Interlaboratory standardization of glycated hemoglobin determinations.
As the clinical utility of glycated hemoglobin (gHb) measurement increases, so does the need for standardization of values between different methods and different laboratories. Using three different methods, we examined the feasibility of interlaboratory standardization of gHb measurement. A liquid-chromatographic (HPLC) system from our research laboratory was designated the reference method. For gHb standards we used erythrocyte hemolysates prepared from blood samples from nondiabetic and diabetic subjects. Values assigned to each standard were based on the mean of multiple gHb determinations by the HPLC method. A clinical laboratory routinely prepared hemolysates and assayed gHb by commercially available ion-exchange ("mini column") and affinity chromatographic methods. For each assay a standard curve was constructed and gHb values were derived from these curves. Samples analyzed in the clinical laboratory were also analyzed in the research laboratory and the curve-derived values were compared with the HPLC-measured values, to determine the accuracy of our interlaboratory standardization procedure. Correlations were excellent (r = 0.99). The lack of significant differences between calculated and HPLC-measured values indicates that interlaboratory standardization is feasible.


Copy number variation at the 7q11.23 segmental duplications is a susceptibility factor for the Williams-Beuren syndrome deletion.
Large copy number variants (CNVs) have been recently found as structural polymorphisms of the human genome of still unknown biological significance. CNVs are significantly enriched in regions with segmental duplications or low-copy repeats (LCRs). Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a heterozygous deletion of contiguous genes at 7q11.23 mediated by nonallelic homologous recombination (NAHR) between large flanking LCRs and facilitated by a structural variant of the region, a approximately 2-Mb paracentric inversion present in 20%-25% of WBS-transmitting progenitors. We now report that eight out of 180 (4.44%) WBS-transmitting progenitors are carriers of a CNV, displaying a chromosome with large deletion of LCRs. The prevalence of this CNV among control individuals and non-transmitting progenitors is much lower (1%, n=600), thus indicating that it is a predisposing factor for the WBS deletion (odds ratio 4.6-fold, P= 0.002). LCR duplications were found in 2.22% of WBS-transmitting progenitors but also in 1.16% of controls, which implies a non-statistically significant increase in WBS-transmitting progenitors. We have characterized the organization and breakpoints of these CNVs, encompassing approximately 100-300 kb of genomic DNA and containing several pseudogenes but no functional genes. Additional structural variants of the region have also been defined, all generated by NAHR between different blocks of segmental duplications. Our data further illustrate the highly dynamic structure of regions rich in segmental duplications, such as the WBS locus, and indicate that large CNVs can act as susceptibility alleles for disease-associated genomic rearrangements in the progeny.


Food labels, autonomy, and the right (not) to know.
Food labelling has been overlooked in the emerging body of literature concerning the normative dimensions of food and drink policies. In this paper, I argue that arguments normally advanced in bioethics and medical ethics regarding the "right to know" and the "right not to know" can provide useful normative guidelines for critically assessing existing and proposed food labelling regimes. More specifically, I claim that food labelling ought to respect the legitimate interests and the autonomy of both consumers who seek knowledge about their food in order to make informed dietary choices and consumers who prefer to remain ignorant about the contents and effects of their food in order to avoid the emotional and psychological harm, or more simply the loss of enjoyment, which may result from receiving that information.


Aspiration of joints and soft tissue injections.
Musculoskeletal and connective tissue disorders are commonly encountered in primary care practice. These disorders include varieties of bursitis, tendinitis, myositis, arthritis, and related conditions. A certain group of these disorders lend themselves to diagnosis by needle aspiration or to treatment by injections. The conditions discussed in this article include subacromial bursitis, supraspinous and bicipital tendinitis, tennis elbow, de Quervain's syndrome, trigger finger, inflammation of the knee, ganglion, and muscle trigger points.


A Case of Suggested Ibuprofen-Induced Acute Pancreatitis.
Drug-induced acute pancreatitis (DIP) is uncommon and may account for 2%-5% of cases, although the incidence may be increasing nowadays. DIP has been documented for more than 160 drugs in the literature. The most common nonsteroidal anti-inflammatory drugs (NSAIDs) that have been reported to cause pancreatitis are sulindac and salicylates. In this report, we present a case of probable ibuprofen-induced pancreatitis. A 60-year-old white woman presented with the sudden onset of mild acute pancreatitis (AP) 5 hours following the ingestion of 6 tablets of ibuprofen (Advil) 200 mg (equivalent to 20.4 mg/kg). She denied any history of alcohol abuse, tobacco smoking, or any other medication use. She has no history of gallstones, choledocholithiasis, abdominal trauma, or hypertriglyceridemia. Laboratory workup revealed elevated amylase and lipase levels more than 3 times the normal limits with complete resolution within 15 hours. Computed tomography scan of abdomen and pelvis and endoscopic ultrasound of the pancreaticobiliary system were within the normal limits. Ibuprofen-induced mild DIP was the most probable diagnosis. She was discharged on her second day of hospitalization with significant improvement in her symptoms. Physicians need to be aware that DIP may occur in patients taking NSAIDs, including ibuprofen. Therefore, all patients with AP of an unknown etiology should be carefully questioned about the usage of NSAIDs, and all patients with idiopathic AP restarted on their medications should be closely monitored, and the drug must be immediately discontinued if symptoms recur.


Regulation of fibronectin receptor distribution by transformation, exogenous fibronectin, and synthetic peptides.
Recent studies have shown that fibronectin and its 140K membrane receptor complex are spatially associated with microfilaments to form cell surface linkage complexes which are thought to mediate adhesive interactions between fibroblasts and their substrata. We examined the regulation of the organization of these cell surface structures in transformed and fibronectin-reconstituted cells as well as in cells treated with a competitive synthetic peptide inhibitor of fibronectin binding to its receptor. Correlative localization experiments with interference reflection microscopy and double-label or triple-label immunofluorescence revealed a concomitant loss of fibronectin, 140K receptor, and alpha-actinin colocalization at cell substratum extracellular matrix contact sites after transformation of chick fibroblasts by wild-type or temperature-sensitive Rous sarcoma viruses (RSV). Western and dot immunoblot analyses established that although similar total quantities of intact 140K molecules were present in the transformed cell cultures, significantly more was released into the culture medium of transformed cells. The 140K molecules on transformed cells were available for interaction with exogenously added fibronectin, which could reconstitute fibronectin-140K linkage complexes. In such fibronectin reconstitution experiments, many cells expressed both fibronectin-140K-actin linkage complexes and RSV pp60src, indicating that the morphological reversion could occur even in the continued presence of RSV transformation. The synthetic peptide Gly-Arg-Gly-Asp-Ser derived from the sequence of the cell-binding region of fibronectin could also prevent the organization of fibronectin-140K linkage complexes. Our results suggest that fibronectin interaction with cells regulates the organization of fibronectin receptor complexes and cytoskeletal components at the cell surface.


Pain sensitivity and opioid activity in genetically and experimentally hypertensive rats.
Pain sensitivity was studied in renal and DOCA-salt hypertensive rats, and in two strains of rats derived from the same parental strain for their sensitivity (H) or immunity (N) to hypertension induced by DOCA-salt treatment. Experimentally hypertensive rats, and H and N rats were less sensitive to painful stimuli than their appropriate controls, as assessed in the hot-plate and paw pinch tests. Naloxone reversed this hypoalgesia in both experimentally and genetically hypertensive rats while it did not affect blood pressure in any rat-type tested. Opioid activity was measured with the radioreceptor assay in several brain regions and pituitary gland of both experimentally and genetically hypertensive rats. Experimentally hypertensive rats had a 45% higher level of opioid activity in the spinal cord compared to control. Rats of the H and N strains both exhibited higher levels of opioid activity in the spinal cord, hypothalamus and pituitary. It is suggested that control systems for blood pressure and pain sensitivity are closely associated in the rat.


Prevalence estimates of mild behavioral impairment in a population-based sample of pre-dementia states and cognitively healthy older adults.
A dearth of population-based epidemiological research examines neuropsychiatric symptom (NPS) in sub-clinical populations across the spectrum from normal aging to mild cognitive impairment (MCI). The construct of mild behavioral impairment (MBI) describes the emergence of sustained and impactful NPS in advance of or in combination with MCI. This is the first epidemiological study to operationalize the recently published diagnostic criteria for MBI and determine prevalence estimates across the spectrum from cognitively normal to MCI. MBI was assessed in 1,377 older (age range 72-79 years; 52% male; MCI ;= 133; cognitively normal, but-at-risk = 397; cognitively healthy = 847). MBI was assessed in accordance with the ISTAART-AA diagnostic criteria for MBI using the neuropsychiatric inventory. 34.1% of participants met the criteria for MBI. High prevalence of MBI across the cognitive spectrum was reported (48.9% vs. 43.1% vs. 27.6%). Irrespective of level of cognitive impairment, impulse dyscontrol (33.8% vs. 28.7% vs. 17.2%) and decreased motivation (32.3% vs. 26.2% vs. 16.3%) were the most frequently met MBI domains. MBI was more prevalent in men (χ2 = 4.98, p = 0.026), especially the domains of decreased motivation and impulse dyscontrol. This study presents the first population-based prevalence estimates for MBI using the recently published ISTAART-AA diagnostic criteria. Findings indicate relatively high prevalence of MBI in pre-dementia clinical states and amongst cognitively healthy older adults. Findings were gender-specific, with MBI affecting more men than women. Knowing the estimates of these symptoms in the population is essential for understanding and differentiating the very early development of clinical disorders.


