPRT protein. Transfection of HPRT-deficient mouse LA9 cells with the purified plasmid leads to the expression of human HPRT enzyme activity in cells stably transfected and selected for enzyme activity in hypoxanthine/aminopterin/thymidine medium.


Nanoscale Evidence Unravels Microalgae Flocculation Mechanism Induced by Chitosan.
Microalgae are a promising resource for biofuel production, although their industrial use is limited by the lack of effective harvesting techniques. Flocculation consists in the aggregation and adhesion of cells into flocs that can be more easily removed from water than individual cells. Although it is an efficient harvesting technique, contamination is a major issue as chemical flocculants are often used. An alternative is to use natural biopolymers flocculants such as chitosan. Chitosan is a biobased nontoxic polymer that has been effectively used to harvest Chlorella vulgaris cells at a pH lower than its pKa (6.5). While the reported flocculation mechanism is said to rely on electrostatic interactions between chitosan and the negative cell surface, no molecular evidence has yet confirmed this mechanism. In this study, we performed force spectroscopy atomic force microscopy (AFM) experiments to probe the interactions between C. vulgaris cells and chitosan at the molecular scale to decipher its flocculation mechanism. Our results showed that at pH 6, chitosan interacts with C. vulgaris cell wall through biological interactions rather than electrostatic interactions. These observations were confirmed by comparing the data with cationically modified cellulose nanocrystals, for which the flocculation mechanism, relying on an electrostatic patch mechanism, has already been described for C. vulgaris. Further AFM experiments also showed that a different mechanism was at play at higher pH, based on chitosan precipitation. Thus, this AFM-based approach highlights the complexity of chitosan-induced flocculation mechanisms for C. vulgaris.


[Current data of the membrane receptors of the vascular smooth muscle fibers].
The cell membrane of vascular smooth muscle is lined with many receptor sensitive to signals emitted by the vessel wall or transported in the blood stream. Recent data on the mechanisms by which these receptors regulate vascular tone enable them to be classified into two main groups. The first group includes the receptors carried by the membrane proteins which are under their direct control; ATP-P2x receptors on Na+ and Ca2+ channels, pharmacological receptors (dihydropyridines, diltiazem, phenylalkylamines) situated on a voltage operated channel, receptors to cromakaline-like substances associated with a potassium channel, receptors to atriopeptines (ANF-B) with guanylate cyclase activity. The second group of receptors act through the intermediary of the G protein (which has a high affinity for guanylic nucleotides); it regulates the activity of an effector which may be an enzyme or an ionic channel. The receptors of this type which have been identified in vascular smooth muscle are: --positively (beta-adrenergic, DA1-dopaminergic, P1 purinergic or H2-histaminic) or negatively coupled (alpha 2-adrenergic) to adrenylate cyclase; --positively coupled to C phospholipase (angiotensin II, vasopressin V1, 5-H-T2, alpha 1-adrenergic, M1-cholinergic, H1-histaminic). In addition, the same receptor may act by different mechanisms (V1-vasopressin, alpha 2-adrenergic, for example). Whatever the initial mechanism of action, all these receptors influence the contraction by changing ionic permeability or by producing secondary relaxing (cyclic AMP, cyclic GMP) or contractility messengers (inositol phosphates, diacylglycerol).(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical holistic medicine: holistic sexology and treatment of vulvodynia through existential therapy and acceptance through touch.
Sexual problems are found in four major forms: lack of libido, lack of arousal and potency, pain and discomfort during intercourse, and lack of orgasm. It is possible to work with a holistic approach to sexology in the clinic in order to find and repair the negative beliefs, repressions of love, and lack of purpose of life, which are the core to problems like arousal, potency, and pain with repression of gender and sexuality. It is important not to focus only on the gender and genitals in understanding the patient"s sexual problems. It is of equal importance not to neglect the body, its parts, and the feelings and emotions connected to them. Shame, guilt, helplessness, fear, disgust, anger, hatred, and other strong feelings are almost always an important part of a sexual problem and these feelings are often "held" by the tissue of the pelvis and sexual organs. The patient with sexual problems can be helped both by healing existence in general and by discharging old painful emotions from the tissues. The later process of local healing is often facilitated by a simple technique: accepting contact via touch. This is a very simple technique, where the self-acceptance of the patient is to be promoted, for example, asking the female patient to put her hand on her stomach (uterus) or vulva, after which the holistic physician puts his hand supportively around hers. When done with care and after obtaining the necessary trust of the patient, this aspect of holding often releases the old negative emotions of shame bound to the touched areas. Afterwards, the emotional problems become a subject for conversational therapy and further holistic processing. Primary vulvodynia seems to be one of the diseases that can be cured after only a few successful sessions of working with acceptance through touch. The technique can be used as an isolated procedure or as a part of a pelvic examination. When touching the genitals with the intention of sexual healing, a written therapeutic contract with the patient is highly recommended and a strict ethical code is necessary to avoid malpractice. As about one woman in three suffers from sexual problems, many of which seemingly can be efficiently alleviated by the simple holistic techniques of "holding and processing", it is very important that the holistic physician is also trained to work in the sexual sphere in order to be able to support his patients fully.


Joint Selection of Influential Users and Locations under Target Region in Location-Based Social Networks.
Influence Maximization problem, selection of a set of users in a social network to maximize the influence spread, has received ample research attention in the social network analysis domain due to its practical applications. Although the problem has been extensively studied, existing works have neglected the location's popularity and importance along with influential users for product promotion at a particular region in Location-based Social Networks. Real-world marketing companies are more interested in finding suitable locations and influential users in a city to promote their product and attract as many users as possible. In this work, we study the joint selection of influential users and locations within a target region from two complementary perspectives; general and specific location type selection perspectives. The first is to find influential users and locations at a specified region irrespective of location type or category. The second perspective is to recommend locations matching location preference in addition to the target region for product promotion. To address general and specific location recommendations and influential users, we propose heuristic-based methods that effectively find influential users and locations for product promotion. Our experimental results show that it is not always an optimal choice to recommend locations with the highest popularity values, such as ratings, check-ins, and so, which may not be a true indicator of location popularity to be considered for marketing. Our results show that not only influential users are helpful for product promotion, but suitable influential locations can also assist in promoting products in the target region.


Palmitoylation of the S0-S1 linker regulates cell surface expression of voltage- and calcium-activated potassium (BK) channels.
S-palmitoylation is rapidly emerging as an important post-translational mechanism to regulate ion channels. We have previously demonstrated that large conductance calcium- and voltage-activated potassium (BK) channels are palmitoylated within an alternatively spliced (STREX) insert. However, these studies also revealed that additional site(s) for palmitoylation must exist outside of the STREX insert, although the identity or the functional significance of these palmitoylated cysteine residues are unknown. Here, we demonstrate that BK channels are palmitoylated at a cluster of evolutionary conserved cysteine residues (Cys-53, Cys-54, and Cys-56) within the intracellular linker between the S0 and S1 transmembrane domains. Mutation of Cys-53, Cys-54, and Cys-56 completely abolished palmitoylation of BK channels lacking the STREX insert (ZERO variant). Palmitoylation allows the S0-S1 linker to associate with the plasma membrane but has no effect on single channel conductance or the calcium/voltage sensitivity. Rather, S0-S1 linker palmitoylation is a critical determinant of cell surface expression of BK channels, as steady state surface expression levels are reduced by ∼55% in the C53:54:56A mutant. STREX variant channels that could not be palmitoylated in the S0-S1 linker also displayed significantly reduced cell surface expression even though STREX insert palmitoylation was unaffected. Thus our work reveals the functional independence of two distinct palmitoylation-dependent membrane interaction domains within the same channel protein and demonstrates the critical role of S0-S1 linker palmitoylation in the control of BK channel cell surface expression.


