Ontological insecurity of inattentiveness: Conceptualizing how risk management practices impact on patient recovery when admitted to an acute psychiatric hospital.
Risk management which assesses and mitigates risks such as suicide and violence is under scrutiny, particularly within psychiatric inpatient settings. Restrictive practices, which result from risk assessment, such as observations, physical restraint and ward seclusion can impact negatively on patient recovery, hindering abilities to develop a meaningful life that emphasizes purpose, hope and autonomy, despite experiencing mental distress. Yet, less is known about the impact from the patient's perspective when first admitted to hospital, a period which among other reasons may come with increasing risk management practices owing to the clinical uncertainties about patient risks. In this grounded theory study, we explore the impact on recovery, interviewing 15 adult participants with patient experiences of being in an acute hospital. The main theme of the study, termed a core category with a grounded theory, was identified as "ontological insecurity of inattentiveness". This highlighted a staff inattentiveness with involving patients with risk management and explaining the purposes of the practice, which raised insecurities about what was happening to the patients when admitted to hospital. Four subcategories support the core category; discounting the patients' experiences to gain a meaningful grasp of risk management, ambiguity about risk management rules, particularly the reasons around their use, forebodingness to the hospital environment and, management from afar, with patients feeling scrutinized from observations without a voice to offer different views. It is hoped these findings will add to the field of patient involvement in psychiatric inpatient settings, proposing attempts to raise understanding and inclusivity of risk management, starting when first admitted to hospital.


Clear cell adenocarcinoma of the urethra: review of the literature.
Clear cell adenocarcinoma of the urethra (CCAU) is extremely rare and a number of clinicians may be unfamiliar with its diagnosis and biological behaviour. To review the literature on CCAU. Various internet databases were used. (i) CCAU occurs in adults and in women in the great majority of cases. (ii) It has a particular association with urethral diverticulum, which has been present in 56% of the patients; is indistinguishable from clear cell adenocarcinoma of the female genital tract but is not associated with endometriosis; and probably does not arise by malignant transformation of nephrogenic adenoma. (iii) It is usually, readily distinguished from nephrogenic adenoma because of greater cytological a-typicality and mitotic activity and does not stain for prostate-specific antigen or prostatic acid phosphatase. (iv) It has been treated by anterior exenteration in women and cystoprostatectomy in men and at times by radiotherapy; chemotherapy has rarely been given. (v) CCAU is aggressive with low 5-year survival rates. (vi) There is no consensus opinion of treatment options that would improve the prognosis. Few cases of CCAU have been reported. Urologists, gynaecologists, pathologists, and oncologists should report cases of CCAU they encounter and enter them into a multicentric trial to determine the best treatment options that would improve the prognosis.


A systematic literature review of recommendations for referral to specialty care for patients with epilepsy.
In epilepsy, patients who receive appropriate care receive treatment that differs substantially from those that do not. Given the need for a more detailed assessment of the role of specialty referral in the care of patients with epilepsy, this systematic literature review identified epilepsy care guidelines and recommendations that specifically address when and why people with epilepsy should be referred to specialty care. This study identified recent (in the last 10 years) publications that made best-practice recommendations for referring people with epilepsy to a neurologist or epileptologist. We searched six databases in December 2018: MEDLINE (PubMed), Cochrane Library, ProQuest, Web of Science, CINAHL (Ebsco), Scopus (Elsevier). Search terms included "Epilepsy" OR "Seizures," "Guideline" OR "Practice Parameter," and "Referral." The 15 full-text articles identified included formal guidelines, summaries of these guidelines, or professional commentary that builds upon existing guidelines. Most of these publications came from the U.K and its National Institute for Health and Care Excellence. Overall, the included recommendations for referral varied considerably both for new-onset and refractory epilepsy. Although these recommendations were not consistent, it is reasonable to refer patients following the failure of 2 anti-seizure medication (ASM) trials. Guidelines and informal recommendations are not consistent regarding best practices for specialty care referral for patients with epilepsy. These guidelines and recommendations should consider the context of care in real-world settings and suggest pragmatic approaches that optimize seizure control and functioning.


CDH17+/CDX2+ Can be Helpful in Providing Support for Small Intestinal Origin Versus Pancreatic or Biliary Origin.
Because of the distinct and complex anatomy of the ampullary region, the exact origin of the periampullary tumors was often difficult to ascertain. In this study, we evaluated 78 patient samples, including 26 small intestinal adenocarcinomas, 35 pancreatic ductal adenocarcinomas, and 17 cholangiocarcinomas by immunohistochemical detection of cadherin-17 (CDH17), CDX2, CK20, and CK19 protein expression. The result showed that CDH17 and CDX2 expression was higher in small intestinal adenocarcinoma (73.1% and 65.4%) than in pancreatic (14.3% and 2.9%) and bile duct (41.2% and 23.5%) cancers, respectively. CK20 expression was low in 78 tumor tissues, but relatively high in small intestinal adenocarcinoma (42.3%). CK19 showed a strong positive expression in all 78 adenocarcinoma tissues. The CDH17-high/CDX2-high pattern was predominantly expressed in small intestinal cancer tissues (75%), whereas the CDH17-low/CDX2-low pattern was observed in pancreatic cancers (63.8%) and bile duct cancers (20.9%). The study concluded that CDH17-high/CDX2-high adenocarcinomas more likely originated from small intestine versus pancreas or bile duct, whereas CDH17-low/CDX2-low ones are more likely of pancreatic origin. The combined use of CDH17 and CDX2 could be helpful in providing support for the histologic origin of periampullary adenocarcinoma.


A highly addressable static droplet array enabling digital control of a single droplet at pico-volume resolution.
Droplet-based microfluidics enabling exquisite liquid-handling has been developed for diagnosis, drug discovery and quantitative biology. Compartmentalization of samples into a large number of tiny droplets is a great approach to perform multiplex assays and to improve reliability and accuracy using a limited volume of samples. Despite significant advances in microfluidic technology, individual droplet handling in pico-volume resolution is still a challenge in obtaining more efficient and varying multiplex assays. We present a highly addressable static droplet array (SDA) enabling individual digital manipulation of a single droplet using a microvalve system. In a conventional single-layer microvalve system, the number of microvalves required is dictated by the number of operation objects; thus, individual trap-and-release on a large-scale 2D array format is highly challenging. By integrating double-layer microvalves, we achieve a "balloon" valve that preserves the pressure-on state under released pressure; this valve can allow the selective releasing and trapping of 7200 multiplexed pico-droplets using only 1 μL of sample without volume loss. This selectivity and addressability completely arranged only single-cell encapsulated droplets from a mixture of droplet compositions via repetitive selective trapping and releasing. Thus, it will be useful for efficient handling of miniscule volumes of rare or clinical samples in multiplex or combinatory assays, and the selective collection of samples.


Involvement of adenosine 3':5'-cyclic monophosphate in the germination of blastospores of Candida albicans.
The germination of blastospores of Candida albicans is accompanied by a rise in the intracellular concentration of adenosine 3':5'-cyclic monophosphate (cyclic AMP). Germination was induced either by peptides isolated from seminal plasma or by an amino acid mixture, and both germination and the rise in cyclic AMP required a temperature of 37 degrees C. The rise occurred during the first hour of incubation, but full germination required a temperature of 37 degrees C for 4 h. Germination and the rise in cyclic AMP, in the presence of suboptimal concentrations of inducers, were stimulated by theophylline. Pre-incubation of cells with dithiothreitol in the absence of inducers inhibited subsequent germination but not the rise in cyclic AMP. Germination and the rise in cyclic AMP were inhibited if dithiothreitol or N-succinimidyl-3-(4-hydroxyphenyl)propionate was present during the induction period.


Associations with experience of non-fatal opioid overdose in British Columbia, Canada: a repeated cross sectional survey study.
Lives lost in North America due to the unregulated drug poisoning emergency are preventable and those who survive an opioid overdose may suffer long-term disability. Rates of opioid overdose more than doubled following the onset of the COVID-19 pandemic in British Columbia, Canada. Our analytical sample was comprised of 1447 participants from the 2018, 2019, and 2021 Harm Reduction Client Survey who responded yes or no to having experienced an opioid overdose in the past 6 months. Participants were recruited from harm reduction sites from across British Columbia. We used logistic regression to explore associations of experiencing an opioid overdose. Overall, 21.8% of participants reported experiencing an opioid overdose in the last six months (18.2% in 2019 and 26.6% in 2021). The following factors were positively associated with increased adjusted odds of experiencing a non-fatal opioid overdose: cis men relative to cis women (AOR 1.49, 95% CI 1.10-2.02), unstably housed compared to people with stable housing (AOR 1.87, 95% CI 1.40-2.50), and participants from 2021 compared to those from 2019 (AOR 3.06, 95% CI 1.57-5.97). The effects of both previous experience of a stimulant overdose and having witnessed an opioid overdose depended on the year of study, with both effects decreasing over subsequent years. Overdoses have increased over time; in 2021 more than one in four participants experienced an overdose. There is an urgent need for policy and program development to meaningfully address the unregulated drug poisoning emergency through acceptable life-saving interventions and services to prevent overdoses and support overdose survivors.


Magnetic property studies of manganese-phosphate complexes.
Phosphoric acid forms two distinct coordination compounds with manganese salts in aqueous media, a two-dimensional layered structure, [Mn(HPO4).(H2O)3], 1, under ambient conditions, and a three-dimensional synthetic mineral, [Mn5(mu-OH2)2(HPO4)2(PO4)2(H2O)2], 2, under hydrothermal procedures, at 120 degrees C. In compound 1, the oxygen atom of the doubly deprotonated phosphoric acid interconnects the metal centers to form a layered structure. The neutral hydrophilic layers of 1 are separated by 5.5 A and may potentially intercalate hydrophilic organic guest molecules. The metal centers in 2 are octahedral and bridged by PO4(3-), HPO4(2-), and OH2 groups to form a complex three-dimensional network. XPS analysis on 1 and 2 confirms that manganese exists in the +2 oxidation state. Compound 2 is a poor ion exchanger, but some improvement is observed on partial dehydration. The magnetic properties of both 1 and 2 were studied in detail to examine the amplitude of the magnetic interactions through phosphate ligand bridges. While 1 reveals dominant antiferromagnetic interactions between the spin carriers, a complete investigation of the magnetic properties of 2 revealed its true nature to be a glassy magnet.


