STUDIES ON EXPERIMENTAL HYPERTENSION : IX. THE EFFECT ON BLOOD PRESSURE OF CONSTRICTION OF THE ABDOMINAL AORTA ABOVE AND BELOW THE SITE OF ORIGIN OF BOTH MAIN RENAL ARTERIES.
Constriction of the aorta just above the origin of both main renal arteries invariably resulted in elevation of the carotid systolic and carotid mean pressure. The hypertension was not immediate, but developed in about the same time as after constriction of the main renal arteries (3). Constriction of the aorta just below the origin of both main renal arteries had no significant effect on the carotid systolic or carotid mean pressure. Since these results were first reported (1), Rytand (88, 89) has shown by an indirect method, namely, the demonstration of the development of cardiac hypertrophy, that hypertension in the upper part of the body can be produced in the rat by constriction of the aorta just above the origin of both main renal arteries. The immediate effect of constriction of the aorta either below or above the main renal arteries is a fall of blood pressure (femoral mean pressure) below the site of the clamp, the extent of the fall being directly dependent upon the degree of constriction of the aorta. Of particular interest is the eventual elevation of the femoral mean pressure above the normal in some animals with the aorta constricted or even occluded above the origin of the main renal arteries. This was most pronounced and persistent in those animals in which, in addition, the aorta below the origin of the renal arteries, and, in some animals, the main renal arteries, also were constricted. The most important factors which determined this elevation of blood pressure in the lower part of the body were probably increased flow of blood into the vascular bed below the clamp and peripheral vasoconstriction of renal and humoral origin, as in the case of the hypertension produced by constriction of the main renal arteries alone (2-86). Although elevation of the carotid systolic or carotid mean pressure occurred invariably within 24 to 48 hours after the constriction of the aorta above the site of origin of both main renal arteries, yet there was a tendency, after a variable period, for the elevated blood pressure to become lower or even to drop to the original level. Increased constriction, and finally occlusion of the aorta, above the origin of the main renal arteries, and even constriction or occlusion of the aorta below the renal arteries, in addition, failed to induce hypertension that persisted for a long time at a high level. In order to produce this effect, it was necessary to constrict the main renal arteries as well. The possible explanation of the failure of the hypertension to persist for a long time after constriction of the aorta alone, is that the initial ischemia of the kidneys disappeared due to the improvement of the blood flow through the kidneys as a result of (a) the increase of the natural accessory circulation to the kidneys; (b) the increased blood pressure above the site of the clamp and consequent increased flow of blood into the part of the aorta below the clamp; (c) increased pressure below the site of the clamp due, in great part, to peripheral vasoconstriction, and in part to the increased inflow of blood into the lower part of the body through the aorta and collateral channels. For the dog, this method is not necessary for the production of persistent hypertension. Constriction of the main renal arteries is easily performed and is effective for the production of generalized hypertension (2-11). However, constriction of the aorta in addition to constriction of the renal arteries results in greatly elevated persistent hypertension. Constriction of the aorta alone above the origin of the main renal arteries would be useful in the dog only for the production of relatively short periods of hypertension in the upper part of the body. For small animals it may be a more effective and useful method. In the dog, the only technical difficulty encountered was the erosion of the wall of the aorta by the clamp. This may not occur in small animals. In previous studies (2-11) that have dealt with the constriction of the main renal arteries, this accident rarely occurred. When the constriction of the aorta above the origin of the main renal arteries was of moderate degree, or was gradually made very great, the resultant hypertension was not accompanied by impairment of renal excretory function, as determined by urea clearance or by the quantity of urea, creatinine or non-protein nitrogen in the blood, the benign phase of hypertension (3). When the constriction of the aorta was suddenly made very great, impairment of the renal excretory function usually followed, and the animal developed fatal convulsive uremia and characteristic vascular lesions, the malignant phase of hypertension (9). These facts, are all indicative of the renal origin of the hypertension which results from the constriction of the aorta just above the origin of both main renal arteries. Hypertension did not persist for a sufficiently long time to permit any conclusive comparison between the effect of the high and low pressures on the structure of the vascular system, above and below the site of the clamp, respectively. During the period of survival of these animals, no significant differences were observed between the appearance of the vascular system of the upper part of the body and that of the lower part of the body, and significant cardiac hypertrophy did not develop. In the aorta and large arteries, intimal arteriosclerosis was not observed. In the aorta of one old animal several small plaques of calcification were found in the media, but these were present in the portion of the aorta below, as well as above the clamp, and they were no larger or more abundant than were observed in some old dogs with normal blood pressure. Dogs 3-50 and 3-83, that are still alive, with very high blood pressure above the site of the aortic clamps, and relatively low pressure (though greater than normal) below the site of the aortic clamps, will be valuable for the determination of possible differences between the effects of the two levels of blood pressure in the large and small blood vessels. In these dogs also, it will be possible to determine the effect of the persistently high blood pressure on the myocardium. The possible application of the results of this study to the problem of the pathogenesis of human eclampsia is mentioned here for consideration. Since this condition occurs in pregnancy only at a time when the uterus is greatly enlarged, it is at least possible that the mass may press on the aorta or both main renal arteries sufficiently to produce renal ischemia. The suddenness with which the uremic convulsive phase of eclampsia develops is in keeping with this idea. In the dog, an aggravating effect of pregnancy on an already established hypertension has not been noted. As a matter of fact, most of the hypertensive dogs that have become pregnant, have shown a slight or moderate fall, rather than an increased rise of pressure. Since the dog stands with the body in a horizontal position, and does not lie on its back, pressure of the pregnant uterus on the aorta and blood vessels is less than in human beings who stand erect and frequently lie on their backs. The soundness of this suggestion could be tested by placing pregnant women, in the early stage of eclampsia, in a position which could relieve possible pressure on the aorta and main renal arteries. A possible explanation of the fall of pressure in the pregnant hypertensive dogs is the compensatory effect of the normal kidneys of the pups, as in the case of an animal with one main renal artery constricted and the other kidney normal. As has been shown (3, 31, 72), the presence of one normal kidney in an animal hypertensive due to constriction of the other main renal artery, results, after a variable period, in a return of the blood pressure to normal. How the normal kidney acts to produce this effect is not known.


CeF3 and PrF3 as UV-visible Faraday rotators.
CeF3 and PrF3 single crystals are investigated as Faraday rotators for the UV-visible region. Their properties are compared with those of the industrial standard reference terbium-gallium-garnet (TGG) single crystal. In contrast to TGG, CeF3 exhibits a higher transparency in the whole near UV-visible-IR, and a remarkable higher figure of merit which rapidly increases towards the cutoff. In the case of PrF3, the transparency extends to even shorter wavelengths, and analogously to CeF3 its figure of merit increases notably in the UV. These results indicate the potential of CeF3 and PrF3 as optical isolators in the UV-visible, where at present there are no alternative candidates.


The Rho-GTPase binding protein IQGAP2 is required for the glomerular filtration barrier.
Podocyte dysfunction impairs the size selectivity of the glomerular filter, leading to proteinuria, hypoalbuminuria, and edema, clinically defined as nephrotic syndrome. Hereditary forms of nephrotic syndrome are linked to mutations in podocyte-specific genes. To identify genes contributing to podocyte dysfunction in acquired nephrotic syndrome, we studied human glomerular gene expression data sets for glomerular-enriched gene transcripts differentially regulated between pretransplant biopsy samples and biopsies from patients with nephrotic syndrome. Candidate genes were screened by in situ hybridization for expression in the zebrafish pronephros, an easy-to-use in vivo assay system to assess podocyte function. One glomerulus-enriched product was the Rho-GTPase binding protein, IQGAP2. Immunohistochemistry found a strong presence of IQGAP2 in normal human and zebrafish podocytes. In zebrafish larvae, morpholino-based knockdown of iqgap2 caused a mild foot process effacement of zebrafish podocytes and a cystic dilation of the urinary space of Bowman's capsule upon onset of urinary filtration. Moreover, the glomerulus of zebrafish morphants showed a glomerular permeability for injected high-molecular-weight dextrans, indicating an impaired size selectivity of the glomerular filter. Thus, IQGAP2 is a Rho-GTPase binding protein, highly abundant in human and zebrafish podocytes, which controls normal podocyte structure and function as evidenced in the zebrafish pronephros.


Prevalence of diabetic retinopathy in the United States, 2005-2008.
The prevalence of diabetes in the United States has increased. People with diabetes are at risk for diabetic retinopathy. No recent national population-based estimate of the prevalence and severity of diabetic retinopathy exists. To describe the prevalence and risk factors of diabetic retinopathy among US adults with diabetes aged 40 years and older. Analysis of a cross-sectional, nationally representative sample of the National Health and Nutrition Examination Survey 2005-2008 (N = 1006). Diabetes was defined as a self-report of a previous diagnosis of the disease (excluding gestational diabetes mellitus) or glycated hemoglobin A(1c) of 6.5% or greater. Two fundus photographs were taken of each eye with a digital nonmydriatic camera and were graded using the Airlie House classification scheme and the Early Treatment Diabetic Retinopathy Study severity scale. Prevalence estimates were weighted to represent the civilian, noninstitutionalized US population aged 40 years and older. Diabetic retinopathy and vision-threatening diabetic retinopathy. The estimated prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was 28.5% (95% confidence interval [CI], 24.9%-32.5%) and 4.4% (95% CI, 3.5%-5.7%) among US adults with diabetes, respectively. Diabetic retinopathy was slightly more prevalent among men than women with diabetes (31.6%; 95% CI, 26.8%-36.8%; vs 25.7%; 95% CI, 21.7%-30.1%; P = .04). Non-Hispanic black individuals had a higher crude prevalence than non-Hispanic white individuals of diabetic retinopathy (38.8%; 95% CI, 31.9%-46.1%; vs 26.4%; 95% CI, 21.4%-32.2%; P = .01) and vision-threatening diabetic retinopathy (9.3%; 95% CI, 5.9%-14.4%; vs 3.2%; 95% CI, 2.0%-5.1%; P = .01). Male sex was independently associated with the presence of diabetic retinopathy (odds ratio [OR], 2.07; 95% CI, 1.39-3.10), as well as higher hemoglobin A(1c) level (OR, 1.45; 95% CI, 1.20-1.75), longer duration of diabetes (OR, 1.06 per year duration; 95% CI, 1.03-1.10), insulin use (OR, 3.23; 95% CI, 1.99-5.26), and higher systolic blood pressure (OR, 1.03 per mm Hg; 95% CI, 1.02-1.03). In a nationally representative sample of US adults with diabetes aged 40 years and older, the prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was high, especially among Non-Hispanic black individuals.


