Sensitivity of axillary specimen x-ray to predict nodal count and positivity.
The number of examined axillary lymph nodes (ALN) has been proposed as an indicator of prognosis along with quality and adequacy in breast cancer surgery. The purpose of this study was to examine the utility of imaging axillary specimens with x-ray (lymphogram) to determine the number of lymph nodes. We sought to determine the sensitivity and specificity of a lymphogram in identifying nodal positivity. Patients who underwent sentinel lymph node (SLN) and axillary lymph node dissections (ALND) were prospectively accrued to this double-blinded, single-institution trial from December 2009 to January 2011. A single physician interpreted all lymphograms for the number of ALNs and positivity determined by size, spiculations, irregularities, and calcifications. Twenty female (age 50.8 ± 14.3 years) patients were accrued to the study. The lymphogram located more lymph nodes compared with pathology in 11 of 16 cases (68.8%). In these 11 cases, lymphogram identified 170 nodes and the pathologist located 132 (77.6%). Of the 16 ALND specimens, 6 were from patients naive to chemotherapy and averaged 13.8 ± 6.6 nodes; 10 were from neoadjuvant chemotherapy patients and had an average number of 14.9 ± 7.4 nodes. In neoadjuvant chemotherapy patients, sensitivity of the lymphogram to detect nodal positivity was 91.7% and specificity was 33.3%. This study demonstrated that lymphogram accurately identifies nodal count. This can be used for documentation of an adequate ALND for reimbursement. Furthermore, there may be potential value of lymphogram in intraoperative determination of nodal positivity.


Whole-body and muscle protein metabolism are not affected by acute deviations from habitual protein intake in older men: the Hormonal Regulators of Muscle and Metabolism in Aging (HORMA) Study.
Acute deviations in protein intake before the quantification of protein kinetics in older humans may explain the controversy over the effects of older age on muscle protein synthesis and proteolysis rates. We hypothesized that an acute decrease in protein intake from the habitual intake is associated with lower muscle protein synthesis and higher proteolysis rates, whereas an acute increase in protein intake from the habitual intake is associated with higher muscle protein synthesis and lower proteolysis rates. In 112 community-dwelling healthy men aged 65-90 y, we quantified resting whole-body [1,2-(13)C(2)]leucine kinetics, muscle mixed protein fractional synthesis rates (FSRs), and muscle proteasome proteolytic enzyme activities after participants consumed for 3 d controlled research meals (0.9-1.1 g protein · kg(-1) · d(-1)) that contained more or less protein than that habitually consumed and that induced alterations in nitrogen balance. Protein kinetic parameters were not significantly different between the groups, despite controlled research protein intakes that were lower (-0.2 to -0.3 g · kg(-1) · d(-1)) or higher (+0.2 g · kg(-1) · d(-1)) than habitual intakes and that induced negative (-22 to -25 mg · kg(-1) · d(-1)) or positive (22-25 mg · kg(-1) · d(-1)) nitrogen balance. Within these acutely altered protein intake and nitrogen balance boundaries, a reduction in protein intake from habitual intake and induction of negative nitrogen balance were not associated with higher proteolysis or lower muscle FSR, and an acute increase in protein intake from habitual intake and induction of positive nitrogen balance were not associated with lower proteolysis or higher muscle FSR. A higher quantitative insulin sensitivity check index was associated with lower whole-body proteolysis rates. The practice of acutely controlling protein intake, even at intakes lower than habitual intakes that induce negative nitrogen balance, before quantifying human protein kinetics does not significantly reduce muscle protein synthesis or increase proteolysis. Factors other than protein intake explain lower muscle protein synthesis rates with advanced age. This trial is registered at clinicaltrials.gov as NCT00183040.


Indication and timing of percutaneous mitral balloon valvotomy and the role of atrial fibrillation.
Percutaneous transvenous mitral balloon valvotomy (PTMV) has been proven to be an effective and safe method for treatment of patients with severe mitral valve stenosis. This technique has become an accepted alternative for surgical commissurotomy, not only in young patients with pliable valves, but also in selected older patients with extensive valvular pathology. This review highlights the significance of coexisting atrial fibrillation, patient selection and timing of PTMV in patients with mitral valve stenosis.


Anticorrelated resting-state functional connectivity in awake rat brain.
Resting-state functional connectivity (RSFC) measured by functional magnetic resonance imaging has played an essential role in understanding neural circuitry and brain diseases. The vast majority of RSFC studies have been focused on positive RSFC, whereas our understanding about its conceptual counterpart - negative RSFC (i.e. anticorrelation) - remains elusive. To date, anticorrelated RSFC has yet been observed without the commonly used preprocessing step of global signal correction. However, this step can induce artifactual anticorrelation (Murphy et al., 2009), making it difficult to determine whether the observed anticorrelation in humans is a processing artifact (Fox et al., 2005). In this report we demonstrated robust anticorrelated RSFC in a well characterized frontolimbic circuit between the infralimbic cortex (IL) and amygdala in the awake rat. This anticorrelation was anatomically specific, highly reproducible and independent of preprocessing methods. Interestingly, this anticorrelated relationship was absent in anesthetized rats even with global signal correction, further supporting its functional significance. Establishing negative RSFC independent of data preprocessing methods will significantly enhance the applicability of RSFC in better understanding neural circuitries and brain networks. In addition, combining the neurobiological data of the IL-amygdala circuit in rodents, the finding of the present study will enable further investigation of the neurobiological basis underlying anticorrelation.


Group and strain-specific neutralization sites of infectious bursal disease virus defined with monoclonal antibodies.
Two somatic cell hybridizations were performed utilizing splenocytes from mice immunized with one or more strains of infectious bursal disease virus (IBDV). Supernatants from hybridoma cell lines were initially screened by the enzyme-linked immunosorbent assay (ELISA) against multiple strains of IBDV. Cell lines that secreted antibodies with ELISA reactivity patterns of interest were cloned, and their monoclonal antibodies (MCAs) were subsequently tested in cross-virus-neutralization tests. Two of the nine MCAs selected exhibited strong neutralizing activity and precipitated IBDV antigens in agar gel precipitin tests as well. MCA B69 significantly neutralized only the cloned D78 strain of IBDV, whereas MCA R63 neutralized all IBDV strains (representing both serotype I and II viruses) against which it was tested. Results of competitive ELISAs that used the R63 and B69 MCAs showed that the two neutralization sites on the D78 strain were not overlapping.


Drosophila tRNAs hyperprocessed in vitro by ribonuclease P.
In transposon copia-related retrovirus-like particles of Drosophila, a 5' half fragment produced by the cleavage of mature initiator methionine tRNA is used as the primer for minus-strand reverse transcription. This cleavage is called hyperprocessing. We have previously reported that the catalytic RNA subunit of RNase P catalyzes this hyperprocessing in vitro and that this cleavage is dependent on the occurrence of an altered conformation of the tRNA substrate. Here, we found that other mature tRNAs of Drosophila were also hyperprocessed by M1 RNA in vitro and that some of such tRNAs were probably alanine and histidine tRNAs. Here we report these two tRNAs can also adopt their alternative conformations very similar to that of initiator methionine tRNA.


Transient and sustained afterdepolarizations in accessory olfactory bulb mitral cells are mediated by distinct mechanisms that are differentially regulated by neuromodulators.
Social interactions between mammalian conspecifics rely heavily on molecular communication via the main and accessory olfactory systems. These two chemosensory systems show high similarity in the organization of information flow along their early stages: social chemical cues are detected by the sensory neurons of the main olfactory epithelium and the vomeronasal organ. These neurons then convey sensory information to the main (MOB) and accessory (AOB) olfactory bulbs, respectively, where they synapse upon mitral cells that project to higher brain areas. Yet, the functional difference between these two chemosensory systems remains unclear. We have previously shown that MOB and AOB mitral cells exhibit very distinct intrinsic biophysical properties leading to different types of information processing. Specifically, we found that unlike MOB mitral cells, AOB neurons display persistent firing responses to strong stimuli. These prolonged responses are mediated by long-lasting calcium-activated non-selective cationic current (Ican). In the current study we further examined the firing characteristics of these cells and their modulation by several neuromodulators. We found that AOB mitral cells display transient depolarizing afterpotentials (DAPs) following moderate firing. These DAPs are not found in MOB mitral cells that show instead robust hyperpolarizing afterpotentials. Unlike Ican, the DAPs of AOB mitral cells are activated by low levels of intracellular calcium and are relatively insensitive to flufenamic acid. Moreover, the cholinergic agonist carbachol exerts opposite effects on the persistent firing and DAPs of AOB mitral cells. We conclude that these phenomena are mediated by distinct biophysical mechanisms that may serve to mediate different types of information processing in the AOB at distinct brain states.


[Computed tomographic studies of fracture healing].
The CT appearances of healing fractures were studied following tibial osteotomy in a dog. Traditional radiological investigations and CT were carried out until healing was complete; CT showed callus on the ninth day, whereas radiographs only showed it after 19 days. After 32 days, callus filled nearly the entire medullary cavity. Similar observations were made in several human situations. CT demonstrates interposed material in the fracture very clearly, even if there is marked callus formation within the fracture.


Rickettsia infection in natural leech populations.
Field-collected specimens of glossiphoniid leeches, Torix tagoi, Torix tukubana, Hemiclepsis marginata, and Hemiclepsis japonica, were surveyed for Rickettsia infection by using a diagnostic PCR assay. Rickettsia was detected in 96% (69/72) of T. tagoi, 83% (24/29) of T. tukubana, 29% (33/113) of H. marginata, and 0% (0/30) of H. japonica. The frequencies of Rickettsia infection were stably maintained in different seasons. In H. marginata and T. tukubana, distant local populations exhibited remarkably different frequencies of Rickettsia infection. Eggs carried by infected females of T. tagoi and H. marginata were all Rickettsia-positive, indicating nearly 100% vertical transmission. Analysis of 16S rDNA sequences revealed that phylogenetic relationship of the leech-associated Rickettsia reflected the specific and populational divisions of the host leeches. However, circumstantial lines of evidence strongly suggested that horizontal transmission of Rickettsia must have occurred in the ancestors of these leeches. In T. tagoi and T. tukubana, infected individuals were remarkably larger in size than uninfected individuals, wheras in H. marginata, infected and uninfected individuals were almost comparable in size. This study first provides information on ecological aspects of leech-bone endocellular bacteria of the genus Rickettsia. On the basis of these data, we discuss possible mechanisms whereby Rickettsia infection is maintained in natural populations of these leeches in the freshwater ecosystem.


