The Role of Nurse in the Multidisciplinary Management of Cancer Cachexia.
Cancer cachexia is a complex syndrome for which multidisciplinary management through collaboration has the potential to improve patient outcomes and efficiency of care, through the integration of nursing into practice. These authors conducted a literature review of PubMed, EBSCO, OVID, and ProQuest for publications on the roles and responsibilities of nurses who are working in multidisciplinary teams for the management of cancer cachexia. We limited our search parameters for the literature review such that: (1) the included papers were published in the English language from January 2000 to February 2021 and (2) the included papers featured an adult patient population. Based on this review, cancer cachexia can be characterized as an involuntary loss of body weight that is combined with a dysregulation in the control of energy homeostasis and protein loss, which leads to poor clinical outcomes in patients. Cancer cachexia has been recognized as having multidimensional etiologies that are related to the nutritional and metabolic systems, as well as other physical and physiological systems, and to symptoms that manifest concurrently to the cachexia. While the clinical identification and taxonomic classification of cancer cachexia are usually associated with an observable degree of weight loss and muscular atrophy in a patient, clinical evidence of inflammation and related symptoms should be considered (in addition to the weight loss and muscular atrophy) in the diagnosis and evaluation of cancer cachexia, as will be argued in this paper. Early diagnosis, appropriate clinical assessment, and evaluation of cancer cachexia are crucial to predicting the onset of the condition and managing its symptoms when it occurs. Various tools have been developed for the clinical evaluation and diagnosis of cancer cachexia which reflect the multitudinous manifestations of the condition. Due to the diversity of its manifestations, multimodal therapy has gained popularity for the management of cancer cachexia. Multimodal therapy includes combined pharmacologic intervention, nutrition supplements, nutritional consultation, physical exercise, and symptom control. As these authors will demonstrate in this paper, this mode of multidisciplinary team management is increasingly supported by scientific evidence and as such, can be seen as essential for high-quality cancer cachexia management. Nursing plays an important role in the multidisciplinary care team model for cancer cachexia management, as nurses are well situated to perform screening, referral, coordination, nutritional consultation, physical exercise consultation, direct nutritional nursing, psychosocial support, symptom control, and hospice care. However, an increased focus on education, skills training, and tool development (as well as adoption of tools) on the part of nurses and other multidisciplinary team members is required to meet the goal of efficient care and improved outcomes for patients with cancer cachexia. These authors demonstrate that increasing roles and responsibilities for nurses in the management of cancer cachexia is a valuable area to explore in the literature and to implement in clinical practice. Our review aims to summarize the etiology and epidemiology, mechanisms-of-action, and multitudinous manifestations of cancer cachexia, the therapies that are used in cancer cachexia care and the management approaches by which this care is organized. Finally, these authors emphasize nurses' responsibilities in this mode of cancer cachexia multidisciplinary team management, which represents a fruitful benefit both in the research literature and in clinical settings.


Pig Movement Estimation by Integrating Optical Flow with a Multi-Object Tracking Model.
Pig husbandry constitutes a significant segment within the broader framework of livestock farming, with porcine well-being emerging as a paramount concern due to its direct implications on pig breeding and production. An easily observable proxy for assessing the health of pigs lies in their daily patterns of movement. The daily movement patterns of pigs can be used as an indicator of their health, in which more active pigs are usually healthier than those who are not active, providing farmers with knowledge of identifying pigs' health state before they become sick or their condition becomes life-threatening. However, the conventional means of estimating pig mobility largely rely on manual observations by farmers, which is impractical in the context of contemporary centralized and extensive pig farming operations. In response to these challenges, multi-object tracking and pig behavior methods are adopted to monitor pig health and welfare closely. Regrettably, these existing methods frequently fall short of providing precise and quantified measurements of movement distance, thereby yielding a rudimentary metric for assessing pig health. This paper proposes a novel approach that integrates optical flow and a multi-object tracking algorithm to more accurately gauge pig movement based on both qualitative and quantitative analyses of the shortcomings of solely relying on tracking algorithms. The optical flow records accurate movement between two consecutive frames and the multi-object tracking algorithm offers individual tracks for each pig. By combining optical flow and the tracking algorithm, our approach can accurately estimate each pig's movement. Moreover, the incorporation of optical flow affords the capacity to discern partial movements, such as instances where only the pig's head is in motion while the remainder of its body remains stationary. The experimental results show that the proposed method has superiority over the method of solely using tracking results, i.e., bounding boxes. The reason is that the movement calculated based on bounding boxes is easily affected by the size fluctuation while the optical flow data can avoid these drawbacks and even provide more fine-grained motion information. The virtues inherent in the proposed method culminate in the provision of more accurate and comprehensive information, thus enhancing the efficacy of decision-making and management processes within the realm of pig farming.


Relationship between cognitive capabilities and social participation among people with traumatic brain injury.
This study attempts to determine the relationship between cognitive capabilities and social participation, over a 1-year period, among people who have experienced traumatic brain-injury (TBI). Using the Disability Creation Process as a basis for making hypotheses, three research questions were examined: (1) Do cognitive capabilities improve over time?; (2) Does social participation improve over time?; and (3) Are these two concepts related over time? The results and their clinical implications on rehabilitation are discussed, along with the limitations of this study.


Peripheral artery disease: how much inter-leg symmetry? A contrast-enhanced magnetic resonance angiography study.
The aim of this observational retrospective study was to qualitatively and quantitatively evaluate the symmetry of atherosclerotic plaques in patients with peripheral artery disease (PAD) undergoing contrast-enhanced magnetic resonance angiography of lower limbs. We retrospectively evaluated the peripheral magnetic resonance angiography of 82 patients considering the iliac, femoral and tibial arteries. Stenosis was scored 0 (none), 1 (<50%), 2 (50%-74%), 3 (75%-99%), and 4 (occluded). Symmetry was quantified as the percentage of bilaterally-diseased arteries and using the inter-leg absolute score difference (0-4). Signs test and Cohen κ were also calculated. Seventy-one (87%) patients had ≥1 bilaterally-diseased artery, and 168 (20%) of 820 artery pairs were bilaterally affected. At least 1 bilateral stenosis was observed from 11% (right internal iliac) to 73% (right superficial femoral). All 10 arteries showed symmetry, none of the inter-leg comparisons being significantly different (P ≥ .100). Cohen κ ranged from 0.208 (common femoral) to 0.533 (internal iliac). This study showed that PAD was symmetrically distributed between the 2 legs, with the internal iliac artery being the most symmetric segment. Symmetry of PAD was quantified in 20%.


Changes in cortical subarachnoid fluid potassium concentrations during hypoxia.
Seventeen rhesus monkeys underwent 20-minute episodes of hypoxia (mean Po2, 18 to 28 mm Hg). In 14 animals that maintained mean blood pressures greater than 60 mm Hg, increases in potassium concentration averaging greater than 1 mEq/liter were observed in the cortical subarachnoid fluid. These changes were reversible with oxygen administration and were usually not associated with morphologic evidence of brain injury. Cisterna magna fluid, sampled in five animals, showed smaller increases in potassium concentration (mean, 0.3 +/- 0.4 mEq/liter). The arteriovenous difference in potassium concentration was consistently positive, suggesting movement of potassium from blood to brain during hypoxia. The amount of potassium accumulation in the cortical subarachnoid fluid was closely related to the severity of the hypoxia. Threshold Po2 levels, below which potassium changes occurred, were estimated at 29 mm Hg for the arterial blood and 20 mm Hg for the jugular venous blood. Massive potassium accumulations in the cortical subarachnoid fluid (greater than 10 mEq/liter) developed in three animals that sustained severe arterial hypotension during hypoxia.


Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation.
A series of basic animal studies using a new subatmospheric pressure technique (The V.A.C.) to expedite wound healing are presented. The technique entails placing an open-cell foam into the wound, sealing the site with an adhesive drape, and applying subatmospheric pressure (125 mmHg below ambient) that is transmitted to the wound in a controlled manner. Utilizing a pig model, four studies were undertaken to determine the effect of subatmospheric pressure on laser Doppler-measured blood flow in the wound and adjacent tissue (N = 5), rate of granulation tissue formation (N = 10), clearance of bacteria from infected wounds (N = 5), and measurement of nutrient flow by random-pattern flap survival (N = 5). Blood flow levels increased fourfold when 125 mmHg subatmospheric pressure was applied. Significantly increased rates of granulation tissue formation (p < or = 0.05) occurred with both continuous (63.3 +/- 26.1%) and intermittent (103% +/- 35.3%) application. Tissue bacterial counts significantly decreased (p < or = 0.05) after 4 days of application. Random-pattern flap survival significantly increased (p < or = 0.05) by 21% compared to controls. We determined that the application of controlled subatmospheric pressure creates an environment that promotes would healing.


AOTF based molecular hyperspectral imaging system and its applications on nerve morphometry.
The neuroanatomical morphology of nerve fibers is an important description for understanding the pathological aspects of nerves. Different from the traditional automatic nerve morphometry methods, a molecular hyperspectral imaging system based on an acousto-optic tunable filter (AOTF) was developed and used to identify unstained nerve histological sections. The hardware, software, and system performance of the imaging system are presented and discussed. The gray correction coefficient was used to calibrate the system's spectral response and to remove the effects of noises and artifacts. A spatial-spectral kernel-based approach through the support vector machine formulation was proposed to identify nerve fibers. This algorithm can jointly use both the spatial and spectral information of molecular hyperspectral images for segmentation. Then, the morphological parameters such as fiber diameter, axon diameter, myelin sheath thickness, fiber area, and g-ratio were calculated and evaluated. Experimental results show that the hyperspectral-based method has the potential to recognize and measure the nerve fiber more accurately than traditional methods.


