The Sydney Centenarian Study: methodology and profile of centenarians and near-centenarians.
The study of exceptionally long-living individuals can inform us about the determinants of successful aging. There are few population-based studies of centenarians and near-centenarians internationally, but none in Australia. Individuals 95 years and older were recruited from seven electoral districts in Sydney using the electoral roll, Medicare lists, and multiple other strategies to obtain a representative sample. Physical and mental health and cognitive status were assessed using standard instruments in multiple sessions, with assessments individually adapted. An informant was interviewed, and participants were invited to donate a blood sample, undergo an MRI scan, and enrol into the brain donation program. Preliminary data on the first 200 participants are reported. Mean age was 97.4 years (range 95-106), with 29.5% being men, and 58.5% living in a private dwelling. Rates of heart disease and diabetes were lower than in octogenarians, but hearing and visual deficits were common. The mean mini-mental state examination (MMSE) score was 21.1, with men performing better. Rates of psychological distress were low and satisfaction with life high (mean 5.91 out of a maximum of 7); 54% scored <24 on MMSE; 39.5% were impaired on both MMSE and a functional measure; and 20% had previous diagnosis of dementia. This is a preliminary report describing the methodology of the study. It provides further evidence that dementia is not inevitable at this age and independent living is common. The study provides an excellent resource to determine the genetic and environmental contributions to long and successful cognitive aging.


Patterns and controls of foliar nutrient stoichiometry and flexibility across United States forests.
Plant element stoichiometry and stoichiometric flexibility strongly regulate ecosystem responses to global change. Here, we tested three potential mechanistic drivers (climate, soil nutrients, and plant taxonomy) of both using paired foliar and soil nutrient data from terrestrial forested National Ecological Observatory Network sites across the USA. We found that broad patterns of foliar nitrogen (N) and foliar phosphorus (P) are explained by different mechanisms. Plant taxonomy was an important control over all foliar nutrient stoichiometries and concentrations, especially foliar N, which was dominantly related to taxonomy and did not vary across climate or soil gradients. Despite a lack of site-level correlations between N and environment variables, foliar N exhibited intraspecific flexibility, with numerous species-specific correlations between foliar N and various environmental factors, demonstrating the variable spatial and temporal scales on which foliar chemistry and stoichiometric flexibility can manifest. In addition to plant taxonomy, foliar P and N:P ratios were also linked to soil nutrient status (extractable P) and climate, especially actual evapotranspiration rates. Our findings highlight the myriad factors that influence foliar chemistry and show that broad patterns cannot be explained by a single consistent mechanism. Furthermore, differing controls over foliar N versus P suggests that each may be sensitive to global change drivers on distinct spatial and temporal scales, potentially resulting in altered ecosystem N:P ratios that have implications for processes ranging from productivity to carbon sequestration.


The staged approach to bladder exstrophy closure and the role of osteotomies.
Since the 1970's, the staged reconstruction of bladder exstrophy has yielded consistent surgical success. The Johns Hopkins Hospital approach begins with early pelvic ring approximation with abdominal wall, bladder, and posterior urethral closure. Within the first 72 hours of life, the malleable pelvis can sometimes be approximated without osteotomies. Beyond this age, the author's prefer a combined vertical iliac and horizontal innominate osteotomy. Second, we typically perform the epispadias closure at 1 year of age. A modified Cantwell-Ransley technique is performed, usually yielding an increase in bladder capacity and very satisfactory results. In the last phase, the modified Young-Dees-Leadbetter continence procedure along with transtrigonal/cephalotrigonal ureteroneocystostomies are performed when the urethra is catheterizable, the bladder capacity is 60 cc or greater, and the child will participate in a postoperative voiding program (typically 4-5 years of age). This applied approach usually results in a continent, voiding patient with pleasing external genitalia and preserved renal function.


Morphology, molecular codes, and circuitry produce the three-dimensional complexity of the cerebellum.
The most noticeable morphological feature of the cerebellum is its folded appearance, whereby fissures separate its anterior-posterior extent into lobules. Each lobule is molecularly coded along the medial-lateral axis by parasagittal stripes of gene expression in one cell type, the Purkinje cells (PCs). Additionally, within each lobule distinct combinations of afferents terminate and supply the cerebellum with synchronized sensory and motor information. Strikingly, afferent terminal fields are organized into parasagittal domains, and this pattern bears a close relationship to PC molecular coding. Thus, cerebellum three-dimensional complexity obeys a basic coordinate system that can be broken down into morphology and molecular coding. In this review, we summarize the sequential stages of cerebellum development that produce its laminar structure, foliation, and molecular organization. We also introduce genes that regulate morphology and molecular coding, and discuss the establishment of topographical circuits within the context of the two coordinate systems. Finally, we discuss how abnormal cerebellar organization may result in neurological disorders like autism.


Effect of ascorbate oxidase on radical intensity and cytotoxic activity of ascorbate.
In order to test whether ascorbyl radical can directly induce apoptotic cell death, it was produced by the reaction of sodium L-ascorbate with L-ascorbate oxidase. Sodium L-ascorbate induced cytotoxicity against both human glioblastoma and promyelocytic leukemic cell lines. The addition of ascorbate oxidase significantly enhanced both degradation and radical generation of ascorbate, but completely eliminated its cytotoxic activity against both of these cells. These data demonstrate that the ascorbyl radical is not the sole determinant of apoptosis induction.


Regulation of lymphocyte proliferation and differentiation by macrophages.
In this paper, we consider the role of a macrophage secretory product in promoting thymocyte differentiation, as well as a macrophage-immune T cell interaction that results in augmented secretion of lymphostimulatory factors. When cultured with the thymocyte-differentiating factor (TDF), thymocytes show a physiological increase in H-2D and K, decreased sensitivity to lysis with anti-TL and complement, and acquisition of responsiveness in the mixed lymphocyte culture. Development of the mature phenotype requires 2 to 3 days of culture and, once attained, is stable. The induced antigenic changes do not require cell division. The activity demonstrated by TDF, which is not attributable to interferon and cannot be replaced by 2-mercaptoethanol, is also displayed by normal thymic macrophages themselves. Enhanced secretion of TDF and of a distinct mitogenic protein follows the interaction of macrophages and immune T cells. This interaction is shown to require physical contact of the two cell types and is regulated by products of the I-A region of the major histocompatibility complex.


The fission yeast cytokinetic contractile ring regulates septum shape and closure.
During cytokinesis, fission yeast and other fungi and bacteria grow a septum that divides the cell in two. In fission yeast closure of the circular septum hole by the β-glucan synthases (Bgs) and other glucan synthases in the plasma membrane is tightly coupled to constriction of an actomyosin contractile ring attached to the membrane. It is unknown how septum growth is coordinated over scales of several microns to maintain septum circularity. Here, we documented the shapes of ingrowing septum edges by measuring the roughness of the edges, a measure of the deviation from circularity. The roughness was small, with spatial correlations indicative of spatially coordinated growth. We hypothesized that Bgs-mediated septum growth is mechanosensitive and coupled to contractile ring tension. A mathematical model showed that ring tension then generates almost circular septum edges by adjusting growth rates in a curvature-dependent fashion. The model reproduced experimental roughness statistics and showed that septum synthesis sets the mean closure rate. Our results suggest that the fission yeast cytokinetic ring tension does not set the constriction rate but regulates septum closure by suppressing roughness produced by inherently stochastic molecular growth processes.


[Thyroid and AIDS].
Two types of thyroid biochemical abnormalities (TBA) are observed in AIDS. The unspecific TBA are similar to TBA reported in the Euthyroid Sick Syndrome. An increased serum TBG of unknown origin and a decreased circulating rT3 are the most specific TBA of AIDS. The latter abnormality may be in relation with an elevated level of TNF. The frequency of serum antithyroid antibodies seems higher than in control groups. Opportunistic infections of the thyroid gland or destruction of the thyroid by Kaposi's sarcoma are also reported in AIDS.


Clinical report of a pure subtelomeric 1qter deletion in a boy with mental retardation and multiple anomalies adds further evidence for a specific phenotype.
Deletions of the 1q telomere have been reported in several studies screening for subtelomeric rearrangements. However, an adequate clinical description is available from only a few patients. We provide a clinical description of a patient with a subtelomeric deletion of chromosome 1q, previously detected by us in a screening study. Comparison of the clinical presentation of our patient with rare cases reported previously provides further evidence for a specific phenotype of 1q patients, including mental retardation, growth retardation, sometimes with prenatal onset, progressive microcephaly, seizures, hand and foot abnormalities and a variety of midline defects, including corpus callosum, cardiac, genital and gastro-esophageal abnormalities. This clinical presentation is reminiscent of that of patients with larger, microscopically visible deletions of chromosome 1q (>3 Mb) characterized by growth and mental retardation, coarse faces with thin upper lip, epilepsy, and variable other anomalies. In addition, the breakpoint region was mapped to a 26 kb region within the RGS7 gene. Among the 17 known genes in the candidate region, are zinc-finger genes. Other members of this gene family have been implicated in different forms of mental retardation.


Human immunodeficiency virus funding and access to treatment in sub-Saharan Africa.
Human immunodeficiency virus (HIV) treatment prevents illness, death, and transmission. The 90-90-90 disease control target is only 73% of people living with HIV virally suppressed. For 2010 to 2019, we abstracted HIV funding data for 40 countries in sub-Saharan Africa (70% of global HIV burden and >99% of HIV burden in the region in 2018). During 2010-2019, there was ∼$52 billion funding for 40 countries (99% Africa HIV burden). Domestic funding ranged from $0 to $3.2 billion. PEPFAR funding was $32 billion (average $1.4 billion; range $0.089-4.3 billion) among 22 countries. Global Fund averaged $306 million ($1.9 million to $1.1 billion) for 40 countries. Among PLHIV, known HIV status averaged 80% (11% to 94%). ART coverage averaged 64% (9% to 90%). Viral suppression among PLHIV ranged from 8% to 87%. Of the 40 countries, 21 reported under 60% of PLHIV to be on treatment and 13 did not report viral suppression for 2018. Achieving 90-90-90 is feasible in challenging settings if resources are used efficiently. Despite the significant investment in the HIV response, many countries have not reached the 90-90-90 target. Greater attention to efficiency and prioritizing important targets will be required to end AIDS in Africa.