Effects of Three Recovery Protocols on Range of Motion, Heart Rate, Rating of Perceived Exertion, and Blood Lactate in Baseball Pitchers During a Simulated Game.
Baseball pitching has been described as an anaerobic activity from a bioenergetics standpoint with short bouts of recovery. Depending on the physical conditioning and muscle fiber composition of the pitcher as well as the number of pitches thrown per inning and per game, there is the possibility of pitchers fatiguing during a game, which could lead to a decrease in pitching performance. Therefore, the purpose of this study was to evaluate the effects of 3 recovery protocols: passive recovery, active recovery (AR), and electrical muscle stimulation (EMS) on range of motion (ROM), heart rate (HR), rating of perceived exertion (RPE), and blood lactate concentration in baseball pitchers during a simulated game. Twenty-one Division I intercollegiate baseball pitchers (age = 20.4 ± 1.4 years; height = 185.9 ± 8.4 cm; weight = 86.5 ± 8.9 kg; percent body fat = 11.2 ± 2.6) volunteered to pitch 3 simulated 5-inning games, with a maximum of 70 fastballs thrown per game while wearing an HR monitor. Range of motion was measured pre, post, and 24 hours postpitching for shoulder internal and external rotation at 90° and elbow flexion and extension. Heart rate was recorded after each pitch and after every 30 seconds of the 6-minute recovery period. Rating of perceived exertion was recorded after the last pitch of each inning and after completing each 6-minute recovery period. Immediately after throwing the last pitch of each inning, postpitching blood lactate concentration (PPLa-) was measured. At the end of the 6-minute recovery period, before the next inning started, postrecovery blood lactate concentration (PRLa-) was measured. Pitchers were instructed to throw each pitch at or above 95% of their best-pitched fastball. This was enforced to ensure that each pitcher was throwing close to maximal effort for all 3 simulated games. All data presented represent group mean values. Results revealed that the method of recovery protocol did not significantly influence ROM (p > 0.05); however, it did significantly influence blood lactate concentration (p < 0.001), HR (p < 0.001), and RPE (p = 0.01). Blood lactate concentration significantly decreased from postpitching to postrecovery in the EMS recovery condition (p < 0.001), but did not change for either the active (p = 0.04) or the passive (p = 0.684) recovery conditions. Rating of perceived exertion decreased from the postpitching to postrecovery in both the passive and EMS recovery methods (p < 0.001), but did not decrease for AR (p = 0.067). Heart rate decreased for all conditions from postpitching to postrecovery (p < 0.001). The use of EMS was the most effective method at reducing blood lactate concentration after 6 minutes of recovery during a simulated game (controlled setting). Although EMS significantly reduced blood lactate concentrations after recovery, blood lactate concentrations after pitching in the simulated games were never high enough to cause skeletal muscle fatigue and decrease pitching velocity. If a pitcher were to throw more than 14 pitches per inning, throw more total pitches than normal per game, and have blood lactate concentrations increase higher than in the simulated games in this study, the EMS recovery protocol may be beneficial to pitching performance by aiding recovery. This could potentially reduce some injuries associated with skeletal muscle fatigue during pitching, may allow a pitcher throw more pitches per game, and may reduce the number of days between pitching appearances.


[Genetic background of atopy].
The paper presents contemporary views on atopic inheritance patterns. Results of molecular studies are presented which map genes linked with disturbances in IgE to chromosomes 5 and 11. The role of HLA antigens in atopic reaction mechanisms is also discussed.


Biliary excretion of some diquaternary ammonium cations in the rat, guinea pig and rabbit.
1. The extent of the excretion in the bile and urine of the (14)C-labelled dications, diquat, paraquat, morfamquat, decamethonium and dimethyltubocurarine in bile-duct-cannulated rats, guinea pigs and rabbits was examined. 2. These compounds were excreted unchanged in bile and urine, except diquat, which was metabolized to a significant extent (18% of the dose) in the rabbit only. 3. The extent of the biliary excretion of diquat (mol wt. of ion 184), paraquat (186), decamethonium (258) and morfamquat (469) was less than 10% of the dose in the three species, whereas that of dimethlytubocurarine (653) was greater than 10% in the rat and rabbit but not in the guinea pig. 4. These results together with data from the literature suggest that the molecular weight at which the excretion of dications in the bile exceeds 10% of the dose is in the region of 500-600, which differs from the values for monocations (Hughes et al., 1973) and anions (Millburn et al., 1967; Hirom et al., 1972).


Chromosome instability in Candida albicans.
Candida albicans maintains genetic diversity by random chromosome alterations, and this diversity allows utilization of various nutrients. Although the alterations seem to occur spontaneously, their frequencies clearly depend on environmental factors. In addition, this microorganism survives in adverse environments, which cause lethality or inhibit growth, by altering specific chromosomes. A reversible loss or gain of one homolog of a specific chromosome in this diploid organism was found to be a prevalent means of adaptation. We found that loss of an entire chromosome is required because it carries multiple functionally redundant negative regulatory genes. The unusual mode of gene regulation in Candida albicans implies that genes in this organism are distributed nonrandomly over chromosomes.


Fruit and vegetable intakes, sources and contribution to total diet in very young children (1-4 years): the Irish National Pre-School Nutrition Survey.
Although the importance of fruit and vegetable (F&V) intakes in the prevention of chronic diseases is well established, there are limited data on intakes in very young children. This study estimates F&V intakes and sources and the contribution to the total diet using data from the National Pre-School Nutrition Survey, a nationally representative sample (n 500) of Irish children aged 1-4 years. A 4-d weighed food record was used to collect food intake data. Of 1652 food codes consumed, 740 had a fruit/vegetable component. The percentage of edible fruits and/or vegetables in each food code was calculated. Intakes (g/d), sources (g/d) and the contribution of F&V to the weight of the total diet (%) were estimated, split by age. All children consumed F&V. Intakes of total fruits, in particular fruit juice, increased with age. The contribution to total fruit intake was discrete fruits (47-56 % range across age), 100 % fruit juice, smoothies and pureés (32-45 %) as well as fruits in composite dishes (7-13 %). Total vegetable intake comprised of discrete vegetables (48-62 % range across age) and vegetables in composite dishes (38-52 %). F&V contributed on average 20 % (15 % fruit; 5 % vegetables) to the weight of the total diet and was <10 % in sixty-one children (12 %). F&V contributed 50 % of vitamin C, 53 % of carotene, 34 % of dietary fibre and 42 % of non-milk sugar intakes from the total diet. F&V are important components of the diet of Irish pre-school children; however, some aspects of F&V intake patterns could be improved in this age group.


Safety Outcomes After Percutaneous Transcatheter Closure of Patent Foramen Ovale.
We sought to evaluate the real-world rate of safety outcomes after patent foramen ovale (PFO) closure in patients with ischemic stroke or transient ischemic attack (TIA). We performed a retrospective cohort study using administrative claims data on all hospitalizations from 2005 to 2013 in New York, California, and Florida. Using International Classification of Diseases, Ninth Revision, Clinical Modification codes, we identified patients who underwent percutaneous transcatheter PFO closure within 1 year of ischemic stroke or TIA. Our outcome was an adverse event occurring during the hospitalization for PFO closure, defined as in prior studies as atrial fibrillation or flutter, cardiac tamponade, pneumothorax, hemothorax, a vascular access complication, or death. Crude rates were reported with exact confidence intervals. We identified 1887 patients who underwent PFO closure after ischemic stroke or TIA. The rate of any adverse outcome during the hospitalization for PFO closure was 7.0% (95% confidence interval [CI], 5.9%-8.2%). Rates of adverse outcomes varied by age and type of preceding cerebrovascular event. In patients >60 years of age, the rate of adverse outcomes was 10.9% (95% CI, 8.6%-13.6%) versus 4.9% (95% CI, 3.8%-6.3%) in patients ≤60 years of age. The rate of adverse outcomes was 9.9% (95% CI, 7.3%-12.5%) in patients with preceding ischemic stroke versus 5.9% (95% CI, 4.7%-7.1%) after TIA. Approximately 1 in 14 patients who underwent percutaneous transcatheter PFO closure after ischemic stroke or TIA experienced a serious periprocedural adverse outcome or death. The risk of adverse outcomes was highest in older patients and in those with preceding ischemic stroke.


Bearing the brunt: co-workers' experiences of work reintegration processes.
Work disability research has found co-worker support to be a significant but under-recognised aspect of work reintegration (WR) processes. Although co-workers work alongside returning workers, their practical contribution to WR success or failure is often invisible to others. This study aimed to gain further insight into the role and contribution of co-workers in WR interventions. An exploratory qualitative pilot study was conducted in Toronto, Canada in 2011. Three focus groups were conducted with 13 co-workers, recruited for their direct experience of 'working alongside' a returning worker. An iterative data gathering and analysis process occurred. Themes were generated from categories in open-ended interview questions and new issues arising from the data. The findings detail co-workers' practical experiences of WR processes and their reflections on social and work conditions that impacted their participation. Co-workers' capacity to support returning workers was related to the quality of the WR arrangements, the relationship with the returning worker, work culture, and the duration of the required support. Workplace privacy and confidentiality requirements were identified as a key challenge for co-worker participation. The effects on co-workers of WR processes ranged from the opportunity to learn new skills to disillusionment and withdrawal from the workplace. In worst case scenarios, 'ripple effects' including emotional distress, physical injury and termination of co-workers' employment had occurred. Co-workers are not a neutral party in WR procedures. Formalizing the co-worker role to include communication, consideration and recognition might improve co-workers' WR experiences.