Effect of Auricular Acupuncture on Propofol Induction Dose: Could Vagus Nerve and Parasympathetic Stimulation Replace Intravenous Co-Induction Agents?
Objective: Auricular acupuncture, through a combination of several points, can produce sedative and analgesic effects. The aim of this study was to compare the induction dose of propofol required to obtain a loss of response to verbal commands, with and without a preoperative combination of auricular points. Materials and Methods: This study involved American Society of Anesthesiologists physical status I and II patients, ages 18- 65, of either sex, having elective ambulatory surgery (digestive or gynecologic) under general anesthesia. The subjects were allocated to 2 groups: (1) patients treated by auricular acupuncture (group AA), compared with (2) patients not treated by auricular acupuncture (group NA). Propofol injection was initiated in each group, 10 mg, every 5 seconds, in order for the anesthetist to determine the minimum dose until there was a loss of response to verbal commands (the clinical hypnotic endpoint). At this point, the main outcome-the dose of propofol given-was noted. Results: There were 32 patients in this study (16 in each group). Age, height, weight, and body mass index were similar in the groups (P ≥ 0.05). The required induction propofol dose was 17.7% lower in group AA than in group NA-a statistically significant difference (P ≤ 0.05). The mean induction dose indexed to weight was 2.18 mg/kg (range: 1.53-3.13 mg/kg) in group NA and 1.79 mg/kg (range: 1.12-2.11 mg/kg) in group AA. There were no complications. Conclusions: Auricular acupuncture is a method for stimulating the vagus nerve and parasympathetic nervous system. Preoperative auricular acupuncture enabled reductions of induction doses of propofol for general anesthesia without any clinically important side-effects.


Diagnostic value of brain tumor neuroendoscopic biopsy and correlation with open tumor resection.
The risks of stereotactic biopsy are increased not only in tumors located in the vicinity of vascular structures, but also in cystic, intraventricular, and periventricular lesions. The use of neuroendoscopy for cystic, intraventricular, or periventricular brain tumors is particularly advantageous because of the possibility of biopsy and immediate hemostasis under direct vision. Neuroendoscopy provides the possibility of controlling tumor-associated obstructive hydrocephalus by means of endoscopic third ventriculostomy or septostomy. The literature gives good evidence for the diagnostic benefits of neuroendoscopic biopsy. The correlation of the histology obtained by neuroendoscopic biopsy and subsequent surgical resection may allow the evaluation of the validity of diagnostic neuroendoscopic biopsy. Between 2003 and 2010, 23 patients with suspected cystic brain tumor (12 males; age range, 21-75 years; mean age, 49.7 years; and 11 females; age range, 22-76 years; mean age, 59.1 years) and 35 patients with intraventricular or periventricular brain tumors (19 males; age range, 6-80 years; mean age, 43.9 years; and 16 females; age range, 11-78 years; mean age, 46.2 years) underwent navigated neuroendoscopic biopsy. Diagnostic samples were obtained in all cystic tumors and in 94.7% of intraventricular or periventricular tumors. Tumor resection after neuroendoscopic biopsy was performed in seven patients with cystic tumors. The results of the histological analysis of samples taken during endoscopic biopsy and surgical resection were identical in five of these patients (70.1%). Four patients with intraventricular or periventricular tumors underwent tumor resection after neuroendoscopic biopsy. The histological results of neuroendoscopic biopsy and tumor resection were identical in three patients (75%). Neuroendoscopic biopsy was performed in six patients with expansive pseudocyst after tumor resection and oncological therapy. The results of the neuroendoscopic biopsy matched the results of open surgery in four patients (66%). In the two remaining patients, there was a difference in tumor grading. The diagnostic accuracy of neuroendoscopic biopsy samples can be compared with the results of stereotactic biopsy. The histological results of endoscopically taken biopsy samples and the final histological results obtained during open surgery correlate in the majority of patients, and underlines the high diagnostic validity of neuroendoscopic biopsy.


The current role of electron microscopy in the diagnosis of epithelial and epithelioid tumors.
Electron microscopy may be applied to the study of epithelial or epithelial-like tumors with benefits similar to those encountered when it is applied to other diseases. Thus, it may complement and allow us to understand the light microscopic appearance of tumors, help in tailoring or reducing the number of antibodies, or lead to diagnosis in cases with paradoxical or nonspecific immunocytochemical results. An important, newly suggested application is to use it as a quality assurance tool in the evaluation of cases already diagnosed by other methods. Tumors with epithelial phenotype are highly prevalent, and therefore the number of problem cases can also be relatively high. In this article, we review the main ultrastructural features used in the differential diagnosis of epithelial and epithelioid tumors and some potential pitfalls. In addition, we summarize the criteria for differential diagnosis in specific topographical areas and analyze some examples of how electron microscopy may improve the accuracy of pathological diagnosis by interacting with currently available immunocytochemical panels.


The Aspergillus flavus rtfA Gene Regulates Plant and Animal Pathogenesis and Secondary Metabolism.
Aspergillus flavus is an opportunistic fungal plant and human pathogen and a producer of mycotoxins, including aflatoxin B1 (AFB1). As part of our ongoing studies to elucidate the biological functions of the A. flavusrtfA gene, we examined its role in the pathogenicity of both plant and animal model systems. rtfA encodes a putative RNA polymerase II (Pol II) transcription elongation factor previously characterized in Saccharomyces cerevisiae, Aspergillus nidulans, and Aspergillus fumigatus, where it was shown to regulate several important cellular processes, including morphogenesis and secondary metabolism. In addition, an initial study in A. flavus indicated that rtfA also influences development and production of AFB1; however, its effect on virulence is unknown. The current study reveals that the rtfA gene is indispensable for normal pathogenicity in plants when using peanut seed as an infection model, as well as in animals, as shown in the Galleria mellonella infection model. Interestingly, rtfA positively regulates several processes known to be necessary for successful fungal invasion and colonization of host tissue, such as adhesion to surfaces, protease and lipase activity, cell wall composition and integrity, and tolerance to oxidative stress. In addition, metabolomic analysis revealed that A. flavusrtfA affects the production of several secondary metabolites, including AFB1, aflatrem, leporins, aspirochlorine, ditryptophenaline, and aflavinines, supporting a role of rtfA as a global regulator of secondary metabolism. Heterologous complementation of an A. flavusrtfA deletion strain with rtfA homologs from A. nidulans or S. cerevisiae fully rescued the wild-type phenotype, indicating that these rtfA homologs are functionally conserved among these three species.IMPORTANCE In this study, the epigenetic global regulator rtfA, which encodes a putative RNA-Pol II transcription elongation factor-like protein, was characterized in the mycotoxigenic and opportunistic pathogen A. flavus Specifically, its involvement in A. flavus pathogenesis in plant and animal models was studied. Here, we show that rtfA positively regulates A. flavus virulence in both models. Furthermore, rtfA-dependent effects on factors necessary for successful invasion and colonization of host tissue by A. flavus were also assessed. Our study indicates that rtfA plays a role in A. flavus adherence to surfaces, hydrolytic activity, normal cell wall formation, and response to oxidative stress. This study also revealed a profound effect of rtfA on the metabolome of A. flavus, including the production of potent mycotoxins.


Activation of plant foliar oxidases by insect feeding reduces nutritive quality of foliage for noctuid herbivores.
The foliage and fruit of the tomato plantLycopersicon esculentum contains polyphenol oxidases (PPO) and peroxidases (POD) that are compartmentally separated from orthodihydroxyphenolic substrates in situ. However, when leaf tissue is damaged by insect feeding, the enzyme and phenolic substrates come in contact, resulting in the rapid oxidation of phenolics to orthoquinones. When the tomato fruitwormHeliothis zea or the beet army-wormSpodoptera exigua feed on tomato foliage, a substantial amount of the ingested chlorogenic acid is oxidized to chlorogenoquinone by PPO in the insect gut. Additionally, the digestive enzymes of the fruitworm have the potential to further activate foliar oxidase activity in the gut. Chlorogenoquinone is a highly reactive electrophilic molecule that readily binds cova-lently to nucleophilic groups of amino acids and proteins. In particular, the -SH and -NH2 groups of amino acids are susceptible to binding or alkylation. In experiments with tomato foliage, the relative growth rate of the fruitworm was negatively correlated with PPO activity. As the tomato plant matures, foliar PPO activity may increase nearly 10-fold while the growth rate of the fruitworm is severely depressed. In tomato fruit, the levels of PPO are highest in small immature fruit but are essentially negligible in mature fruit. The growth rate of larvae on fruit was also negatively correlated with PPO activity, with the fastest larval growth rate occurring when larvae fed on mature fruit. The reduction in larval growth is proposed to result from the alkylation of amino acids/protein byo-quinones, and the subsequent reduction in the nutritive quality of foliage. This alkylation reduces the digestibility of dietary protein and the bioavailability of amino acids. We believe that this mechanism of digestibility reduction may be extrapolatable to other plant-insect systems because of the ubiquitous cooccurrence of PPO and phenolic substrates among vascular plant species.


Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node.
Invariant patterning of left-right asymmetry during embryogenesis depends upon a cascade of inductive and repressive interactions between asymmetrically expressed genes. Different cascades of asymmetric genes distinguish the left and right sides of the embryo and are maintained by a midline barrier. As such, the left and right sides of an embryo can be viewed as distinct and autonomous fields. Here we describe a series of experiments that indicate that the initiation of these programs requires communication between the two sides of the blastoderm. When deprived of either the left or the right lateral halves of the blastoderm, embryos are incapable of patterning normal left-right gene expression at Hensen's node. Not only are both flanks required, suggesting that there is no single signaling source for LR pattern, but the blastoderm must be intact. These results are consistent with our previously proposed model in which the orientation of LR asymmetry in the frog, Xenopus laevis, depends on large-scale partitioning of LR determinants through intercellular gap junction channels (M. Levin and M. Mercola (1998) Developmental Biology 203, 90-105). Here we evaluate whether gap junctional communication is required for the LR asymmetry in the chick, where it is possible to order early events relative to the well-characterized left and right hierarchies of gene expression. Treatment of cultured chick embryos with lindane, which diminishes gap junctional communication, frequently unbiased normal LR asymmetry of Shh and Nodal gene expression, causing the normally left-sided program to be recapitulated symmetrically on the right side of the embryo. A survey of early expression of connexin mRNAs revealed that Cx43 is present throughout the blastoderm at Hamburger-Hamilton stage 2-3, prior to known asymmetric gene expression. Application of antisense oligodeoxynucleotides or blocking antibody to cultured embryos also resulted in bilateral expression of Shh and Nodal transcripts. Importantly, the node and primitive streak at these stages lack Cx43 mRNA. This result, together with the requirement for an intact blastoderm, suggests that the path of communication through gap junction channels circumvents the node and streak. We propose that left-right information is transferred unidirectionally throughout the epiblast by gap junction channels in order to pattern left-sided Shh expression at Hensen's node.


