Theoretical Loss and Gambling Intensity (Revisited): A Response to Braverman et al. (2013).
In this paper, we provide a brief response to Braverman et al. (J Gambl Stud. doi: 10.1007/s10899-013-9428-z , 2013b) critique of our 'Theoretical Loss' metric as a measure of monetary gambling intensity (Auer and Griffiths in J Gambl Stud. doi: 10.1007/s10899-013-9376-7 , 2013a; Auer et al. in Gaming Law Rev Econ 16:269-273, 2012). We argue that 'gambling intensity' and 'gambling involvement' are essentially the same construct as descriptors of monetary gambling activity. Additionally, we acknowledge that playing duration (i.e., the amount of time—as opposed to money—actually spent gambling) is clearly another important indicator of gambling involvement-something that we have consistently noted in our previous studies including our empirical studies on gambling using behavioural tracking data. Braverman and colleagues claim that the concept of Theoretical Loss is nullified when statistical analysis focuses solely on one game type as the house edge is constant across all games. In fact, they state, the correlation between total amount wagered and Theoretical Loss is perfect. Unfortunately, this is incorrect. To disprove the claim made, we demonstrate that in sports betting (i.e., a single game type), the amount wagered does not reflect monetary gambling involvement using actual payout percentage data (based on 52,500 independent bets provided to us by an online European bookmaker). After reviewing the arguments presented by Braverman and colleagues, we are still of the view that when it comes to purely monetary measures of 'gambling intensity', the Theoretical Loss metric is a more robust and accurate measure than other financial proxy measures such as 'amount wagered' (i.e., bet size) as a measure of what players are prepared to financially risk while gambling.


Facial emotion recognition in autism spectrum disorders: a review of behavioral and neuroimaging studies.
Behavioral studies of facial emotion recognition (FER) in autism spectrum disorders (ASD) have yielded mixed results. Here we address demographic and experiment-related factors that may account for these inconsistent findings. We also discuss the possibility that compensatory mechanisms might enable some individuals with ASD to perform well on certain types of FER tasks in spite of atypical processing of the stimuli, and difficulties with real-life emotion recognition. Evidence for such mechanisms comes in part from eye-tracking, electrophysiological, and brain imaging studies, which often show abnormal eye gaze patterns, delayed event-related-potential components in response to face stimuli, and anomalous activity in emotion-processing circuitry in ASD, in spite of intact behavioral performance during FER tasks. We suggest that future studies of FER in ASD: 1) incorporate longitudinal (or cross-sectional) designs to examine the developmental trajectory of (or age-related changes in) FER in ASD and 2) employ behavioral and brain imaging paradigms that can identify and characterize compensatory mechanisms or atypical processing styles in these individuals.


RAMOBoost: Ranked Minority Oversampling in Boosting.
In recent years, learning from imbalanced data has attracted growing attention from both academia and industry due to the explosive growth of applications that use and produce imbalanced data. However, because of the complex characteristics of imbalanced data, many real-world solutions struggle to provide robust efficiency in learning-based applications. In an effort to address this problem, this paper presents Ranked Minority Oversampling in Boosting (RAMOBoost), which is a RAMO technique based on the idea of adaptive synthetic data generation in an ensemble learning system. Briefly, RAMOBoost adaptively ranks minority class instances at each learning iteration according to a sampling probability distribution that is based on the underlying data distribution, and can adaptively shift the decision boundary toward difficult-to-learn minority and majority class instances by using a hypothesis assessment procedure. Simulation analysis on 19 real-world datasets assessed over various metrics-including overall accuracy, precision, recall, F-measure, G-mean, and receiver operation characteristic analysis-is used to illustrate the effectiveness of this method.


[Xenotransplantation: recent developments and futur clinical applications].
The aim of xenotransplantation is to allow the transplantation of animal organs or cells to humans. This approach would immediately eliminate the human organ shortage that is responsible for a significant mortality of patients on the waiting list for transplantation of organs. The immune differences between pig and human induce an immediate rejection of porcine tissues by humans. This rejection has recently been partially controlled by genetic engineering of pigs, the use of new immunosuppressive drugs and encapsulation of isolated cells. However, due to the risk of transmission of animal infectious agents to humans, the WHO recommends that clinical application of xenotransplantation only takes place if adequate regulations are in place.


Ocular lesions in the blue rubber bleb naevus syndrome.
Investigations of a neonate presenting with multiple pleomorphic vascular skin lesions enabled a clinical and histological diagnosis of blue rubber bleb naevus syndrome to be made. This child had lesions in the conjunctiva, iris, and retina, associated with local haemorrhages at the time of birth. All the lesions regressed spontaneously, and a conservative approach to management of the ocular lesions in this syndrome is therefore suggested.


Visceral fat is a strong predictor of insulin resistance regardless of cardiorespiratory fitness in non-diabetic people.
Abdominal adiposity and low cardiorespiratory fitness are associated with insulin resistance in people with impaired glucose tolerance and type 2 diabetes. However, little is known about which factor precedes insulin resistance in people with impaired glucose tolerance and type 2 diabetes, and which is the stronger predictor of insulin resistance in non-diabetic people. The purpose of this study was to examine the relationship between insulin resistance and cardiorespiratory fitness, visceral fat, and subcutaneous fat in non-diabetic people. Subjects included 87 men and 77 women aged 30-72 y (mean+/-SD, 51.3+/-12.3 y). Cardiorespiratory fitness was assessed by measuring the maximal oxygen uptake (VO2max) in a progressive continuous test to exhaustion on a cycle ergometer. The visceral and subcutaneous fat areas were measured by magnetic resonance imaging. The homeostasis model assessment of insulin resistance (HOMA-R) was calculated from the fasting concentrations of glucose and insulin. Stepwise multiple linear regression analysis revealed that visceral and subcutaneous fat were significant correlates of HOMA-R, explaining 24% and 6% of the variance, respectively, whereas sex, age, and VO2max were not significant independent determinants. Abdominal fat deposition rather than cardiorespiratory fitness is a significant predictor of insulin resistance in non-diabetic people; visceral fat is the most important factor.


Systemic hyperoxia and retinal vasomotor responses.
Several studies have investigated the changes in retinal vessel diameter during physiological stress or pathologic conditions. These studies were principally based on individual fundus photographs and as such did not allow the evaluation of vessel dynamics over time. The research objective was to detail the time course and amplitude changes in the diameter of arteries and veins across all retinal quadrants, during and after hyperoxic vascular stress. The dynamics of changes in retinal vessel diameter were quantified with a retinal vessel analyzer, which digitizes fundus images in real time and simultaneously quantifies vessel diameter. The arterial and venous diameters within one disc diameter of the optic nerve head in each quadrant were studied. Twenty young adults participated in this study in which the vessel diameters were measured during successive phases of breathing either room air or pure oxygen. The oxygen saturation level (SaO(2)), end-tidal carbon dioxide (EtCO(2)), pulse rate (PR), respiratory rate (RR), and blood pressure (BP) were also monitored throughout testing. Breathing 100% O(2) caused an increase in SaO(2) and a decrease in the EtCO(2). All other systemic parameters measured (PR, RR, BP, and ocular perfusion pressure [OPP]) remained unchanged. However, the retinal veins and arteries constricted by approximately 14% and approximately 9% respectively, in all retinal quadrants. After experimental hyperoxia, inhalation of room air was associated with a progressive increase in the caliber of vessels toward their pretest size. The amplitude and overall profile of vessel reactivity to and recovery from hyperoxia was the same across retinal quadrants. These data indicate that, during systemic hyperoxic stress, the retinal vessels change in caliber uniformly across retinal quadrants in healthy young adults. This type of physiological vascular provocation could be used to investigate the quality of vascular regulation during aging and in vascular diseases of the eye.


Blocking effect of a monoclonal antibody against recombinant Pvs25 on sporozoite development in Anopheles sinensis.
To develop a vaccine to block the transmission of vivax malaria, the gene encoding the ookinete surface protein Pvs25 was cloned from a Korean malaria patient. The Pvs25 gene was 660 bp long, encoding 219 amino acids. It was subcloned into the expression vector pQE30 and expressed in Escherichia coli. The expressed recombinant protein, named rPvs25, showed a molecular mass of approximately 25 kDa by SDS-PAGE analysis. An anti-rPvs25 monoclonal antibody produced in BALB/c mice was able to inhibit sporozoite development in the mosquito Anopheles sinensis, which is known as the malaria transmission vector in the Republic of Korea. In addition, rPvs25 produced a relatively high antibody titer in BALB/c mice that lasted for more than 6 months. Based on these results, we suggest that recombinant Pvs25 could be a useful antigen in the development of a vaccine to prevent local malaria transmission in the Republic of Korea.


Statistically-based methodology for revealing real contagion trends and correcting delay-induced errors in the assessment of COVID-19 pandemic.
COVID-19 pandemic has reshaped our world in a timescale much shorter than what we can understand. Particularities of SARS-CoV-2, such as its persistence in surfaces and the lack of a curative treatment or vaccine against COVID-19, have pushed authorities to apply restrictive policies to control its spreading. As data drove most of the decisions made in this global contingency, their quality is a critical variable for decision-making actors, and therefore should be carefully curated. In this work, we analyze the sources of error in typically reported epidemiological variables and usual tests used for diagnosis, and their impact on our understanding of COVID-19 spreading dynamics. We address the existence of different delays in the report of new cases, induced by the incubation time of the virus and testing-diagnosis time gaps, and other error sources related to the sensitivity/specificity of the tests used to diagnose COVID-19. Using a statistically-based algorithm, we perform a temporal reclassification of cases to avoid delay-induced errors, building up new epidemiologic curves centered in the day where the contagion effectively occurred. We also statistically enhance the robustness behind the discharge/recovery clinical criteria in the absence of a direct test, which is typically the case of non-first world countries, where the limited testing capabilities are fully dedicated to the evaluation of new cases. Finally, we applied our methodology to assess the evolution of the pandemic in Chile through the Effective Reproduction Number Rt , identifying different moments in which data was misleading governmental actions. In doing so, we aim to raise public awareness of the need for proper data reporting and processing protocols for epidemiological modelling and predictions.