Entrainment of motor-unit discharges as a neuronal mechanism of synchronization.
The neuronal mechanism which gives rise to the synchronization of motor-unit discharges has been inferred from an analysis of the interspike intervals of individual motor-unit discharges recorded from the soleus muscle. The motor units were divided into two groups on the basis of characteristic changes in their spike trains. The first group maintained a stationary discharge pattern throughout the process of synchronization with a firing rate of approximately 10 spikes/s. Small unidentified units simultaneously recorded gradually grouped around the individual spikes of the first group motor unit and with this process, high-frequency force oscillation appeared phase-locked with each of grouped discharges. The mean period of force oscillation was almost identical to the mean discharge interval. Therefore, the first group motor unit was considered as a pacemaker of this force-oscillation. The second group motor unit underwent from its initially stationary process to a transitional process characterized by spike dropouts from an otherwise regular spike train. When both groups of motor units were recorded by the same electrode, it was found that the firing rate of the second group motor unit discharges gradually approached that of the first group, and the spikes of the first and the second group motor units occurred near or at the same time. The number of double intervals decreased in a highly predictable fashion with an increase in a firing rate. It was furthermore observed that the spikes of a given motor unit whose discharges interval-to-period ratio is smaller at the beginning of transitional process was entrained to the first group motor-unit discharges with a faster time course than the unit whose discharge interval-to-period ratio is larger. The synchronizing process was described from the relations between shorter discharge interval-to-period ratios and the longer-to-shorter interval ratios obtained at several stages from the beginning of transitional process to the final synchronization. Their relations were best drawn by the second-order regression lines. The faster time course of synchronization was reflected in the larger value of coefficient a in the equation. The results of this and previous study (23) further provided evidence to justify that interaction of motor-unit discharges is responsible for the synchronization. Although the neuronal limiting device of the firing-rate control to approximately 10 spikes/s still remains unsolved, the possibility was considered that a disinhibitory neuronal network first acts to synchronize independently firing motoneurons and leads to the oscillation of the stretch reflex loop. This closed-loop system was considered as a site for the stored motor program and the use of disinhibitory neuronal network was discussed in relation to the Harmon's model of neuromimes.


The effects of oral doses of theophylline and fenoterol on exercise-induced asthma.
The effects of oral doses of theophylline and a beta-adrenergic agonist, fenoterol, were examined in 18 asthmatic young adults. Significant bronchodilation was seen with high-dose theophylline (FEV1 increased 14 percent) and with full 10-mg doses of fenoterol (FEV1 increased 10 percent). Low-dose theophylline alone (130 mg) increased FEV1 by 5 percent, but when combined with 5 mg of fenoterol, a 14 percent improvement was seen, demonstrating significant (P = .003) additive effects. The ability of the two drugs to prevent the asthmatic response to exercise was not additive. The mean fall in FEV1 was not statistically different when subjects exercised after receiving a placebo (32 percent) 130 mg of theophylline (27 percent), or 130 mg of theophylline with 5 mg of fenoterol (18 percent). Furthermore, side effects associated with the two drugs, such as tachycardia, tremor, or CNS stimulation, were significantly increased when the two drugs were given simultaneously. Thus, little therapeutic benefit was gained from simultaneous therapy. Both bronchodilation and toxicity were equivalent to that seen with larger therapeutic doses of either drug given alone, and protection from the effects of a frequently encountered stress was not significantly enhanced.


Comparison of the DNA-alkylating properties and mutagenic responses of a series of S-(2-haloethyl)-substituted cysteine and glutathione derivatives.
The mutagenicity of 1,2-dibromoethane is highly dependent upon its conjugation to glutathione by the enzyme glutathione S-transferase. The conjugates thus formed can react with DNA and yield almost exclusively N7-guanyl adducts. We have synthesized the S-haloethyl conjugates of cysteine and glutathione, as well as selected methyl ester and N-acetyl derivatives, and compared them for ability to produce N7-guanyl adducts with calf thymus DNA. The cysteine compounds were found to be more reactive toward calf thymus DNA and yielded higher adduct levels than did the glutathione compounds. Adduct levels tended to be suppressed when there was a net charge on the compound and were not affected by substitution of bromine for chlorine, as expected for a mechanism known to involve an intermediate episulfonium ion. Sequence-selective alkylation of fragments of pBR322 DNA was investigated. The compounds produced qualitatively similar patterns of alkylation, with higher levels of alkylation at runs of guanines. The compounds were also tested for their ability to act as direct mutagens in Salmonella typhimurium TA98 and TA100. None of the compounds caused mutations in the TA98 frameshift mutagenesis assay. In the strain TA100, where mutation of a specific guanine by base-pair substitution produces reversion, all compounds were found to produce mutations, but the levels of mutagenicity did not correlate at all with the levels of DNA alkylation. The ratio of mutations to adducts varied at least 14-fold among the various N7-guanyl adducts examined.(ABSTRACT TRUNCATED AT 250 WORDS)


A Set of Global Metabolomic Biomarker Candidates to Predict the Risk of Dry Eye Disease.
We used ultraperformance liquid chromatography coupled with quadrupole/time-of-flight tandem mass spectrometry (UPLC-Q/TOF-MS/MS) to analyze the metabolic profile of reflex tears obtained from patients with dry eye disorders. We performed a cross-sectional study involving 113 subjects: 85 patients diagnosed with dry eye syndrome (dry eye group) and 28 healthy volunteers (control group). Reflex tears (20-30 μl) were collected from the tear meniscus of both eyes of each subject using a Schirmer I test strip. MS data were acquired with a standard workflow by UPLC-Q/TOF-MS/MS. Metabolites were quantitatively analyzed and matched with entries in the Metlin, Massbank, and HMDB databases. Least absolute shrinkage and selection operator (LASSO) regression was conducted to detect important metabolites. Multiple logistic regression was used to identify the significant metabolic biomarker candidates for dry eye syndrome. Open database sources, including the Kyoto Encyclopedia of Genes and Genomes and MetaboAnalyst, were used to identify metabolic pathways. After the LASSO regression and multiple logistic regression analysis, 4 of 20 metabolic biomarker candidates were significantly correlated with Ocular Surface Disease Index score, 42 of 57 with fluorescein breakup time, and 26 of 57 with fluorescein staining. By focusing on the overlap of these three sets, 48 of 51 metabolites contributed to the incidence of dry eye and there were obvious changes in different age groups. Metabolic pathway analysis revealed that the main pathways were glucose metabolism, amino acid metabolism, and glutathione metabolism. Dry eye syndrome induces changes in the metabolic profile of tears, and the trend differs with age. This evidence reveals the relationship between changes in metabolites, symptoms of dry eye syndrome, and age.


Synthesis and photochemical properties of 12-substituted versus 13-substituted chlorins.
Understanding the effects of substituents on natural photosynthetic pigments is essential for the rational design of artificial photosynthetic systems. The long-wavelength absorption of chlorins derives from a transition that encompasses rings A and C, which includes the 2,3- and 12,13-positions, respectively. Chlorophylls bear a 3-vinyl group and a 13-keto group, as well as a full complement of substituents at the other beta-pyrrole sites. Prior studies of sparsely substituted synthetic chlorins to probe the effects of substituents yielded 3,13-substituted chlorins that contain a geminal dimethyl group in the pyrroline ring (for stability) and a mesityl group at the 10-position. Attempts to prepare analogous chlorins lacking the 10-mesityl substituent encountered unexpected difficulties during construction of the Eastern half precursor (8,9-dibromo-1-formyldipyrromethane) to the 13-bromochlorin. Direct bromination of 1-formyldipyrromethane with 2 mol equiv of NBS at -78 degrees C led to an isomeric mixture of the desired 8,9-dibromodipyrromethane (minor) and the unexpected 7,9-dibromodipyrromethane (major). Hence, a new rational route was developed for the synthesis of 8,9-dibromo-1-formyldipyrromethane that entailed (i) InCl(3)-catalyzed condensation of 4-bromo-2-(hydroxymethyl)pyrrole and pyrrole to give the 8-bromodipyrromethane, (ii) 1-formylation, and (iii) 9-bromination. Two new substituted chlorins carrying auxochromes at the 3- and 13-positions were synthesized. The photophysical and redox properties of the 13-substituted chlorins were compared with those of isomeric 12-substituted chlorins, synthesized previously via a 7,9-dibromo-1-formyldipyrromethane. Such studies (static absorption and fluorescence spectroscopy, time-resolved fluorescence spectroscopy, electrochemistry of the zinc chelates, and density functional theoretical calculations) reveal only very slight differences between the isomeric 12- and 13-substituted chlorins.


Selective storage and maintenance of an object's features in visual working memory.
It has been shown that we have a highly capacity-limited representational space with which to store objects in visual working memory. However, most objects are composed of multiple feature attributes, and it is unknown whether observers can voluntarily store a single attribute of an object without necessarily storing all of its remaining features. In this study, we used a masking paradigm to measure the efficiency of encoding, and neurophysiological recordings to directly measure visual working memory maintenance while subjects viewed multifeature objects and were required to remember only a single feature or all of the features of the objects. We found that measures of both encoding and maintenance varied systematically as a function of which object features were task relevant. These experiments show that individuals can control which features of an object are selectively stored in working memory.


Relaxation of bovine mesenteric lymphatics in response to transmural stimulation.
The responses of isolated quiescent segments of bovine mesenteric lymphatics to 10-s trains of pulses (50 V for 0.3 ms at 2 Hz) administered transmurally have been studied using various drugs. Each train of pulses consistently produced a brief contraction that was completely blocked by tetrodotoxin, alpha-adrenoceptor antagonists, bretylium, and guanethidine. Cocaine potentiated the contractions. Tyramine caused an increase in the basal tone, some spontaneous contractions, and an inhibition of contraction. The contraction was sometimes followed by a relaxation that could be of short duration or long lasting. Both types of relaxation were abolished by tetrodotoxin. Propranolol reduced both types of relaxation, causing more suppression of the short type. Bretylium completely blocked the short type of relaxation and slightly reduced the long-lasting type. Hexamethonium and atropine had no effect on any of the responses. These findings suggest that the contraction resulting from transmural stimulation is due to the action of excitatory postganglionic sympathetic nerves. It is concluded that both types of relaxation occur mainly in response to beta-adrenergic inhibitory stimulation. The possibility of nonadrenergic inhibitory innervation in bovine mesenteric lymphatics is also discussed.