Massive eosinophilic reaction to desipramine in conjunction with pneumonia.
The authors report on a female patient with bipolar affective disorder who presented with marked eosinophilia in conjunction with pneumonia five days after a medication change from amitriptyline to desipramine (for intolerable dry mouth). She improved with discontinuance of medications and supportive management, and her eosinophilia normalized. Reinstitution of desipramine was followed by prompt appearance of asymptomatic eosinophilia, which resolved with discontinuation of desipramine. A subsequent depression managed with amitriptyline was followed by no abnormal white blood count findings. Eosinophilia is occasionally encountered in imipramine or desipramine therapy and, although usually asymptomatic, appears to be manageable by switching to amitriptyline or nortriptyline.


Patient Quality of Life Improvement in Bullous Disease: A Review of Primary Literature and Considerations for the Clinician.
Autoimmune and inherited bullous disorders are rare skin diseases that may have a profound negative impact on quality of life (QOL). Common symptoms include pain, pruritus, and scarring, and complications may result in the loss of the ability to perform daily tasks. Diagnosis may have a negative psychological impact, and ongoing management may require a significant allocation of time and resources by both patients and providers. To provide patient-centered care, consideration of these factors is of utmost importance for the dermatologist treating patients with bullous disorders. Herein, we present a review of the primary literature evaluating QOL in autoimmune and inherited bullous disorders, including pemphigus, pemphigoid, epidermolysis bullosa, and Hailey-Hailey disease.


Hemoporfin-mediated photodynamic therapy on normal vasculature: implications for phototherapy of port-wine stain birthmarks.
Port-wine stain (PWS) birthmarks currently are treated using a pulsed dye laser (PDL) combined with transient cooling of the epidermis. PDL treatment protocols utilize short pulses of light (585 or 595 nm wavelength) to heat selectively the microvasculature due to absorption by intravascular hemoglobin. Although most patients respond to PDL therapy, few experience complete removal of the PWS. An alternate treatment option to PDL therapy of PWS is photodynamic therapy (PDT). Research groups have reported on various photosensitizers for PDT of PWS, including Hemoporfin, Benzoporphyrin Derivative monoacid ring A, and talaporfin sodium. Our aim was to evaluate, with an established preclinical in-vivo model, the efficacy of photodynamic therapy (PDT) with Hemoporfin to achieve persistent vascular shutdown. To monitor the microvasculature, a dorsal window chamber was surgically installed on 24 adult mice. The PDT excitation source emitted 150mW of 532nm light, with an irradiance of 100mW/cm2. A retroorbital injection of Hemoporfin (2 mg/kg) was performed to deliver the drug into the bloodstream. Laser irradiation was initiated immediately after injection. To monitor blood-flow dynamics in response to PDT, we used laser speckle imaging. We employed a dose-response experimental design to study the efficacy of Hemoporfin-mediated PDT to achieve persistent vascular shutdown observed on Day 7 after PDT. We observed four general hemodynamic responses to PDT: (1) At low radiant exposures, we did not observe any persistent vascular shutdown; (2) at intermediate radiant exposures, we observed delayed vascular shutdown effect with significant change to the vascular structure; (3) at intermediate radiant exposures, we observed an acute vascular shutdown effect with gradual restoration of blood flow and no significant changes to the vascular structure; and (4) at high radiant exposures, we observed acute vascular shutdown that persisted during the entire 7-day monitoring period, with no change in vascular structure. With light dose-response analysis, we estimated a characteristic radiant exposure of 359 J/cm2 that was required to achieve persistent vascular shutdown observed on Day 7 after PDT. The experimental data collectively suggest that Hemoporfin-mediated PDT can achieve persistent vascular shutdown of normal microvasculature. However, compared with our previous data using Talaporfin Sodium as photosensitizer, Hemoporfin-mediated PDT is less efficient and requires a considerably longer (~four times) irradiation time. Patients with PWS lesions may benefit from the advantages that PDT potentially offers over conventional PDL therapy. PDT potentially is safer for patients of all skin types and more effective at treatment of recalcitrant lesions. Although clinical data suggest that Hemoporfin-mediated PDT is a promising alternative to PDL therapy, our results suggest that additional study of other photosensitizers is warranted.


A novel algorithm to enhance P300 in single trials: application to lie detection using F-score and SVM.
The investigation of lie detection methods based on P300 potentials has drawn much interest in recent years. We presented a novel algorithm to enhance signal-to-noise ratio (SNR) of P300 and applied it in lie detection to increase the classification accuracy. Thirty-four subjects were divided randomly into guilty and innocent groups, and the EEG signals on 14 electrodes were recorded. A novel spatial denoising algorithm (SDA) was proposed to reconstruct the P300 with a high SNR based on independent component analysis. The differences between the proposed method and our/other early published methods mainly lie in the extraction and feature selection method of P300. Three groups of features were extracted from the denoised waves; then, the optimal features were selected by the F-score method. Selected feature samples were finally fed into three classical classifiers to make a performance comparison. The optimal parameter values in the SDA and the classifiers were tuned using a grid-searching training procedure with cross-validation. The support vector machine (SVM) approach was adopted to combine with an F-score because this approach had the best performance. The presented model F-score_SVM reaches a significantly higher classification accuracy for P300 (specificity of 96.05%) and non-P300 (sensitivity of 96.11%) compared with the results obtained without using SDA and compared with the results obtained by other classification models. Moreover, a higher individual diagnosis rate can be obtained compared with previous methods, and the presented method requires only a small number of stimuli in the real testing application.


Effects of glia-conditioned medium on primary cultures of central neurons.
The effects of glia conditioned media on the survival and differentiation of embryonic neuron cultures of the Central Nervous System is described. We established glial cultures of peritumoral areas and the culture medium was changed serially and collected as glia conditioned medium (GCM). Neuron enriched cultures plated on poly-L-lysine coated Petri dishes and after 4 days in vitro, the neuronal cultures were treated for the inhibition of glial cells. We established two groups of neuronal cultures that were respectively exposed to the GCM and to conventional culture medium. We evaluated the survival and differentiation of neuronal population in each group of cultures by contrast-phase microscopy and cellular uptake of Horse Radish Peroxidase. The cell cultures exposed to GCM showed a survival during the in vitro stages and an organization and differentiation pattern of mature neurons larger than the control cultures. This fact suggests that the glial cultures produce a diffusible neurotrophic factor that influences the neuronal response in vitro.


Optical Electrophysiology in the Developing Heart.
The heart is the first organ system to form in the embryo. Over the course of development, cardiomyocytes with differing morphogenetic, molecular, and physiological characteristics are specified and differentiate and integrate with one another to assemble a coordinated electromechanical pumping system that can function independently of any external stimulus. As congenital malformation of the heart presents the leading class of birth defects seen in humans, the molecular genetics of heart development have garnered much attention over the last half century. However, understanding how genetic perturbations manifest at the level of the individual cell function remains challenging to investigate. Some of the barriers that have limited our capacity to construct high-resolution, comprehensive models of cardiac physiological maturation are rapidly being removed by advancements in the reagents and instrumentation available for high-speed live imaging. In this review, we briefly introduce the history of imaging approaches for assessing cardiac development, describe some of the reagents and tools required to perform live imaging in the developing heart, and discuss how the combination of modern imaging modalities and physiological probes can be used to scale from subcellular to whole-organ analysis. Through these types of imaging approaches, critical insights into the processes of cardiac physiological development can be directly examined in real-time. Moving forward, the synthesis of modern molecular biology and imaging approaches will open novel avenues to investigate the mechanisms of cardiomyocyte maturation, providing insight into the etiology of congenital heart defects, as well as serving to direct approaches for designing stem-cell or regenerative medicine protocols for clinical application.


A review of dietary phytochemicals and their relation to oxidative stress and human diseases.
Phytochemicals refer to active substances in plant-based diets. Phytochemicals found in for example fruits, vegetables, grains and seed oils are considered relatively safe for consumption due to mammal-plant co-evolution and adaptation. A number of human diseases are related to oxidative stress caused by for example chemical environmental contaminants in air, water and food; while also lifestyle including smoking and lack of exercise and dietary preferences are important factors for disease development in humans. Here we explore the dietary sources of antioxidant phytochemicals that have beneficial effects on oxidative stress, cardiovascular and neurological diseases as well as cancer. Plant-based diets usually contain phenolic acids, flavonoids and carotenoids, which have strong antioxidant properties, and therefore remove the excess of active oxygen in the body, and protect cells from damage, reducing the risk of cardiovascular and Alzheimer's disease. In most cases, obesity is related to diet and inactivity and plant-based diets change lipid composition and metabolism, which reduce obesity related hazards. Cruciferous and Allium vegetables are rich in organic sulphides that can act on the metabolism of carcinogens and therefore used as anti-cancer and suppressing agents while dietary fibres and plant sterols may improve intestinal health and prevent intestinal diseases. Thus, we recommend a diet rich in fruits, vegetables, and grains as its content of phytochemicals may have the potential to prevent or improve a broad sweep of various diseases.


Nitrogen Uptake by Two Plants in Response to Plant Competition as Regulated by Neighbor Density.
Plant species may acquire different forms of nitrogen (N) to reduce competition for the same resource, but how plants respond to neighbors with different densities in their N uptake is still poorly understood. We investigated the effects of competition regime on the uptake of different N forms by two hygrophytes, Carex thunbergii and Polygonum criopolitanum, by conducting a hydroponic test of excised roots and an in situ experiment in a subtropical wetland ecosystem. The two species were grown either in monocultures or mixtures with various neighbor densities. Root functional traits and N uptake rates of different N forms were measured. Our results showed that N uptake was mainly determined by N form, rather than species identity. Both species were able to use organic N sources, but they took up relatively more N supplied as NO 3 - than as NH 4 + or glycine, irrespective of competition treatments. Both species preferred NO 3 - when grown in monoculture, but in the presence of competitors, the preference of fast-growing C. thunbergii persisted while P. criopolitanum acquired more NH 4 + and glycine, with stronger responses being observed at the highest neighbor density. The hydroponic test suggested that these divergences in N acquisition between two species might be partially explained by different root functional traits. To be specific, N uptake rates were significantly positively correlated with root N concentration and specific root length, but negatively correlated with root dry matter content. Our results implicated that C. thunbergii has a competitive advantage with relatively more stable N acquisition strategy despite a lower N recovery than P. criopolitanum, whereas P. criopolitanum could avoid competition with C. thunbergii via a better access to organic N sources, partly mediated by competition regimes.