[Reactivity of the adrenal cortex and the renin-angiotensin system in young rats with spontaneous hypertension].
Corticosteroid biosynthesis from 14C-progesterone by the adrenal glands in vitro, 14C-aldosterone metabolism by the liver, plasma aldosterone content, and also angiotensin I concentration and blood plasma renin activity were studied in Okamoto rats with spontaneous hypertension and in Wistar rats with normal blood pressure, 4--5 weeks of age. Acute immobilization stress induced in rats with normal blood pressure caused activation of the adrenal cortex glucocorticoid function without increase of aldosterone biosynthesis or of its blood content, whereas in rats with hypertension the same stress led to adrenal cortex mineralocorticoid function activation and to the sharp blood plasma aldosterone elevation. In rats with normal blood pressure there is a reduction of renin activity and an increase in the angiotensin I content during stress, whereas in rats with hypertension the activity of the renin-angiotensin system remains unchanged. An increase in the mineralocorticoid concentration in rats with spontaneous hypertension can play an important role under these conditions in the elevation of arterial pressure.


Simple modifications of branched PEI lead to highly efficient siRNA carriers with low toxicity.
Polymer carriers like PEI which proved their efficiency in DNA delivery were found to be far less effective for the applications with siRNA. In the current study, we generated a number of nontoxic derivates of branched PEI through modification of amines by ethyl acrylate, acetylation of primary amines, or introduction of negatively charged propionic acid or succinic acid groups to the polymer structure. The resulting products showed high efficiency in siRNA-mediated knockdown of target gene. In particular, succinylation of branched PEI resulted in up to 10-fold lower polymer toxicity in comparison to unmodified PEI. Formulations of siRNA with succinylated PEI were able to induce remarkable knockdown (80% relative to untreated cells) of target luciferase gene at the lowest tested siRNA concentration of 50 nM in Neuro2ALuc cells. The polyplex stability assay revealed that the efficiency of formulations which are stable in physiological saline is independent of the affinity of siRNA to the polymer chain. The improved properties of modified PEI as siRNA carrier are largely a consequence of the lower polymer toxicity. In order to achieve significant knockdown of target gene, the PEI-based polymer has to be applied at higher concentrations, required most probably for sufficient accumulation and proton sponge effects in endosomes. Unmodified PEI is highly toxic at such polymer concentrations. In contrast, the far less toxic modified analogues can be applied in concentrations required for the knockdown of target genes without side effects.


[Effect of a derivative of GABA, phenibut, on behavior and the activity of visual cortex neurons of the rabbit during elaboration of a defensive reflex and internal inhibition].
In experiments on alert non-immobilized rabbits the effect of subcutaneous administration of the GABA-derivate--phenibut on behaviour, slow potentials and impulse activity of neurones of the visual cortex was studied during elaboration of a defensive reflex to light flashes and of conditioned inhibition. During the action of phenibut late negative-positive components of the evoked potentials to flashes, corresponding inhibitory pauses and postinhibitory activation gradually increased; then stable predominance of slow high-amplitude potential oscillations and corresponding neuronal group bursts appeared, separated by inhibitory pauses and in intersignal periods. Reinforcing stimulus, as before phenibut administration, lowered the amplitudes of slow potential oscillations and weakened inhibitory pauses in neuronal impulse activity. Dynamics of movements in response to the stimuli was of a phasic character. 3 hours after phenibut administration the discrimination of reinforced and inhibitory light flashes has distinctly improved. The obtained results confirm the initial concept of the significant role of the GABA-ergic inhibitory system in the process of elaboration of internal inhibition.


Effects of intermittent and continuous cocaine administration on dopamine release and uptake regulation in the striatum: in vitro voltammetric assessment.
Chronic daily injections of cocaine induce behavioral sensitization to subsequent cocaine challenge, while continuous infusion induces tolerance. Following a 7-day withdrawal period, we examined the effects of these two dosing regimens on: (1) baseline dopamine efflux and uptake following single-pulse electrical stimulation, (2) inhibition of uptake by cocaine; and (3) inhibition of efflux by autoreceptor activation. Cocaine (40 mg/kg per day) was administered to rats for 14 days either continuously by osmotic minipumps or intermittently by once-a-day injections. Minipumps containing saline were implanted in the control group. After 7 days of withdrawal, dopamine kinetics in the caudate was examined using in vitro fast-scan cyclic voltammetry. This technique provides very rapid measurements of dopamine in the extracellular space. Thus, when combined with endogenous dopamine efflux evoked by single-pulse, electrical stimulations, it was possible directly to measure the release and uptake components of the efflux. In the absence of pharmacological agents, no group differences were found in the amount of baseline dopamine released or in the uptake kinetics; the potency of bath-applied cocaine (0.03-60 microM) in inhibiting the uptake was also unaltered in either group. In contrast, the potency of quinpirole (an autoreceptor agonist, 5-250 nM) was significantly decreased and increased in the cocaine injection and pump groups, respectively. Thus, the cocaine administration regimen which produces sensitization results in a functional subsensitivity of release-modulating autoreceptors, while the tolerance-producing regimen results in autoreceptor supersensitivity.


Transcutaneous magnetic stimulation of the quadriceps via the femoral nerve.
We investigated the efficacy of different frequencies and intensities of magnetic stimulation for activating the quadriceps muscles; a painless method for stimulating the quadriceps would be useful in the rehabilitation of patients who have difficulty in voluntarily activating their muscles after injury or surgery. Eleven subjects underwent magnetic stimulation of the femoral nerve over a range of frequencies and intensities using a MagStim Rapid magnetic stimulator. Magnetic stimulation at 30 Hz at 80% of the power output of the stimulator used was capable of generating 72% of quadriceps maximal voluntary contraction torque. Subjects reported little or no pain during the procedure. Magnetic stimulation of the femoral nerve is a well-tolerated way to activate the quadriceps muscles.


[Establishment of LAMP Detection for Toxoplasma gondii Based on the 529 bp Repeat Sequence].
To establish the loop mediated isothermal amplification(LAMP) technique for determining Toxoplama gondii. The primers for LAMP of the conserved 529 bp sequence was designed by the Primer Explorer 4.0 software. The LAMP reaction was made on the constructed pMD-19T-529 bp recombinant plasmid as a template, and was optimized in loop primer, concentrations of betaine and MgSO4, and reaction temperature. The optimized LAMP and PCR were performed in ultra-pure water, on pig genome, Cryptosporidium parvum genome, Isospora suis genome, and pMD-19T-529 bp, respectively, to test the sensitivity of LAMP. The pMD-19T-529 bp was serially diluted to 109-100 copies/ml to test the specificity of LAMP. LAMP using the designed primers amplified the 529 bp fragment of T. gondii. The optimized LAMP system had a total reaction volume of 25 μl, with the optimal concentrations of betaine and MgSO4 being 0.4 mol/L and 6 mmol/L, respectively. The amplification efficiency of 30 min reaction in the presence of loop primer was comparable to that of 60 min reaction without loop primer, which indicated that addition of loop primer shortened the reaction time by 30 min. The optimal reaction condition was 63 ℃ 30 min, 80 ℃ 3 min. The established LAMP method specifically amplifed the 529 bp fragment of T. gondii, and its efficiency was 10 times of PCR(detection threshold 103 copies/ml vs. 104 copies/ml). The established LAMP for detecting Toxoplama gondii 529 bp repeat sequence shows high specificity and sensitivity.


Conspecifics, not pollen, reduce omnivore prey consumption.
Pollen can decrease (via reduced consumption) or increase (via numerical response) an omnivores consumption of animal prey. Although pollen can increase predation pressure through numerical responses of omnivores, pollen may also suppress predation by increasing omnivore interactions with conspecifics. Despite this potential, studies of the impacts of pollen on predation by omnivores often overlook the effect of these tissues on intraspecific interactions between omnivores. We designed three studies to examine how Spartina foliosa pollen and conspecific density impact scale insect prey consumption by ladybeetle (Naemia seriata) omnivores. First, we assessed how pollen impacts scale insect consumption by isolated ladybeetles. Second, we measured how pollen influences ladybeetle prey suppression when numerical responses were possible. Third, because initial experiments suggested the consumption rates of individual ladybeetles depended on conspecific density, we compared per capita consumption rates of ladybeetles across ladybeetle density. Pollen did not influence prey consumption by isolated ladybeetles. When numerical responses were possible, pollen did not influence total predation on prey despite increasing ladybeetle density, suggesting that pollen decreased per capita prey consumption by ladybeetles. The discrepancy between these studies is likely a consequence of differences in ladybeetle density-the presence of only two other conspecifics decreased per capita prey consumption by 76%. Our findings suggest that pollen may not alter the population level effects of omnivores on prey when omnivore numerical responses are offset by reductions in per capita predation rate.


Tomographic mapping of human cerebral metabolism visual stimulation and deprivation.
Positron computed tomography was used to investigate changes in the local cerebral metabolic rate for glucose (LCMRGlc) of the visual cortex. Progressive increases in LCMRGlc were found from eyes-closed control to stimulation with white light, alternating black/white checkerboard pattern, and a complex visual scene of a park, with the associative visual cortex increasing at a faster rate than the primary visual cortex as the visual scene complexity increased. A graded decrease in LCMRGlc of the visual cortex was found with a stepwise deletion of spontaneous cell firing at the retinal, geniculate and cortical level due to lesions. Left/right metabolic symmetry of the visual cortex during monocular stimulation confirms 50% crossing of the human visual system. Neonatal blindness showed no apparent degeneration of the visual cortex and was equivalent to eyes-closed controls. The interictal state of a patient with visual seizures demonstrated a hypometabolic visual cortex with a 2.5-fold increase in metabolism during an ictal visual hallucination.