Improved assessment of ex vivo brainstem neuroanatomy with high-resolution MRI and DTI at 7 Tesla.
The aim of the present work was to provide the topography of the main gray nuclei and white matter tracts of the human brainstem at 7 Tesla (7 T) high-field magnetic resonance imaging (MRI) using structural imaging (T1) and diffusion tensor imaging (DTI). Both imaging techniques represent a new field of increasing interest for its potential neuroanatomic and neuropathologic value. Brainstems were obtained postmortem from human donors, fixated by intracarotid perfusion of 10% neutral buffered formalin, and scanned in a Bruker BioSpec 7 T horizontal scanner. 3D-data sets were acquired using the modified driven equilibrium Fourier transform (MDEFT) sequence and Spin Echo-DTI (SE-DTI) sequence was used for DTI acquisition. High-resolution structural MRI and DTI of the human brainstem acquired postmortem reveals its basic cyto- and myeloar-chitectonic organization, only visualized to this moment by histological techniques and higher magnetic field strengths. Brainstem structures that are usually not observed with lower magnetic fields were now topographically identified at midbrain, pons, and medullar levels. The application of high-resolution structural MRI will contribute to precisely determine the extension and topography of brain lesions. Indeed, the current findings will be useful to interpret future high-resolution in vivo MRI studies in living humans.


Stability of strong species interactions resist the synergistic effects of local and global pollution in kelp forests.
Foundation species, such as kelp, exert disproportionately strong community effects and persist, in part, by dominating taxa that inhibit their regeneration. Human activities which benefit their competitors, however, may reduce stability of communities, increasing the probability of phase-shifts. We tested whether a foundation species (kelp) would continue to inhibit a key competitor (turf-forming algae) under moderately increased local (nutrient) and near-future forecasted global pollution (CO(2)). Our results reveal that in the absence of kelp, local and global pollutants combined to cause the greatest cover and mass of turfs, a synergistic response whereby turfs increased more than would be predicted by adding the independent effects of treatments (kelp absence, elevated nutrients, forecasted CO(2)). The positive effects of nutrient and CO(2) enrichment on turfs were, however, inhibited by the presence of kelp, indicating the competitive effect of kelp was stronger than synergistic effects of moderate enrichment of local and global pollutants. Quantification of physicochemical parameters within experimental mesocosms suggests turf inhibition was likely due to an effect of kelp on physical (i.e. shading) rather than chemical conditions. Such results indicate that while forecasted climates may increase the probability of phase-shifts, maintenance of intact populations of foundation species could enable the continued strength of interactions and persistence of communities.


Anionic Polymer and Quantum Dot Excipients to Facilitate siRNA Release and Self-Reporting of Disassembly in Stimuli-Responsive Nanocarrier Formulations.
The incorporation of anionic excipients into polyplexes is a promising strategy for modulating siRNA binding versus release and integrating diagnostic capabilities; however, specific design criteria and structure-function relationships are needed to facilitate the development of nanocarrier-based theranostics. Herein, we incorporated poly(acrylic acid) (PAA) and quantum dot (QD) excipients into photolabile siRNA polyplexes to increase gene silencing efficiencies by up to 100% and enable self-reporting of nanocarrier disassembly. Our systematic approach identified the functional relationships between gene silencing and key parameters such as excipient loading fractions and molecular weights that facilitated the establishment of design rules for optimization of nanocarrier efficacy. For example, we found that PAA molecular weights ∼10-20× greater than that of the coencapsulated siRNA exhibited the most efficient release and silencing. Furthermore, siRNA release assays and RNAi modeling allowed us to generate a PAA "heat map" that predicted gene silencing a priori as a function of PAA molecular weight and loading fraction. QDs further promoted selective siRNA release and provided visual as well as Förster resonance energy transfer (FRET)-based monitoring of the dynamic changes in nanostructure in situ. Moreover, even with the addition of anionic components, our formulations exhibited substantially improved stability and shelf life relative to typical formulations, with complete stability after a week of storage and full activity in the presence of serum. Taken together, this study enabled synergistic improvements in siRNA release and diagnostic capabilities, along with the development of mechanistic insights that are critical for advancing the translation of nucleic acid theranostics into the clinic.


[Diffuse arterial calcified elastopathy].
Diffuse arterial calcified elastopathy was observed in 6 pediatric patients presenting with severe renovascular hypertension. Renal ultrasonography showed a characteristic pattern, the dotted corticomedullary junction, related to the increased echogenicity of the interlobar and/or arcuate arteries. Superficial temporal artery biopsy demonstrated the presence and the extension of the calcifying process involving the elastic layers of the muscular arteries. This clinicopathological syndrome may be heterogeneous from an etiological point of view: etiologic investigations led to the diagnosis of pseudoxanthoma elasticum in 2 patients; no etiology could be found in the others.


FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer.
Low-affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FcγRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FcγRIIIa expression, suggesting that FcγRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FcγRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FcγRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FcγRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FcγRIIIa protein expression. Similarly, inhibition of PIP5K1α decreased FcγRIIIa expression in PCa cells. FcγRIIIa physically interacted with PIP5K1α and AR via formation of protein-protein complexes, suggesting that FcγRIIIa is functionally associated with AR and PIP5K1α in PCa cells. Our study identified FcγRIIIa as an important factor in promoting PCa growth and invasion. Further, the elevated activation of FcγRIII and AR and PIP5K1α pathways may cooperatively promote PCa growth and invasion. Thus, FcγRIIIa may serve as a potential new target for improved treatment of metastatic and castration-resistant PCa.


Impact of smoking on one year functional outcomes after thrombectomy for young stroke patients.
The incidence of stroke in young patients (20-50 years old) has increased in recent decades. Unlike the use of good functional outcomes to evaluate prognosis, excellent functional outcomes are a better indicator of return to work among younger patients. The rate of return to work increases with time after stroke. This study investigated the short term (3 months) and long term (1 year) predictors of excellent functional outcomes in young patients after endovascular thrombectomy (EVT). We included young patients who underwent EVT for acute ischemic stroke (AIS) due to large vessel occlusion within 6 hours after stroke onset between 2015 and 2021. Patients with intracerebral hemorrhage on pretreatment CT were excluded. The associations between clinical, imaging, and procedure variables, and excellent functional outcomes were analyzed using univariate and multivariable logistic regression analyses. An excellent functional outcome was defined as a modified Rankin Scale score of ≤1. Of the 361 patients with AIS eligible for EVT, 55 young patients (aged 24-50 years) were included. Of these, 36.4% and 41.8% achieved excellent functional outcomes at 3 and 12 months, respectively. Multivariate analysis revealed that smoking was the independent negative predictor of both 3 month (adjusted OR (aOR) 0.232, 95% CI 0.058 to 0.928; p=0.039) and 12 month (aOR 0.180, 95% CI 0.044 to 0.741; p=0.018) excellent functional outcomes. Current or former smoking habit was an independent negative predictor of both short term and long term excellent functional outcomes in young adults with AIS.


In-hospital falls of newborn infants: data from a multihospital health care system.
The fall of a newborn infant to the hospital floor is an error that has received little or no attention in medical publications. We sought to analyze the circumstances surrounding all such falls that occurred in an 18-hospital health care system during a 3-year period. Information was located by using electronic and risk-management records. Demographic features, circumstances of the fall, and outcomes were tabulated for each event. During the study period, 88774 live births occurred at the Intermountain Healthcare hospitals. Fourteen neonatal in-hospital falls were identified during this period (incidence estimate: 1.6 falls per 10000 births). Seven falls occurred when a parent, holding the infant in a hospital bed or reclining chair, fell asleep and the infant fell to the floor. Six of these 7 falls occurred between 1:30 am and 9:00 am. Four falls occurred in the delivery room, 2 in the hallway while a nurse was wheeling a bassinette, and 1 from an infant swing. No deaths occurred. One patient sustained a depressed skull fracture and was transported to the regional children's hospital. At hospital discharge, 13 of the 14 were reported to have a normal examination. No specific protocols for preventing in-hospital falls of neonates were in place. If the incidence of a neonatal in-hospital fall in this study is representative, then 600 to 700 such falls occur annually in the United States. Relatively few scenarios explain the majority of falls. We speculate that the prevalence of this error could be reduced significantly by enacting programs aimed at eliminating or monitoring the most common circumstances under which these falls occur.


Elective delivery in diabetic pregnant women.
In pregnancies complicated by diabetes the major concerns during the third trimester are fetal distress and the potential for birth trauma associated with fetal macrosomia. The objective of this review was to assess the effect of a policy of elective delivery, as compared to expectant management, in term diabetic pregnant women, on maternal and perinatal mortality and morbidity. We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register (last searched July 1999). All available randomized controlled trials of elective delivery, either by induction of labour or by elective caesarean section, compared to expectant management in diabetic pregnant women at term. The reports of the only available trial were analysed independently by the three co-reviewers to retrieve data on maternal and perinatal outcomes. Results are expressed as relative risks (RR) and 95% confidence intervals (CI). The participants in the one trial included in this review were 200 insulin-requiring diabetic women. Most had gestational diabetes, except 13 women with type 2 preexisting diabetes (class B). The trial compared a policy of active induction of labour at 38 completed weeks of pregnancy, to expectant management until 42 weeks. The risk of caesarean section was not statistically different between groups (RR 0.81, 95% CI 0.52 - 1.26). The risk of macrosomia was reduced in the active induction group (RR 0.56, 95%CI 0.32 - 0. 98) and 3 cases of mild shoulder dystocia were reported in the expectant management group. No other perinatal morbidity was reported. There is very little evidence to support either elective delivery or expectant management at term in pregnant women with insulin-requiring diabetes. Limited data from a single randomized controlled trial suggest that induction of labour in women with gestational diabetes treated with insulin reduces the risk of macrosomia. Although the small sample size does not permit one to draw conclusions, the risk of maternal or neonatal morbidity was not modified. Women's views on elective delivery and on prolonged surveillance and treatment with insulin should be assessed in future trials.