Comparative effects of supplementing beef steers with zilpaterol hydrochloride, ractopamine hydrochloride, or no beta agonist on strip loin composition, raw and cooked color properties, shear force, and consumer assessment of steaks aged for fourteen or twenty-one days postmortem.
Beef steers (n = 1,914) were assigned to 1 of 3 β-adrenergic agonist (βAA) supplementation treatments-zilpaterol hydrochloride (ZH; 8.3 mg/kg of DM for 20 d with 3-d withdrawal), ractopamine hydrochloride (RH; 308 mg·head(-1)·d(-1) for 28 d), or no βAA (CON)-to determine the effects on consumer eating quality. Strip loins (n = 1,101; CON = 400, RH = 355, and ZH = 346) were obtained and fabricated into 2.5-cm-thick steaks for proximate, Warner-Bratzler shear force (WBSF), slice shear force (SSF), and consumer analyses; steaks were aged until 14 or 21 d postmortem. Fat and moisture contents were not affected by βAA supplementation (P > 0.05), but strip steaks from steers fed ZH had more protein (P < 0.01) than those from steers fed CON or RH, which were similar. An interaction between βAA and aging was observed (P < 0.01) for WBSF but not SSF. Within steaks aged 14 d, ZH steaks required the most force to shear, RH steaks were intermediate, and CON steaks had the lowest WBSF values; however, RH steaks had a stronger response to aging than CON or ZH steaks, resulting in the lowest WBSF values at 21 d. Slice shear force values were greater (P < 0.01) in steaks from steers fed ZH than in steaks from steers fed CON or RH, which did not differ. Following shear force analyses, steaks within 2 SD of each treatment mean for WBSF were selected randomly for consumer assessment of eating quality. Consumer testing (n = 400; 200/postmortem aging period) was arranged in a 3 × 3 factorial representing 3 quality grades (Select, Low Choice, and Premium Choice) and 3 treatments (ZH, RH, and CON). In steaks aged 14 d, βAA supplementation affected (P < 0.01) tenderness, flavor, and overall liking and tenderness acceptability, resulting in lower consumer scores for ZH than CON and RH; however, juiciness, flavor, and overall acceptability were similar (P > 0.05). In steaks aged 21 d, feeding βAA influenced (P < 0.01) only tenderness and juiciness scores. Despite these differences, βAA did not affect (P > 0.05) acceptability. Quality grade impacted (P < 0.01) all traits and acceptability in steaks aged 14 and 21 d. In 14-d steaks, Premium Choice typically was scored higher than Low Choice or Select; however, consumers rated 21-d Low Choice and Premium Choice similarly-both receiving greater scores than Select. Consumers detected several differences in eating quality at 14 d because of βAA supplementation. Increasing aging from 14 to 21 d mitigated differences in shear force and tenderness scores because of feeding ZH, so that tenderness and overall acceptability were similar between ZH, RH, and CON.


The X-ray structure of the plant like 5-aminolaevulinic acid dehydratase from Chlorobium vibrioforme complexed with the inhibitor laevulinic acid at 2.6 A resolution.
5-Aminolaevulinic acid dehydratase (ALAD), an early enzyme of the tetrapyrrole biosynthesis pathway, catalyses the dimerisation of 5-aminolaevulinic acid to form the pyrrole, porphobilinogen. ALAD from Chlorobium vibrioforme is shown to form a homo-octameric structure with 422 symmetry in which each subunit adopts a TIM-barrel fold with a 30 residue N-terminal arm extension. Pairs of monomers associate with their arms wrapped around each other. Four of these dimers interact principally via their arm regions to form octamers in which each active site is located on the surface. The active site contains two invariant lysine residues (200 and 253), one of which (Lys253) forms a Schiff base link with the bound substrate analogue, laevulinic acid. The carboxyl group of the laevulinic acid forms hydrogen bonds with the side-chains of Ser279 and Tyr318. The structure was examined to determine the location of the putative active-site magnesium ion, however, no evidence for the metal ion was found in the electron density map. This is in agreement with previous kinetic studies that have shown that magnesium stimulates but is not required for activity. A different site close to the active site flap, in which a putative magnesium ion is coordinated by a glutamate carboxyl and five solvent molecules may account for the stimulatory properties of magnesium ions on the enzyme.


Role of Ly-6 in lymphocyte activation. I. Characterization of a monoclonal antibody to a nonpolymorphic Ly-6 specificity.
In studies with alloantisera and monoclonal antibodies (mAb) a number of antigenic determinants have been defined that are the products of the Ly-6 locus on murine chromosome 2 and that are expressed primarily on B and T lymphoid cells. It remains controversial whether these antigenic determinants are encoded by a single gene or a multigene complex. We have characterized a new rat mAb, D7, which recognizes a cell surface antigen whose expression on nonactivated peripheral lymphocytes varies from strain to strain. The phenotype of the staining profile, i.e., high or low percentage of D7-positive cells, mapped to the Ly-6 locus as assayed by strain distribution studies, RI lines, and Ly-6 congenic strains. The binding of D7 to Ly-6.1-positive strains could be inhibited by mAb directed to the Ly-6E.1 specificity, whereas D7 could inhibit the binding of mAb specific for Ly-6A.2 to cells from Ly-6.2-positive strains. Coprecipitation studies followed by Western blot analysis confirmed that D7 reacts with both Ly-6E.1- and Ly-6A.2-bearing molecules. The most likely explanation for these findings is that Ly-6A.2 and Ly-6E.1 represent allelic specificities. Further dissection of the complexity of the Ly-6 antigen system and determination of its possible functional importance in lymphocyte activation should be greatly facilitated by the availability of xenogeneic mAb that recognize framework determinants on multiple Ly-6 products.


Ethylene glycol monomethyl ether effects on health and reproduction in male rabbits.
Male Dutch rabbits were weighed and randomly assigned within each weight group to five groups of six animals each (plus one more in the highest dose group). They received 0, 12.5, 25.0, 37.5, or 50.0 mg of ethylene glycol monomethyl ether (EGME) per kg of body weight in the drinking water 5 d/week for 12 weeks. Feed and water consumption were monitored daily and body weight weekly. All animals consumed the water and feed, maintained body weight, and were in good health throughout the experiment. Semen was collected twice weekly for 12 weeks, and 96% of the ejaculates were obtained. By weeks 6 and 9, most males in groups receiving 50.0 or 37.5 mg of EGME per kg were oligospermic. Only minor changes in other characteristics of sperm obtained from treated animals were found, as measured by computer-assisted sperm analysis. Fertility of the males still producing sufficient sperm during week 12 to use for insemination was tested with 96 does producing 2839 oocytes, and fertility of treated males (41%) was not lower (P > 0.05) than 47% in controls. At necropsy, all vital organs were grossly normal, with no notable histopathology. However, the groups of animals receiving 37.5 and 50 mg of EGME per kg of body weight produced fewer sperm and had smaller testes than controls (P < 0.05). Although all rabbits appeared grossly normal, there was a marked disruption of spermatogenesis as ingestion of EGME increased above 25 mg/kg of body weight. Rabbit testes appear to be more sensitive to EGME than testes of rats or mice.


Evaluation of an internally controlled real-time PCR targeting the ospA gene for detection of Borrelia burgdorferi sensu lato DNA in cerebrospinal fluid.
This study reports the development and evaluation of an internally controlled real-time PCR targeting the ospA gene for detection of Borrelia burgdorferi sensu stricto, Borrelia garinii, Borrelia afzelii and Borrelia valaisiana. DNA was extracted using QIAamp DNA Blood Mini kit columns. DNA from 33 B. burgdorferi sensu lato strains reacted in the assay, whereas no reactivity was observed with DNA from four relapsing fever Borrelia spp., 11 unrelated spirochaetes, and 31 unrelated microorganisms. The quantitative sensitivity of the assay was 1-10 fg of Borrelia DNA and one to five cultured Borrelia spirochaetes. Cerebrospinal fluid (CSF) specimens from 70 patients sent for routine testing for neuroborreliosis, and three CSF specimens containing B. garinii were also tested. Positive PCR results were obtained with all three culture-confirmed neuroborreliosis specimens, five of ten neuroborreliosis specimens with specific antibodies in CSF and pleocytosis, none of nine specimens from possible cases of early neuroborreliosis (antibodies in serum, CSF pleocytosis, no antibodies in CSF), one of 15 specimens from patients with active or past Lyme disease with neurological signs (antibodies in serum, no pleocytosis or antibodies in CSF), and none of 36 specimens from patients without Lyme borreliosis (no antibodies in serum or CSF). Overall, the real-time PCR assay enabled sensitive and specific detection of all B. burgdorferi sensu lato species tested. The PCR had a sensitivity of 50% in patients with neuroborreliosis. The main diagnostic role of the assay could be to confirm neuroborreliosis in patients for whom the diagnosis is doubtful.


The mutational spectrum of the NF1 gene in neurofibromatosis type I patients from UAE.
Germline heterozygous mutations in the tumor suppresser NF1 gene cause a cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). This disease is one of the most common multisystem disorders with an estimated incidence of 1 in 3,000 to 1 in 4,000 births. Clinically, NF1 patients are prone to develop "café au lait" spots, neurofibromas, Lisch nodules, freckling of the axillary, or inguinal region and optic nerve gliomas. In the present study, we report clinical and molecular findings of five unrelated patients and seven cases from four families with NF1 from UAE. To reveal the genetic defects underlying NF1 in our cohort of patients, we screened the whole coding and splice site regions of the NF1 gene. In addition, MLPA or CGH array has been used to screen for structural variations including deletions, indels, and complex rearrangements. This resulted in the identification of five distinct novel mutations and two previously reported ones. These variations included three missense and one nonsense mutations, one single base, one dinucleotide, and one large deletion. Four mutations were inherited, and the remaining were absent from both parents and therefore are "de novo" mutations. This analysis represents the spectrum of NF1 mutations in UAE and supports the premise of absence of hotspot mutations in the NF1 gene. Moreover, no obvious genotype-phenotype correlations were observed in our patients.