Supermolecular-chromophore-sensitized near-infrared-to-visible photon upconversion.
Selective near-IR (NIR) excitation (780 nm) of the conjugated supermolecule ruthenium(II) [15-(4'-ethynyl-(2,2';6',2''-terpyridinyl))-bis[(5,5',-10,20-di(2',6'-bis(3,3-dimethylbutoxy)phenyl)porphinato)zinc(II)]ethyne][4'-pyrrolidin-1-yl-2,2';6',2''-terpyridine] bis(hexafluorophosphate) (Pyr(1)RuPZn(2)) in solutions containing N,N-bis(ethylpropyl)perylene-3,4,9,10-tetracarboxylicdiimide (PDI) or tetracene gives rise to a substantial anti-Stokes energy gain (PDI, 0.70 eV; tetracene, 0.86 eV). Experimental data clearly demonstrate that this upconverted fluorescence signal is produced via Pyr(1)RuPZn(2)-sensitized triplet-triplet annihilation (TTA) photochemistry. The TTA process was confirmed by the quadratic dependence of the integrated (1)PDI* emission centered at 541 nm derived from 780 nm laser excitation. The T(1)→T(n) excited state absorption decay of Pyr(1)RuPZn(2), monitored at 900 nm as a function of PDI concentration, revealed Stern-Volmer and bimolecular quenching constants of 10 048 M(-1) and 5.9 × 10(8) M(-1) s(-1), respectively, for the PDI triplet sensitization process. The T(1)→T(n) PDI extinction coefficient at 560 nm (ε(T) = 6.6 × 10(4) M(-1) cm(-1)) was determined through the triplet energy transfer method utilizing anthracene as the donor chromophore. (3)PDI* transient triplet absorption dynamics observed as a function of 485 nm incident nanosecond pump laser fluence demonstrate a bimolecular (3)PDI*-(3)PDI* TTA rate constant (k(TT) = 1.0 ± 0.2 × 10(9) M(-1) s(-1)). The maximum quantum yield of the supermolecule-sensitized PDI upconverted emission (Φ(UC) = 0.0075 ± 0.0002) was determined relative to [Os(phen)(3)][PF(6)](2) at an incident laser power of 22 mW at 780 nm. This study successfully demonstrates NIR-to-visible photon upconversion and achieves a new record anti-Stokes shift of 0.86 eV for sensitized TTA, using the supermolecular Pyr(1)RuPZn(2)sensitizer. The stability of the Pyr(1)RuPZn(2)/PDI chromophore combination is readily apparent as continuous irradiation at 780 nm produces 541 nm centered fluorescence with no significant decrease in intensity measured over time domains exceeding several hours. The molecular components of these NIR-to-vis upconverting compositions illustrate that substantial anti-Stokes energy gains via a TTA process can be effortlessly realized.


Sphingolipid and ceramide homeostasis: potential therapeutic targets.
Sphingolipids are ubiquitous in eukaryotic cells where they have been attributed a plethora of functions from the formation of structural domains to polarized cellular trafficking and signal transduction. Recent research has identified and characterised many of the key enzymes involved in sphingolipid metabolism and this has led to a heightened interest in the possibility of targeting these processes for therapies against cancers, Alzheimer's disease, and numerous important human pathogens. In this paper we outline the major pathways in eukaryotic sphingolipid metabolism and discuss these in relation to disease and therapy for both chronic and infectious conditions.


3D-Printed Regenerative Magnesium Phosphate Implant Ensures Stability and Restoration of Hip Dysplasia.
Osteoarthritis of the hip is a painful and debilitating condition commonly occurring in humans and dogs. One of the main causes that leads to hip osteoarthritis is hip dysplasia. Although the current surgical methods to correct dysplasia work satisfactorily in many circumstances, these are associated with serious complications, tissue resorption, and degeneration. In this study, a one-step fabrication of a regenerative hip implant with a patient-specific design and load-bearing properties is reported. The regenerative hip implant is fabricated based on patient imaging files and by an extrusion assisted 3D printing process using a flexible, bone-inducing biomaterial. The novel implant can be fixed with metallic screws to host bone and can be loaded up to physiological loads without signs of critical permanent deformation or failure. Moreover, after exposing the hip implant to accelerated in vitro degradation, it is confirmed that it is still able to support physiological loads even after losing ≈40% of its initial mass. In addition, the osteopromotive properties of the novel hip implant is demonstrated as shown by an increased expression of osteonectin and osteocalcin by cultured human mesenchymal stem cells after 21 days. Overall, the proposed hip implant provides an innovative regenerative and mechanically stable solution for hip dysplasia treatment.


Relationship between glycocalyx and povidone-iodine resistance in Pseudomonas aeruginosa (ATCC 27853) biofilms.
Biofilm-embedded bacteria are generally more resistant to antimicrobial agents than are planktonic bacteria. Two possible mechanisms for biofilm resistance are that the glycocalyx matrix secreted by cells in a biofilm reacts with and neutralizes the antimicrobial agent and that the matrix creates a diffusion barrier to the antimicrobial agent. This study was therefore conducted to examine the relationship between glycocalyx and enhanced povidone-iodine resistance in biofilms of Pseudomonas aeruginosa (ATCC 27853). Biofilms were generated by inoculation of polycarbonate membranes with broth-grown cells and incubation of them on the surfaces of nutrient agar plates. The quantities of glycocalyx material per cell were found not to be significantly different between biofilm and planktonic samples. Transmission electron microscopy showed that the distributions of glycocalyx material around cells differed in biofilm and in planktonic samples. Addition of alginic acid to planktonic cell suspensions resulted in a slight increase in resistance to povidone-iodine, suggesting some neutralizing interaction. However, the iodine demands created by biofilm and planktonic samples of equivalent biomass were not significantly different and, therefore, do not explain the contrast in resistance observed between biofilm and planktonic samples. Examination of the relationship between cell death and biomass detachment from the glycocalyx matrix revealed that most cell death occurred in the fraction of biomass that detached from a biofilm during treatment. The overall rate of iodine diffusion through biofilms was not different from that of planktonic cells collected on a polycarbonate membrane.(ABSTRACT TRUNCATED AT 250 WORDS)


Sense of coherence, off-job crafting, and mental well-being: A path of positive health development.
Our study examines the core concept of salutogenesis-sense of coherence (SOC)-in relation to off-job crafting (OJC) and mental well-being (MWB). The original salutogenic model of health mainly addresses the protective function of SOC against adversity. In our study, we focus on the recently proposed path of positive health development that captures how SOC can contribute to positive health and thriving. We present and test our theoretical assumptions about one such path, examining OJC as a possible mechanism how SOC translates into MWB. We tested our proposed model using cross-lagged panel model with three waves of panel data from Swiss and German employees (N = 2217). We compared our model to alternative nested models and conducted indirect effect analysis to test longitudinal mediation. Our hypothesized model fitted the data well and we found support for our main hypothesis that OJC partially mediates the relationship between SOC and MWB. Further, we identified positive reciprocal relationships between SOC and MWB, as well as between OJC and MWB. Overall, our study provides evidence that OJC is one mechanism underlying the recently postulated path of positive health development in the salutogenic model. For health promotion, this implies that promoting SOC and OJC may help to strengthen individual well-being and lead to positive feedback loops that foster personal development and thriving.


Downregulated Kv4.3 expression in the RVLM as a potential mechanism for sympathoexcitation in rats with chronic heart failure.
Elevated central angiotensin II (ANG II) plays a critical role in the sympathoexcitation of chronic heart failure (CHF) by stimulating upregulated ANG II type 1 receptors (AT(1)R) in the rostral ventrolateral medulla (RVLM). However, the link between enhanced ANG II signaling and alterations in the electrophysiological characteristics of neurons in the RVLM remains unclear. In the present experiments, we screened for potentially altered genes in the medulla of rats with CHF that are directly related to neuronal membrane conductance using the Rat Genome 230 2.0 Array GeneChip. We found that CHF rats exhibited a 2.1-fold reduction in Kv4.3 gene expression, one of the main voltage-gated K(+) channels, in the medulla. Real-time RT-PCR and Western blot analysis confirmed the downregulation of Kv4.3 in the RVLM of CHF rats. In intact animals, we found that microinjection of the voltage-gated potassium channel blocker, 4-aminopyridine, into the RVLM evoked a sympathoexcitation and hypertension in both normal and CHF rats. CHF rats exhibited smaller responses to 4-aminopyridine than did normal rats. Finally, we used a neuronal cell line (CATH.a neurons) to explore the effect of ANG II on Kv4.3 expression and function. We found that ANG II treatment significantly downregulated mRNA and protein expression of Kv4.3 and decreased the A-type K(+) current. Employing this cell line, we also found that the ANG II-induced inhibition of Kv4.3 mRNA expression was attenuated by the superoxide scavenger Tempol and the p38 MAPK inhibitor SB-203580. The effects of ANG II were abolished by the AT(1)R antagonist losartan. We conclude that the sympathoexcitation observed in the CHF state may be due, in part, to an ANG II-induced downregulation of Kv4.3 expression and subsequent decrease in K(+) current, thereby increasing the excitability of neurons in the RVLM. The ANG II-induced inhibition of Kv4.3 mRNA expression was mediated by ANG II-AT(1)R-ROS-p38 MAPK signaling.


Analysis of cardiomyocyte development using immunofluorescence in embryonic mouse heart.
During heart development, the generation of myocardial-specific structural and functional units including sarcomeres, contractile myofibrils, intercalated discs, and costameres requires the coordinated assembly of multiple components in time and space. Disruption in assembly of these components leads to developmental heart defects. Immunofluorescent staining techniques are used commonly in cultured cardiomyocytes to probe myofibril maturation, but this ex vivo approach is limited by the extent to which myocytes will fully differentiate in culture, lack of normal in vivo mechanical inputs, and absence of endocardial cues. Application of immunofluorescence techniques to the study of developing mouse heart is desirable but more technically challenging, and methods often lack sufficient sensitivity and resolution to visualize sarcomeres in the early stages of heart development. Here, we describe a robust and reproducible method to co-immunostain multiple proteins or to co-visualize a fluorescent protein with immunofluorescent staining in the embryonic mouse heart and use this method to analyze developing myofibrils, intercalated discs, and costameres. This method can be further applied to assess cardiomyocyte structural changes caused by mutations that lead to developmental heart defects.