PACAP and acetylcholine cause distinct Ca2+ signals and secretory responses in chromaffin cells.
The adrenomedullary chromaffin cell transduces chemical messages into outputs that regulate end organ function throughout the periphery. At least two important neurotransmitters are released by innervating preganglionic neurons to stimulate exocytosis in the chromaffin cell-acetylcholine (ACh) and pituitary adenylate cyclase activating polypeptide (PACAP). Although PACAP is widely acknowledged as an important secretagogue in this system, the pathway coupling PACAP stimulation to chromaffin cell secretion is poorly understood. The goal of this study is to address this knowledge gap. Here, it is shown that PACAP activates a Gαs-coupled pathway that must signal through phospholipase C ε (PLCε) to drive Ca2+ entry and exocytosis. PACAP stimulation causes a complex pattern of Ca2+ signals in chromaffin cells, leading to a sustained secretory response that is kinetically distinct from the form stimulated by ACh. Exocytosis caused by PACAP is associated with slower release of peptide cargo than exocytosis stimulated by ACh. Importantly, only the secretory response to PACAP, not ACh, is eliminated in cells lacking PLCε expression. The data show that ACh and PACAP, acting through distinct signaling pathways, enable nuanced and variable secretory outputs from chromaffin cells.


[Biofilm on a metal surface as a factor of microbial corrosion].
Main attention was given in the present review to the research methods, phases of biofilm's forming, exopolymer compounds of bacteria as main biofilm forming factor. A microbial corrosion as a result of interaction between the biofilm and metal surface was considered. The interaction was displayed in biomineralization. The future trends of biofilms study were bound with research of their architecture. That architecture was determined by the structure and function of biofilms compounds: biopolymers and biominerals.


How I treat acute myeloid leukemia.
More than one quarter of a million adults throughout the world are diagnosed annually with acute myeloid leukemia (AML). Despite considerable progress during the past 3 decades in the therapy of AML, two-thirds of young adults and 90% of older adults still die of their disease. The reported median age has increased over the past few decades, mostly because of a greater willingness of physicians to diagnose and treat older patients, and now is 72 years. The greatest challenge is in this age group. However, much improvement in therapy is needed for all adults with AML. Recent advances in allogeneic transplantation, a better understanding of prognostic factors, and development of targeted agents have only modestly improved overall outcome when large populations of patients are considered. Although an explosion in knowledge about the molecular pathogenesis of AML has outpaced treatment advances, such insights hold promise for the development of new therapies directed at specific molecular abnormalities that perturb malignant cell survival pathways. The current approach in 2010 to the management of this disease is presented through a discussion of illustrative cases.


Comparison of data analysis strategies for intent-to-treat analysis in pre-test-post-test designs with substantial dropout rates.
The pre-test-post-test design (PPD) is predominant in trials of psychotherapeutic treatments. Missing data due to withdrawals present an even bigger challenge in assessing treatment effectiveness under the PPD than under designs with more observations since dropout implies an absence of information about response to treatment. When confronted with missing data, often it is reasonable to assume that the mechanism underlying missingness is related to observed but not to unobserved outcomes (missing at random, MAR). Previous simulation and theoretical studies have shown that, under MAR, modern techniques such as maximum-likelihood (ML) based methods and multiple imputation (MI) can be used to produce unbiased estimates of treatment effects. In practice, however, ad hoc methods such as last observation carried forward (LOCF) imputation and complete-case (CC) analysis continue to be used. In order to better understand the behaviour of these methods in the PPD, we compare the performance of traditional approaches (LOCF, CC) and theoretically sound techniques (MI, ML), under various MAR mechanisms. We show that the LOCF method is seriously biased and conclude that its use should be abandoned. Complete-case analysis produces unbiased estimates only when the dropout mechanism does not depend on pre-test values even when dropout is related to fixed covariates including treatment group (covariate-dependent: CD). However, CC analysis is generally biased under MAR. The magnitude of the bias is largest when the correlation of post- and pre-test is relatively low.


Survival trends and prognostic factors of patients with newly diagnosed multiple myeloma accompanied with extramedullary disease.
Background: Extramedullary disease (EMD) is an unusual event in patients with MM. This study aimed to assess the prognostic impact of EMD and develop an EMD-based risk model to estimate the survival of patients with newly diagnosed multiple myeloma (NDMM).Methods: A total of 518 patients were enrolled in this study, of which 121 presented with EMD at the initial diagnosis. Patients were divided into non-EMD, extramedullary-bone-related (EM-B) and extramedullary-extraosseous (EM-E) groups. Clinical characteristics were compared using the chi-squared test or Fisher's exact test. Survival curves were plotted using the Kaplan-Meier method, and a nomogram was constructed based on the Cox proportional hazards model.Results: Compared to patients without EMDs, patients with EM-E were younger (p = 0.028), and those with EM-B had less renal damage (p < 0.001). The EM-E group had the worst progression-free survival (PFS) and overall survival (OS). In addition, patients with multiple sites of EMD invasion or high Ki67 expression had poor OS. Lenalidomide-based treatment showed the worst outcome, and autologous stem cell transplantation (ASCT) remarkably improved the survival of patients with EMD. A prognostic model (MM prognostic index, MM-PI) comprising lactate dehydrogenase (LDH), circulating plasma cells (CPC), del(17p), and type of extramedullary involvement was developed, and a 4-factor nomogram.Conclusions: We established a risk model incorporating extramedullary disease that provides accurate and individualized survival estimates for patients with NDMM.


Detecting treatment-covariate interactions using permutation methods.
The primary objective of a Randomized Clinical Trial usually is to investigate whether one treatment is better than its alternatives on average. However, treatment effects may vary across different patient subpopulations. In contrast to demonstrating one treatment is superior to another on the average sense, one is often more concerned with the question that, for a particular patient, or a group of patients with similar characteristics, which treatment strategy is most appropriate to achieve a desired outcome. Various interaction tests have been proposed to detect treatment effect heterogeneity; however, they typically examine covariates one at a time, do not offer an integrated approach that incorporates all available information, and can greatly increase the chance of a false positive finding when the number of covariates is large. We propose a new permutation test for the null hypothesis of no interaction effects for any covariate. The proposed test allows us to consider the interaction effects of many covariates simultaneously without having to group subjects into subsets based on pre-specified criteria and applies generally to randomized clinical trials of multiple treatments. The test provides an attractive alternative to the standard likelihood ratio test, especially when the number of covariates is large. We illustrate the proposed methods using a dataset from the Treatment of Adolescents with Depression Study.


Application of molecular techniques to the study of hospital infection.
Nosocomial infections are an important source of morbidity and mortality in hospital settings, afflicting an estimated 2 million patients in United States each year. This number represents up to 5% of hospitalized patients and results in an estimated 88,000 deaths and 4.5 billion dollars in excess health care costs. Increasingly, hospital-acquired infections with multidrug-resistant pathogens represent a major problem in patients. Understanding pathogen relatedness is essential for determining the epidemiology of nosocomial infections and aiding in the design of rational pathogen control methods. The role of pathogen typing is to determine whether epidemiologically related isolates are also genetically related. To determine molecular relatedness of isolates for epidemiologic investigation, new technologies based on DNA, or molecular analysis, are methods of choice. These DNA-based molecular methodologies include pulsed-field gel electrophoresis (PFGE), PCR-based typing methods, and multilocus sequence analysis. Establishing clonality of pathogens can aid in the identification of the source (environmental or personnel) of organisms, distinguish infectious from noninfectious strains, and distinguish relapse from reinfection. The integration of molecular typing with conventional hospital epidemiologic surveillance has been proven to be cost-effective due to the associated reduction in the number of nosocomial infections. Cost-effectiveness is maximized through the collaboration of the laboratory, through epidemiologic typing, and the infection control department during epidemiologic investigations.


[Still no proof of the efficacy of acupuncture in the prevention of migraine].
Besides pharmacological treatments for migraine, alternative non-pharmacological treatment strategies might be effective. In 2001, a Cochrane review concluded that acupuncture might be effective in migraine. The authors of a recent large trial also claimed that acupuncture might reduce the frequency of migraine attacks. However, this study failed to provide a clear answer due to serious methodological short-comings, for example with respect to randomisation and the clinical relevance of the main findings. In another recent, large, randomised controlled trial, the efficacy of acupuncture was not significantly different from that of the sham procedure. In conclusion, acupuncture is probably not effective in the prevention of migraine.


[The effect of the delta sleep-inducing peptide on NMDA-induced seizure activity in rats].
The ED100 of the NMDA inducing clonic seizures (0.53 mcg) or tonic extension of forelimbs (5.02 mcg) increased their efficiency 2.3-fold and 4.46-fold, resp., due to the delta-sleep-inducing peptide administration in rats. The data obtained suggests a neuroprotective effect of the peptide on agonists of excitatory amino acid receptors action.


Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability.
Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1.9 mutation (L1302F) that is associated with insensitivity to pain. We investigated the effects of L1302F and a previously reported mutation (L811P) on neuronal excitability. In transfected heterologous cells, the L1302F mutation caused a large hyperpolarizing shift in the voltage-dependence of activation, leading to substantially enhanced overlap between activation and steady-state inactivation relationships. In transfected small rat dorsal root ganglion neurons, expression of L1302F and L811P evoked large depolarizations of the resting membrane potential and impaired action potential generation. Therefore, our findings implicate a cellular loss of function as the basis for impaired pain sensation. We further demonstrated that a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why NaV1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain.