[Sevoflurane alleviates ventilator-induced lung injury in rats by down-regulating the TRPV4/C-PLA2 signaling pathway].
To explore the mechanism underlying the protective effect of sevoflurane against ventilator-induced lung injury (VILI). Thirty-two SD rats were randomized into mechanical ventilation (MV) group, MV+sevoflurane group (MS group), MV+sevoflurane+transient receptor potential vanillate subtype 4 (TRPV4) agonist group (MST group) and MV+ sevoflurane + vehicle group (MSV group). Arachidonic acid (AA) in the lung tissues was quantified with ELISA. TRPV4, cytoplasmic phospholipase A2 (C-PLA2) and myosin light chain kinase (MLCK) protein expressions were detected by Western blotting. Lung injury in the rats was evaluated by assessing MLCK protein expression level, pulmonary permeability index, lung wet/dry ratio, leukocyte count in the bronchoalveolar lavage fluid (BALF), myeloperoxidase content in lung tissue, and histological score of the lungs. The rats in MV group showed significantly increased TRPV4 and C-PLA2 expression levels in the lung tissues with increased lung permeability and obvious lung inflammation compared with those in the other 3 groups (P < 0.05). No significant differences were found in the parameters associated with lung injuries between MS group and MSV group. Compared with those in MST group, the rats in MS group and MSV group showed significantly reduced AA production and TRPV4 and C-PLA2 expressions in the lungs (P < 0.05) with alleviated lung hyper-permeability and inflammation (P < 0.05). Sevoflurane protects against VILI in rats by down-regulating the TRPV4/C-PLA2 signaling pathway.


Neonatal bacterial meningitis at the newborn unit of Kenyatta National Hospital.
Meningitis occurs in up to one third of neonates with septicaemia. Diagnosis is difficult due to its non-specificity of signs and symptoms. While neonatal septicaemia is a common problem at Kenyatta National Hospital (KNH), there are no recent data on the incidence and clinical characteristics of neonatal meningitis at the hospital. To evaluate the prevalence and the bacterial aetiology of meningitis in neonates at the Newborn Unit (NBU) of KNH. Descriptive cross-sectional study. Newborn Unit of Kenyatta National Hospital, Nairobi, Kenya. Lumbar punctures were performed on eighty-four neonates with suspected sepsis based on specified clinical criteria. Cases were defined as meningitis if the cerebrospinal fluid (CSF) was positive for bacteria by Gram stain, aerobic bacterial culture or latex particle agglutination assay. The prevalence of meningitis amongst cases of suspected sepsis was 17.9%. The male:female ratio was 1.5:1 mean birth weight 2116.7 grams (1682.2-2551.2) mean gestational age 35.7 weeks (32.6-38.8) and the mean postnatal age was 4.1 days (2.7-5.4) with none of the parameters being significantly different from those without meningitis. Feed intolerance and lethargy were the most common clinical features, present in 73.3% and 60% of patients with meningitis respectively. Neonates with meningitis had a higher mean CSF protein value (2.67 g/L vs 1.97 g/L, p=0.367) and a significantly higher mean CSF white cell count (21 cells/mL vs 7 cells/mL, p=0.001). The most common aetiological agents were Escherichia coli (46.7%). Group B. Streptococci (26.7%) and Klebsiella pneumoniae (13.3%). Most blood and CSF isolates were resistant to ampicillin and gentamicin but showed good in-vitro sensitivities to amikacin, cefuroxime and the third generation cephalosporins (ceftriaxone, ceftazidime and cefotaxime). Blood cultures were positive in only 53.3% of neonates with meningitis. Neonatal bacterial meningitis is an important clinical problem at KNH with a prevalence of 17.9% amongst cases of suspected sepsis. E. coli and Group B Streptococci were the most common aetiological pathogens. Blood cultures were negative in almost half of the patients with meningitis. Resistance to the commonly employed first-line antibiotics (penicillin and gentamicin) is high and a change of empirical antibiotic use for neonates with suspected sepsis is recommended.


Sequence and expression of a neuropeptide Y receptor cDNA.
The polymerase chain reaction was used to isolate novel GTP-binding protein (G protein)-coupled receptors from bovine locus coeruleus (LC), a brain region enriched in the neuropeptide Y (NPY) system, using degenerate primers derived from the third and sixth transmembrane domains of known G protein-coupled receptors. Partial sequence analysis revealed that the polymerase chain reaction cDNA fragments were homologous to other G protein-coupled receptors. One of these cDNA fragments was used to isolate a full length cDNA clone, referred to as LCR1, from an LC cDNA library. LCR1 is 1.7 kilobases in length and encodes a predicted protein of 353 amino acids, with a membrane topology similar to that of other G protein-coupled receptors. Expression of LCR1 in mammalian cells revealed saturable and specific high affinity binding for 125I-NPY but not for any of the other ligands tested. Northern blot analysis revealed that labeled LCR1 DNA hybridized with a predominate mRNA transcript of approximately 1.7 kilobases, which was found to be most abundant in LC, cerebellum, and pons, intermediate in dorsal raphe, substantia nigra, and thalamus, and lowest in cerebral cortex and neostriatum. Significant levels of LCR1 mRNA were also present in heart, kidney, lung, and liver. This cDNA clone will be useful for studies of the regulation and function of NPY receptors, as well as for the isolation of related NPY receptor subtypes.


Is nephrocalcinosis in preterm neonates harmful for long-term blood pressure and renal function?
The aim of our study was to examine long-term effects of nephrocalcinosis in prematurely born children. Preterm neonates (gestational age <32 weeks) with (n = 42) and without (n = 32) nephrocalcinosis were prospectively studied at a mean age of 7.5 (+/-1.0) years. Blood pressure did not differ in ex-preterm infants with and without nephrocalcinosis but was significantly higher than expected for healthy children. In comparison to healthy children, more ex-preterm infants with neonatal nephrocalcinosis had (mild) chronic renal insufficiency (glomerular filtration rate: <85 mL/min per 1.73 m2; 6 of 40); this is in contrast to ex-preterm infants without neonatal nephrocalcinosis (2 of 32). Tubular phosphate reabsorption and plasma bicarbonate were significantly lower in children with nephrocalcinosis compared with children without nephrocalcinosis. In addition, more ex-preterm infants with and without nephrocalcinosis than expected had low values for plasma bicarbonate and early-morning urine osmolality compared with healthy children. Kidney length of ex-preterm infants with and without nephrocalcinosis was significantly smaller than expected in healthy children of the same height. Nephrocalcinosis persisted long-term in 4 of 42 children but was not related to blood pressure, kidney length, or renal function. Nephrocalcinosis in preterm neonates can have long-term sequelae for glomerular and tubular function. Furthermore, prematurity per se is associated with high blood pressure, relatively small kidneys, and (distal) tubular dysfunction. Long-term follow-up of blood pressure and renal glomerular and tubular function of preterm neonates, especially with neonatal nephrocalcinosis, seems warranted.


Use of vegetation sampling and analysis to detect a problem within a portion of a prairie restoration project.
In June 2005, the Department of Energy (DOE) began establishing the 60-ha Howell Prairie around the disposal cell at the DOE Weldon Spring Site (WSS). Prairies were historically present in the area of the site. Quantitative Cover sampling was used to quantify Total Cover, Native Grass Cover, Non-Native Grass Cover, Native Forb Cover, Non-Native Forb Cover, Warm Season (C4 Grass), Cool Season (C3 Grass), Perennial Cover and Annual Cover, Litter, and Bare Ground. Four permanent vegetation sampling plots were established. The first 4 years of vegetation measurements at Howell Prairie were made during above-average rainfall years on burned and unburned plots. The fifth-year (2012) vegetation measurements were made after below-average rainfall. Five years of results not only document the consistency of the restoration effort in three areas, but also demonstrate deficiencies in Grass Cover in a fourth area. The results are not only useful for Howell Prairie, but will be useful for restoration work throughout the region. Restoration work suffers from a lack of success monitoring and in this case from a lack of available reference areas. Floristic Quality Indices are used to make qualitative comparisons of the site to Konza Prairie sites.


The plant defense and pathogen counterdefense mediated by Hevea brasiliensis serine protease HbSPA and Phytophthora palmivora extracellular protease inhibitor PpEPI10.
Rubber tree (Hevea brasiliensis Muell. Arg) is an important economic crop in Thailand. Leaf fall and black stripe diseases caused by the aggressive oomycete pathogen Phytophthora palmivora, cause deleterious damage on rubber tree growth leading to decrease of latex production. To gain insights into the molecular function of H. brasiliensis subtilisin-like serine proteases, the HbSPA, HbSPB, and HbSPC genes were transiently expressed in Nicotiana benthamiana via agroinfiltration. A functional protease encoded by HbSPA was successfully expressed in the apoplast of N. benthamiana leaves. Transient expression of HbSPA in N. benthamiana leaves enhanced resistance to P. palmivora, suggesting that HbSPA plays an important role in plant defense. P. palmivora Kazal-like extracellular protease inhibitor 10 (PpEPI10), an apoplastic effector, has been implicated in pathogenicity through the suppression of H. brasiliensis protease. Semi-quantitative RT-PCR revealed that the PpEPI10 gene was significantly up-regulated during colonization of rubber tree by P. palmivora. Concurrently, the HbSPA gene was highly expressed during infection. To investigate a possible interaction between HbSPA and PpEPI10, the recombinant PpEPI10 protein (rPpEPI10) was expressed in Escherichia coli and purified using affinity chromatography. In-gel zymogram and co-immunoprecipitation (co-IP) assays demonstrated that rPpEPI10 specifically inhibited and interacted with HbSPA. The targeting of HbSPA by PpEPI10 revealed a defense-counterdefense mechanism, which is mediated by plant protease and pathogen protease inhibitor, in H. brasiliensis-P. palmivora interactions.


Bladder capacity in an elimination communication infant: a case report.
Bladder capacity is essential in assessing children with voiding dysfunction, yet it is currently unclear how best to determine a benchmark bladder capacity; various formulas have been proposed. This report details the unique case of an elimination communication Caucasian infant (< 2 years old) who achieved nighttime and daytime dryness by 6 months of age. His first morning voids were measured from 8 to 20 months of age and compared with three formulas: (1) the Koff formula, a widely used formula based on fill volumes in anesthetized infants; (2) the Kaefer formula, a formula based on fill volume in nonanesthetized infants; and (3) the Holmdahl formula, a formula based on frequency-volume charts in normal infants. This infant's first morning void was found to be most consistent with Kaefer's formula. Further research is required to determine if formulas based on fill volume in nonanesthetized infants provide the more accurate benchmark bladder capacity in infants.