Exact group sequential designs for two-arm experiments with Poisson distributed outcome variables.
We describe and compare two methods for the group sequential design of two-arm experiments with Poisson distributed data, which are based on a normal approximation and exact calculations respectively. A framework to determine near-optimal stopping boundaries is also presented. Using this framework, for a considered example, we demonstrate that a group sequential design could reduce the expected sample size under the null hypothesis by as much as 44% compared to a fixed sample approach. We conclude with a discussion of the advantages and disadvantages of the two presented procedures.


A genetic link between an mRNA-specific translational activator and the translation system in yeast mitochondria.
Translation of the Saccharomyces cerevisiae mitochondrial mRNA encoding cytochrome c oxidase subunit III (coxIII) specifically requires the products of at least three nuclear genes, PET122, PET494 and PET54. pet122 mutations that remove 24-67 amino acid residues from the carboxyterminus of the gene product were found to be suppressed by unlinked nuclear mutations. These unlinked suppressors fail to suppress both a pet122 missense mutation and a complete pet122 deletion. One of the suppressor mutations causes a heat-sensitive nonrespiratory growth phenotype in an otherwise wild-type strain and reduces translation of all mitochondrial gene products in cells grown at high temperature. This suppressor maps to a newly identified gene on chromosome XV termed PET123. The sequence of a DNA fragment carrying PET123 contains one major open reading frame encoding a basic protein of 318 amino acids. Inactivation of the chromosomal copy of PET123 by interruption of this open reading frame causes cells to become rho- (sustain large deletions in their mtDNA). This phenotype is characteristic for null alleles of genes whose products are essential for general mitochondrial protein synthesis. Thus our data strongly suggest that the PET123 protein is a component of the mitochondrial translation apparatus that interacts directly with the coxIII-mRNA-specific translational activator PET122.


A versatile electrochemical cell for the preparation and characterisation of model electrocatalytic systems.
An electrochemical cell for the controllable modification and comprehensive electrochemical characterisation of model electro-catalytic surfaces has been developed. In-depth electrochemical characterisation of stationary electrodes as well as rotating disc electrode (RDE) measurements in hanging meniscus configuration becomes possible. Additionally, the temperature of the electrodes in contact with electrolytes can be accurately controlled between room temperature and 70-80 °C. It is of particular importance for model electro-catalytic studies that in one experimental set-up (i) electrochemical metal and non-metal deposition to adjust the amount of the foreign atoms at the surface, (ii) controllable thermal treatment to vary the position of these atoms at the surface and subsurface regions, and (iii) state-of-the-art techniques common in electrocatalysis to characterise the resulting samples are possible. The deposition and annealing procedures under various atmospheres allow accurate control over the position of the foreign atoms at the electrode surface as overlayers, surface alloys and sub-surface (or near-surface) alloys, where the solute element is preferentially located in the second atomic layer of the host metal. The cell enables us to perform all operations without exposing the samples to the laboratory atmosphere at any of the experimental stages. To demonstrate the performance and advantages of the developed cell, we use model experiments with Pt(111) single crystal electrodes and Pt(111) surfaces modified with (sub)monolayer amounts of copper.


Celiac-associated lymphoma. A single institution experience of 30 cases in the combination chemotherapy era.
Celiac sprue (CS) is frequently complicated by malignancy, most commonly small intestinal lymphoma. Our study was performed in an area with a high prevalence of CS to define the clinical features, response to treatment, and outcome of this tumor. Of a total of 31 lymphomas complicating CS identified, 30 case records and 24 tumor specimens were reviewed. Overall 1-year survival was 9 of 29 (31%) and 5-year survival 3 of 27 (11%). Seven previously diagnosed celiac patients developed lymphoma; length on gluten-free diet ranged from 12 to 252 months (median 44 months). In this group, presentation was nonspecific, diagnosis difficult, and survival poor (lymphoma diagnosed in life in four of seven, mean survival 2.25 months). Twenty-three patients had CS and lymphoma diagnosed during the same illness. In this group, 14 of 23 presented with a surgical emergency and were treated with tumor resection and chemotherapy. Nine are disease-free and alive or died of another cause after 10-196 months (mean 74 follow-up). Celiac-associated lymphoma is a frequent, difficult to diagnose, and commonly fatal complication of CS. An aggressive diagnostic approach, including laparoscopy, is recommended. Long-term survival can be expected in a significant number of these patients and in our series was almost exclusively confined to those treated with chemotherapy.


Compositional bimodality of the nuclear genome of tobacco.
We have studied the compositional distribution of six genes (or small multigene families) and of one family of transposable elements, Tnt1, in DNA fractions from tobacco (Nicotiana tabacum) separated according to base composition. We have shown that gene distribution is bimodal and that such bimodality is due to the different base composition of the two parental genomes of tobacco (N.sylvestris and N.tomentosiformis) and to the different parental origin of the genes tested. These results indicate a physical separation and an absence of extensive recombination of the parental genomes, which have been together in the tobacco nucleus for a small span of their evolutionary life, and a conservation of their compositional patterns, including gene localization.


Suicide Acceptability and Sexual Orientation: Results from the General Social Survey 2008-2014.
Lesbian, gay, and bisexual (LGB) individuals have higher prevalence of lifetime suicide ideation and attempt than their heterosexual peers, but less is known about differences in suicide acceptability (i.e., believing suicide is a viable answer to a problem). The purpose of this study was to examine if LGB adults had greater suicide acceptability than heterosexual adults. A total of 4 items in the General Social Surveys from 2008 to 2014 assessed whether a nationally representative sample of U.S. adult respondents (n = 5,037) thought it acceptable for individuals to kill themselves if one: goes bankrupt, dishonors their family, is tired of living, or has an incurable disease. Multiple logistic regression analyses were used to assess the association of sexual orientation with suicide acceptability items after adjusting for confounding factors. Compared with heterosexuals, lesbians/gays had higher odds of reporting suicide acceptability if one goes bankrupt (OR = 1.92; 95% CI: 1.06, 3.46), dishonors family (OR = 1.83; 95% CI: 1.01, 3.28), or is tired of living (OR = 2.25; 95% CI: 1.30, 3.90). Bisexual and heterosexual groups were largely similar across the 4 suicide acceptability items. No sexual orientation differences were observed for reporting acceptability of suicide in the instance of an incurable disease. Post hoc analyses revealed significant interactions between sex and sexual orientation, such that differences in suicide acceptability seemed to be driven by sexual minority women rather than by sexual minority men. Suicide acceptability differs by sexual orientation, and community-level interventions around changing norms about suicide may be a prevention strategy for sexual minority individuals.


Changes in the Cervical Microbiota of Women with Different High-Risk Human Papillomavirus Loads.
The cervical microbiota is essential in female sexual health, and its altered states seem to have a central role in the dynamic of high-risk papillomavirus (hrHPV) infections. This study aimed to evaluate the variation in bacterial communities' compositions according to hrHPV. We collected two samples per woman, with a difference of 12 ± 1 months between them, and performed a follow-up on 66 of these women. The viral load (VL) of the hrHPV was estimated by quantitative PCR (qPCR), then it was normalized (using the HMBS gene as reference) and transformed to the Log10 scale to facilitate the interpretation. The VL was categorized as Negative, without hrHPV copies; Low, less than 100 hrHPV copies; Medium, between 100 to 102 hrHPV copies; and High, >102 hrHPV copies. The microbiota composition was described through the Illumina Novaseq PE250 platform. The diversity analyses revealed changes regarding the hrHPV VL, where women with low VL (<100 hrHPV copies) presented high diversity. The community state type (CST) IV was the most common. However, in women with high VL, a lower association with Lactobacillus depletion was found. Lactobacillus gallinarum and L. iners were the most abundant species in women with high VL, whereas women with low VL had a 6.06 greater probability of exhibiting Lactobacillus dominance. We identified conspicuous differences in the abundance of 78 bacterial genera between women with low and high VL, where 26 were depleted (e.g., Gardnerella) and 52 increased (e.g., Mycoplasma). A multilevel mixed-effects linear regression showed changes in the diversity due to the interaction between the measurement time and the VL, with a decrease in diversity in the second follow-up in women with low VL (Coeff. = 0.47), whereas the women with medium VL displayed an increase in diversity (Coeff. = 0.58). Here, we report for the first time that the cervical microbiota is influenced by the number of copies of hrHPV, where a decrease in the abundance of Lactobacillus, greater diversity, and enrichment of bacterial taxa is relevant in women with low VL.


Serial diffusion tensor images during infancy and their relationship to neuromotor outcomes in preterm infants.
Even preterm infants with normal magnetic resonance imaging (MRI) results are at greater risk for neuromotor dysfunction. Our aim was to compare serial diffusion tensor imaging (DTI) data from preterm infants without apparent brain abnormalities on magnetic resonance imaging with those from term controls and to investigate the white matter (WM) region associated with neuromotor outcomes. We obtained serial DTIs from 21 preterm infants at term-equivalent age (TEA) and 1 year of corrected age. As controls, 15 term neonates and 20 newly recruited term infants aged 1 year underwent DTI. Preterm and term infants at 1 year of age were assessed with the Bayley Scales of Infant Development, second edition. Tract-based spatial statistics and regions of interest were used for analysis. At TEA, the entire WM development was delayed in the preterm infants compared with the term controls, but at 1 year of age, the WM development, except for that of the corpus callosum (CC), had reached the development level of the term controls. The psychomotor developmental index was positively correlated with the fractional anisotropy (FA) in the CC (particularly in the body and splenium) at 1 year of age after correcting for gestational age, chronic lung disease, and postnatal infection. The CC of the preterm infants was consistently underdeveloped compared with that of the term controls. The FA in the CC, particularly in the body and splenium at 1 year of age, well reflected the degree of motor function in infants without apparent brain abnormalities.