Surfactant lipidomics in healthy children and childhood interstitial lung disease.
Lipids account for the majority of pulmonary surfactant, which is essential for normal breathing. We asked if interstitial lung diseases (ILD) in children may disrupt alveolar surfactant and give clues for disease categorization. Comprehensive lipidomics profiles of broncho-alveolar lavage fluid were generated in 115 children by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Two reference populations were compared to a broad range of children with ILD. Class and species composition in healthy children did not differ from that in children with ILD related to diffuse developmental disorders, chronic tachypnoe of infancy, ILD related to lung vessels and the heart, and ILD related to reactive lymphoid lesions. As groups, ILDs related to the alveolar surfactant region, ILD related to unclear respiratory distress syndrome in the mature neonate, or in part ILD related to growth abnormalities reflecting deficient alveolarisation, had significant alterations of some surfactant specific phospholipids. Additionally, lipids derived from inflammatory processes were identified and differentiated. In children with ABCA3-deficiency from two ILD causing mutations saturated and monounsaturated phosphatidylcholine species with 30 and 32 carbons and almost all phosphatidylglycerol species were severely reduced. In other alveolar disorders lipidomic profiles may be of less diagnostic value, but nevertheless may substantiate lack of significant involvement of mechanisms related to surfactant lipid metabolism. Lipidomic profiling may identify specific forms of ILD in children with surfactant alterations and characterized the molecular species pattern likely to be transported by ABCA3 in vivo.


A novel method for the rapid sensing of H2O2 using a colorimetric AuNP probe and its DFT study.
Hydrogen peroxide (H2O2) has tremendous applications in industry, medicine and in our day-to-day lives. It is toxic to human health upon exposure at a high concentration. Therefore, a green and cost-effective sensing technique is greatly needed for the sensitive naked eye detection of peroxide. This study is mainly focused on the synthesis of Au nanoparticles (AuNPs) using an aqueous extract of Elsholtzia blanda, a flower that is widely available in the North Eastern part of India, the characterization of which was carried out using different analytical techniques. The bioactive molecule (epigallocatechin gallate) present in the aqueous extract was identified, isolated and confirmed through high-performance liquid chromatography-photodiode array, high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy analysis which could be responsible for the reduction of Au3+ ions. By approaching this greener route, the synthesized nanomaterial was further used as a colorimetric probe for the detection of H2O2 and the degradation of AuNPs was observed. The limit of detection was found to be 0.7435 μM in the present work. The degradation of the AuNPs was found to be linearly dependent on peroxide concentration. Along with these results, kinetic studies were carried out by considering different effects to monitor the sensing speed of the AuNPs. The plausible mechanism of the work was supported by density functional theory study.


Multi-region phase calibration of liquid crystal SLM for holographic display.
The liquid crystal spatial light modulator (SLM) is able to provide flexible wavefront control, whereas the initial phase and its response distortions will heavily influence the modulation accuracy. The currently existing calibration methods are tedious and time consuming. A novel multi-region calibration method for minimizing those distortions is proposed. The entire panel is divided into several local regions based on the similarity of phase response characteristic. The nonlinear phase response and static phase distortion of each local region are calibrated in the iterative division procedure. The calibration method is theoretically analyzed and experimentally verified. For the Jasper 4 K SLM panel, when five local regions are built, the root mean error of linear phase shifts is reduced to 0.1 rad and the compensation accuracy of the static phase distortion reaches 0.24 wavelength. The calibrated SLM is applied for the color holographic display and the results show that the reconstructed image quality is improved significantly. The proposed method is simpler and faster because of the reasonable regional division and lower calibration complexity. It could be used for the calibration of various phase only or complex modulators with high space bandwidth product in the future.


Operatively treated type IV tibial tubercle apophyseal fractures.
Displaced tibial tubercle apophyseal fractures in children and adolescents are typically treated with closed reduction or open reduction with anterior to posterior screw fixation. Since the original classification by Watson-Jones and Ogden, an important variant with a posterior metaphyseal fracture line (type IV) was later described. However, there has been a lack of information regarding type IV tibial tubercle apophyseal fractures and its implications for surgical fixation. Twenty-four type IV tibial tubercle fractures in 23 children and adolescents were reviewed. Operative reports and clinic records were used to identify the patient demographics, fracture type, and clinical results. Available imaging was also used to characterize these fractures. Minimum follow-up was 2 years. Type IV fractures accounted for 18.5% (24/130) of all tibial tubercle apophyseal fractures. Three type IV fractures were identified that had an additional epiphyseal split. These were categorized as type IV-B, whereas the rest were considered type IV-A. There were 19 males and 4 females (average age, 14.8 y; range, 11.8 to 16 y). The most common mechanism was an eccentric quadriceps contraction during basketball. Three patients were initially treated with closed reduction and casting and were noted to have loss of reduction. All patients were treated definitively with open reduction and internal fixation or percutaneous screw placement. In addition to AP compression screws, 4 patients required supplemental plate fixation to stabilize the proximal tibia. Major complications included 1 compartment syndrome and 1 large DVT. All fractures healed and there were no growth disturbances. Type IV tibial tubercle apophyseal fractures are an important variant that requires careful assessment to ensure adequate stabilization of the proximal tibia when surgery is warranted. IV (prognostic case series).


Validity and reliability of a nutrition screening tool in hospitalized patients.
The British nutrition screening tool is a questionnaire designed to assess the nutrition status of hospitalized patients by nurses. The aim of this study was to evaluate the validity and reliability of this questionnaire in patients on admission to the hospital in Tehran. For 6 mo, 446 patients aged over 18 y admitted to different wards of a general hospital were studied within the first 24 h of admission. A nutritionist undertook nutritional assessment in all patients to determine their nutritional status as an objective standard. Then a nurse completed the screening tool for patients. Results obtained using the screening tool were compared with those of the nutritional assessment to calculate the sensitivity, specificity, and predictive values. The interrater reliability of the tool was assessed by two nurses who completed the screening tool separately during the first 24 h following admission of each patient. It was also completed by a nurse within 2-d period of admission to test the intrarater reliability. Study participants included 229 women and 217 men with mean age of 49.5 ± 16.0 y. Sensitivity and specificity of the questionnaire were 86.7% (95% CI: 83.9-90.3%) and 61.7% (95% CI: 57.5-66.5%), respectively. Positive and negative predictive values were 79.1% (95% CI: 68.9-77.1%) and 73.1% (95% CI: 75.1-82.9), respectively. The sensitivity of the tool was over 80% for both genders, for all body mass index grades, and for data obtained from gastroenterology, transplant, oncology, and hematology wards. The interrater reliability of screening tool was interpreted as substantial, being k = 0.68 and k = 0.74 on both the first and second days, respectively. The intrarater reliability of the screening tool was also interpreted as substantial, being k = 0.77. The nutrition screening tool is a simple, valid, and reliable tool that can be used by nurses to facilitate identification of patients requiring nutritional interventions.


PARP Inhibitors in Prostate Cancer.
The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential "BRCAness" of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.


Role of uteroferrin in placental iron transport in swine: relationship between uteroferrin levels and iron deposition in the conceptus during gestation.
This study was to examine the relationship between uteroferrin and Fe, and Fe and Cu in the fetal pig. In Exp. 1, conceptus tissues and fluids were obtained on d 30, 45, 60, 75 and 90 of gestation for Fe and Cu analyses. In fetus minus liver, total Fe and Cu increased constantly between d 30 and 90, but Fe and Cu concentrations (microgram/g dry tissue) both decreased between d 30 and 45 and then remained relatively constant to d 90. For fetal liver, total Fe increased from d 30 (27 micrograms) to d 90 (3,222 micrograms), as did total Cu (14 micrograms on d 30 to 960 micrograms on d 90). Fetal liver Fe concentration (microgram/g dry tissue) decreased from d 30 (1,021) to d 60 (472) and then increased to d 90 (1,082), whereas Cu concentration increased between d 30 (537) and 60 (830) and then decreased between d 60 (471) and 90 (329). In allantoic fluid, both total Fe and Cu increased between d 30 and 60 and then decreased to d 90. Data from this study indicated a close temporal relationship between Fe and Cu in the fetal tissues and fluids examined. In Exp. 2, the relationship between Fe and uteroferrin in fetal tissues and fluids was studied. Uteroferrin, measured indirectly by acid phosphatase activity and Fe in fetal tissues and fluid underwent closely related temporal changes between d 30 and 112 of gestation. Changes in total Fe and Fe concentration during gestation were similar to those described for Exp. 1 in fetus minus liver, fetal liver and allantoic fluid. In addition, total Fe and Fe concentration in placental and endometrial tissues were analyzed. It was concluded that uteroferrin provides a major source of Fe in endometrial secretion and that it may be stored in placental and endometrial tissues. The relationship between Fe and Cu in conceptus tissues and erythropoiesis also is discussed.


Human endothelial dysfunction: EDCFs.
Human studies, conducted in the presence of clinical conditions characterized by endothelial dysfunction, evidenced that endothelial cells, in response to different agonists and physical stimuli, become a source of endothelium-derived contracting factors (EDCFs), mainly cyclooxygenase (COX)-derived prostanoids. Their production has been documented in several human diseases, mostly in essential hypertension and aging. The EDCF production was at first identified as responsible for impaired endothelium-dependent vasodilation in the forearm microcirculation of patients with essential hypertension. Subsequent studies demonstrated that COX-dependent EDCF products are also a characteristic of the aging process, and essential hypertension seems to only anticipate the phenomenon. Of note, in aging and hypertension, both indomethacin, a COX inhibitor, and vitamin C, an antioxidant, totally reverse the blunted vasodilation to acetylcholine by restoring NO availability, thus suggesting that EDCFs could be one of the major sources of oxygen free radicals. The presence of EDCFs was documented also in other clinical setting, such as coronary artery disease and estrogen deprivation. In conclusion, many human pathological conditions characterized by a decline in endothelial function are associated with a progressive decrease in NO bioavailability and increase in the production of EDCFs. The mechanisms that regulate the balance between NO and EDCFs and the processes transforming the endothelium from a protective organ to a source of vasoconstrictor, proaggregatory and promitogenic mediators, remain to be determined.