A multiscale model for tropical intraseasonal oscillations.
The tropical intraseasonal 40- to 50-day oscillation (TIO) is the dominant component of variability in the tropical atmosphere with remarkable planetary-scale circulation generated as envelopes of complex multiscale processes. A new multiscale model is developed here that clearly demonstrates the fashion in which planetary-scale circulations sharing many features in common with the observational record for the TIO are generated on intraseasonal time scales through the upscale transfer of kinetic and thermal energy generated by wave trains of organized synoptic-scale circulations having features in common with observed superclusters. The appeal of the multiscale models developed below is their firm mathematical underpinnings, simplicity, and analytic tractability while remaining self-consistent with key features of the observational record. The results below demonstrate, in a transparent fashion, the central role of organized vertically tilted synoptic-scale circulations in generating a planetary circulation resembling the TIO.


Prevalence, distribution on host's body, and chemical control of camel ticks Hyalomma dromedarii in the United Arab Emirates.
Camel farming remains a part of the culture of the Arabian Peninsula although modern methods have greatly increased camel densities in the entire region. In the United Arab Emirates (UAE), camel production is threatened by tick parasitism. However, no study has considered assessing the magnitude of the problem in the UAE. We conducted a study evaluating tick richness, abundance, and spatial distribution of ticks on camels in farms near Al Ain, UAE. In addition, we conducted a survey of farm owners to determine the control methods used to eliminate camel ticks. Tick counts were made on 502 camels (Camelus dromedarius). For each examined animal, visual counts of ticks were made on the entire body segregating the counts by head, neck, forelegs, hump, abdomen, back legs, and tail area. In addition, a total of 70 camel owners from the study area were randomly selected and surveyed about the tick control methods. Hyalomma dromedarii was the only species found during the study. The prevalence of ticks was 98% among the sampled animals. The mean intensity (tick load) was 25.8±2.4 ticks/host and the maximum number of ticks per animal was 102. Ticks were found in five vicinities that are on the border with Oman. The highest number of ticks on the body of the camel occurred on the tail area followed by the abdomen. Cypermethrin was the most commonly used acaricide (46.9%). The high abundance of ticks reported in this study calls for the establishment of a good management strategy. In addition, finding ticks in vicinities in the UAE that are on the border with Oman suggests a cross-border movement between the two countries. Therefore, studying this movement is important to understand its role in the global circulation of some H. dromedarii tick-borne diseases and the movement of acaricide resistance alleles among tick populations.


Maintenance haemodialysis and renal transplantation facilities in South Africa-July 1974.
A survey of facilities available in South Africa for patients suffering from chronic renal failure was made in July 1974. This showed that 14 maintenance haemodialysis centres had a total of 59 dialysing stations with a capacity for treating 154 patients. Five centres had established programmes for renal transplantation. The total number of renal failure survivors on treatment included 129 patients on maintenance dialysis and 177 with grafts. This represents a 31% increase in the number of patients on treatment since a similar survey was made in July 1973.


Spin labels as a probe of the molecular environment of covalently bound ligands in an hydrophobic and an hydrophilic polymer.
The molecular motions of spin-labelled ligands covalently bound by spacer groups to an hydrophobic and an hydrophilic polymer matrix were evaluated by ESR spectroscopy. The ligands were prepared by alkylation of 4-N-methylamino-TEMPO with the omega-bromocarboxylic esters, Br(CH2)nCOOEt, n = 1,4 and 10. The hydrolysed esters were coupled to a cross-linked aminoethylated polyacrylamide hydrogel (n = 1,4,10) and to a surface hydroxylated elastomeric polyester (n = 4). The rotational correlation times (tau c) of the nitroxide label in the hydrogels were measured in the dry state and after exposure to water at pH 4, 7.4 and 10.5. The tau c of the nitroxide label was insensitive to the length of the spacer group and to the degree of protonation of the tertiary amino group of the ligand. There was no evidence of self-association of the ligand and spacer, or more than a single phase within the polyacrylamide hydrogel. The tau c of the nitroxide labelled polyester was similarly insensitive to pH, but was sensitive to organic solvents. The low mobility of the spin label and its high concentration were consistent with the spin label being covalently bound within the hydrophobic polyester matrix to a depth of at least 5 microns.


Gamma Knife robotic microradiosurgery of pituitary adenomas invading the cavernous sinus: treatment concept and results in 89 cases.
The objective of the present retrospective study was evaluation of results of "robotic microradiosurgery" of pituitary adenomas invading the cavernous sinus. Eighty-nine patients with such tumors underwent management using Leksell Gamma Knife model C with automatic positioning system. There were 77 residual and 12 recurrent neoplasms. The applied radiosurgical treatment plan was based on the use of multiple isocenters, mainly of smaller size, which were positioned compactly within the border of the lesion with resultant improved dose homogeneity, increased average dose within the target, and sharp dose fall outside the treated volume. The marginal dose varied from 12 to 25 Gy (mean, 18.2 Gy) in non-functional pituitary adenomas (43 cases), and from 12 to 35 Gy (mean, 25.2 Gy) in hormone-secreting ones (46 cases). The length of follow-up after treatment ranged from 24 to 76 months (mean, 36 months). Control of the tumor growth was attained in 86 cases (97%), whereas actual shrinkage of the lesion was marked in 57 cases (64%). In 18 out of 46 secreting neoplasms (39%), normalization of the excess of the pituitary hormone production was noted after radiosurgery. Treatment-associated morbidity was limited to transitory cranial nerve palsy in two patients (2%). No patient with either non-functional or hormone secreting tumor exhibited new pituitary hormone deficit after treatment. In conclusion, highly precise microanatomy-based Gamma Knife robotic microradiosurgery provides an opportunity for effective management of pituitary adenomas invading the cavernous sinus with preservation of the adjacent functionally important neuronal structures.


[Between Hengshanhuangqi and Chuanhuangqi based on metabolomics and ITS2 sequences].
To compare the differences between Hengshanhuangqi (HH) and Chuanhuangqi (CH) at molecular level, 1H NMR based plant metabolomics approach was used to reveal the chemical difference between HH and CH. Then, the contents of astragaloside IV and calycosin-7-O-beta-D-glucoside, the marker compounds specified in China Pharmacopoeia, were determined. In addition, the ITS2 fragments of HH and CH were sequenced. Twenty-three metabolites were identified in the 1H NMR spectrum, and the principal component analysis showed CH and HH could be separated clearly. HH contained more aspartic acid, GABA, citric acid, astragaloside IV and calycosin-7-O-beta-D-glucoside, while CH contained more threonine, alanine, acetic acid, choline, arginine, fructose and sucrose. And the astragaloside IV is almost undetectable in CH. In addition, the ITS2 fragment sequences of HH and CH were different at eight bases. Thus, the HH and CH showed significant differences chemically and genetically.


Daptomycin and AgNP co-loaded rGO nanocomposites for specific treatment of Gram-positive bacterial infection in vitro and in vivo.
In order to improve the stability of AgNPs and decrease the dosage of Daptomycin for killing bacteria, a reduced graphene oxide (rGO) was used for simultaneously anchoring AgNPs and Daptomycin to prepare rGO@Ag@Dap nanocomposites. In vitro experiments showed that the nanocomposites can efficiently kill four kinds of pathogenic bacteria, especially two kinds of Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) through damaging cell integrity, producing ROS, decreasing ATP and GSH and disrupting bacterial metabolism. Against Gram-positive bacteria, the rGO@Ag@Dap nanocomposites showed a cooperative antibacterial effect. Moreover, in vivo experiments showed that rGO@Ag@Dap can improve the healing of wounds infected with bacteria by efficiently killing the bacteria on the wounds and further promoting skin regeneration and dense collagen deposition. In summary, the above results suggest that the cooperative function of AgNPs with Daptomycin can significantly improve antibacterial efficiency against infectious diseases caused by bacteria, especially for therapies made ineffective due to the drug resistance of pathogenic bacteria.


Oseltamivir (Tamiflu) increases dopamine levels in the rat medial prefrontal cortex.
Oseltamivir (Tamiflu), a neuraminidase inhibitor, is effective for treating both seasonal flu and H5N1 influenza A virus infection. Oseltamivir is generally well tolerated, and its most common adverse effects are nausea and vomiting. However, neuropsychiatric behaviors including jumping and falling from balconies by young patients being treated by oseltamivir have been reported from Japan; this has led to warnings against its prescribing by many authorities. The pharmacological mechanism of the neuropsychiatric effects of oseltamivir remains unclear. Many studies reported that changes in neurotransmission and abnormal behaviors are closely related. We investigated the changes in dopamine and serotonin metabolism after systemic administration of oseltamivir in the medial prefrontal cortex (mPFC) of rats by using microdialysis. After systemic administration of oseltamivir (25mg/kg or 100mg/kg; intraperitoneally (i.p.)), extracellular dopamine in the mPFC was significantly increased as compared to the control values; 3,4-dihydroxyphenylacetic acid and homovanillic acid, the metabolites of dopamine, had also increased significantly. Serotonin was unchanged after the administration of oseltamivir. These findings suggest that oseltamivir increased dopamine release in the mPFC; further, they suggest that the increase in dopamine during oseltamivir treatment may have caused abnormal behaviors in young patients. In cases where oseltamivir is prescribed to children, close observation is required.


Hearing impairment associated with chronic renal failure.
The auditory sensitivity of 67 patients with chronic end-stage renal failure was assessed. In order to determine the incidence of hearing loss and to describe the impairment and possible contributing factors, one group of 39 patients was assessed prior to treatment by hemodialysis. Twelve of these subjects were then followed for 1 year as they are treated by hemodialysis. The remaining 27 patients, not treated by hemodialysis, were also retested in one year. A second group of 28 patients who ad been receiving hemodialysis over periods of 1 1/2, 3, and 6 years was also evaluated. A high incidence of high-frequency impairment was obtained which could not be attributed to age, noise exposure, ototoxicity, or hereditary. An association between this high-frequency impairment and both the renal disease and its treatment was suggested. Clinically significant sensorineural hearing loss did not appear associated with non-genetic kidney disease.


