Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with nonsmall cell lung cancer survival.
The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing genotyping data from two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with nonsmall cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a singlelocus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression modeling of the PLCO dataset identified three potentially functional and independent SNPs (i.e., KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 (95% confidence interval [CI] = 0.79-0.94, p = 0.0007), 1.31 (1.16-1.47, p = 6.0 × 10-5 ) and 1.27 (1.12-1.44, p = 0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (ptrend < 0.0001 for OS and ptrend < 0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes.


Cystatin C: a candidate biomarker for amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurologic disease characterized by progressive motor neuron degeneration. Clinical disease management is hindered by both a lengthy diagnostic process and the absence of effective treatments. Reliable panels of diagnostic, surrogate, and prognostic biomarkers are needed to accelerate disease diagnosis and expedite drug development. The cysteine protease inhibitor cystatin C has recently gained interest as a candidate diagnostic biomarker for ALS, but further studies are required to fully characterize its biomarker utility. We used quantitative enzyme-linked immunosorbent assay (ELISA) to assess initial and longitudinal cerebrospinal fluid (CSF) and plasma cystatin C levels in 104 ALS patients and controls. Cystatin C levels in ALS patients were significantly elevated in plasma and reduced in CSF compared to healthy controls, but did not differ significantly from neurologic disease controls. In addition, the direction of longitudinal change in CSF cystatin C levels correlated to the rate of ALS disease progression, and initial CSF cystatin C levels were predictive of patient survival, suggesting that cystatin C may function as a surrogate marker of disease progression and survival. These data verify prior results for reduced cystatin C levels in the CSF of ALS patients, identify increased cystatin C levels in the plasma of ALS patients, and reveal correlations between CSF cystatin C levels to both ALS disease progression and patient survival.


Confirming the phylogeny of mammals by use of large comparative sequence data sets.
The ongoing generation of prodigious amounts of genomic sequence data from myriad vertebrates is providing unparalleled opportunities for establishing definitive phylogenetic relationships among species. The size and complexities of such comparative sequence data sets not only allow smaller and more difficult branches to be resolved but also present unique challenges, including large computational requirements and the negative consequences of systematic biases. To explore these issues and to clarify the phylogenetic relationships among mammals, we have analyzed a large data set of over 60 megabase pairs (Mb) of high-quality genomic sequence, which we generated from 41 mammals and 3 other vertebrates. All sequences are orthologous to a 1.9-Mb region of the human genome that encompasses the cystic fibrosis transmembrane conductance regulator gene (CFTR). To understand the characteristics and challenges associated with phylogenetic analyses of such a large data set, we partitioned the sequence data in several ways and utilized maximum likelihood, maximum parsimony, and Neighbor-Joining algorithms, implemented in parallel on Linux clusters. These studies yielded well-supported phylogenetic trees, largely confirming other recent molecular phylogenetic analyses. Our results provide support for rooting the placental mammal tree between Atlantogenata (Xenarthra and Afrotheria) and Boreoeutheria (Euarchontoglires and Laurasiatheria), illustrate the difficulty in resolving some branches even with large amounts of data (e.g., in the case of Laurasiatheria), and demonstrate the valuable role that very large comparative sequence data sets can play in refining our understanding of the evolutionary relationships of vertebrates.


Chronic Recurrent Multifocal Osteomyelitis - A Case Series from India.
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory disease of the bone. It tends to be multifocal and usually the symptoms tend to run for months and years before diagnosis is usually made. The objective of our study was to understand the clinical presentation and short-term response to treatment of CRMO patients. A retrospective analysis of patients diagnosed with CRMO between 2011 and 2016 was done. Case records of these were retrospectively reviewed for clinical features, investigations and treatment received. Six patients were diagnosed with CRMO. The median age of onset and time to diagnosis from onset of symptoms was 8 and 3.5 years respectively. Lower limb bones were the most commonly involved. There is significant delay in diagnosis of CRMO and this could be because of a lack of awareness of this condition amongst clinicians. Our case series with only male affection is rather unique as compared to other case series reported in medical literature which tend to have more female predilection. Pain with or without swelling was the most common symptom. Most of patients responded to combination therapy.


Raman spectroscopy as a novel tool for monitoring biochemical changes and inter-donor variability in stored red blood cell units.
Individual units of donated red blood cells (RBCs) do not ordinarily undergo analytical testing prior to transfusion. This study establishes the utility of Raman spectroscopy for analyzing the biochemistry of stored RBC supernatant and reveals interesting storage-related changes about the accumulation of lactate, a chemical species that may be harmful to certain patients. The data show measurable variations in supernatant composition and demonstrate that some units of donated RBCs accumulate lactate much more readily than others. The spectra also indicate a higher relative concentration of lactate in units collected from male donors than female donors (p = 0.004) and imply that there is a greater degree of variability at later stages of storage in units from older male donors (>45 years). The study proves that Raman analysis has promise for elucidating the relationship between the metabolism of stored RBCs and donor characteristics. It also suggests that there may be benefit in developing a Raman instrument for the rapid non-invasive assessment of blood-bag biochemistry by measuring through plastic over-layers.


NEMO mutation as a cause of familial occurrence of Behçet's disease in female patients.
Behçet's disease is a chronic, relapsing, multisystem inflammatory disease of unknown etiology. Nuclear factor κB (NF-κB) essential modulator (NEMO) that is required for the activation of NF-κB plays an important role in inflammation. To investigate the role of NEMO in the pathogenesis of Behçet's disease, we analyzed NEMO gene and its expression pattern in tissues in a family with Behçet's disease. We found a heterozygous mutation (1217A> T, D406V) in a 6-year-old girl and her mother. Skewed X-chromosome inactivation was not observed in the peripheral blood mononuclear cells as well as in oral and intestinal mucosa of the patients. Accordingly, there was a significant proportion of peripheral blood monocytes that did not produce sufficient intracellular tumor necrosis factor-α with the stimulation of lipopolysaccharide. Heterozygous NEMO mutation is a cause of familial occurrence of Behçet's disease in female patients.


Quorum sensing integrates environmental cues, cell density and cell history to control bacterial competence.
Streptococcus pneumoniae becomes competent for genetic transformation when exposed to an autoinducer peptide known as competence-stimulating peptide (CSP). This peptide was originally described as a quorum-sensing signal, enabling individual cells to regulate competence in response to population density. However, recent studies suggest that CSP may instead serve as a probe for sensing environmental cues, such as antibiotic stress or environmental diffusion. Here, we show that competence induction can be simultaneously influenced by cell density, external pH, antibiotic-induced stress, and cell history. Our experimental data is explained by a mathematical model where the environment and cell history modify the rate at which cells produce or sense CSP. Taken together, model and experiments indicate that autoinducer concentration can function as an indicator of cell density across environmental conditions, while also incorporating information on environmental factors or cell history, allowing cells to integrate cues such as antibiotic stress into their quorum-sensing response. This unifying perspective may apply to other debated quorum-sensing systems.Peptide CSP regulates natural competence in pneumococci and has been proposed as a quorum-sensing signal or a probe for sensing environmental cues. Here, the authors show that CSP levels can indeed act as an indicator of cell density and also incorporate information on environmental factors or cell history.


Effects of let-7a microRNA and C-C chemokine receptor type 7 expression on cellular function and prognosis in esophageal squamous cell carcinoma.
C-C chemokine receptor type 7 (CCR7) participates in chemotactic and metastatic responses in various cancers, including in esophageal squamous cell carcinoma (ESCC). The microRNA (miRNA) let-7a suppresses migration and invasion of various types of cancer cells by downregulating CCR7 expression. The expression levels of CCR7 and let-7a were measured in the cell lines, tumor, and peritumoral tissues of ESCC patients. KYSE cell lines were transfected with synthetic let-7a miRNA and a let-7a miRNA inhibitor, and their CCR7 expression levels as well as invasive ability were evaluated. A highly invasive cell line was established via an invasion assay, and CCR7 expression level along with let-7a level was subsequently evaluated. Cancer cells overexpressing CCR7 were injected subcutaneously into mice, and the animals were monitored for tumor growth along with lymph node metastasis. A negative correlation between CCR7 and let-7a expression was observed in the ESCC cell lines as well as in tissue samples from patients. Synthetic let-7a decreased CCR7 expression level, while the let-7a inhibitor increased it. In vitro, the established highly invasive cancer cells with high and low levels of CCR7 and let-7a expression, respectively, exhibited a greater invasive ability than the wild-type cell line. The cells were associated with tumor growth and lymph node metastasis in mice. Patients in the high-CCR7/low-let-7a group had the worst prognosis, with a five-year recurrence free survival (5-RFS) rate of 37.5%, followed by the high-CCR7/high-let-7a (5-RFS: 60.0%) and low-CCR7 (5-RFS: 85.7%; p = 0.038) groups. The expression of CCR7 was downregulated by let-7a miRNA in esophageal cancer cells. The decrease in let-7a expression level led to the increased expression level of CCR7 in ESCC cells, consequently increasing their invasive ability and malignancy and resulting in a worse prognosis for ESCC patients. Retrospectively registered.