A Mobile Application for Keyword Search in Real-World Scenes.
Keyword search in a cluttered environment is difficult in general, and even more challenging for people with low vision. While magnification can help in reading for low vision people, it does not facilitate efficient visual search due to the constriction of the field of view. The motivating observation for this study is that, in a large number of visual search tasks, people know what are they looking for (i.e., they know the keywords), they just do not know where to find them in the scene. We have developed a mobile application that allows the users to input keywords (by voice or by typing), uses an optical character recognition (OCR) engine to search for the provided keyword in the scene captured by the smartphone camera, and zooms in on the instances of the keyword detected in the captured images, to facilitate efficient information acquisition. In this paper we describe the development and evaluation of various aspects of the application, including comparing the various mainstream OCR engines that power the app, and an evaluation study comparing the app to the conventional optical magnifier vision aid. Normally sighted adults, while wearing blur glasses to lower their visual acuity, performed keyword searches for a series of items ranging from easy to difficult with the app and with a handheld magnifier. While there was no difference in the search times between the two methods for the easier tasks, the app was significantly faster than the magnifier for the difficult tasks.


Improving Outcomes by Implementing a Pressure Ulcer Prevention Program (PUPP): Going beyond the Basics.
A multidisciplinary process improvement program was initiated at the University of Miami Hospital (UMH) in 2009 to identify the prevalence of hospital-acquired pressure ulcers (HAPU) at the institution and to implement interventions to reduce the incidence of HAPU. This deliberate and thoughtful committee-driven process evaluated care, monitored results, and designed evidence-based strategic initiatives to manage and reduce the rate of HAPU. As a result all inpatient beds were replaced with support surfaces, updated care delivery protocols were created, and monitored, turning schedules were addressed, and a wound, ostomy, and continence (WOC) nurse and support staff were hired. These initial interventions resulted in a decrease in the prevalence of HAPU at UMH from 11.7% of stage II to IV ulcers in the second quarter, 2009 to 2.1% the third quarter. The rate remained at or near the 2009 UMH benchmark of 3.1% until the first quarter of 2012 when the rate rose to 4.1%. At that time new skin products were introduced into practice and continuing re-education was provided. The rate of HAPU dropped to 2.76% by the second quarter of 2012 and has remained steadily low at 1%-2% for nine consecutive quarters.


Using Event-related Potentials to Inform the Neurocognitive Processes Underlying Knowledge Extension through Memory Integration.
To build a general knowledge base, it is imperative that individuals acquire, integrate, and further extend knowledge across experiences. For instance, in one episode an individual may learn that George Washington was the first president. In a separate episode they may then learn that Washington was the commander of the Continental Army. Integration of the information in memory may then support self-derivation of the new knowledge that the leader of the Continental Army was also the first president. Despite a considerable amount of fMRI research aimed at further elucidating the neuroanatomical regions supporting this ability, a consensus has yet to be reached with regards to the precise neurocognitive processes involved. In the present research, we capitalized on the high temporal resolution of event-related potentials (ERPs) to inform the time course of processes elicited during successful integration and further extension of new factual knowledge. Adults read novel, related stem facts and were tested for self-derivation of novel integration facts while ERPs were recorded. Consistent with current theoretical models, memory integration was first triggered by novelty detection within 400 msec of experience of a second, related stem fact. Two additional temporally staged encoding processes were then observed interpreted to reflect (1) explicit meaning comprehension and (2) representation of the integrated relation in memory. During the test for self-derivation, a single ERP was elicited, which presumably reflected retrieval and/or recombination of previously integrated knowledge. Together, the present research provides important insight into the time course of neurocognitive processing associated with the formation of a knowledge base.


The classification of bulimic eating disorders: a community-based cluster analysis study.
There is controversy over how best to classify eating disorders in which there is recurrent binge eating. Many patients with recurrent binge eating do not meet diagnostic criteria for other of the two established eating disorders, anorexia nervosa or bulimia nervosa. The present study was designed to derive an empirically based, and clinically meaningful, diagnostic scheme by identifying subgroups from among those with recurrent binge eating, testing the validity of these subgroups and comparing their predictive validity with that of the DSM-IV scheme. A general population sample of 250 young women with recurrent binge eating was recruited using a two-stage design. Four subgroups among the sample were identified using a Ward's cluster analysis. The first subgroup had either objective or subjective bulimic episodes and vomiting or laxative misuse; the second had objective bulimic episodes and low levels of vomiting or laxative misuse; the third had subjective bulimic episodes and low levels of vomiting or laxative misuse; and the fourth was heterogeneous in character. This cluster solution was robust to replication. It had good descriptive and predictive validity and partial construct validity. The results support the concept of bulimia nervosa and its division into purging and non-purging subtypes. They also suggest a possible new binge eating syndrome. Binge eating disorder, listed as an example of Eating Disorder Not Otherwise Specified within DSM-IV, did not emerge from the cluster analysis.


Beneficial effect of serum on the fertilizability of mouse oocytes matured in vitro.
Mouse oocytes matured in vitro in chemically defined medium were not penetrated by spermatozoa. The time required for dissolution of the zona pellucida of such oocytes by alpha-chymotrypsin was much longer than that for ovulated oocytes. Addition of fetal calf serum to the medium for maturation of oocytes improved the incidence of sperm penetration and shortened the time of enzymic dissolution of the zona pellucida. These results suggest that the low rate of fertilization of oocytes matured in vitro is mainly due to qualitative changes of the zona pellucida, which could be overcome by a factor or factors in fetal calf serum.


Adherence of bacteria to intraocular lenses: a prospective study.
The study was designed to investigate the bacterial flora of the operating field during routine cataract surgery and the source of intraocular lens contamination during the surgery. The normal flora of the external eye and fornices of 17 patients undergoing selective cataract surgery was determined preoperatively. Swabs taken from the eyelid surface and lashes showed coagulase negative staphylococci (CNS) in 90%, Propionibacterium acnes in 62%, Corynebacterium sp in 18%, and Peptostreptococcus in 3% of the patients. The lower fornices of 70% had CNS, 47% P acnes, 6% Staphylococcus aureus, 6% Corynebacterium sp, and 6% Candida. A sterile PMMA intraocular lens was touched on the upper bulbar conjunctiva immediately before the surgery. Eighty two per cent of lenses grew CNS, 18% P acnes, 18% Bacillus sp, 12% S aureus, and 6% Corynebacterium sp. A second sterile PMMA intraocular lens was left on the drape and near the eye during surgery. Forty seven per cent of these cultured CNS, 12% Corynebacterium sp, and 6% Bacillus sp. A high count of bacteria in the operating field, especially CNS and P acnes can contribute to postoperative inflammation and endophthalmitis. Special measures are needed before and during the surgery to reduce the chance of intraocular inoculation of these bacteria. Use of proper culture media and techniques are necessary to identify these organisms, especially anaerobes, in postoperative inflammation.


Estimating the effects of prescription drug coverage for Medicare beneficiaries.
To identify the effect of insurance coverage on prescription utilization by Medicare beneficiaries. Secondary data from the 1999 Medicare Current Beneficiary Survey (MCBS) Cost and Use files, a nationally representative survey of Medicare enrollees. The paper uses a cross-sectional design with (1) a standard regression framework to estimate the impact of prescription coverage on utilization controlling for potential selection bias with covariate control based on the Diagnostic Cost Group/Hierarchical Condition Category (DCG/HCC) risk adjuster, and (2) a multistage residual inclusion method using instrumental variables to control for selection bias and identify the insurance coverage effect. Data were extracted from the 1999 MCBS. Study inclusion criteria are community-dwelling MCBS respondents with full-year Medicare enrollment and supplemental medical insurance with or without full-year drug benefits. The final sample totaled 5,270 Medicare beneficiaries. Both the model using the DCG/HCC risk adjuster and the model using the residual inclusion method produced similar results. The estimated price elasticity of demand for prescription drugs for the Medicare beneficiaries in our sample was -0.54. Our results confirm that selection into prescription coverage is predictable based on observable health. Our results further confirm prior estimates of price sensitivity of prescription drug demand for Medicare beneficiaries, though our estimate is slightly above prior results.


Development of a beam optimization method for absorption-based tomography.
Absorption tomography is an imaging technique that has been used simultaneously to image multiple scalar parameters, such as temperature and species concentration for combustion diagnostics. Practical combustors, such as internal combustion engines and gas turbine engines, only allow limited optical access, and typically a few (ca. 20-40) beams are available to probe the domain of interest. With such limited spatial sampling, it is non-trivial to optimize beam arrangement for a faithful reconstruction. Previous efforts on beam optimization rely on either heuristic/empirical methods lacking rigorous mathematical derivation or were derived by assuming certain prior information in the tomographic inversion. This paper aims to develop an approach that is expected to be especially useful when prior information is not easily available or intended to be included in the inversion processes. We demonstrate that the orthogonality between rows of the weight matrix directly correlates with reconstruction fidelity and can be used as an effective predictor for beam optimization. A systematic comparison between our method and the existing ones in the literature suggests the validity of our method. We expect this method to be valuable for not only the absorption tomography but also other tomographic modalities.