The Importance of Taking a Patient-Centered, Community-Based Approach to Preventing and Managing Frailty: A Public Health Perspective.
Across the world, life expectancy is increasing. However, the years of life gained do not always correspond to healthy life years, potentially leading to an increase in frailty. Given the extent of population aging, the association between frailty and age and the impact of frailty on adverse outcomes for older people, frailty is increasingly being recognized to be a significant public health concern. Early identification of the condition is important to help older adults regain function and to prevent the negative outcomes associated with the syndrome. Despite the importance of diagnosing frailty, there is no definitive evidence or consensus of whether screening should be routinely implemented. A broad range of screening and assessment instruments have been developed taking a biopsychosocial approach, characterizing frailty as a dynamic state resulting from deficits in any of the physical, psychological and social domains, which contribute to health. All these aspects of frailty should be identified and addressed using an integrated and holistic approach to care. To achieve this goal, public health and primary health care (PHC) need to become the fulcrum through which care is offered, not only to older people and those that are frail, but to all individuals, favoring a life-course and patient-centered approach centered around integrated, community-based care. Public health personnel should be trained to address frailty not merely from a clinical perspective, but also in a societal context. Interventions should be delivered in the individuals' environment and within their social networks. Furthermore, public health professionals should contribute to education and training on frailty at a community level, fostering community-based interventions to support older adults and their caregivers to prevent and manage frailty. The purpose of this paper is to offer an overview of the concept of frailty for a public health audience in order to raise awareness of the multidimensional aspects of frailty and on how these should be addressed using an integrated and holistic approach to care.


Psoriasis of the external auditory canal: prevalence, clinical features and impact on quality of life.
Psoriasis of the external auditory canal (PsEAC) is often under-recognized. The aims of this study were to assess the prevalence of PsEAC, its association with a particular psoriasis subtype and its impact on quality of life (QoL). A prospective study was carried out in two Spanish university hospitals, enrolling consecutive patients who attended a consultation for psoriasis. The clinical features of psoriasis and PsEAC were recorded and the Dermatology Life Quality Index (DLQI) and Itch Numerical Rating Scale (Itch-NRS) were distributed to patients. Overall, 188 of 1000 patients (18.8%) included in the study had PsEAC, which was associated with severity of psoriasis, presence of inverse psoriasis and involvement of the scalp, nails and genitals, but not with obesity or psoriatic arthritis. PsEAC was the main reason for consultation in 27 patients, with itching being the main symptom. In this study, PsEAC had a prevalence of 18.8%. The occurrence of PsEAC was associated with poorer QoL, as measured by DLQI and Itch-NRS.


Oral Health Status of Down's Syndrome Patients in Aseer, Saudi Arabia.
It was observed that compared to the general population, mentally challenged subjects have higher rates of poor oral hygiene. Gingivitis is a common finding with moderate or severe variety reported most commonly. Periodontal disease is the most significant oral health problem, which can even lead to mobility of tooth and tooth loss. It is essential to generate oral health precautionary agendas and familiarize it with them. Four Centres of rehabilitation in the Aseer region of Saudi Arabia were included and subjects of 3-24 year age group was examined. Written informed consent was obtained from directors of Centres. Caries, oral hygiene status, soft-tissue and hard-tissue lesions were evaluated and statistically analyzed. Higher Decayed, Missing and Filled Teeth score was observed in the present study in contrast to many other studies. Periodontal disease was seen in higher age group with higher percentages. Poor oral hygiene was seen in 27.3% of males and 66.7% of females. Tongue lesions comprised 85.7%, which accounted for the major part of soft-tissue abnormality. Various occlusal abnormalities (75%) and developmental tooth disturbances (53.6%) constitute the higher portion in hard-tissue abnormality. Dentists should be conscious of the range of oral anomalies that can manifest in this group of the patients. The microbial or serological investigation was not done which could have explained the etiology behind these lesions. In spite of these confines, the survey result have provided information regarding the oral health status of Down's syndrome subjects and the necessity of focusing on oral health need.


Extant ape dental topography and its implications for reconstructing the emergence of early Homo.
Dental topography reflects diet accurately in several extant and extinct mammalian clades. However, dental topographic dietary reconstructions have high success rates only when closely related taxa are compared. Given the dietary breadth that exists among extant apes and likely existed among fossil hominins, dental topographic values from many species and subspecies of great apes are necessary for making dietary inferences about the hominin fossil record. Here, we present the results of one metric of dental topography, Dirichlet normal energy (DNE), for seven groups of great apes (Pongo pygmaeus pygmaeus, Pan paniscus, Pan troglodytes troglodytes and schweinfurthii, Gorilla gorilla gorilla, Gorilla beringei graueri and beringei). Dirichlet normal energy was inadequate at differentiating folivores from frugivores, but was adequate at predicting which groups had more fibrous diets among sympatric African apes. Character displacement analyses confirmed there is substantial dental topographic and relative molar size (M1:M2 ratio; length, width, and area) divergence in sympatric apes when compared to their allopatric counterparts, but character displacement is only present in relative molar size when DNE is also considered. Presence of character displacement is likely due to indirect competition over similar food resources. Assuming similar ecological conditions in the Plio-Pleistocene, the derived masticatory apparatuses of the robust australopiths and early Homo may be due to indirect competition over dietary resources between the taxa, causing dietary niche partitioning. Our results imply that dental topography cannot be used to predict dietary categories in fossil hominins without consideration of ecological factors, such as dietary and geographic overlap. In addition, our results may open new avenues for understanding the community compositions of early hominins and the formation of specific ecological niches among hominin taxa.


Implementing Pediatric Asthma Pathways in Community Hospitals: A National Qualitative Study.
Pathways can improve the quality of care and outcomes for children with asthma; however, we know little about how to successfully implement pathways across diverse hospital settings. Prior studies of pathways have focused on determining clinical effectiveness and the majority were conducted in children's hospitals. These approaches have left crucial gaps in our understanding of how to successfully implement pathways in community hospitals, where most of the children with asthma are treated nationally. The aim of this study was to identify the key determinants of successful pediatric asthma pathway implementation in community hospitals. We conducted a qualitative study of healthcare providers that served as project leaders in a national collaborative to improve pediatric asthma care. Data were collected by recording semi-structured discussions between project leaders and external facilitators (EF) from December 2017 to April 2018. Using inductive thematic analysis, we identified the themes that describe the key determinants of pathway implementation. Project leaders (n = 32) from 18 hospitals participated in this study. The key determinants of pathway implementation in community hospitals included (1) building an implementation infrastructure (eg, forming a team of local champions, modifying clinical workflows, delivering education/skills training), (2) engaging and motivating providers (eg, obtaining project buy-in, facilitating multidisciplinary collaboration, handling conflict), (3) addressing organizational and resource limitations (eg, support for electronic medical record integration), and (4) devising implementation solutions with EFs (eg, potential workflow modifications). Our identification of the key determinants of pathway implementation may help guide pediatric quality improvement efforts in community hospitals. EFs may play an important role in successfully implementing pathways in community settings.


Resting heart rate and metabolic syndrome in patients with diabetes and coronary artery disease in bypass angioplasty revascularization investigation 2 diabetes (BARI 2D) trial.
The relation between the metabolic syndrome (MetS) and resting heart rate (rHR) in patients with diabetes and coronary artery disease is unknown. The authors examined the cross-sectional association at baseline between components of the MetS and rHR and between rHR and left ventricular ejection fraction in the population from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized clinical trial. The mean rHR in the MetS group was significantly higher than in those without (68.4+/-12.3 vs 65.6+/-11.8 beats per min, P=.0017). The rHR was higher (P<.001 for trend) with increasing number of components for MetS. Linear regression analyses demonstrated that as compared to individuals without MetS, rHR was significantly higher in participants with MetS (regression coefficient, 2.9; P=.0015). In patients with type 2 diabetes and coronary artery disease, the presence of higher rHR is associated with increasing number of criteria of MetS and the presence of ventricular dysfunction.


Sonochemical polymerization of miniemulsions in organic liquids/water mixtures.
The sonochemical oil-in-water miniemulsion polymerization of n-butyl methacrylate (BMA) has been studied in mixtures with a range of aliphatic and aromatic hydrocarbon liquids under ambient conditions. Measurements of monomer conversion percentage and molecular weights of the BMA polymers were performed to investigate the effect of the various organic liquids on the kinetics of the polymerization process and on the properties of the resultant polymers. Both the rates of polymerization and the molecular weights of the polymers formed were found to be dependent on the amount and type of the organic liquid present in the emulsion. The experimental results revealed that when the organic liquids were aliphatic, there were no significant changes in the rates of BMA polymerization whereas when the organic liquids were aromatic, the rates of polymerization were greatly reduced. Molecular weight data of the BMA polymers showed that in the presence of an organic liquid, the size of the polymer significantly decreased. The results have been interpreted in terms of the formation of a radical complex between the propagating radical and the organic liquid in the oil mixture, as well as chain transfer reactions that affect the kinetics of the polymerization process.