[Asymptomatic Ball Thrombus in Right Atrium Under Anticoagulant Therapy:Report of a Case].
A rare case of isolated right atrial thrombus under anticoagulant therapy for atrial fibrillation is reported herein. The patient was an 81-year-old man undergoing anticoagulant therapy with oral warfarin for atrial fibrillation. During preoperative screening for eye surgery, echocardiography revealed a mobile mass in the right atrium, and emergency hospital admission was indicated. Excision of the right atrial thrombus was performed, and no residual thrombus was detected on postoperative imaging studies. This case was considered a good indication for surgical resection because of potential risk of fatal embolism.


The Middle Ear Cleft Status in a "Natural" Cohort With Eustachian Tube Dysfunction.
The Eustachian tube (ET) has a major role in the middle ear (ME) pressure homeostasis. ET dysfunction is the accepted paradigm for pressure-related ME disorders. We studied the ME status in patients with severely diminished ET opening abilities, and anticipated to find ME disorders in most of them. ME status was evaluated in unconscious adults, who were hospitalized in a rehabilitation center with severe brain damage, requiring tracheotomy and gastrostomy. These patients were unable to swallow, produce valsalva, yawn, and needed oral suctioning. Examination included fiberoptic nasopharyngoscopy, gag reflex and soft palate assessments, otoscopy, and tympanometry. Nineteen patients (38 ears) were evaluated: 14 men and 5 women, aged 18 to 93 years (average 59). Duration of gastrostomy and tracheotomy were between 3 months and 18 years. All the patients lacked gag reflex, palatal movements, or supraglottic sensation. Eighteen ears (47%) had otitis media with effusion (OME) (versus ∼3% in the general population, p = 0.00001), none had significant tympanic membrane atelectasis, but 20 (53%) ears were normal. Twenty-two ears (59%) had tympanometry types B/C and 16 (41%) had type A. Cerumen impaction incidence (26 ears, 68%) was significantly higher than in normal adults (10%), mentally retarded (36%), and nursing homes residents (57%). A dysfunctional ET predisposed ME disorders. Yet, ∼50% of the ears were normal, in contrast to the current paradigm. This implies that ME pressure homeostasis is maintained by factors that can compensate for ET dysfunction. Treating cerumen impaction and OME may be beneficial for rehabilitation.


Potentiating Cancer Immunotherapy Using Papaya Mosaic Virus-Derived Nanoparticles.
The recent development of novel immunotherapies is revolutionizing cancer treatment. These include, for example, immune checkpoint blockade, immunomodulation, or therapeutic vaccination. Although effective on their own, combining multiple approaches will most likely be required in order to achieve the maximal therapeutic benefit. In this regard, the papaya mosaic virus nanoparticle (PapMV) has shown tremendous potential as (i) an immunostimulatory molecule, (ii) an adjuvant, and (iii) a vaccine platform through its intrinsic capacity to activate the innate immune response in an IFN-α-dependent manner. Here, we demonstrate that intratumor administration of PapMV significantly slows down melanoma progression and prolongs survival. This correlates with enhanced chemokine and pro-inflammatory-cytokine production in the tumor and increased immune-cell infiltration. Proportions of total and tumor-specific CD8(+) T cells dramatically increase following PapMV treatment whereas those of myeloid-derived suppressor cells (MDSC) concomitantly decrease. Moreover, systemic PapMV administration prevents metastatic tumor-implantation in the lungs. Importantly, PapMV also synergistically improves the therapeutic benefit of dendritic cell (DC)-based vaccination and PD-1 blockade by potentiating antitumor immune responses. This study illustrates the immunostimulatory potential of a plant virus-derived nanoparticle for cancer therapy either alone or in conjunction with other promising immunotherapies in clinical development.


A new ab initio ground-state dipole moment surface for the water molecule.
A valence-only (V) dipole moment surface (DMS) has been computed for water at the internally contracted multireference configuration interaction level using the extended atom-centered correlation-consistent Gaussian basis set aug-cc-pV6Z. Small corrections to these dipole values, resulting from core correlation (C) and relativistic (R) effects, have also been computed and added to the V surface. The resulting DMS surface is hence called CVR. Interestingly, the C and R corrections cancel out each other almost completely over the whole grid of points investigated. The ground-state CVR dipole of H(2) (16)O is 1.8676 D. This value compares well with the best ab initio one determined in this study, 1.8539+/-0.0013 D, which in turn agrees well with the measured ground-state dipole moment of water, 1.8546(6) D. Line intensities computed with the help of the CVR DMS shows that the present DMS is highly similar to though slightly more accurate than the best previous DMS of water determined by Schwenke and Partridge [J. Chem. Phys. 113, 16 (2000)]. The influence of the precision of the rovibrational wave functions computed using different potential energy surfaces (PESs) has been investigated and proved to be small, due mostly to the small discrepancies between the best ab initio and empirical PESs of water. Several different measures to test the DMS of water are advanced. The seemingly most sensitive measure is the comparison between the ab initio line intensities and those measured by ultralong pathlength methods which are sensitive to very weak transitions.


Distribution and expression of brain-derived neurotrophic factor, nerve growth factor, and neurotrophic factor-3 in refractory epilepsy-associated focal cortical dysplasia.
To investigate the expression and distribution of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophic factor-3 (NT-3) in refractory epilepsy-associated type I focal cortical dysplasia (FCD I) and FCD IIA patients, and to explore their effects on pathogenesis of FCD I and FCD IIA. 19 subjects who received surgery at the Department of Neurosurgery, First Affiliated Hospital, Fujian Medical University, China between June 2010 and May 2012, were enrolled in this study. They were pathologically diagnosed as FCD IIA (n = 7) and FCD I (n = 12) after surgery and were considered as two experimental groups. Temporal lobe samples of 10 subjects who had suffered craniocerebral injury but did not have nervous system disease were collected as a control group. Immunohistochemical methods and Western blot assays were used to detect the expression and distribution of BDNF, NGF, and NT-3 in temporal lobes, and differences in their expression and distribution were compared between experimental and control groups. BDNF expression was slightly higher in the FCD IIA group compared to that in the FCD I group and was significantly greater when compared with the control group. Compared with the control group, NGF and NT-3 expression was higher in the FCD groups. However, no significant difference was observed between the FCD IIA and FCD I group. Abnormal distribution and expression of BDNF, NGF, and NT-3 may play an important role in the mechanism of FCD I and FCD IIA-induced epilepsy. .


Approach to Isolated Trapezoid Fractures.
Background: The trapezoid is the least commonly fractured carpal bone, comprising 4% of all carpal fractures. To date, few articles have been published on isolated trapezoid fractures. Mechanisms of injury have typically been reported as an axial load, with or without forced wrist flexion/extension, that is transmitted from the second metacarpal indirectly to the trapezoid. Case Reports: Two patients presenting with symptoms of nonspecific wrist pain after acute trauma were initially worked up with plain film x-rays. Physical examinations identified nonspecific wrist pain in both patients. Mechanisms of injury involved direct trauma and an axial force transmitted through the scaphoid region of an extended wrist in each patient. Plain x-rays were negative for trapezoid fracture in both patients. Computed tomography and magnetic resonance imaging revealed the diagnoses. Conservative management consisted of splinting and immobilization, with full recovery reported at 2.5- and 3-month follow-up. Conclusion: Isolated fractures of the trapezoid require a high index of suspicion as they are rare, and localizing signs and symptoms are typically vague and may mimic those of scaphoid fractures. When athletes present with dorsal wrist pain, swelling, and snuffbox tenderness in the setting of negative plain x-rays, the most likely mechanisms of injury are associated with athletic activity. Treatment depends on the degree of displacement and other associated injuries and ranges from activity modification or immobilization to open reduction with internal fixation.


A pathological scoring system to predict renal outcome in diabetic nephropathy.
With the association between diabetic nephropathy (DN) and renal outcome being increasingly clear, we aimed at creating a new DN pathological scoring system that could predict the renal outcome. We studied 205 patients with DN confirmed by renal biopsy, sometime between March 1985 and January 2010, who met the inclusion criteria. Renal biopsy included clinical parameters and Tervaert classifications. Hazard ratios (HRs) for death-censored end-stage renal disease (ESRD) were estimated by adjusted Cox proportional-hazards regression. The overall pathological risk score (D-score) was calculated by summing the products of beta coefficient and bootstrap-inclusion fractions, its predictive utility evaluated by Kaplan-Meier methods and c-statistics for a 10-year risk of ESRD. The D-scores of glomerular classes 1, 2A, 2B, 3, and 4 were, respectively, 0, 3, 4, 6, and 6. Those of interstitial fibrosis and tubular atrophy classes 0, 1, 2, and 3 were 0, 7, 9, and 11, and those of interstitial inflammation classes 0, 1, and 2 were 0, 3, and 4, respectively. The D-score of hyalinosis class 2 was 3 and that of arteriosclerosis class 2 was 1. So, a patient's D-score could be 0-25. HRs for ESRD in patients with D-score ≤14, 15-18, 19-21, and 22-25 were, respectively, 1.00 (reference) 16.21 (95% confidence interval (CI), 1.86-140.90), 19.78 (95% CI, 2.15-182.40), and 45.46 (95% CI, 4.63-446.68) after adjusting for clinical factors. The c-statistics suggested a better predictive ability for a 10-year renal death with models that included the D-score. Prediction of DN patients' renal outcome was better with the D-score than without it. Patients with a D-score ≤14 had excellent renal prognosis.