Dissecting the Metabolic Role of Mitochondria during Developmental Leaf Senescence.
The functions of mitochondria during leaf senescence, a type of programmed cell death aimed at the massive retrieval of nutrients from the senescing organ to the rest of the plant, remain elusive. Here, combining experimental and analytical approaches, we showed that mitochondrial integrity in Arabidopsis (Arabidopsis thaliana) is conserved until the latest stages of leaf senescence, while their number drops by 30%. Adenylate phosphorylation state assays and mitochondrial respiratory measurements indicated that the leaf energy status also is maintained during this time period. Furthermore, after establishing a curated list of genes coding for products targeted to mitochondria, we analyzed in isolation their transcript profiles, focusing on several key mitochondrial functions, such as the tricarboxylic acid cycle, mitochondrial electron transfer chain, iron-sulfur cluster biosynthesis, transporters, as well as catabolic pathways. In tandem with a metabolomic approach, our data indicated that mitochondrial metabolism was reorganized to support the selective catabolism of both amino acids and fatty acids. Such adjustments would ensure the replenishment of α-ketoglutarate and glutamate, which provide the carbon backbones for nitrogen remobilization. Glutamate, being the substrate of the strongly up-regulated cytosolic glutamine synthase, is likely to become a metabolically limiting factor in the latest stages of developmental leaf senescence. Finally, an evolutionary age analysis revealed that, while branched-chain amino acid and proline catabolism are very old mitochondrial functions particularly enriched at the latest stages of leaf senescence, auxin metabolism appears to be rather newly acquired. In summation, our work shows that, during developmental leaf senescence, mitochondria orchestrate catabolic processes by becoming increasingly central energy and metabolic hubs.


Factors Associated with Health Information Seeking, Processing, and Use Among HIV Positive Adults in the Dominican Republic.
Effective treatment and management of human immunodeficiency virus (HIV) depend on patients' ability to locate, comprehend, and apply health information. This study's purpose was to identify characteristics associated with these skills among HIV positive adults in the Dominican Republic. An information behavior survey was administered to 107 participants then three logistic regressions were conducted to identify characteristics associated with information seeking, processing, and use. Never having cared for someone who was sick was significantly associated with less information seeking, processing, and use. Males were more likely to be active information seekers and those who had attended the clinic for six or fewer years were less likely to actively seek information. Younger individuals had increased odds of higher information processing and those without comorbidities had increased odds of more information use. Results may inform researchers, organizations, and providers about how patients interact with health information in limited resource settings.


Fucoxanthin Ameliorates Atopic Dermatitis Symptoms by Regulating Keratinocytes and Regulatory Innate Lymphoid Cells.
Fucoxanthin (FX) is a xanthophyll that is contained abundantly in marine plants. The biological action of FX includes its antioxidant and anti-lipogenic activities, while the precise action of its mechanisms on skin cells has not yet been clarified. The current study examined the effect of FX in comparison with tacrolimus (TAC) on NC/Nga mice, which are an atopic dermatitis (AD) model. FX topical treatment dramatically ameliorated itching behavior over the TAC treatment, which was insufficient for improvement of AD symptoms. In Nc/Nga mice, FX or TAC applied to the skin inhibited eosinophil infiltration with decreased expression of Il-33. FX also stimulated Il-2, Il-5, Il-13, Il-10, and TGF-β expression levels, and Sca1+Il-10+TGF-β+ regulatory innate lymphoid cells (ILCreg) were dominantly observed in FX treated skin epidermal keratinocytes and dermal layers. This combined evidence demonstrated that FX exerts anti-inflammatory effects on keratinocytes and ameliorates AD symptoms by regulating ILCreg to normalize immune responses in an atopic dermatitis model.


Neuroendocrine effects of sumatriptan.
The neuroendocrine effects of the 5-HT receptor agonist, sumatriptan (6 mg subcutaneously), were studied in 11 healthy male subjects using a placebo-controlled, cross-over design. Compared to placebo, sumatriptan significantly lowered levels of plasma prolactin but increased those of plasma growth hormone. There was no effect on plasma cortisol concentrations. The neuroendocrine effects of sumatriptan differ from those of previously described 5-HT-receptor agonists, and may be a consequence of selective activation of 5-HT1D or 5-HT1B receptors. However, the present data cannot exclude the possibility that the neuroendocrine changes reflect nonspecific stress responses or changes in pituitary blood flow.


Bcl-2 prevents apoptosis induced by perforin and granzyme B, but not that mediated by whole cytotoxic lymphocytes.
Two pathways have been implicated in the induction of apoptosis by cytotoxic T cells: the granule exocytosis pathway and a pathway using CD95 (Fas/APO-1). To test whether apoptosis induced by either of these pathways could be blocked by Bcl-2, we exposed bcl-2-transfected cells to CTL derived from normal, perforin-deficient, or CD95 ligand mutant (gld) mice. Although the levels of Bcl-2 expression achieved were able to protect FDC-P1 and Yac-1 transfectants from a variety of apoptotic stimuli, the cells were not protected from cytolysis mediated by CTL from any of these sources, by NK cells, or granules isolated from CTL. However, Bcl-2 expression significantly inhibited apoptosis induced by purified granzyme B and perforin. These results suggest that while Bcl-2 is capable of inhibiting the apoptotic pathway utilized by perforin and granzyme B, other granule components can bypass this block. We conclude that CTL harbor potent killing mechanism(s) in addition to those provided by CD95 ligand or perforin and granzyme B that cannot be overcome by Bcl-2.


Brain atrophy in peritoneal dialysis and CKD stages 3-5: a cross-sectional and longitudinal study.
Brain atrophy has been reported in patients with end-stage renal disease receiving hemodialysis, although its mechanism is unknown. However, little is known regarding brain atrophy in patients receiving peritoneal dialysis (PD). Therefore, we examined brain volume and its annual change over 2 years in PD patients compared with patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). Cross-sectional and longitudinal cohort. 62 PD patients and 69 patients with NDD-CKD with no history of cerebrovascular disease who underwent brain magnetic resonance imaging (MRI) were recruited in a cross-sectional study. Among them, 34 PD patients and 61 patients with NDD-CKD, who underwent a second brain MRI after 2 years, were recruited in a longitudinal study. PD therapy versus NDD-CKD. T1-weighted magnetic resonance images were analyzed. Total gray matter volume (GMV), total white matter volume (WMV), and cerebrospinal fluid space volume were segmented, and each volume was quantified using statistical parametric mapping software. Normalized GMV and WMV values were calculated by division of GMV and WMV by intracranial volume to adjust for variations in head size. We compared normalized GMV and normalized WMV between PD patients and patients with NDD-CKD in the cross-sectional study and the annual change in normalized GMV in the longitudinal study. In the cross-sectional study, normalized GMV, which was correlated inversely with age, was lower in PD patients than in patients with NDD-CKD. However, normalized WMV, which was not correlated with age, was comparable between the groups. Annual change in normalized GMV was significantly higher in PD patients than in patients with NDD-CKD. These differences remained significant even after adjustment for potential confounding factors. A short observation period and high dropout rate in the longitudinal study. Decline in normalized GMV is faster in PD patients than in patients with NDD-CKD.


[A cross-sectional study on nonionizing radiation to male fertility].
To investigate the relationship between microwave radiation and male reproductivity. After filling out questionnaire and body check, we carried out molecular epidemiological studies, using single cell gel electrophoresis (SCGE) and sperm automatic analysis among people working on radar. Quality of semen and semi-clinical injury of sperm among the people working on radar had changed when radar electromagnetic wave frequency distance, intensity, lasting time and protection shield were changing. Dose-response relationship was noticed and the increase of sperm dysmorphia played a principal role. The results between exposed group and control group showed significant difference (P < 0.01). People working on radar who suffered from non-ionization for long time and had bad radar shield protection would show semi-clinical injury on sperm and bad semen quality. However, it did not affect the male reproductive function. It was necessary to reinforce the protection of non-ionization and to improve male reproductive health care of people working on radar.


Paleoclimate. Synchronization of North Pacific and Greenland climates preceded abrupt deglacial warming.
Some proposed mechanisms for transmission of major climate change events between the North Pacific and North Atlantic predict opposing patterns of variations; others suggest synchronization. Resolving this conflict has implications for regulation of poleward heat transport and global climate change. New multidecadal-resolution foraminiferal oxygen isotope records from the Gulf of Alaska (GOA) reveal sudden shifts between intervals of synchroneity and asynchroneity with the North Greenland Ice Core Project (NGRIP) δ(18)O record over the past 18,000 years. Synchronization of these regions occurred 15,500 to 11,000 years ago, just prior to and throughout the most abrupt climate transitions of the last 20,000 years, suggesting that dynamic coupling of North Pacific and North Atlantic climates may lead to critical transitions in Earth's climate system.


Preventing tobacco-caused cancer: a call to action.
Nicotine addiction is the most common serious medical problem in the country. Tobacco use is responsible for 30% of cancer deaths in the United States and 90% of all lung cancer deaths. The physical addiction to nicotine explains why over 30% of Americans continue to smoke or use tobacco despite their desires and efforts to quit. The testimony summarized in this paper recommends four broad strategies for preventing tobacco-caused cancers in the United States: a) mandating and reimbursing effective treatments for nicotine addiction; b) increasing Federal and state tobacco excise taxes and earmarking a fraction of tax revenues for tobacco prevention and cessation; c) enacting other policy changes to prevent tobacco use and addiction among children, including expanded clean indoor air legislation, comprehensive youth tobacco access legislation, and the regulation of tobacco products and their advertising and promotion; and d) expanding tobacco control research and critical Federal research support. Specific recommendations are given for each broad strategy.


New drug targets in psychiatry: Neurobiological considerations in the genomics era.
After a period of withdrawal, pharmaceutical companies have begun to reinvest in neuropsychiatric disorders, due to improvements in our understanding of these disorders, stimulated in part by genomic studies. However, translating this information into disease insights and ultimately into tractable therapeutic targets is a major challenge. Here we consider how different sources of information might be integrated to guide this process. We review how an understanding of neurobiology has been used to advance therapeutic candidates identified in the pre-genomic era, using catechol-O-methyltransferase (COMT) as an exemplar. We then contrast with ZNF804A, the first genome-wide significant schizophrenia gene, and draw on some of the lessons that these and other examples provide. We highlight that, at least in the short term, the translation of potential targets for which there is orthogonal neurobiological support is likely to be more straightforward and productive than that those relying solely on genomic information. Although we focus here on information from genomic studies of schizophrenia, the points are broadly applicable across major psychiatric disorders and their symptoms.