Use of a microfluidic platform to uncover basic features of energy and environmental stress responses in individual cells of Bacillus subtilis.
Bacteria use a variety of stress-sensing systems to sense and respond to diverse stressors and to ensure their survival under adverse conditions. The gram-positive bacterium Bacillus subtilis responds to energy stress (ATP depletion) and to environmental stressors using two distinct stress-sensing pathways that converge on the alternative sigma factor σB to provoke a general stress response. Past efforts to study the σB stress response in bulk culture and on agarose pads were unable to visualize the responses of individual cells under tightly controlled conditions for extended periods of time. Here we use a microfluidics-based strategy to discern the basic features of σB activation in single cells in response to energy and environmental stress, both immediately upon stressor exposure and for tens of generations thereafter. Upon energy stress at various levels of stressor, cells exhibited fast, transient, and amplitude-modulated responses but not frequency modulation as previously reported. Upon environmental stress, which is mediated by the stressosome complex, wild-type cells primarily exhibited a transient and amplitude-modulated response. However, mutant cells producing only one of the four paralogous RsbR stressosome proteins showed striking and previously unseen differences. Whereas RsbRA-only cells mimicked the wild type, RsbRC-only cells displayed a slower but sustained overall response composed of repeated activation events in single cells.


Impact of high platelet turnover on the platelet transcriptome: Results from platelet RNA-sequencing in patients with sepsis.
Sepsis is associated with high platelet turnover and elevated levels of immature platelets. Changes in the platelet transcriptome and the specific impact of immature platelets on the platelet transcriptome remain unclear. Thus, this study sought to address whether and how elevated levels of immature platelets affect the platelet transcriptome in patients with sepsis. Blood samples were obtained from patients with sepsis requiring vasopressor therapy (n = 8) and from a control group of patients with stable coronary artery disease and otherwise similar demographic characteristics (n = 8). Immature platelet fraction (IPF) was determined on a Sysmex XE 2100 analyser and platelet function was tested by impedance aggregometry. RNA from leukocyte-depleted platelets was used for transcriptome analysis by Next Generation Sequencing integrating the use of unique molecular identifiers. IPF (median [interquartile range]) was significantly elevated in sepsis patients (6.4 [5.3-8.7] % vs. 3.6 [2.6-4.6] %, p = 0.005). Platelet function testing revealed no differences in adenosine diphosphate- or thrombin receptor activating peptide-induced platelet aggregation between control and sepsis patients. Putative circular RNA transcripts were decreased in platelets from septic patients. Leukocyte contamination defined by CD45 abundance levels in RNA-sequencing was absent in both groups. Principal component analysis of transcripts showed only partial overlap of clustering with IPF levels. RNA sequencing showed up-regulation of 524 and down-regulation of 118 genes in platelets from sepsis patients compared to controls. Upregulated genes were mostly related to catabolic processes and protein translation. Comparison to published platelet transcriptomes showed a large overlap of changes observed in sepsis and COVID-19 but not with reticulated platelets from healthy donors. Patients with sepsis appear to have a less degraded platelet transcriptome as indicated by increased levels of immature platelets and decreased levels of putative circular RNA transcripts. The present data suggests that increased protein translation is a characteristic mechanism of systemic inflammation.


An interview with J. Jarrett Clinton. Interview by Carmella A. Bacchino.
Medical effectiveness initiatives, outcomes research, and practice guidelines--the new buzz words for the 90s--will change the way health care services are delivered and allocated. The focal point for medical effectiveness and health services research for the federal government is the Public Health Service's newest agency, the Agency for Health Care Policy and Research. The agency is headed by J. Jarrett Clinton, MD, MPH, administrator, who also served as acting administrator since the creation of the agency in December 1989 until April 1991. In this interview, Dr. Clinton discusses the agency's responsibilities, his perspective on the agency's work, and the effect of health services research on the U.S. health care delivery system.


Effects of hypergravity on lung carcinoma cells maintained in continuous organotypic culture.
The effects of hypergravity levels ranging from 1 to 15 g were studied on A549 lung adenocarcinoma cell line, cultivated as nodules. This organotypic culture model preserves as closely as possible the cellular structures and differentiation functions of the in vivo situation. Nodules submitted to hypergravity conditions for 27 d did not show any change of cell growth, protein and DNA contents, compared with controls. Also, cellular differentiation, as regards intracellular phospholipid composition and more particularly phosphatidylcholine content, appeared undisturbed. The only obvious effect of hypergravity was a modification of the structural organization, with a disappearance of the large alveoli present at the surrounding of control nodules and the development of a dense cellular mass instead.


Beta- and gamma-band cortico-cortical interactions support naturalistic reading of continuous text.
Large-scale integration of information across cortical structures, building on neural connectivity, has been proposed to be a key element in supporting human cognitive processing. In electrophysiological neuroimaging studies of reading, quantification of neural interactions has been limited to the level of isolated words or sentences due to artefacts induced by eye movements. Here, we combined magnetoencephalography recording with advanced artefact rejection tools to investigate both cortico-cortical coherence and directed neural interactions during naturalistic reading of full-page texts. Our results show that reading versus visual scanning of text was associated with wide-spread increases of cortico-cortical coherence in the beta and gamma bands. We further show that the reading task was linked to increased directed neural interactions compared to the scanning task across a sparse set of connections within a wide range of frequencies. Together, the results demonstrate that neural connectivity flexibly builds on different frequency bands to support continuous natural reading.


Effect of VEGF trap on normal retinal vascular development and oxygen-induced retinopathy in the dog.
Purpose. To evaluate the effects of a vascular endothelial growth factor trap (VEGF Trap) on retinal vascular development and pathologic neovascularization (NV) in the canine model of oxygen-induced retinopathy (OIR). Methods. Newborn dogs (postnatal day [P]1) were exposed to 100% O(2) and then returned to room air on P5. VEGF Trap (5, 25, or 250 μg) was injected intravitreally in one eye and human FC (hFc) injected in the fellow eye of air control and oxygen-treated dogs on P8. The retinal vasculature and NV were evaluated on P21. Other oxygen-exposed animals received 5 μg of VEGF Trap or hFc on P22 after confirmation of retinopathy of prematurity (ROP)-like pathology and were evaluated at P45. Results. In air controls, both the vascularized area of the retina and the density of superficial capillaries were reduced in 250 or 25 μg VEGF Trap-injected eyes, and deep capillaries were absent. Eyes that received the 5 μg dose were indistinguishable from controls. In oxygen-treated animals, all eyes injected with VEGF Trap exhibited markedly less intravitreal NV than that of hFc-injected fellow eyes, irrespective of dose. Retinal vascular area in OIR animals was significantly reduced in eyes injected with 250 or 25 μg of VEGF Trap, but the 5 μg dose did not inhibit retinal revascularization. Eyes with existing NV that received 5 μg VEGF Trap at P22 exhibited substantial resolution of OIR pathology at P45. Conclusions. The VEGF Trap inhibited the formation of NV, but higher doses also inhibited revascularization of retina when injected at P8. In contrast, the lowest dose tested effectively blocked NV and caused regression of existing NV, without appreciably affecting vasculogenesis or retinal revascularization. These findings suggest that dose selection is an important variable when considering the use of VEGF-targeting agents for the treatment of ROP.


Propagation of uncertainties and applications in numerical modeling: tutorial.
Some inputs of computational models are commonly retrieved from external sources (handbooks, articles, dedicated measurements), and therefore are subject to uncertainties. The known experimental dispersion of the inputs can be propagated through the numerical models to produce samples of outputs. The stemming propagation of uncertainties is already significant in metrology but also has applications in optimization and inverse problem resolution of the modeled physical system. Moreover, the information on uncertainties can be used to characterize and compare models, and to deduce behavior laws. This tutorial gives tools and applications of the propagation of experimental uncertainties through models. To illustrate the method and its applications, we propose to investigate the scattering of light by gold nanoparticles, which also enables the comparison of the full Mie theory and the dipole approximation. The position of the localized surface plasmon resonance and the corresponding value of the scattering efficiency are more specifically studied.


The role of the stomach in eating.
The paper is concerned with the locus of provenance of satiety signals, what these are generated by, and pathways by which they reach the brain. Satiety signals are generated by the stomach and are of two kinds: distention at high volume and nutrient content. The former, but not the latter, are relayed to the brain via the vagus. Receptors that signal nutrient respond to digestive breakdown product of such nutrient. Further experiments are summarized to show that the gastric nutrient signals are calibrated through learning by association with various flavors. Previous to such learning, when food is novel, gastric controls do not operate, but regulation occurs through oropharyngeal metering.


[Stromal vessels of invasive ductal mammary gland carcinoma].
With the use of antibodies against factor VIII, vascular bed (number, surface and caliber of vessels) was studied in 64 cases of invasive ductal carcinoma and in normal breast tissue. The trend to a decrease of the vessels number with growing size of the tumor and emergence of lymph node metastases was observed. No difference was found in the development of vascular bed depending on the degree of malignancy, clinical course, tumor or normal breast tissue.


[Effect of tiapride in acute manifestations of alcohol withdrawal].
The purpose of this trial was to evaluate the effect of tiapride in alcohol withdrawal. The same very strict protocol was applied to each of 90 hospitalized male patients. Starting from 12 intravenous vials daily, in 4 doses, dosage was slowly brought down to 3 tablets per day, in 3 doses, by the 5th day. Effectiveness of Tiapride proved excellent, as soon as the first four days, mainly on psychiatric and digestive manifestations, while it was satisfactory on pain and less so on tremor. Overall tolerance was good. Attention is drawn to the very rapid action of Tiapride, which results in a 50% decrease in the duration of the hospital stay.


Inhibition of tobacco mosaic virus infection by quercetin and vitexin.
The flavonoids, quercetin and vitexin were proved to reduce lesion number in the local hosts Datura stramonium and Chenopodium amaranticolor infected with Tobacco mosaic virus (TMV). Both flavonoids also reduced the virus concentration in systemically infected tobacco plants. This effect was restricted to an early stage of infection and correlated with an induced synthesis of salicylic acid (SA) and kaempferol suggesting their possible defensive role in the infected plant tissue. Since the tested flavonoids did not bind to the virus particles, their antiphytoviral activity was probably not based on a direct virus inactivation.