Are two-dimensional materials radiation tolerant?
Two-dimensional (2D) materials have many unique properties, which can be exploited in various applications. In particular, electronic devices based on 2D materials should ideally be suited for the operation in outer cosmic space due to their low weight, small size and low power consumption. This brings about the issue of their radiation hardness, or tolerance, which has recently been addressed in a number of studies. The results of these investigations are somewhat counterintuitive: although one can naively expect that atomically thin structures should easily be destroyed by the beams of energetic particles, the devices made from 2D materials were reported to exhibit extraordinary radiation hardness. In this Focus article, an overview of the recent studies on the subject is given, followed by the discussion of the origin of the reported high tolerance, which is inherently related to the response of 2D materials, the systems with the reduced dimensionality, to irradiation. The analysis of the experimental and theoretical data on the behavior of 2D systems under irradiation indicates that although free-standing 2D materials can indeed be referred to as radiation resilient systems under irradiation conditions corresponding to the outer space, this is generally not the case, as the environment, e.g., the substrate, can strongly influence the radiation tolerance of 2D materials and devices based on these systems.


Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy.
Patients with hepatocellular carcinoma (HCC) at the same clinical stage can have extremely different prognoses, and molecular subtyping provides an opportunity for individualized precision treatment. In this study, genomic, transcriptomic, proteomic, and phosphoproteomic profiling of primary tumor tissues and paired para-tumor tissues from HCC patients (N = 160) are integrated. Proteomic profiling identifies three HCC subtypes with different clinical prognosis, which are validated in three publicly available external validation sets. A simplified panel of nine proteins associated with metabolic reprogramming is further identified as a potential subtype-specific biomarker for clinical application. Multi-omics analysis further reveals that three proteomic subtypes have significant differences in genetic alterations, microenvironment dysregulation, kinase-substrate regulatory networks, and therapeutic responses. Patient-derived cell-based drug tests (N = 26) show personalized responses for sorafenib in three proteomic subtypes, which can be predicted by a machine-learning response prediction model. Overall, this study provides a valuable resource for better understanding of HCC subtypes for precision clinical therapy.


The history of facial prostheses.
This article provides a brief sortie into the history of facial prostheses with a view to illuminating man's ingenuity and wit in his endeavors to maintain a resemblance of normality. The author identifies examples of compassion and the skills that have been employed by a variety of craftsmen working in many countries in their attempt to rebuild facial contour and appearance with natural and synthetic materials.


Comparison of publication trends in dermatology among Japan, South Korea and Mainland China.
We previously showed that the number of publications in dermatology is increasing year by year, and positively correlates with improved economic conditions in mainland China, a still developing Asian country. However, the characteristics of publications in dermatology departments in more developed Asian countries such as Japan and South Korea are unknown. In the present study, publications from 2003 through 2012 in dermatology in Japan, South Korea and mainland China were characterized. All data were obtained from http://www.pubmed.com. Dermatology departments in Japan published 4,094 papers, while mainland China and South Korea published 1528 and 1,758 articles, respectively. 48% of articles from dermatology in Japan were original research and 36% were case reports; The number of publications in Japan remained stable over time, but the overall impact factors per paper increased linearly over the last 10 year period (p < 0.05). In mainland China, 67% of articles from dermatology were original research, while 19% were case reports; The number of publications and their impact factors per paper increased markedly. In South Korea, 65% of articles from dermatology were original research and 20% were case reports. The impact factors per paper remained unchanged, despite of the fact that the number of publications increased over the last 10 year period (r2 = 0.6820, p = 0.0032). Only mainland China showed a positive correlation of the number of publications with gross domestic product per capita during this study period. These results suggest that the total number of publications in dermatology correlates with economic conditions only in developing country, but not in more developed countries in Asia. The extent of economic development could determine both the publication quantity and quality.


Computed tomographic, magnetic resonance imaging, and cross-sectional anatomic features of the manus in cadavers of dogs without forelimb disease.
OBJECTIVE-To provide a detailed description of cross-sectional anatomic structures of the manus in canine cadavers in association with corresponding features in computed tomographic (CT) and magnetic resonance (MR) images. SAMPLE POPULATION-7 cadavers of adult large-breed-type dogs (weight range, 25 to 30 kg) without forelimb disease. PROCEDURES-Forelimbs were removed from the cadavers within 4 hours after euthanasia and frozen. The right forelimbs of 3 cadavers were cut into 4-mm sections by use of a band saw; 1 limb each was sectioned in the transverse, dorsal, or sagittal plane. Sections were cleaned and then photographed. After thawing, transverse CT images of the right forelimbs of 3 additional cadavers were obtained, and the right forelimb of a seventh cadaver underwent MR imaging in the transverse, sagittal, and dorsal planes. The evaluated regions extended from the digits to the carpus. Features in CT and MR images that corresponded to clinically important anatomic structures in tissue sections were identified. RESULTS-For most of the anatomic structures evident in tissue sections, corresponding CT and MR imaging features were identified. Osseous and musculotendinous structures of the manus were readily detected in CT and MR images, whereas vascular structures were only rarely identified by use of the imaging techniques. CONCLUSIONS AND CLINICAL RELEVANCE-Results of the detailed assessment of anatomic structures of the canine manus in association with corresponding features in CT and MR images will facilitate detection of pathological conditions and be beneficial in planning surgical procedures for diseases of the manus in dogs.


Weight Perceptions and Weight-Related Behaviors among Low Income Postpartum Women.
Minority and low-income women have higher rates of postpartum weight retention, contributing to increased rates of obesity in these populations. Weight perceptions may be an important factor contributing to the adoption of weight-management behaviors. The purpose of this study was to examine the relationships between weight perceptions and weight-related behaviors among overweight low-income women during postpartum enrolled in a weight loss intervention study. This is a cross-sectional analysis of the Fresh Start study baseline data among overweight and obese low-income women during postpartum (N = 132). General linear regression models assessed the association between weight perceptions and energy intake, energy expenditure, self-monitoring, and self-regulation. Women who perceived themselves to be very overweight had significantly lower self-regulation (β = -4.0, SE = 1.6, p = 0.014) and higher energy expenditure (β = 1.3, SE = 0.7, p = 0.05) compared to women who perceived themselves to be moderately overweight or a little overweight. There were no significant associations between weight perceptions and self-monitoring or energy intake. This study found that weight perceptions among these women are important factors to consider for weight loss. Future research should focus on investigating the impact of tailoring interventions to weight perceptions to impact engagement in weight-related behaviors in diverse low-income women during postpartum.


Managing haemophilia for life: 4th Haemophilia Global Summit.
The 4th Haemophilia Global Summit was held in Potsdam, Germany, in September 2013 and brought together an international faculty of haemophilia experts and delegates from multidisciplinary backgrounds. The programme was designed by an independent Scientific Steering Committee of haemophilia experts and explored global perspectives in haemophilia care, discussing practical approaches to the optimal management of haemophilia now and in the future. The topics outlined in this supplement were selected by the Scientific Steering Committee for their relevance and potential to influence haemophilia care globally. In this supplement from the meeting, Jan Astermark reviews current understanding of risk factors for the development of inhibitory antibodies and discusses whether this risk can be modulated and minimized. Factors key to the improvement of joint health in people with haemophilia are explored, with Carlo Martinoli and Víctor Jiménez-Yuste discussing the utility of ultrasound for the early detection of haemophilic arthropathy. Other aspects of care necessary for the prevention and management of joint disease in people with haemophilia are outlined by Thomas Hilberg and Sébastian Lobet, who highlight the therapeutic benefits of physiotherapy and sports therapy. Riitta Lassila and Carlo-Federico Perno describe current knowledge surrounding the risk of transmission of infectious agents via clotting factor concentrates. Finally, different types of extended half-life technology are evaluated by Mike Laffan, with a focus on the practicalities and challenges associated with these products.