The sun compass revisited.
Many animals, and birds in particular, are thought to use directional information from the sun in the form of a time-compensated sun compass, with predictably deviated orientation under clock shift being regarded as the litmus test of this. We suggest that this paradigm obscures a number of other ways in which solar-derived information could be important in animal orientation. We distinguish between the known use of the sun's azimuth to provide absolute geographical direction (compass mechanism) and its possible use to detect changes in heading (heading indicator mechanism). Just as in an aircraft, these two kinds of information may be provided by separate mechanisms and used for different functions, for example for navigation versus steering. We also argue that although a solar compass must be time-referenced to account for the sun's apparent diurnal movement, this need not entail full time compensation. This is because animals might also use time-dependent solar information in an associatively acquired, and hence time-limited, way. Furthermore, we show that a solar heading indicator, when used on a sufficiently short timescale, need not require time compensation at all. Finally, we suggest that solar-derived cues, such as shadows, could also be involved in navigation in ways that depend explicitly upon position, and are therefore not strictly compass-related. This could include giving directionality to landmarks, or acting as time-dependent landmarks involved in place recognition. We conclude that clock shift experiments alone are neither necessary nor sufficient to identify the occurrence of all conceivable uses of solar information in animal orientation, so that a predictable response to clock shift should not be regarded as an acid test of the use of solar information in navigation.


Prazosin: preliminary clinical and pharmacological observations.
1. Prazosin had a considerable anti-hypertensive effect in both lying and standing posture in a mixed group of twenty-four patients in an open clinical trial. The drug was well tolerated and side-effects were few. 2. Tested on rat blood vessels, prazosin was ten times more potent on a molar basis than phentolamine in blocking the vasoconstrictor effects of noradrenaline. In the absence of vasoconstrictor nervous activity, no vasodilatation was observed. 3. In genetically hypertensive rats, prazosin in large doses caused a substantial fall in blood pressure, total exchangeable sodium and extracellular fluid volume. Tolerance to these effects started to develop within 20 days. In normotensive rats, blood pressure was lowered but total exchangeable sodium and extracellular fluid volume were not affected.


High-Throughput Single-Cell Transcriptome Profiling of Plant Cell Types.
Single-cell transcriptome profiling of heterogeneous tissues can provide high-resolution windows into developmental dynamics and environmental responses, but its application to plants has been limited. Here, we used the high-throughput Drop-seq approach to profile >12,000 cells from Arabidopsis roots. This identified numerous distinct cell types, covering all major root tissues and developmental stages, and illuminated specific marker genes for these populations. In addition, we demonstrate the utility of this approach to study the impact of environmental conditions on developmental processes. Analysis of roots grown with or without sucrose supplementation uncovers changes in the relative frequencies of cell types in response to sucrose. Finally, we characterize the transcriptome changes that occur across endodermis development and identify nearly 800 genes with dynamic expression as this tissue differentiates. Collectively, we demonstrate that single-cell RNA-seq can be used to profile developmental processes in plants and show how they can be altered by external stimuli.


Sleep homeostasis and models of sleep regulation.
According to the two-process model of sleep regulation, the timing and structure of sleep are determined by the interaction of a homeostatic and a circadian process. The original qualitative model was elaborated to quantitative versions that included the ultradian dynamics of sleep in relation to the non-REM-REM sleep cycle. The time course of EEG slow-wave activity, the major marker of non-REM sleep homeostasis, as well as daytime alertness were simulated successfully for a considerable number of experimental protocols. They include sleep after partial sleep deprivation and daytime napping, sleep in habitual short and long sleepers, and alertness in a forced desynchrony protocol or during an extended photoperiod. Simulations revealed that internal desynchronization can be obtained for different shapes of the thresholds. New developments include the analysis of the waking EEG to delineate homeostatic and circadian processes, studies of REM sleep homeostasis, and recent evidence for local, use-dependent sleep processes. Moreover, nonlinear interactions between homeostatic and circadian processes were identified. In the past two decades, models have contributed considerably to conceptualizing and analyzing the major processes underlying sleep regulation, and they are likely to play an important role in future advances in the field.


An Investigation of the Utility of the Addenbrooke's Cognitive Examination III in the Early Detection of Dementia in Memory Clinic Patients Aged over 75 Years.
To examine the validity of Addenbrooke's Cognitive Examination III (ACE-III) in detecting early dementia in UK memory clinic patients aged 75-85 years. The ACE-III was administered to 59 patients prior to diagnosis. The extent to which scores predicted the membership of the dementia or no-dementia group was explored using receiver operating characteristic curve analysis and other parameters of diagnostic performance. Thirty-three participants (55.9%) were diagnosed with dementia (Alzheimer's disease = 56.3%, Alzheimer's disease with cerebrovascular disease = 31.3%, and vascular dementia = 12.5%). The optimal cut-off for detecting dementia was 81/100 (scores <81 indicating dementia with a sensitivity of 0.79, a specificity of 0.96, and a positive predictive value of 0.96), with superiority over published cut-offs (88/100 and 82/100) at medium and lower prevalence rates. The number of years of full-time education had a significant positive relationship to total ACE-III scores (r = 0.697, p < 0.001) for the no-dementia group. Exploratory analysis indicated that optimal cut-offs were different for higher versus lower education groups. The ACE-III has excellent accuracy for the detection of dementia in day-to-day clinical practice. Lower cut-offs than those specified in the index paper, and the consideration of the patients' years of full-time education may be necessary for optimal diagnostic performance.


Evolution of late steps in exocytosis: conservation and specialization of the exocyst complex.
Background: The eukaryotic endomembrane system most likely arose via paralogous expansions of genes encoding proteins that specify organelle identity, coat complexes and govern fusion specificity. While the majority of these gene families were established by the time of the last eukaryotic common ancestor (LECA), subsequent evolutionary events has moulded these systems, likely reflecting adaptations retained for increased fitness. As well as sequence evolution, these adaptations include loss of otherwise canonical components, the emergence of lineage-specific proteins and paralog expansion. The exocyst complex is involved in late exocytosis and additional trafficking pathways and a member of the complexes associated with tethering containing helical rods (CATCHR) tethering complex family. CATCHR includes the conserved oligomeric Golgi (COG) complex, homotypic fusion and vacuole protein sorting (HOPS)/class C core vacuole/endosome tethering (CORVET) complexes and several others. The exocyst is integrated into a complex GTPase signalling network in animals, fungi and other lineages. Prompted by discovery of Exo99, a non-canonical subunit in the excavate protist Trypanosoma brucei, and availability of significantly increased genome sequence data, we re-examined evolution of the exocyst. Methods: We examined the evolution of exocyst components by comparative genomics, phylogenetics and structure prediction. Results: The exocyst composition is highly conserved, but with substantial losses of subunits in the Apicomplexa and expansions in Streptophyta plants, Metazoa and land plants, where for the latter, massive paralog expansion of Exo70 represents an extreme and unique example. Significantly, few taxa retain a partial complex, suggesting that, in general, all subunits are probably required for functionality. Further, the ninth exocyst subunit, Exo99, is specific to the Euglenozoa with a distinct architecture compared to the other subunits and which possibly represents a coat system. Conclusions: These data reveal a remarkable degree of evolutionary flexibility within the exocyst complex, suggesting significant diversity in exocytosis mechanisms.


The association between serum 25-hydroxyvitamin D level and recurrent falls in the elderly population: a cohort study.
Serum vitamin D concentration is a major contributing factor for increasing the risk of fall and fall-related injuries in older adults. However, when prescribed and supplemented for these populations, the outcomes are controversial, and in several cases no improvement has been reported in reducing the risk of recurrent falls. This study aimed to examine the association between serum vitamin D concentration and recurrent falls in Iranian older adults. This cohort study was conducted in the emergency departments of two university hospitals. A cohort of 82 elderly participants aged over 60 and suffered from an unintentional episode of falling was evaluated six months after their first ED visit. A structured, self-administered checklist was developed to obtain the participants' demographic and clinical information. Participants also were asked about any recurrent fall experience during follow-up. The mean (SD) age of the study population was 75 (8). Over half of the participants were male (57.3%). The mean (median) serum 25-hydroxyvitamin D (25 (OH)D) concentration was 38 (34) ng/ml. Mean serum 25(OH)D levels varied slightly between gender groups (p=0.450). An inverse but insignificant association was found between the age of participants and their serum 25(OH)D levels (r=-0.03, p=0.7). A small but insignificant association also was found between the mean serum 25(OH)D level and the number of recurrent falls in elderly patients irrespective of their age, gender, or physical activity groups (OR=1.008, p=0.992). In contrast to previous studies, no significant association of serum 25(OH)D concentration was found with recurrent falls in Iranian older adults.


Complete genome sequencing and comparative genomic analysis of functionally diverse Lysinibacillus sphaericus III(3)7.
Lysinibacillus sphaericus III(3)7 is a native Colombian strain, the first one isolated from soil samples. This strain has shown high levels of pathogenic activity against Culex quinquefaciatus larvae in laboratory assays compared to other members of the same species. Using Pacific Biosciences sequencing technology we sequenced, annotated (de novo) and described the genome of strain III(3)7, achieving a complete genome sequence status. We then performed a comparative analysis between the newly sequenced genome and the ones previously reported for Colombian isolates L. sphaericus OT4b.31, CBAM5 and OT4b.25, with the inclusion of L. sphaericus C3-41 that has been used as a reference genome for most of previous genome sequencing projects. We concluded that L. sphaericus III(3)7 is highly similar with strain OT4b.25 and shares high levels of synteny with isolates CBAM5 and C3-41.