Chemical roots of biological evolution: the origins of life as a process of development of autonomous functional systems.
In recent years, an extension of the Darwinian framework is being considered for the study of prebiotic chemical evolution, shifting the attention from homogeneous populations of naked molecular species to populations of heterogeneous, compartmentalized and functionally integrated assemblies of molecules. Several implications of this shift of perspective are analysed in this critical review, both in terms of the individual units, which require an adequate characterization as self-maintaining systems with an internal organization, and also in relation to their collective and long-term evolutionary dynamics, based on competition, collaboration and selection processes among those complex individuals. On these lines, a concrete proposal for the set of molecular control mechanisms that must be coupled to bring about autonomous functional systems, at the interface between chemistry and biology, is provided.


Enhanced moisture stability of cesium lead iodide perovskite solar cells - a first-principles molecular dynamics study.
An understanding of the interaction of water with perovskite is crucial in improving the structural stability of the perovskite. Hence, in this study, the structural and electronic properties of the γ-CsPbI3(220) perovskite surface upon the adsorption of water molecules have been investigated based on density functional theory calculations. Also, we perform first-principles ab initio molecular dynamics simulations (AIMD) to explore the structural stability of the γ-CsPbI3(220) perovskite surface in the presence of water molecules, and the results are compared with the conventional cubic CH3NH3PbI3(100) perovskite surface. The water molecules show stronger interactions with the (220) surface of γ-CsPbI3 than the (100) surface of CH3NH3PbI3. However, AIMD results demonstrate that the former is much more stable, and no trace of surface degradation was observed upon the adsorption of water molecules.


Polymers with embedded chemical indicators as an artificial olfactory mucosa.
Physiological investigations suggest that the olfactory mucosa probably plays an ancillary role in the recognition of odours introducing a sort of chromatographic separation that, together with the zonal distribution of olfactory receptors, gives place to selective spatio-temporal response patterns. It has been recently suggested that this behaviour may be simulated by chemical sensors embedded in continuous polymer layers. In this paper, in analogy to the biology of olfaction, a simple and compact platform able to separate and detect gases and vapours on the basis of their diffusion properties is proposed. In such a system, broadly selective colour indicators, such as metalloporphyrins, are embedded in continuous layers of polymers with different sorption properties. The exposure to various alcohols and amines shows that the porphyrins are mainly responsible for the recognition of the molecular family, while the occurring spatio-temporal signal patterns make possible the identification of the individual chemical species.


Super-resolution microscopy of mitochondria.
Mitochondria, the powerhouses of the cell, are essential organelles in eukaryotic cells. With their complex inner architecture featuring a smooth outer and a highly convoluted inner membrane, they are challenging objects for microscopy. The diameter of mitochondria is generally close to the resolution limit of conventional light microscopy, rendering diffraction-unlimited super-resolution light microscopy (nanoscopy) for imaging submitochondrial protein distributions often mandatory. In this review, we discuss what can be expected when imaging mitochondria with conventional diffraction-limited and diffraction-unlimited microscopy. We provide an overview on recent studies using super-resolution microscopy to investigate mitochondria and discuss further developments and challenges in mitochondrial biology that might by addressed with these technologies in the future.


Skin Microcirculatory Changes in Relation to Arteriovenous Fistula Maturation.
Maturation of arteriovenous fistula (AVF) involves complex vascular remodeling. In this study, we evaluated the changes of skin microvascular perfusion over the extremity with AVF maturation using the laser Doppler fluximetry (LDF). A total of 45 patients with chronic kidney disease, Stages IV-V, were included; they had undergone AVF creation from July 2014 to June 2016 at our institute. The measurement of skin microvascular perfusion was accomplished proximal and distal to the fistula anastomosis site: pre- and post-operative day 1, week 2, week 6, and week 12. Thirty-two patients with mean age of 55.6 had achieved AVF maturation. There were 40.6% radial-based and 59.4% brachial-based AVF. There was a 32.8% reduction of mean skin perfusion distal to the fistula by day 1 compared to the baseline perfusion; however, perfusion increased 47% by week 2 compared to day 1 and no dramatic change was subsequently noted. There was an increase of mean skin perfusion, proximal to fistula anastomosis, over 12 weeks with 35.8% at day 1 from the baseline. However, the changes of the mean skin perfusion were not statistically significant. There was no significant relation of skin perfusion changes with the type of fistula, diabetes mellitus, hypertension, and hyperlipidemia. LDF successfully detected the subclinical change of skin microvascular perfusion in relation to AVF creation. Reduction of skin perfusion distal to the fistula suggests that in patients with existing perfusion inadequacy of extremities, they may experience ischemic symptoms as early as day 1 postoperation, and require close monitoring for distal limb ischemic-related complications.


Trajectories and associations of symptoms of mental health and well-being with insulin resistance and metabolic health in women with gestational diabetes.
Gestational diabetes mellitus (GDM) is characterized by increased insulin resistance and carries perinatal and long-term risks for the mother and her offspring. There is a link between perinatal depression or anxiety and GDM. Mental health problems are associated with higher insulin resistance and could explain the underlying association between GDM and depression or anxiety symptoms. We investigated the trajectories and associations between symptoms of mental health and well-being with insulin resistance and metabolic health in women with GDM. This study included the control group (n = 106) of a randomized controlled trial in women with GDM that were followed-up during pregnancy and up to 1-year postpartum. We measured symptoms of mental health (Edinburgh Postnatal Depression Scale (EPDS), Anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A), well-being (The World Health Organization Well-Being Index (WHO-5)) and metabolic health, including insulin resistance variables (HOMA-insulin resistance (IR) and Matsuda Index of insulin sensitivity) as well as weight during pregnancy and in the postpartum. Participants' pre pregnancy weight and BMI were 69.7 kg ± 16.1 and 25.9 kg/m2 ± 5.5 respectively. HOMA-IR was higher during pregnancy compared to 6-8 weeks postpartum and increased between 6-8 weeks and 1-year postpartum (all p < 0.05). Matsuda index decreased between 6-8 weeks and 1-year postpartum (p < 0.001). EPDS scores decreased between pregnancy and both 6-8 weeks and 1-year postpartum (all p < 0.05). HADS-A scores did not change between pregnancy and the postpartum. WHO-5 scores improved significantly from pregnancy and both 6-8 weeks and 1-year postpartum (p < 0.001). Correlation coefficients within outcome at the three different time points were high for metabolic measures and ranged between 0.94 and 0.96 for weight, from 0.77 to 0.89 for HOMA-IR and 0.64 for the Matsuda index (all p < 0.001). Mental health and well-being variables were moderately correlated in all three time points including r = 0.36-0.55 for the EPDS (p < 0.001), r = 0.58 for HADS (p < 0.001), and r = 0.43-0.52 for the WHO-5 (p < 0.01). After adjustment for age and pre-pregnancy BMI, Matsuda index was negatively associated with EPDS scores and positively associated to WHO-5 scores at 6-8 weeks postpartum. No other association between insulin resistance and mental health or well-being outcomes were found. While insulin resistance fluctuated with values being lowest in the early postpartum and increasing thereafter, both depression and well-being scores decreased between pregnancy and the postpartum and did not change in the postpartum period. Intraindividual variability was larger for mental health and well-being than for metabolic health outcomes at different time points, indicating a higher plasticity for mental health and well-being outcomes that could be acted upon. We found only few associations between mental health and well-being and metabolic health outcomes.


NMNAT3 is protective against the effects of neonatal cerebral hypoxia-ischemia.
To determine whether the NAD+ biosynthetic protein, nicotinamide mononucleotide adenylyltransferase-3 (NMNAT3), is a neuroprotective inducible enzyme capable of decreasing cerebral injury after neonatal hypoxia-ischemia (H-I) and reducing glutamate receptor-mediated excitotoxic neurodegeneration of immature neurons. Using NMNAT3-overexpressing mice we investigated whether increases in brain NMNAT3 reduced cerebral tissue loss following H-I. We then employed biochemical methods from injured neonatal brains to examine the inducibility of NMNAT3 and the mechanism of NMNAT3-dependent neuroprotection. Using AAV8-mediated vectors for in vitro neuronal NMNAT3 knockdown, we then examine the endogenous role of this protein on immature neuronal survival prior and following NMDA receptor-mediated excitotoxicity. NMNAT3 mRNA and protein levels increased after neonatal H-I. In addition, NMNAT3 overexpression decreased cortical and hippocampal tissue loss 7 days following injury. We further show that the NMNAT3 neuroprotective mechanism involves a decrease in calpastatin degradation, and a decrease in caspase-3 activity and calpain-mediated cleavage. Conversely, NMNAT3 knockdown of cortical and hippocampal neurons in vitro caused neuronal degeneration and increased excitotoxic cell death. The neurodegenerative effects of NMNAT3 knockdown were counteracted by exogenous upregulation of NMNAT3. Our observations provide new insights into the neuroprotective mechanisms of NMNATs in the injured developing brain, adding NMNAT3 as an important neuroprotective enzyme in neonatal H-I via inhibition of apoptotic and necrotic neurodegeneration. Interestingly, we find that endogenous NMNAT3 is an inducible protein important for maintaining the survival of immature neurons. Future studies aimed at uncovering the mechanisms of NMNAT3 upregulation and neuroprotection may offer new therapies against the effects of hypoxic-ischemic encephalopathy.