Three-Dimensional Imaging of Biological Tissue by Cryo X-Ray Ptychography.
High-throughput three-dimensional cryogenic imaging of thick biological specimens is valuable for identifying biologically- or pathologically-relevant features of interest, especially for subsequent correlative studies. Unfortunately, high-resolution imaging techniques at cryogenic conditions often require sample reduction through sequential physical milling or sectioning for sufficient penetration to generate each image of the 3-D stack. This study represents the first demonstration of using ptychographic hard X-ray tomography at cryogenic temperatures for imaging thick biological tissue in a chemically-fixed, frozen-hydrated state without heavy metal staining and organic solvents. Applied to mammalian brain, this label-free cryogenic imaging method allows visualization of myelinated axons and sub-cellular features such as age-related pigmented cellular inclusions at a spatial resolution of ~100 nanometers and thicknesses approaching 100 microns. Because our approach does not require dehydration, staining or reduction of the sample, we introduce the possibility for subsequent analysis of the same tissue using orthogonal approaches that are expected to yield direct complementary insight to the biological features of interest.


Elevation of fumarase attenuates hypertension and can result from a nonsynonymous sequence variation or increased expression depending on rat strain.
The activity of fumarase, an enzyme in the tricarboxylic acid cycle, is lower in Dahl salt-sensitive SS rats compared with SS.13BN rats. SS.13BN rats have a Brown Norway (BN) allele of fumarase and exhibit attenuated hypertension. The SS allele of fumarase differs from the BN allele by a K481E sequence variation. It remains unknown whether higher fumarase activities can attenuate hypertension and whether the mechanism is relevant without the K481E variation. We developed SS-TgFh1 transgenic rats overexpressing fumarase on the background of the SS rat. Hypertension was attenuated in SS-TgFh1 rats. Mean arterial pressure in SS-TgFh1 rats was 20 mmHg lower than transgene-negative SS littermates after 12 days on a 4% NaCl diet. Fumarase overexpression decreased H2O2, while fumarase knockdown increased H2O2 Ectopically expressed BN form of fumarase had higher specific activity than the SS form. However, sequencing of more than a dozen rat strains indicated most rat strains including salt-insensitive Sprague-Dawley (SD) rats had the SS allele of fumarase. Despite that, total fumarase enzyme activity in the renal medulla was still higher in SD rats than in SS rats, which was associated with higher expression of fumarase in SD. H2O2 can suppress the expression of fumarase. Renal medullary interstitial administration of fumarase siRNA in SD rats resulted in higher blood pressure on the high-salt diet. These findings indicate elevation of total fumarase activity attenuates the development of hypertension and can result from a nonsynonymous sequence variation in some rat strains and higher expression in other rat strains.


Production of pulsed, mass-selected beams of metal and semiconductor clusters.
We report on the development of a beam line for mass-selected metal and semiconductor clusters. The cluster source combines the principles of plasma sputtering and gas condensation. Both techniques together allow to produce clusters in a wide size range. With the aid of a time-of-flight system, small clusters (i.e., Cu(n)(+), n<100) are selected and pure beams containing only one cluster size are provided. For large clusters (containing several thousands of atoms), a beam with a narrow size distribution is obtained. A 90 degrees quadrupole deviator is used to separate charged clusters from neutral ones.


Assessment of pulmonary toxicity of MgO nanoparticles in rats.
In this study, we have evaluated the pulmonary toxicity of MgO nanoparticles (MgO NPs) in rats following their exposure. NPs in phosphate buffered saline + 1% Tween 80 were exposed via intratracheal instillation at a doses of 1 mg/kg or 5 mg/kg into rat lungs and evaluated for various tissue damage markers like alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid and histopathology of lungs at 1, 7, and 30 days of post-exposure intervals. A dose-dependant increase in ALP and LDH activity was observed in BAL fluids of rat lungs than sham control at all post-exposure periods (P <0.05), and a dose-dependant infiltration of interstitial lymphocytes, peribronchiolar lymphocytic infiltration, and dilated and/or congested vessels at 1 day post-exposure period, worsened at 1 week period, and were reduced at 1 month at histology, indicating the pulmonary toxicity of MgO NPs. In conclusion, MgO NPs exposure produced a dose-dependent pulmonary toxicity in rats and was comparable with that of Quartz particles.


Hemophagocytic lymphohistiocytosis: pathogenesis and treatment.
Hemophagocytic lymphohistiocytosis (HLH) is not an independent disease but rather a life-threatening clinical syndrome that occurs in many underlying conditions and in all age groups. HLH is the consequence of a severe, uncontrolled hyperinflammatory reaction that in most cases is triggered by an infectious agent. Persistent stimulation of lymphocytes and histiocytes results in hypercytokinemia, leading to the characteristic symptoms of HLH. Genetic defects in familial HLH and in immunodeficiency syndromes associated with albinism affect the transport, processing, and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes. This leads to defective killing of target cells and a failure to contract the immune response. The defects are increasingly found also in adolescents and adults. Acquired HLH occurs in autoinflammatory and autoimmune diseases (macrophage activation syndrome) and in patients with iatrogenic immunosuppression or with malignancies, but also in otherwise healthy persons with infections. Treatment of HLH aims at suppressing hypercytokinemia and eliminating the activated and infected cells. In genetic HLH, hematopoietic stem cell transplantation (HSCT) is needed for the correction of the immune defect. Treatment modalities include immunosuppressive, immunomodulatory, and cytostatic drugs; T-cell antibodies; and anticytokine agents. Using immunochemotherapy, familial HLH, which had been invariably fatal, has become a curable disease with more than 50% survivors. Reduced intensity conditioning for HSCT, which is associated with less transplantation-related mortality, will further improve cure rates.


Effects of Lactobacillus johnsonii and Lactobacillus reuteri on gut barrier function and heat shock proteins in intestinal porcine epithelial cells.
Heat shock proteins (HSPs) are a set of highly conserved proteins that can serve as intestinal gate keepers in gut homeostasis. Here, effects of a probiotic, Lactobacillus rhamnosus GG (LGG), and two novel porcine isolates, Lactobacillus johnsonii strain P47-HY and Lactobacillus reuteri strain P43-HUV, on cytoprotective HSP expression and gut barrier function, were investigated in a porcine IPEC-J2 intestinal epithelial cell line model. The IPEC-J2 cells polarized on a permeable filter exhibited villus-like cell phenotype with development of apical microvilli. Western blot analysis detected HSP expression in IPEC-J2 and revealed that L. johnsonii and L. reuteri strains were able to significantly induce HSP27, despite high basal expression in IPEC-J2, whereas LGG did not. For HSP72, only the supernatant of L. reuteri induced the expression, which was comparable to the heat shock treatment, which indicated that HSP72 expression was more stimulus specific. The protective effect of lactobacilli was further studied in IPEC-J2 under an enterotoxigenic Escherichia coli (ETEC) challenge. ETEC caused intestinal barrier destruction, as reflected by loss of cell-cell contact, reduced IPEC-J2 cell viability and transepithelial electrical resistance, and disruption of tight junction protein zonula occludens-1. In contrast, the L. reuteri treatment substantially counteracted these detrimental effects and preserved the barrier function. L. johnsonii and LGG also achieved barrier protection, partly by directly inhibiting ETEC attachment. Together, the results indicate that specific strains of Lactobacillus can enhance gut barrier function through cytoprotective HSP induction and fortify the cell protection against ETEC challenge through tight junction protein modulation and direct interaction with pathogens.


Predictive power of isolated high home systolic blood pressure for cardiovascular outcomes in individuals with type 2 diabetes mellitus: KAMOGAWA-HBP study.
Isolated high home systolic blood pressure (IHHSBP) is a risk for cardiovascular disease (CVD). However, no study has shown an association between IHHSBP and CVD in diabetes. We examined the association between IHHSBP and CVD in type 2 diabetes. This retrospective cohort study included 1082 individuals with type 2 diabetes, aged 20 to 90 years, without a history of macrovascular complications. Home blood pressure (HBP) was measured three times every morning and evening for 14 days. Cox proportional hazards models were used to examine the relationship between IHHSBP and CVD incidence. With the normal HBP group as the reference, the adjusted hazard ratio (HR) (95% confidence interval [CI]) for CVD was 1.58 (1.02-2.43) in the IHHSBP group. Correcting for antihypertensive medication use did not change HR. Based on sex, the adjusted HR (95% CI) for CVD was 1.25 (0.74-2.13) in males and 2.28 (1.01-5.15) in females. In individuals with type 2 diabetes, those with IHHSBP had a higher HR for cardiovascular disease than those with normal HBP. But, Isolated high home diastolic blood pressure and high HBP were not. The association between IHHSBP and CVD was stronger in females than in males.