Formaldehyde chemistry in cometary ices: the case of HOCH2OH formation.
Laboratory experiments devoted to simulate the chemistry occurring in interstellar and cometary ice analogues are of paramount importance to understand the formation of complex organic molecules that are detected throughout the universe. These laboratory simulations provide relevant hints on the fundamental physical and chemical steps associated with the increase of the molecular complexity in space and, moreover, give benchmark results for dedicated space missions. In the present work, we study the thermally promoted reactivity of H2O-dominated and D2O-dominated cometary ice analogues that contain various amounts of H2CO and NH3 by means of Fourier-transform infrared spectroscopy (FTIR), mass spectrometry and DFT calculations. Experimental measurements show that methyleneglycol (HOCH2OH) and D2-methyleneglycol (DOCH2OD, the corresponding isotopologue) are formed from the H2O- and D2O-dominated ices, respectively, only if ammonia is present. We also reported for the first time the mass spectrum of methyleneglycol and D2-methyleneglycol. B3LYP calculations have also been used to characterize the potential energy surface of the mechanistic steps associated with the formation of HOCH2OH as well as to simulate the IR spectrum of this compound. The fruitful interplay between theory and experiment has allowed us to elucidate the exact role of ammonia during the warming, which essentially stands for the formation and stabilization of the NH4(+)/OH(-) ion pair, thus enabling the OH(-) species to react with formaldehyde. The present results reproduce the heating of circumstellar ices in star formation regions and can be applied to the late thermal evolution of comets. In addition, the mass spectrum of methyleneglycol represents a benchmark for the analysis of the data coming from the ROSINA on-board instrument of the Rosetta mission.


Genetic Diversity of Cameroon Cattle and a Putative Genomic Map for Resistance to Bovine Tuberculosis.
Bovine Tuberculosis (bTB) caused by Mycobacterium bovis is a livestock disease of global economic and public health importance. There are currently no effective vaccines available for livestock and so control relies on animal level surveillance and pasteurization of dairy products. A new alternative control approach is to exploit the genetic variability of the host; recent studies have demonstrated that breeding European taurine cattle, such as Holsteins for increased resistance to bTB is feasible. The utility of such an approach is still unknown for African cattle populations. This study aims to assess genetic variation in bTB resistance and the underlying genomic architecture of cattle in Cameroon. We conducted a cross-sectional study of 2,346 slaughter cattle in Cameroon. Retropharyngeal lymph node samples were collected and cultured on Lowenstein Jensen media and the BACTEC MGIT 960 system, and M. bovis was identified using the Hain® Genotype kits. A total of 153 cattle were positive for M. bovis and were archived along with a random selection of negative samples. In this study, we genotyped archived samples from 212 cattle. Their genomic diversity was characterized using PCA, hierarchical clustering and admixture analysis. We assessed genetic variation in bTB resistance using heritability analysis and compared quantitative trait loci. Previous research on this study population have shown that Fulani cattle are more susceptible to bTB than mixed breeds. However, here we show that these apparent phenotypic differences in breeds are not reflected by clear genomic differences. At the genetic level, both the Fulani and mixed cattle show similar patterns of admixture with evidence of both taurine and indicine ancestry. There was little European taurine introgression within the studied population. Hierarchical clustering showed clusters of cattle that differed in their susceptibility to bTB. Our findings allude to bTB resistance being polygenic in nature. This study highlights the potential for genetic control of bTB in Africa and the need for further research into the genetics of bTB resistance within African cattle populations.


Low vs. high glycemic index carbohydrate gel ingestion during simulated 64-km cycling time trial performance.
We examined the effect of low and high glycemic index (GI) carbohydrate (CHO) feedings during a simulated 64-km cycling time trial (TT) in nine subjects ([mean +/- SEM], age = 30 +/- 1 years; weight = 77.0 +/- 2.6 kg). Each rider completed three randomized, double blind, counter-balanced, crossover rides, where riders ingested 15 g of low GI (honey; GI = 35) and high GI (dextrose; GI = 100) CHO every 16 km. Our results showed no differences between groups for the time to complete the entire TT (honey = 128 minutes, 42 seconds +/- 3.6 minutes; dextrose = 128 minutes, 18 seconds +/- 3.8 minutes; placebo = 131 minutes, 18 seconds +/- 3.9 minutes). However, an analysis of total time alone may not portray an accurate picture of TT performance under CHO-supplemented conditions. For example, when the CHO data were collapsed, the CHO condition (128 minutes, 30 seconds) proved faster than placebo condition (131 minutes, 18 seconds; p < 0.02). Furthermore, examining the percent differences and 95% confidence intervals (CI) shows the two CHO conditions to be generally faster, as the majority of the CI lies in the positive range: placebo vs. dextrose (2.36% [95% CI; -0.69, 4.64]) and honey (1.98% [95% CI; -0.30, 5.02]). Dextrose vs. honey was 0.39% (95% CI; -3.39, 4.15). Within treatment analysis also showed that subjects generated more watts (W) over the last 16 km vs. preceding segments for dextrose (p < 0.002) and honey (p < 0.0004) treatments. When the final 16-km W was expressed as a percentage of pretest maximal W, the dextrose treatment was greater than placebo (p < 0.05). A strong trend was noted for the honey condition (p < 0.06), despite no differences in heart rate (HR) or rate of perceived exertion (RPE). Our results show a trend for improvement in time and wattage over the last 16 km of a 64-km simulated TT regardless of glycemic index.


In vivo analysis of p53 tumor suppressor function using genetically engineered mouse models.
p53 is a crucial tumor suppressor, as evidenced by the high propensity for p53 mutation during human cancer development. Already more than a decade ago, p53 knockout mice confirmed that p53 is critical for preventing tumorigenesis. More recently, a host of p53 knock-in mouse strains has been generated, with the aim of either more precisely modeling p53 mutations in human cancer or better understanding p53's regulation and downstream activities. In the first category, several mouse strains expressing mutant p53 proteins corresponding to human-tumor-derived mutants have demonstrated that mutant p53 is not equivalent to loss of p53 but additionally exhibits gain-of-function properties, promoting invasive and metastatic phenotypes. The second class of p53 knock-in mouse models expressing engineered p53 mutants has also provided new insight into p53 function. For example, mice expressing p53 mutants lacking specific posttranslational modification sites have revealed that these modifications serve to modulate p53 responses in vivo in a cell-type- and stress-specific manner rather than being absolutely required for p53 stabilization and activation as suggested by in vitro experiments. Additionally, studies of p53 mouse models have established that both p53-driven cell-cycle arrest and apoptosis responses contribute to tumor suppression and that activation of p53 by oncogenic stress imposes an important barrier to tumorigenesis. Finally, the use of mouse strains expressing temporally regulatable p53 has demonstrated that p53 loss is not only required for tumor development but also required for tumor maintenance, suggesting that p53 restoration in human cancer patients may be a promising therapeutic strategy. These sophisticated p53 mouse models have taught us important lessons, and new mouse models will certainly continue to reveal interesting and perhaps surprising aspects of p53's complex biology.


Rabbit Carcasses for Use in Feline Diets: Amino Acid Concentrations in Fresh and Frozen Carcasses With and Without Gastrointestinal Tracts.
Whole-prey diets for exotic feline species are common, and this practice has also increased in popularity for domestic cats. However, prior analyses of prey indicate possible essential amino acid inadequacy, and dilated cardiomyopathy from taurine deficiency was reported in cats fed whole ground rabbit. Crude protein, body water, and amino acid concentrations were evaluated in fresh and frozen ground rabbits with (n=10) or without (n = 10) gastrointestinal tracts. Amino acids were greater in fresh samples without gastrointestinal tracts (p < 0.05) except taurine, glycine, and cysteine. When normalized for protein content, only glutamate, alanine, methionine, isoleucine, tyrosine, lysine, histidine, and arginine were greater in fresh rabbits without gastrointestinal tracts (g/16 g N basis; p < 0.05). Freezing at -18°C for 30 days had no effect on crude protein or body water content. After freezing, only methionine was lower and only proline was higher when gastrointestinal tracts were omitted (g/16 g N basis; p < 0.05). Regardless, all essential amino acids except taurine exceeded Association of American Feed Control Officials and National Research Council nutrient recommendations for all feline life stages. In contrast, there was minimal impact of treatment on taurine concentrations. However, although feline taurine requirements for prey and other raw or fresh food diets remain undefined, none of the rabbit samples met any recommendation for taurine concentrations for commercial canned or dry extruded diets, ranging from 20 to 90% of the minimum values. Taurine supplementation is recommended when feeding rabbit to cats. Determination of taurine requirements of cats fed whole-prey diets is warranted.


Developmental links of very early phonological and language skills to second grade reading outcomes: strong to accuracy but only minor to fluency.
The authors examined second grade reading accuracy and fluency and their associations via letter knowledge to phonological and language predictors assessed at 3.5, 4.5, and 5.5 years in children in the Jyväskylä Longitudinal Study of Dyslexia. Structural equation modeling showed that a developmentally highly stable factor (early phonological and language processing [EPLP]) behind key dyslexia predictors (i.e., phonological awareness, short-term memory, rapid naming, vocabulary, and pseudoword repetition) could already be identified at 3.5 years. EPLP was significantly associated with reading and spelling accuracy and by age with letter knowledge. However, EPLP had only a minor link with reading fluency, which was additionally explained by early letter knowledge. The results show that reading accuracy is well predicted by early phonological and language skills. Variation in fluent reading skills is not well explained by early skills, suggesting factors other than phonological core skills. Future research is suggested to explore the factors behind the development of fast and accurate decoding skills.