Li-Fraumeni Exploration Consortium Data Coordinating Center: Building an Interactive Web-Based Resource for Collaborative International Cancer Epidemiology Research for a Rare Condition.
The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented. The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research. The primary scientific and technological objective to create an online central repository into which data from all participating sites could be deposited, harmonized, aggregated, disseminated, and analyzed was completed. The cohort now include 2,193 participants from six contributing sites, including 1,354 individuals from families with a pathogenic or likely variant in TP53. Data on cancer diagnoses are also available. Challenges and lessons learned are summarized. The methods leveraged mitigate challenges associated with successfully developing a DCC's technical infrastructure, data harmonization efforts, communications, and software development and applications. These methods can serve as a framework in establishing other collaborative research efforts. Data from the consortium will serve as a great resource for collaborative research to improve knowledge on, and the ability to care for, individuals and families with Li-Fraumeni syndrome.


Batrachotoxin-modified sodium channels in planar lipid bilayers. Ion permeation and block.
Batrachotoxin-modified, voltage-dependent sodium channels from canine forebrain were incorporated into planar lipid bilayers. Single-channel conductances were studied for [Na+] ranging between 0.02 and 3.5 M. Typically, the single-channel currents exhibited a simple two-state behavior, with transitions between closed and fully open states. Two other conductance states were observed: a subconductance state, usually seen at [NaCl] greater than or equal to 0.5 M, and a flickery state, usually seen at [NaCl] less than or equal to 0.5 M. The flickery state became more frequent as [NaCl] was decreased below 0.5 M. The K+/Na+ permeability ratio was approximately 0.16 in 0.5 and 2.5 M salt, independent of the Na+ mole fraction, which indicates that there are no interactions among permeant ions in the channels. Impermeant and permeant blocking ions (tetraethylammonium, Ca++, Zn++, and K+) have different effects when added to the extracellular and intracellular solutions, which indicates that the channel is asymmetrical and has at least two cation-binding sites. The conductance vs. [Na+] relation saturated at high concentrations, but could not be described by a Langmuir isotherm, as the conductance at low [NaCl] is higher than predicted from the data at [NaCl] greater than or equal to 1.0 M. At low [NaCl] (less than or equal to 0.1 M), increasing the ionic strength by additions of impermeant monovalent and divalent cations reduced the conductance, as if the magnitude of negative electrostatic potentials at the channel entrances were reduced. The conductances were comparable for channels in bilayers that carry a net negative charge and bilayers that carry no net charge. Together, these results lead to the conclusion that negative charges on the channel protein near the channel entrances increase the conductance, while lipid surface charges are less important.


The new senior volunteer: a bold initiative to expand the supply of independent living services to older adults.
This article presents findings of the evaluation of the Experience Corps for Independent Living (ECIL) initiative. The ECIL initiative was a two-year demonstration program designed to test innovative ways to use the experience, time, and resources of volunteers over 55 to significantly expand the size and scope of volunteer efforts on behalf of independent living services for frail elders and their caregivers in specific communities. Six demonstration sites were selected to participate in this initiative. The intensive volunteers, the critical component of the program, were more highly skilled than typical volunteers from existing senior volunteer programs. ECIL volunteers collaborated with agency partners to develop new programs, supervise direct service activities, and enhance the performance of the agencies being served. The ECIL initiative was particularly successful in meeting its goals of expanding the supply of independent living services to frail elders and their families in the communities served.


Nitrogen doped graphene nanosheet supported platinum nanoparticles as high performance electrochemical homocysteine biosensors.
Functional carbon nanomaterials are significantly important for the development of high performance sensitive and selective electrochemical biosensors. In this study, graphene supported platinum nanoparticles (GN-PtNPs) and nitrogen doped graphene supported platinum nanoparticles (N-GN-PtNPs) were synthesized by a simple chemical reduction method and explored as high performance nanocatalyst supports, as well as doped nanocatalyst supports, toward electrochemical oxidation of homocysteine (HCY) for the first the time. Our studies demonstrate that N-doped graphene supported PtNPs show higher electrocatalytic activity for HCY with an experimental detection limit of 200 pM. Moreover, N-doped graphene supported Pt was demonstrated to have excellent selectivity in the electrochemical oxidation of HCY i.e., the detection of HCY is successful in the presence of a 20-fold excess of ascorbic acid (AA). The practical application of N-doped graphene supported PtNP materials is effectively shown for the determination of HCY in both human blood serum and urine samples, by differential pulse voltammetry under optimized conditions. Our findings conclude that N-doped graphene supported PtNPs can be developed as a high performance and versatile nano-electrocatalyst for electrochemical biosensor applications.


Turnover of serotonin in brain of an anoxia-tolerant vertebrate, the crucian carp.
Serotonin (5-HT) is a neurotransmitter in the vertebrate brain. Estimates of 5-HT turnover times range between 1 h (mammals) and 10 h (goldfish). Synthesis and catabolism of 5-HT are dependent on molecular oxygen, hence, 5-HT turnover comes to a halt during anoxia. Nevertheless, a few vertebrates, such as the crucian carp (Carassius carassius L.), tolerate anoxia for several weeks. To assess the ability of the crucian carp brain to tolerate a stop in 5-HT turnover during anoxia, it is essential to know its normoxic rate of 5-HT turnover. The turnover of 5-HT was estimated in different brain regions of winter-acclimatized crucian carp held in normoxia at 8 degrees C using two different methods, i.e., 1) by measuring the increase seen in 5-HT after monoamine oxidase inhibition (by pargyline), and 2) by measuring the rate of 5-hydroxytryptophan (5-HTP) accumulation, after the conversion of 5-HTP to 5-HT had been inhibited (by N-m-hydroxybenzylhydrazine). Both methods suggested similar turnover rates (approximately 10-20 pmol/g h) and turnover times (1-3 days). This is probably the slowest 5-HT turnover ever measured in a vertebrate (less than 1/100 of that of mammals). The slow 5-HT turnover could be explained by a high degree of recycling of the same 5-HT molecules, in combination with a decreased turnover at low temperatures. Moreover, the slow 5-HT turnover might be a prerequisite for preserving the functional integrity of the 5-HT system during anoxia.


Deconstructing Chronic Low Back Pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment. Part VI: Lumbar Spinal Stenosis.
. To present the sixth in a series of articles designed to deconstruct chronic low back pain (CLBP) in older adults. This article focuses on the evaluation and management of lumbar spinal stenosis (LSS), the most common condition for which older adults undergo spinal surgery. . The evaluation and treatment algorithm, a table articulating the rationale for the individual algorithm components, and stepped-care drug recommendations were developed using a modified Delphi approach. The Principal Investigator, a five-member content expert panel and a nine-member primary care panel were involved in the iterative development of these materials. The illustrative clinical case was taken from the clinical practice of a contributor's colleague (SR). . We present an algorithm and supportive materials to help guide the care of older adults with LSS, a condition that occurs not uncommonly in those with CLBP. The case illustrates the importance of function-focused management and a rational approach to conservative care. . Lumbar spinal stenosis exists not uncommonly in older adults with CLBP and management often can be accomplished without surgery. Treatment should address all conditions in addition to LSS contributing to pain and disability.


A novel antibody-dependent cellular cytotoxicity mechanism involved in defense against malaria requires costimulation of monocytes FcgammaRII and FcgammaRIII.
Clinical experiments have shown that the Ab-dependent cell-mediated inhibition of Plasmodium falciparum is a major mechanism controlling malaria parasitemia and thereby symptoms. In this study, we demonstrate that a single merozoite per monocyte (MN) is sufficient to trigger optimal antiparasitic activity. Using particulate Ag as pseudomerozoites, we show that only Ags, and no other parasite-derived factor, are required to trigger MN activation and that a single Ag is as potent as the complex combination of Ags constituting the merozoite surface. Moreover, we found that soluble Ags binding at least two Abs are as effective as the parasite at stimulating MN and that nonmalarial Ags are as efficient provided they are targeted by cytophilic Abs. Indeed, only cytophilic IgGs are potent and, in agreement with immunoepidemiological findings, IgG3 is superior to IgG1. Very low Ab concentrations (>700 pM), i.e., in the range of molecules having a hormonal effect, are effective, in contrast to Abs having a direct, neutralizing effect. Finally, Ab-dependent cell-mediated inhibition proved to require the synergistic activation of both FcgammaRIIa and FcgammaRIIIa which both distinguish it from other Ab-dependent cellular cytotoxicity and implies that all MN are not equally effective. These findings have both fundamental and practical implications, particularly for vaccine discovery.


Immunoexpression of vascular endothelial growth factor and B-cell lymphoma 2 in the uterine tissue of rats treated with melatonin in the estrus phase1.
To investigate the effect of melatonin on uterine tissue in the ovariectomized rat model. Fourty Wistar albino rats were divided into four groups for histologic and immunohistochemical examination. The rats were first numbered randomly and then randomly divided into 4 equal groups: control (group 1), torsion (group 2), torsion+detorsion (group 3) and torsion+detorsion+melatonin (group 4) groups. In addition, four Wistar albino rats were used for western blot analysis in each group. And also, malondialdehyde (MDA) levels were measured biochemically in all rats. The histopathological examination of the uterine tissue in rats ovarectomized showed a degeneration in uterine glands, dilation of blood vessels in the internal layer with a thrombosis and bleeding, abnormal nucleuses and vacuolated cytoplasm above and below the nucleus. In torsion group, the apoptotic cells increased in luminal epithelium and gland cells. In the melatonin group showed that the Bcl2 negative effect on the uterine epithelium and did not lead to apoptotic cells. The increase in vascular endothelial growth factor expression resulted in the rearrangement of endothelial cell growth and the induction of angiogenesis.