Lipid A Has Significance for Optimal Growth of Coxiella burnetii in Macrophage-Like THP-1 Cells and to a Lesser Extent in Axenic Media and Non-phagocytic Cells.
Lipid A is an essential basal component of lipopolysaccharide of most Gram-negative bacteria. Inhibitors targeting LpxC, a conserved enzyme in lipid A biosynthesis, are antibiotic candidates against Gram-negative pathogens. Here we report the characterization of the role of lipid A in Coxiella burnetii growth in axenic media, monkey kidney cells (BGMK and Vero), and macrophage-like THP-1 cells by using a potent LpxC inhibitor -LPC-011. We first determined the susceptibility of C. burnetii LpxC to LPC-011 in a surrogate E. coli model. In E. coli, the minimum inhibitory concentration (MIC) of LPC-011 against C. burnetii LpxC is < 0.05 μg/mL, a value lower than the inhibitor's MIC against E. coli LpxC. Considering the inhibitor's problematic pharmacokinetic properties in vivo and Coxiella's culturing time up to 7 days, the stability of LPC-011 in cell cultures was assessed. We found that regularly changing inhibitor-containing media was required for sustained inhibition of C. burnetii LpxC in cells. Under inhibitor treatment, Coxiella has reduced growth yields in axenic media and during replication in non-phagocytic cells, and has a reduced number of productive vacuoles in such cells. Inhibiting lipid A biosynthesis in C. burnetii by the inhibitor was shown in a phase II strain transformed with chlamydial kdtA. This exogenous KdtA enzyme modifies Coxiella lipid A with an α-Kdo-(2 → 8)-α-Kdo epitope that can be detected by anti-chlamydia genus antibodies. In inhibitor-treated THP-1 cells, Coxiella shows severe growth defects characterized by poor vacuole formation and low growth yields. Coxiella progenies prepared from inhibitor-treated cells retain the capability of normally infecting all tested cells in the absence of the inhibitor, which suggests a dispensable role of lipid A for infection and early vacuole development. In conclusion, our data suggest that lipid A has significance for optimal development of Coxiella-containing vacuoles, and for robust multiplication of C. burnetii in macrophage-like THP-1 cells. Unlike many bacteria, C. burnetii replication in axenic media and non-phagocytic cells was less dependent on normal lipid A biosynthesis.


Scientists want more children.
Scholars partly attribute the low number of women in academic science to the impact of the science career on family life. Yet, the picture of how men and women in science--at different points in the career trajectory--compare in their perceptions of this impact is incomplete. In particular, we know little about the perceptions and experiences of junior and senior scientists at top universities, institutions that have a disproportionate influence on science, science policy, and the next generation of scientists. Here we show that having fewer children than wished as a result of the science career affects the life satisfaction of science faculty and indirectly affects career satisfaction, and that young scientists (graduate students and postdoctoral fellows) who have had fewer children than wished are more likely to plan to exit science entirely. We also show that the impact of science on family life is not just a woman's problem; the effect on life satisfaction of having fewer children than desired is more pronounced for male than female faculty, with life satisfaction strongly related to career satisfaction. And, in contrast to other research, gender differences among graduate students and postdoctoral fellows disappear. Family factors impede talented young scientists of both sexes from persisting to research positions in academic science. In an era when the global competitiveness of US science is at risk, it is concerning that a significant proportion of men and women trained in the select few spots available at top US research universities are considering leaving science and that such desires to leave are related to the impact of the science career on family life. Results from our study may inform university family leave policies for science departments as well as mentoring programs in the sciences.


Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations.
Hereditary hearing loss (HHL) is a common disorder characterized by a huge genetic heterogeneity. The definition of a correct molecular diagnosis is essential for proper genetic counseling, recurrence risk estimation, and therapeutic options. From 20 to 40% of patients carry mutations in GJB2 gene, thus, in more than half of cases it is necessary to look for causative variants in the other genes so far identified (~100). In this light, the use of next-generation sequencing technologies has proved to be the best solution for mutational screening, even though it is not always conclusive. Here we describe a combined approach, based on targeted re-sequencing (TRS) of 96 HHL genes followed by high-density SNP arrays, aimed at the identification of the molecular causes of non-syndromic HHL (NSHL). This strategy has been applied to study 103 Italian unrelated cases, negative for mutations in GJB2, and led to the characterization of 31% of them (i.e., 37% of familial and 26.3% of sporadic cases). In particular, TRS revealed TECTA and ACTG1 genes as major players in the Italian population. Furthermore, two de novo missense variants in ACTG1 have been identified and investigated through protein modeling and molecular dynamics simulations, confirming their likely pathogenic effect. Among the selected patients analyzed by SNP arrays (negative to TRS, or with a single variant in a recessive gene) a molecular diagnosis was reached in ~36% of cases, highlighting the importance to look for large insertions/deletions. Moreover, copy number variants analysis led to the identification of the first case of uniparental disomy involving LOXHD1 gene. Overall, taking into account the contribution of GJB2, plus the results from TRS and SNP arrays, it was possible to reach a molecular diagnosis in ~51% of NSHL cases. These data proved the usefulness of a combined approach for the analysis of NSHL and for the definition of the epidemiological picture of HHL in the Italian population.


Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease.
Inhibition of airway epithelial sodium channel (ENaC) function enhances mucociliary clearance (MCC). ENaC is positively regulated by channel-activating proteases (CAPs), and CAP inhibitors are therefore predicted to be beneficial in diseases associated with impaired MCC. The aims of the present study were to 1) identify low-molecular-weight inhibitors of airway CAPs and 2) to establish whether such CAP inhibitors would translate into a negative regulation of ENaC function in vivo, with a consequent enhancement of MCC. To this end, camostat, a trypsin-like protease inhibitor, provided a potent (IC(50) approximately 50 nM) and prolonged attenuation of ENaC function in human airway epithelial cell models that was reversible upon the addition of excess trypsin. In primary human bronchial epithelial cells, a potency order of placental bikunin > camostat > 4-guanidinobenzoic acid 4-carboxymethyl-phenyl ester > aprotinin >> soybean trypsin inhibitor = alpha1-antitrypsin, was largely consistent with that observed for inhibition of prostasin, a molecular candidate for the airway CAP. In vivo, topical airway administration of camostat induced a potent and prolonged attenuation of ENaC activity in the guinea pig trachea (ED(50) = 3 microg/kg). When administered by aerosol inhalation in conscious sheep, camostat enhanced MCC out to at least 5 h after inhaled dosing. In summary, camostat attenuates ENaC function and enhances MCC, providing an opportunity for this approach toward the negative regulation of ENaC function to be tested therapeutically.


Engineering and Modeling the Electrophoretic Trapping of a Single Protein Inside a Nanopore.
The ability to confine and to study single molecules has enabled important advances in natural and applied sciences. Recently, we have shown that unlabeled proteins can be confined inside the biological nanopore Cytolysin A (ClyA) and conformational changes monitored by ionic current recordings. However, trapping small proteins remains a challenge. Here, we describe a system where steric, electrostatic, electrophoretic, and electro-osmotic forces are exploited to immobilize a small protein, dihydrofolate reductase (DHFR), inside ClyA. Assisted by electrostatic simulations, we show that the dwell time of DHFR inside ClyA can be increased by orders of magnitude (from milliseconds to seconds) by manipulation of the DHFR charge distribution. Further, we describe a physical model that includes a double energy barrier and the main electrophoretic components for trapping DHFR inside the nanopore. Simultaneous fits to the voltage dependence of the dwell times allowed direct estimates of the cis and trans translocation probabilities, the mean dwell time, and the force exerted by the electro-osmotic flow on the protein (≅9 pN at -50 mV) to be retrieved. The observed binding of NADPH to the trapped DHFR molecules suggested that the engineered proteins remained folded and functional inside ClyA. Contact-free confinement of single proteins inside nanopores can be employed for the manipulation and localized delivery of individual proteins and will have further applications in single-molecule analyte sensing and enzymology studies.


Environmental and nutrition impact of achieving new School Food Plan recommendations in the primary school meals sector in England.
The aim of this modelling study was to estimate the expected changes in the nutritional quality and greenhouse gas emissions (GHGEs) of primary school meals due to the adoption of new mandatory food-based standards for school meals. Nationally representative random sample of 136 primary schools in England was selected for the Primary School Food Survey (PSFS) with 50% response rate. A sample of 6690 primary students from PSFS who consumed school meals. Primary School Food Plan (SFP) nutritional impact was assessed using both macronutrient and micronutrient quality. The environmental impact was measured by GHGEs. The scenario tested was one in which every meal served in schools met more than half of the food-based standards mentioned in the SFP (SFP scenario). We used findings from a systematic review to assign GHGE values for each food item in the data set. The GHGE value and nutritional quality of SFP scenario meals was compared with the average primary school meal in the total PSFS data set (pre-SFP scenario). Prior to introduction of the SFP (pre-SFP scenario), the primary school meals had mandatory nutrient-based guidelines. The percentage of meals that met the protein standard increased in the SFP scenario and the proportion of meals that met the standards for important micronutrients (eg, iron, calcium, vitamin A and C) also increased. However, the SFP scenario did not improve the salt, saturated fat and free sugar levels. The mean GHGE value of meals which met the SFP standards was 0.79 (95% CI 0.77 to 0.81) kgCO2e compared with a mean value of 0.72 (0.71 to 0.74) kgCO2e for all meals. Adopting the SFP would increase the total emissions associated with primary school meals by 22 000 000 kgCO2e per year. The universal adoption of the new food-based standards, without reformulation would result in an increase in the GHGEs of school meals and improve some aspects of the nutritional quality, but it would not improve the average salt, sugar and saturated fat content levels.


Cloning and expression of two carbonyl reductase-like 20beta-hydroxysteroid dehydrogenase cDNAs in ovarian follicles of rainbow trout (Oncorhynchus mykiss).
In salmonid fish, 20beta-hydroxysteroid dehydrogenase (20beta-HSD) is a key enzyme involved in the production of oocyte maturation-inducing hormone (MIH), 17alpha, 20beta-dihydroxy-4-pregnen-3-one. Here we report the isolation of two cDNAs which encode proteins with high homology to carbonyl reductase-like 20beta-HSD (CR/20beta-HSD) from rainbow trout (Oncorhynchus mykiss) ovarian follicles. Genomic DNA analysis showed that the two CR/20beta-HSD cDNAs are derived from two different genes. Northern blot and RT PCR analysis demonstrated that trout CR/20beta-HSDs are broadly expressed in various tissues. Enzymatic characterization using recombinant CR/20beta-HSD proteins produced in E. coli showed that the product of one of the two cDNAs had both 20beta-HSD and CR activity, but the other had neither activity. Although the functional significance of the two genes remains unresolved, these results clearly demonstrate the presence of two distinct CR/20beta-HSD transcripts in the trout ovary.