[Bone and soft tissue sarcomas].
Great progress has been made both in the treatment of metastatic sarcomas and in adjuvant treatment of Ewing's, rhabdomyo- and osteogenic sarcomas. This is due partly to new and more effective cytostatic drugs and combinations, but to a greater extent to an improved systematic multimodal approach. In patients with metastatic sarcoma, better and longer remissions can be achieved, whereas real cures are possible in Ewing's, rhabdomyo- and osteosarcoma if properly managed using an interdisciplinary approach. Patients with these rare malignancies should be referred to specialized cancer centers, in view of the problems and possible complications of their necessarily intensive therapy.


DTIC therapy in metastatic malignant melanoma: a simplified dose schedule.
Ninety-seven patients with metastatic malignant melanoma were treated with DTIC, 850 mg/m2 given in single doses at 3--6 week intervals, either alone or in combination with cyclophosphamide (750 mg/m2) and vincristine (2 mg/m2) (DCV). Eighteen patients (19%) had objective disease regression, with a median response duration of 151 days. There was no difference in response rate, response duration, or survival between the group treated with DTIC alone and the group treated with DCV but there was greater gastrointestinal and hematopoietic toxicity in the DCV group. Tumor regression with this single-dose DTIC regimen is similar to that obtained with 5-day courses of DTIC and toxicity is not increased.


MicroRNAs Involved in Anti-Tumour Immunity.
MicroRNAs (miRNAs) are a category of small RNAs that constitute a new layer of complexity to gene regulation within the cell, which has provided new perspectives in understanding cancer biology. The deregulation of miRNAs contributes critically to the development and pathophysiology of a number of cancers. miRNAs have been found to participate in cell transformation and multiplication by acting as tumour oncogenes or suppressors; therefore, harnessing miRNAs may provide promising cancer therapeutics. Another major function of miRNAs is their activity as critical regulatory vehicles eliciting important regulatory processes in anti-tumour immunity through their influence on the development, differentiation and activation of various immune cells of both innate and adaptive immunity. This review aims to summarise recent findings focusing on the regulatory mechanisms of the development, differentiation, and proliferative aspects of the major immune populations by a diverse profile of miRNAs and may enrich our current understanding of the involvement of miRNAs in anti-tumour immunity.


Internal medicine training in the 21st century.
Many are calling for changes for internal medicine training, arguing that changes in the practice environment mandate changes in how the internal medicine residency is structured. Residency could be shorter, more conducive to role differentiation among general internists, and more supportive of subspecialization. Training could provide more experience in ambulatory care, multidisciplinary team-based care, chronic disease management, and quality improvement. The authors contend that the claim that internal medicine training ought to mirror internal medicine practice is mistaken. Many changes now proposed would likely damage if not destroy the consultant-generalist ideal of traditional internal medicine training which remains critical to effective medical care in the 21st century. The authors propose a model for training similar in structure but different in spirit from contending models. This model, like others, would involve a core experience in the first two years with tracking in the final year; unlike others, it would provide a conceptually coherent experience based on internal medicine's traditional ideal. Outpatient experience would be subsidiary to a predominantly inpatient experience, and it would be structured in blocks rather than continuity clinics. Twenty-first-century internists will continue to face what has always been the internist's task: the resolution of complex and ill-defined patient problems into proper diagnoses and therapeutic options. Contemporary internal medicine training must fit trainees for that task and must, thus, continue to offer the training experience necessary for the realization of the Oslerian ideal: a substantial apprenticeship taking care of inpatients with a wide range of medical illnesses.


Clinical presentation and risk behaviors of patients with acquired immunodeficiency syndrome in Thailand, 1994--1998: regional variation and temporal trends.
From 1994 through 1998, the clinical and demographic features and risk behaviors of 101,945 adolescent and adult patients with acquired immunodeficiency syndrome (AIDS) were reported to the Ministry of Public Health in Thailand. The number of reported cases of AIDS infection increased from 12,005 in 1994 to 24,722 in 1997. Nearly 40% of the cases were reported from the northern provinces, which contained only approximately 20% of the adult population. About 80% of cases were among male patients, and 87% had been acquired via sexual contact. Tuberculosis was the most commonly reported opportunistic infection, occurring in 28.9% of patients; it was more commonly reported among injection drug abusers, especially in Bangkok. Pneumocystis carinii pneumonia and cryptococcal meningitis each occurred in nearly 20% of patients and were more frequently reported in patients with risk factors related to sex than in injection drug abusers. Penicillium marneffei infections were reported in 6.8% of patients from the northern provinces but less frequently elsewhere. These data suggest that AIDS is common in Thailand, and human immunodeficiency virus-infected persons should be given prophylaxis for tuberculosis, fungal infections, and P. carinii pneumonia.


Imaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis.
Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced hypophysitis.


The research assessment exercise in nursing: learning from the past, looking to the future.
The aim of the study was to enable those planning to make submissions to the 2008 Research Assessment Exercise to make informed decisions regarding their research strategies. The objective of the study was to identify the factors that distinguish those units of assessment (Universities and Higher Education Institutions) that were highly rated from those that received a low rating for nursing in the Research Assessment Exercise of 2001. Nursing research differs in kind from other types of biomedical research. There is a tendency for research in nursing to be characterized by an inward-looking focus and dominated by a concern with the profession itself. The examination of the research output of nursing. Data from the abstracts of journal articles submitted to the 2001 Research Assessment Exercise for nursing were extracted, classified, collated and analysed. The publications submitted by those in the higher-rated units showed a greater tendency than those submitted by those in the lower-rated units to report on a study involving the collection of primary data; to be multi-authored; to use either qualitative methodology or randomized-controlled trials; and to focus upon clinical issues and have patients as the subjects of the research. Nursing research is in a process of change and growth and is still of variable quality. The development of research towards patient care and clinical issues, and away from issues relating to the profession itself, is most evident among those units of assessment rated highly in the 2001 Research Assessment Exercise. The study indicates that the best of current nursing research is focused upon clinical issues and patient care.


Dexmedetomidine for an awake fiber-optic intubation of a parturient with Klippel-Feil syndrome, Type I Arnold Chiari malformation and status post released tethered spinal cord presenting for repeat cesarean section.
Patients with Klippel-Feil Syndrome (KFS) have congenital fusion of their cervical vertebrae due to a failure in the normal segmentation of the cervical vertebrae during the early weeks of gestation and also have myriad of other associated anomalies. Because of limited neck mobility, airway management in these patients can be a challenge for the anesthesiologist. We describe a unique case in which a dexmedetomidine infusion was used as sedation for an awake fiber-optic intubation in a parturient with Klippel-Feil Syndrome, who presented for elective cesarean delivery. A 36-year-old female, G2P1A0 with KFS (fusion of cervical vertebrae) who had prior cesarean section for breech presentation with difficult airway management was scheduled for repeat cesarean delivery. After obtaining an informed consent, patient was taken in the operating room and non-invasive monitors were applied. Dexmedetomidine infusion was started and after adequate sedation, an awake fiber-optic intubation was performed. General anesthetic was administered after intubation and dexmedetomidine infusion was continued on maintenance dose until extubation. Klippel-Feil Syndrome (KFS) is a rare congenital disorder for which the true incidence is unknown, which makes it even rare to see a parturient with this disease. Patients with KFS usually have other congenital abnormalities as well, sometimes including the whole thoraco-lumbar spine (Type III) precluding the use of neuraxial anesthesia for these patients. Obstetric patients with KFS can present unique challenges in administering anesthesia and analgesia, primarily as it relates to the airway and dexmedetomidine infusion has shown promising result to manage the airway through awake fiberoptic intubation without any adverse effects on mother and fetus.


[Morphologic and functional features of hemopoietic microenvironment in acute lymphoblastic leukemia].
Data of the histological, ultrastructural and culture cell investigations of bone marrow microenvironment in 20 patients with acute lymphoblastic leukemia (ALL) are presented. Morphological and functional peculiarities of the patients' bone marrow stroma different from that in healthy subjects were identified. They included distorted histotopographic patterns of stroma-hemopoietic cell-to-cell interaction, obliteration of sinusoid counts, resorption on the sites of internal bone support structures, a changed stromal cells ratio, formation of reticular cell clusters in the subendosteal and perivascular bone marrow areas, fibroid centers, the presence of nuclear bodies in stromal cell nuclei and an intensified proliferation of stromal cell precursors in organ tissue cultures. Morphological and functional changes in bone marrow microenvironment were detected in ALL patients, which could have been caused both by malignant cell clones and stromal defects.


One-step facile surface engineering of hydrophobic nanocrystals with designer molecular recognition.
High quality nanocrystals have demonstrated substantial potential for biomedical applications. However, being generally hydrophobic, their use has been greatly limited by complicated and inefficient surface engineering that often fails to yield biocompatible nanocrystals with minimal aggregation in biological fluids and active targeting toward specific biomolecules. Using chimeric DNA molecules, we developed a one-step facile surface engineering method for hydrophobic nanocrystals. The procedure is simple and versatile, generating individual nanocrystals with multiple ligands. In addition, the resulting nanocrystals can actively and specifically target various molecular addresses, varying from nucleic acids to cancer cells. Together, the strategy developed here holds great promise in generating critical technologies needed for biomedical applications of nanocrystals.