Health care utilization and overall costs based on opioid dependence in patients undergoing surgery for degenerative spondylolisthesis.
OBJECTIVE Opioid abuse is highly prevalent in patients with back pain. The aim of this study was to identify health care utilization and overall costs associated with opioid dependence in patients undergoing surgery for degenerative spondylolisthesis (DS). METHODS The authors queried the MarketScan database using ICD-9 and CPT-4 codes from 2000 to 2012. Opioid dependency was defined as having a diagnosis of opioid use disorder, having a prescription for opioid use disorder, or having 10 or more opioid prescriptions. Opioid dependency was evaluated in 12-month period leading to surgery and in the period 3-15 months following the procedure. Patients were segregated into 4 groups based on opioid dependence before and after surgery: group NDND (prior nondependent who remain nondependent), group NDD (prior nondependent who become dependent), group DND (prior dependent who become nondependent), and group DD (prior dependent who remain dependent). The outcomes of interest were discharge disposition, hospital length of stay (LOS), complications, and health care resource costs. The 4 groups were compared using the Kruskal-Wallis test and linear contrasts built from generalized regression models. RESULTS A total of 10,708 patients were identified, with 81.57%, 3.58%, 8.54%, and 6.32% of patients in groups NDND, NDD, DND, and DD, respectively. In group DD, 96.31% of patients had decompression with fusion, compared with 93.59% in group NDND. Patients in group NDD, DND, and DD had longer hospital LOS compared with those in group NDND. Patients in group DD were less likely to be discharged home compared with those in group NDND (odds ratio 0.639, 95% confidence interval 0.52-0.785). At 3-15 months postdischarge, patients in group DD incurred 21% higher hospital readmission costs compared with those in group NDND. However, patients in groups NDD and DD were likely to incur 2.8 times the overall costs compared with patients in group NDND (p < 0.001) at 3-15 months after surgery (median overall payments: group NDD $20,033 and group DD $19,654, vs group NDND $7994). CONCLUSIONS Patients who continued to be opioid dependent or became opioid dependent following surgery for DS incurred significantly higher health care utilization and costs within 3 months and in the period 3-15 months after discharge from surgery.


Efficacy of Adaptogens in Patients with Long COVID-19: A Randomized, Quadruple-Blind, Placebo-Controlled Trial.
Currently, no effective treatment of comorbid complications or COVID-19 long-haulers during convalescence is known. This randomized, quadruple-blind, placebo-controlled trial aimed to assess the efficacy of adaptogens on the recovery of patients with Long COVID symptoms. One hundred patients with confirmed positive SARS-CoV-2 test, discharged from COVID Hotel isolation, Intensive Care Unit (ICU), or Online Clinics, and who experienced at least three of nine Long COVID symptoms (fatigue, headache, respiratory insufficiency, cognitive performance, mood disorders, loss of smell, taste, and hair, sweatiness, cough, pain in joints, muscles, and chest) in the 30 days before randomization were included in the study of the efficacy of Chisan®/ADAPT-232 (a fixed combination of adaptogens Rhodiola, Eleutherococcus, and Schisandra) supplementation for two weeks. Chisan® decreased the duration of fatigue and pain for one and two days, respectively, in 50% of patients. The number of patients with lack of fatigue and pain symptoms was significantly less in the Chisan® treatment group than in the placebo group on Days 9 (39% vs. 57%, pain relief, p = 0.0019) and 11 (28% vs. 43%, relief of fatigue, * p = 0.0157). Significant relief of severity of all Long COVID symptoms over the time of treatment and the follow-up period was observed in both groups of patients, notably decreasing the level of anxiety and depression from mild and moderate to normal, as well as increasing cognitive performance in patients in the d2 test for attention and increasing their physical activity and workout (daily walk time). However, the significant difference between placebo and Chisan® treatment was observed only with a workout (daily walk time) and relieving respiratory insufficiency (cough). A clinical assessment of blood markers of the inflammatory response (C-reactive protein) and blood coagulation (D-dimer) did not reveal any significant difference over time between treatment groups except significantly lower IL-6 in the Chisan® treatment group. Furthermore, a significant difference between the placebo and Chisan® treatment was observed for creatinine: Chisan® significantly decreased blood creatinine compared to the placebo, suggesting prevention of renal failure progression in Long COVID. In this study, we, for the first time, demonstrate that adaptogens can increase physical performance in Long COVID and reduce the duration of fatigue and chronic pain. It also suggests that Chisan®/ADAPT-232 might be useful for preventing the progression of renal failure associated with increasing creatinine.


Arterial indices and serum cystatin C level in individuals with occupational wide band noise exposure.
Chronic exposure to noise is known to cause a wide range of health problems including extracellular matrix (ECM) proliferation and involvement of cardiovascular system. There are a few studies to investigate noise-induced vascular changes using noninvasive methods. In this study we used carotid artery intima-media thickness (CIMT) and aortic augmentation as indices of arterial properties and cystatin C as a serum biomarker relating to ECM metabolism. Ninety-three male participants were included in this study from aeronautic technicians: 39 with and 54 without a history of wide band noise (WBN) exposure. For better discrimination, the participants were divided into the two age groups: <40 and >40 years old. Adjusted aortic augmentation index (AI) for a heart rate equal to 75 beats per minute (AIx@HR75) were calculated using pulse wave analysis (PWA). CIMT was measured in 54 participants who accepted to undergo Doppler ultrasonography. Serum cystatin C was also measured. Among younger individuals the mean CIMT was 0.85 ± 0.09 mm and 0.75 ± 0.22 mm in the in the exposed and the control groups respectively. Among older individuals CIMT had a mean of 1.04 ± 0.22 mm vs. 1.00 ± 0.25 mm for the exposed vs. the control group. However, in both age groups the difference was not significant at the 0.05 level. A comparison of AIx@HR75 between exposure group and control group both in younger age group (5.46 ± 11.22 vs. 8.56 ± 8.66) and older age group (17.55 ± 10.07 vs. 16.61 ± 5.77) revealed no significant difference. We did not find any significant correlation between CIMT and AIx@HR75 in exposed group (r = 0.314, P value = 0.145) but the correlation was significant in control group (r = 0.455, P value = 0.019). Serum cystatin C level was significantly lower in individuals with WBN exposure compared to controls (441.10 ± 104.70 ng/L vs. 616.89 ± 136.14, P value < 0.001) both in younger and older groups. We could not find any evidence for the association of WBN exposure with arterial properties, but cystatin C was significantly lower in the exposed group.


Development of Response Evaluation and Decision (RED) and antisocial behavior in childhood and adolescence.
Using longitudinal data on 585 youths (48% female; 17% African American, 2% other ethnic minority), the authors examined the development of social response evaluation and decision (RED) across childhood (Study 1; kindergarten through Grade 3) and adolescence (Study 2; Grades 8 and 11). Participants completed hypothetical-vignette-based RED assessments, and their antisocial behaviors were measured by multiple raters. Structural equation modeling and linear growth analyses indicated that children differentiate alternative responses by Grade 3, but these RED responses were not consistently related to antisocial behavior. Adolescent analyses provided support for a model of multiple evaluative domains of RED and showed strong relations between aggressive response evaluations, nonaggressive response evaluations, and antisocial behavior. Findings indicate that RED becomes more differential (or specific to response style) and is increasingly related to youths' antisocial conduct across development.


Galectin-3 binds Neisseria meningitidis and increases interaction with phagocytic cells.
Galectin-3 is expressed and secreted by immune cells and has been implicated in multiple aspects of the inflammatory response. It is a glycan binding protein which can exert its functions within cells or exogenously by binding cell surface ligands, acting as a molecular bridge or activating signalling pathways. In addition, this lectin has been shown to bind to microorganisms. In this study we investigated the interaction between galectin-3 and Neisseria meningitidis, an important extracellular human pathogen, which is a leading cause of septicaemia and meningitis. Immunohistochemical analysis indicated that galectin-3 is expressed during meningococcal disease and colocalizes with bacterial colonies in infected tissues from patients. We show that galectin-3 binds to N. meningitidis and we demonstrate that this interaction requiresfull-length, intact lipopolysaccharide molecules. We found that neither exogenous nor endogenous galectin-3 contributes to phagocytosis of N. meningitidis; instead exogenous galectin-3 increases adhesion to monocytes and macrophages but not epithelial cells. Finally we used galectin-3 deficient (Gal-3(-/-) ) mice to evaluate the contribution of galectin-3 to meningococcal bacteraemia. We found that Gal-3(-/-) mice had significantly lower levels of bacteraemia compared with wild-type mice after challenge with live bacteria, indicating that galectin-3 confers an advantage to N. meningitidis during systemic infection.


Human-specific loss of regulatory DNA and the evolution of human-specific traits.
Humans differ from other animals in many aspects of anatomy, physiology, and behaviour; however, the genotypic basis of most human-specific traits remains unknown. Recent whole-genome comparisons have made it possible to identify genes with elevated rates of amino acid change or divergent expression in humans, and non-coding sequences with accelerated base pair changes. Regulatory alterations may be particularly likely to produce phenotypic effects while preserving viability, and are known to underlie interesting evolutionary differences in other species. Here we identify molecular events particularly likely to produce significant regulatory changes in humans: complete deletion of sequences otherwise highly conserved between chimpanzees and other mammals. We confirm 510 such deletions in humans, which fall almost exclusively in non-coding regions and are enriched near genes involved in steroid hormone signalling and neural function. One deletion removes a sensory vibrissae and penile spine enhancer from the human androgen receptor (AR) gene, a molecular change correlated with anatomical loss of androgen-dependent sensory vibrissae and penile spines in the human lineage. Another deletion removes a forebrain subventricular zone enhancer near the tumour suppressor gene growth arrest and DNA-damage-inducible, gamma (GADD45G), a loss correlated with expansion of specific brain regions in humans. Deletions of tissue-specific enhancers may thus accompany both loss and gain traits in the human lineage, and provide specific examples of the kinds of regulatory alterations and inactivation events long proposed to have an important role in human evolutionary divergence.