Treatment-Related Changes in Heart Rate Variability in Children with Sleep Apnea.
Heart rate variability (HRV), a noninvasive indicator of autonomic regulation of cardiac rhythm, may represent the physiologic burden of obstructive sleep apnea (OSA). We hypothesized that the treatment-related effects of OSA on HRV in children are causally attributable to the improvement in OSA severity. Secondary analysis of outcomes from the Childhood Adenotonsillectomy Trial (CHAT). Analysis of database. Time- and frequency-domain HRV parameters along with polysomnographic (PSG) and demographic variables were obtained from the CHAT study, which compared early adenotonsillectomy (eAT) to watchful waiting (WW) in children with OSA. The relative contributions of PSG variables and covariates to each HRV parameter were quantified. The proportion of changes in HRV parameters causally attributable to changes in OSA severity, measured by the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI), was estimated. In total, 404 children aged 5 to 10 years were included. The median (interquartile range) age was 6 (3-9) years. The median body mass index percentile was 82 (53), 195 (48%) children were male, and 147 (36%) were African American. The average heart rate during PSG was the strongest independent predictor of each HRV parameter (P < .001). Although eAT resulted in statistically significant changes in the majority of HRV parameters, these effects were not causally attributable to treatment-related changes in AHI or ODI. The average heart rate strongly modulates HRV in children with OSA. Although eAT results in discernible changes in HRV, it appears to not be causally attributable to specific treatment-related changes in AHI or ODI.


[Mechanisms of contractile reaction changes and efficiency of oxygen utilization by portal vein smooth muscles in experimental diabetes mellitus].
On the rat portal vein isolated strips the essential reduction of contractive response, increase of stiffness of vascular smooth muscles at their stretching and increase of oxygen value of smooth muscles' work are revealed in conditions of experimental diabetes mellitus. The possible mechanism of such infringements is chronic hyperglycemia, which results in development of oxidative stress and reduction of NO synthesis by constitutive NOS. Indeed, the significant decrease of activity of constitutive NO-synthase and increase of the oxidative stress markers contents are shown at experimental diabetes mellitus. The similar infringements are marked at in vitro model of hyperglycemia, blockade of NO-synthase and in conditions of oxidative stress. Additional confirmation of a role of NO synthesis blockade and oxidative stress in development of such infringements at diabetes is fact that application of antioxidant melatonin and L-arginine, a precursor of NO to diabetic animals results in partial restoration of contractive reactions, reduction of stiffness and oxygen value of smooth muscles' work.


Is elevated norepinephrine an etiological factor in some cases of Alzheimer's disease?
Loss of norepinephrine (NE) releasing neurons, in the locus coeruleus of the brainstem, is well documented to occur in Alzheimer's disease (AD). However, this process does not necessarily result in decreased release of NE, since compensatory mechanisms may produce increased release of this neurotransmitter. Independent of potential loss of locus coeruleus cells, brain NE levels may be elevated in some persons with AD, both before and during disease progression. Here I examine evidence that elevated, endogenous brain NE is an etiological factor in some cases of AD, and not merely an epiphenomenon of the disease. To explore this etiological hypothesis in AD, I examine the following eight lines of evidence: 1) direct evidence of elevated NE or its metabolites in AD; 2) studies of tricyclic antidepressants, which may principally boost NE; 3) studies of clonidine and other alpha2 adrenergic agonist drugs, which may principally lower the concentration of NE; 4) studies of beta adrenoceptor blocking drugs, including propranolol; 5) comorbidity of AD and bipolar disorder, where both disorders may involve elevated NE; 6) comorbidity of AD and hypertension; 7) comorbidity of AD and obesity; and 8) potential interaction between AD and psychological stress, where stressors are known to release NE. These lines of evidence tend to support the elevated NE etiological hypothesis.


Clinical outcomes of secondary stent-in-stent self-expanding metal stent placement for primary stent malfunction in malignant gastric outlet obstruction.
Although a substantial number of patients require secondary stents insertion due to primary stent malfunction in malignant gastric outlet obstruction, data on the outcomes of secondary self-expanding metal stents are sparse. To investigate clinical outcomes and factors related with secondary stent malfunction in patients with malignant gastric outlet obstruction given secondary stent-in-stent self-expanding metal stent insertion. For this retrospective study, a total 77 patients who underwent secondary stent-in-stent self-expanding metal stent placement for primary stent malfunction in malignant gastric outlet obstruction were enrolled. We compared the effectiveness and complications of secondary covered and uncovered stents and explored the predictive factors for stent malfunction. Stent-in-stent self-expanding metal stent placements were technically successful in all patients. Both groups also had comparable clinical success rates (covered stent, 87.2% and uncovered stent, 90.0%, P = 1.000). Stent malfunction rates (31.9% and 36.7% respectively, P = 0.805) and median patency time of stent (165 [95% confidence interval: 112-218] and 165 [95% confidence interval: 126-204] days, respectively, P = 0.358) were similar between secondary covered and uncovered stents. Longer patients' survival time (≥ 100 days) was associated with increased risk of stent malfunction (odds ratio: 4.598; 95% confidence interval: 1.473-14.355; P = 0.009). Secondary stent-in-stent self-expanding metal stent placement is feasible and effective treatment for primary stent malfunctions in malignant gastric outlet obstruction. Covered and uncovered stent are equally acceptable in terms of stent-related complications and stent patency, regardless of primary stent type.


Most appropriate animal models to study the efficacy of statins: a systematic review.
In animal models and clinical trials, statins are reported as effective in reducing cholesterol levels and lowering the risk of cardiovascular diseases. We have aggregated the findings in animal models - mice, rats and rabbits - using the technique of systematic review and meta-analysis to highlight differences in the efficacy of statins. We searched Medline and Embase. After examining all eligible articles, we extracted results about total cholesterol and other blood parameters, blood pressure, myocardial infarction and survival. Weighted and standard mean difference random effects meta-analysis was used to measure overall efficacy in prespecified species, strains and subgroups. We included in systematic review 161 animal studies and we analysed 120 studies, accounting for 2432 animals. Statins lowered the total cholesterol across all species, although with large differences in the effect size: -30% in rabbits, -20% in mice and -10% in rats. The reduction was larger in animals fed on a high-cholesterol diet. Statins reduced infarct volume but did not consistently reduce the blood pressure or effect the overall survival. Few studies considered strains at high risk of cardiovascular diseases or hard outcomes. Although statins showed substantial efficacy in animal models, few preclinical data considered conditions mimicking human pathologies for which the drugs are clinically indicated and utilized. The empirical finding that statins are more effective in lowering cholesterol derived from an external source (i.e. diet) conflicts with statin's supposed primary mechanism of action.


Excess body mass is associated with T cell differentiation indicative of immune ageing in children.
Obesity has been associated with accelerated biological ageing and immunosenescence. As the prevalence of childhood obesity is increasing, we wanted to determine if associations between obesity and immunosenescence would manifest in children. We studied 123 Mexican American adolescents aged 10-14 (mean 12·3 ± 0·7) years, with body weights ranging from 30·1 to 115·2 kg (mean 52·5 ± 14·5 kg). Blood samples were obtained to determine proportions of naive, central memory (CM), effector memory (EM), senescent and early, intermediate and highly differentiated subsets of CD4(+) and CD8(+) T cells. Overweight and obese children had significantly lowered proportions of early CD8(+) T cells (B = -11·55 and -5·51%, respectively) compared to healthy weight. Overweight children also had more EM (B = +7·53%), late (B = +8·90%) and senescent (B = +4·86%) CD8(+) T cells than healthy weight children, while obese children had more intermediate CD8(+) (B = +4·59%), EM CD8(+) (B = +5·49%), late CD4(+) (B = +2·01%) and senescent CD4(+) (B = +0·98%) T cells compared to healthy weight children. These findings withstood adjustment for potentially confounding variables, including age, gender and latent cytomegalovirus and Epstein-Barr virus infections. We conclude that excess body mass, even in adolescence, may accelerate immunosenescence and predispose children to increased risks of incurring immune-related health problems in adulthood.


Impaired emotional empathy and related social network deficits in cocaine users.
Chronic cocaine users consistently display neurochemical and functional alterations in brain areas involved in social cognition (e.g. medial and orbitofrontal cortex). Although social functioning plays a crucial role in the development and treatment of drug dependence, studies investigating social cognition in cocaine users are lacking. Therefore, we investigated mental perspective taking ('theory of mind') and emotional and cognitive empathy in recreational (RCU) and dependent (DCU) cocaine users. Furthermore, we related these measures to real-life indicators of social functioning. One-hundred cocaine users (69 RCU, 31 DCU) and 68 stimulant-naïve healthy controls were tested with the Multifaceted Empathy Test (MET), Movie for the Assessment of Social Cognition (MASC) and Reading the Mind in the Eyes Test (RMET). The Social Network Questionnaire was conducted to assess social network size. Furthermore, participants provided information on committed criminal offenses. RCU and DCU showed less emotional empathy compared to controls (MET), whereas cognitive empathy was not impaired (MET, RMET). Additionally, DCU made more errors in mental perspective taking (MASC). Notably, cocaine users committed more criminal offenses and displayed a smaller social network and higher cocaine use was correlated with less social contacts. Diminished mental perspective taking was tentatively correlated with more intense cocaine use as well. Finally, younger age of onset of cocaine use was associated with more pronounced empathy impairment. In conclusion, social cognition impairments in cocaine users were related to real-life social functioning and should therefore be considered in therapy and prevention strategies.


Prediction of binding constants of alpha-cyclodextrin complexes.
Proceeding from a phenomenological theory of pairwise interactions (solvent-solvent, solvent-solute, and solute-solute), the binding constant K11 (in M-1) for 1:1 complex formation by alpha-cyclodextrin at a substrate binding site, at 25 degrees C in water, is given by log K11 = -1.74 - [Z] + 0.032(-delta A), where [Z] incorporates solvent-solute (solvation) and solute-solute interactions and delta A is the decrease in nonpolar surface area (in A2 molecule-1) on the substrate that is exposed to solvent when the binding site enters the cyclodextrin cavity. delta A is estimated from the structure of the binding site. Three levels of approximation are described for estimating [Z]. At the third (highest) level, the procedure when applied to 569 complex systems generated predicted values of log K11 that agreed within 0.30 unit of the experimental values in 58% of cases, and that agreed within 1.00 unit in 95% of cases.