Effectiveness and tolerability of a standardized extract from Ageratina pichinchensis in patients with diabetic foot ulcer: a randomized, controlled pilot study.
Previous works have shown that extracts obtained from Ageratina pichinchensis are capable of reducing the time needed for wounds to heal. By means of a randomized, double-blind pilot study, the objective of this work was to evaluate the effectiveness and tolerability of a phytopharmaceutical developed with a standardized extract (5 %, cream formulation) of A. pichinchensis, topically administered in patients with diabetic foot ulcer. Micronized silver sulfadiazine (1 %) was employed as a control treatment. Treatments were randomly assigned to each patient, and clinical evolution was evaluated weekly until complete healing of the wound. All patients who concluded the study achieved complete healing of their ulcers. After six weeks of treatment, patients in the experimental group exhibited a wound-healing process of 77.5 %, while that of patients in the control group was 69.8 %. A statistically significant difference was not found between groups. The average time needed for complete wound healing was 65.47 ± 47.08 days for patients treated with the A. pichinchensis extract and 77.46 ± 50.8 days for patients in the control group (p = 0.509). There was no case in either of the groups in which adverse side effects were identified. Thus, it was concluded that the A. pichinchensis extract showed the ability to improve the healing process in patients with diabetic foot ulcer; however, no statistically significant differences were observed when compared with results obtained in patients administered the control treatment (micronized silver sulfadiazine). Some limitations of this study must be addressed, such as small sample size. This work comprises a pilot study that could be useful in a future clinical trial with a greater number of patients.


Vascular Robo4 restricts proangiogenic VEGF signaling in breast.
Formation of the vascular system within organs requires the balanced action of numerous positive and negative factors secreted by stromal and epithelial cells. Here, we used a genetic approach to determine the role of SLITs in regulating the growth and organization of blood vessels in the mammary gland. We demonstrate that vascularization of the gland is not affected by loss of Slit expression in the epithelial compartment. Instead, we identify a stromal source of SLIT, mural cells encircling blood vessels, and show that loss of Slit in the stroma leads to elevated blood vessel density and complexity. We examine candidate SLIT receptors, Robo1 and Robo4, and find that increased vessel angiogenesis is phenocopied by loss of endothelial-specific Robo4, as long as it is combined with the presence of an angiogenic stimulus such as preneoplasia or pregnancy. In contrast, loss of Robo1 does not affect blood vessel growth. The enhanced growth of blood vessels in Robo4(-/-) endothelium is due to activation of vascular endothelial growth factor (VEGF)-R2 signaling through the Src and FAK kinases. Thus, our studies present a genetic dissection of SLIT/ROBO signaling during organ development. We identify a stromal, rather than epithelial, source of SLITs that inhibits blood vessel growth by signaling through endothelial ROBO4 to down-regulate VEGF/VEGFR2 signaling.


First-Time Sports-Related Concussion Recovery: The Role of Sex, Age, and Sport.
Concussion is one of the most common injuries in athletes. Current concussion consensus statements propose that female sex may be a modifying factor in concussion management and recovery. To determine whether female athletes in middle school and high school with a first-time, sports-related concussion remained symptomatic longer than their male counterparts. A retrospective medical record analysis was performed among athletes who sustained a concussion between 2011 and 2013. Inclusion criteria consisted of age between 11 and 18 years and diagnosis of first-time concussion sustained while playing organized sports. Using the documented notes in the medical record, length of time that each athlete was symptomatic from his or her concussion was calculated. A total of 110 male and 102 female athletes (N=212) met the eligibility criteria for the study. A significant difference was found in the median number of days female athletes remained symptomatic (28 days) when compared with male athletes (11 days) (P<.001). No statistically significant difference was found in symptom duration between age groups. When matched for sex, no statistically significant differences were found in symptom duration between the type of sports played. Female athletes aged 11 to 18 years with first-time, sports-related concussions remained symptomatic for a longer period when compared with male athletes of similar age, regardless of sport played. The mechanism behind this difference needs to be further elucidated.


Narrowing the gap between rhetoric and the reality of medical ethics.
A major challenge for academic medical education is to sensibly balance the needs of students and residents for hands-on training with the rights of patients to receive the highest quality of care. Two aspects of the debate over this issue have received a great deal of attention: the appropriate degree of patient control over the makeup of the treatment team, and the proper role of supervision and accountability for attending physicians. Although the law has ostensibly resolved the conflict between the goals of student participation and the principles of patient autonomy and informed consent, the record of medical practices is too often inapposite. The divergence of law and reality is primarily a reflection of the law's flawed medical model, which poorly matches the dynamics of the physician-patient relationship and ineffectually attempts to reshape it. But the dissonance is also attributable to medicine's autonomous professional culture, which undervalues patient involvement and reinforces benign paternalism. Coherent policy requires a recrystallization of both the legal ideal and the medical reality. Lawyers and ethicists should loosen their rigid consumerist conception of medicine, and physicians should become more conscious of the infiltration of paternalism and instrumentalism into their decisions.


Ecology and genomics of Actinobacteria: new concepts for natural product discovery.
Actinobacteria constitute a highly diverse bacterial phylum with an unrivalled metabolic versatility. They produce most of the clinically used antibiotics and a plethora of other natural products with medical or agricultural applications. Modern 'omics'-based technologies have revealed that the genomic potential of Actinobacteria greatly outmatches the known chemical space. In this Review, we argue that combining insights into actinobacterial ecology with state-of-the-art computational approaches holds great promise to unlock this unexplored reservoir of actinobacterial metabolism. This enables the identification of small molecules and other stimuli that elicit the induction of poorly expressed biosynthetic gene clusters, which should help reinvigorate screening efforts for their precious bioactive natural products.


Beta-2-microglobulin in myeloma: optimal use for staging, prognosis, and treatment--a prospective study of 160 patients.
Previous reports have shown that serum beta-2-microglobulin (S beta2M) is a reliable marker of presenting tumor mass, response to chemotherapy, and prognosis of patients with multiple myeloma (MM). In order to more thoroughly evaluate the optimal use of S beta2M in plasma cell dyscrasias (PCD), S beta2M levels were serially measured in 160 patients with MM, in comparison with 37 normal controls (NC) and 28 patients with monoclonal gammopathy of undetermined significance (MGUS). In MGUS, S beta2M did not differ significantly from that of NC, but was significantly lower than that of MM (p less than 0.001), including low cell mass MM (p less than 0.02). In MM, S beta 2M was highly correlated with the total body burden of myeloma cells as derived from the staging of Durie and Salmon, both at diagnosis and in remission (residual tumor mass) (p less than 0.001). During the plateau phase, S beta 2M remained very stable and was always within the normal range for patients with greater than or equal to 75% tumor regression. The most striking finding was that S beta 2M gave an extremely reliable fit for survival prediction at (1) diagnosis, (2) remission, and (3) early relapse, with higher S beta 2M levels in each instance being in favor of poorer prognosis. We conclude that S beta 2M is an extremely useful marker in initial stratification and follow-up of patients with MM.


Use of antidepressants in Parkinson's disease: A Swedish register-based study of over 1.5 million older people.
It has been suggested that depression in Parkinson's Disease (PD) is often unrecognized and undertreated. However, few previous studies have studied the use of antidepressants in a large sample of both home-dwelling and institutionalized elderly persons with PD. We aimed to study the use of antidepressants in older persons using anti-parkinson drugs (APD, used as a proxy for PD), stratified by residential setting. We analyzed individual data on age, sex, residential setting and drug use in over 1.5 million older persons in the Swedish Prescribed Drug Register on 31th of December 2013. Twenty-two percent of the home-dwellers and 50% of the institutionalized elderly persons with APD used antidepressants. Persons with APD had a higher probability of use of any antidepressant compared to persons without APD. A selective serotonin reuptake inhibitor (SSRI) was the most commonly used antidepressants in both settings followed by mirtazapin. The high use of antidepressants among older persons with APD warrants further studies on the quality of treatment of depression in PD.


Binocular luminance summation in infants. A test for stereopsis?
The difference in pupil diameter between monocular and binocular viewing conditions has been found to be significantly different in human infants at an age of onset that is positively correlated with the age of onset for stereopsis. We attempted to use this information on binocular luminance summation (BLS) to devise a simple objective test using a direct ophthalmoscope in a modified two-part swinging-flashlight test. We evaluated 67 subjects with varying degrees of known heterotropia ranging in age from 16 hours to 20 years in an effort to determine a threshold measure of stereo-acuity or degree of heterotropia at which the test result might reproducibly change. We found BLS to be normally absent until about 4 months of age. All subjects older than 4 months manifested summation regardless of the extent of heterotropia, thus making our test unusable. We conclude that BLS is more than an ipsilateral consensual pupillary response, and we concur with others that these visual pathways must undergo maturation beyond the time of birth.