Motor coordination via a tug-of-war mechanism drives bidirectional vesicle transport.
The microtubule motors kinesin and dynein function collectively to drive vesicular transport. High-resolution tracking of vesicle motility in the cell indicates that transport is often bidirectional, characterized by frequent directional changes. However, the mechanisms coordinating the collective activities of oppositely oriented motors bound to the same cargo are not well understood. To examine motor coordination, we purified neuronal transport vesicles and analyzed their motility via automated particle tracking with nanometer resolution. The motility of purified vesicles reconstituted in vitro closely models the movement of LysoTracker-positive vesicles in primary neurons, where processive bidirectional motility is interrupted with frequent directional switches, diffusional movement, and pauses. Quantitative analysis indicates that vesicles copurify with a low number of stably bound motors: one to five dynein and one to four kinesin motors. These observations compare well to predictions from a stochastic tug-of-war model, where transport is driven by the force-dependent kinetics of teams of opposing motors in the absence of external regulation. Together, these observations indicate that vesicles move robustly with a small complement of tightly bound motors and suggest an efficient regulatory scheme for bidirectional motility where small changes in the number of engaged motors manifest in large changes in the motility of cargo.


Fatal exacerbation of peripheral neuropathy during lamivudine therapy: evidence for iatrogenic mitochondrial damage.
A 57-year-old man with mild neuropathy who was positive for hepatitis B and C viruses was treated with lamivudine 300 mg.day(-1). After 3 months he presented with dysphonia and progressive muscle weakness. Subsequently, he developed tetraparesis followed by acute respiratory failure requiring mechanical ventilation, which was complicated by sudden cardiac arrest. After lamivudine was stopped, the neuropathy improved and respiratory capacity improved. Unfortunately, the patient died suddenly in spite of haemodynamic, ventilatory and metabolic support. Electrophysiological studies showed evidence of a sensory-motor axonal neuropathy. Nerve biopsy, muscle biopsy, biochemistry and mitochondrial DNA molecular genetics suggested possible widespread iatrogenic mitochondrial damage. Mitochondrial DNA dysfunction could be a potential cause of the sudden cardiac arrest. Stopping lamivudine treatment sooner after the onset of peripheral neuropathy or its exacerbation is important as continued therapy could lead to acute respiratory failure requiring mechanical ventilation and intensive care unit admission.


Psychedelics and Psychotherapy.
Psychedelics have shown great promise in modern clinical trials for treating various psychiatric conditions. As a transdiagnostic treatment that exerts its effects through subjective experiences that leave enduring effects, it is akin to psychotherapy. To date, there has been insufficient discussion of how psychedelic therapy is similar to and different from conventional psychotherapy. In this article, we review the shared features of effective conventional psychotherapies and situate therapeutic psychedelic effects within those. We then discuss how psychedelic drug effects might amplify conventional psychotherapeutic processes-particularly via effects on meaning and relationship-as well as features that make psychedelic treatment unique. Taking into account shared features of conventional psychotherapies and unique psychedelic drug effects, we create a framework for understanding why psychedelics are likely to be effective with very diverse types of psychotherapies. We also review the formal psychotherapies that have been adjunctively included in modern psychedelic trials and extend the understanding of psychedelics as psychotherapy towards implications for clinical ethics and trial design. We aim to provide some common conceptual vocabulary that can be used to frame therapeutic psychedelic effects beyond the confines of any one specific modality.


Is Traumatic Anterior Stove-In Chest Truly so Rare? A Single Institution Experience.
The anterior stove-in chest (ASIC) is a rare form of flail chest involving bilateral rib or sternal fractures resulting in an unstable chest wall that caves into the thoracic cavity. Given ASIC has only been described in a handful of case reports, this study sought to review our institution's experience in the surgical management of ASIC injuries. A retrospective review of patients with ASIC was conducted at our level I trauma center from 1//2021 to 3//2023. Information pertaining to patient demographics, fracture pattern, operative management, and outcomes was obtained and compared across patients in the case series. 6 patients met inclusion criteria, all males aged 37-78 years. 5 suffered motor vehicle collisions, and 1 was a pedestrian struck by an automobile. The median injury severity score was 28. All received ORIF within 5 days of admission, most commonly for ongoing respiratory distress. Patients 2 and 4 underwent bilateral ORIF of the ribs and sternum while patients 1, 5, and 6 underwent left-sided repair. Patient 3 required ORIF of left ribs and the sternum to stabilize their injuries. 5 of 6 patients were liberated from the ventilator and survived to discharge. This study demonstrates successful operative management of 6 patients with ASIC and suggests that early operative intervention with ORIF for affected segments may improve respiratory mechanics, ability to wean from the ventilator, and overall survival. Further research is needed to generate standardized guidelines for the management of this uncommon and complex thoracic injury.


Bis(μ-diisopropyl-hydoxylaminato)-κ(2) O:N;κ(2) O:O-bis-[(diisopropyl-hydoxylaminato-κO)beryllium].
The title compound, [Be2(C6H14NO)4], was prepared from a solution of BeCl2 in diethyl ether and two equivalents of O-lithia-ted N,N-diisopropyl-hydoxyl-amine. The mol-ecular structure is composed of a dinuclear unit forming a central five-membered planar Be-O-Be-O-N ring (sum of inter-nal angles = 540.0°; r.m.s. deviation from planarity = 0.0087 Å). Both Be atoms show the unusual coordination number of three, with one Be atom coordinated by three O atoms and the other by two O atoms and one N atom, both in distorted trigonal-planar environments. The Be-O distances are in the range 1.493 (5)-1.600 (5) Å and the Be-N distance is 1.741 (5) Å.


Glassy behavior of denatured DNA films studied by differential scanning calorimetry.
We use differential scanning calorimetry (DSC) to study the properties of DNA films, made of oriented fibers, heated above the thermal denaturation temperature of the double helical form. The films show glassy properties that we investigate in two series of experiments, a slow cooling at different rates followed by a DSC scan upon heating and aging at a temperature below the glass transition. Introducing the fictive temperature to characterize the glass allows us to derive quantitative information on the relaxations of the DNA films, in particular to evaluate their enthalpy barrier. A comparison with similar aging studies on PVAc highlights some specificities of the DNA samples.


Task-induced deactivation in diverse brain systems correlates with interindividual differences in distinct autonomic indices.
Neuroimaging research has shown that different cognitive tasks induce relatively specific activation patterns, as well as less task-specific deactivation patterns. Here we examined whether individual differences in Autonomic Nervous System (ANS) activity during task performance correlate with the magnitude of task-induced deactivation. In an fMRI study, participants performed a continuous mental arithmetic task in a task/rest block design, while undergoing combined fMRI and heart/respiration rate acquisitions using photoplethysmograph and respiration belt. As expected, task performance increased heart-rate and reduced the RMSSD, a cardiac index related to vagal tone. Across participants, higher heart rate during task was linked to increased activation in fronto-parietal regions, as well as to stronger deactivation in ventromedial prefrontal regions. Respiration frequency during task was associated with similar patterns, but in different regions than those identified for heart-rate. Finally, in a large set of regions, almost exclusively limited to the Default Mode Network, lower RMSSD was associated with greater deactivation, and furthermore, the vast majority of these regions were task-deactivated at the group level. Together, our findings show that inter-individual differences in ANS activity are strongly linked to task-induced deactivation. Importantly, our findings suggest that deactivation is a multifaceted construct potentially linked to ANS control, because distinct ANS measures correlate with deactivation in different regions. We discuss the implications for current theories of cortical control of the ANS and for accounts of deactivation, with particular reference to studies documenting a "failure to deactivate" in multiple clinical states.


Cognitive measure stability in siblings following early nutritional supplementation.
Cognitive data were obtained on 19 of the 21 pairs of siblings who had been in the authors' earlier study of behavioral outcomes associated with participation in the Special Supplemental Food Program for Women, Infants, and Children (WIC). The timing of WIC participation differed for the members of the sibling pairs, beginning in the perinatal period for one sibling and after 1 year of age for the other. The perinatally supplemented siblings received WIC services for an average of 22 months longer than the siblings whose supplementation began at 1 year of age. The present study determined that enhancements in IQ scores proved stable on blind retesting 32 months after the original study, with those siblings who were supplemented perinatally (and for a longer duration) continuing to exhibit higher scores. The group differences in school grade point averages were in the expected direction at followup, but fell short of statistical significance.