Educating the next generation of family caregivers through the use of dynamic case studies.
Between 2008 and 2016, students in an Introduction to Gerontology course were required to complete a dynamic case study project simulating caregiving arrangement decision making. Students were divided into groups representing typical multigenerational families and were required to determine how to develop caregiving arrangements to respond to an older family member' s changing levels of need. The assignment concluded with students writing a final paper summarizing what they learned. This study examined the themes emerging from student group case study papers to gain an understanding of the challenges students face in understanding the dynamics of making family-based caregiving decisions. This is of particular importance as many students were seeking careers in human services and would be assisting clients in such decision-making processes, as well as involvement in decision making for their own family members. Themes that emerged from group papers and the implications related to gerontology education and policy are discussed.


Genetic testing legislation: a review of the past two years.
The American Council of Life Insurance is a national trade association that represents the interests of legal reserve life insurance companies in legislative, regulatory and judicial matters at the federal, state and municipal levels of government and at the National Association of Insurance Commissioners. Its member companies hold more than 90 percent of the life insurance in force in the United States.


Intrasubject repeatability of in vivo intervertebral motion parameters using quantitative fluoroscopy.
In vivo quantification of intervertebral motion through imaging has progressed to a point where biomarkers for low back pain are emerging. This makes possible deeper study of the condition's biometrics. However, the measurement of change over time involves error. The purpose of this prospective investigation is to determine the intrasubject repeatability of six in vivo intervertebral motion parameters using quantitative fluoroscopy. Intrasubject reliability (ICC) and minimal detectable change (MDC) of baseline to 6-week follow-up measurements were calculated for six lumbar spine intervertebral motion parameters in 109 healthy volunteers. A standardised quantitative fluoroscopy (QF) protocol was used to provide measurements in the coronal and sagittal planes using both passive recumbent and active weight-bearing motion. Parameters were: intervertebral range of motion (IV-RoM), laxity, motion sharing inequality (MSI), motion sharing variability (MSV), flexion translation and anterior disc height change during flexion. The best overall intrasubject reliability (ICC) and agreement (MDC) were for disc height (ICC 0.89, MDC 43%) and IV-RoM (ICC 0.96, MDC 60%), and the worst for MSV (ICC 0.04, MDC 408%). Laxity, MSI and translation had acceptable reliability (most ICCs > 0.60), but not agreement (MDC > 85%). Disc height and IV-RoM measurement using QF could be considered for randomised trials, while laxity, MSI and translation could be considered for moderators, correlates or mediators of patient-reported outcomes. MSV had both poor reliability and agreement over 6 weeks. These slides can be retrieved under Electronic Supplementary Material.


[Detection of non-A rotavirus in Tucumán].
A case of infectious gastroenteritis (GEI) caused by a non-A Rotavirus (RV) in the province of Tucumán is reported. Fecal sample analysis for group A RV by enzyme immunoassay (ELISA) gave a negative result. Polyacrylamide gel electrophoresis (PAGE) of the viral RNA showed a genomic pattern coincident with that described by Pedley for RV belonging to group C. To our knowledge, this is the first communication on the detection of non-A RV as an etiological agent of human GEI in Argentina.


Flower cells of tropical descent: a challenging case of adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive disease associated with human T-lymphotropic virus type 1 infection, with a very high prevalence in tropical areas but exceptionally rare in Europe and Western countries. We describe a challenging case of ATLL in a young male patient with Brazilian origin and adopted as a child by an Italian family, presenting to our clinic with atypical T-lymphocytosis and life-threatening lung infections. Diagnosis of ATLL outside of endemic areas can be difficult, requiring a high index of clinical suspicion with careful evaluation of the patient's clinical history. Prognosis is affected by disease stage at presentation and degree of immunosuppression. Few effective treatments are available, although new molecular insights have highlighted the role of host immune response and immune checkpoint blockade inhibitors, given the overexpression of PD-L1 on lymphoma cells and on microenvironment cells.


Long-term body weight variability is associated with elevated C-reactive protein independent of current body mass index among Japanese men.
To elucidate the effect of long-term weight variability on C-reactive protein (CRP) levels. Cross-sectional study of the circulating CRP. A total of 637 Japanese men aged 40-49 y in1997. Serum CRP levels, body mass index in 1997 (current BMI), the slope of weight on age (weight-slope) representing an individual's weight trend of direction and magnitude, and the root mean square error around the slope of weight on age (weight-RMSE) representing the weight fluctuation magnitude, as calculated by a simple linear regression model in which each value of the subject's five actual weights (aged 20, 25, 30 y, five years ago, and current) was a dependent variable and the subject's ages independent variables. After adjustment for age and confounders, including smoking and health status, the odds ratios of elevated CRP (> or =0.06 mg/dl) were 1.83 (95% CI: 1.25-2.69), 2.63 (1.69-4.11), and 10.31 (2.17-48.98) for upper normal-weight (BMI: 22-<25 kg/m(2)), overweight (25-<30), and obese (> or =30) persons, respectively, compared with lower normal-weight persons (18.5-<22). Adjusting for age, confounders, and current BMI, weight-slope was positively associated with CRP level especially among subjects with BMI> or =25 kg/m(2) (trend P<0.01), and weight-RMSE was positively associated with CRP level particularly among subjects with BMI <25 kg/m(2) (trend P<0.05). Our results suggest a state of low-grade systemic inflammation not only in overweight and obese persons, but also in normal-weight persons with large weight fluctuation, possibly explaining in part the positive association between weight fluctuation and CVD.


Real-world evidence of the use of glucocorticoids for severe COVID-19.
Currently, only glucocorticoids have proved to impact adverse outcomes in COVID-19. However, their risk/benefit balance remains inconclusive and populations' characteristics should be considered. The objective was to evaluate the real-life use of glucocorticoids in patients with severe COVID-19 hospitalized in a third-level referral center and to determine the type, accumulated doses, and the in-hospital outcomes related with their use. We evaluated a retrospective cohort of 737 patients with criteria for severe COVID-19 and a positive polymerase chain reaction (PCR) test for SARS-CoV-2. We extracted data for epidemiological analysis, medical history, and medications, as well as baseline laboratory tests. Data were analyzed using SPSS 21.0 and nonparametric tests, medians, and interquartile ranges (IQR). A p < 0.05 was considered significant. A total of 65.3% were men, with a median age of 59 years (IQR 46-70) and a median of 10 days of hospital stay (IQR 6-16), more than 40% had diabetes, hypertension, and/or obesity, and 0.8% used steroids chronically. At the time of the study, 54.0% had been discharged due to improvement and 40.8% died. The most common treatment used was dexamethasone 6 mg/day/10 days (46.6%). Patients with a complete dexamethasone scheme [as proposed by the Randomized Evaluation of COVID-19 Therapy (RECOVERY) study] had a lower mortality risk [hazard ratio (HR) 0.441, 95% confidence interval (CI) 0.232-0.840] in comparison with patients with lower doses (HR 1.803, 95% CI 1.080-3.012). Patients with methylprednisolone or several steroids tended to have higher cumulative doses (equivalent to >675 mg of prednisolone). The use of steroids in severe COVID-19 reduces mortality only at the dose proposed in the RECOVERY study in the younger population. No benefit of the use of steroids was observed in patients with older age or higher number of comorbidities.


Tachyarrhythmias, bradyarrhythmias and acute coronary syndromes.
The incidence of bradyarrhythmias in patients with acute coronary syndrome (ACS) is 0.3% to 18%. It is caused by sinus node dysfunction (SND), high-degree atrioventricular (AV) block, or bundle branch blocks. SND presents as sinus bradycardia or sinus arrest. First-degree AV block occurs in 4% to 13% of patients with ACS and is caused by rhythm disturbances in the atrium, AV node, bundle of His, or the Tawara system. First- or second-degree AV block is seen very frequently within 24 h of the beginning of ACS; these arrhythmias are frequently transient and usually disappear after 72 h. Third-degree AV blocks are also frequently transient in patients with infero-posterior myocardial infarction (MI) and permanent in anterior MI patients. Left anterior fascicular block occurs in 5% of ACS; left posterior fascicular block is observed less frequently (incidence <0.5%). Complete bundle branch block is present in 10% to 15% of ACS patients; right bundle branch block is more common (2/3) than left bundle branch block (1/3). In patients with bradyarrhythmia, intravenous (IV) atropine (1-3 mg) is helpful in 70% to 80% of ACS patients and will lead to an increased heart rate. The need for pacemaker stimulation (PS) is different in patients with inferior MI (IMI) and anterior MI (AMI). Whereas bradyarrhythmias are frequently transient in patients with IMI and therefore do not need permanent PS, there is usually a need for permanent PS in patients with AMI. In these patients bradyarrhythmias are mainly caused by septal necrosis. In patients with ACS and ventricular arrhythmias (VTA) amiodarone is the drug of choice; this drug is highly effective even in patients with defibrillation-resistant out-of-hospital cardiac arrest. There is general agreement that defibrillation and advanced life support is essential and is the treatment of choice for patients with ventricular flutter/fibrillation. If defibrillation is not available in patients with cardiac arrest due to VTA, cardiopulmonary resuscitation is mandatory.


Antimicrobial efficacy of zinc oxide quantum dots against Listeria monocytogenes, Salmonella Enteritidis, and Escherichia coli O157:H7.
Zinc oxide quantum dots (ZnO QDs) are nanoparticles of purified powdered ZnO. These were evaluated for antimicrobial activity against Listeria monocytogenes, Salmonella Enteritidis, and Escherichia coli O157:H7. The ZnO QDs were utilized as a powder, bound in a polystyrene film (ZnO-PS), or suspended in a polyvinylprolidone gel (ZnO-PVP). Bacteria cultures were inoculated into culture media or liquid egg white (LEW) and incubated at 22 degrees C. The inhibitory efficacies of ZnO QDs against 3 pathogens were concentration dependent and also related to type of application. The ZnO-PVP (3.2 mg ZnO/mL) treatment resulted in 5.3 log reduction of L. monocytogenes and 6.0 log reduction of E. coli O157:H7 in growth media after 48 h incubation, as compared to the controls. Listeria cells in the LEW control increased from 3.8 to 7.2 log CFU/mL during 8 d incubation, while the cells in the samples treated with 1.12 and 0.28 mg ZnO/mL were reduced to 1.4 and 3.0 log CFU/mL, respectively. After 8 d incubation, the cell populations of Salmonella in LEW in the presence of 1.12 and 0.28 mg ZnO/mL were reduced by 6.1 and 4.1 log CFU/mL over that of controls, respectively. ZnO powder and ZnO-PVP showed significant antimicrobial activities against all 3 pathogens in growth media and LEW. ZnO-PVP coating had less inhibitory effect than the direct addition of ZnO-PVP. No antimicrobial activities of ZnO-PS film were observed. This study suggested that the application of ZnO nanoparticles in food systems may be effective at inhibiting certain pathogens.