Urothelial carcinoma of the upper urinary tract: inverted growth pattern is predictive of microsatellite instability.
Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of hereditary nonpolyposis colorectal cancer syndrome (HNPCC), a disorder characterized by mutation or inactivation of a number of DNA mismatch repair genes and detectable as microsatellite instability (MSI). Some urothelial carcinomas display areas of endophytic, or inverted, growth. In this study, urothelial cancers of the upper urinary tract (n = 132) from patients treated at 2 tertiary care centers were studied to identify an association between growth pattern and MSI. Thirty-five neoplasms were microsatellite unstable (26.5%), and MSI was more frequent in papillary lesions than in sessile urothelial cancers (P = .033). The amount of inverted growth was estimated as a percentage of the total tumor. The interobserver and intraobserver concordance in recognizing inverted growth was good, and 65.7% of microsatellite-unstable tumors exhibited at least 20% of an inverted growth component, compared with only 17.5% of microsatellite-stable tumors (P < .0001). In this series, inverted growth predicted MSI with a sensitivity and specificity of .82. Inverted growth in urothelial carcinomas of the upper urinary tract may serve as a marker lesion for MSI and may help identify patients who should be offered testing for HNPCC.


Opportunistic health promotion among overweight children.
To explore children's nurses' attitudes to providing health promotion advice to overweight children and their families during hospital admissions. Individual semi-structured interviews were conducted in a private room in the ward setting. Interviews were recorded and transcribed, and thematic analysis of the transcripts was undertaken. The six themes generated from responses were: responsibility for health promotion; sensitivity of the topic; long-term benefits; parents--a barrier; need for training; and need for institutional support. Further research with acute care children's nurses in the UK is required to validate the study findings. More work is also needed to explore the ethics of health promotion in the acute care setting.


[Argas reflexus, the pigeon tick. A case report].
The importance of this case, an episode of anaphylactic reaction for Argas reflexus, the pigeon tick, is due to the ever-increasing presence in urban areas of the pigeon. The knowledge of existence of this parasite and of his biological characteristics is essential to make a correct and timely diagnosis, to avoid the frequent relapse of symptoms, to take the necessary therapeutical and preventive measures.


BarMap: RNA folding on dynamic energy landscapes.
Dynamical changes of RNA secondary structures play an important role in the function of many regulatory RNAs. Such kinetic effects, especially in time-variable and externally triggered systems, are usually investigated by means of extensive and expensive simulations of large sets of individual folding trajectories. Here we describe the theoretical foundations of a generic approach that not only allows the direct computation of approximate population densities but also reduces the efforts required to analyze the folding energy landscapes to a one-time preprocessing step. The basic idea is to consider the kinetics on individual landscapes and to model external triggers and environmental changes as small but discrete changes in the landscapes. A "barmap" links macrostates of temporally adjacent landscapes and defines the transfer of population densities from one "snapshot" to the next. Implemented in the BarMap software, this approach makes it feasible to study folding processes at the level of basins, saddle points, and barriers for many nonstationary scenarios, including temperature changes, cotranscriptional folding, refolding in consequence to degradation, and mechanically constrained kinetics, as in the case of the translocation of a polymer through a pore.


Ultrastretchable Analog/Digital Signal Transmission Line with Carbon Nanotube Sheets.
Stretchable conductors can be used in various applications depending on their own characteristics. Here, we demonstrate simple and robust elastomeric conductors that are optimized for stretchable electrical signal transmission line. They can withstand strains up to 600% without any substantial change in their resistance (≤10% as is and ≤1% with passivation), and exhibit suppressed charge fluctuations in the medium. The inherent elasticity of a polymeric rubber and the high conductivity of flexible, highly oriented carbon nanotube sheets were combined synergistically, without losing both properties. The nanoscopic strong adhesion between aligned carbon nanotube arrays and strained elastomeric polymers induces conductive wavy folds with microscopic bending of radii on the scale of a few micrometers. Such features enable practical applications such as in elastomeric length-changeable electrical digital and analog signal transmission lines at above MHz frequencies. In addition to reporting basic direct current, alternating current, and noise characterizations of the elastomeric conductors, various examples as a stretchable signal transmission line up to 600% strains are presented by confirming the capability of transmitting audio and video signals, as well as low-frequency medical signals without information distortion.


Homeotic proteins participate in the function of human-DNA replication origins.
Recent evidence points to homeotic proteins as actors in the crosstalk between development and DNA replication. The present work demonstrates that HOXC13, previously identified as a new member of human DNA replicative complexes, is a stable component of early replicating chromatin in living cells: it displays a slow nuclear dynamics due to its anchoring to the DNA minor groove via the arginine-5 residue of the homeodomain. HOXC13 binds in vivo to the lamin B2 origin in a cell-cycle-dependent manner consistent with origin function; the interaction maps with nucleotide precision within the replicative complex. HOXC13 displays in vitro affinity for other replicative complex proteins; it interacts also in vivo with the same proteins in a cell-cycle-dependent fashion. Chromatin-structure modifying treatments, disturbing origin function, reduce also HOXC13-origin interaction. The described interactions are not restricted to a single origin nor to a single homeotic protein (also HOXC10 binds the lamin B2 origin in vivo). Thus, HOX complexes probably contribute in a general, structure-dependent manner, to origin identification and assembly of replicative complexes thereon, in presence of specific chromatin configurations.


The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials.
A cornerstone of conventional dietary advice is the recommendation to replace saturated fatty acids (SFA) with mostly n-6 polyunsaturated fatty acids (PUFA) to reduce the risk of coronary heart disease (CHD). Many clinical trials aimed to test this advice and have had their results pooled in several meta-analyses. However, earlier meta-analyses did not sufficiently account for major confounding variables that were present in some of those trials. Therefore, the aim of the study was to account for the major confounding variables in the diet heart trials, and emphasise the results from those trials that most accurately test the effect of replacing SFA with mostly n-6 PUFA. Clinical trials were identified from earlier meta-analyses. Relevant trials were categorised as 'adequately controlled' or 'inadequately controlled' depending on whether there were substantial dietary or non-dietary differences between the experimental and control groups that were not related to SFA or mostly n-6 PUFA intake, then were subject to different subgroup analyses. When pooling results from only the adequately controlled trials there was no effect for major CHD events (RR = 1.06, CI = 0.86-1.31), total CHD events (RR = 1.02, CI = 0.84-1.23), CHD mortality (RR = 1.13, CI = 0.91-1.40) and total mortality (RR = 1.07, CI = 0.90-1.26). Whereas, the pooled results from all trials, including the inadequately controlled trials, suggested that replacing SFA with mostly n-6 PUFA would significantly reduce the risk of total CHD events (RR = 0.80, CI = 0.65-0.98, P = 0.03), but not major CHD events (RR = 0.87, CI = 0.70-1.07), CHD mortality (RR = 0.90, CI = 0.70-1.17) and total mortality (RR = 1.00, CI = 0.90-1.10). Available evidence from adequately controlled randomised controlled trials suggest replacing SFA with mostly n-6 PUFA is unlikely to reduce CHD events, CHD mortality or total mortality. The suggestion of benefits reported in earlier meta-analyses is due to the inclusion of inadequately controlled trials. These findings have implications for current dietary recommendations.


Eighteen years follow-up study of the clinical manifestations and progression of Dupuytren's disease.
To evaluate the clinical manifestations and progression of Dupuytren's disease. In 1981-82 a total of 1297 men were examined for Dupuytren's disease, and of these 19.2% had the disease. In 1999 those with signs of the disease in 1981-82 were invited for a follow-up study. As controls symptom free individuals from the study in 1981-82 were invited. A total of 53 individuals from the control group had developed Dupuytren's disease in 1999. Men with palmar nodules/fibrous cord in 1981-82 were more likely to develop contracted fingers than those without Dupuytren's disease. Patients with young age at disease onset more often required operations than those with later onset. Of the men who had been operated 70% still had finger contractures in 1999. The incidence of Dupuytren's disease is high in elderly men. Dupuytren's disease is progressive in nature and most operated patients have recurrent finger contractures.


Isolated posterior fibular malleolar fracture. Case report and literature review.
The authors describe a case involving an isolated posterior fibular malleolar fracture in an 80-year-old female, which was identified on multiple lateral radiographs of the involved ankle and confirmed by computed tomography. The patient was treated conservatively with 10 weeks of walking cast immobilization, resulting in poorly acceptable radiographic and clinical results. The authors review the anatomy of the area of involvement. A literature review, the clinical case study, and a discussion of the difficulty in evaluation of these types of fibular fractures are presented along with a protocol for the diagnosis and treatment of these fractures.


Endoscopy during a missile attack: a military dilemma for civilians.
In modern warfare, civilian populations may find themselves under immediate personal danger with very little warning. While there are ways to minimize this danger, there is a paucity of literature discussing this modern dilemma, and it is therefore important to try to address these situations in advance both logistically and ethically. Discussion of this case includes several relevant ethical principles.


Civic Ecology Uplifts Low-Income Communities, Improves Ecosystem Services and Well-Being, and Strengthens Social Cohesion.
Ecosystem services enhance well-being and the livelihoods of disadvantaged communities. Civic ecology can enhance social-ecological systems; however, their contributions to ecosystem services are rarely measured. We analysed the outcomes of civic ecology interventions undertaken in Durban, South Africa, as part of the Wise Wayz Water Care programme (the case study). Using mixed methods (household and beneficiary (community members implementing interventions) surveys, interviews, field observations, and workshops), we identified ecosystem service use and values, as well as the benefits of six interventions (solid waste management and removal from aquatic and terrestrial areas, recycling, invasive alien plant control, river water quality monitoring, vegetable production, and community engagement). Ecosystem services were widely used for agriculture, subsistence, and cultural uses. River water was used for crop irrigation, livestock, and recreation. Respondents noted numerous improvements to natural habitats: decrease in invasive alien plants, less pollution, improved condition of wetlands, and increased production of diverse vegetables. Improved habitats were linked to enhanced ecosystem services: clean water, agricultural production, harvesting of wood, and increased cultural and spiritual activities. Key social benefits were increased social cohesion, education, and new business opportunities. We highlight that local communities can leverage natural capital for well-being and encourage policy support of civic ecology initiatives.


Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression.
Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response, e.g. through a direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones resistant to the antiproliferative effects of IFNs may contribute to immunoediting of tumours, leading to more aggressive disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that six weeks exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines, most prominently in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours. In both, long-term IFN selection and in dedifferentiated tumour cell lines, we found IFNAR2 expression to be substantially reduced, suggesting the receptor complex to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.