Neurocognitive correlates of emotional stimulus processing in pediatric bipolar disorder: a review.
Despite low prevalence rates in epidemiological studies, recent research suggests that bipolar disorder (BD) is being diagnosed at increasingly high rates in children and adolescents. To clarify the nosological boundaries of the disorder, studies of the clinical presentation of bipolar youth should be complemented with examinations of cognitive and neural functioning. More specifically, delineating the neurocognitive functioning of youth with BD when processing emotional stimuli may best elucidate how certain emotional contexts elicit symptoms that characterize pediatric BD. This information has the potential to clarify causes of pediatric BD, and to confirm the diagnosis of BD in youth. In this article, we discuss the affective, behavioral, cognitive, and neurological functioning of youth with BD when processing emotional stimuli. We focus on studies that have employed paradigms involving pictures and words with emotional valence, faces with emotional expressions, and responses to reward and punishment. The most consistent results on behavior are from studies involving facial stimuli, which find that youth with BD display a tendency to mislabel face emotions. Neurological data demonstrate that emotion-processing deficits in pediatric BD involve dysfunction within a distributed fronto-striatal-limbic network, including the dorsolateral and ventrolateral prefrontal cortex, anterior cingulate cortex, striatum, and amygdala. These data may begin to clarify why BD youth present with poor social functioning and deficits in regulating their affect and behavior.


Synthesis, photophysical and electronic properties of tetra-donor- or acceptor-substituted ortho-perylenes displaying four reversible oxidations or reductions.
Via regioselective Ir-catalyzed C-H borylation and subsequent reactions (i.e., via Br4-Per or (BF3K)4-Per intermediates), we have introduced strong π-donors and acceptors at the 2,5,8,11-positions of perylene leading to unusual properties. Thus, incorporation of four donor diphenylamine (DPA) or four acceptor Bmes2 (mes = 2,4,6-Me3C6H2) moieties yields novel compounds which can be reversibly oxidized or reduced four times, respectively, an unprecedented behavior for monomeric perylene derivatives. Spectroelectrochemical measurements show NIR absorptions up to 3000 nm for the mono-cation radical of (DPA)4-Per and a strong electronic coupling over the perylene bridge was observed indicative of fully delocalized Robin-Day Class III behavior. Both (DPA)4-Per and (Bmes2)4-Per derivatives possess unusually long intrinsic singlet lifetimes (τ 0), e.g., 94 ns for the former one. The compounds are emissive in solution, thin films, and the solid state, with apparent Stokes shifts that are exceptionally large for perylene derivatives. Transient absorption measurements on (DPA)4-Per reveal an additional excited state, with a long lifetime of 500 μs, which sensitizes singlet oxygen effectively.


Analysis of gene expression in transgenic plants.
Recent years have seen a huge increase and improvement in techniques for analysis of transgene expression in plants. The analysis of RNA frequently provides a vital link between changes in enzyme levels and/or metabolites and the phenotype. This chapter focuses on RNA-based techniques for the analysis of transgene expression, beginning with the extraction of RNA and its evaluation in terms of purity and integrity by spectrophotometry and gel electrophoresis, respectively. Common methods of transcript analysis by Northern and dot-blot hybridizations using nonradioactive probing methods are described. A protocol for reverse-transcriptase polymerase chain reaction (RT-PCR) as a method of establishing transgene expression qualitatively, as well as a procedure for quantitative RT-PCR for comparing relative abundance of transcript levels of two or more genes are described. Lastly, a protocol for localization of RNA transcripts within tissues by in situ hybridization is included.


[Hemoglobin as a predictor of cardiovascular problems].
Analyzed were data of longitudinal studies of health and peripheral blood of AF pilots and navigators at the age of 20, 25, 30, 35, 40 and 45. The survey of 846 men 30 years and older was conducted in two 5-yr cycles. In this cohort, 329 had diagnosed neurocirculatory dystonia (NCD), vegetovascular dystonia, and class I essential hypertension. Sixty nine men were afflicted with myocardium dystrophy or cardiosclerosis. The dispersion analysis provided evidence that 15 to 5 years prior to establishment of the NCD diagnosis hemoglobin first increases and then decreases. The dispersion analysis applied to the data of repeated measurement attested to the predictive meaning of the hemoglobin rise and decrease. Results support the hypothesis according to which hemoglobin is but a stable individual risk factor but reflects pre-clinic developments in organism.


Coriander essential oil and linalool - interactions with antibiotics against Gram-positive and Gram-negative bacteria.
The aim of this study was to evaluate the antibacterial activity of coriander essential oil and its major constituent, linalool, in combination with antibiotics against Gram-positive (methicillin-susceptible and methicillin-resistant Staphylococcus aureus, S. epidermidis) and Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli). The chemical composition of coriander essential oil was analyzed by gas chromatography with flame ionization and mass spectrometry detection. The antibacterial activity of coriander essential oil, linalool and their combinations with antibiotics were assessed by the broth microdilution and checkerboard assays respectively. Thirty-four compounds were identified in coriander essential oil, linalool (70·11%) being predominant. Coriander essential oil and linalool showed synergistic interactions with antibiotics (oxacillin, amoxicillin, gentamicin, ciprofloxacin, tetracycline) against both Gram-positive and Gram-negative bacteria. In these synergistic combinations, minimum inhibitory concentrations of antibiotics were markedly reduced; even antibiotic resistance reversal activity was recorded. These findings are very promising for the development of new therapeutic options for bacterial infections. SIGNIFICANCE AND IMPACT OF THE STUDY: Methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative bacteria are still major threats to human health and, therefore, identification of new antibacterial agents or combinations with high potency is needed. Our study found synergistic interactions between coriander essential oil/linalool and antibiotics against MRSA and other Gram-positive bacteria (methicillin-susceptible S. aureus, S. epidermidis), but also Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli). Increase in antibiotic susceptibility and reversal of antibiotic resistance were also demonstrated. Combinations of coriander essential oil/linalool and antibiotics are thus very promising for the development of novel antibacterials.


Description of Desulfotomaculum sp. Groll as Desulfotomaculum gibsoniae sp. nov.
Strain GrollT, isolated from fresh water, is a mesophilic, spore-forming, sulfate-reducing bacterium that uses a large variety of substrates as electron donors ranging from simple organic compounds to long-chain fatty acids and several aromatic compounds. Sulfate, thiosulfate and sulfite are used as electron acceptors. Homoacetogenic growth occurs under sulfate-free conditions. Substrate oxidation is usually complete, leading to CO2, but acetate or other fatty acids can accumulate at high substrate concentrations. The G + C content of the DNA is 54.8 mol%. Strain GrollT was found to be phenotypically and phylogenetically different from known members of the genus Desulfotomaculum. 16S rRNA gene sequence analyses show that this organism falls within the radiation of the genus Desulfotomaculum cluster and has < 96% sequence similarity to previously described species. The name Desulfotomaculum gibsoniae sp. nov. is proposed for this strain; the type strain is GrollT (= DSM 7213T).


Challenges of antibacterial discovery.
The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.


250 years of hybridization between two biennial herb species without speciation.
Hybridization between plant species can generate novel morphological diversity and lead to speciation at homoploid or polyploid levels. Hybrids between biennial herbs Tragopogon pratensis and T. porrifolius have been studied in experimental and natural populations for over 250 years. Here we examine their current status in natural populations in southeast England. All hybrids found were diploid; they tended to grow taller and with more buds than their parental species; many showed partial fertility; a few showed evidence of backcrossing. However, we found no evidence to suggest that the hybrids are establishing as a new species, nor can we find literature documenting speciation of these hybrids elsewhere. This lack of speciation despite at least 250 years of hybridization contrasts with the fact that both parental species have formed new allopolyploid species through hybridization with another diploid, T. dubius. Understanding why hybrids often do not speciate, despite repeated opportunities, would enhance our understanding of both the evolutionary process and risk assessments of invasive species.