Optoelectronic crystal of artificial atoms in strain-textured molybdenum disulphide.
The isolation of the two-dimensional semiconductor molybdenum disulphide introduced a new optically active material possessing a band gap that can be facilely tuned via elastic strain. As an atomically thin membrane with exceptional strength, monolayer molybdenum disulphide subjected to biaxial strain can embed wide band gap variations overlapping the visible light spectrum, with calculations showing the modified electronic potential emanating from point-induced tensile strain perturbations mimics the Coulomb potential in a mesoscopic atom. Here we realize and confirm this 'artificial atom' concept via capillary-pressure-induced nanoindentation of monolayer molybdenum disulphide from a tailored nanopattern, and demonstrate that a synthetic superlattice of these building blocks forms an optoelectronic crystal capable of broadband light absorption and efficient funnelling of photogenerated excitons to points of maximum strain at the artificial-atom nuclei. Such two-dimensional semiconductors with spatially textured band gaps represent a new class of materials, which may find applications in next-generation optoelectronics or photovoltaics.


A critical role for the hippocampus and perirhinal cortex in perceptual learning of scenes and faces: complementary findings from amnesia and FMRI.
It is debated whether subregions within the medial temporal lobe (MTL), in particular the hippocampus (HC) and perirhinal cortex (PrC), play domain-sensitive roles in learning. In the present study, two patients with differing degrees of MTL damage were first exposed to pairs of highly similar scenes, faces, and dot patterns and then asked to make repeated same/different decisions to preexposed and nonexposed (novel) pairs from the three categories (Experiment 1). We measured whether patients would show a benefit of prior exposure (preexposed > nonexposed) and whether repetition of nonexposed (and preexposed) pairs at test would benefit discrimination accuracy. Although selective HC damage impaired learning of scenes, but not faces and dot patterns, broader MTL damage involving the HC and PrC compromised discrimination learning of scenes and faces but left dot pattern learning unaffected. In Experiment 2, a similar task was run in healthy young participants in the MRI scanner. Functional region-of-interest analyses revealed that posterior HC and posterior parahippocampal gyrus showed greater activity during scene pattern learning, but not face and dot pattern learning, whereas PrC, anterior HC, and posterior fusiform gyrus were recruited during discrimination learning for faces, but not scenes and dot pattern learning. Critically, activity in posterior HC and PrC, but not the other functional region-of-interest analyses, was modulated by accuracy (correct > incorrect within a preferred category). Therefore, both approaches revealed a key role for the HC and PrC in discrimination learning, which is consistent with representational accounts in which subregions in these MTL structures store complex spatial and object representations, respectively.


Human thyroperoxidase in its alternatively spliced form (TPO2) is enzymatically inactive and exhibits changes in intracellular processing and trafficking.
Thyroid peroxidase (TPO1) is a membrane-bound heme-containing glycoprotein that catalyzes the synthesis of thyroid hormones. We generated stable cell lines expressing TPO1 and the alternatively spliced isoform TPO2. Pulse-chase studies showed that TPO2 half-life was dramatically decreased as compared with TPO1. The sensitivity of TPO2 to endo-beta-N-acetylglucosaminidase H indicated that the protein is processed through the endoplasmic reticulum and bears high mannose-type structures. Cell surface biotinylation experiments showed that the two isoforms also differ in their intracellular trafficking. TPO2 was totally retained in the cell, whereas 15% of TPO1 reached the cell surface. The inability of TPO2 to come out of the intracellular compartments was related to structural changes in the molecule. Evidence of these changes was obtained through the lack of recognition of TPO2 by half of the 13 TPO monoclonal antibodies tested in immunoprecipitation experiments. Our data suggest that because of an improper folding, TPO2 is trapped in the endoplasmic reticulum and rapidly degraded. The failure of incorporation of [14C]aminolevulinic acid in the cultured cells showed that TPO2 did not bind to heme, whereas TPO1 did. This result was confirmed through a guaiacol assay showing that TPO2 is enzymatically inactive.


Accuracy of death certificates for motor neuron disease and multiple sclerosis in the province of Palermo in southern Italy.
Mortality studies based on death certificates (DCs) are relatively inexpensive and easy to conduct. Therefore, they are frequently used to evaluate variations of geographical and temporal patterns, particularly in uncommon diseases. Recent surveys of motor neuron disease (MND) and multiple sclerosis (MS) based on official mortality statistics in Italy showed a decreasing trend of mortality from northern to southern Italy. To evaluate if DCs are homogeneously recorded in Italy and whether or not they can be considered a good instrument for mortality studies, we assessed the accuracy of DCs for MND and MS in the province of Palermo, Italy, and compared our results with those reported in other studies. We searched the archives of the neurological clinic of the University of Palermo for patients affected by one of the two diseases who were residents and were diagnosed in Palermo province. We found 157 patients with definite MND and 360 with clinically definite MS. Seventy-eight out of the 157 MND patients and 43 out of the 360 MS patients had died. Considering the underlying cause of death, the true-positive rate was 48% [95% confidence interval (CI) 36-60%] for MND and 46% (95% Cl 30-62%) for MS. The rates we found for MND were lower than those reported either in Italy or worldwide. This result suggests caution in formulating gradient hypotheses for MND. Concerning MS, the rate we found was low, but similar to that found by others. This indicates that a mortality survey of MS based on DCs is unlikely to be contributory.


Reactive oxygen species upregulate expression of muscle atrophy-associated ubiquitin ligase Cbl-b in rat L6 skeletal muscle cells.
Unloading-mediated muscle atrophy is associated with increased reactive oxygen species (ROS) production. We previously demonstrated that elevated ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) resulted in the loss of muscle volume (Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, Okumura Y, Nonaka I, Yasutomo K, Baldwin KM, Kominami E, Higashibata A, Nagano K, Tanaka K, Yasui N, Mills EM, Takeda S, Nikawa T. Mol Cell Biol 29: 4798-4811, 2009). However, the pathological role of ROS production associated with unloading-mediated muscle atrophy still remains unknown. Here, we showed that the ROS-mediated signal transduction caused by microgravity or its simulation contributes to Cbl-b expression. In L6 myotubes, the assessment of redox status revealed that oxidized glutathione was increased under microgravity conditions, and simulated microgravity caused a burst of ROS, implicating ROS as a critical upstream mediator linking to downstream atrophic signaling. ROS generation activated the ERK1/2 early-growth response protein (Egr)1/2-Cbl-b signaling pathway, an established contributing pathway to muscle volume loss. Interestingly, antioxidant treatments such as N-acetylcysteine and TEMPOL, but not catalase, blocked the clinorotation-mediated activation of ERK1/2. The increased ROS induced transcriptional activity of Egr1 and/or Egr2 to stimulate Cbl-b expression through the ERK1/2 pathway in L6 myoblasts, since treatment with Egr1/2 siRNA and an ERK1/2 inhibitor significantly suppressed clinorotation-induced Cbl-b and Egr expression, respectively. Promoter and gel mobility shift assays revealed that Cbl-b was upregulated via an Egr consensus oxidative responsive element at -110 to -60 bp of the Cbl-b promoter. Together, this indicates that under microgravity conditions, elevated ROS may be a crucial mechanotransducer in skeletal muscle cells, regulating muscle mass through Cbl-b expression activated by the ERK-Egr signaling pathway.


Discovery of a phosphine-mediated cycloisomerization of alkynyl hemiketals: access to spiroketals and dihydropyrazoles via tandem reactions.
Reported here are details on the discovery of a phosphine-catalyzed isomerization of hemiketals and subsequent reactions of the cyclic keto enol ether products. The new cycloisomerization complements a previously reported amine-catalyzed process that gave oxepinones from the same hemiketal starting materials. In the absence of functionality (R(2)) on the cyclic keto enol ether, a rapid and facile dimerization occurs, giving spiroketal products. When the enone is substituted (i.e., R(2) = Ph), the cyclic keto enol ether is sufficiently stable so that it can be isolated; it can then be further reacted in the same pot to provide the corresponding dihydropyrazoles. Both the spiroketal and dihydropyrazole products arise by a tandem reaction that begins with the novel cycloisomerization. The method allows for the rapid introduction of complexity in the products from relatively simple starting materials. It should find application in the synthesis of natural product-like molecules.


Introduction of SV40ER and hTERT into mammospheres generates breast cancer cells with stem cell properties.
Emerging evidence suggests that cancers arise in stem/progenitor cells. Yet, the requirements for transformation of these primitive cells remains poorly understood. In this study, we have exploited the 'mammosphere' system that selects for primitive mammary stem/progenitor cells to explore their potential and requirements for transformation. Introduction of Simian Virus 40 Early Region and hTERT into mammosphere-derived cells led to the generation of NBLE, an immortalized mammary epithelial cell line. The NBLEs largely comprised of bi-potent progenitors with long-term self-renewal and multi-lineage differentiation potential. Clonal and karyotype analyses revealed the existence of heterogeneous population within NBLEs with varied proliferation, differentiation and sphere-forming potential. Significantly, injection of NBLEs into immunocompromised mice resulted in the generation of invasive ductal adenocarcinomas. Further, these cells harbored a sub-population of CD44(+)/CD24(-) fraction that alone had sphere- and tumor-initiating potential and resembled the breast cancer stem cell gene signature. Interestingly, prolonged in vitro culturing led to their further enrichment. The NBLE cells also showed increased expression of stemness and epithelial to mesenchymal transition markers, deregulated self-renewal pathways, activated DNA-damage response and cancer-associated chromosomal aberrations-all of which are likely to have contributed to their tumorigenic transformation. Thus, unlike previous in vitro transformation studies that used adherent, more differentiated human mammary epithelial cells our study demonstrates that the mammosphere-derived, less-differentiated cells undergo tumorigenic conversion with only two genetic elements, without requiring oncogenic Ras. Moreover, the striking phenotypic and molecular resemblance of the NBLE-generated tumors with naturally arising breast adenocarcinomas supports the notion of a primitive breast cell as the origin for this subtype of breast cancer. Finally, the NBLEs represent a heterogeneous population of cells with striking plasticity, capable of differentiation, self-renewal and tumorigenicity, thus offering a unique model system to study the molecular mechanisms involved with these processes.