Plasma exosomal miR-320d, miR-4479, and miR-6763-5p as diagnostic biomarkers in epithelial ovarian cancer.
Exosomal miRNA had been proved as the promising biomarkers for multiple cancers including epithelial ovarian cancer (EOC). This study aimed to validate the diagnostic accuracy of exosomal miR-320d, miR-4479, and miR-6763-5p for EOC. Exosomes isolated from the plasma by ultracentrifugation were verified using TEM, qNano and western blot. MiRNAs sequencing was used to screen out the differential exosomal miRNAs and miR-320d, miR-4479, and miR-6763-5p were selected as candidates, which were further verified by RT-qPCR in 168 healthy donors and 161 primary EOC patients. Besides, the diagnostic accuracy of these three exosomal miRNAs were evaluated using the receiver operating characteristic curve (ROC). MiRNAs sequencing revealed 95 differential exosomal miRNAs between EOC patients and healthy donors. Subsequently, exosomal miR-320d, miR-4479, and miR-6763-5p were significantly down regulated in EOC patients compared with healthy controls and benign patients. More importantly, these three miRNAs could serve as circulating diagnostics biomarkers for EOC, possessing areas under the curve (AUC) of 0.6549, 0.7781, and 0.6834, respectively. Moreover, these three exosomal miRNAs levels were closely associated with lymph node metastasis, meanwhile exosomal miR-320d and miR-4479 expression was related to tumor stage. Exosomal miR-320d, miR-4479, and miR-6763-5p might serve as potential biomarkers for EOC.


Using Different Methods to Access the Difficult Task of Delimiting Species in a Complex Neotropical Hyperdiverse Group.
The genus Rineloricaria is a Neotropical freshwater fish group with a long and problematic taxonomic history, attributed to the large number of species and the pronounced similarity among them. In the present work, taxonomic information and different molecular approaches were used to identify species boundaries and characterize independent evolutionary units. We analyzed 228 samples assembled in 53 distinct morphospecies. A general mixed yule-coalescent (GMYC) analysis indicated the existence of 70 entities, while BOLD system analyses showed the existence of 56 distinct BINs. When we used a new proposed integrative taxonomy approach, mixing the results obtained by each analysis, we identified 73 OTUs. We suggest that Rineloricaria probably has some complexity in the known species and several species not formally described yet. Our data suggested that other hyperdiverse fish groups with wide distributions can be further split into many new evolutionary taxonomic units.


Preattentive control of serial auditory processing in dichotic listening.
Dichotic listening performance was examined in an auditory selective attention task where subjects responded to occasional consonant-vowel (CV) or shaped broadband noise-burst (NB) targets in rapid serial auditory presentation (RASP). Trial types were randomized and included monaural CVs and NBs as well as dichotic CV-CV and CV-NB pairings. CVs were spoken by two different voices (male and female), and the two NB stimuli differed in their filter slopes at higher frequencies. The target was designated by stimulus category (/ba/, /da/, /ga/, or NB) and voice (e.g., "female /ba/"). Performance was compared for targets in the left and right ears on monaural and dichotic trials using accuracy and reaction time (RT) measures. Right ear advantages (REAs) were present for CV targets with either CV or NB distractors, but not for monaural CVs. The REA found for monaural NB targets was eliminated by CV distractors, yielding a left ear advantage (LEA) for the distractor effect of CVs on NB targets. The pattern of results suggests initial preprocessing of speech stimuli through phonetic feature analysis, followed by serial attentional processing of the objects in the auditory field. REAs are attributed to a rightward asymmetry in the preattentive control of auditory attention similar to that found in visual search.


Aortic pressure augmentation predicts adverse cardiovascular events in patients with established coronary artery disease.
Pulse pressure (PP), a marker of arterial stiffness, predicts cardiovascular risk. We aimed to determine whether augmentation pressure (AP) derived from the aortic pressure waveform predicts major adverse cardiovascular events (MACE) and death independently of PP in patients with established coronary artery disease (CAD). We prospectively followed-up 297 males undergoing coronary angiography for 1186+/-424 days. Ascending aortic pressure tracings obtained during catheterization were used to calculate AP (difference between the second and the first systolic peak). Augmentation index (AIx) was defined as AP as a percentage of PP. We evaluated whether AP and AIx can predict the risk of MACE (unstable angina, acute myocardial infarction, coronary revascularization, stroke, or death) and death using Cox regression. All models evaluating AP included PP to assess whether AP adds to the information already provided by PP. Both AP and AIx significantly predicted MACE. The hazard ratio (HR) per 10 mm Hg increase in AP was 1.20 (95% confidence interval [CI], 1.08 to 1.34; P<0.001); the HR for each 10% increase in AIx was 1.28 (95% CI, 1.11 to 1.48; P=0.004). After adjusting for other univariate predictors of MACE, age, and other potential confounders, AP remained a significant predictor of MACE (HR per 10 mm Hg increase=1.19; 95% CI, 1.06 to 1.34; P=0.002), as did AIx (adjusted HR, 1.28; 95% CI, 1.09 to 1.50; P=0.003). AP was a significant predictor of death (HR per 10 mm Hg increase=1.18; 95% CI, 1.02 to 1.39; P=0.03). Higher AIx was associated with a trend toward increased mortality (HR=1.22; 95% CI, 0.98 to 1.52; P=0.056). Aortic AP predicts adverse outcomes in patients with CAD independently of PP and other risk markers.


The methyltransferase TrmA facilitates tRNA folding through interaction with its RNA-binding domain.
tRNAs are the most highly modified RNAs in all cells, and formation of 5-methyluridine (m5U) at position 54 in the T arm is a common RNA modification found in all tRNAs. The m5U modification is generated by the methyltransferase TrmA. Here, we test and prove the hypothesis that Escherichia coli TrmA has dual functions, acting both as a methyltransferase and as a tRNA chaperone. We identify two conserved residues, F106 and H125, in the RNA-binding domain of TrmA, which interact with the tRNA elbow and are critical for tRNA binding. Co-culture competition assays reveal that the catalytic activity of TrmA is important for cellular fitness, and that substitutions of F106 or H125 impair cellular fitness. We directly show that TrmA enhances tRNA folding in vitro independent of its catalytic activity. In conclusion, our study suggests that F106 and H125 in the RNA-binding domain of TrmA act as a wedge disrupting tertiary interactions between tRNA's D arm and T arm; this tRNA unfolding is the mechanistic basis for TrmA's tRNA chaperone activity. TrmA is the second tRNA modifying enzyme next to the pseudouridine synthase TruB shown to act as a tRNA chaperone supporting a functional link between RNA modification and folding.


Rearing experience with ramps improves specific learning and behaviour and welfare on a commercial laying farm.
To access resources in commercial laying houses hens must move between levels with agility to avoid injury. This study considered whether providing ramps during rear improved the ability of birds to transition between levels. Twelve commercial flocks (2000 birds/flock) on a multi-age site were examined between 1 and 40 weeks of age. All birds had access to elevated perching structures from 4 days of age. Six treatment flocks were also provided with ramps during rear to facilitate access to these structures. Flocks were visited three times during rear and three times at lay to record transitioning behaviour and use of the elevated structures, together with scores for keel bone and feather damage. Ramp reared flocks used the elevated structures to a greater extent at rear (P = 0.001) and at lay, when all flocks had ramps, showed less hesitancy [i.e. pacing (P = 0.002), crouching (P = 0.001) and wing-flapping (P = 0.001)] in accessing levels. Mean levels of keel bone damage were reduced in ramp reared flocks (52%) compared with control flocks (64.8%) at 40 weeks of age (P = 0.028). The early life experience of the ramp reared flocks enabled specific learning that translated and persisted in later life and resulted in overall welfare benefits.


Identification of Amino Acids within Nonstructural Proteins 10 and 14 of the Avian Coronavirus Infectious Bronchitis Virus That Result in Attenuation In Vivo and In Ovo.
The Gammacoronavirus infectious bronchitis virus (IBV) is a highly contagious global pathogen prevalent in all types of poultry flocks. IBV is responsible for economic losses and welfare issues in domestic poultry, resulting in a significant risk to food security. IBV vaccines are currently generated by serial passage of virulent IBV field isolates through embryonated hens' eggs. The different patterns of genomic variation accumulated during this process means that the exact mechanism of attenuation is unknown and presents a risk of reversion to virulence. Additionally, the passaging process adapts the virus to replicate in chicken embryos, increasing embryo lethality. Vaccines produced in this manner are therefore unsuitable for in ovo application. We have developed a reverse genetics system, based on the pathogenic IBV strain M41, to identify genes which can be targeted for rational attenuation. During the development of this reverse genetics system, we identified four amino acids, located in nonstructural proteins (nsps) 10, 14, 15, and 16, which resulted in attenuation both in vivo and in ovo. Further investigation highlighted a role of amino acid changes, Pro85Leu in nsp 10 and Val393Leu in nsp 14, in the attenuated in vivo phenotype observed. This study provides evidence that mutations in nsps offer a promising mechanism for the development of rationally attenuated live vaccines against IBV, which have the potential for in ovo application. IMPORTANCE The Gammacoronavirus infectious bronchitis virus (IBV) is the etiological agent of infectious bronchitis, an acute, highly contagious, economically important disease of poultry. Vaccination is achieved using a mixture of live attenuated vaccines for young chicks and inactivated vaccines as boosters for laying hens. Live attenuated vaccines are generated through serial passage in embryonated hens' eggs, an empirical process which achieves attenuation but retains immunogenicity. However, these vaccines have a risk of reversion to virulence, and they are lethal to the embryo. In this study, we identified amino acids in the replicase gene which attenuated IBV strain M41, both in vivo and in ovo. Stability assays indicate that the attenuating amino acids are stable and unlikely to revert. The data in this study provide evidence that specific modifications in the replicase gene offer a promising direction for IBV live attenuated vaccine development, with the potential for in ovo application.