Recommendations for Laboratory Containment and Management of Gene Drive Systems in Arthropods.
Versatile molecular tools for creating driving transgenes and other invasive genetic factors present regulatory, ethical, and environmental challenges that should be addressed to ensure their safe use. In this article, we discuss driving transgenes and invasive genetic factors that can potentially spread after their introduction into a small proportion of individuals in a population. The potential of invasive genetic factors to increase their number in natural populations presents challenges that require additional safety measures not provided by previous recommendations regarding accidental release of arthropods. In addition to providing physical containment, invasive genetic factors require greater attention to strain management, including their distribution and identity confirmation. In this study, we focus on insects containing such factors with recommendations for investigators who are creating them, institutional biosafety committees charged with ensuring safety, funding agencies providing support, those managing insectaries handling these materials who are responsible for containment, and other persons who will be receiving insects-transgenic or not-from these facilities. We give specific examples of efforts to modify mosquitoes for mosquito-borne disease control, but similar considerations are relevant to other arthropods that are important to human health, the environment, and agriculture.


Lung function decline in cystic fibrosis patients and timing for lung transplantation referral.
To determine risk factors associated with an accelerated decline in lung function in cystic fibrosis (CF), and whether longitudinal changes in FEV(1) would be a better predictor of the need for referral for lung transplantation than any single value for FEV(1.) The rate of decline in pulmonary function was determined by standard linear regression from each patient's calendar year's best percentage of predicted FEV(1) (%FEV(1)) over at least 4 years, and patients were classified into three cohorts based on their rate of decline. Differences between groups in age, weight-for-age z score, gender, genotype, pancreatic status, diabetes, and the presence of various lung microbial isolates were analyzed. A subset of 30 patients referred for lung transplantation were further analyzed, and a prediction model for lung transplantation referral was created using the patient's rate of decline in lung function, the mean waiting time for donor organs, and the average level of lung function of patients prior to lung transplantation. One hundred fifty-three patients with CF followed up at the Washington University Adult Cystic Fibrosis Center. Younger age, malnutrition, and concurrent infection with both Pseudomonas aeruginosa and Staphylococcus aureus were significant (p < 0.05) risk factors for rapidly declining lung function. Among patients with rapidly declining lung function, referral for lung transplantation would have occurred 8.4 months earlier than actual referral age (p < 0.05) if the prediction model had been used, possibly resulting in additional patient salvage in several cases. Rate of decline in lung function should be routinely evaluated in patients with CF, and a prediction model utilizing the rate of decline in %FEV(1), and the median regional waiting period for donor lungs for patients with CF may assist in the timing of referral for lung transplantation and more rapidly declining lung function.


Assessment of inactivating stop codon mutations in forty Saccharomyces cerevisiae strains: implications for [PSI] prion- mediated phenotypes.
The yeast prion [PSI(+)] has been implicated in the generation of novel phenotypes by a mechanism involving a reduction in translation fidelity causing readthrough of naturally occurring stop codons. Some [PSI(+)] associated phenotypes may also be generated due to readthrough of inactivating stop codon mutations (ISCMs). Using next generation sequencing we have sequenced the genomes of two Saccharomyces cerevisiae strains that are commonly used for the study of the yeast [PSI(+)] prion. We have identified approximately 26,000 and 6,500 single nucleotide polymorphisms (SNPs) in strains 74-D694 and G600 respectively, compared to reference strain S288C. In addition to SNPs that produce non-synonymous amino acid changes we have also identified a number of SNPs that cause potential ISCMs in these strains, one of which we show is associated with a [PSI(+)]-dependent stress resistance phenotype in strain G600. We identified twenty-two potential ISCMs in strain 74-D694, present in genes involved in a variety of cellular processes including nitrogen metabolism, signal transduction and oxidative stress response. The presence of ISCMs in a subset of these genes provides possible explanations for previously identified [PSI(+)]-associated phenotypes in this strain. A comparison of ISCMs in strains G600 and 74-D694 with S. cerevisiae strains sequenced as part of the Saccharomyces Genome Resequencing Project (SGRP) shows much variation in the generation of strain-specific ISCMs and suggests this process is possible under complex genetic control. Additionally we have identified a major difference in the abilities of strains G600 and 74-D694 to grow at elevated temperatures. However, this difference appears unrelated to novel SNPs identified in strain 74-D694 present in proteins involved in the heat shock response, but may be attributed to other SNP differences in genes previously identified as playing a role in high temperature growth.


A novel type of secondary modification of two CCGG residues in the human gamma delta beta-globin gene locus.
The majority of the CCGG residues in the human gamma delta beta-globin gene locus are cleaved by Msp I, irrespective of the tissue of origin of the DNA, although these sites show differential sensitivity to Hap II as a result of methylation of the internal C residue of the cleavage site (ref 6). Two CCGG sites, at homologous positions 54 nucleotides in front of the G gamma- and A gamma-globin genes respectively, are not cleaved by Msp I in DNA from several human tissues, although DNA from placenta, foetal liver and from some established cell lines is cut at these sites. We have cloned the A gamma-globin gene from foetal blood DNA where the relevant CCGG site is not cut by Msp I. After cloning, the CCGG site can be cut by Msp I. The failure to cleave at this CCGG site in foetal blood DNA therefore, is not the result of a change in the DNA sequence of the cleavage site. Most likely the external C residue and perhaps both C residues are blocked by methylation at these two specific sites.


Types of Psychiatric Beds and Mental Health Services in 16 Latin American Countries, 1990-2020.
Latin America has undergone major changes in psychiatric services over the past three decades. The authors aimed to assess the availability of service data and changes in psychiatric services in this region during the 1990-2020 period. The authors formed a research network to collect data on psychiatric service indicators gathered between 1990 and 2020 from national registries in Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Panama, Paraguay, Peru, and Uruguay. Indicators included psychiatric beds in psychiatric and general hospitals overall, for children and adolescents, and for forensic populations; residential beds for substance use treatment; treatment slots in residential facilities and day hospitals; and outpatient facilities. Data availability varied among countries, service indicators, and time points. The median prevalence of psychiatric beds decreased in psychiatric hospitals from 5.1 to 3.0 per 100,000 people (-42%) and in general hospitals from 1.0 to 0.8 (-24%). The median prevalence estimates of specialized psychiatric beds for children and adolescents (0.18) and for forensic populations (0.04) remained unchanged. Increases in prevalence were observed for residential beds for substance use treatment (from 0.40 to 0.57, 43% increase), available treatment slots in residential facilities (0.67 to 0.79, 17%), treatment slots in day hospitals (0.41 to 0.54, 32%), and outpatient facilities (0.39 to 0.93, 138%). The findings indicate that treatment capacity shifted from inpatient to outpatient and community care. Most countries had a bed shortage for acute psychiatric care, especially for children and adolescents and forensic patients. More comprehensive and standardized mental health service registries are needed.


Rostock Glare Perimeter: a distinctive method for quantification of glare.
Disability glare induced by headlights of oncoming cars has been associated with reduced quality of vision. This study aimed at developing the Rostock Glare Perimeter to quantify dysphotopsia effects under simulated realistic conditions. Sixty phakic subjects of different ages were dazzled by a bright light source centered at a projection screen 3.30 m away from the subject's eye. Using a projected marker moving outward from the screen center with angular steps of 0.25° in 12 directions, the area where the subject cannot distinguish the white spot from the glare effects of the light source was determined. A corresponding mean radius in a field angle relative to the subject's eye was defined as a measure for disability glare. Monocular and binocular measurements were performed, and a separate repeatability and reproducibility study was executed to determine the precision of the Rostock Glare Perimeter. A significant mean positive correlation of disability glare with age (r = 0.534, p < 0.001) was found. The disability glare ranged from 0.33° to 1.8°, and a strong (r = 0.93, p < 0.0002) binocular summation effect was found. The repeatability and reproducibility limit of the Rostock Glare Perimeter method is 0.14° for 95% confidence interval. The Rostock Glare Perimeter method is sensitive to detect age-related disability glare differences and to find binocular summation for disability glare in a healthy population for small field angles with high angular resolution. These findings suggest that the Rostock Glare Perimeter method is a helpful device to quantify symptoms of glare.


Task positive and default mode networks during a parametric working memory task in obstructive sleep apnea patients and healthy controls.
Functional magnetic resonance imaging (fMRI) studies enable the investigation of neural correlates underlying behavioral performance. We investigate the working memory (WM) function of patients with untreated obstructive sleep apnea (OSA) from the view point of task positive and default mode networks (TPN and DMN, respectively) and compare the results to those of healthy controls (HC). A parametric fMRI experiment with 4 levels of visuospatial N-back task was used to investigate the pattern of cortical activation in 17 men with untreated moderate or severe OSA and 7 age-matched HC. Categorical and parametrical analysis of the data was performed. Multiple regression analysis of fMRI data of OSA patients was performed with AHI, nocturnal desaturation time, and BMI as covariates. OSA patients demonstrate compensatory spatial recruitment of the TPN (maximal at 3-back) and of the DMN (maximal at 2-back). HC had a different patten of spatial recruitment and deactivation of the DMN at the maximal load of task (3-back). Nocturnal desaturation had significant positive correlation with BOLD signal in bilateral frontal, temporal, and occipital regions, and negative correlations in bilateral frontal and left parietal regions; whereas BMI showed only negative correlations with BOLD signal, predominantly in the PFC. AHI was positively correlated with BOLD signal in bilateral frontal regions. Both TPN and DMN are affected in OSA patients, with nocturnal desaturation affecting both networks; whereas BMI appears to be the major negative factor influencing the TPN and has a significant negative correlation with behavioral performance.