Clostridium perfringens alpha-toxin recognizes the GM1a-TrkA complex.
Clostridium perfringens alpha-toxin is the major virulence factor in the pathogenesis of gas gangrene. Alpha-toxin is a 43-kDa protein with two structural domains; the N-domain contains the catalytic site and coordinates the divalent metal ions, and the C-domain is a membrane-binding site. The role of the exposed loop region (72-93 residues) in the N-domain, however, has been unclear. Here we show that this loop contains a ganglioside binding motif (H … SXWY … G) that is the same motif seen in botulinum neurotoxin and directly binds to a specific conformation of the ganglioside Neu5Acα2-3(Galβ1-3GalNAcβ1-4)Galβ1-4Glcβ1Cer (GM1a) through a carbohydrate moiety. Confocal microscopy analysis using fluorescently labeled BODIPY-GM1a revealed that the toxin colocalized with GM1a and induced clustering of GM1a on the cell membranes. Alpha-toxin was only slightly toxic in β1,4-N-acetylgalactosaminyltransferase knock-out mice, which lack the a-series gangliosides that contain GM1a, but was highly toxic in α2,8-sialyltransferase knock-out mice, which lack both b-series and c-series gangliosides, similar to the control mice. Moreover, experiments with site-directed mutants indicated that Trp-84 and Tyr-85 in the exposed alpha-toxin loop play an important role in the interaction with GM1a and subsequent activation of TrkA. These results suggest that binding of alpha-toxin to GM1a facilitates the activation of the TrkA receptor and induces a signal transduction cascade that promotes the release of chemokines. Therefore, we conclude that GM1a is the primary cellular receptor for alpha-toxin, which can be a potential target for drug developed against this pathogen.


Risk Factors Associated with the Development of Metastases in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Retrospective Analysis.
Neuroendocrine tumors develop from systemic endocrine and nerve cells, and their occurrence has increased recently. Since these tumors are heterogeneous, pathological classification has been based on the affected organ. In 2019, the World Health Organization introduced a change expected to influence neuroendocrine tumor research, as gastroenteropancreatic neuroendocrine tumors are now included within a unified classification. This retrospective study aimed to investigate the characteristics (e.g., lymph node metastases and all other metastases) of gastroenteropancreatic neuroendocrine tumors using this new classification in 50 cases. Tumor size, depth, MIB-1 index, lymphatic invasion, venous invasion, and neuroendocrine tumor grade were significantly correlated with lymph node metastasis and other metastases. The venous invasion was more strongly correlated with lymph node metastasis and all other types of metastases than with lymphatic invasion. Identification rates for lymphatic invasion were considered lower because of structural problems such as lymphatic vessels being much thinner than veins. However, venous invasion was considered effective in compensating for the low identification rate in cases of lymphatic invasion. In future research, a unified classification and standardized framework for assessment will be important when analyzing the characteristics of neuroendocrine tumors, and large-scale studies are required.


Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.
Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear. The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event. To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a BRAF(V600E) mouse model. In mice expressing BRAF(V600E) in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Here we show that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma, but only provided partial protection. The UVR-exposed tumours showed increased numbers of single nucleotide variants and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in approximately 40% of cases. TP53 is an accepted UVR target in human non-melanoma skin cancer, but is not thought to have a major role in melanoma. However, we show that, in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma. Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans. Furthermore, we identify TP53/Trp53 as a UVR-target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.


[The psychic state of women suffering infertility in the old reproductive age].
A total 60 infertile women aged 36-42 years treated by ART were examined to evaluate their psychic condition using CES-D and Spielberg-Khanin scales, SF-36 questionnaire. 15 (25%) patients were found (CES-D) to have mild depressive disorder; it was more pronounced in one woman. More than half of the patients exhibited enhanced anxiety, with 32 (53.3%) and 19 (31.6%) having generalized and strong anxiety respectively. Estimation of the quality of life revealed difficulties in maintaining social contacts up to complete isolation, low self-assessment of psychic health and prospects for recovery. It is concluded that comprehensive diagnostics and combined treatment are needed to manage infertile women of old reproductive age with the use of both traditional and psychocorrective methods.


Self-immolative polycations as gene delivery vectors and prodrugs targeting polyamine metabolism in cancer.
Polycations are explored as carriers to deliver therapeutic nucleic acids. Polycations are conventionally pharmacological inert with the sole function of delivering therapeutic cargo. This study reports synthesis of a self-immolative polycation (DSS-BEN) based on a polyamine analogue drug N(1),N(11)-bisethylnorspermine (BENSpm). The polycation was designed to function dually as a gene delivery carrier and a prodrug targeting dysregulated polyamine metabolism in cancer. Using a combination of NMR and HPLC, we confirm that the self-immolative polycation undergoes intracellular degradation into the parent drug BENSpm. The released BENSpm depletes cellular levels of spermidine and spermine and upregulates polyamine catabolic enzymes spermine/spermidine N(1)-acetyltransferase (SSAT) and spermine oxidase (SMO). The synthesized polycations form polyplexes with DNA and facilitate efficient transfection. Taking advantage of the ability of BENSpm to sensitize cancer cells to TNFα-induced apoptosis, we show that DSS-BEN enhances the cell killing activity of TNFα gene therapy. The reported findings validate DSS-BEN as a dual-function delivery system that can deliver a therapeutic gene and improve the outcome of gene therapy as a result of the intracellular degradation of DSS-BEN to BENSpm and the subsequent beneficial effect of BENSpm on dysregulated polyamine metabolism in cancer.


Psychological impact of being wrongfully accused of criminal offences: A systematic literature review.
Being wrongfully accused of criminal offences can lead to serious negative consequences to those wrongfully accused and their families. However, there is little research on the psychological and psychosocial impacts of wrongful accusations. We conducted a systematic literature review to collate the existing literature, searching four electronic literature databases and reference lists of relevant articles. Data were extracted from 20 relevant papers, and thematic analysis was conducted on the data. Eight main themes were identified: loss of identity; stigma; psychological and physical health; relationships with others; attitudes towards the justice system; impact on finances and employment; traumatic experiences in custody; and adjustment difficulties. The psychological consequences of wrongful accusations appear to affect the lives of those accused seriously, even after exoneration or overturning of convictions. Strategies for improving public perception of wrongful convictions should be explored, and specific mental-health systems should be established to support those who are wrongfully accused.


Effects of a Community-Based Program for Oral Health and Nutrition on Cost-Effectiveness by Preventing Disability in Japanese Frail Elderly: A Quasi-Experimental Study Using Propensity Score Matching.
In the Japanese Long-Term Care Insurance (LTCI) system, a community-based program for oral health and nutrition (OHN program) has been implemented with the aim of reducing incident disability and care costs. However, the effectiveness of this program has not been confirmed epidemiologically. The purpose of the present study was to test the hypothesis that the OHN program does reduce incident disability and care costs. A prospective study with a 28-month follow-up period was conducted using data from administrative databases at Tagajo City, Japan. Among frail elderly persons (aged 65 years or more) who were enrolled in the LTCI program in Tagajo, 64 participants in the OHN program and 128 controls (nonparticipants) were selected by propensity score matching. We used 2 types of outcome measure: composite outcome (incident disability and death) and care cost. Data on incident disability were retrieved from the public LTCI database. Care cost was defined as the total amount of LTCI service cost added to medical care cost. The hazard ratio of composite outcome was significantly lower for the intervention group than for the control group (hazard ratio = 0.32, 95% confidence interval 0.12-0.82). Even when we set incident disability as an outcome, the hazard ratio for the intervention group did not change (hazard ratio = 0.33, 95% confidence interval 0.11-0.97). The mean cumulative care cost during the 28 months tended to be lower for the intervention group ($4893) than that for the control group ($5770), but this was not statistically significant by the gamma regression model (cost ratio = 0.85, P = .513). The mean care cost per unit follow-up period (1 month) for the intervention group was significantly lower (cost ratio = 0.54, P = .027). The results of this study suggest that the OHN program is effective for preventing incident disability and, consequently, for saving care costs per unit survival period.


Intercostal artery hemorrhage with hemothorax following combined lateral and posterior lumbar interbody fusion: a case report.
Lateral lumbar interbody fusion (LLIF) is a safe treatment for degenerative spine conditions. However, risk of complications such as vascular injuries remains. We report a unique case of an intercostal artery (ICA) hemorrhage with hemothorax following LLIF. One hour after a right-sided LLIF L3-4 with posterior decompression L2-4 and L3-5 instrumentation, the patient became hypotensive, anemic and required vasopressor support. Evaluation revealed a right-sided hemothorax, which was caused by a bleeding intercostal artery, laterally at the 10th intercostal space. A lateral thoracotomy was performed to stop the bleeding. After vessel ligation and placement of two chest tubes, the patients' hemodynamics improved. The patient remained intubated overnight and was extubated on the first postoperative day. Vascular injury is a rare complication of LLIF procedures. Most vascular injuries are segmental vessel lacerations, which resolve postoperatively. This is the first case description of ICA bleeding associated with LLIF surgery. Spontaneous ICA bleeding exists, but surgeons should be aware of careful handling in patients with vascular risk factors, especially with regard to patient positioning required in certain spinal surgical approaches. Timely vascular injury identification is critical for hemostasis and clinical management.


Finnish immigrants' experience of community pharmacy services in Spain: an example of a developing E.U. issue.
Emigration within the European Union has increased, especially toward southern countries. This places complex demands on health care providers and community pharmacists, yet there is no E.U. policy that harmonizes health care services and pharmacy practice across member countries. This exploratory study examined immigrants' experiences with community pharmacy services. A survey of 1000 Finnish immigrants living in Spain's Costa del Sol region was performed in 2002, using a questionnaire that included structured and open-ended questions. Respondents were mostly satisfied with pharmacy services; however, some services had higher medication safety risks-related to medication counseling (for prescription and nonprescription medicines) and obtaining some prescription drugs without a prescription-due mainly to lack of a common language. Pharmacy services in the European Union may not provide adequate assurances of medication safety for immigrants. Consistent E.U.-wide minimum pharmacy practice standards for immigrant populations are needed.