On the mechanism of electrochemical vesicle cytometry: chromaffin cell vesicles and liposomes.
The mechanism of mammalian vesicle rupture onto the surface of a polarized carbon fiber microelectrode during electrochemical vesicle cytometry is investigated. It appears that following adsorption to the surface of the polarized electrode, electroporation leads to the formation of a pore at the interface between a vesicle and the electrode and this is shown to be potential dependent. The chemical cargo is then released through this pore to be oxidized at the electrode surface. This makes it possible to quantify the contents as it restricts diffusion away from the electrode and coulometric oxidation takes place. Using a bottom up approach, lipid-only transmitter-loaded liposomes were used to mimic native vesicles and the rupture events occurred much faster in comparison with native vesicles. Liposomes with added peptide in the membrane result in rupture events with a lower duration than that of liposomes and faster in comparison to native vesicles. Diffusional models have been developed and suggest that the trend in pore size is dependent on soft nanoparticle size and diffusion of the content in the nanometer vesicle. In addition, it appears that proteins form a barrier for the membrane to reach the electrode and need to move out of the way to allow close contact and electroporation. The protein dense core in vesicles matrixes is also important in the dynamics of the events in that it significantly slows diffusion through the vesicle.


Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research.
Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1CreER knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1CreER KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4 Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1CreER KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions.


Finding European bioethical literature: an evaluation of the leading abstracting and indexing services.
In this study the author aimed to provide information for researchers to help them with the selection of suitable databases for finding medical ethics literature. The quantity of medical ethical literature that is indexed in different existing electronic bibliographies was ascertained. Using the international journal index Ulrich's Periodicals Directory, journals on medical ethics were identified. The electronic bibliographies indexing these journals were analysed. In an additional analysis documentalists indexing bioethical literature were asked to name European journals on medical ethics. The bibliographies indexing these journals were examined. Of 290 journals on medical ethics 173 were indexed in at least one bibliography. Current Contents showed the highest coverage with 66 (22.8%) journals indexed followed by MEDLINE (22.1%). By a combined search in the top ten bibliographies with the highest coverage, a maximum coverage of 45.2% of all journals could be reached. All the bibliographies showed a tendency to index more North American than European literature. This result was verified by the supplementary analysis of a sample of continental European journals. Here EMBASE covered the highest number of journals (20.6%) followed by the Russian Academy of Sciences Bibliographies (19.2%). A medical ethics literature search has to be carried out in several databases in order to reach an adequate collection of literature. The databases one wishes to combine should be carefully chosen. There seems to be a regional bias in the most popular databases, favouring North American periodicals compared with European literature on medical ethics.


Immunosenescence increases the rate of acceptance of kidney allotransplants in elderly recipients through exhaustion of CD4+ T-cells.
Compromised immunity is the hallmark of ageing. Paradoxically, it may be "an ally" in facilitating acceptance of allogeneic grafts in the elderly. In this retrospective study we looked for biomarkers of immunosenescence that distinguish elderly recipients less prone to reject kidney allografts. Recruited kidney recipients aged > or = 60 or < 60 were designated 'elderly' and 'young', respectively. Both age-groups were divided according to the history of acute rejection. The phenotype, length of telomeres, expression of FoxP3 and proliferative responses were assessed in CD4(+) and CD8(+) T-cell subsets. In addition, IL6, IL10 and TGFbeta were measured on the level of mRNA and serum protein. Acute-rejection-free history in elderly transplant recipients was associated with short telomeres, a decreased proportion of CD28(+) T-cells associated with CMV-seropositivity and low proliferation of CD4(+) T-cells. In contrast, elderly recipients who experienced acute rejection kept preserved telomere length, had a higher number of functional CD4(+)CD28(+) cells and exhibited vigorous proliferation in vitro. These differences were not found in the young group. The major conclusion of this study is that the impaired condition of CD4(+) T-cells, so-called immunosenescence, renders transplant recipients less responsive to an allogeneic kidney graft, an effect that was limited to transplant recipients of > 60 years of age.


Induced abortions and unintended pregnancies in pakistan.
During the past decade, unmet need for family planning has remained high in Pakistan and gains in contraceptive prevalence have been small. Drawing upon data from a 2012 national study on postabortion-care complications and a methodology developed by the Guttmacher Institute for estimating abortion incidence, we estimate that there were 2.2 million abortions in Pakistan in 2012, an annual abortion rate of 50 per 1,000 women. A previous study estimated an abortion rate of 27 per 1,000 women in 2002. After taking into consideration the earlier study's underestimation of abortion incidence, we conclude that the abortion rate has likely increased substantially between 2002 and 2012. Varying contraceptive-use patterns and abortion rates are found among the provinces, with higher abortion rates in Baluchistan and Sindh than in Khyber Pakhtunkhwa and Punjab. This suggests that strategies for coping with the other wise uniformly high unintended pregnancy rates will differ among provinces. The need for an accelerated and fortified family planning program is greater than ever, as is the need to implement strategies to improve the quality and coverage of postabortion services.


Identification of the 37-kDa protein displaying a variable interaction with the erythroid cell membrane as glyceraldehyde-3-phosphate dehydrogenase.
In previous studies from this laboratory we isolated and characterized a 37-kDa protein that was associated with the membrane of erythroid cells. The polypeptide appeared to undergo a lineage-specific alteration in its interaction with the membrane during erythroid development and migrated as a family of isoelectric focusing variants during analyses on two-dimensional gels. We report here that the 37-kDa protein is homologous to the enzyme glyceraldehyde-3-phosphate dehydrogenase (EC 220.127.116.11). This conclusion was reached from the results of several experimental approaches comparing the biochemical and genetic properties of the 37-kDa protein (p37) with authentic glyceraldehyde-3-phosphate dehydrogenase. Peptide maps of highly purified p37 and glyceraldehyde-3-phosphate dehydrogenase, generated with Staphylococcus V8 protease, were identical. The nucleotide sequence of a cDNA clone encoding p37 was nearly identical to the published sequence for genes encoding glyceraldehyde-3-phosphate dehydrogenase. These results suggest that the interaction of the enzyme with the red cell membrane is more complex than previously envisioned. The existence of subpopulations of glyceraldehyde-3-phosphate dehydrogenase molecules is envisioned that exhibit different levels of enzyme activity and bind to the red cell membrane with varying affinities.


Electrophysiology and ultrastructure of canine subendocardial Purkinje cells isolated from control and 24-hour infarcted hearts.
Ventricular arrhythmias that accompany myocardial infarction in dogs may be secondary to the altered electrophysiological properties of the subendocardial Purkinje fibers that survive 24 hours after the coronary occlusion. To better understand the ionic mechanisms that underlie the altered electrical activity of these fibers, we have dispersed, using an enzymatic technique, Purkinje cells from the subendocardium of the infarcted ventricle (IZPCs) and compared their electrical and structural properties to Purkinje cells dispersed from fiber strands (SPCs) and from the subendocardium of the noninfarcted ventricle (NZPCs). Ultrastructural analysis of these cells shows that IZPCs contain an increased number of lipid droplets when compared with the SPCs and NZPCs. In addition, transmembrane action potentials of IZPCs have reduced resting potentials, action potential amplitudes, and upstroke velocity and are increased in duration when compared with either SPCs or NZPCs. Input resistance of IZPCs is increased over that measured in control cells (SPCs and NZPCs). Furthermore, the time course of the process of electrical restitution of action potential duration is altered in IZPCs with long action potentials. Finally, using K+-sensitive microelectrode techniques, we have determined that intracellular free K+ activity (aKi) in IZPCs (93.7 +/- 15 mM) is not significantly different from control aKi measurements (SPC, 106 +/- 13 mM; NZPC, 103 +/- 12 mM). Thus a reduction in aKi does not provide a basis for the reduced resting potentials observed in IZPCs. By studying the relation between the resting potential and log [K+]o we determined that in IZPCs with reduced resting potentials, there is a significant increase in the PNa/PK ratio when compared with control. In summary, to better understand the cellular basis of ventricular arrhythmias postinfarction, we have developed a single cell model that will allow for more rigorous electrophysiological studies of the specific ionic currents that underlie the abnormal electrophysiology.


Disease and health management in Asian aquaculture.
Asia contributes more than 90% to the world's aquaculture production. Like other farming systems, aquaculture is plagued with disease problems resulting from its intensification and commercialization. This paper describes the various factors, providing specific examples, which have contributed to the current disease problems faced by what is now the fastest growing food-producing sector globally. These include increased globalization of trade and markets; the intensification of fish-farming practices through the movement of broodstock, postlarvae, fry and fingerlings; the introduction of new species for aquaculture development; the expansion of the ornamental fish trade; the enhancement of marine and coastal areas through the stocking of aquatic animals raised in hatcheries; the unanticipated interactions between cultured and wild populations of aquatic animals; poor or lack of effective biosecurity measures; slow awareness on emerging diseases; the misunderstanding and misuse of specific pathogen free (SPF) stocks; climate change; other human-mediated movements of aquaculture commodities. Data on the socio-economic impacts of aquatic animal diseases are also presented, including estimates of losses in production, direct and indirect income and employment, market access or share of investment, and consumer confidence; food availability; industry failures. Examples of costs of investment in aquatic animal health-related activities, including national strategies, research, surveillance, control and other health management programmes are also provided. Finally, the strategies currently being implemented in the Asian region to deal with transboundary diseases affecting the aquaculture sector are highlighted. These include compliance with international codes, and development and implementation of regional guidelines and national aquatic animal health strategies; new diagnostic and therapeutic techniques and new information technology; new biosecurity measures including risk analysis, epidemiology, surveillance, reporting and planning for emergency response to epizootics; targeted research; institutional strengthening and manpower development (education, training and extension research and diagnostic services).