Bayesian T-optimal discriminating designs.
The problem of constructing Bayesian optimal discriminating designs for a class of regression models with respect to the T-optimality criterion introduced by Atkinson and Fedorov (1975a) is considered. It is demonstrated that the discretization of the integral with respect to the prior distribution leads to locally T-optimal discriminating design problems with a large number of model comparisons. Current methodology for the numerical construction of discrimination designs can only deal with a few comparisons, but the discretization of the Bayesian prior easily yields to discrimination design problems for more than 100 competing models. A new efficient method is developed to deal with problems of this type. It combines some features of the classical exchange type algorithm with the gradient methods. Convergence is proved and it is demonstrated that the new method can find Bayesian optimal discriminating designs in situations where all currently available procedures fail.


Estimating Demand for and Supply of Pediatric Preventive Dental Care for Children and Identifying Dental Care Shortage Areas, Georgia, 2015.
Demand for dental care is expected to outpace supply through 2025. The objectives of this study were to determine the extent of pediatric dental care shortages in Georgia and to develop a general method for estimation that can be applied to other states. We estimated supply and demand for pediatric preventive dental care for the 159 counties in Georgia in 2015. We compared pediatric preventive dental care shortage areas (where demand exceeded twice the supply) designated by our methods with dental health professional shortage areas designated by the Health Resources & Services Administration. We estimated caries risk from a multivariate analysis of National Health and Nutrition Examination Survey data and national census data. We estimated county-level demand based on the time needed to perform preventive dental care services and the proportion of time that dentists spend on pediatric preventive dental care services from the Medical Expenditure Panel Survey. Pediatric preventive dental care supply exceeded demand in Georgia in 75 counties: the average annual county-level pediatric preventive dental care demand was 16 866 hours, and the supply was 32 969 hours. We identified 41 counties as pediatric dental care shortage areas, 14 of which had not been designated by the Health Resources & Services Administration. Age- and service-specific information on dental care shortage areas could result in more efficient provider staffing and geographic targeting.


[Study of hemodynamics in patients with acromegaly by means of radiocardiography].
Determination of the indices of central hemodynamics by means of radiocardiography shows them to be essentially changed in patients with acromegaly in the active stage. A clear correlative relationship has been established between the shifts in hemodynamics and the heart volume determined by X-ray. The diagnosis of preclinical stage of circulatory insufficiency is based on revealing a statistically significant increase in the stroke index and a decrease in the circulation volume and total peripheral resistance. In the early stage of acromegaly there is a statistically significant increase in the minute and stroke indices, in the index of minute work, and in the coefficient of circulation effectiveness. With an increase in the duration of the disease, these indices decrease considerably, which denotes hemodynamics deterioration.


Using deep learning for quantification of cellularity and cell lineages in bone marrow biopsies and comparison to normal age-related variation.
Cellularity estimation forms an important aspect of the visual examination of bone marrow biopsies. In clinical practice, cellularity is estimated by eye under a microscope, which is rapid, but subjective and subject to inter- and intraobserver variability. In addition, there is little consensus in the literature on the normal variation of cellularity with age. Digital image analysis may be used for more objective quantification of cellularity. As such, we developed a deep neural network for the segmentation of six major cell and tissue types in digitized bone marrow trephine biopsies. Using this segmentation, we calculated the overall bone marrow cellularity in a series of biopsies from 130 patients across a wide age range. Using intraclass correlation coefficients (ICC), we measured the agreement between the quantification by the neural network and visual estimation by two pathologists and compared it to baseline human performance. We also examined the age-related changes of cellularity and cell lineages in bone marrow and compared our results to those found in the literature. The network was capable of accurate segmentation (average accuracy and dice score of 0.95 and 0.76, respectively). There was good neural network-pathologist agreement on cellularity measurements (ICC=0.78, 95% CI 0.58-0.85). We found a statistically significant downward trend for cellularity, myelopoiesis and megakaryocytes with age in our cohort. The mean cellularity began at approximately 50% in the third decade of life and then decreased ±2% per decade to 40% in the seventh and eighth decade, but the normal range was very wide (30-70%).


Motion correction in dual gated cardiac PET using mass-preserving image registration.
Respiratory and cardiac motion leads to image degradation in positron emission tomography (PET) studies of the human heart. In this paper we present a novel approach to motion correction based on dual gating and mass-preserving hyperelastic image registration. Thereby, we account for intensity modulations caused by the highly nonrigid cardiac motion. This leads to accurate and realistic motion estimates which are quantitatively validated on software phantom data and carried over to clinically relevant data using a hardware phantom. For patient data, the proposed method is first evaluated in a high statistic (20 min scans) dual gating study of 21 patients. It is shown that the proposed approach properly corrects PET images for dual-cardiac as well as respiratory-motion. In a second study the list mode data of the same patients is cropped to a scan time reasonable for clinical practice (3 min). This low statistic study not only shows the clinical applicability of our method but also demonstrates its robustness against noise obtained by hyperelastic regularization.


Fucosidosis type 2.
Two siblings, 9 and 4 1/2 years old, had alpha-L-fucosidase deficiency, angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facila features, and dysostosis multiplex. It appears that genetic heterogeneity is present in fucosidosis; there are at least two types. In type 1, patients have no vascular lesions, but have rapid psychomotor regression, severe and rapidly progressing neurologic signs, elevated sodium and chloride excretion in the sweat, and fatal outcome before the sixth year. In type 2, patients have angiokeratoma, milder psychomotor retardation and neurologic signs, longer survival, and normal salinity in the sweat. Quantitative studies on erythrocytes and in saliva disclosed severely increased expressions of Lea and Leb. Biopsies of skin and gingiva showed alterations as seen in angiokeratoma. There was also evidence of lysosomal storage in vascular endothelium, eccrine sweat gland epithelium, and fibroblasts of the skin.


Multiple Errands Test-Revised (MET-R): a performance-based measure of executive function in people with mild cerebrovascular accident.
OBJECTIVE. This article describes a performance-based measure of executive function, the Multiple Errands Test-Revised (MET-R), and examines its ability to discriminate between people with mild cerebrovascular accident (mCVA) and control participants. METHOD. We compared the MET-R scores and measures of CVA outcome of 25 participants 6 mo post-mCVA and 21 matched control participants. RESULTS. Participants with mCVA showed no to minimal impairment on measures of executive function at hospital discharge but reported difficulty with community integration at 6 mo. The MET-R discriminated between participants with and without mCVA (p ≤ .002). CONCLUSION. The MET-R is a valid and reliable measure of executive functions appropriate for the evaluation of clients with mild executive function deficits who need occupational therapy to fully participate in community living.


Antigenic structure of chimeras of type 1 and type 3 poliovirus involving antigenic site 1.
Chimeric polioviruses have been prepared in which part of the antigenic site 1-encoding sequence of the Sabin strain of type 1 poliovirus has been replaced by sequences based on those found in the homologous region of the Sabin type 3 strain. The chimeras were analysed for their reaction with polyclonal and monoclonal antibodies raised against type 1 and type 3 viruses, and with polyclonal antipeptide sera, as well as for their immunogenicity in animals. The effectiveness with which the type 3 site was presented antigenically varied in ways which were partially predictable, based on the behaviour of type 3 mutants with monoclonal antibodies. However, other factors were implicated which may include conformational effects and other components of the site in addition to those altered in the chimeras. The ability of the chimeras to induce antibodies reacting with type 3 polioviruses paralleled their antigenic reactivity, and evidence is presented for the induction of strain-specific antibodies.


Zac1 (Lot1), a potential tumor suppressor gene, and the gene for epsilon-sarcoglycan are maternally imprinted genes: identification by a subtractive screen of novel uniparental fibroblast lines.
Imprinted genes are expressed from one allele according to their parent of origin, and many are essential to mammalian embryogenesis. Here we show that the epsilon-sarcoglycan gene (Sgce) and Zac1 (Lot1) are both paternally expressed imprinted genes. They were identified in a subtractive screen for imprinted genes using a cDNA library made from novel parthenogenetic and wild-type fibroblast lines. Sgce is a component of the dystrophin-sarcoglycan complex, Zac1 is a nuclear protein inducing growth arrest and/or apoptosis, and Zac1 is a potential tumor suppressor gene. Sgce and Zac1 are expressed predominantly from their paternal alleles in all adult mouse tissues, except that Zac1 is biallelic in the liver and Sgce is weakly expressed from the maternal allele in the brain. Sgce and Zac1 are broadly expressed in embryos, with Zac1 being highly expressed in the liver primordium, the umbilical region, and the neural tube. Sgce, however, is strongly expressed in the allantoic region on day 9.5 but becomes more widely expressed throughout the embryo by day 11.5. Sgce is located at the proximal end of mouse chromosome 6 and is a candidate gene for embryonic lethality associated with uniparental maternal inheritance of this region. Zac1 maps to the proximal region of chromosome 10, identifying a new imprinted locus in the mouse, homologous with human chromosome 6q24-q25. In humans, unipaternal disomy for this region is associated with fetal growth retardation and transient neonatal diabetes mellitus. In addition, loss of expression of ZAC has been described for a number of breast and ovarian carcinomas, suggesting that ZAC is a potential tumor suppressor gene.


Analysis of superoxide anion production in tissue.
Endothelial production of oxygen free radicals, especially superoxide anion (O(2)-), is an important mechanism of vascular dysfunction in hypertension. Overproduction of oxygen free radicals, mainly O(2)- occurs in human hypertension and in a wide variety of animal models. Thus, analysis of O(2)- generation represents a useful tool for identifying oxidative stress in hypertension. Among the methods used for O(2)- detection, the chemiluminescent probe lucigenin has been widely shown to be a useful method for detecting and quantifying the O(2)- formation. On the other hand, staining by the oxidative fluorescent probe dihydroethidine, which is freely permeable to cell membranes, is suitable to monitor in situ production of O(2)- and to provide a reliable marker of its intracellular presence. Dihydroethidine is oxidized in the presence of O(2)- to a fluorescent marker product, which is rapidly intercalated into DNA. Thus, nuclei are the primary fluorescent structures labeled. By simply incubating experimental samples in the presence of dihydroethidine followed by analysis of fluorescence, this method allows rapid and specific detection of intracellular oxidative stress due to superoxide anion generation.