Role of Multivoxel Intermediate TE 2D CSI MR Spectroscopy and 2D Echoplanar Diffusion Imaging in Grading of Primary Glial Brain Tumours.
Preoperative tumour grading is imperative owing to difference in invasive, aggressive tendencies of different grades of glial tumours implying varied prognosis, therapeutic options. Histopathological examination has inherent sampling errors. Magnetic Resonance Spectroscopy (MRS) and Diffusion Weighted Imaging (DWI) can provide non invasive information about internal mileu hence, aiding in tumour grading by adding to information provided by conventional MRI sequences. To evaluate the role of multivoxel intermediate TE 2D CSI MRS and 2D echoplanar diffusion imaging in grading of primary glial brain tumours. A prospective study was conducted in Department of Radiology, Teerthanker Mahaveer Medical College and Research Centre, Uttar Pradesh, India, from April 2015 to August 2016 after obtaining necessary approvals from Institutional Ethical Committee and written informed consent from all participants on histopathological proven cases of glial brain tumours that underwent multivoxel MRS using intermediate TE 2D chemical shift imaging and DWI using 2D echoplanar imaging. Tumour grade calculated on MRI using MRS and DWI was compared with histopathological grading. Positive Predictive Value (PPV), Negative Predictive Value (NPV), Sensitivity, specificity and accuracy were calculated for each parameter and statistical significance was evaluated using two tailed Pearson test. Choline: N Acetyl aspartate (Cho: NAA) and Choline: creatinine (Cho: Cr) ratios from MRS as well as Apparent Diffusion Coffecient (ADC) values from DWI were significantly higher with increasing severity of tumour grade. Accuracy of 58.6% was obtained with DWI while it was 83% with MRS. MRS and DWI used together provided 88.4% accuracy. All parameters evaluated showed statistical significance. Both DWI as well as MRS were found to have statistically significant roles in grading of glial brain tumours. MRS was found to be more useful than DWI.


Recurrent hepatocellular carcinoma after liver transplant: identifying the high-risk patient.
Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is rarely curable. However, in view of the advent of new treatments, it is critical that patients at high risk for recurrence are identified. Patients undergoing LT for HCC at a single centre between 2002 and 2010 were reviewed and data on clinical parameters and explant pathology were analysed to determine factors associated with HCC recurrence. All necrotic and viable tumour nodules were included in explant staging. All patients underwent LT according to the United Network for Organ Sharing (UNOS) Model for End-stage Liver Disease (MELD) tumour exception policies. Liver transplantation was performed in 122 patients with HCC during this period. Rates of recurrence-free survival in the entire cohort at 1 year and 3 years were 95% and 89%, respectively. Thirteen patients developed HCC recurrence at a median of 14 months post-LT. In univariate analysis the factors associated with HCC recurrence were bilobar tumours, vascular invasion, and stage exceeding either Milan or University of California San Francisco (UCSF) Criteria. Multivariate analysis showed pathology outside UCSF Criteria was the major predictor of recurrence; when pathology outside UCSF Criteria was found in combination with vascular invasion, the predicted 3-year recurrence-free survival was only 26%. Explant pathology can be used to predict the risk for recurrent HCC after LT, which may allow for improved adjuvant and management strategies.


A pseudo-beta-glucosidase in Arabidopsis thaliana: correction by site-directed mutagenesis, heterologous expression, purification, and characterization.
Since At2g25630 is an intronless gene with a premature stop codon, its cDNA encoding the predicted mature beta-glucosidase isoenzyme was synthesized from the previously isolated Arabidopsis thaliana genomic DNA. The stop codon was converted to a sense codon by site-directed mutagenesis. The native and mutated cDNA sequences were separately cloned into the vector pPICZalphaB and expressed in Pichia pastoris. Only the cells transformed with mutated cDNA-vector construct produced the active protein. The mutated recombinant beta-glucosidase isoenzyme was chromatographically purified to apparent homogeneity. The molecular mass of the protein is estimated as ca. 60 kD by SDS-PAGE. The pH optimum of activity is 5.6, and it is fairly stable in the pH range of 5.0-8.5. The purified recombinant beta-glucosidase is effectively active on para-/ortho-nitrophenyl-beta-D-glucopyranosides (p-/o-NPG) and 4-methylumbelliferyl-beta-D-glucopyranoside (4-MUG) with K(m) values of 1.9, 2.1, 0.78 mM and k(cat) values of 114, 106, 327 nkat/mg, respectively. It also exhibits different levels of activity against para-/ortho-nitrophenyl-beta-D-fucopyranosides (p-/o-NPF), amygdalin, prunasin, cellobiose, gentiobiose, and salicin. The enzyme is competitively inhibited by gluconolactone and p-nitrophenyl-1-thio-beta-D-glucopyranoside with p-NPG, o-NPG, and 4-MUG as substrates. The enzyme is found to be very tolerant to glucose inhibition. The catalytic role of nucleophilic glutamic acid in the motif YITENG of beta-glucosidases and mutated recombinant enzyme is discussed.


Thinking like an expert: surgical decision making as a cyclical process of being aware.
Education researchers are studying the practices of high-stake professionals as they learn how to better train for flexibility under uncertainty. This study explores the "Reconciliation Cycle" as the core element of an intraoperative decision-making model of how experienced surgeons assess and respond to challenges. We analyzed 32 semistructured interviews using constructivist grounded theory to develop a model of intraoperative decision making. Using constant comparison analysis, we built on this model with 9 follow-up interviews about the most challenging cases described in our dataset. The Reconciliation Cycle constituted an iterative process of "gaining" and "transforming information." The cyclical nature of surgeons' decision making suggested that transforming information requires a higher degree of awareness, not yet accounted by current conceptualizations of situation awareness. This study advances the notion of situation awareness in surgery. This characterization will support further investigations on how expert and nonexpert surgeons implement strategies to cope with unexpected events.


Critical Roles of Tumor Extracellular Vesicles in the Microenvironment of Thoracic Cancers.
Extracellular vesicles (EVs), such as exosomes, are critical mediators of intercellular communication between tumor cells and other cells located in the microenvironment but also in more distant sites. Exosomes are small EVs that can carry a variety of molecules, such as lipids, proteins, and non-coding RNA, especially microRNAs (miRNAs). In thoracic cancers, including lung cancers and malignant pleural mesothelioma, EVs contribute to the immune-suppressive tumor microenvironment and to tumor growth and metastasis. In this review, we discuss the recent understanding of how exosomes behave in thoracic cancers and how and why they are promising liquid biomarkers for diagnosis, prognosis, and therapy, with a special focus on exosomal miRNAs.


The bispectral index: a measure of depth of sleep?
How does physiological sleep affect the Bispectral Index (BIS)? We collected electroencephalographic (EEG) data from five subjects during the early part of the night, comparing the changes in the BIS with the conventional EEG stages of sleep. We found that the BIS was a consistent marker of depth of sleep. Light sleep occurred at BIS values of 75-90, slow-wave sleep occurred at BIS values of 20-70, and rapid eye movement sleep occurred at BIS values of 75-92. The effects of natural sleep on the BIS seem to be similar to the effects of general anesthesia on the BIS. The BIS may have a role in monitoring depth of sleep. Electroencephalographic data were collected from five subjects during sleep. We found that the Bispectral Index decreased during increasing depth of sleep in a fashion very similar to the decrease in Bispectral Index that occurs during general anesthesia. This study further highlights the electroencephalographic similarities of states of sleep and general anesthesia.


Identifying consensus disease pathways in Parkinson's disease using an integrative systems biology approach.
Parkinson's disease (PD) has had six genome-wide association studies (GWAS) conducted as well as several gene expression studies. However, only variants in MAPT and SNCA have been consistently replicated. To improve the utility of these approaches, we applied pathway analyses integrating both GWAS and gene expression. The top 5000 SNPs (p<0.01) from a joint analysis of three existing PD GWAS were identified and each assigned to a gene. For gene expression, rather than the traditional comparison of one anatomical region between sets of patients and controls, we identified differentially expressed genes between adjacent Braak regions in each individual and adjusted using average control expression profiles. Over-represented pathways were calculated using a hyper-geometric statistical comparison. An integrated, systems meta-analysis of the over-represented pathways combined the expression and GWAS results using a Fisher's combined probability test. Four of the top seven pathways from each approach were identical. The top three pathways in the meta-analysis, with their corrected p-values, were axonal guidance (p = 2.8E-07), focal adhesion (p = 7.7E-06) and calcium signaling (p = 2.9E-05). These results support that a systems biology (pathway) approach will provide additional insight into the genetic etiology of PD and that these pathways have both biological and statistical support to be important in PD.


Prevalence of Hepatitis A virus (HAV) and Hepatitis E virus (HEV) in the patients presenting with acute viral hepatitis.
Hepatitis A virus (HAV) and Hepatitis E virus (HEV) are both enterically transmitted, resulting in acute viral hepatitis (AVH) in developing countries. They pose major health problems in our country. This study was done to determine prevalence of HAV and HEV in patients presenting with AVH and the co-infection of HAV and HEV in these patients. A cross-sectional study of 2-years duration was conducted in the Department of Microbiology, KMC, Mangalore. A non-random sampling of 958 patients presenting with AVH was considered in the study. On the basis of history, serum samples were analysed for IgM anti-HAV and IgM anti-HEV for the detection of HAV and HEV, respectively using commercially available ELISA kits. Data collected was analysed by using Statistical Package for the Social Sciences (SPSS) version 11.5. The seroprevalence of HAV- and HEV-positive patients were 19.31% and 10.54%, respectively. The seroprevalence of both HAV and HEV in patients with acute viral hepatitis was 11.5%. The prevalence of HAV and HEV among males (68% and 31%) was higher than in females (31% and 20%) and was predominantly seen among young adults. These infections were predominantly seen during end of monsoons and beginning of winter. Though the prevalence of HAV is much higher than that of HEV, co-infection rate of 11.5% mandates the screening for HEV which will be of immense importance in pregnant women and improving levels of personal hygiene among higher socio-economic population. These data will be essential for planning of future vaccination strategies and for better sanitation programme in this part of the country.