Regulation of MMP-9 (92 kDa type IV collagenase/gelatinase B) expression in stromal cells of human giant cell tumor of bone.
Matrix metalloproteinases (MMPs) play an important regulatory role in tissue morphogenesis, cell differentiation, tumor invasion and metastasis. Several authors have reported a direct correlation between the production of 72 kDa (MMP-2) and 92 kDa (MMP-9) type IV collagenases/gelatinases and the metastatic potential of cancer cells. Recently, we have identified the expression of both MMP-2 and MMP-9 in primary cultures of human giant cell tumor (GCT) of bone in vitro, and in tissue extracts in vivo. Interestingly, MMP-9 is not secreted by late-passaged GCT cells. It is possible that the production of MMP-9 is regulated by certain factor(s) secreted by the multinucleated giant cells in the primary culture. In order to test this hypothesis, the effect of primary-culture-conditioned medium on the expression of MMP-9 by late-passaged mononuclear stromal cells was examined. Adding conditioned medium from the primary GCT culture to the late-passaged stromal cells induced MMP-9, as evidenced by the presence of lytic bands at M(r) 92,000 and 72,000 on a gelatin zymogram. These enzyme activities were inhibited by EDTA, a well-known inhibitor of the MMPs. We confirmed these results by Western blotting using specific antibodies and RT-PCR for MMP-2 and MMP-9. Immunofluorescence studies with specific antibodies to MMP-9 further confirmed its expression by the passaged stromal cells cultured in the primary-culture-conditioned medium. The data indicate that MMP-2 and MMP-9 are produced by the mononuclear stromal cells when cultured in GCT primary-culture-conditioned medium. This suggests that multinucleated giant cells in primary cultures secrete a factor(s) that stimulates stromal cells to produce MMP-9, which, in turn, may contribute to the aggressive behavior of GCT.


Imaging features of a gelatin-thrombin matrix hemostatic agent in the intracranial surgical bed: a unique space-occupying pseudomass.
Absorbable gelatin-thrombin matrix is increasingly being used in neurosurgical procedures; unlike other hemostats, the stable matrix is left undisturbed and fills the surgical bed after achieving hemostasis. We investigated the immediate postoperative radiographic imaging appearance of the gelatin-thrombin matrix in intracranial operative beds. Thirty-one consecutive patients (18 men, 13 women; mean age, 59 years) with 34 surgical cavities, had 31 brain MRIs and 9 head CTs performed ≤ 48 hours postoperatively. They were retrospectively reviewed. Images were evaluated independently by 2 neuroradiologists blinded to the surgical techniques. Surgical beds were evaluated for the presence of the gelatin-thrombin matrix, which appeared as pseudoair material (Hounsfield units ≤ -100) on CT, had characteristic T2-hypointense speckles in a T2-hyperintense background, and demonstrated complete gradient-recalled echo hypointensity on MR imaging. To determine the diagnostic performance of imaging features for the detection of the gelatin-thrombin matrix, the Fisher exact test for the association between imaging features and the presence of the gelatin-thrombin matrix and κ analysis for interobserver agreement were performed. Hemostasis was achieved with standard methods in 12 surgical beds and with the gelatin-thrombin matrix in 22 beds. Interobserver agreement was substantial. The gelatin-thrombin matrix demonstrated pseudoair hypoattenuation (88% sensitivity, 100% specificity, 90% accuracy; P = .067, κ = 0.74) and distinctive T2-hypointense speckles in a background of T2-hyperintensity (81% sensitivity, 85% specificity, 82% accuracy; P = <.001, κ = 0.76). Combined characteristic T2 speckles and gradient-recalled echo hypointensity increased the specificity (81% sensitivity, 100% specificity, 88% accuracy; P = < .001). The unique appearance (pseudoair on CT, T2 speckles with gradient-recalled echo hypointensity) of the gelatin-thrombin matrix should not be mistaken for gossypiboma, pneumocephalus, and/or hematoma.


Antilipolytic effects of alpha 2-adrenergic agonists, neuropeptide Y, adenosine, and PGE1 in mammal adipocytes.
Lipolysis is stimulated by different hormones, depending on the species, but is also regulated by antilipolytic modulators, such as catecholamines (alpha 2-agonists), neuropeptide Y (NPY), adenosine, and prostaglandin E1 (PGE1), for which species-specific variations are poorly described. Comparison of the efficiency of these antilipolytic systems showed that PGE1 or phenylisopropyladenosine was able to totally inhibit lipolysis activation in nine mammalian species. However, the antilipolytic responses to clonidine or UK-14304 were fully developed in hamster and rabbit but blunted in the adipocytes of jerboa, rat, guinea pig, garden dormouse, and dormouse. A powerful antilipolytic effect of NPY was found only in the garden dormouse. Only human and dog adipocytes exhibited antilipolytic responses to alpha 2-adrenergic and NPY stimulation. These observations were explained by differences in alpha 2-adrenergic and NPY/peptide YY receptor number. Thus, inhibitory regulation of lipolysis in white adipocytes seems to be composed of two systems: a constitutive one that is related to paracrine mediators (adenosine, prostaglandins) and a regulatory one including neuroendocrine messengers such as catecholamines and NPY.


Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis.
Ocular allergy is an inflammatory response of the conjunctival mucosa that also affects the cornea and eyelids. Allergic conjunctivitis includes seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC) and giant papillary conjunctivitis (GPC). In general, allergic conditions involve mast cell degranulation that leads to release of inflammatory mediators and activation of enzymatic cascades generating pro-inflammatory mediators. In chronic ocular inflammatory disorders associated with mast cell activation such as VKC and AKC constant inflammatory response is observed due to predominance of inflammatory mediators such as eosinophils and Th2-generated cytokines. Antihistamines, mast-cell stabilizers, nonsteroidal anti-inflammatory agents, corticosteroids and immunomodulatory agents are commonly indicated for the treatment of acute and chronic allergic conjunctivitis. In recent years newer drug molecules have been introduced in the treatment of allergic conjunctivitis. This article reviews recent patents and emerging therapeutics in the treatment of allergic conjunctivitis.


Women's Choice to Deliver at Home: Understanding the Psychosocial and Cultural Factors Influencing Birthing Choices for Unskilled Home Delivery among Women in Southwestern Uganda.
Utilization of perinatal services in Uganda remains low, with correspondingly high rates of unskilled home deliveries, which can be life-threatening. We explored psychosocial and cultural factors influencing birthing choices for unskilled home delivery among postpartum women in rural southwestern Uganda. We conducted in-depth qualitative face-to-face interviews with 30 purposively selected women between December 2018 and March 2019 to include adult women who delivered from their homes and health facility within the past three months. Women were recruited from 10 villages within 20 km from a referral hospital. Using the constructs of the Health Utilization Model (HUM), interview topics were developed. Interviews were conducted and digitally recorded in a private setting by a native speaker to elicit choices and experiences during pregnancy and childbirth. Translated transcripts were generated and coded. Coded data were iteratively reviewed and sorted to derive categories using inductive content analytic approach. Eighteen women (60%) preferred to deliver from home. Women's referent birth location was largely intentional. Overall, the data suggest women choose home delivery (1) because of their financial dependency and expectation for a "natural" and normal childbirth, affecting their ability and need to seek skilled facility delivery; (2) as a means of controlling their own birth processes; (3) out of dissatisfaction with facility-based care; (4) out of strong belief in fate regarding birth outcomes; (5) because they have access to alternative sources of birthing help within their communities, perceived as "affordable," "supportive," and "convenient"; and (6) as a result of existing gender and traditional norms that limit their ability and freedom to make family or health decisions as women. Women's psychosocial and cultural understandings of pregnancy and child birth, their established traditions, birth expectations, and perceptions of control, need, and quality of maternity care at a particular birthing location influenced their past and future decisions to pursue home delivery. Interventions to address barriers to healthcare utilization through a multipronged approach could help to debunk misconceptions, increase perceived need, and motivate women to seek facility delivery.


Surgical site infections in genital reconstruction surgery for gender reassignment, Detroit: 1984-2008.
Gender reassignment surgery (i.e., male-to-female or female-to-male) entails a series of complex surgical procedures. We conducted a study to explore epidemiologic characteristics of patients who underwent genital reconstruction operations as components of gender reassignment and to analyze risk factors for surgical-site infections (SSIs) following these operations. The study was a retrospective cohort study conducted from 1984-2008 at Harper University Hospital, a tertiary hospital with 625 beds in Detroit, Michigan. Surgical site infection was defined according to established criteria. Records were available for 82 patients who underwent a total of 1,383 operations as part of genital-reconstruction processes. Thirty-nine (47.6%) of the patients underwent female-to-male reassignment (FTM) and 43 (52.4%) underwent male-to-female reassignment (MTF). The average age of the study cohort was 39.5±9.8 y. Of the patients in the cohort, 56 (68.3%) were Caucasian and 67 (81.7%) were single. The average number of operative encounters per patient was 11.8±4.6 for FTM and 4.9±2.4 for MTF. Forty-three (52.4%) patients developed an SSI at least once during their genital reconstruction process, of whom 34 (87%) were in the FTM group and nine (21%) in the MTF group (p<0.001). Staphylococci were the most common pathogens (61%) isolated in these infections, followed by Enterobacteriaceae (50%), Enterococcus (39%), and Pseudomonas aeruginosa (33.3%). Surgical site infection was associated independently with an increased frequency of operative procedures and operating room encounters. More than 50% of patients who underwent genital reconstruction operations developed an SSI at some point during the genital reconstruction process. Surgical site infections are more common in FTM than in MTF reconstruction operations, and for both FTM and MTF, SSIs are associated independently with an increased frequency of total operative procedures and encounters.


Withaferin A attenuates ovalbumin induced airway inflammation.
The molecular mechanism of how airway inflammation develops is not fully understood. Withaferin A (WA) is a natural phytochemical isolated from the plant Withania somnifera. It is a well-investigated bioactive compound that possesses a variety of health-promoting effects, including anti-inflammatory and anti-oxidative activities. In the present study, the effect of WA on ovalbumin (OVA)-induced airway inflammation in mice was investigated. The results indicated that pre-treatment with WA inhibited OVA-induced lung injury and fibrosis progression in mice. Furthermore, WA significantly downregulated inflammatory cell infiltration into the bronchoalveolar lavage fluid and significantly reduced pro-inflammatory cytokine expression in the lung tissue specimens. Additionally, WA significantly suppressed transforming growth factor-b1 expression in lung tissues. WA also caused the downregulation of collagen I, collagen III, α-smooth muscle actin and tissue inhibitor of metalloproteinase-1, as well as SMADs and extracellular signal related kinase 1/2 inactivation. Notably, WA significantly reduced the activation of the NLRP3 inflammasome. The results indicate that WA may be an effective novel candidate for the treatment of airway inflammation.