Depressive symptoms and food insufficiency among HIV-infected crack users in Atlanta and Miami.
Depression contributes to worse general and HIV-related clinical outcomes. We examined the prevalence of and factors associated with depressive symptomatology among HIV-infected crack cocaine users recruited for Project HOPE (Hospital Visit is an Opportunity for Prevention and Engagement with HIV-positive Crack Users). We used multiple logistic regression to determine sociodemographic correlates associated with screening in for depression. Among 291 participants, three-quarters (73.5%) were identified as depressed. Higher odds of screening in for depression was associated with food insufficiency and monthly income below $600. Alcohol and crack use were not associated with screening in for depression. Depressive symptomatology is extremely prevalent among HIV-infected crack cocaine users and is associated with food insufficiency and lower income. Screening for depression and food insecurity should be included in HIV prevention and treatment programs. Improved recognition and mitigation of these conditions will help alleviate their contribution to HIV-related adverse health outcomes.


An Integrated X-Ray/Optical Tomography System for Pre-clinical Radiation Research.
The current Small Animal Radiation Research Platform (SARRP) is poor for localizing small soft tissue targets for irradiation or tumor models growing in a soft tissue environment. Therefore, an imaging method complementary to x-ray CT is required to localize the soft tissue target's Center of Mass (CoM) to within 1 mm. In this paper, we report the development of an integrated x-ray/bioluminescence imaging/tomography (BLI/BLT) system to provide a pre-clinical, high resolution irradiation system. This system can be used to study radiation effects in small animals under the conebeam computed tomography (CBCT) imaging guidance by adding the bioluminescence imaging (BLI) system as a standalone system which can also be docked onto the SARRP. The proposed system integrates two robotic rotating stages and an x-ray source rated at maximum 130 kVp and having a small variable focal spot. A high performance and low noise CCD camera mounted in a light-tight housing along with an optical filter assembly is used for multi-wavelength BL tomography. A three-mirror arrangement is implemented to eliminate the need of rotating the CCD camera for acquiring multiple views. The mirror system is attached to a motorized stage to capture images in angles between 0-90° (for the standalone system). Camera and CBCT calibration are accomplished.


Genetic diversity of oceanic island Lasaea (Mollusca: Bivalvia) lineages exceeds that of continental populations in the northwestern Atlantic.
Direct-developing lineages of the intertidal marine bivalve Lasaea have colonized both upstream mainland (southeastern Florida) and downstream oceanic island (Bermuda) locations in the western North Atlantic. Replicate samples from these two regional populations, separated by about 1500 km of open ocean, were sequenced for a 655-nucleotide portion of the mitochondrial (mt) cytochrome oxidase subunit I gene. Twelve haplotypes (2 Floridian and 10 Bermudan) were obtained that differed by a maximum of four substitutions among pairwise comparisons. Phylogenetic analysis yielded a parsimony network within which the mainland lineages clustered in one of the terminal branches; a mirror image of a priori expectations based on regional surface-current polarity. It is difficult, however, to envisage a plausible countercurrent dispersal mechanism. This tree topology may stem from divergent demographic processes operating on these two evolutionarily recent regional populations. The starlike phylogenetic pattern of Bermudan lineages is consistent with a history of rapid population growth. The restricted genetic repertoire and relative ecological scarcity of Floridian lineages imply either a recent founder event by unstudied Caribbean source populations or else a history of pronounced bottlenecks in population size. Bermuda's impoverished Caribbean marine biota may allow western North Atlantic Lasaea lineages to escape severe competitive interactions impacting other parts of their geographic range.


Regulation of fibroblast growth factor 2 expression in melanoma cells by the c-MYB proto-oncoprotein.
Dysregulated expression of basic fibroblast growth factor [fibroblast growth factor 2 (FGF-2)] mediates autocrine growth of melanoma cells. The presence of a consensus Myb binding site in the human FGF-2 promoter prompted us to investigate whether this transcription factor could regulate FGF-2 expression in melanomas. We report that c-MYB mRNA is overexpressed in melanoma cell lines compared to normal melanocytes and that ectopic expression of murine c-Myb in SK-MEL-2 human melanoma cells resulted in increased expression of FGF-2 mRNA and FGF-2 protein. Furthermore, murine c-Myb transactivated a reporter plasmid containing the human FGF-2 promoter region in contransfected SK-MEL-2 human melanoma cells. Although a functional DNA-binding domain was required for transactivation, responsiveness to c-Myb was independent of the putative Myb binding site and mapped to two regions of the FGF-2 promoter that did not bind c-Myb in vitro. We suggest that c-MYB contributes to FGF-2-mediated autocrine growth of melanomas by indirectly regulating the FGF-2 promoter.


Some chemical properties of isolated pea nucleoli.
Isolated nuclei and nucleoli of ungerminated pea embryos have been analyzed chemically for their content of DNA, RNA, zinc, iron, phosphorus, and protein sulfhydryl groups. The values obtained cannot be considered to represent the whole of the living nucleolar body as an undetermined amount of material is extracted from nucleoli in the course of their isolation. Only negligible amounts of DNA have been found in the isolated nucleoli; most of the DNA released on disruption of nuclei appears in a fraction showing very few structures under the light microscope. RNA is more concentrated in the nucleolus than in the nucleus or cytoplasm, but since nucleolar protein is 6 per cent of nuclear and less than 1 per cent of cytoplasmic protein, the total amount of nucleolar RNA is comparatively small. None of the other components listed occurs in high concentration in either nucleus or nucleolus.


The Effect of Remote Digital Services on Health Care Inequalities Among People Under Long-Term Dermatology Follow-Up: Cross-Sectional Questionnaire Study.
Given the expansion of remote digital dermatology services from the National Health Service, particularly during the COVID-19 pandemic, there is a need for methods that identify patients at risk of digital exclusion to guide equitable representation in service co-design processes and tailor remote services to the needs of their patient population. This quality improvement project aims to inform the redesign of remote services to optimally support the ongoing needs of patients with chronic skin diseases, ensuring that the services are tailored to patients' digital health literacy requirements. We profiled the digital health literacy of 123 people with chronic skin conditions who require long-term surveillance in 2 specialist clinics (London, United Kingdom) using the Multidimensional Readiness and Enablement Index for Health Technology (READHY) questionnaire alongside the Optimizing Health Literacy and Access (Ophelia) process for hierarchical cluster analysis. The cluster analysis of READHY dimensions in responding participants (n=116) revealed 7 groups with distinct digital and health literacy characteristics. High READHY scores in groups 1 (n=22, 19%) and 2 (n=20, 17.2%) represent those who are confident with managing their health and using technology, whereas the lower-scoring groups, 6 (n=4, 3.4%) and 7 (n=12, 10.3%), depended on traditional services. Groups 3 (n=27, 23.3%), 4 (n=23, 19.8%), and 5 (n=8, 6.9%) had varying digital skills, access, and engagement, highlighting a population that may benefit from a co-designed dermatology service. By identifying patient groups with distinguishable patterns of digital access and health literacy, our method demonstrates that 63.8% (n=74) of people attending specialist clinics in our center require support in order to optimize remote follow-up or need an alternative approach. Future efforts should streamline the READHY question profile to improve its practicality and use focus groups to elicit strategies for engaging patients with digital services.


Texture density adaptation can be bidirectional.
Texture density has previously been thought of as a scalar attribute on the assumption that texture density adaptation only reduces, not enhances, perceived density (Durgin & Huk, 1997). This "unidirectional" property of density adaptation is in contradistinction to the finding that simultaneous density contrast (SDC) is "bidirectional"; that is, not only do denser surrounds reduce the perceived density of a lower density region, but sparser surrounds enhance it (Sun, Baker, & Kingdom, 2016). Here we reexamine the directionality of density adaptation using random dot patterns and a two-alternative forced choice task in which observers compare the perceived density of adapted test patches with unadapted match stimuli. In the first experiment, we observed a unidirectional density aftereffect when test and match were presented simultaneously as in previous studies. However, when they were presented sequentially, bidirectionality was obtained. This bidirectional aftereffect remained when the presentation order of test and match was reversed (second experiment). In the third experiment, we used sequential presentation to measure the density aftereffect for a wide range of adaptor densities (0-73 dots/deg2) and test densities (1.6, 6.4, and 25.6 dots/deg2). We found bidirectionality for all combinations of adaptor and test densities, consistent with our previous SDC results. This evidence supports the idea that there are multiple channels selective to texture density in human vision.


Migraine-related disability: impact and implications for sufferers' lives and clinical issues.
Migraine is a common, debilitating disorder that imposes a large personal burden on sufferers and high economic costs on society. Sufferers have a significant level of migraine-related disability in all aspects of their daily lives, including employment, household work, and non-work activities. Despite this burden of illness, physicians often do not diagnose or treat the illness effectively. Physicians consider that specific treatment is necessary when disability information is known but, until recently, no criteria have been available for assessment of migraine severity. Two studies indicate that information on disability is an important criterion in assessing migraine severity and influences physicians in their judgments of illness severity and treatment needs. However, physicians and patients often do not seek or share migraine-associated disability, which may contribute to suboptimal management. Efforts to improve knowledge of headache-related disability in the consultation have the potential to improve migraine management. An assessment tool that could reliably quantify headache-related disability has the potential for grading migraine severity and improving care.


Investigational positive inotropic agents for acute heart failure.
Acute heart failure represents a major public health problem due to its high prevalence, high rates of mortality and readmissions and significant healthcare costs. Patients with AHF and low cardiac output represent a small subgroup of patients with very high mortality rates that require inotropic support to improve cardiac systolic function. Classical inotropic agents, such as beta1-adrenergic agonists (dobutamine, dopamine) and phosphodiesterase III inhibitors (milrinone, enoximone) improve symptoms and hemodynamics by increasing free intracellular Ca(2+) levels, but also increase myocardial O(2) demands and exert arrhythmogenic effects. These actions explain why these drugs increase both short- and long-term mortality, particularly in patients with AHF and coronary artery disease. Thus, we need new inotropic agents that do not increase cytosolic Ca(2+) or myocardial oxygen demands or produce arrhythmogenesis for the treatment of high-risk patients with acute heart failure and low cardiac output. This review describes three new classes of investigational agents: levosimendan, a calcium sensitizer and potassium channel opener, istaroxime, the first new luso-inotropic agent and cardiac myosin activators.