Control of plasma levels of growth hormone, glucagon and insulin in ducklings: roles of free fatty acids and somatostatin.
The effects of plasma free fatty acids (FFA) and somatostatin-14 (S-14) on concentrations of plasma GH, glucagon and insulin were investigated in juvenile ducks. Oleic acid, S-14 or both were infused into 4- to 7-week-old birds and plasma GH, glucagon-like immunoreactivity (GLI), immunoreactive insulin (IRI) and FFA were measured. An increase in plasma GH and a decrease in GLI but no change in IRI was observed after infusion of 9 mg oleic acid/kg per min. A decrease in plasma GH, FFA and IRI and an increase in plasma GLI was seen after infusion of 800 ng S-14/kg per min. These effects of S-14 on IRI and GLI were abolished when S-14 was infused simultaneously with oleic acid. It is concluded that FFA have a direct stimulatory effect on GH secretion and an inhibitory effect on glucagon secretion. Somatostatin-14 directly inhibits the secretion of GH and its stimulatory effect on the secretion of glucagon is mediated by a depression in concentrations of plasma FFA. Finally, S-14 has no effect on plasma insulin when basal levels of plasma FFA are maintained.


Evidence for structural dissimilarity in the neurotransmitter binding region of purified acetylcholine receptors from human muscle and Torpedo electric organ.
Acetylcholine receptor (AChR) purified from human skeletal muscle affinity-alkylated with bromoacetyl[methyl-3H]choline bromide ([3H]BAC) in mildly reducing conditions to yield a specifically radiolabeled polypeptide, Mr 44,000, the alpha-subunit. The binding of [125I]alpha-bungarotoxin to AChR was completely inhibited by affinity-alkylation, indicating that the human AChR's binding site for alpha-bungarotoxin is closely associated with the alpha-subunit's acetylcholine binding site. Structures in the vicinity of the alpha-bungarotoxin binding sites of AChRs from human muscle and Torpedo electric organ were compared by varying the conditions of alkylation. Under optimal conditions of reduction and alkylation, both human and Torpedo AChR incorporated BAC in equivalence to the number of alpha-bungarotoxin binding sites. However, with limited conditions of reduction but sufficient BAC to alkylate 100% of the alpha-bungarotoxin binding sites of human AChR, only 71% of the Torpedo AChR's binding sites were alkylated. In optimal conditions of reduction but with the minimal concentration of BAC that permitted 100% alkylation of the human AChR's alpha-bungarotoxin sites, only 74% of the Torpedo AChR's binding sites were alkylated. These data suggest that the neurotransmitter binding region of human muscle AChR is structurally dissimilar from that of Torpedo electric organ, having a higher binding affinity for BAC and an adjacent disulfide bond that is more readily accessible to reducing agents.


Tolerance of debility in elderly dependants by supporters at home: its significance for hospital practice.
Some 12% of all geriatric admissions to University College Hospital and Whittington Hospital are for patients whose relatives or friends can no longer cope with them at home. The person principally involved with home support was interviewed in 50 such cases. The causes of inability to cope were identified on a quantitative and qualitative basis. The supporters were asked to assess which of the problems identified would have to be alleviated to restore a tolerable situation at home; 46 (92%) were able to do so. Identification of the "alleviation factors" forms a therapeutic and prognostic guideline in this type of admission and may have far-reaching social and economic implications.


Medical Education Partnership Initiative (MEPI) in Zimbabwe: Outcomes and Challenges.
Sub-Saharan Africa has an inadequate number of health professionals, leading to a reduced capacity to respond to health challenges, including HIV/AIDS. From 2010 to 2015, the Medical Education Partnership Initiative (MEPI)-sponsored by the U.S. Presidents Emergency Plan for AIDS Relief (PEPFAR) and the National Institutes of Health (NIH)-was enthusiastically taken up by the University of Zimbabwe College of Health Sciences (UZCHS) and 12 other sub-Saharan African universities to develop models of training to improve medical education and research capacity. In this article, we describe the outcomes and challenges of MEPI in Zimbabwe. UZCHS in partnership with the University of Colorado, Denver; Stanford University; University of Cape Town; University College London; and King's College London designed the Novel Education Clinical Trainees and Researchers (NECTAR) program and 2 linked awards addressing cardiovascular disease and mental health to pursue MEPI objectives. A range of medical education and research capacity-focused programs were implemented, including faculty development, research support, mentored scholars, visiting professors, community-based education, information and technology support, cross-cutting curricula, and collaboration with partner universities and the ministries of health and education. We analyzed quantitative and qualitative data from several data sources, including annual surveys of faculty, students, and other stakeholders; workshop exit surveys; and key informant interviews with NECTAR administrators and leaders and the UZCHS dean. Improved Internet connectivity and electronic resource availability were early successes of NECTAR. Over the 5-year period, 69% (115 of 166) of faculty members attended at least 1 of 15 faculty development workshops. Forty-one faculty members underwent 1-year advanced faculty development training in medical education and leadership. Thirty-three mentored research scholars were trained under NECTAR, and 52 and 12 in cardiovascular and mental health programs, respectively. Twelve MEPI scholars had joined faculty by 2015. Full-time faculty grew by 36% (122 to 166), annual postgraduate and medical student enrollment increased by 61% (75 to 121) and 71% (123 to 210), respectively. To institutionalize and sustain MEPI innovations, the Research Support Center and the Department of Health Professions Education were established at UZCHS. MEPI has synergistically revitalized medical education, research capacity, and leadership at UZCHS. Investments in creating a new research center, health professions education department, and, programs have laid the foundation to help sustain faculty development and research capacity in the country.


Tree, sex and size: Ecological determinants of male vs. female fecundity in three Fagus sylvatica stands.
Interindividual variation in fecundities has major consequences on population evolutionary potential, through genetic drift and selection. Using two spatially explicit mating models that analyse the genotypes of seeds and seedlings, we investigated the variation of male and female fecundities within and among three European beech (Fagus sylvatica) stands situated along an altitudinal gradient. Female and male individual fecundity distributions were both skewed in this monoecious species, and we found a higher variance in female as compared to male fecundities. Both female and male fecundities increased with tree size and decreased with density and competition in the neighbourhood, the details of these effects suggesting sex-specific strategies to deal with the impact of limited resource on fecundity. The studied populations were functionally male-biased. Among-individual variations in functional gender were not driven by tree size but by density and competition in the neighbourhood. Femaleness decreased under limited resource availability, an expected consequence of the higher cost of female reproduction. Considering the variation of gene flow and genetic drift across elevation, our results suggest that the adaptive potential could be enhanced by low genetic drift at low elevation, and by high pollen-mediated gene flow at high elevation. Finally, this study predicts a more efficient response to selection for traits related to male vs. female fitness, for a given selection intensity.


Mobile fiber-optic sensor for detection of oral and cervical cancer in the developing world.
Oral and cervical cancers are a growing global health problem that disproportionately impacts women and men living in the developing world. The high death rate in developing countries is largely due to the fact that these countries do not have the appropriate medical infrastructure and resources to support the organized screening and diagnostic programs that are available in the developed world. Diffuse reflectance spectroscopy (DRS) with a fiber-optic probe can noninvasively quantify the optical properties of epithelial tissues and has shown the potential as a cost-effective, easy-to-use, and sensitive tool for diagnosis of early precancerous changes in the cervix and oral cavity. However, current fiber-optic DRS systems have not been designed to be robust and reliable for use in developing countries. They are subject to various sources of systematic or random errors, arising from the uncontrolled probe-tissue interface and lack of real-time calibration, use bulky and expensive optical components, and require extensive training. This chapter describes a portable DRS device that is specifically designed for detection of oral and cervical cancers in resource-poor settings. The device uses an innovative smart fiber-optic probe to eliminate operator bias, state-of-the-art photonics components to reduce size and power consumption, and automated software to reduce the need of operator training. The size and cost of the smart fiber-optic DRS system may be further reduced by incorporating a smartphone based spectrometer.


The status of color fields today.
Pathology of the visual system can alter perception in the central and peripheral visual field. Pseudoisochromatic plates and pigment panel tests can be used to study macular color vision. Perimetric techniques using color targets extends testing to the peripheral field. This facilitates detection of early, sometimes subtle defects that are missed with conventional white-target perimetry. The stimulus conditions and methods of color perimetry are reviewed in this paper, particularly recent methodological advancements which offer a potential for increased sensitivity in detection of pathology.


Hypermethylation of the cap structure of both yeast snRNAs and snoRNAs requires a conserved methyltransferase that is localized to the nucleolus.
The m(7)G caps of most spliceosomal snRNAs and certain snoRNAs are converted posttranscriptionally to 2,2,7-trimethylguanosine (m(3)G) cap structures. Here, we show that yeast Tgs1p, an evolutionarily conserved protein carrying a signature of S-AdoMet methyltransferase, is essential for hypermethylation of the m(7)G caps of both snRNAs and snoRNAs. Deletion of the yeast TGS1 gene abolishes the conversion of the m(7)G to m(3)G caps and produces a cold-sensitive splicing defect that correlates with the retention of U1 snRNA in the nucleolus. Consistently, Tgs1p is also localized in the nucleolus. Our results suggest a trafficking pathway in which yeast snRNAs and snoRNAs cycle through the nucleolus to undergo m(7)G cap hypermethylation.


Inactivation of Ascaris suum in a biodrying compost system.
Pathogen contamination of waterways is a serious concern in dairy farming areas where livestock waste is applied to agricultural fields. As an alternative, a biodrying composting system dries collected livestock waste, reduces the strong odors, and has been proposed as a means of reducing, and even eliminating pathogens present in the waste. Therefore, the survival of pathogens in a biodrying composting system was investigated. Dairy farm livestock waste was piled in a biodrying storage shed where forced aeration and natural decomposition processes heated a major portion of the waste pile to temperatures exceeding 55 degrees C. Ascaris suum eggs were used as the surrogate species and inoculated into special chambers and placed at three different elevations at different intervals along the length of the pile. Control chambers were stored in water at 4 degrees C in the laboratory. Both compost and control chambers were removed at Day 4, 8, 12, 16, and 20. The eggs were extracted from the chamber medium and analyzed for viability. No viable eggs were recovered from any of the chambers removed from the compost pile, while >or=90% viability was observed in the control chambers. High temperatures and continued drying were the major contributing factors to the inactivation of the helminth eggs. The complete inactivation of A. suum eggs by the biodrying process encourages the storage and treatment of manure to high temperatures and reduced moisture conditions before field spreading to reduce the risk of harmful pathogens contaminating waterways and potential drinking water supplies.