Does the internet change how we die and mourn? Overview and analysis.
The article outlines the issues that the internet presents to death studies. Part 1 describes a range of online practices that may affect dying, the funeral, grief and memorialization, inheritance and archaeology; it also summarizes the kinds of research that have been done in these fields. Part 2 argues that these new online practices have implications for, and may be illuminated by, key concepts in death studies: the sequestration (or separation from everyday life) of death and dying, disenfranchisement of grief, private grief, social death, illness and grief narratives, continuing bonds with the dead, and the presence of the dead in society. In particular, social network sites can bring dying and grieving out of both the private and public realms and into the everyday life of social networks beyond the immediate family, and provide an audience for once private communications with the dead.


[Botulinum toxin in the elderly to the care of limbs spastic hypertonia and toes or fingers dystonias].
To show the botulinum toxin interest and limits in the elderly presenting a limbs spastic hypertonia and/or a dystonia, through a clinical study and a literature review. We report a 6 years and 8 months retrospective single center study, concerning 49 patients, all of them was more than 70 years old and had received one or several botulinum toxin injections for a limbs spastic hypertonia and/or a dystonia. The population average was 76,9 years old (70 to 92 years old). It was possible to realize several sessions for the same patient if respecting a three months interval between two sessions. No major side effects was noticed. More than half of the patients felt a significant improvement of their life quality, their functional status and/or on pain. A multidisciplinary care was systematically associated with the botulinum toxin. The botulinum toxin is an additional asset for the spasticity care of the geriatric patient in rehabilitation, if indications and contraindications are advisedly targeted. The age cannot be considered as a limitating factor.


The predictive value of serum procalcitonin for non-invasive positive pressure ventilation in the patients with acute exacerbation of chronic obstructive pulmonary disease.
This study aimed to estimate the value of serum procalcitonin (PCT) for non-invasive positive pressure ventilation (NIPPV) prediction in the patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD).A total of 220 AECOPD patients were divided into NIPPV group (n = 121) and control group (routine treatment, n = 99) based on the routine standards and physicians' experience. Logistic regression analysis was performed to identify the independent factors for NIPPV treatment. Additionally, the predictive values of the factors were measured through receiver operation characteristic (ROC) curve.NIPPV group and control group showed significant differences in respiratory rate (RR), PaO2, PaCO2, pH, oxygenation index, erythrocyte sedimentation rate (ESR), neutrophil, CRP (C-reaction protein), and PCT (P < .05 for all). PCT, CRP, PaCO2, RR, and neutrophil were independently correlated with NIPPV treatment in AECOPD. ROC curve showed that PCT had superior predictive value, with AUC of 0.899, the sensitivity of 86%, and the specificity of 91.9%. The cut-off value of serum PCT for NIPPV prediction was 88.50 ng/l.AECOPD patients who require NIPPV treatment frequently have high levels of PCT, CRP, PaCO2, RR and neutrophil. Serum PCT may be employed as an indicator for NIPPV treatment in AECOPD patients.


Carbon Clusters: Thermochemistry and Electronic Structure at High Temperatures.
This paper studies the thermochemistry and electronic structure of small carbon clusters and hydrocarbons, which are major constituents of pyrolysis gases released into the boundary layer of ablating heat shields. Our focus lies on clusters of up to four carbon atoms. Among other molecules, thermochemistry data for molecules such as C3H and C4H have been determined using the Weizmann-1 (W1) method. These molecules have very limited thermochemistry data recorded in the literature, thereby necessitating new and accurate computations of required properties such as electronic energies of low-lying states, heats of formation, harmonic frequencies, and rotational constants. A study of electronically excited states of these molecules computed using the equations of motion coupled cluster singles doubles method revealed C4 and C4H to be potential sources of radiation absorption in the boundary layer. The excited electronic states of interest are studied further to obtain their optimum geometries, rotational constants, and vibrational frequencies. Moreover, we also study the effect of low-lying excited electronic states on the partition function to assess their effect on the thermodynamics of these pyrolysis gases in the high-temperature regime. Neglecting the excited electronic states records a maximum difference of 12% in the computed specific heat capacity values, Cp values. Finally, comparisons of the equilibrium mole fractions obtained using the thermodynamics computed in this paper with the existing state-of-the-art tables used for hypersonic applications (e.g., JANAF and Gurvich Tables) show an order of magnitude difference in the mixture compositions. It is shown that the rhombic isomer of C4 (1Ag), which is energetically close to the ground state (3Σg-) and usually neglected in composition calculations, contributes to a 28% increase in the equilibrium mole fraction of the C4 molecule.


[Dynamics of the health labor market in Brazil, 1979-1983].
The author reviews the situation of the labor market in Brazil with special reference to occupations in the health services delivery sector, which, owing to factors of urbanization, industrialization, an increase in the number of workers subscribing to the social security system, etc., is now absorbing a large percentage of the manpower pool and thereby generating an explosion of higher education in the health field. The writer urges the need for an improved regional distribution of medical professionals and for better training and more schooling for auxiliary personnel in particular.


Effect of oxidised regenerated cellulose/collagen matrix on proteases in wound exudate of patients with chronic venous ulceration.
Oxidised regenerated cellulose/collagen matrix (ORC/collagen matrix) modifies wound microenvironments by binding and inactivating excess levels of proteases such as elastase, plasmin and gelatinases in wound exudates. To compare levels of the gelatinases matrix metalloproteinase 2 (MMP-2), elastase and plasmin in wound exudates collected from chronic venous insufficiency patients with venous leg ulcers treated with either an ORC/collagen matrix or a standard control therapy. During a 12-week treatment period, wound exudate samples were obtained from a control group of 10 patients treated with a hydrocolloid dressing and a treatment group of 17 patients treated with a combination of ORC/collagen matrix and hydrocolloid dressing. On admission and days 5, 14 and every subsequent 14th day, ulcers were photographed to determine healing rate and changes in ulcer appearance, and MMP-2 concentration and the gelatinase, elastase and plasmin activities were analysed from wound exudates. The patients treated with ORC/collagen matrix showed a significant decrease in elastase, plasmin and gelastinase activity as compared with the control group, with no significant difference in the MMP-2 concentrations between the two groups. The results show a significant and immediate reduction in protease activity in wound exudates from venous leg ulcers treated with ORC/collagen.


[Spatiotemporal dynamics of maize water suitability and assessment of agricultural drought in Liaoning Province, China from 1981 to 2010].
Maize water suitability (MWS) model was developed at growth stage scale. Frequency and severity of drought were evaluated by combining MWS estimates and agricultural meteorological drought indexes. The MWS at each growth stage was calculated by using maize observational data and conventional meteorological data at 52 sites in Liaoning during the period from 1981 to 2010. Based on the climatic trend and abrupt change analysis, spatiotemporal dynamics of MWS were investigated. Meanwhile, occurrence of agricultural drought and its severity were also estimated. The results showed that the variation of MWS largely differed at different growth stages. Climatic abrupt change happened in 1994, 1996 and 1999 at the stages of emergence to seven leaves (II), jointing to tasseling (IV) and physiological maturity to maturity (VI). During the past 30 years, MWS showed an obvious increasing trend at the stages of sowing to emergence(I) , seven leaves to jointing(III), IV and tasseling to physiological maturity(V), while it showed a decreasing trend at the stages of II and VI, and that at VI stage was statistically significant. In addition, the climatic trend of MWS showed apparently spatial variability. The frequencies of drought at different severities varied with maize growth stages. Areas of high variability of MWS were located in the Northwest and South of Liaoning at the stages of I , II , III and VI, where were also the regions of high frequency of mid- and severe-drought. At the stages of IV and V, the frequency of drought was low and only light- and mid-drought occurred in few areas. In conclusion, the regional mean MWS could be capable to reasonably assess the agricultural drought in Liaoning at the regional scale.


Community participation in health services development, implementation, and evaluation: A systematic review of empowerment, health, community, and process outcomes.
Community participation is widely believed to be beneficial to the development, implementation and evaluation of health services. However, many challenges to successful and sustainable community involvement remain. Importantly, there is little evidence on the effect of community participation in terms of outcomes at both the community and individual level. Our systematic review seeks to examine the evidence on outcomes of community participation in high and upper-middle income countries. This review was developed according to PRISMA guidelines. Eligible studies included those that involved the community, service users, consumers, households, patients, public and their representatives in the development, implementation, and evaluation of health services, policy or interventions. We searched the following databases from January 2000 to September 2016: Medline, Embase, Global Health, Scopus, and LILACs. We independently screened articles for inclusion, conducted data extraction, and assessed studies for risk of bias. No language restrictions were made. 27,232 records were identified, with 23,468 after removal of duplicates. Following titles and abstracts screening, 49 met the inclusion criteria for this review. A narrative synthesis of the findings was conducted. Outcomes were categorised as process outcomes, community outcomes, health outcomes, empowerment and stakeholder perspectives. Our review reports a breadth of evidence that community involvement has a positive impact on health, particularly when substantiated by strong organisational and community processes. This is in line with the notion that participatory approaches and positive outcomes including community empowerment and health improvements do not occur in a linear progression, but instead consists of complex processes influenced by an array of social and cultural factors. This review adds to the evidence base supporting the effectiveness of community participation in yielding positive outcomes at the organizational, community and individual level. Prospero record number: CRD42016048244.


Role of in situ resultant H₂O₂ in the visible-light-driven photocatalytic inactivation of E. coli using natural sphalerite: a genetic study.
This study investigated how a natural sphalerite (NS) photocatalyst, under visible light irradiation, supports photocatalytic bacterial inactivation. This was done by comparing parent E. coli BW25113, and its two isogenic single-gene knock-out mutants, E. coli JW0797-1 (dps(-) mutant) and JW1721-1 (katE(-) mutant), where both dps and KatE genes are likely related to H2O2 production. NS could inactivate approximately 5-, 7- and 7-log of E. coli BW25113, JW0797-1, and JW1721-1 within 6 h irradiation, respectively. The two isogenic mutants were more susceptible to photocatalysis than the parental strain because of their lack of a defense system against H2O2 oxidative stress. The ability of in situ resultant H2O2 to serve as a defense against photocatalytic inactivation was also confirmed using scavenging experiments and partition system experiments. Studying catalase activity further revealed that in situ H2O2 played an important role in these inactivation processes. The destruction of bacterial cells from the cell envelope to the intracellular components was also observed using field emission-scanning electron microscopy. Moreover, FT-IR was used to monitor bacterial cell decomposition, key functional group evolution, and bacterial cell structures. This is the first study to investigate the photocatalytic inactivation mechanism of E. coli using single-gene deletion mutants under visible light irradiation.