Evaluation of computed tomographic anatomy of the equine metacarpophalangeal joint.
To determine the detailed computed tomography (CT) anatomy of the metacarpophalangeal (MCP) joint in healthy horses. 10 cadaveric forelimbs from 10 adult horses without orthopedic disease. CT of the MCP joint was performed on 4 forelimbs. In 1 of the limbs, CT was also performed after intra-articular injection of 30 mL of contrast medium (40 mg of iodine/mL). Transverse slices 1-mm thick were obtained, and sagittal and dorsal planes were reformatted with a slice thickness of 2 mm. The CT images were matched with corresponding anatomic slices from 6 additional forelimbs. The third metacarpal bone, proximal sesamoid bones, and proximal phalanx could be clearly visualized. Common digital extensor tendon; accessory digital extensor tendon; lateral digital extensor tendon; superficial digital flexor tendon (including manica flexoria); deep digital flexor tendon; branches of the suspensory ligament (including its attachment); extensor branches of the suspensory ligament; collateral ligaments; straight, oblique, and cruciate distal sesamoidean ligaments; intersesamoidean ligament; annular ligament; and joint capsule could be seen. Collateral sesamoidean ligaments and short distal sesamoidean ligaments could be localized but not at all times clearly identified, whereas the metacarpointersesamoidean ligament could not be identified. The cartilage of the MCP joint could be assessed on the postcontrast sequence. CT of the equine MCP joint can be of great value when results of radiography and ultrasonography are inconclusive. Images obtained in this study may serve as reference for CT of the equine MCP joint.


Rheumatoid arthritis--atlanto-axial subluxation and its clinical presentation.
The clinical picture, radiological findings and treatment of 22 patients with atlantoaxial subluxation and rheumatoid arthritis are described. This lesion, untreated, may result in damage to the spinal cord, paresis or sudden death. Occipital headache, present in 13 of 22 patients, was often aggravated by working with the head in forward flexion. Paresthesias were present in six patients. The spine of the axis was often prominent. In three patients there was objective evidence of cord compression with sensory and/or pyramidal signs. In eight the lesion was asymptomatic and discovered by routine lateral radiography in flexion, the position of maximum subluxation.Conservative treatment involved the continuous use of a cervical collar to limit neck flexion. This usually relieved subjective symptoms including headaches. Successful surgical fixation was performed in two individuals. Surgical indications included acute or chronic cord compression or severe symptoms unrelieved by a collar.


Automatic Differentiation of Normal and Continuous Adventitious Respiratory Sounds Using Ensemble Empirical Mode Decomposition and Instantaneous Frequency.
Differentiating normal from adventitious respiratory sounds (RS) is a major challenge in the diagnosis of pulmonary diseases. Particularly, continuous adventitious sounds (CAS) are of clinical interest because they reflect the severity of certain diseases. This study presents a new classifier that automatically distinguishes normal sounds from CAS. It is based on the multiscale analysis of instantaneous frequency (IF) and envelope (IE) calculated after ensemble empirical mode decomposition (EEMD). These techniques have two major advantages over previous techniques: high temporal resolution is achieved by calculating IF-IE and a priori knowledge of signal characteristics is not required for EEMD. The classifier is based on the fact that the IF dispersion of RS signals markedly decreases when CAS appear in respiratory cycles. Therefore, CAS were detected by using a moving window to calculate the dispersion of IF sequences. The study dataset contained 1494 RS segments extracted from 870 inspiratory cycles recorded from 30 patients with asthma. All cycles and their RS segments were previously classified as containing normal sounds or CAS by a highly experienced physician to obtain a gold standard classification. A support vector machine classifier was trained and tested using an iterative procedure in which the dataset was randomly divided into training (65%) and testing (35%) sets inside a loop. The SVM classifier was also tested on 4592 simulated CAS cycles. High total accuracy was obtained with both recorded (94.6% ± 0.3%) and simulated (92.8% ± 3.6%) signals. We conclude that the proposed method is promising for RS analysis and classification.


[Preeclampsia: oxidative stress, inflammation and endothelial dysfunction].
Preeclampsia is a systemic syndrome characterized by inflammatory and antiangiogenic states. The pathogenesis of preeclampsia involves deficient trophoblast invasion that is responsible for altered uterine blood flow and placental oxidative stress. The damaged placenta produces higher concentrations of sFlt-1, a soluble receptor for VEGF and PlGF that is released in the maternal circulation and is involved in endothelial dysfunction. Actually, all processes involved in inflammation, endothelial dysfunction and oxidative stress are strongly correlated and act in a synergistic way. Recent data have shown that an increase in serum concentrations of sFlt-1 initiates 5 to 6 weeks before the clinical manifestations of preeclampsia and these alterations correlate with a decrease in serum concentrations of PlGF. Therefore, both sFlt-1 and PlGF have been suggested to be useful for an early-diagnosis of preeclampsia. The knowledge about the role of antiangiogenic factors in the pathogenesis of preeclampsia has raised the possibility of a therapy involving these factors.In this article we revisited the pathogenesis of preeclampsia addressing its antiangiogenic and inflammatory states.In conclusion, we correlated these alterations with the higher risk for cardiovascular diseases presented by these women in future life.


The "continuum of care" for older adults: design and evaluation of an educational series.
Geriatricians work within a continuum of health services designed to meet the diverse care needs of older adults. They must develop expertise in these care models and be able to guide safe and efficient transitions. This article describes a 9-week educational series designed to review the evidence base and practical aspects of implementing key services that span the continuum of care for older adults. The sessions in the series covered geriatric assessment, ambulatory care, acute hospital, house call, hospital-at-home, Program of All-Inclusive Care for the Elderly, assisted living, inpatient consultation, rehabilitation, nursing home, chronic hospital, and palliative care and hospice. To assess the educational effect of these sessions, evaluations were collected at the end of each session, including one "summative evaluation" after the completion of the entire 9-week series. The vast majority (97%) of survey responses evaluating individual sessions were positive (scores of 4 or 5 on a 5-point Likert scale), and 89% of responses on the summative evaluation were in that range. This educational series efficiently provides a sequential "tour" of health services for older adults, allowing learners to appreciate the continuum of geriatric care models and relationships between services. Feedback from attendees suggests that this format increases knowledge of health services along the continuum of care for older adults and does so in an efficient manner for learners at different levels of training.


An insertion in the RSPO2 gene correlates with improper coat in the Portuguese water dog.
We recently showed that genes at 3 loci account for the majority of variation in canine fur. Allelic variation at genes controlling length of fur, texture, and curl is responsible for the striking phenotypic variety observed among purebred dogs in the United States today. In this paper, we investigate the phenomenon of "improper coat" (IC) or a coat that is not typical of the breed. IC is occasionally observed among specific breeds, such as the Portuguese Water Dog (PWD), and is characterized by short hair on the head, face, and lower legs, rather than a thick and even coat covering the whole body. The IC is reminiscent of that observed on the curly or flat-coated retriever, thus making such dogs unable to compete effectively in conformation events. We have found that the presence of the wild-type allele, rather than the expected variant allele at the R-spondin 2 (RSPO2) gene, accounts for this phenotype. The development of a genetic test that distinguishes these 2 allelic types would allow breeders to easily avoid producing PWD with ICs.


Two recurrent neural networks for local joint torque optimization of kinematically redundant manipulators.
This paper presents two neural network approaches to real-time joint torque optimization for kinematically redundant manipulators. Two recurrent neural networks are proposed for determining the minimum driving joint torques of redundant manipulators for the eases without and with taking the joint torque limits into consideration, respectively. The first neural network is called the Lagrangian network and the second one is called the primal-dual network. In both neural-network-based computation schemes, while the desired accelerations of the end-effector for a specific task are given to the neural networks as their inputs, the signals of the minimum driving joint torques are generated as their outputs to drive the manipulator arm. Both proposed recurrent neural networks are shown to be capable of generating minimum stable driving joint torques. In addition, the driving joint torques computed by the primal-dual network are shown never exceeding the joint torque limits.


Acetaminophen (Paracetamol) Induces Hypothermia During Acute Cold Stress.
Acetaminophen is an over-the-counter drug used to treat pain and fever, but it has also been shown to reduce core temperature (T c) in the absence of fever. However, this side effect is not well examined in humans, and it is unknown if the hypothermic response to acetaminophen is exacerbated with cold exposure. To address this question, we mapped the thermoregulatory responses to acetaminophen and placebo administration during exposure to acute cold (10 °C) and thermal neutrality (25 °C). Nine healthy Caucasian males (aged 20-24 years) participated in the experiment. In a double-blind, randomised, repeated measures design, participants were passively exposed to a thermo-neutral or cold environment for 120 min, with administration of 20 mg/kg lean body mass acetaminophen or a placebo 5 min prior to exposure. T c, skin temperature (T sk), heart rate, and thermal sensation were measured every 10 min, and mean arterial pressure was recorded every 30 min. Data were analysed using linear mixed effects models. Differences in thermal sensation were analysed using a cumulative link mixed model. Acetaminophen had no effect on T c in a thermo-neutral environment, but significantly reduced T c during cold exposure, compared with a placebo. T c was lower in the acetaminophen compared with the placebo condition at each 10-min interval from 80 to 120 min into the trial (all p < 0.05). On average, T c decreased by 0.42 ± 0.13 °C from baseline after 120 min of cold exposure (range 0.16-0.57 °C), whereas there was no change in the placebo group (0.01 ± 0.1 °C). T sk, heart rate, thermal sensation, and mean arterial pressure were not different between conditions (p > 0.05). This preliminary trial suggests that acetaminophen-induced hypothermia is exacerbated during cold stress. Larger scale trials seem warranted to determine if acetaminophen administration is associated with an increased risk of accidental hypothermia, particularly in vulnerable populations such as frail elderly individuals.