Trivalent methylated arsenic metabolites induce apoptosis in human myeloid leukemic HL-60 cells through generation of reactive oxygen species.
Arsenic trioxide (As2O3) has remarkable therapeutic efficacy against leukemia. However, after As2O3 biotransformation, the role of arsenic metabolites in the clinical efficacy against leukemia still needs to be elucidated. Therefore, to explore the contribution of trivalent methylated arsenicals in the therapeutic effects, we investigated and compared the effects of arsenite (iAs(III)), monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) on HL-60 cells. Methylated arsenic species MMA(III) and DMA(III) showed potentially reduced cell survival with IC50 values of 3 and 2 μM, respectively. We found that methylated metabolites caused apoptosis through oxidative stress and loss of mitochondrial membrane potential. Furthermore, we found that the caspase-9 and -3 were markedly activated by exposure to methylated metabolites, with cleavage of poly-ADP ribose polymerase (PARP). Conversely, cellular apoptosis, generation of ROS, activation of caspase-3, -9 as well as PARP cleavage were significantly attenuated by pretreatment with an antioxidant, N-acetylcysteine (NAC). DNA damage was also markedly observed in HL-60 cells exposed to either MMA(III) or DMA(III), while iAs(III) did not show any relevant effects in HL-60 cells. Likewise, phosphorylation of the histone H2A variant (γ-H2AX), a biomarker of DNA damage, significantly occurred in cellular nuclei following exposure to two methylated species, which was reduced in the presence of NAC, suggesting that the induction of DNA damage was predominantly caused by the two metabolites via oxidative stress. In conclusion, we suggest that arsenic intermediate metabolites; MMA(III) and DMA(III) might prove to be of clinical relevance in future as such approaches may help in the treatment of leukemia and other types of cancers.


Evaluation of treatment with doxorubicin and piroxicam or doxorubicin alone for multicentric lymphoma in dogs.
To evaluate the antitumor and toxic effects of treatment with doxorubicin combined with piroxicam or doxorubicin alone for multicentric lymphoma in dogs. Nonrandomized clinical trial. 75 dogs with multicentric lymphoma. 33 dogs were treated with doxorubicin (30 mg/m2, IV, q 21 d, for 3 doses) and piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h); results were compared with a historical control group of 42 dogs treated with doxorubicin (30 mg/M2, IV, q 21 d, for 3 doses) alone. Results-The percentages of dogs that had remission with doxorubicin-piroxicam treatment (79%) or doxorubicin treatment alone (74%) were not significantly different. Median duration of first remission was 130 days with doxorubicin-piroxicam and 147 days with doxorubicin alone; these values were not significantly different. Severe toxicosis was observed in 22% of dogs treated with doxorubicin-piroxicam and 17% of dogs treated with doxorubicin alone. Both treatment protocols were efficacious and well tolerated. The doxorubicin-piroxicam treatment was no more effective regarding response rate, remission duration, or survival duration, compared with the control group treated with doxorubicin alone.


Diving under the influence: issues in researching personality and inert gas narcosis.
This paper considers the relationship between measures of personality and mood states, and susceptibility to inert gas narcosis. It briefly reviews the topics of inert gas narcosis affecting personality, and personality affecting the susceptibility to inert gas narcosis. There appears to be is a theoretical argument for a possible relationship between measures of personality, mood states, and susceptibility to narcosis. Practically, such a relationship may speak to issues in selection, training and preparation, risk assessments, and even accident investigation in the diving and/or hyperbaric environment. Twenty one divers completed measures of personality and mood states, and were then compressed to 709 kPa (equivalent to 60 msw) in a dry compression chamber, where they completed a task measuring speed of information processing, and a scale measuring subjective narcosis. The main finding was the absence of any significant correlations between measures of personality traits and mood, and susceptibility to inert gas narcosis. Although the study found no evidence of any major relationship, it is presented as a case study to highlight some of the issues and pitfalls involved in such research. The lessons learned - including the careful defining and describing of concepts, and choosing of samples and measurements - are used to discuss some of the methodological and conceptual issues and future directions for researchers to consider.


Celiac-superior mesenteric artery anastomosis in pancreatic transplantation: a new technique.
In whole organ pancreas transplantation, the vascular anastomosis is routinely based on the portal vein and a Carrel patch of the aorta containing the origin of the celiac artery and superior mesenteric artery. For end-to-side anastomosis to the external iliac, extensive dissection is necessary. A new technique involving bench surgery has been developed to avoid this large anastomosis between the Carrel patch and the external iliac artery. The single artery end-to-side anastomosis is accomplished between the distal end of the superior mesenteric artery and the external iliac, after anastomosis of the celiac artery to the proximal end of the superior mesenteric artery.


Inadequate Palliative Care in Chronic Lung Disease. An Issue of Health Care Inequality.
Patients with chronic lung diseases suffer higher symptom burden, lower quality of life, and greater social isolation compared with patients with other diagnoses, such as cancer. These conditions may be alleviated by palliative care, yet palliative care is used less by patients with chronic lung disease compared with patients with cancer. Underuse is due, in part, to poor implementation of primary palliative care and inadequate referral to specialty palliative care. Lack of primary and specialty palliative care in patients with chronic lung disease falls short of the minimum standard of competent health care, and represents a disparity in health care and a social injustice. We invoke the ethical principles of justice and sufficiency to highlight the importance of this issue. We identify five barriers to implementing palliative care in patients with chronic lung disease: uncertainty in prognosis; lack of provider skill to engage in discussions about palliative care; fear of using opioids among patients with chronic lung disease; fear of diminishing hope; and perceived and implicit bias against patients with smoking-related lung diseases. We propose mechanisms for improving implementation of palliative care for patients with chronic lung disease with the goal of enhancing justice in health care.


A Vernonia Diacylglycerol Acyltransferase Can Increase Renewable Oil Production.
Increasing the production of plant oils such as soybean oil as a renewable resource for food and fuel is valuable. Successful breeding for higher oil levels in soybean, however, usually results in reduced protein, a second valuable seed component. This study shows that by manipulating a highly active acyl-CoA:diacylglycerol acyltransferase (DGAT) the hydrocarbon flux to oil in oilseeds can be increased without reducing the protein component. Compared to other plant DGATs, a DGAT from Vernonia galamensis (VgDGAT1A) produces much higher oil synthesis and accumulation activity in yeast, insect cells, and soybean. Soybean lines expressing VgDGAT1A show a 4% increase in oil content without reductions in seed protein contents or yield per unit land area. Incorporation of this trait into 50% of soybeans worldwide could result in an increase of 850 million kg oil/year without new land use or inputs and be worth ∼U.S.$1 billion/year at 2012 production and market prices.


Comparing Rates of Adverse Events and Medical Errors on Inpatient Psychiatric Units at Veterans Health Administration and Community-based General Hospitals.
There is limited knowledge about how general hospitals and Veterans Health Administration (VHA) hospitals fare relative to each other on a broad range of inpatient psychiatry-specific patient safety outcomes.This research compares data from 2 large-scale epidemiological studies of adverse events (AEs) and medical errors (MEs) in inpatient psychiatric units, one in VHA hospitals and the other in community-based general hospitals. Retrospective medical record reviews assessed the prevalence of AEs and MEs in a sample of 4371 discharges from 14 community-based general hospitals (derived from 69,081 discharges at 85 hospitals) and a sample of 8005 discharges from 40 VHA hospitals (derived from 92,103 discharges at 105 medical centers). Rates of AEs and MEs across hospital systems were calculated, controlling for relevant patient and hospital characteristics. The overall rate of AEs and MEs in inpatient psychiatric units of VHA hospitals was 7.11 and 1.49 per 100 patient discharges; at community-based acute care hospitals, these rates were 13.48 and 3.01 per 100 patient discharges. The adjusted odds ratio of a patient experiencing an AE and a ME at community-based hospitals as compared with VHA hospitals was 2.11 and 2.08, respectively. Although chart reviews may not document the complete nature and outcomes of care, even after controlling for differences in patient and hospital characteristics, psychiatric inpatients at community-based hospitals were twice as likely to experience AEs or MEs as inpatients at VHA hospitals. While community-based hospitals may lag behind VHA hospitals, both hospital systems should continue to pursue evidence-based improvements in patient safety. Future research aimed at changing hospital practices should draw on established strategies for bridging the gap from research to practice in order to improve the quality of care for this vulnerable patient population.


Impact of COVID-19 on international medical education and the future plans of medical students in Japan.
Background: The aim of this study was to assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on the current study methods and future plans of medical students compared to those in the pre-pandemic period. Methods: Second-grade medical students reported their academic experiences, study methods, and future career plans before (between 2016 and 2019) and during the pandemic (2020) using a questionnaire-based survey at Hokkaido University, Japan (n = 534). Results: From 2016 to 2019, we found an increasing trend for participation in short-term international exchange programs, taking the United States Medical Licensing Examination (USMLE), clinical training, and undertaking research abroad among the students. However, these percentages significantly declined (to 35.5%) during the COVID-19 pandemic in 2020 for all the assessed future plans, including short-term exchange programs (-27.9%), taking USMLE (-19.8%), clinical training (-24.5%), and undertaking research abroad (-13.2%) compared to 2019, wherein 67.9% of the students wished to have at least one of these four above-mentioned academic activities. Conclusions: The COVID-19 pandemic adversely and significantly influenced our medical students' plans to go abroad for clinical and research training. Future studies are warranted to assess the long-term influence of this pandemic on the career planning of medical students.