Mechanistic insights into the photogeneration and quenching of guanine radical cation via one-electron oxidation of G-quadruplex DNA.
Herein, mechanistic aspects of the photogeneration and quenching of guanine radical cation through one-electron oxidation of the G-quadruplex of G2T2G2TGTG2T2G2 (TBA) sequence were investigated by a combined quantum mechanical/molecular mechanical (QM/MM) approach at the CASPT2//CASSCF/AMBER level of theory. Herein, one electron promotion of the oxygen lone pair of the photo-excited photosensitizer peroxydisulfate to its O-O σ* orbital was first demonstrated to become tunable through the varied reduction ability of the G base in the presence or absence of interbase hydrogen bonding, thereby dynamically controlling the deprotonation site in G-quadruplex TBA. The quenching of G radical cation mediated by the formation of SO42-via photoinduced electron transfer can be triggered effectively by the deprotonation reaction of free proton rather than that of the hydrogen-bonded proton in G-G (G-quartet) and G-T (loop) aqueous surrounding. By calculating the deprotonation paths for the G radical cation, the deprotonation reactions in G-quadruplex TBA were verified to proceed predominantly along the site of imino proton (N1-H) in the loop moiety; this showed the coexisting occurrence of amino (N2-H) deprotonation in the G-quartet part. The mechanistic features discussed in this study represent significant advances in the understanding of DNA radical chemistry.


Different measures of human hematopoietic cell culture performance are optimized under vastly different conditions.
Hematopoiesis, the formation of mature blood cells from stem (LTC-IC) and progenitor (CFU-GM) cells in the bone marrow, is a complex tissue-forming process that leads to many important physiological functionalities. Consequently, a functioning ex vivo hematopoietic system has a variety of basic scientific and clinical uses. The design and operation of such a system presents the tissue engineer with challenges and choices. In this study, three culture variables were used to control ex vivo human hematopoiesis. Systematic variation of inoculum density (ID), medium exchange interval (MEI), and the use of preformed stroma (PFS) showed that (1) all three variables significantly influenced culture performance, (2) the three variables interacted strongly, and (3) the variables could be manipulated to achieve the optimization of different performance criteria. Donor-to-donor variability in culture performance was great at low ID but was minimized at higher ID. PFS had a large positive effect on cell and CFU-GM output at low ID, but had minimal effect at higher ID. In fact, PFS caused a decrease in LTC-IC output at high ID. The effects of PFS indicated that stromal cell elements became more limiting than proliferative cell elements as ID was reduced.In cultures without PFS, maximum cell output was obtained with high ID using a short MEI, whereas the greatest cell expansion ratio was obtained at low ID with an intermediate MEI. Maximum CFU-GM output was obtained from cultures with high ID using a short to intermediate MEI, whereas the greatest CFU-GM expansion ratio was obtained at intermediate ID with an intermediate MEI. The addition of PFS altered the locations of these maxima. In general, PFS moved the maxima to lower ID, and culture output became more sensitive to MEI. Therefore, the optimization of one performance criterion always resulted in a decline of the others. This study demonstrates that ex vivo tissue function is sensitive to many culture variables in an interactive fashion and that systematic multivariable studies are required to characterize tissue function. Once the effects of individual variables and their interactions are known, this knowledge can be used to optimize tissue performance with respect to desired criteria.


A cognitive model of dangerous delusional misidentification syndromes.
The hallmark of the delusional misidentification syndromes is the presence of a misidentification delusion of the self or others. Delusional misidentification may present with an increased risk for dangerous behaviors. Individuals suffering from delusional misidentification syndromes may express hostility in ways ranging from serious verbal threats to homicidal acts. The causes of dangerous misidentification delusions remain for the most part undetermined. In this article, we report a series of six cases of individuals who harbored dangerous misidentification delusions. These individuals were studied phenomenologically and forensically. They were also studied biologically, including neuropsychological testing. A cognitive hypothesis aimed at explaining dangerousness and delusional misidentification is proposed. Implications of the hypothesis for further research are briefly outlined.


Medical therapy in venous thromboembolism.
Immediate intense anticoagulation with parenteral anticoagulants (heparin or fondaparinux) followed by vitamin K antagonists is the current standard therapy for deep vein thrombosis (DVT) or nonmassive pulmonary embolism. In the future, new oral anticoagulants may replace not only vitamin K antagonists but also initial parenteral anticoagulation. Duration of anticoagulation should be at least 3 months because shorter courses double the recurrence rates. More prolonged anticoagulation therapy may be warranted in the presence of specific clinical risk factors. Global markers of coagulation, particularly D-dimer, may discriminate low- and high-risk patients. Models that combine clinical characteristics and laboratory markers further improve prediction of the recurrence risk in individual patients, but these models await validation before they can be applied in routine care.


Relationship of race/ethnicity to caregivers' coping, appraisals, and distress after traumatic brain injury.
The objective of the current study was to determine the relationship between race/ethnicity and caregivers' coping, appraisals of the caregiving role, and distress after traumatic brain injury (TBI). Participants were 195 caregivers (75% white; 25% black/Hispanic) of persons with TBI who were admitted to comprehensive inpatient rehabilitation at one of three participating centers and were followed up at 1 year after injury. Caregivers completed interview and self-report questionnaires, including the Ways of Coping Questionnaire, Caregiver Appraisal Scale, and Brief Symptom Inventory. Compared to whites, blacks/Hispanics reported lower levels of education, lower annual household income, and were more likely to be caring for an extended family member. After adjusting for relationship to the person with injury, age, education and income, race/ethnicity significantly predicted caregivers' use of the coping strategies distancing and accepting responsibility. Blacks/Hispanics made greater use of these strategies compared to whites. Blacks/Hispanics also showed more traditional beliefs regarding the caregiving role. Race/ethnicity was not predictive of distress. However, an interaction was noted between race/ethnicity and caregiver ideology. For Blacks/Hispanics, more traditional ideology was associated with increased distress. Future research using a larger sample of non-whites and including measures of acculturation is warranted.


[Primary sclerosing cholangitis: contribution of retrograde cholangiography in follow-up: apropos of 15 case reports].
From 1975 to 1989, primary sclerosing cholangitis (PSC) was diagnosed in 15 patients especially based on cholangiographic features associated with clinical, biological and histological findings. 93 p. cent of patients had altered liver enzymes at the diagnosis time but only 26% was asymptomatic. 33 p. cent had a concomittant inflammatory bowel disease. Retrograde cholangiography showed injuries of the intrahepatic ducts in 93 p. cent; the more frequently observed lesions were short and multifocal strictures, associated with irregularities of the biliary wall or decreased arborization of intrahepatic bile ducts, but without marked dilatation. Mean follow-up was 44 months (3 to 120). Actuarial survival was 48 p. cent at 5 years. In 4 patients, because of poor clinical and biological (serum bilirubin greater than or equal to 4 mg/dl) evolution, a second retrograde cholangiography was performed showing in all cases apparition of marked ductal dilatation in extra-hepatic (one case) or in intra-hepatic bile ducts (three cases). We diagnosed one benign extra-hepatic stricture, two cholangiocarcinoma and one biliary cirrhosis complicating PSC. We concluded that retrograde cholangiography is necessary if jaundice appears to diagnose every complications of PSC. Apparition of marked ductal dilatation should be the witness of pejorative evolution, especially apparition of cholangiocarcinoma that must be excluded.


Meta-analysis of pediatric tympanoplasty.
To determine which preoperative conditions or surgical techniques may influence the success of tympanoplasty in the pediatric population. A MEDLINE search of the English-language literature from 1966 to May 1997 was conducted using the search terms pediatric or child and tympanoplasty or myringoplasty. Articles that provided age-specific data on tympanoplasty or myringoplasty were included. Of the original 651 studies retrieved, 30 were accepted for inclusion. The principal reason for exclusion was inability to separate adult and pediatric results in series that combined both patient populations. Success was defined as an intact tympanic membrane for the purpose of this review. Data were tabulated by consensus of 2 reviewers. The effect of surgical technique, prior adenoidectomy, presence of active infection, size of perforation, status of the contralateral ear, age, and eustachian tube function on healing of the tympanic membrane after surgery was assessed. Only those studies providing data on a given parameter of interest could be included when comparing each variable. Weighted means were compared and subjected to sensitivity analysis. Simple linear regression analysis was used to assess the effect of age on outcome. Greater success in healing of the tympanic membrane following tympanoplasty in children is seen with advancing age. None of the other parameters studied was shown to be a significant predictor of success. Guidelines for reporting results of tympanoplasty are presented.


Fine-Tuning the Performance of Ultraflexible Organic Complementary Circuits on a Single Substrate via a Nanoscale Interfacial Photochemical Reaction.
Flexible electronics has paved the way toward the development of next-generation wearable and implantable healthcare devices, including multimodal sensors. Integrating flexible circuits with transducers on a single substrate is desirable for processing vital signals. However, the trade-off between low power consumption and high operating speed is a major bottleneck. Organic thin-film transistors (OTFTs) are suitable for developing flexible circuits owing to their intrinsic flexibility and compatibility with the printing process. We used a photoreactive insulating polymer poly((±)endo,exo-bicyclo[2.2.1]hept-ene-2,3-dicarboxylic acid, diphenylester) (PNDPE) to modulate the power consumption and operating speed of ultraflexible organic circuits fabricated on a single substrate. The turn-on voltage (V on) of the p- and n-type OTFTs was controlled through a nanoscale interfacial photochemical reaction. The time-of-flight secondary ion mass spectrometry revealed the preferential occurrence of the PNDPE photochemical reaction in the vicinity of the semiconductor-dielectric interface. The power consumption and operating speed of the ultraflexible complementary inverters were tuned by a factor of 6 and 4, respectively. The minimum static power consumption was 30 ± 9 pW at transient and 4 ± 1 pW at standby. Furthermore, within the tuning range of the operating speed and at a supply voltage above 2.5 V, the minimum stage delay time was of the order of hundreds of microseconds. We demonstrated electromyogram measurements to emphasize the advantage of the nanoscale interfacial photochemical reaction. Our study suggests that a nanoscale interfacial photochemical reaction can be employed to develop imperceptible and wearable multimodal sensors with organic signal processing circuits that exhibit low power consumption.