Quantitative analysis of long-term survival and neuritogenesis in vitro: cochleovestibular ganglion of the chick embryo in BDNF, NT-3, NT-4/5, and insulin.
The dynamics of survival and growth were examined for cochleovestibular ganglion (CVG) cells maintained in long-term cultures. CVG cells were explanted from chick embryos after 90 h of incubation into a defined-medium containing BDNF, NT-3, or NT-4/5 and an insulin, transferrin, selenium, and progesterone supplement. Explant survival and neuritogenesis was measured for 23 to 24 days in vitro. All three neurotrophins prolonged CVG survival in a dose-dependent manner although insulin acted as a cofactor. In 0.872 microM insulin-containing medium the ED50 for BDNF and NT-3 was 100 pg/ml, whereas the ED50 for NT-4/5 was 600-1200 pg/ml. However, at later ages in vitro, survival decreased with concentrations of BDNF greater than 2 ng/ml. In insulin-free medium, concentrations of 5-200 ng/ml of BDNF or 30-200 ng/ml of NT-4/5 maintained the survival of explants at a rate that was equivalent to or less than the survival rate of cultures treated with insulin but not with neurotrophin. In contrast, NT-3-treated explants in insulin-free medium did not survive the duration of the experiment. Dose-dependent effects of BDNF and NT-3 on explant neuritogenesis were reflected as an initial delay in outgrowth, whereas NT-4/5 had no effect. Insulin regulation of neuritogenesis was suggested when outgrowth decreased in the presence of an antibody to the insulin receptor. These data suggest that while all three of these neurotrophins protect the CVG from death the long-term consequences of cofactors and certain dose levels should be considered when treating CVG cells in vivo.


Application of biomaterials to in vitro pluripotent stem cell disease modeling of the skeletal system.
Disease-specific pluripotent stem cells can be derived through genetic manipulation of embryonic stem cells or by reprogramming somatic cells (induced pluripotent stem cells). These cells are a valuable tool to study human diseases in vitro in order to dissect their pathomechanisms and develop novel therapeutics. Although pluripotent stem cell-derived models have successfully recapitulated the abnormalities of some skeletal diseases in vitro, this field is still at its early stages, and it could greatly benefit from the direct application of biomaterial research. Biomaterial-based systems may be utilized to enhance the differentiation processes of pluripotent stem cells in order to create more homogeneous and physiologically relevant in vitro disease models. Moreover, inducing the disease phenotype may be facilitated by the guidance of biomaterials. This review presents a comprehensive summary of existing biomaterial applications in human disease modeling and their potential on skeletal disease models. By utilizing disease-specific pluripotent stem cells, current biomaterial-based systems for in vitro models could be extrapolated to study skeletal diseases in a petri dish.


Characterising food environment exposure at home, at work, and along commuting journeys using data on adults in the UK.
Socio-ecological models of behaviour suggest that dietary behaviours are potentially shaped by exposure to the food environment ('foodscape'). Research on associations between the foodscape and diet and health has largely focussed on foodscapes around the home, despite recognition that non-home environments are likely to be important in a more complete assessment of foodscape exposure. This paper characterises and describes foodscape exposure of different types, at home, at work, and along commuting routes for a sample of working adults in Cambridgeshire, UK. Home and work locations, and transport habits for 2,696 adults aged 29-60 were drawn from the Fenland Study, UK. Food outlet locations were obtained from local councils and classified by type - we focus on convenience stores, restaurants, supermarkets and takeaway food outlets. Density of and proximity to food outlets was characterised at home and work. Commuting routes were modelled based on the shortest street network distance between home and work, with exposure (counts of food outlets) that accounted for travel mode and frequency. We describe these three domains of food environment exposure using descriptive and inferential statistics. For all types of food outlet, we found very different foodscapes around homes and workplaces (with overall outlet exposure at work 125% higher), as well as a potentially substantial exposure contribution from commuting routes. On average, work and commuting environments each contributed to foodscape exposure at least equally to residential neighbourhoods, which only accounted for roughly 30% of total exposure. Furthermore, for participants with highest overall exposure to takeaway food outlets, workplaces accounted for most of the exposure. Levels of relative exposure between home, work and commuting environments were poorly correlated. Relying solely on residential neighbourhood characterisation greatly underestimated total foodscape exposure in this sample, with levels of home exposure unrelated to levels of away from home exposure. Such mis-estimation is likely to be expressed in analyses as attenuated parameter estimates, suggesting a minimal 'environmental' contribution to outcomes of interest. Future work should aim to assess exposure more completely through characterising environments beyond the residential neighbourhood, where behaviours related to food consumption are likely to occur.


A(2A) receptor dependent and A(2A) receptor independent effects of extracellular adenosine on murine thymocytes in conditions of adenosine deaminase deficiency.
Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) and is accompanied by T-cell depletion and accumulation of both intracellular and extracellular adenosine (extAdo) and deoxyadenosine. To better understand the causes of T-cell depletion in vivo and to discriminate between extracellular and intracellular effects of exogenously added adenosine in vitro, we investigated mechanisms of 2 different effects of adenosine on murine thymocytes. These effects of adenosine include direct induction of apoptosis in about 6% to 15% thymocytes and inhibition of T-cell receptor (TCR)-induced activation of the majority of thymocytes with inhibited ADA. A(2A) adenosine receptors, but not A(2B), A(1), or A(3) receptors, are shown to be mostly responsible for extAdo-triggered signaling (cyclic adenosine monophosphate [cAMP] accumulation) in murine thymocytes and this prompted studies of the effects of extAdo on thymocytes from A(2A)R gene-deficient mice. It is found that direct apoptotic effects of extAdo on CD4(+)CD8(+) double positive (DP) thymocytes are completely accounted for by signaling through A(2A)R, with no contribution of intracellular lymphotoxicity or of compensating A(2B)Rs because only A(2A)R +/+, but not A(2A)R -/- thymocytes were susceptible to apoptotic effects of extAdo. Studies of the effects of cAMP-raising agents support observations of extAdo/A(2A)R/cAMP-triggered apoptosis in DP thymocytes. Unexpectedly, the extAdo strongly inhibited TCR-triggered activation of both A(2A)R +/+ and A(2A)R -/- thymocytes in the presence of ADA inhibitors. This was confirmed with thymocytes from ADA gene-deficient mice, suggesting the existence of A(2A)R-independent effects of extAdo on thymocytes. The presented data raises questions about the identity and functional role of A(2A)R-expressing thymocytes in T-cell differentiation and of the role of TCR-antagonizing effects of extAdo in conditions of ADA SCID. (Blood. 2000;95:3859-3867)


Software development for medical instrumentation.
Computer-assisted medical instrumentation has recently become more common. For accuracy and precision, the computer and interfacing circuit with the associated digital signal processing algorithm can be used for the evaluation of biological signal. The measurement system based on this structure has a very high degree of efficiency and flexibility because different algorithms can be used. In addition, the system can employ some newly developed software packages. This paper will submit a procedure for computer-assisted medical instrumentation, and also will show a specific application on blood flow.


Intervention Trials with the Mediterranean Diet in Cardiovascular Prevention: Understanding Potential Mechanisms through Metabolomic Profiling.
Large observational epidemiologic studies and randomized trials support the benefits of a Mediterranean dietary pattern on cardiovascular disease (CVD). Mechanisms postulated to mediate these benefits include the reduction of low-grade inflammation, increased adiponectin concentrations, decreased blood coagulation, enhanced endothelial function, lower oxidative stress, lower concentrations of oxidized LDL, and improved apolipoprotein profiles. However, the metabolic pathways through which the Mediterranean diet influences CVD risk remain largely unknown. Investigating specific mechanisms in the context of a large intervention trial with the use of high-throughput metabolomic profiling will provide more solid public health messages and may help to identify key molecular targets for more effective prevention and management of CVD. Although metabolomics is not without its limitations, the techniques allow for an assessment of thousands of metabolites, providing wide-ranging profiling of small molecules related to biological status. Specific candidate plasma metabolites that may be associated with CVD include branched-chain and aromatic amino acids; the glutamine-to-glutamate ratio; some short- to medium-chain acylcarnitines; gut flora metabolites (choline, betaine, and trimethylamine N-oxide); urea cycle metabolites (citrulline and ornithine); and specific lipid subclasses. In addition to targeted metabolites, the role of a large number of untargeted metabolites should also be assessed. Large intervention trials with the use of food patterns for the prevention of CVD provide an unparalleled opportunity to examine the effects of these interventions on plasma concentrations of specific metabolites and determine whether such changes mediate the benefits of the dietary interventions on CVD risk.


Investigating oral fluid and exhaled breath as alternative matrices for anti-doping testing: Analysis of 521 matched samples.
Current anti-doping testing is primarily conducted in urine and blood. Recently, due to confounding factors with urine and blood collections such as invasiveness, cost, and stringent shipping conditions, there has been a push for the use of alternative sample matrices to ameliorate these issues. Gaining support within the anti-doping field is the use of oral fluid, and more recently exhaled breath, as viable alternative or complementary matrices to traditional urine and blood for drug testing. Thus, we designed a first-in-field study with the purpose of investigating the utility of oral fluid and exhaled breath testing, and the preference of athlete participants, comparative to conventional anti-doping methods of urine testing. To accomplish this, 521 total matched samples, consisting of exhaled breath, oral fluid, and urine samples, were collected and analyzed, and the results compared across matrices. Participants in this study preferred the exhaled breath collection (rated 4.90 ± 0.34 out of 5, mean ± SD) over the oral fluid collection procedure (4.29 ± 0.85), and most preferred both over urine collections. Exhaled breath resulted in the shortest collection time (2.58 ± 1.00 min, mean ± SD), followed by urine (3.08 ± 1.50 min), and finally oral fluid (4.14 ± 1.94 min). Prohibited substances from the drug categories of stimulants, narcotics, cannabinoids, diuretics, glucocorticoids, beta-blockers, and others, were analyzed in this study for a comparison of testing efficacy. Of the total findings 49% were detectable in only urine, 38% in urine + oral fluid, and 9% in all three matrices. Of the unique findings 3% were detectable in only oral fluid, 1% in oral fluid + breath, and 0% of unique findings were present only in exhaled breath. The findings from this study provide a strong foundation for the future use of oral fluid and exhaled breath as viable alternative or complementary matrices for in-competition anti-doping testing.