Risk factors for erosive esophagitis: a multivariate analysis based on the ProGERD study initiative.
Gastroesophageal reflux disease can be divided into three categories: nonerosive GERD (NERD), erosive GERD (ERD), and Barrett's esophagus. A shift among these categories rarely occurs. The aim of the present study was to elucidate potential patient-associated risk factors associated with ERD. A total of 6,215 patients with troublesome heartburn were recruited to a large, prospective, multicenter open cohort study comprising an initial treatment phase and a 5-yr follow-up phase. Each center planned to recruit an equal number of patients with NERD and ERD. All patients underwent an interview based on standardized questionnaires, a physical examination, and endoscopy with biopsies. Data were analyzed by multiple logistic regression analysis. Risk factor analysis was performed on 5,289 patients (NERD: n = 2,834; ERD: n = 2,455), which was the intent-to-treat population excluding patients with suspected/proven complicated reflux disease. Stepwise regression analysis identified the following independent predictors of ERD: male gender, overweight, regular use of alcohol, a history of GERD >1 yr, and smoker or ex-smoker. A higher level of education and a positive Helicobacter pylori (H. pylori) status were associated with a lower risk of ERD. Some patient-associated factors increase the risk of erosive esophagitis as opposed to nonerosive reflux disease. However, no single factor or combination of factors is capable of predicting mucosal damage with clinically sufficient certainty. Thus, endoscopy is still required in all GERD patients if valid information on the state of the esophageal mucosa is needed.


The Unified Parkinson's Disease Rating Scale as a predictor of peak aerobic capacity and ambulatory function.
The Unified Parkinson's Disease Rating Scale (UPDRS) is a widely applied index of disease severity. Our objective was to assess the utility of UPDRS for predicting peak aerobic capacity (VO2 peak) and ambulatory function. Participants (n = 70) underwent evaluation for UPDRS (Total and Motor ratings), VO2 peak, 6-minute walk distance (6MW), and 30-foot self-selected walking speed (SSWS). Using regression, we determined the extent to which the Total and Motor UPDRS scores predicted each functional capacity measure after adjusting for age and sex. We also tested whether adding the Hoehn and Yahr scale (H-Y) to the model changed predictive power of the UPDRS. Adjusted for age and sex, both the Total UPDRS and Motor UPDRS subscale failed to predict VO2 peak. The Total UPDRS did weakly predict 6MW and SSWS (both p < 0.05), but the Motor UPDRS subscale did not predict these ambulatory function tests. After adding H-Y to the model, Total UPDRS was no longer an independent predictor of 6MW but remained a predictor of SSWS. We conclude that Total and Motor UPDRS rating scales do not predict VO2 peak, but that a weak relationship exists between Total UPDRS and measures of ambulatory function.


A longitudinal analysis of respiratory symptoms in people with cystic fibrosis with advanced lung disease on and off ETI.
People with CF (PwCF), particularly those with advanced lung disease (ALD), experience frequent respiratory symptoms. A major CF breakthrough was the approval of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019, which has been shown to improve symptoms and lung function in the CF population, and decrease pulmonary exacerbations. The purpose of this study was to analyze longitudinal changes in respiratory symptoms over 24 months in ETI-treated and untreated PwCF with ALD Symptoms were measured among CF adults with ppFEV1 < 40% (N = 48, 24 ETI-treated, 24 untreated) using the CFRSD-CRISS and the CFQ-R [respiratory]. Two multilevel growth models assessed the rate of change in symptoms overall and within the ETI-treated and untreated groups. PwCF on ETI had significantly lower symptom severity over 24 months than those not on ETI as measured by the CRISS and CFQ-R. The ETI-treated group maintained an -11.7 and +19.3 point difference(p<0.01) in CRISS and CFQ-R scores over the study compared to the non-ETI group, achieving minimal clinically important differences on average between groups on both instruments. No change in the symptom burden trajectory between groups was observed (p = 0.58). Even with ALD, ETI-treated PwCF have a lower respiratory burden than those not on ETI. This may be confounded by survivorship bias in the non-ETI group. Of note, in this ALD cohort, neither instrument demonstrated ceiling effects. Our results suggest that, while ETI has significantly improved the lived experience, PwCF with ALD are still plagued by respiratory symptoms.


Care and outcomes of elderly patients with acute myocardial infarction by physician specialty: the effects of comorbidity and functional limitations.
Whether patients with acute myocardial infarction who are treated by cardiologists have better outcomes than patients treated by generalist physicians is controversial. Because some of the survival benefit associated with cardiology care may be due to baseline differences in patient characteristics, we evaluated how differences in case-mix of comorbid illness and functional limitations may explain the association between specialty care and survival. We examined the records of 109,243 Medicare beneficiaries hospitalized for myocardial infarction from 1994 to 1995 from the national Cooperative Cardiovascular Project to evaluate the association of physician specialty with 30-day and 1-year mortality. We assessed the extent to which this relation was mediated by differences in the use of guideline-supported therapies (aspirin, beta-blockers, reperfusion, angiotensin-converting enzyme inhibitors) or differences in the clinical characteristics of the patients. Patients who had board-certified cardiologists as attending physicians had the least number of comorbid conditions, whereas patients who had general practitioners or internal medicine subspecialists as attending physicians usually had the most comorbidities. Cardiologists had the greatest use of most guideline-supported therapies, and general practitioners had the lowest use. After adjustment for severity of myocardial infarction, clinical presentation, and hospital characteristics, patients treated by cardiologists were less likely to die within 1 year (relative risk [RR] = 0.92, 95%, confidence interval [CI]: 0.89 to 0. 95), and patients cared for by other general practitioners were more likely to die within 1 year (RR = 1.09, 95% CI: 1.03 to 1.14), than patients cared for by general internists. After adjusting for additional measures of comorbid illness and functional limitations, the 1-year survival benefit associated with cardiology care was attenuated relative to internists (RR = 0.97, 95% CI: 0.94 to 1.0), and the excess mortality associated with general practitioners decreased (RR = 1.05, 95% CI: 1.00 to 1.11). After further adjustment for the use of guideline-supported therapies, both differences in 1-year survival between patients treated by cardiologists or general practitioners were not significantly different from those of patients treated by internists. Studies comparing outcomes by physician specialties that do not adjust adequately for differences in patient characteristics may attribute more benefit than is appropriate to specialists who treat patients who have fewer comorbid conditions. Some of the remaining benefit-at least among patients with myocardial infarction-may be attributable to greater use of recommended therapies.


Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses.
Up to 10% of the population reports an allergy to penicillin, yet more than 80% of these individuals lack penicillin-specific IgE antibodies. A negative result on a penicillin skin test is highly accurate in identifying who can safely receive the antibiotic at the time of testing. However, its negative predictive value for future courses is unknown because it is uncertain whether patients with a history of penicillin allergy are at risk of becoming resensitized. To determine the rate of penicillin resensitization in adult patients with a history of penicillin allergy after they are challenged with repeated courses of oral penicillin. Adult patients with a history of penicillin allergy consistent with an IgE-mediated mechanism were recruited and underwent penicillin skin testing. Those with negative skin test results were challenged with 3 successive 10-day courses of penicillin V potassium (250 mg by mouth 3 times a day), providing their penicillin skin test results remained negative prior to each course. Patients with positive skin test results were not challenged. Of 53 patients with initially negative skin test results, 46 completed the protocol, and each tolerated all 3 courses of penicillin with negative skin test results throughout. No patients had a converted skin test result from negative to a positive, yielding a resensitization rate of 0% (upper 95% confidence interval, 2.1%). Adult patients with a history of penicillin allergy are not at increased risk of resensitization after receiving 3 courses of oral penicillin. Because a negative penicillin skin test result is predictive for subsequent oral administrations beyond the time of testing, adult patients with a history of penicillin allergy can be skin tested electively, which may avoid unnecessary treatment with alternate broad-spectrum antibiotics.


Spatial localization after strabismus surgery: evidence for inflow.
Strabismics pointed to targets (without sight of the hand) before and again after surgery that altered the position of the deviating eye in its orbit. Patients having this surgery for the first time were able to use proprioceptively derived information about the surgically altered eye position. In contrast, patients who had similar operations, but on muscles that had been operated on one or more times in the past, were apparently deprived of this information. The important afference may be supplied by the tendon organs.


Central immune overactivation in the presence of reduced plasma corticosterone contributes to swim stress-induced hyperalgesia.
Although it is widely known that immunological, hormonal and nociceptive mechanisms are altered by exposure to repeated stress, the interplaying roles of each function in the development of post-stress hyperalgesia are not completely clear. Thus, we wanted to establish how interleukin 1-beta (IL-1β), corticosterone and microglia interact to contribute in the development of hyperalgesia following repeated forced swim. Rats were subjected to either forced swim, sham swim or non-conditioned. Each group was then treated with minocycline, ketoconazole, or saline. Thermal nociception was measured via the hot plate test, before and after the behavioral conditioning, whereas blood and lumbar spinal cord tissue samples were obtained at the end of the protocol. Serum levels of corticosterone, spinal tissue concentration of IL-1β and spinal OX-42 labeling (microglial marker) were determined. Rats exposed to forced swim stress developed thermal hyperalgesia along with elevated spinal tissue IL-1β, increased OX-42 labeling and relatively diminished serum corticosterone. Pre-treatment with minocycline and ketoconazole prevented the development of thermal hyperalgesia and the increase in IL-1β, without significantly modifying serum corticosterone. These results suggest that the development of forced swim-induced thermal hyperalgesia requires the simultaneous presence of increased spinal IL-1β, microglial activation, and relatively decreased serum corticosterone.


Animal cell shape changes and gene expression.
Cell shape and cell contacts are determined by transmembrane receptor-mediated associations of the cytoskeleton with specific extracellular matrix proteins and with ligands on the surface of adjacent cells. The cytoplasmic domains of these microfilament-membrane associations at the adherens junction sites, also localize a variety of regulatory molecules involved in signal transduction and gene regulation. The stimulation of cells with soluble polypeptide factors leads to rapid changes in cell shape and microfilament component organization. In addition, this stimulation also activates the phosphoinositide signaling pathway. Recently, a linkage between actin-binding proteins and the phosphoinositide signaling pathway, was discovered. It is suggested that by the association with the second messenger system, and/or by controlling the localization of regulatory molecules, the cytoskeleton may regulate gene expression.