Cognitive and clinical moderators of recognition memory in schizophrenia: a meta-analysis.
Recognition memory performance in schizophrenia has been shown to vary greatly across studies. To identify the conditions under which recognition memory is significantly impaired, we used a meta-analytic strategy to quantify the moderating effects of several cognitive and clinical variables. Eighty-four studies (from 1965 to July 2003) provided recognition memory data for both a schizophrenia and control group. The overall group comparison for recognition memory yielded a significant mean weighted effect size of d=0.76. Material specificity was the most significant cognitive variable found, with patients exhibiting greater impairment for figural than verbal recognition. A yes-no recognition format and auditory encoding also led to significantly greater effect sizes for recognition memory relative to forced-choice recognition tests and visual encoding, respectively. Furthermore, the effect size for recognition memory as measured by false alarm was smaller than the effect size as measured by hit rate or by d-prime and its related measures. Among clinical variables that were associated with higher effect sizes, chronicity was the most significant, but different trends linking poor performance to negative symptoms and general symptomatology were also observed. Thus, a recognition memory deficit moderated by both cognitive and clinical variables is clearly present in schizophrenia.


Portable XRF analysis of occupational air filter samples from different workplaces using different samplers: final results, summary and conclusions.
This paper concludes a five-year program on research into the use of a portable X-ray fluorescence (XRF) analyzer for analyzing lead in air sampling filters from different industrial environments, including mining, manufacturing and recycling. The results from four of these environments have already been reported. The results from two additional metal processes are presented here. At both of these sites, lead was a minor component of the total airborne metals and interferences from other elements were minimal. Nevertheless, only results from the three sites where lead was the most abundant metal were used in the overall calculation of method accuracy. The XRF analyzer was used to interrogate the filters, which were then subjected to acid digestion and analysis by inductively-coupled plasma optical-emission spectroscopy (ICP-OES). The filter samples were collected using different filter-holders or "samplers" where the size (diameter), depth and homogeneity of aerosol deposit varied from sampler to sampler. The aerosol collection efficiencies of the samplers were expected to differ, especially for larger particles. The distribution of particles once having entered the sampler was also expected to differ between samplers. Samplers were paired to allow the between-sampler variability to be addressed, and, in some cases, internal sampler wall deposits were evaluated and compared to the filter catch. It was found, rather surprisingly, that analysis of the filter deposits (by ICP-OES) of all the samplers gave equivalent results. It was also found that deposits on some of the sampler walls, which in some protocols are considered part of the sample, could be significant in comparison to the filter deposit. If it is concluded that wall-deposits should be analyzed, then XRF analysis of the filter can only give a minimum estimate of the concentration. Techniques for the statistical analysis of field data were also developed as part of this program and have been reported elsewhere. The results, based on data from the three workplaces where lead was the major element present in the samples, are summarized here. A limit of detection and a limit of quantitation are provided. Analysis of some samples using a second analyzer with a different X-ray source technology indicated reasonable agreement for some metals (but this was not evaluated for lead). Provided it is only necessary to analyze the filters, most personal samplers will provide acceptable results when used with portable XRF analysis for lead around applicable limit values.


Environmental drivers interactively affect individual tree growth across temperate European forests.
Forecasting the growth of tree species to future environmental changes requires a better understanding of its determinants. Tree growth is known to respond to global-change drivers such as climate change or atmospheric deposition, as well as to local land-use drivers such as forest management. Yet, large geographical scale studies examining interactive growth responses to multiple global-change drivers are relatively scarce and rarely consider management effects. Here, we assessed the interactive effects of three global-change drivers (temperature, precipitation and nitrogen deposition) on individual tree growth of three study species (Quercus robur/petraea, Fagus sylvatica and Fraxinus excelsior). We sampled trees along spatial environmental gradients across Europe and accounted for the effects of management for Quercus. We collected increment cores from 267 trees distributed over 151 plots in 19 forest regions and characterized their neighbouring environment to take into account potentially confounding factors such as tree size, competition, soil conditions and elevation. We demonstrate that growth responds interactively to global-change drivers, with species-specific sensitivities to the combined factors. Simultaneously high levels of precipitation and deposition benefited Fraxinus, but negatively affected Quercus' growth, highlighting species-specific interactive tree growth responses to combined drivers. For Fagus, a stronger growth response to higher temperatures was found when precipitation was also higher, illustrating the potential negative effects of drought stress under warming for this species. Furthermore, we show that past forest management can modulate the effects of changing temperatures on Quercus' growth; individuals in plots with a coppicing history showed stronger growth responses to higher temperatures. Overall, our findings highlight how tree growth can be interactively determined by global-change drivers, and how these growth responses might be modulated by past forest management. By showing future growth changes for scenarios of environmental change, we stress the importance of considering multiple drivers, including past management and their interactions, when predicting tree growth.


Terahertz-field-induced insulator-to-metal transition in vanadium dioxide metamaterial.
Electron-electron interactions can render an otherwise conducting material insulating, with the insulator-metal phase transition in correlated-electron materials being the canonical macroscopic manifestation of the competition between charge-carrier itinerancy and localization. The transition can arise from underlying microscopic interactions among the charge, lattice, orbital and spin degrees of freedom, the complexity of which leads to multiple phase-transition pathways. For example, in many transition metal oxides, the insulator-metal transition has been achieved with external stimuli, including temperature, light, electric field, mechanical strain or magnetic field. Vanadium dioxide is particularly intriguing because both the lattice and on-site Coulomb repulsion contribute to the insulator-to-metal transition at 340 K (ref. 8). Thus, although the precise microscopic origin of the phase transition remains elusive, vanadium dioxide serves as a testbed for correlated-electron phase-transition dynamics. Here we report the observation of an insulator-metal transition in vanadium dioxide induced by a terahertz electric field. This is achieved using metamaterial-enhanced picosecond, high-field terahertz pulses to reduce the Coulomb-induced potential barrier for carrier transport. A nonlinear metamaterial response is observed through the phase transition, demonstrating that high-field terahertz pulses provide alternative pathways to induce collective electronic and structural rearrangements. The metamaterial resonators play a dual role, providing sub-wavelength field enhancement that locally drives the nonlinear response, and global sensitivity to the local changes, thereby enabling macroscopic observation of the dynamics. This methodology provides a powerful platform to investigate low-energy dynamics in condensed matter and, further, demonstrates that integration of metamaterials with complex matter is a viable pathway to realize functional nonlinear electromagnetic composites.


The State of Long Non-Coding RNA Biology.
Transcriptomic studies have demonstrated that the vast majority of the genomes of mammals and other complex organisms is expressed in highly dynamic and cell-specific patterns to produce large numbers of intergenic, antisense and intronic long non-protein-coding RNAs (lncRNAs). Despite well characterized examples, their scaling with developmental complexity, and many demonstrations of their association with cellular processes, development and diseases, lncRNAs are still to be widely accepted as major players in gene regulation. This may reflect an underappreciation of the extent and precision of the epigenetic control of differentiation and development, where lncRNAs appear to have a central role, likely as organizational and guide molecules: most lncRNAs are nuclear-localized and chromatin-associated, with some involved in the formation of specialized subcellular domains. I suggest that a reassessment of the conceptual framework of genetic information and gene expression in the 4-dimensional ontogeny of spatially organized multicellular organisms is required. Together with this and further studies on their biology, the key challenges now are to determine the structure⁻function relationships of lncRNAs, which may be aided by emerging evidence of their modular structure, the role of RNA editing and modification in enabling epigenetic plasticity, and the role of RNA signaling in transgenerational inheritance of experience.


Thermophoretic transport of ionic liquid droplets in carbon nanotubes.
Thermal-gradient induced transport of ionic liquid (IL) and water droplets through a carbon nanotube (CNT) is investigated in this study using molecular dynamics simulations. Energetic analysis indicates that IL transport through a CNT is driven primarily by the fluid-solid interaction, while fluid-fluid interactions dominate in water-CNT systems. Droplet diffusion analysis via the moment scaling spectrum reveals sub-diffusive motion of the IL droplet, in contrast to the self-diffusive motion of the water droplet. The Soret coefficient and energetic analysis of the systems suggest that the CNT shows more affinity for interaction with IL than with the water droplet. Thermophoretic transport of IL is shown to be feasible, which can create new opportunities in nanofluidic applications.


Patients With Dry Eye Disease and Low Subbasal Nerve Density Are at High Risk for Accelerated Corneal Endothelial Cell Loss.
To evaluate changes in corneal endothelial cell density over time in patients with dry eye disease (DED) and to correlate endothelial cell loss with corneal subbasal nerve density. This retrospective study included 40 eyes of 20 patients with DED. Laser in vivo confocal microscopy had been performed in the central cornea of both eyes at an initial visit and repeated after a mean follow-up of 33.2 ± 10.2 months. The densities of corneal endothelial cells and subbasal nerves were measured in both visits and compared with 13 eyes of 13 normal age-matched controls. At the initial visit, the DED group had lower densities of corneal endothelial cells (2620 ± 386 cells/mm) and subbasal nerves (17.8 ± 7.5 mm/mm) compared with the control group (2861 ± 292 cells/mm and 22.8 ± 3.0 mm/mm, with P = 0.08 and P = 0.01, respectively). At the end of follow-up, although there was no significant change in subbasal nerve density (16.7 ± 7.2 mm/mm, P = 0.43), the mean corneal endothelial cell density significantly decreased to 2465 ± 391 cells/mm (P = 0.01), with a mean corneal endothelial cell loss of 2.1 ± 3.6% per year. The endothelial cell loss showed a statistically significant negative correlation with the initial subbasal nerve density (Rs = -0.55, P = 0.02). Patients with DED have an accelerated corneal endothelial cell loss compared with that reported in the literature for normal aging. Those with lower subbasal nerve density, in particular, are at a higher risk for endothelial cell loss over time.