Abnormal renal responses to calcium entry blockade in normotensive offspring of hypertensive parents.
In nine young normotensive subjects with no family history of hypertension and nine age-matched normotensive subjects with one parent with essential hypertension, effective renal plasma flow (p-aminohippuric acid clearance), glomerular filtration rate (inulin clearance), and excretion of sodium and exogenously administered lithium were measured for 90 minutes before and after administration of a single 20-mg oral dose of the calcium entry blocker nifedipine. Segmental tubular handling of fluid and sodium was estimated using lithium clearance as a marker of proximal tubular reabsorption. Nifedipine did not cause any change in subjects with no family history of hypertension, but in those with one hypertensive parent there was a marked increase in effective renal plasma flow (from 644 +/- 39 to 847 +/- 42 [SEM] ml/min x 1.73 m2; p less than 0.001) and a decrease in filtration fraction (from 17.6 +/- 1.0 to 12.6 +/- 0.4%; p less than 0.001), while the glomerular filtration rate was unchanged, thus suggesting a prevailing efferent vasodilation. Sodium excretion rate (p less than 0.02) and fractional sodium excretion (p less than 0.025) increased slightly but significantly in subjects with one hypertensive parent, but not in normotensive subjects with no family history of hypertension. Lithium clearance also rose (from 29.0 +/- 2.0 to 32.8 +/- 1.9 ml/min, p less than 0.001), and the derived value of fractional proximal reabsorption diminished (from 75.8 +/- 1.0 to 71.3 +/- 1.2%, p less than 0.001). Estimated distal delivery of sodium and absolute distal sodium reabsorption both increased significantly (p less than 0.005), while fractional distal sodium reabsorption was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)


[Pharmacologic and non-pharmacologic pain-therapy in neonatology: synopsis of the current data].
There is increasing knowledge about the negative consequences of early pain experiences on the acute and long-term outcome of preterm and term neonates. Despite of it, pain is common in neonatal intensive care. Pharmacologic and nonpharmacologic methods of pain therapy with variable analgesic efficacy exist. The aim of this article is to give a compendium of the actual strategies of pain therapies for invasive procedures, endotracheal suctioning, eye-examination and for mechanical ventilation of preterm and term neonates. An evaluation of benefits and drawbacks of the single pain alleviating measures will be done.


A novel in vitro wound biofilm model used to evaluate low-frequency ultrasonic-assisted wound debridement.
Bacterial biofilms remain difficult to treat. The biofilm mode of growth enables bacteria to survive antibiotic treatment and the inflammatory reaction. Low-frequency ultrasound has recently been shown to improve healing in a variety of settings. It is hypothesised that ultrasound disrupts the biofilm leaving bacteria more vulnerable to antiseptic or antibiotic treatment. The objective of this study is to develop a realistic model to elucidate the effect of ultrasound on biofilms. A novel in vitro wound biofilm model was developed. Biofilms of Staphylococcus aureus were casted in a semi-solid agar gel composed of either tryptic soy broth (TSB) or a wound simulating media (WSM; composed of Bolton broth with blood and plasma), to resemble the non-surface attached aggregates. The model was used to evaluate the antibiofilm effect of an ultrasonic-assisted wound debridement device (UAW) in the presence of saline irrigation and treatment with a polyhexamethylene biguanide (PHMB)-containing antiseptic. Confocal microscopy was used to evaluate the effect of treatments on biofilm disruption and cell viability counting measured the antibacterial effects. Confocal microscopy showed that application of 10 seconds of moderate-intensity UAW could effectively disrupt semi-solid biofilms grown on both media settings. This treatment only had a small effect on the cell viability. A 24-hour treatment with PHMB was able to reduce the number of bacteria but not eradicate the biofilm in both media settings. Interestingly, the efficacy of the PHMB antiseptic was significantly higher when applied on biofilms grown in the more complex WSM media. However, we found a significant improvement in reducing the number of viable bacteria grown on both media when applying UAW before administration of the PHMB solution. Applying UAW in the presence of PHMB further improved the efficacy. Using a realistic in vitro biofilm wound model, we show combining UAW with a PHMB-containing antiseptic has potential as an antibiofilm strategy in wound care. The manufacturer of the ultrasonic-assisted wound debridement device, Söring GmbH, Germany, has supported the ultrasound studies. The funding company had no role in the design, data collection, analysis, review, or approval of the manuscript.


Religious moral beliefs as mental health protective factor of war veterans suffering from PTSD, depressiveness, anxiety, tobacco and alcohol abuse in comorbidity.
Our aim was to investigate is there association between level of religious moral beliefs and severity of PTSD symptoms, depressiion symptoms, anxiety and severity of alcohol abuse we tested 152 war veterans on presence of PTSD, depression symptoms, anxiety, alcohol misuse and level of religious moral beliefs. We used Harvard trauma questionnaire (HTQ), Hopkins Check Scale SBCL 25, check list for alcohol misuse MAST. Subjects were assessed with regard to the level of belief in some basic ethical principles that arise from religious moral values. The score of religious moral belief index was used to correlate with severity of PTSD symptoms, depression symptoms, anxiety and severity of alcohol misuse. Mean age of tested subjects was 40.8 (SD=6.6) years. The score of the moral belief index was negatively correlated to PTSD symptom severity and depressiveness (Pearson's r=-0.325, p<0.001; r=-0.247, p=0.005, respectively). Besides that the score of moral belief index negatively correlated with presented anxiety (Pearson's r=-0.199,p=0.026). Related to severity of tobacco and alcohol misuse we found negative association of these with the moral belief index (Pearson's r=-0.227, p=0.011; r=-0.371, p<0.001, respectively). A higher index of religious moral beliefs in war veterans enables better control distress, providing better mental health stability. It enables post traumatic conflicts typical for combatants' survivors to be more easily overcome. It also causes healthier reactions to external stimuli. A higher index of religious moral beliefs of war veterans provides a healthier and more efficient mechanism of tobacco and alcohol misuse control. In this way, it helps overcoming postwar psychosocial problems and socialization of the personality, leading to the improvement in mental health.


Emerging role for drug transporters at the blood-testis barrier.
Drug transporters are integral membrane proteins that transport a broad range of substrates into and out of cells, usually against a concentration gradient. Studies have shown that efflux pumps such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) localize at the blood-testis barrier (BTB), where they protect the testis from drugs and xenobiotics that are detrimental to spermatogenesis. At the same time, efflux pumps might also preclude entry of non-hormonal contraceptives to the testis. In more recent studies, P-gp function was correlated with BTB integrity. In this review, we discuss findings that have made a significant impact on our understanding of efflux pumps in the testis. Modulation of efflux pump function via specific inhibitors could help to deliver contraceptives to the testis in the future.


Abnormal self-schema in semantic memory in major depressive disorder: Evidence from event-related brain potentials.
An overly negative self-schema is a proposed cognitive mechanism of major depressive disorder (MDD). Self-schema - one's core conception of self, including how strongly one believes one possesses various characteristics - is part of semantic memory (SM), our knowledge about concepts and their relationships. We used the N400 event-related potential (ERP) - elicited by meaningful stimuli, and reduced by greater association of the stimulus with preceding context - to measure association strength between self-concept and positive, negative, and neutral characteristics in SM. ERPs were recorded from MDD patients (n=16) and controls (n=16) who viewed trials comprising a self-referential phrase followed by a positive, negative, or neutral adjective. Participants' task was to indicate via button-press whether or not they felt each adjective described themselves. Controls endorsed more positive adjectives than did MDD patients, but the opposite was true for negative adjectives. Patients had smaller N400s than controls specifically for negative adjectives, suggesting that MDD is associated with stronger than normal functional neural links between self-concept and negative characteristics in SM.


Medial thickening of hepatic artery branches in biliary atresia. A morphometric study.
Medial layer hypertrophy of hepatic arterial branches may be associated with biliary atresia (BA) pathogenesis. This study aimed at evaluating medial layer thickness in hepatic arterial branches at portoenterostomy and liver transplantation. The authors evaluated 1274 arterial branches both in BA cases and in control subjects involving a total of 1108 arterioles and 166 arteries. Arterial branch characteristics were morphometrically evaluated in 47 BA patients at the time of portoenterostomy. Controls were patients with intrahepatic cholestasis (n = 3), immature neonates (n = 7), and infants (n = 7) without liver disease. Progression of medial layer thickening between the time of portoenterostomy and transplantation was evaluated in 7 BA patients. Biliary atresia patients at the time of transplantation were compared with non-BA-transplanted patients (n = 4). The arterial medial layer of BA cases at portoenterostomy was thicker than that of infants without liver disease ( P = .03). The arterial medial thickness increased during the interval between portoenterostomy and transplantation ( P = .05). Arterioles and arteries with thickened medial layers were found in transplanted BA patients but not in patients transplanted for other liver diseases (P = .05 and P = .01). Thickening of the medial layer of the hepatic arteries was associated with focal distribution of interlobular bile ducts in portal spaces in BA ( P = .02). In BA, there is a progressive thickening of the arterial medial layer, suggestive of vascular remodeling, which is associated to the disappearance of interlobular bile ducts.


Amperometric glucose sensors: sources of error and potential benefit of redundancy.
Amperometric glucose sensors have advanced the care of patients with diabetes and are being studied to control insulin delivery in the research setting. However, at times, currently available sensors demonstrate suboptimal accuracy, which can result from calibration error, sensor drift, or lag. Inaccuracy can be particularly problematic in a closed-loop glycemic control system. In such a system, the use of two sensors allows selection of the more accurate sensor as the input to the controller. In our studies in subjects with type 1 diabetes, the accuracy of the better of two sensors significantly exceeded the accuracy of a single, randomly selected sensor. If an array with three or more sensors were available, it would likely allow even better accuracy with the use of voting.