Gene expression profiles for an immunoscore model in bone and soft tissue sarcoma.
Immune infiltration is a prognostic marker to clinical outcomes in various solid tumors. However, reports that focus on bone and soft tissue sarcoma are rare. The study aimed to analyze and identify how immune components influence prognosis and develop a novel prognostic system for sarcomas. We retrieved the gene expression data from 3 online databases (GEO, TCGA, and TARGET). The immune fraction was estimated using the CIBERSORT algorithm. After that, we re-clustered samples by K-means and constructed immunoscore by the least absolute shrinkage and selection operator (LASSO) Cox regression model. Next, to confirm the prognostic value, nomograms were constructed. 334 samples diagnosed with 8 tumor types (including osteosarcoma) were involved in our analysis. Patients were next re-clustered into three subgroups (OS, SAR1, and SAR2) through immune composition. Survival analysis showed a significant difference between the two soft tissue groups: patients with a higher proportion of CD8+ T cells, macrophages M1, and mast cells had favorable outcomes (p=0.0018). Immunoscore models were successfully established in OS and SAR2 groups consisting of 12 and 9 cell fractions, respectively. We found immunosocre was an independent factor for overall survival time. Patients with higher immunoscore had poor prognosis (p<0.0001). Patients with metastatic lesions scored higher than those counterparts with localized tumors (p<0.05). Immune fractions could be a useful tool for the classification and prognosis of bone and soft tissue sarcoma patients. This proposed immunoscore showed a promising impact on survival prediction.


Neurointerventional experience with an arteriotomy suture device.
We describe our experience with an arteriotomy closure device that has become a routine tool for the management of most patients in our neurointerventional service. In our experience, this device contributes significantly to patient comfort by allowing mobilization within 2 hours of a procedure, even with anticoagulants. Efficacy and safety of this suture device requires proctoring during initial experience.


[Transnasal-transsphenoidal endoscopic surgery of the sellar region].
Transnasal transsphenoidal endoscopic approach to the sella turcica has recently become an option to the pituitary surgery which could predominate in a near future. To evaluate through the analysis of our results whether it is possible to perform in our Hospital the endoscopic transnasal transsphenoidal approach to the sella with results at least as good as those we obtain with the microscopic sublabial transseptal transsphenoidal approach. As the first stage of a three stage randomized trial, this is a prospective study of 10 patients operated on, using transnasal transsphenoidal endoscopic approach between august 2002 and August 2003 at the department of neurosurgery of "Hermanos Ameijeiras Hospital". Six patients had pituitary macroadenomas and four had cerebrospinal fluid leak through the sellar floor. In five of six macroadenomas total tumor resection was obtained and in the other one a subtotal resection was performed. Two of four patients with cerebrospinal fluid leak could be cured while the other two patients do not. Complications were present in 30% of cases, but in only 1 (10%) it reached the postoperatory period. Transnasal transsphenoidal endoscopic approach to the sella can be done save enough in our Hospital to justify the start of the second stage of one randomized trial to determine if the endoscopic technique is better than the usual transsphenoidal approach.


Risk of basal cell and squamous cell skin cancers after ionizing radiation therapy. For The Skin Cancer Prevention Study Group.
Human evidence that ionizing radiation is carcinogenic first came from reports of nonmelanoma skin cancers (NMSCs) on the hands of workers using early radiation devices. An increased risk of NMSC has been observed among uranium miners, radiologists, and individuals treated with x rays in childhood for tinea capitis (ringworm of the scalp) or for thymic enlargement; NMSC is one of the cancers most strongly associated with the atomic bombing of Hiroshima and Nagasaki. Although exposure to ionizing radiation is a known cause of NMSC, it is not yet clear whether therapeutic radiation causes both major histologic types of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Additionally, the potentially modifying effects, such as latency, age when treated, and type of treatment, are not well understood. We investigated the relative risks of BCC and SCC associated with previous radiation therapy and evaluated these risks in relation to age and time since initial treatment and the medical condition for which radiation therapy was given. The study group comprised individual diagnosed with at least one BCC or SCC from January 1980 through February 1986, who were recruited to participate in a skin cancer prevention trial designed to test whether oral beta-carotene supplementation would reduce the risk of new NMSCs. Patients were identified through the dermatology and pathology records of academic medical centers in Hanover, NH; Los Angeles, CA; San Francisco, CA; and Minneapolis, MN. Each participant completed a questionnaire detailing lifetime residence, pigmentary characteristics, occupational and recreational sun exposure, and history of radiation therapy. At enrollment, a study dermatologist assessed skin type (tendency to burn or tan) and extent of actinic skin damage. Participants were followed with an annual dermatologic examination for an average of 4 years. Of the 5232 potentially eligible individuals, 1805 were enrolled in the trial. We excluded 112 patients who reported previous radiation therapy for skin cancer only and three with missing information on whether they were ever treated with radiation therapy, leaving 1690 patients for the analysis. Approximately 4% of the patients died or discontinued participation for other reasons during each study year. We examined time to occurrence of first new histopathologically confirmed BCC and SCC during the follow-up period in relation to history of radiation therapy (for reasons other than NMSC) using a proportional hazards model. A multiple end points survival model was used to compare the rate ratios (RRs) for BCC and SCC. We also used a longitudinal method of analysis to compute the RR of total new BCC and SCC tumors per person per study year associated with radiation therapy. Using this method, we additionally assessed the potential modifying effects of age at treatment, latency, and type of therapy. All P values were derived from two-sided statistical tests of significance. Among the participants we studied, 597 developed a new BCC (n = 1553 tumors) and 118 developed a new SCC (n = 179 tumors). The time to first new BCC, but not SCC, was associated with prior radiation therapy (RR = 1.7; 95% confidence interval [CI] = 1.4-2.0 and RR = 1.0; 95% CI = 0.6-1.7, respectively; P = .03 for the difference between the RRs). The RR of total BCC tumors was slightly higher (RR = 2.3; 95% CI = 1.7-3.1), but it was still unity for SCC (RR = 1.0; 95% CI = 0.5-1.9). BCC risk appeared to increase with younger age at exposure and time since initially treated, although these effects were only marginally statistically significant (P for trend = .06 and .07, respectively). Also, risk of BCC was more strongly related to treatment for acne (RR = 3.3; 95% CI = 2.1-5.2) than other conditions. Our data suggest that exposure to therapeutic radiation is associated with BCC but not with SCC.


Contraceptive efficacy of a novel spermicidal microbicide used with a diaphragm: a randomized controlled trial.
Women need products that protect against both pregnancy and sexually transmitted infections, including human immunodeficiency virus (HIV). The acid buffering gel is a nondetergent spermicide that may provide this dual protection by reinforcing normal vaginal acidity to inactivate both sperm and acid-sensitive sexually transmitted pathogens. The objective of this study was to assess the gel's contraceptive effects, safety, and acceptability. We conducted a multicenter, randomized, double-masked, noninferiority study at 11 centers, comparing 621 women who used an acid buffering gel plus diaphragm with 300 women who used a nonoxynol-9 spermicide plus diaphragm for 6 months. A double-masked study extension followed 234 women for an additional 6 months of use. The 6-month pregnancy rate per hundred women was 10.1% (95% confidence interval [CI] 7.1-13.1%) for acid buffering gel and 12.3 (95% CI 7.7-16.9) for nonoxynol-9 spermicide users. The difference in rates was -2.2% with a 95% CI -7.7 to 3.3%. Consistent and correct use 6-month pregnancy rates were 4.7% for acid buffering gel and 6.1% for nonoxynol-9 spermicide users, calculated from those cycles where diary entries indicated such use. Adverse events and acceptability were similar between the two groups. Pregnancy probabilities were similar between groups participating in the 12-month study extension. An acid buffering gel used with a diaphragm is a safe, acceptable contraceptive with efficacy comparable to that of a common commercial spermicide with diaphragm. ClinicalTrials.gov, www.ClinicalTrials.gov, NCT00065858 I.