BET proteins are associated with the induction of small airway fibrosis in COPD.
In COPD, small airway fibrosis occurs due to increased extracellular matrix (ECM) deposition in and around the airway smooth muscle (ASM) layer. Studies of immune cells and peripheral lung tissue have shown that epigenetic changes occur in COPD but it is unknown whether airway mesenchymal cells are reprogrammed. Determine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1). Primary human ASM cells from COPD and non-COPD smoking patients were stimulated with TGF-β1. Gene array analysis performed to identify differences in ECM expression. Airway accumulation of collagen 15α1 and tenascin-C proteins was assessed. Aforementioned ASM cells were stimulated with TGF-β1 ± epigenetic inhibitors with qPCR quantification of COL15A1 and TNC. Global histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity were assessed. chromatin immunoprecipitation (ChIP)-qPCR for histone H3 and H4 acetylation at COL15A1 and TNC promoters was carried out. Effects of bromoterminal and extraterminal domain (BET) inhibitor JQ1(+) on expression and acetylation of ECM target genes were assessed. COPD ASM show significantly higher COL15A1 and TNC expression in vitro and the same trend for higher levels of collagen 15α1 and tenascin-c deposited in COPD airways in vivo. Epigenetic screening indicated differential response to HDAC inhibition. ChIP-qPCR revealed histone H4 acetylation at COL15A1 and TNC promoters in COPD ASM only. ChIP-qPCR found JQ1(+) pretreatment significantly abrogated TGF-β1 induced histone H4 acetylation at COL15A1 and TNC. BET protein binding to acetylated histones is important in TGF-β1 induced expression of COL15A1 and TNC and maintenance of TGF-β1 induced histone H4 acetylation in cell progeny.


HIV seroincidence among patients at clinics for sexually transmitted diseases in nine cities in the United States.
Although the numbers of newly reported diagnoses of AIDS decreased in the 1990s, it is not clear whether they reflect a decreasing number of new HIV infections. Direct measurement of HIV incidence through follow-up cohort studies is difficult and costly. We estimated HIV incidence and trends in incidence among men who have sex with men (MSM) and heterosexual men and women at clinics for sexually transmitted diseases (STDs) by using a recently developed serologic testing algorithm that requires only a single blood specimen. Cross-sectional anonymous serosurveys were conducted at 13 STD clinics in nine cities in the United States from 1991 through 1997. Before anonymous HIV testing, demographic and clinical information was abstracted. Of 129,774 specimens tested, 362 (0.28%) were from persons estimated to be recently infected. Incidence among MSM was 7.1% (95% confidence interval (CI): 4.8-10.3), 14 times higher than that among heterosexuals, which was 0.5% (CI: 0.4- 0.7). Incidence among MSM and heterosexuals remained unchanged during the time studied. Decreasing rates of new AIDS diagnoses in the 1990s do not reflect stable rates of new HIV infections among MSM and heterosexual patients attending these clinics.


Indirect calorimetry in critical illness: a new standard of care?
Review recent literature on the role of indirect calorimetry in critical care nutrition management. Critical illness demands objective, targeted nutritional therapy to prevent adverse effects of underfeeding/over feeding. Thus, all recent societal guidelines recommend indirect calorimetry use to determine energy needs. Very recently, indirect calorimetry technology has finally evolved to allow for accurate, simple, and routine utilization in a wider range of ICU patients. Recent data continues to confirm poor correlation between measured and equation-predicted energy expenditure emphasizing need for indirect calorimetry to be standard of care. This may be particularly true in COVID-19, where significant progressive hypermetabolism and variability in energy expenditure has been shown. Metabolic physiology can change frequently during ICU stay in response to changes in clinical condition or care. Thus, repeated longitudinal indirect calorimetry measures are needed throughout ICU stay to optimize care, with initial data showing improved clinical outcomes when indirect calorimetry targets are utilized. Personalized ICU care demands objective data to guide therapy. This includes use of indirect calorimetry to determine energy expenditure and guide ICU nutrition therapy. Long-awaited new innovations in indirect calorimetry technology should finally lead to indirect calorimetry to becoming a fundamental component of modern ICU standard of care and clinical research moving forward.


Outcome of patients with IgD and IgM multiple myeloma undergoing autologous hematopoietic stem cell transplantation: a retrospective CIBMTR study.
Immunoglobulin D (IgD) and IgM multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% and 0.5% of cases, respectively. Limited information is available regarding the prognosis of these isotypes, but they have been considered to have a more aggressive course than the more common immunoglobulin G (IgG) and IgA isotypes. In particular, the outcome after autologous hematopoietic stem cell transplantation (auto-HCT) has not been well defined. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 36 patients with IgD and 11 patients with IgM myeloma among 3578 myeloma patients who received intensive therapy and auto-HCT over a 10-year period. The progression-free and overall survival probabilities at 3 years were 38% (95% CI, 21%-56%) and 69% (95% CI, 51%-84%) for IgD myeloma, and 47% (95% CI, 17%-78%) and 68% (95% CI, 36%-93%), respectively, for IgM disease. Although formal statistical analysis was limited by the small sample size, these results were comparable to those for IgG and IgA patients autografted during the same time period. Transplantation-related mortality and disease relapse/progression of myeloma were also similar for all isotypes. This analysis demonstrates comparable outcomes in all immunoglobulin isotypes. Therefore, auto-HCT should be offered to eligible patients with IgD and IgM myeloma.


Elevated Urinary Connective Tissue Growth Factor in Diabetic Nephropathy Is Caused by Local Production and Tubular Dysfunction.
Connective tissue growth factor (CTGF; CCN2) plays a role in the development of diabetic nephropathy (DN). Urinary CTGF (uCTGF) is elevated in DN patients and has been proposed as a biomarker for disease progression, but it is unknown which pathophysiological factors contribute to elevated uCTGF. We studied renal handling of CTGF by infusion of recombinant CTGF in diabetic mice. In addition, uCTGF was measured in type 1 DN patients and compared with glomerular and tubular dysfunction and damage markers. In diabetic mice, uCTGF was increased and fractional excretion (FE) of recombinant CTGF was substantially elevated indicating reduced tubular reabsorption. FE of recombinant CTGF correlated with excretion of endogenous CTGF. CTGF mRNA was mainly localized in glomeruli and medullary tubules. Comparison of FE of endogenous and recombinant CTGF indicated that 60% of uCTGF had a direct renal source, while 40% originated from plasma CTGF. In DN patients, uCTGF was independently associated with markers of proximal and distal tubular dysfunction and damage. In conclusion, uCTGF in DN is elevated as a result of both increased local production and reduced reabsorption due to tubular dysfunction. We submit that uCTGF is a biomarker reflecting both glomerular and tubulointerstitial hallmarks of diabetic kidney disease.


Antifungal mechanism of [RuIII(NH3)4catechol]+ complex on fluconazole-resistant Candida tropicalis.
Candidiasis, a major opportunistic mycosis caused by Candida sp., may comprise life-threatening systemic infections. The incidence of non-albicans species is rising, particularly in South America and they are frequently drug resistant, causing unresponsive cases. Thus, novel antimycotic agents are required. Here we tested the antifungal activity of [RuIII(NH3)4catechol]+ complex (RuCat), approaching possible action mechanisms on fluconazole-resistant Candida tropicalis. RuCat significantly (P < 0.05) inhibited the growth and viability of C. tropicalis dose-dependently (IC50 20.3 μM). Cytotoxicity of RuCat upon murine splenocytes was lower (Selectivity Index = 16). Scanning electron microscopy analysis showed pseudohyphae formation, yeast aggregation and surface damage. RuCat-treated samples investigated by transmission electron microscopy showed melanin granule trafficking to cell surfaces and extracellular milieu. Surface-adherent membrane fragments and extracellular debris were also observed. RuCat treatment produced intense H2DCFDA labeling, indicating reactive oxygen species (ROS) production which caused increased lipoperoxidation. ROS are involved in the fungicidal effect as N-acetyl-L-cysteine completely restored cell viability. Calcofluor White chitin staining suggests that 70 or 140 μM RuCat treatment for 2 h affected cell-wall structure. PI labeling indicated necrotic cell death. The present data indicate that RuCat triggers ROS production, lipoperoxidation and cell surface damage, culminating in selective necrotic death of drug-resistant C. tropicalis.


Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis.
Stepwise degradation of the invariant chain (Ii) is required for the binding of antigenic peptides to MHC class II molecules. Cathepsin (Cat) L in the murine thymus and Cat S in peripheral APCs have both been implicated in the last step of Ii degradation that gives rise to the class II-associated invariant chain peptides (CLIP). Cat V has been recently described as highly homologous to Cat L and exclusively expressed in human thymus and testis, but with no mouse orthologue. We report that Cat V is the dominant cysteine protease in cortical human thymic epithelial cells, while Cat L and Cat S seem to be restricted to dendritic and macrophage-like cells. Active Cat V in thymic lysosomal preparations was demonstrated by active-site labeling. Recombinant Cat V was capable of converting Ii into CLIP efficiently, suggesting that Cat V is the protease that controls the generation of alphabeta-CLIP complexes in the human thymus, in analogy to Cat L in mouse. Comparison of Cat V expression between thymi from patients with myasthenia gravis and healthy controls revealed a significantly higher expression level in the pathological samples, suggesting a potential involvement of this protease in the immunopathogenesis of myasthenia gravis, an autoimmune disease almost invariably associated with thymic pathology.


Effects of aging on automatic and effortful processes in bimanual coordination.
Two experiments are reported that compared younger and older adults on their performance of two bimanual temporal coordination tasks at varying movement speeds. In many cases, older adults performed as well as younger adults at all speeds of an in-phase coordination pattern and at slow speeds of an anti-phase pattern for both coordination accuracy and stability. Age differences tended to emerge most prominently at high speeds for the anti-phase pattern. These findings are consistent with the aging literature regarding automatic and effortful processing distinctions, suggesting that relative age differences become magnified when effortful resources are required for motor performance.