Rotating night shift work and physical activity of nurses and midwives in the cross-sectional study in Łódź, Poland.
Shift work have been thought to restrict participation in leisure time activities, but the knowledge about physical activity in rotating night shift nurses has been limited so far. We investigated the associations between the rotating night shift work and physical activity using data from a cross-sectional study among nurses and midwives. This study included 354 nurses and midwives (aged 40-60) currently working rotating night shifts and 371 ones working days only. The information on the work characteristics and potential covariates was collected via a personal interview. Weight and height were measured and BMI was calculated. Physical activity was assessed according to the international questionnaire on physical activity - IPAQ, and four domains: leisure time, occupational, transport related and household were analyzed. Women who reported none leisure time activity were defined as recreationally "inactive". The associations were examined with multiple linear or logistic regression models adjusted for age, season of the year, number of full term births, marital status and BMI. Total and occupational physical activity was significantly higher among nurses working rotating night shifts. However, leisure time activity was significantly affected among rotating night shift nurses and midwives, compared to women working during the days only, with increased odds ratio for recreational "inactivity" (OR = 1.57, 95% CI: 1.11-2.20). Rotating night shift work among nurses and midwives is associated with higher occupational physical activity but lower leisure time activity. Initiatives supporting exercising among night shift workers are recommended.


The Affordable Care Act's Marketplaces Expanded Insurance Coverage For Adults With Chronic Health Conditions.
The Affordable Care Act (ACA) made private nongroup health insurance more accessible to nonelderly adults with chronic conditions, with enrollment growth occurring through the federal and state-based Marketplaces. During the July through December reference period in 2014-15, 45 percent of Marketplace enrollees ages 18-64 were treated for chronic conditions, compared with 35 percent of non-Marketplace nongroup enrollees and 38 percent of adults with employer-sponsored insurance. Marketplace enrollees also had higher service use than other privately insured adults did, which likely contributed to rising premiums in the nongroup market. As repeal of the ACA individual mandate takes effect in 2019, protecting coverage gains for adults with chronic conditions while stabilizing nongroup premiums may depend on state-level efforts to spread the risk of Marketplace enrollees' health care costs across a balanced insurance pool.


MAP4-dependent regulation of microtubule formation affects centrosome, cilia, and Golgi architecture as a central mechanism in growth regulation.
Numerous genes are involved in human growth regulation. Recently, autosomal-recessive inherited variants in centrosomal proteins have been identified in Seckel syndrome, primary microcephaly, or microcephalic osteodysplastic primary dwarfism. Common hallmarks of these syndromic forms are severe short stature and microcephaly. In a consanguineous family with two affected children with severe growth retardation and normocephaly, we used homozygosity mapping and next-generation sequencing to identify a homozygous MAP4 variant. MAP4 is a major protein for microtubule assembly during mitosis. High-expression levels in the somite boundaries of zebrafish suggested a role in growth and body segment patterning. The identified variant affects binding sites of kinases necessary for dynamic instability of microtubule formation. We found centrosome amplifications in mitotic fibroblast cells in vivo and in vitro. These numeric centrosomal aberrations were also present during interphase resulting in aberrant ciliogenesis. Furthermore, affected cells showed a dysfunction of the microtubule-dependent assembly of the Golgi apparatus, indicated by a significant lack of compactness of Golgi membranes. These observations demonstrated that MAP4 mutations contribute to the clinical spectrum of centrosomal defects and confirmed the complex role of a centrosomal protein in centrosomal, ciliary, and Golgi regulation associated with severe short stature.


Chronic condition management and self-management in Aboriginal communities in South Australia: outcomes of a longitudinal study.
This paper describes the longitudinal component of a larger mixed methods study into the processes and outcomes of chronic condition management and self-management strategies implemented in three Aboriginal communities in South Australia. The study was designed to document the connection between the application of structured systems of care for Aboriginal people and their longer-term health status. The study concentrated on three diverse Aboriginal communities in South Australia; the Port Lincoln Aboriginal Health Service, the Riverland community, and Nunkuwarrin Yunti Aboriginal Health Service in the Adelaide metropolitan area. Repeated-measure clinical data were collected for individual participants using a range of clinical indicators for diabetes (type 1 and 2) and related chronic conditions. Clinical data were analysed using random effects modelling techniques with changes in key clinical indicators being modelled at both the individual and group levels. Where care planning has been in place longer than in other sites overall improvements were noted in BMI, cholesterol (high density and low density lipids) and HbA1c. These results indicate that for Aboriginal patients with complex chronic conditions, participation in and adherence to structured care planning and self-management strategies can contribute to improved overall health status and health outcomes. The outcomes reported here represent an initial and important step in quantifying the health benefits that can accrue for Aboriginal people living with complex chronic conditions such as diabetes, heart disease and respiratory disease. The study highlights the benefits of developing long-term working relationships with Aboriginal communities as a basis for conducting effective collaborative health research programs. WHAT IS KNOWN ABOUT THE TOPIC? Chronic condition management and self-management programs have been available to Aboriginal people in a range of forms for some time. We know that some groups of patients are keen to engage with care planning and self-management protocols and we have anecdotal evidence of this engagement leading to improved quality of life and health outcomes for Aboriginal people. WHAT DOES THIS PAPER ADD? This paper provides early evidence of sustained improvement over time for a cohort of Aboriginal people who are learning to deal with a range of chronic illnesses through accessing structured systems of support and care. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? This longitudinal evidence of improved outcomes for Aboriginal people is encouraging and should lead on to more definitive studies of outcomes accruing for people engaged in structured systems of care. Not only does this finding have implications for the overall management of chronic illness in Aboriginal communities, but it points the way to how health services might best invest their resources and efforts to improve the health status of people with chronic conditions and, in the process, close the gap between the life expectancy of Aboriginal people and that of other community groups in Australia.


Towards Low Energy Atrial Defibrillation.
A wireless powered implantable atrial defibrillator consisting of a battery driven hand-held radio frequency (RF) power transmitter (ex vivo) and a passive (battery free) implantable power receiver (in vivo) that enables measurement of the intracardiac impedance (ICI) during internal atrial defibrillation is reported. The architecture is designed to operate in two modes: Cardiac sense mode (power-up, measure the impedance of the cardiac substrate and communicate data to the ex vivo power transmitter) and cardiac shock mode (delivery of a synchronised very low tilt rectilinear electrical shock waveform). An initial prototype was implemented and tested. In low-power (sense) mode, >5 W was delivered across a 2.5 cm air-skin gap to facilitate measurement of the impedance of the cardiac substrate. In high-power (shock) mode, >180 W (delivered as a 12 ms monophasic very-low-tilt-rectilinear (M-VLTR) or as a 12 ms biphasic very-low-tilt-rectilinear (B-VLTR) chronosymmetric (6ms/6ms) amplitude asymmetric (negative phase at 50% magnitude) shock was reliably and repeatedly delivered across the same interface; with >47% DC-to-DC (direct current to direct current) power transfer efficiency at a switching frequency of 185 kHz achieved. In an initial trial of the RF architecture developed, 30 patients with AF were randomised to therapy with an RF generated M-VLTR or B-VLTR shock using a step-up voltage protocol (50-300 V). Mean energy for successful cardioversion was 8.51 J ± 3.16 J. Subsequent analysis revealed that all patients who cardioverted exhibited a significant decrease in ICI between the first and third shocks (5.00 Ω (SD(σ) = 1.62 Ω), p < 0.01) while spectral analysis across frequency also revealed a significant variation in the impedance-amplitude-spectrum-area (IAMSA) within the same patient group (|∆(IAMSAS1-IAMSAS3)[1 Hz - 20 kHz] = 20.82 Ω-Hz (SD(σ) = 10.77 Ω-Hz), p < 0.01); both trends being absent in all patients that failed to cardiovert. Efficient transcutaneous power transfer and sensing of ICI during cardioversion are evidenced as key to the advancement of low-energy atrial defibrillation.


Dependence of the evolution of carbon dynamics in the northern permafrost region on the trajectory of climate change.
We conducted a model-based assessment of changes in permafrost area and carbon storage for simulations driven by RCP4.5 and RCP8.5 projections between 2010 and 2299 for the northern permafrost region. All models simulating carbon represented soil with depth, a critical structural feature needed to represent the permafrost carbon-climate feedback, but that is not a universal feature of all climate models. Between 2010 and 2299, simulations indicated losses of permafrost between 3 and 5 million km2 for the RCP4.5 climate and between 6 and 16 million km2 for the RCP8.5 climate. For the RCP4.5 projection, cumulative change in soil carbon varied between 66-Pg C (1015-g carbon) loss to 70-Pg C gain. For the RCP8.5 projection, losses in soil carbon varied between 74 and 652 Pg C (mean loss, 341 Pg C). For the RCP4.5 projection, gains in vegetation carbon were largely responsible for the overall projected net gains in ecosystem carbon by 2299 (8- to 244-Pg C gains). In contrast, for the RCP8.5 projection, gains in vegetation carbon were not great enough to compensate for the losses of carbon projected by four of the five models; changes in ecosystem carbon ranged from a 641-Pg C loss to a 167-Pg C gain (mean, 208-Pg C loss). The models indicate that substantial net losses of ecosystem carbon would not occur until after 2100. This assessment suggests that effective mitigation efforts during the remainder of this century could attenuate the negative consequences of the permafrost carbon-climate feedback.


Gene directed enzyme prodrug therapy for cancer.
One strategy for gene therapy in malignant disease is gene directed enzyme prodrug therapy (GDEPT). An exogenous enzyme gene is delivered to tumour cells. The enzyme, when expressed, can convert a non-toxic prodrug into a cytotoxic species that is capable of killing the cell in which it has been produced. The most frequently used systems are HSV thymidine kinase with ganciclovir and E. coli cytosine deaminase with 5-fluorocytosine. The bystander effect is of key importance to GDEPT: This describes the local spread of active species from cells that express the enzyme to kill adjacent, untransduced cells. The ultimate success of GDEPT will depend on the ability to achieve efficient gene delivery to and expression in target cells, whilst minimising expression in other tissues. A variety of techniques exist to achieve this goal, including loco-regional administration, manipulation of tumour blood supply and use of tumour-specific promoters to drive enzyme gene expression.