Genome-Wide Analysis of Flax (Linum usitatissimum L.) Growth-Regulating Factor (GRF) Transcription Factors.
Flax is an important cash crop globally with a variety of commercial uses. It has been widely used for fiber, oil, nutrition, feed and in composite materials. Growth regulatory factor (GRF) is a transcription factor family unique to plants, and is involved in regulating many processes of growth and development. Bioinformatics analysis of the GRF family in flax predicted 17 LuGRF genes, which all contained the characteristic QLQ and WRC domains. Equally, 15 of 17 LuGRFs (88%) are predicted to be regulated by lus-miR396 miRNA. Phylogenetic analysis of GRFs from flax and several other well-characterized species defined five clades; LuGRF genes were found in four clades. Most LuGRF gene promoters contained cis-regulatory elements known to be responsive to hormones and stress. The chromosomal locations and collinearity of LuGRF genes were also analyzed. The three-dimensional structure of LuGRF proteins was predicted using homology modeling. The transcript expression data indicated that most LuGRF family members were highly expressed in flax fruit and embryos, whereas LuGRF3, LuGRF12 and LuGRF16 were enriched in response to salt stress. Real-time quantitative fluorescent PCR (qRT-PCR) showed that both LuGRF1 and LuGRF11 were up-regulated under ABA and MeJA stimuli, indicating that these genes were involved in defense. LuGRF1 was demonstrated to be localized to the nucleus as expected for a transcription factor. These results provide a basis for further exploration of the molecular mechanism of LuGRF gene function and obtaining improved flax breeding lines.


Type II collagen-hyaluronan hydrogel--a step towards a scaffold for intervertebral disc tissue engineering.
Intervertebral disc regeneration strategies based on stem cell differentiation in combination with the design of functional scaffolds is an attractive approach towards repairing/regenerating the nucleus pulposus. The specific aim of this study was to optimise a composite hydrogel composed of type II collagen and hyaluronic acid (HA) as a carrier for mesenchymal stem cells. Hydrogel stabilisation was achieved by means of 1-ethyl-3(3-dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) cross-linking. Optimal hydrogel properties were determined by investigating different concentrations of EDC (8 mM, 24 mM and 48 mM). Stable hydrogels were obtained independent of the concentration of carbodiimide used. The hydrogels cross-linked by the lowest concentration of EDC (8 mM) demonstrated high swelling properties. Additionally, improved proliferation of seeded rat mesenchymal stem cells (rMSCs) and hydrogel stability levels in culture were observed with this 8 mM cross-linked hydrogel. Results from this study indicate that EDC/NHS (8 mM) cross-linked type II collagen/HA hydrogel was capable of supporting viability of rMSCs, and furthermore their differentiation into a chondrogenic lineage. Further investigations should be conducted to determine its potential as scaffold for nucleus pulposus regeneration/repair.


GABRR1 and GABRR2, encoding the GABA-A receptor subunits rho1 and rho2, are associated with alcohol dependence.
The genes encoding several GABA-A receptor subunits, including GABRA2, have been associated with alcoholism, suggesting that variations in gaba signaling contribute to risk. Therefore, as part of a comprehensive evaluation of the GABA receptor genes, we evaluated the potential association of GABRR1 and GABRR2, which encode the rho1 and rho2 subunits of the pentameric GABA-A/GABA-C receptors. GABRR1 and GABRR2 lie in a head to tail orientation spanning 137 kb on chromosome 6q14-16. We genotyped 73 single nucleotide polymorphisms (SNPs), covering both genes and extending 31 kb upstream of GABRR2 and 95 kb downstream of GABRR1, in a sample of 1923 European Americans from 219 multiplex alcohol-dependent families. Family-based association analyses demonstrated that SNPs in both GABRR1 and GABRR2 were significantly associated with alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) in GABRR2. Secondary analysis using a median split for age of onset suggests that the association is strongest when the analysis is focused upon those with earlier onset of alcohol dependence. Haplotypes in each gene were significantly overtransmitted to family members who did not meet criteria for alcohol dependence (P < 0.04), and a haplotype in GABRR2 was significantly overtransmitted to family members who met a broader definition of alcoholism (P = 0.002) as well as DSM-IV dependence (P = 0.04).


Plant responses to abiotic stresses: heavy metal-induced oxidative stress and protection by mycorrhization.
The aim of this review is to assess the mode of action and role of antioxidants as protection from heavy metal stress in roots, mycorrhizal fungi and mycorrhizae. Based on their chemical and physical properties three different molecular mechanisms of heavy metal toxicity can be distinguished: (a) production of reactive oxygen species by autoxidation and Fenton reaction; this reaction is typical for transition metals such as iron or copper, (b) blocking of essential functional groups in biomolecules, this reaction has mainly been reported for non-redox-reactive heavy metals such as cadmium and mercury, (c) displacement of essential metal ions from biomolecules; the latter reaction occurs with different kinds of heavy metals. Transition metals cause oxidative injury in plant tissue, but a literature survey did not provide evidence that this stress could be alleviated by increased levels of antioxidative systems. The reason may be that transition metals initiate hydroxyl radical production, which can not be controlled by antioxidants. Exposure of plants to non-redox reactive metals also resulted in oxidative stress as indicated by lipid peroxidation, H(2)O(2) accumulation, and an oxidative burst. Cadmium and some other metals caused a transient depletion of GSH and an inhibition of antioxidative enzymes, especially of glutathione reductase. Assessment of antioxidative capacities by metabolic modelling suggested that the reported diminution of antioxidants was sufficient to cause H(2)O(2) accumulation. The depletion of GSH is apparently a critical step in cadmium sensitivity since plants with improved capacities for GSH synthesis displayed higher Cd tolerance. Available data suggest that cadmium, when not detoxified rapidly enough, may trigger, via the disturbance of the redox control of the cell, a sequence of reactions leading to growth inhibition, stimulation of secondary metabolism, lignification, and finally cell death. This view is in contrast to the idea that cadmium results in unspecific necrosis. Plants in certain mycorrhizal associations are less sensitive to cadmium stress than non-mycorrhizal plants. Data about antioxidative systems in mycorrhizal fungi in pure culture and in symbiosis are scarce. The present results indicate that mycorrhization stimulated the phenolic defence system in the Paxillus-Pinus mycorrhizal symbiosis. Cadmium-induced changes in mycorrhizal roots were absent or smaller than those in non-mycorrhizal roots. These observations suggest that although changes in rhizospheric conditions were perceived by the root part of the symbiosis, the typical Cd-induced stress responses of phenolics were buffered. It is not known whether mycorrhization protected roots from Cd-induced injury by preventing access of cadmium to sensitive extra- or intracellular sites, or by excreted or intrinsic metal-chelators, or by other defence systems. It is possible that mycorrhizal fungi provide protection via GSH since higher concentrations of this thiol were found in pure cultures of the fungi than in bare roots. The development of stress-tolerant plant-mycorrhizal associations may be a promising new strategy for phytoremediation and soil amelioration measures.


Recurrent activating mutations of PPARγ associated with luminal bladder tumors.
The upregulation of PPARγ/RXRα transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARγ-dependent and modulates the tumor microenvironment to favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARγ overexpression and to recurrent activating point mutations of RXRα. Here, we report recurrent mutations of PPARγ that also activate the PPARγ/RXRα pathway, conferring PPARγ-dependency and supporting a crucial role of PPARγ in luminal bladder cancer. These mutations are found throughout the protein-including N-terminal, DNA-binding and ligand-binding domains-and most of them enhance protein activity. Structure-function studies of PPARγ variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARγ/RXRα pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.


Replacement mutagenesis of the human cytomegalovirus genome: US10 and US11 gene products are nonessential.
The US6 gene family, located within the unique short region (US) of the human cytomegalovirus (HCMV) genome, contains six open reading frames (US6 through US11) which may encode glycoproteins, such as gcII (D. Gretch, B. Kari, R. Gehrz, and M. Stinski, J. Virol. 62:1956-1962, 1988). By homologous recombination, several different recombinant HCMV were created which contain a marker gene, beta-glucuronidase, inserted within this gene family. It was demonstrated that beta-glucuronidase has utility as a marker gene for the identification of recombinants in this herpesvirus system, without the occurrence of deletions in other regions of the viral genome. DNA and RNA blot analyses attested to the fidelity of the recombination. Immunoprecipitation experiments using monospecific polyclonal antisera indicated that the US10 and/or US11 gene products were not expressed in the recombinants, as predicted. These results, along with single-cycle growth analyses, indicated that the US10 and US11 gene products are nonessential for virus replication and growth in tissue culture. HCMV recombinants expressing beta-glucuronidase seemed to be genetically stable.


Oxidative stress induces p38MAPK-dependent senescence in the feto-maternal interface cells.
This study tested the mechanism of the oxidative stress (OS)-induced senescence pathway at the feto-maternal interface cells. Primary amnion mesenchymal cells (AMCs), chorion and decidual cells isolated from the placental membranes of women at normal term (not in labor) were exposed to OS-inducing cigarette smoke extract (CSE) for 48 h. Reactive oxygen species (ROS) was measured using 2'7'-dichlorodihydrofluorescein. Western blot analysis determined phosphorylated (P) p38MAPK and p53 expression. Senescence-associated β-Galactosidase (SA-β-Gal) and matrix metallopeptidase 9 (MMP9) histochemistry were used to measure senescence and inflammation respectively. Cotreatment of cells with the antioxidant, N-acetyl cysteine (NAC), or the p38MAPK inhibitor, SB203580 (SB), verified the activation specificity. CSE increased ROS production from AMCs, chorion cells, and decidual cells (P < 0.05) compared to controls. Western blot analysis determined that CSE induced p38MAPK activation (P < 0.05) and cotreatment with NAC inhibited ROS production and p38MAPK activation (P < 0.05) in all cell types. CSE did not increase p53 phosphorylation in any of the cells; however, AMCs showed constitutive P-p53 expression. CSE increased senescence in AMCs and chorion cells compared to controls (P = 0.01 and P = 0.003, respectively); however, senescence was not observed in decidual cells. Senescence was significantly reduced following cotreatment with SB and NAC (AMCs; P = 0.01 and chorion; P = 0.009). CSE increased MMP9 in all cells that was reduced by NAC. OS induced p38MAPK activation and inflammation in all cell types that was associated with senescence in fetal cells but not in maternal cells.