The effect of cycloheximide on the accumulation and stability of functional alpha-mRNA in cells infected with herpes simplex virus.
Cells were infected with herpes simplex virus type 2, HSV-2(G), and incubated in the presence of cycloheximide (CX). When CX was removed and actinomycin D (Act D) added, alpha-polypeptides ICP 0 and ICP 4 were synthesized at low rates. If CX was removed without adding Act D, the rate of production of ICP 4 increased while that of ICP 0 remained constant. In cells treated with azetidine to enhance the production of ICP 4 and 0, accumulation of functional mRNA for ICP 4 (determined indirectly by translation in vivo) was reduced by concentrations of CX between 0.5 and 5.0 micrograms/ml, whereas mRNA for ICP 0 was unaffected by 50 micrograms/ml CX. CX apparently either inhibits the synthesis of ICP 4 mRNA or enhances its inactivation without affecting the production or degradation of ICP 0 mRNA. The accumulation of ICP 4 or ICP 0 mRNA of HSV-1(F) was unaffected by CX. The low levels of ICP 4 and ICP 0 mRNAs of HSV-2(G) that accumulated in the presence of CX disappeared rapidly after adding Act D, in contrast to those of HSV-1(F) which were stable. The ICP 4 mRNA of HSV-2(G) was stable, however, if made without CX or if in mixed infection with HSV-1(F) in the presence of CX. It is suggested that rapid inactivation may account for the low level of accumulation of functional ICP 4 and ICP 0 mRNAs of HSV-2(G) in the presence of CX, and that ICP 4 mRNA is protected by a protein made soon after normal infection. Such a protein may be carried in the virion of HSV-1(F).


Finding the needle in the haystack: why high-throughput screening is good for your health.
High-throughput screening is an essential component of the toolbox of modern technologies that improve speed and efficiency in contemporary cancer drug development. This is particularly important as we seek to exploit, for maximum therapeutic benefit, the large number of new molecular targets emerging from the Human Genome Project and cancer genomics. Screening of diverse collections of low molecular weight compounds plays a key role in providing chemical starting points for iterative optimisation by medicinal chemistry. Examples of successful drug discovery programmes based on high-throughput screening are described, and these offer potential in the treatment of breast cancer and other malignancies.


High spatial resolution diffusion weighted imaging on clinical 3 T MRI scanners using multislab spiral acquisitions.
A diffusion weighted imaging (DWI) approach that is signal-to-noise ratio (SNR) efficient and can be applied to achieve sub-mm resolutions on clinical 3 T systems was developed. The sequence combined a multislab, multishot pulsed gradient spin echo diffusion scheme with spiral readouts for imaging data and navigators. Long data readouts were used to keep the number of shots, and hence total imaging time, for the three-dimensional acquisition short. Image quality was maintained by incorporating a field-inhomogeneity-corrected image reconstruction to remove distortions associated with long data readouts. Additionally, multiple shots were required for the high-resolution images, necessitating motion induced phase correction through the use of efficiently integrated navigator data. The proposed approach is compared with two-dimensional (2-D) acquisitions that use either a spiral or a typical echo-planar imaging (EPI) acquisition to demonstrate the improved SNR efficiency. The proposed technique provided 71% higher SNR efficiency than the standard 2-D EPI approach. The adaptability of the technique to achieve high spatial resolutions is demonstrated by acquiring diffusion tensor imaging data sets with isotropic resolutions of 1.25 and 0.8 mm. The proposed approach allows for SNR-efficient sub-mm acquisitions of DWI data on clinical 3 T systems.


Consideration of online rainfall measurement and nowcasting for RTC of the combined sewage system.
In Berlin, Germany, the demand for enhanced protection of the environment and the growing economic pressure have led to an increased application of control concepts within the sewage system. A global control strategy to regulate the pumpage of the combined sewage system to the treatment plant was developed and evaluated in a theoretical study. The objective was to reduce CSO. In this paper an extension of the existing control algorithm by information from online rainfall measurement and radar nowcasting is described. The rainfall information is taken into account by two additive terms describing the predicted volume from rainfall runoff. On the basis of numerical simulation the potential of these two complementary forecast terms in the global control algorithm to further reduce CSO is evaluated. The investigations are based on long-time simulations that are conducted with the dynamic flow routing model InfoWorks for three subcatchments of the Berlin drainage system. The results show that at the current Berlin system a CSO reduction of only 0.8% is possible. The effect of the forecast terms is limited by operational constraints. Limits are set to both, the delivery from each individual pump station and the total pumpage to the treatment plant.


Short report: knowledge and perceptions of health workers that strengthen adherence for paediatric and adolescent clients on the intensive adherence counselling program in Kampala, Uganda: a qualitative study.
Health care workers (HWs) support HIV positive children and adolescents with detectable HIV viral loads on the intensive adherence counselling (IAC) program to achieve viral suppression through individual adherence counselling. Low re-suppression rates of 23% showed low program effectiveness in fifteen public health facilities. We set out to determine the knowledge and perceptions of HWs that support this program to improve its effectiveness. We conducted a qualitative study where five HWs that oversee clinical care for children on ART were interviewed about the program. Data on their knowledge of the program, and perceptions on why it was not effective was collected. Thematic analysis using the inductive approach was used. Transcripts were read, coded and emergent themes determined. Five HWs participated and all were knowledgeable about the program. Two themes emerged as barriers to IAC program effectiveness, patient factors and health system factors. Patient factors were failure to attend appointments, failure to change adherence practices, and lack of consent. Health system factors were work overload, delay in getting results and drug stock outs. HWs are knowledgeable about the IAC program and client specific barriers should be addressed to improve viral suppression for children.


Correction of cryptotia using an external stretching device.
An external stretching device was devised for the correction of cryptotia. A total of 27 cases of cryptotia received correction with this device. Patient age ranged from 10 to 40 years. During an earlier trial, patients were corrected with the external stretching device only. To make a definite and permanent projection of the upper ear, the external device had to be applied and maintained for more than 5 months. In some patients pin site infection developed during the treatment, which resulted in cessation of treatment. Recently, for cryptotia with marked cartilage adhesion, surgical release of the adhesion with a skin graft was supplemented with the application of the external stretching device. The device was maintained for 2 months and the long-term follow-up showed excellent outcome with well-maintained projection and a satisfactory auricular shape. The author suggests that the external stretching device is a useful alternative in the correction of cryptotia with severe cartilage adhesion in older children or adults.


Effects of anti-thrombospondin monoclonal antibodies on the agglutination of erythrocytes and fixed, activated platelets by purified thrombospondin.
A monoclonal antibody (Mab) has been raised against native thrombospondin (TSP), the endogenous lectin of human platelets, that inhibits the hemagglutination of trypsinized, glutaraldehyde-fixed human erythrocytes by purified TSP. This Mab, designated A2.5, also inhibits the agglutination of fixed, activated platelets by TSP. Mab A2.5 immunoprecipitates a 25-kilodalton (kDa) peptide from chymotryptic digests of TSP that is not disulfide bonded to any other region of the TSP molecule. This fragment represents the previously characterized heparin binding domain of TSP [Dixit, V.M., Grant, G.A., Santoro, S.A., & Frazier, W.A. (1984) J. Biol. Chem. 259, 10100-10105]. In agreement with this assignment, heparin inhibits the binding of Mab A2.5 to TSP. Another Mab, designated C6.7, also blocks TSP-mediated hemagglutination, yet has no effect on the agglutination of fixed, activated platelets by TSP. This Mab has been shown to inhibit the thrombin-stimulated aggregation of live platelets and to immunoprecipitate an 18-kDa fragment from chymotryptic digests, which is distinct from the heparin binding domain [Dixit, V.M., Haverstick, D.M., O'Rourke, K.M., Hennessy, S.W., Grant, G.A., Santoro, S.A., & Frazier, W.A. (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 3472-3476].