Treatment of chronic obstructive pulmonary disease with roflumilast, a new phosphodiesterase 4 inhibitor.
Recent advances in chronic obstructive pulmonary disease (COPD) treatment offer symptom relief, but disease modification remains an unmet goal of pharmacotherapy. Reducing the frequency and severity of COPD exacerbations may help slow disease progression and reduce the morbidity, mortality, and costs associated with these major events. Other desirable characteristics for a COPD treatment include a once-daily dosing schedule, an oral formulation, and a low frequency of systemic side effects. Phosphodiesterase 4 inhibitors have been in clinical development for some years and roflumilast is currently the most advanced of these agents. In this review, the preclinical evidence, clinical safety, and efficacy of roflumilast available in published reports are considered. The data reviewed here suggest that the clinical efficacy of roflumilast occurs through a mechanism unrelated to bronchodilation and may be due to the suppression of lung inflammation. Lung function improved with roflumilast treatment and in some studies, the reduction in exacerbations was substantial and statistically significant. Notably, this effect appeared to be greatest in the subgroup of patients with more severe disease and more severe exacerbations. The evaluation of roflumilast safety largely centers on gastrointestinal adverse events, with diarrhea, nausea, and weight loss occurring more frequently with the drug than placebo. If approved for general use, we expect roflumilast to find its role initially as a substitute for inhaled corticosteroids in the maintenance treatment of severe and very severe disease, particularly in patients who have frequent acute exacerbations, and perhaps as a supplementary drug when symptoms are not adequately controlled by current conventional COPD therapy.


Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): An auditory evoked potential study of the duration-evoked mismatch negativity (MMN).
We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing, a critical cue in speech perception. Given decrements in speech and language skills associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. Data from individuals with CLN3 disease (N=21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N=41; ages 6-26 years). Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.


Susceptibility of transgenic mice expressing chimeric sheep, bovine and human PrP genes to sheep scrapie.
The use of Transgenic (Tg) mice expressing chimeric sheep/mouse (Sh/Mo) prion protein (PrP) and chimeric bovine/mouse (Bo/Mo) PrP genes was evaluated as a sheep scrapie model. We also investigated the potential for the transmission of sheep scrapie to a human/mouse (Hu/Mo) PrP Tg mouse line. The Sh/Mo PrP and Bo/Mo PrP Tg Prnp(+/+) or Prnp(0/0) mouse lines were inoculated intracerebrally with brain homogenates from three sheep with natural scrapie (KU, Y5 or S2). Incubation periods were slightly shorter in Sh/Mo PrP Tg Prnp(+/+), than in non-Tg mice inoculated with KU brain homogenate. In contrast, the incubation period was significantly prolonged (p<0.05) in Bo/Mo PrP Tg Prnp(+/+) mice inoculated with KU brain homogenate. The incubation period was significantly longer in all Tg Prnp(+/+) and Prnp(0/0), than in non-Tg mice (p<0.01) inoculated withY5 brain homogenate. None of the Tg Prnp(0/0) mice inoculated with S2 brain homogenate developed clinical signs and PrP(Sc) was undetectable in their brains. These results suggested that expression of the Sh/Mo PrP or Bo/Mo PrP transgenes does not confer susceptibility to sheep prions upon mice, and thus none of the Tg mouse lines could be a suitable model of sheep scrapie. Hu/Mo PrP Tg Prnp(0/0) mice inoculated with natural and experimental scrapie or mouse prions did not develop clinical signs of scrapie and PrP(Sc) was undetectable. These results suggested that neither sheep nor mouse strains of scrapie are highly transmissible to humans.


Use of endoscopic ultrasound in the preoperative staging of gastric cancer: a multi-institutional study of the US gastric cancer collaborative.
Endoscopic ultrasound (EUS) can be used to guide the therapeutic plan for patients with gastric adenocarcinoma (GAC), but data on its use and accuracy remain poorly defined. We sought to define the use of EUS, as well as characterize the diagnostic accuracy of EUS among patients with GAC. We identified 960 patients who underwent resection of GAC between 2000 and 2012 from 7 major academic institutions participating in the US Gastric Cancer Collaborative. Clinicopathologic and EUS data were collected and analyzed using chi and kappa statistics. Of 960 patients, 223 (23.2%) underwent evaluation with preoperative EUS. Among patients who underwent EUS, 74 (33.2%) received neoadjuvant chemotherapy; 149 (66.8%) proceeded directly to resection. Among patients who did not receive neoadjuvant therapy and received curative intent gastric resection, the EUS T classifications were T1 (33.3%), T2 (35.6%), T3 (18.9%), T4 (12.1%) and the N classifications were N0 (68.1%) and N ≥ 1 (31.9%). In contrast, when tumor stage was based on the final surgical specimen, there was a higher proportion of cases with more advanced T stage (T1, 36.4%; T2, 14.4%; T3, 23.5%; T4, 25.7%) and N stage (N0, 51.3%; N ≥ 1, 48.7%). The agreement of preoperative EUS compared with surgical staging for T (kappa = 0.28, p < 0.001) and N (kappa = 0.33, p < 0.001) classification was only fair. Less than one-quarter of patients with GAC underwent preoperative EUS staging. In patients who did not receive preoperative chemotherapy, tumor stage on EUS often did not correlate with T stage and N stage on final pathologic analysis. Endoscopic ultrasound should be combined with other staging modalities to optimize staging of patients with GAC.


[Temperature compensation for enzyme activity in homoiothermal animals].
The dependence of lactate gehydrogenase activity on body temperature of homoiothermal animals upon hypothermia was studied. New data indicating the induction of thermal compensation for enzymic activity in warm-blooded under these conditions were obtained.


Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer's disease.
Neurodegeneration and cell death in Alzheimer's disease might be associated with aberrant proliferative mechanisms and activation of cell-cycle related events. We reported previously on the elevated expression of the cyclin dependent kinase inhibitor p16INK4a in Alzheimer's disease closely associated with neurofibrillary degeneration. In the present study, we demonstrate that other members of the INK4-family of cyclin dependent kinase inhibitors such as p15INK4b, p18INK4c and p19INK4d that bind directly to cdk4/6 or to complexes of cdk4/6 with D-type cyclins are all elevated. In contrast, no indication of altered expression of the cyclin dependent kinase inhibitors p21Cip1 and p27Kip1 were observed. Inhibitors of the INK4-family were strongly expressed in tangle-bearing neurones and neuritic components of plaques. A much lower expression was also seen in astrocytes. These findings add further evidence to the suggestion that a dysfunction of cell cycle regulation is of critical importance in the pathomechanism of Alzheimer's disease.


The Long Isoform of Intersectin-1 Has a Role in Learning and Memory.
Down syndrome is caused by partial or total trisomy of chromosome 21 and is characterized by intellectual disability and other disorders. Although it is difficult to determine which of the genes over-expressed on the supernumerary chromosome contribute to a specific abnormality, one approach is to study each gene in isolation. This can be accomplished either by using an over-expression model to study increased gene dosage or a gene-deficiency model to study the biological function of the gene. Here, we extend our examination of the function of the chromosome 21 gene, ITSN1. We used mice in which the long isoform of intersectin-1 was knocked out (ITSN1-LKO) to understand how a lack of the long isoform of ITSN1 affects brain function. We examined cognitive and locomotor behavior as well as long term potentiation (LTP) and the mitogen-activated protein kinase (MAPK) and 3'-kinase-C2β-AKT (AKT) cell signaling pathways. We also examined the density of dendritic spines on hippocampal pyramidal neurons. We observed that ITSN1-LKO mice had deficits in learning and long term spatial memory. They also exhibited impaired LTP, and no changes in the levels of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2. The amount of phosphorylated AKT was reduced in the ITSN1-LKO hippocampus and there was a decrease in the number of apical dendritic spines in hippocampal neurons. Our data suggest that the long isoform of ITSN1 plays a part in normal learning and memory.


Global habitat suitability models of terrestrial mammals.
Detailed large-scale information on mammal distribution has often been lacking, hindering conservation efforts. We used the information from the 2009 IUCN Red List of Threatened Species as a baseline for developing habitat suitability models for 5027 out of 5330 known terrestrial mammal species, based on their habitat relationships. We focused on the following environmental variables: land cover, elevation and hydrological features. Models were developed at 300 m resolution and limited to within species' known geographical ranges. A subset of the models was validated using points of known species occurrence. We conducted a global, fine-scale analysis of patterns of species richness. The richness of mammal species estimated by the overlap of their suitable habitat is on average one-third less than that estimated by the overlap of their geographical ranges. The highest absolute difference is found in tropical and subtropical regions in South America, Africa and Southeast Asia that are not covered by dense forest. The proportion of suitable habitat within mammal geographical ranges correlates with the IUCN Red List category to which they have been assigned, decreasing monotonically from Least Concern to Endangered. These results demonstrate the importance of fine-resolution distribution data for the development of global conservation strategies for mammals.


The retinal chromophore/chloride ion pair: structure of the photoisomerization path and interplay of charge transfer and covalent states.
Ab initio multi-reference second-order perturbation theory computations are used to explore the photochemical behavior of two ion pairs constituted by a chloride counterion interacting with either a rhodopsin or bacteriorhodopsin chromophore model (i.e., the 4-cis-gamma-methylnona-2,4,6,8-tetraeniminium and all-trans-nona-2,4,6,8-tetraeniminium cations, respectively). Significant counterion effects on the structure of the photoisomerization paths are unveiled by comparison with the paths of the same chromophores in vacuo. Indeed, we demonstrate that the counterion (i) modulates the relative stability of the S0, S1, and S2 energy surfaces leading to an S1 isomerization energy profile where the S1 and S2 states are substantially degenerate; (ii) leads to the emergence of significant S1 energy barriers along all of the isomerization paths except the one mimicking the 11-cis --> all-trans isomerization of the rhodopsin chromophore model; and (iii) changes the nature of the S1 --> S0 decay funnel that becomes a stable excited state minimum when the isomerizing double bond is located at the center of the chromophore moiety. We show that these (apparently very different) counterion effects can be rationalized on the basis of a simple qualitative electrostatic model, which also provides a crude basis for understanding the behavior of retinal protonated Schiff bases in solution.