Retrospective Association Analysis of Longitudinal Binary Traits Identifies Important Loci and Pathways in Cocaine Use.
Longitudinal phenotypes have been increasingly available in genome-wide association studies (GWAS) and electronic health record-based studies for identification of genetic variants that influence complex traits over time. For longitudinal binary data, there remain significant challenges in gene mapping, including misspecification of the model for phenotype distribution due to ascertainment. Here, we propose L-BRAT (Longitudinal Binary-trait Retrospective Association Test), a retrospective, generalized estimating equation-based method for genetic association analysis of longitudinal binary outcomes. We also develop RGMMAT, a retrospective, generalized linear mixed model-based association test. Both tests are retrospective score approaches in which genotypes are treated as random conditional on phenotype and covariates. They allow both static and time-varying covariates to be included in the analysis. Through simulations, we illustrated that retrospective association tests are robust to ascertainment and other types of phenotype model misspecification, and gain power over previous association methods. We applied L-BRAT and RGMMAT to a genome-wide association analysis of repeated measures of cocaine use in a longitudinal cohort. Pathway analysis implicated association with opioid signaling and axonal guidance signaling pathways. Lastly, we replicated important pathways in an independent cocaine dependence case-control GWAS. Our results illustrate that L-BRAT is able to detect important loci and pathways in a genome scan and to provide insights into genetic architecture of cocaine use.


Spectroscopic microvascular blood detection from the endoscopically normal colonic mucosa: biomarker for neoplasia risk.
We previously used a novel biomedical optics technology, 4-dimensional elastically scattered light fingerprinting, to show that in experimental colon carcinogenesis the predysplastic epithelial microvascular blood content is increased markedly. To assess the potential clinical translatability of this putative field effect marker, we characterized the early increase in blood supply (EIBS) in human beings in vivo. We developed a novel, endoscopically compatible, polarization-gated, spectroscopic probe that was capable of measuring oxygenated and deoxygenated (Dhb) hemoglobin specifically in the mucosal microcirculation through polarization gating. Microvascular blood content was measured in 222 patients from the endoscopically normal cecum, midtransverse colon, and rectum. If a polyp was present, readings were taken from the polyp tissue along with the normal mucosa 10-cm and 30-cm proximal and distal to the lesion. Tissue phantom studies showed that the probe had outstanding accuracy for hemoglobin determination (r(2) = 0.99). Augmentation of microvasculature blood content was most pronounced within the most superficial ( approximately 100 microm) layer and dissipated in deeper layers (ie, submucosa). EIBS was detectable within 30 cm from the lesion and the magnitude mirrored adenoma proximity. This occurred for both oxygenated hemoglobin and DHb, with the effect size being slightly greater for DHb. EIBS correlated with adenoma size and was not engendered by nonneoplastic (hyperplastic) polyps. We show, herein, that in vivo microvascular blood content can be measured and provides an accurate marker of field carcinogenesis. This technological/biological advance has numerous potential applications in colorectal cancer screening such as improved polyp detection and risk stratification.


Distinct prognostic factors in patients with chronic heart failure and chronic kidney disease.
Impaired renal function is a strong predictor of mortality in chronic heart failure (CHF). However, the impact of chronic kidney disease (CKD) on prognostic factors has not been rigorously examined in CHF. The purpose of this study was to compare prognostic factors between CHF patients with and without CKD. Consecutive 505 patients with CHF, who performed cardiopulmonary exercise testing before discharge, were enrolled. Patients were divided into two groups: CKD group (eGFR < 60 mL/minute/1.73 m2, n = 213) and non-CKD group (eGFR ≥ 60 mL/minute/1.73 m2, n = 292). The patients were followed up to register cardiac events including cardiac death and re-hospitalization due to worsening heart failure. There were 115 events during the follow-up period (746 ± 238 days), and the cardiac event rate was higher in the CKD group than in the non-CKD group (34% versus 14%, P < 0.001). Multivariate Cox hazard analysis demonstrated that body mass index (P < 0.001), log BNP (P < 0.001), peak VO2 (P < 0.05), and left atrial dimension (P < 0.05) were independent parameters to predict cardiac events after discharge in the non-CKD group. In contrast, peak VO2 (P < 0.01), log BNP (P < 0.01), and the concentrations of hemoglobin (P < 0.05) and uric acid (P < 0.05) were independent prognostic factors in the CKD group. Prognostic factors were different between CHF patients with and without CKD, and this should be considered when managing CHF patients with CKD.


Recast Therapy for Treating Syntax in Bilingual Children With Developmental Language Disorder: A Feasibility and Early Efficacy Study Examining the Role of Language of Intervention on Outcomes.
The purpose of this study is to examine the feasibility of the delivery of complex syntax recast therapy via telepractice to Spanish-English bilingual children and provide preliminary evidence of the efficacy of this approach. Fifteen bilingual children with developmental language disorders were stratified based on language proficiency and randomized to one of three treatment conditions: Spanish only (n = 5), English only (n = 6), or Spanish + English (n = 4). Using a within-subject design, we hypothesized that we could document treatment efficacy based on change in the treated structure in the absence of change in an untreated comparison structure. All 15 children completed ~16 hr of treatment via telepractice and participated in pre- and posttesting of their production of conditional adverbs (treated structure) and subject relative clauses (untreated structure) carried out by a masked assessor. Analyses included all participants. Treatment fidelity was high, and participant attendance was remarkable, indicating feasibility. Regarding efficacy, recast therapy led to group-level gains on treated syntactic structures that exceeded those observed for the untreated comparison structure. For the 11 children who received therapy in only one language, approximately equal gains were observed in both the treated and untreated languages for conditional adverbials. Preliminary evidence suggests that for highly overlapping structures like conditional adverbials, recast therapy is effective and leads to change in both of the child's languages. Larger studies are required to understand how language of administration and proficiency may affect outcomes. https://doi.org/10.23641/asha.23739996.


Characterization of X-linked recessive lethal mutations affecting embryonic morphogenesis in Drosophila melanogaster.
This study attempted to assay the zygotic contribution of X chromosome genes to the genetic control of embryonic morphogenesis in Drosophila melanogaster. A systematic screen for X-linked genes which affect the morphology of the embryo was undertaken, employing the phenotype of whole mount embryos as the major screening criterion. Of 800 EMS-induced lethal mutations analyzed, only 14% were embryonic lethal, and of these only a minority affected embryonic morphogenesis. By recombination and complementation analyses, the mutations that affected embryonic morphogenesis were sequestered into 26 complementation groups. Fourteen of the loci correspond to genes previously identified in a large-scale screen in which fixed cuticles were examined, and 12 new loci have been identified. Most of the mutations which disrupt embryonic morphology had specific and uniform mutant phenotypes. Mutations were recovered which disrupt major morphogenetic events such as gastrulation, germ band retraction and head involution. No mutations were found which arrest the embryos prior to blastoderm formation. However, a novel class was found, one comprised of mutations which interfere with the development of internal structures but not cuticular structures. Nevertheless, saturation of the X chromosome for genes important for embryonic morphogenesis is probably incomplete.


The Relationships Between Weight Bias, Perceived Weight Stigma, Eating Behavior, and Psychological Distress Among Undergraduate Students in Hong Kong.
Weight bias issues are rarely discussed in Asian. Therefore, we examined the relationships between weight bias, perceived weight stigma (PWS), eating behavior, and psychological distress among Hong Kong people. Using cross-sectional design, 400 undergraduate students (175 men) completed questionnaires and were assigned into a self-reported overweight (n = 61) or nonoverweight group (n = 339) using body mass index, and a self-perceived overweight (n = 84) or nonoverweight group (n = 316) based on self-perception. For self-reported and self-perceived overweight groups, more weight bias was related to higher depression (β = -0.403; p = 0.004). Self-perceived group additionally showed that weight bias was related to PWS and inappropriate eating behaviors; PWS related to inappropriate eating behaviors. For self-reported and self-perceived nonoverweight groups, weight bias was related to PWS, inappropriate eating behaviors, anxiety, and depression (β = -0.228 to -0.148; p's < 0.05); PWS was associated with inappropriate eating behaviors, anxiety, and depression. Thus, weight bias issues should not be ignored for both overweight and nonoverweight people.


Tumor metastasis is not due to adaptation of cells to a new organ environment.
Murine B16 melanoma cells were adapted for lung survival and growth by allowing them to attach to Bio-Carrier beads and injecting the beads intravenously into normal mice. The beads lodged mechanically in the microcirculation of the lung. When the melanoma cells had grown into visible tumors from the arrested beads, the tumors were removed and the cells were dispersed, cultured to remove normal cells, and reattached to new beads. The process was repeated nine times. Previously another B16 subline was injected intravenously as a suspension of separate tumor cells. Those cells that survived and colonized the lungs were harvested, cultured, and injected again. This selection process was also repeated nine times. Only the subline that was injected in suspension was more metastatic than the parental line, indicating that metastasis involves selection of preexistent metastatic cells and is not an adaptive process by which all cells gradually acquire the ability to grow at particular organ sites.


Temporal dynamics of zero-delay second order correlation function and spectral entanglement of two photons emitted from ladder-type atomic three-level systems.
We theoretically investigate temporal dynamics of the second order cross correlation function at zero delay time (G12(2)(t)) and spectral entanglement of two photons emitted from an atomic three-level cascade. In Heisenberg's picture, a closed set of quantum kinetic equations of motion for G12(2)(t) is derived within density matrix formalism with cluster expansion rule. G12(2)(t) shows qualitatively distinctive features depending on the spectral entanglement of two photons. Although incoherent photon pairs generated from spontaneous radiation of the excited electron are not entangled, their correlation and anti-correlation properties can be found in G12(2)(t) depending on the radiative decay rates. In the coherent excitation regime where the light emitter is located in a high Q-cavity, and its atomic polarizations are predominantly initialized, spectral entanglement between two coherent photons is established. We show that G12(2)(t) is well fitted by the entanglement criterion by Duan-Giedke-Cirac-Zoller and explain the close relationship between them by means of the optically forbidden transition in the three-level cascade.