Heutagogy: An alternative practice based learning approach.
Education has explored and utilised multiple approaches in attempts to enhance the learning and teaching opportunities available to adult learners. Traditional pedagogy has been both directly and indirectly affected by andragogy and transformational learning, consequently widening our understandings and approaches toward view teaching and learning. Within the context of nurse education, a major challenge has been to effectively apply these educational approaches to the complex, unpredictable and challenging environment of practice based learning. While not offered as a panacea to such challenges, heutagogy is offered in this discussion paper as an emerging and potentially highly congruent educational framework to place around practice based learning. Being an emergent theory its known conceptual underpinnings and possible applications to nurse education need to be explored and theoretically applied. Through placing the adult learner at the foreground of grasping learning opportunities as they unpredictability emerge from a sometimes chaotic environment, heutagogy can be argued as offering the potential to minimise many of the well published difficulties of coordinating practice with faculty teaching and learning.


Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms.
The insulin-like growth factor (IGF)2/IGF1 receptor (IGF1R) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients. Here, we show that IGF2 was specifically induced in the tumor stroma of CRC and identified cancer-associated fibroblasts (CAFs) as the major source. Further, we provide functional evidence that stromal IGF2, via the paracrine IGF1R/insulin receptor axis, activated pro-survival AKT signaling in CRC cell lines. In addition to its effects on malignant cells, autocrine IGF2/IGF1R signaling in CAFs induced myofibroblast differentiation in terms of alpha-smooth muscle actin expression and contractility in floating collagen gels. This was further augmented in concert with transforming growth factor-β (TGFβ) signaling suggesting a cooperative mechanism. However, we demonstrated that IGF2 neither induced TGFβ/smooth muscle actin/mothers against decapentaplegic (SMAD) signaling nor synergized with TGFβ to hyperactivate this pathway in two dimensional and three dimensional cultures. IGF2-mediated physical matrix remodeling by CAFs, but not changes in extracellular matrix-modifying proteases or other secreted factors acting in a paracrine manner on/in cancer cells, facilitated subsequent tumor cell invasion in organotypic co-cultures. Consistently, colon cancer cells co-inoculated with CAFs expressing endogenous IGF2 in mouse xenograft models exhibited elevated invasiveness and dissemination capacity, as well as increased local tumor regrowth after primary tumor resection compared with conditions with IGF2-deficient CAFs. In line, expression of IGF2 correlated with elevated relapse rates and poor survival in CRC patients. In agreement with our results, high-level coexpression of IGF2 and TGFβ was predicting adverse outcome with higher accuracy than increased expression of the individual genes alone. Taken together, we demonstrate that stroma-induced IGF2 promotes colon cancer progression in a paracrine and autocrine manner and propose IGF2 as potential target for tumor stroma cotargeting strategies.


[Nuclear magnetic resonance tomography in the diagnosis of muscular diseases].
Forty-nine patients with various systemic muscle diseases were examined by MR using a 1 Tesla magnet and the appearances of different conditions are analysed. Emphasis was placed on the analysis of patients with progressive muscular dystrophies, myositis, myotonia dystrophica and other muscle diseases. The investigation was begun in March 1984 and was continued until September 1985. Certain characteristic patterns of selectively involved muscles could be recognised. The pattern corresponds to our present understanding of the early phases of muscle diseases, whether inflammatory or due to fatty degeneration. The T1 and T2 relaxation times in various patients were quantified and changes in the normal pattern were analysed. Attention is drawn to the value of MR when carrying out a biopsy and for treatment of muscle diseases.


Opioid abuse in the United States and Department of Health and Human Services actions to address opioid-drug-related overdoses and deaths.
On March 26, 2015, the Office of the Assistant Secretary for Planning and Evaluation of the U.S. Department of Health and Human Services (HSS) published an online Issue Brief that addresses opioid abuse in the United States and (HHS) actions to address opioid-drug-related overdoses and deaths. This report, which contains the full content of the Issue Brief, is adapted from that document.


Role of obesity and fat distribution in non-insulin-dependent diabetes mellitus in Mexican Americans and non-Hispanic whites.
Recent data have suggested that central obesity is related positively to the prevalence of non-insulin-dependent diabetes mellitus (NIDDM). We examined whether central obesity (measured by the ratio of subscapular to triceps skinfold) was predictive of NIDDM prevalence independently of overall obesity (measured by body mass index, BMI) in 1231 Mexican Americans and 939 non-Hispanic whites who participated in the San Antonio Heart Study, a population-based survey of diabetes and cardiovascular risk factors. Mexican Americans are characterized by higher rates of NIDDM, greater overall obesity, and more central body fat distribution than age-matched non-Hispanic whites. Using multiple logistic regression with age, ethnicity, BMI, and central obesity as covariates, overall obesity was positively associated with NIDDM prevalence in both sexes (P less than 0.001) but central obesity was related to NIDDM prevalence only in women. Our data suggest that the effect of centrality decreases at higher levels of centrality. While both BMI and centrality narrow the ethnic difference in NIDDM prevalence, Mexican Americans still have an increased risk of NIDDM (odds ratio = 2.33 in men and 1.80 in women), suggesting that other factors, possibly genetic, may also be important determinants of the ethnic differences in NIDDM prevalence.


EGFR Signaling Causes Morphine Tolerance and Mechanical Sensitization in Rats.
The safety and efficacy of opioids are compromised as analgesic tolerance develops. Opioids are also ineffective against neuropathic pain. Recent reports have suggested that inhibitors of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), may have analgesic effects in cancer patients suffering from neuropathic pain. It has been shown that the platelet-derived growth factor receptor-β (PDGFR-β), an RTK that has been shown to interact with the EGFR, mediates opioid tolerance but does not induce analgesia. Therefore, we sought to determine whether EGFR signaling was involved in opioid tolerance and whether EGFR and PDGFR signaling could induce pain in rats. We found that gefitinib, an EGFR antagonist, eliminated morphine tolerance. In addition, repeated EGF administration rendered animals unresponsive to subsequent analgesic doses of morphine, a phenomenon we call "pre-tolerance." Using a nerve injury model, we found that gefitinib alone was not analgesic. Rather, it reversed insensitivity to morphine analgesia (pre-tolerance) caused by the release of EGF by injured nerves. We also showed that repeated, but not acute EGF or PDGF-BB administration induced mechanical hypersensitivity in rats. EGFR and PDGFR-β signaling interacted to produce this sensitization. EGFR was widely expressed in primary sensory afferent cell bodies, demonstrating a neuroanatomical substrate for our findings. Taken together, our results suggest a direct mechanistic link between opioid tolerance and mechanical sensitization. EGFR antagonism could eventually play an important clinical role in the treatment of opioid tolerance and neuropathic pain that is refractory to opioid treatment.


An outbreak of Salmonella Paratyphi A in a boarding school: a community-acquired enteric fever and carriage investigation.
Salmonella Paratyphi A (SPA) is rapidly becoming a common cause of enteric fever in South East Asia. A large outbreak of SPA occurred in a boarding middle school in China in 2004. There were 394 suspected cases; 95·5% were students. The highest incidence was in the youngest children (7th grade). Forty-four of 151 (29%) blood cultures and 4/54 (7·4%) rectal swabs were positive for SPA; three were from kitchen workers. The geometric mean levels of serum IgG anti-lipopolysaccharide (anti-LPS) from patients was higher than from healthy individuals [35·25 vs. 5·20 ELISA units (EU), P<0·001]. A kitchen worker with a positive rectal swab, negative blood culture and a high level of serum IgG anti-LPS (529·65 EU), was identified as a possible SPA carrier. No SPA was isolated from water or food samples. A survey of students' habits indicated drinking unboiled water as being the main reason for contracting the disease. Hand washing was the second most important factor. A food handler with possible SPA carriage could also have been a risk factor. Attention to maintaining a safe water supply, enhancing food-handler hygiene and proper hand washing can help to prevent similar outbreaks in the future.