Salvage of ischemic myocardium by dipyridamole in the conscious dog.
We investigated the effect of i.v. dipyridamole, a potent small-vessel coronary vasodilator, on myocardial infarct size in conscious dogs. Dipyridamole, 7-9.7 microgram/kg; 15 dogs) or saline (15 dogs) was infused for 6 hours beginning 10 minutes after acute permanent occlusion of the mid-circumflex coronary artery. After sacrifice, 48 hours after occlusion, stereoscopic postmortem angiography was used to define the mass of the occluded coronary bed. Infarct size was determined by planimetry of weighed, unstained left ventricular slices. Dipyridamole produced a striking reduction in mean infarct mass compared with control (3.1 g vs 13.2 g, p less than 0.001), while mean occluded bed mass was similar (30.3 g vs 32.7 g, NS). As a percentage of the occluded bed, mean infarct size was reduced from 36.8% to 8.6% ( p less than 0.001). Mean arterial blood pressure declined approximately 10% after dipyridamole. Heart rate and left atrial pressure did not change significantly. Collateral blood flow, measured with 8- mu radioactive microspheres, increased in all regions during dipyridamole infusion. The infarct center and border regions had sustained increases over 6 hours of 23-80%, while nonischemic regions demonstrated a diminishing response over time, with a large (98-125%) increase 10 minutes after infusion and a smaller (22-25%) increase 6 hours later. Although antiplatelet or local metabolic effects cannot be excluded, the myocardial salvage produced by dipyridamole was most likely due to the increase in collateral blood flow.


The future orientation of constructive memory: An evolutionary perspective on therapeutic hypnosis and brief psychotherapy.
We explore a new distinction between the future, prospective memory system being investigated in current neuroscience and the past, retrospective memory system, which was the original theoretical foundation of therapeutic hypnosis, classical psychoanalysis, and psychotherapy. We then generalize a current evolutionary theory of sleep and dreaming, which focuses on the future, prospective memory system, to conceptualize a new evolutionary perspective on therapeutic hypnosis and brief psychotherapy. The implication of current neuroscience research is that activity-dependent gene expression and brain plasticity are the psychobiological basis of adaptive behavior, consciousness, and creativity in everyday life as well as psychotherapy. We summarize a case illustrating how this evolutionary perspective can be used to quickly resolve problems with past obstructive procrastination in school to facilitate current and future academic success.


Beyond efficacy testing: introducing preventive cardiology into primary care.
The interventions of documented efficacy that have been developed for the treatment of cardiovascular disease risk factors have been neither rapidly nor completely incorporated into clinical practice. This may be due to not recognizing that there is a fundamental conflict between the attributes of the ideal protocol for testing the efficacy of an intervention and the attributes of ideal patient care. For example, when testing an intervention for efficacy, benefit to the subject must be made secondary to the goal of increasing the community's fund of knowledge. When caring for patients, increasing the community's fund of knowledge must be secondary to the goal of benefiting the patient who is receiving care. Therefore, the ideal efficacy-testing program is minimally responsive to the needs of the individual subject; the ideal treatment program is maximally responsive to the needs of the individual patient. A second reason for the slow incorporation of preventive cardiology into patient care is the current lack of a supporting structure. An understanding of the attributes of good patient care and the need for a structure to support preventive cardiology interventions should further the incorporation of preventive cardiology interventions into routine patient care while allowing patient care systems to be scrutinized with efficacy-testing protocols.


High-speed exercise history and catastrophic racing fracture in thoroughbreds.
To investigate the relation between several racing speed history characteristics and risk of fatal skeletal injury (FSI) in racing Thoroughbreds. 64 Thoroughbreds euthanatized during a 9-month period in 1991 at a California racemeet because of a catastrophic fracture incurred while racing (cases), identified retrospectively. For each race in which an FSI occurred, 1 control horse was randomly selected from the noncatastrophically injured participants. Racing and officially timed workout histories were obtained for each horse. Several history characteristics were calculated to summarize racing career patterns and high-speed exercise schedules prior to date of injury and included age at first race, proportion of career spent laid up, average duration of laid up periods, average lifetime racing frequency, time from last lay up to date of injury, and total and rate of distance accumulated 1 to 6 months prior to date of injury. History characteristics associated with FSI were screened by paired t-test and studied in detail, using conditional logistic regression. High total and high average daily rates of exercise distance accumulation within a 2-month period were associated with higher risks for FSI during racing, yet career patterns, such as age at first race or total proportion of career spent laid up, were not found to be associated with risk for FSI. A horse that had accumulated a total of 35 furlongs of race and timed-work distance in 2 months, compared with a horse with 25 furlongs accumulated, had an estimated 3.9-fold increase in risk for racing-related FSI (95% confidence interval = 2.1, 7.1). A horse that had accumulated race and timed-work furlongs at an average rate of 0.6 furlong/d within a 2-month period, compared with a horse with an average of 0.5 furlong/d, had an estimated 1.8-fold increase in risk for racing-related FSI (95% confidence interval = 1.4, 2.6). Thoroughbred racehorses that either accumulate large total high-speed distances or rapidly accumulate high-speed distances within a 2-month period may be at increased risk for FSI during racing.


A high-conductance solute channel in the chloroplastic outer envelope from Pea.
The pea chloroplastic outer envelope protein OEP24 can function as a general solute channel. OEP24 is present in chloroplasts, etioplasts, and non-green root plastids. The heterologously expressed protein forms a voltage-dependent, high-conductance (Lambda = 1.3 nS in 1 M KCl), and slightly cation-selective ion channel in reconstituted proteoliposomes. The highest open probability (P open approximately 0. 8) is at 0 mV, which is consistent with the absence of a transmembrane potential across the chloroplastic outer envelope. The OEP24 channels allow the flux of triosephosphate, dicarboxylic acids, positively or negatively charged amino acids, sugars, ATP, and Pi. Structure prediction algorithms and circular dichroism spectra indicate that OEP24 contains seven amphiphilic beta strands. The primary structure of OEP24 shows no homologies to mitochondrial or bacterial porins on a primary sequence basis, and OEP24 is functionally not inhibited by cadaverine, which is a potent inhibitor of bacterial porins. We conclude that OEP24 represents a new type of solute channel in the plastidic outer envelope.


Effect of Environmental Pollutants PM2.5, CO, NO2, and O3 on the Incidence and Mortality of SARS-CoV-2 Infection in Five Regions of the USA.
In recent decades, environmental pollution has become a significant international public problem in developing and developed nations. Various regions of the USA are experiencing illnesses related to environmental pollution. This study aims to investigate the association of four environmental pollutants, including particulate matter (PM2.5), carbon monoxide (CO), Nitrogen dioxide (NO2), and Ozone (O3), with daily cases and deaths resulting from SARS-CoV-2 infection in five regions of the USA, Los Angeles, New Mexico, New York, Ohio, and Florida. The daily basis concentrations of PM2.5, CO, NO2, and O3 were documented from two metrological websites. Data were obtained from the date of the appearance of the first case of (SARS-CoV-2) in the five regions of the USA from 13 March to 31 December 2020. Regionally (Los Angeles, New Mexico, New York, Ohio, and Florida), the number of cases and deaths increased significantly along with increasing levels of PM2.5, CO, NO2 and O3 (p < 0.05), respectively. The Poisson regression results further depicted that, for each 1 unit increase in PM2.5, CO, NO2 and O3 levels, the number of SARS-CoV-2 infections significantly increased by 0.1%, 14.8%, 1.1%, and 0.1%, respectively; for each 1 unit increase in CO, NO2, and O3 levels, the number of deaths significantly increased by 4.2%, 3.4%, and 1.5%, respectively. These empirical estimates demonstrate an association between the environmental pollutants PM2.5, CO, NO2, and O3 and SARS-CoV-2 infections, showing that they contribute to the incidence of daily cases and daily deaths in the five different regions of the USA. These findings can inform health policy decisions about combatting the COVID-19 pandemic outbreak in these USA regions and internationally by supporting a reduction in environmental pollution.


Prospects for Antibacterial Discovery and Development.
The rising prevalence of multidrug-resistant bacteria is an urgent health crisis that can only be countered through renewed investment in the discovery and development of antibiotics. There is no panacea for the antibacterial resistance crisis; instead, a multifaceted approach is called for. In this Perspective we make the case that, in the face of evolving clinical needs and enabling technologies, numerous validated antibacterial targets and associated lead molecules deserve a second look. At the same time, many worthy targets lack good leads despite harboring druggable active sites. Creative and inspired techniques buoy discovery efforts; while soil screening efforts frequently lead to antibiotic rediscovery, researchers have found success searching for new antibiotic leads by studying underexplored ecological niches or by leveraging the abundance of available data from genome mining efforts. The judicious use of "polypharmacology" (i.e., the ability of a drug to alter the activities of multiple targets) can also provide new opportunities, as can the continued search for inhibitors of resistance enzymes with the capacity to breathe new life into old antibiotics. We conclude by highlighting available pharmacoeconomic models for antibacterial discovery and development while making the case for new ones.


Contrasting duplication patterns reflect functional diversities of ubiquitin and ubiquitin-like protein modifiers in plants.
Ubiquitin (Ub) and Ub-like proteins, collectively forming the ubiquiton family, regulate nearly all aspects of cellular processes via post-translational modifications. Studies devoted to specific members suggested a large expansion of this family in plants; however, a lack of systematic analysis hinders the comparison of individual members at both evolutionary history and functional divergence levels, which may provide new insight into biological functions. In this work, we first retrieved a total of 5856 members of 17 known ubiquiton subfamilies in 50 plant genomes by searching both prior annotations and missing loci in each genome. We then applied this list to analyze the duplication history of major ubiquiton subfamilies in plants. We show that autophagy-related protein 8 (ATG8), membrane-anchored Ub-fold (MUB), small Ub-like modifier (SUMO) and Ub loci encode 88% of the plant ubiquiton family. Although whole genome duplications (WGDs) significantly expanded the family, we discovered contrasting duplication patterns both in species and in subfamilies. Within the family, the ATG8 and MUB members were primarily duplicated through WGDs, whereas a significant number of Ub and SUMO loci were generated through retroposition and tandem duplications, respectively. Although Ub coding regions are highly conserved in plants, promoter activity analysis demonstrated lineage-specific expression patterns of polyUb genes in Oryza sativa (rice) and Arabidopsis, confirming their retroposition origin. Based on the theory of dosage balance constraints, our study suggests that ubiquiton members duplicated through WGDs play crucial roles in plants, and that the regulatory pathways involving ATG8 and MUB are more conserved than those controlled by Ub and SUMO.