Moore's Law revisited through Intel chip density.
Gordon Moore famously observed that the number of transistors in state-of-the-art integrated circuits (units per chip) increases exponentially, doubling every 12-24 months. Analysts have debated whether simple exponential growth describes the dynamics of computer processor evolution. We note that the increase encompasses two related phenomena, integration of larger numbers of transistors and transistor miniaturization. Growth in the number of transistors per unit area, or chip density, allows examination of the evolution with a single measure. Density of Intel processors between 1959 and 2013 are consistent with a biphasic sigmoidal curve with characteristic times of 9.5 years. During each stage, transistor density increased at least tenfold within approximately six years, followed by at least three years with negligible growth rates. The six waves of transistor density increase account for and give insight into the underlying processes driving advances in processor manufacturing and point to future limits that might be overcome.


Annual Psychological Screening in Youth and Young Adults with Type 1 Diabetes.
Youth and young adults with type 1 diabetes are at a great risk for developing depression and diabetes specific distress, therefore, systematic psychological screening is recommended. Routine psychological screening was implemented in Slovene diabetes clinic for children, adolescents and young adults in 2012. One-year results are presented. Adolescents and young adults (N = 159, aged 11 - 25 years), attending the obligatory yearly educational outpatient visit at University Children's Hospital, Ljubljana, Slovenia, were examined using questionnaires measuring depression (depression scale from Slovene version of Trauma Symptom Checklist for Children) and diabetes distress (Diabetes Distress Screening Scale). Six additional items were included to assess the fear of hypoglycemia and family support. Socio-demographic and diabetes-related data were collected. Questionnaires were analyzed by a psychologist, and the patients that scored above cut-off point were invited to an individual psychological assessment. Of the sample, 1.3 % reached the threshold for elevated depressive symptoms, and 32.7 % reported significant diabetes distress. The need for psychological support from a specialist was expressed by 5.0 %. There were statistically significant associations between all psychological variables; moreover, better glycemic control was associated with lower diabetes distress and better family support. Nine patients (5.7 %) started with psychological treatment according to the referrals after screening. The results after one year of psychological screening in Slovene type 1 diabetes population displayed small rates of depression and a large proportion of diabetes distress. Only a small percentage of patients attended the offered individual psychological assessment.


Increased myocardial contractility during endotoxin shock in dogs.
The slope of the left ventricular (LV) end-systolic pressure-diameter relationship (Ees) was analyzed in open-chest, pentobarbital-anesthetized dogs before and after endotoxin administration. A lead II electrocardiogram, systemic arterial pressure, LV pressure, LV dP/dt, and LV minor axis diameter were measured. After control measurements were taken, dogs were given either 1 mg/kg Salmonella enteritidis endotoxin (n = 5) or an equivalent volume of saline (n = 4). Control dogs were followed for 240 min. Endotoxic dogs were monitored until death (246 +/- 44 min). There were no significant changes in Ees in control dogs (17 +/- 3 mmHg/mm), which were hemodynamically stable for 4 h. Ees was significantly increased in endotoxic dogs even into the late stages of shock (41 +/- 11 mmHg/mm, P less than 0.01). Only during the terminal phase did Ees fall significantly below control (11 +/- 2 mmHg/mm, P less than 0.05). End-diastolic diameter decreased following endotoxin administration (P less than 0.05) but returned toward control by the terminal stage. Peak + LV dP/dt was depressed following endotoxin injection. Myocardial contractility was not depressed except as a terminal event. Early depression of cardiovascular performance in endotoxic dogs was therefore due to decreased preload and not cardiac dysfunction.


Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study.
This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib.21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1-81) months).Median age was 52 years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42 (8-74) months before PAH diagnosis. No bone morphogenic protein receptor-2 (BMPR2) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306 (0-660) to 430 (165-635) m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30-70) to 26 (17-50) mmHg (p<0.01) and pulmonary vascular resistance from 6.1 (3.2-27.3) to 2.6 (1.2-5.9) Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients.Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential.


Examining the impact of COVID-19 in ethnically diverse families with young children with intellectual and developmental disabilities.
The COVID-19 pandemic introduced challenges to families with young children with developmental delays. Beyond the widespread concerns surrounding illness, loss of employment and social isolation, caregivers are responsible for overseeing their children's educational and therapeutic programmes at home often without the much needed support of professionals. The present study sought to examine the impact of COVID-19 in 77 ethnically, linguistically and socioeconomically diverse families with young children with intellectual and developmental disabilities (IDDs) in California and Oregon, who were participating in larger intervention studies. Parents responded to five interview questions about the impact of the pandemic, services for their child, silver linings or positive aspects, coping and their concerns about the long-term impact of the pandemic. Parents reported that their biggest challenge was being at home caring for their children with the loss of many essential services. Parents reported some positive aspects of the pandemic, especially being together as a family. Although there were positive aspects of the situation, many parents expressed concern about long-term impacts of the pandemic on their children's development, given the loss of services, education and social engagement opportunities. Results suggest that parents of young children with IDD report significant challenges at home during the pandemic. Professional support, especially during the reopening phases, will be critical to support family well-being and child developmental outcomes.


Early childhood nutrition, education and fertility milestones in Guatemala.
Data on fertility milestones were collected in 1994 and linked to information collected in a trial conducted in eastern Guatemala between 1969 and 1977, to examine whether early childhood nutrition was associated with the timing of fertility milestones. In the original trial, two pairs of villages were randomly allocated to receive either a high energy, high protein supplement (Atole) or a low energy, no-protein supplement (Fresco). Mean age at follow-up was 23.47 y (n = 240). About 62% of women had experienced first birth (median age at first birth = 19.83 y). The median intervals from menarche to first intercourse and from first intercourse to first birth were 5.67 and 0.95 y; they were 1.68 and 0.06 y shorter, respectively, for the Atole group than for the Fresco group. Women who had received Atole in utero and/or during early childhood experienced earlier milestones even after adjusting for socioeconomic status (SES), education and age at the prior event. Median age at first birth was 1.17 y earlier for the Atole group. Better growth during early childhood (not severely stunted) led to earlier milestones (median age at first birth was 1.04 y earlier), primarily among women with illiterate fathers. Completion of primary school significantly delayed fertility milestones; the median age at first birth was 4.27 y later for those who completed primary school compared with those who did not (P < 0.05). In sum, improved nutrition during early childhood results in earlier fertility milestones, but the effects of schooling in delaying fertility milestones are greater in magnitude. Intervention programs that improve early childhood nutrition should be accompanied by investments in education that ensure that girls complete primary school.


Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis.
p53 is a tumor suppressor gene whose regulation is crucial to maintaining genome stability and for the apoptotic elimination of abnormal, potentially cancer-predisposing cells. C. elegans contains a primordial p53 gene, cep-1, that acts as a transcription factor necessary for DNA damage-induced apoptosis. In a genetic screen for negative regulators of CEP-1, we identified a mutation in GLD-1, a translational repressor implicated in multiple C. elegans germ cell fate decisions and related to mammalian Quaking proteins. CEP-1-dependent transcription of proapoptotic genes is upregulated in the gld-1(op236) mutant and an elevation of p53-mediated germ cell apoptosis in response to DNA damage is observed. Further, we demonstrate that GLD-1 mediates its repressive effect by directly binding to the 3'UTR of cep-1/p53 mRNA and repressing its translation. This study reveals that the regulation of cep-1/p53 translation influences DNA damage-induced apoptosis and demonstrates the physiological importance of this mechanism.


Establishment, characterization, and viral susceptibility of two cell lines derived from goldfish Carassius auratus muscle and swim bladder.
Goldfish Carassius auratus are common aquarium fish and have a significant economic and research value, having considerable worth to fisheries as a baitfish and the ability to adapt to a range of habitats. Two cell lines were established from goldfish muscle and swim bladder tissue, in order to create a biological monitoring tool for viral diseases. Cell lines were optimally maintained at 30 degrees C in Leibovitz-15 medium supplemented with 20% fetal bovine serum. Propagation of goldfish cells was serum dependent, with a low plating efficiency (>16%). Karyotyping analysis indicated that both cell lines remained diploid, with a mean chromosomal count of 104. Results of viral challenge assays revealed that both cell lines shared similar patterns of viral susceptibility and production to infectious hematopoietic necrosis virus, infectious pancreatic necrosis virus, snakehead rhabdovirus, and spring viremia carp virus. Both cell lines demonstrated a higher sensitivity and significantly larger viral production than control brown bullhead cells for channel catfish virus. These newly established cell lines will be used as a diagnostic tool for viral diseases in this fish species and also for the isolation and study of goldfish viruses in the future.


Driving the Downward Spiral: Alcohol-Induced Dysregulation of Extended Amygdala Circuits and Negative Affect.
Alcohol use disorder (AUD) afflicts a large number of individuals, families, and communities globally. Affective disturbances, including stress, depression, and anxiety, are highly comorbid with AUD, contributing in some cases to initial alcohol use and continued use. Negative affect has a particularly strong influence on the withdrawal/abstinence stage of addiction as individuals with AUD frequently report stressful events, depression, and anxiety as key factors for relapse. Treatment options for negative affect associated with AUD are limited and often ineffective, highlighting the pressing need for preclinical studies examining the underlying neural circuitry driving AUD-associated negative affect. The extended amygdala (EA) is a set of brain areas collectively involved in generating and regulating affect, and extensive research has defined a critical role for the EA in all facets of substance use disorder. Here, we review the expansive historical literature examining the effects of ethanol exposure on the EA, with an emphasis on the complex EA neural circuitry driving negative affect in all phases of the alcohol addiction cycle. Specifically, this review focuses on the effects of alcohol exposure on the neural circuitry in 2 key components of the EA, the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Additionally, future directions are proposed to advance our understanding of the relationship between AUD-associated negative affect and neural circuitry in the EA, with the long-term goal of developing better diagnostic tools and new pharmacological targets aimed at treating negative affect in AUD. The concepts detailed here will serve as the foundation for a companion review focusing on the potential for the endogenous cannabinoid system in the EA as a novel target for treating the stress, anxiety, and negative emotional state driving AUD.