Influence of uncontrolled diabetes mellitus on periodontal tissues during orthodontic tooth movement: a systematic review of animal studies.
Diabetes mellitus (DM) may adversely affect periodontal tissues during orthodontic tooth movement (OTM). The aim of this review is to systematically analyze and review animal studies investigating the effect of DM on periodontal tissues during OTM. An electronic search was conducted via PubMed/Medline, Google Scholar, Embase, ISI Web of Knowledge, and Cochrane Central Register of Controlled Trials (CONTROL) using the keywords "diabetes," "orthodontics," and "tooth movement" for studies published between January 2000 and August 2016. After elimination of duplicate items, the primary search resulted in 89 articles. After exclusion of irrelevant articles on the basis of abstract and title, full texts of 25 articles were read to exclude additional irrelevant studies. Seven animal studies were included in this review for qualitative analysis. When compared to healthy animals, more bone resorption and diminished bone remodeling were observed in diabetic animals in all studies. Furthermore, DM decreased the rate of OTM in one study, but in another study, DM accelerated OTM. DM may adversely affect bone remodeling and tooth movement during application of orthodontic forces. However, a number of potential sources of bias and deficiencies in methodology are present in studies investigating the association between OTM and DM. Hence, more long-term and well-designed studies are required before the exact mechanism and impact of DM on outcomes of orthodontic treatment is understood.


Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1.
Orthotopic liver transplantation remains the only curative therapy for inborn errors of metabolism. Given the tremendous success for primary immunodeficiencies using ex-vivo gene therapy with lentiviral vectors, there is great interest in developing similar curative therapies for metabolic liver diseases. We have previously generated a pig model of hereditary tyrosinemia type 1 (HT1), an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). Using this model, we have demonstrated curative ex-vivo gene and cell therapy using a lentiviral vector to express FAH in autologous hepatocytes. To further evaluate the long-term clinical outcomes of this therapeutic approach, we continued to monitor one of these pigs over the course of three years. The animal continued to thrive off the protective drug NTBC, gaining weight appropriately, and maintaining sexual fecundity for the course of his life. The animal was euthanized 31 months after transplantation to perform a thorough biochemical and histological analysis. Biochemically, liver enzymes and alpha-fetoprotein levels remained normal and abhorrent metabolites specific to HT1 remained corrected. Liver histology showed no evidence of tumorigenicity and Masson's trichrome staining revealed minimal fibrosis and no evidence of cirrhosis. FAH-immunohistochemistry revealed complete repopulation of the liver by transplanted FAH-positive cells. A complete histopathological report on other organs, including kidney, revealed no abnormalities. This study is the first to demonstrate long-term safety and efficacy of hepatocyte-directed gene therapy in a large animal model. We conclude that hepatocyte-directed ex-vivo gene therapy is a rational choice for further exploration as an alternative therapeutic approach to whole organ transplantation for metabolic liver disease, including HT1.


Routes of odd-even harmonic emission from oriented polar molecules.
We study odd-even high-harmonic generation (HHG) from oriented asymmetric molecules with different symmetries in strong laser fields. A model based on strong-field approximations is used which allows us to resolve the contributions of different emission routes to odd-even HHG. The comparison between the HHG yields of all routes versus one certain route demonstrates that the routes in which the electron ionizes from the gerade component of the asymmetric orbital contribute mainly to odd-even HHG. We show that the potential mechanism is associated with effects of intramolecular interference in tunneling ionization as the bound electron passes through the barrier formed by the laser field and the asymmetric Coulomb potential. The influences of different emission routes on asymmetric orbital imagining with odd-even HHG are also addressed.


Pre-injury crime, substance abuse, and neurobehavioural functioning after traumatic brain injury.
There is limited information regarding the effects of pre-injury history of arrest or history of substance use on neurobehavioural functioning after brain injury. The current study included 211 patients with traumatic brain injury, who were seen for a follow-up neuropsychological evaluation in an outpatient setting. An effort was made to distinguish between (1) patients with a history of pre-injury arrests and patients without a history of pre-injury arrests, (2) patients classified as substance abusers and non-abusers, and (3) patients with and without a history of pre-injury illicit drug use on the basis of demographic characteristics, injury characteristics, and neurobehavioural functioning. Results indicate significant differences between patients with a history of pre-injury arrests and patients without a history of pre-injury arrests in terms of demographic and injury characteristics. Differences were also noted between persons classified as substance abusers and non-abusers in terms of demographic and injury characteristics, and neurobehavioural functioning. Clinical implications and future research are discussed.


Influence of normal mammary epithelium on breast cancer progression: the protective role of early pregnancy.
The microenvironment has a well recognized role in breast cancer progression. Despite different theories, the mechanism of early pregnancy protection in mammary carcinogenesis is unknown. Since pregnancy is responsible for mammary gland differentiation, we tested the hypothesis that differentiated mammary epithelial cells may inhibit breast cancer progression. In other words, the protective role of early pregnancy could be due to the inhibitory influences of the more differentiated mammary tissue. In order to test our hypothesis, we used 30 female Balb/c nude mice and MCF-7 cells of breast adenocarcinoma. The female mice were divided into two test groups, group I (GI) and group II (GII), and a control group. In GII, the animals were submitted to epithelial removal in the left fourth inguinal mammary gland at 3 weeks of age. Both groups were given continuous hormonal treatment to simulate the pregnancy development of the mammary gland. Two million MCF-7 cells were then injected into the fourth inguinal mammary gland (GI) or in the respective cleared mammary fat pad (GII). Five weeks later the mice were sacrificed and their tumors removed. Tumor development rates and tumor volumes were determined and proliferation and apoptosis were evaluated by immunohistochemistry. Tumors of GII mice had a larger mean volume than those of GI mice (P = 0.001, Mann-Whitney U-test) and an apparent increase in proliferation, demonstrated by a higher staining intensity for proliferating cell nuclear antigen (PCNA). As tumors presented caspase 8 staining, there may be apoptotic activation involved in cell death, mainly through an extrinsic pathway. These results suggest that a differentiated intact mammary gland may have an inhibitory influence on mammary tumor growth in mice.


Association of maternal depression and anxiety with toddler social-emotional and cognitive development in South Africa: a prospective cohort study.
A robust literature has identified associations between prenatal maternal depression and adverse child social-emotional and cognitive outcomes. The majority of prior research is from high-income countries despite increased reporting of perinatal depression in low/middle-income countries (LMICs). Additionally, despite the comorbidity between depression and anxiety, few prior studies have examined their joint impact on child neurodevelopment. The objective of the current analysis was to examine associations between prenatal maternal depression and anxiety with child social-emotional and cognitive development in a cohort from the Western Cape Province of South Africa. Prenatal maternal depression and anxiety were measured using the Edinburgh Postnatal Depression Scale and the State-Trait Anxiety Inventory Scale at 20-24 weeks' gestation. Child neurobehaviour was assessed at age 3 using the Brief Infant-Toddler Social Emotional Assessment and the Bayley Scales of Infant Development III Screening Test (BSID-III ST). We used linear regression models to examine the independent and joint association between prenatal maternal depression, anxiety and child developmental outcomes. Participants consisted of 600 maternal-infant dyads (274 females; gestational age at birth: 38.89 weeks±2.03). Children born to mothers with both prenatal depression and trait anxiety had higher social-emotional problems (mean difference: 4.66; 95% CI 3.43 to 5.90) compared with children born to mothers with no prenatal depression or trait anxiety, each condition alone, or compared with mothers with depression and state anxiety. Additionally, children born to mothers with prenatal maternal depression and trait anxiety had the greatest reduction in mean cognitive scores on the BSID-III ST (mean difference: -1.04; 95% CI -1.99 to -0.08). The observed association between comorbid prenatal maternal depression and chronic anxiety with subsequent child social-emotional and cognitive development underscores the need for targeting mental health support among perinatal women in LMICs to improve long-term child neurobehavioural outcomes.


Social integration in young adulthood and the subsequent onset of substance use and disorders among a community population of urban African Americans.
This paper examines the association between social integration in young adulthood and the later onset of substance use and disorders through mid-adulthood. Design Data come from a community cohort of African Americans followed longitudinally from age 6-42 years with four assessment periods. The cohort all lived in the Woodlawn neighborhood of Chicago in 1966, an urban disadvantaged setting. All Woodlawn first graders in 1966 were asked to participate; 13 families declined (n = 1242). Substance use was measured via interview at age 42 and includes the onset of alcohol and drug use disorders and the onset of cocaine/heroin use between ages 32 and 42 years. Social integration measures were assessed via interview at age 32 and include social roles (employee, spouse, parent), participation in religious and social organizations and a measure of overall social integration. Control variables were measured in childhood and later in the life course. Multivariate regression analyses suggest that unemployment, being unmarried, infrequent religious service attendance and lower overall social integration in young adulthood predict later adult-onset drug use disorders, but not alcohol use disorders once confounders are taken into consideration. Unemployment and lower overall social integration predict onset of cocaine/heroin use later in adulthood. Results show meaningful onset of drug use and substance use disorders during mid-adulthood and that social integration in young adulthood seems to play a role in later onset of drug use and drug disorders, but not alcohol disorders.