Endocrine relationships of Meishan and White composite females after weaning and during the luteal phase of the estrous cycle.
Endocrine differences between European crossbred and Chinese Meishan females have been somewhat modest. Indwelling jugular cannulas were placed in Meishan (n = 7) and White composite (n = 6) multiparous sows before weaning, and blood was sampled from 4 h before to 240 h after removal of litters. Temporal changes in FSH, triiodothyronine (T3), and tetraiodothyronine (T4) after weaning differed between Meishan and White composite sows. Plasma cortisol concentrations were higher in Meishan sows than in White composite sows (P < 0.01), but there were no temporal differences between breeds after weaning. Other hormones monitored (prolactin, GH, IGF-I, and inhibin) were not different between breeds. In the second experiment, Meishan gilts (n = 7) and sows (n = 7) and White composite sows (n = 9) were cannulated during the luteal phase of the estrous cycle and sampled after treatments consisting of GnRH (15 and 150 ng/kg BW), ovariectomy, estradiol cypionate challenge after ovariectomy (10 microg/kg BW), and GnRH antagonist. In response to GnRH challenge, White composite sows had elevated (P < 0.05) concentrations of gonadotropins compared with Meishan. Cortisol concentrations were elevated in Meishan as compared with White composite females (P < 0.01) but unaffected by GnRH treatment. After ovariectomy, LH concentrations increased 3 h sooner in White composite than in Meishan females. After GnRH antagonist, declines in gonadotropins were comparable in both breeds, but LH increased in Meishan females by 20 h but not until after 54 h in White composite females. White composite females demonstrated only a short decline in FSH in response to the GnRH antagonist, but Meishan females had a prolonged decline in FSH concentrations. Consistently elevated cortisol concentrations in Meishan females may positively impact ovarian function; thus, the assumption that high plasma cortisol concentration as an index of stress that impairs reproductive function should be reevaluated in swine. There were few endocrine differences that would relate to or explain increased ovulation rates found in the Meishan breed; thus, other mechanisms must exist to explain the increase in ovarian function in the Meishan breed.


The genetic structure of natural populations of Drosophila melanogaster. XXII. Comparative study of DNA polymorphisms in northern and southern natural populations.
Restriction map variation in four gene regions (Adh, Amy, Pu and Gpdh) was surveyed for 86 second chromosomes from northern (Aomori) and southern (Ogasawara) Japanese populations of Drosophila melanogaster (43 chromosomes from each population). The regions examined cover a total of 62 kilobases. Estimates of nucleotide diversity (pi) were approximately constant across the gene regions and populations examined. The distribution of restriction site polymorphisms was compatible with the expectation from the neutral mutation-random genetic drift hypothesis, but insertion/deletion polymorphisms were not consistent with it. While the two populations shared a majority of restriction site polymorphisms, frequencies of individual restriction site variants were significantly different between the two populations at 7 out of 35 segregating sites. In addition, an insertion in the Amy region was found in 15 chromosomes from the Ogasawara sample but absent in the Aomori sample. A considerable difference was observed in the number of rare insertions and deletions between the two populations. The numbers of aberrations uniquely represented were 16 in the Ogasawara sample and only 3 in the Aomori sample. These findings suggest that the two populations were differentiated from each other to some degree by means of random genetic drift and/or other factors.


Personal exposure of PM2.5 and metabolic syndrome markers of pregnant women in South Korea: APPO study.
We examined the association between exposure to PM2.5, focused on individual exposure level, and metabolic dysfunction during pregnancy. APPO study (Air Pollution on Pregnancy Outcome) was a prospective, multicenter, observational cohort study conducted from January 2021 to March 2023. Individual PM2.5 concentrations were calculated using a time-weighted average model. Metabolic dysfunction during pregnancy was assessed based on a modified definition of metabolic syndrome and its components, accounting for pregnancy-specific criteria. Exposure to PM2.5 during pregnancy was associated with worsened metabolic parameters especially glucose metabolism. In comparison to participants exposed to the low PM2.5 group, those exposed to high PM2.5 levels exhibited increased odds of gestational diabetes mellitus (GDM) after adjusting for confounding variables in different adjusted models. Specifically, in model 1, the adjusted odds ratio (aOR) was 3.117 with a 95% confidence interval (CI) of 1.234-7.870; in model 2, the aOR was 3.855 with a 95% CI of 1.255-11.844; in model 3, the aOR was 3.404 with a 95% CI of 1.206-9.607; and in model 4, the aOR was 2.741 with a 95% CI of 0.712-10.547. Exposure to higher levels of PM2.5 during pregnancy was associated with a tendency to worsen metabolic dysfunction markers specifically in glucose homeostasis. Further research is needed to investigate the mechanisms underlying the effects of ambient PM2.5 on metabolic dysfunction during pregnancy.


Living with Chronic Heart Failure: Exploring Patient, Informal Caregiver, and Healthcare Professional Perceptions.
Due to the complexity of heart failure (HF) and its treatment process, a high level of patient and informal caregiver engagement is required for management results. We aimed to explore the views of HF patients, informal caregivers, and healthcare professionals about personal experiences, perceived needs, and barriers to optimal HF management. A qualitative study using semi-structured interviews with HF patients (n = 32), their informal caregivers (n = 21), and healthcare professionals (n = 5) was conducted in the outpatient HF clinic in Slovenia in 2018. A content analysis method was used to analyze the data. Negative emotional response to disease and its limitations (especially the inability to continue with work) and changes in family roles were the most prevalent topics regarding the impact of HF on livelihood. Among the most common barriers to HF self-care, were the difficulties in changing lifestyle, financial difficulties due to the disease, traditional cuisine/lack of knowledge regarding a healthy diet and lack of self-confidence regarding physical activity. Despite psychological and social difficulties due to HF being highlighted by patients and informal caregivers, only healthcare professionals emphasized the need to address psychosocial aspects of care in HF management. Established differences could inform the implementation of necessary support mechanisms in HF management.


An intracellular P2X receptor required for osmoregulation in Dictyostelium discoideum.
P2X receptors are membrane ion channels gated by extracellular ATP that are found widely in vertebrates, but not previously in microbes. Here we identify a weakly related gene in the genome of the social amoeba Dictyostelium discoideum, and show, with the use of heterologous expression in human embryonic kidney cells, that it encodes a membrane ion channel activated by ATP (30-100 muM). Site-directed mutagenesis revealed essential conservation of structure-function relations with P2X receptors of higher organisms. The receptor was insensitive to the usual P2X antagonists but was blocked by nanomolar concentrations of Cu2+ ions. In D. discoideum, the receptor was found on intracellular membranes, with prominent localization to an osmoregulatory organelle, the contractile vacuole. Targeted disruption of the gene in D. discoideum resulted in cells that were unable to regulate cell volume in hypotonic conditions. Cell swelling in these mutant cells was accompanied by a marked inhibition of contractile vacuole emptying. These findings demonstrate a new functional role for P2X receptors on intracellular organelles, in this case in osmoregulation.


Variation in hydroclimate sustains tropical forest biomass and promotes functional diversity.
The fate of tropical forests under climate change is unclear as a result, in part, of the uncertainty in projected changes in precipitation and in the ability of vegetation models to capture the effects of drought-induced mortality on aboveground biomass (AGB). We evaluated the ability of a terrestrial biosphere model with demography and hydrodynamics (Ecosystem Demography, ED2-hydro) to simulate AGB and mortality of four tropical tree plant functional types (PFTs) that operate along light- and water-use axes. Model predictions were compared with observations of canopy trees at Barro Colorado Island (BCI), Panama. We then assessed the implications of eight hypothetical precipitation scenarios, including increased annual precipitation, reduced inter-annual variation, El Niño-related droughts and drier wet or dry seasons, on AGB and functional diversity of the model forest. When forced with observed meteorology, ED2-hydro predictions capture multiple BCI benchmarks. ED2-hydro predicts that AGB will be sustained under lower rainfall via shifts in the functional composition of the forest, except under the drier dry-season scenario. These results support the hypothesis that inter-annual variation in mean and seasonal precipitation promotes the coexistence of functionally diverse PFTs because of the relative differences in mortality rates. If the hydroclimate becomes chronically drier or wetter, functional evenness related to drought tolerance may decline.


miR-148a Affects Polarization of THP-1-Derived Macrophages and Reduces Recruitment of Tumor-Associated Macrophages via Targeting SIRPα.
The objective of this study was to investigate the effect of miR-148a on the polarization and recruitment of tumor-associated macrophages (TAMs). In human monocyte THP-1 cells, M1 or M2 differentiation was induced by phorbol 12-myristate 13-acetate (PMA) with specific induction supplements and identified using flow cytometry and ELISA. To alter cellular miR-148a expression level, THP-1 cells were transfected with miR-148a mimics or inhibitors. A dual-luciferase assay was used to determine whether miR-148a could directly regulate the expression of signal regulatory protein α (SIRPα). Expression of miR-148a and SIRPα was detected with RT-PCR or Western blot. A co-culture system of THP-1 cells and colorectal cancer SW480 cells was used for TAM induction. The recruitment of macrophage to SW480 cells was measured using chemotaxis assay. In SW480 cells, apoptosis induced by macrophages was detected using flow cytometry and a xenograft assay. Macrophage infiltration was detected by immunofluorescence assay in tumor tissues. miR-148a over-expression increased M1-related CD86 expression in THP-1 cells and promoted differentiation to M1-like macrophages. Inhibition of miR-148a increased M2-related CD206 expression and promoted differentiation to M2-like macrophages. In the co-culture system, THP-1 cells were induced to the M2-like state by SW480 cells. The level of miR-148a negatively correlated with the levels of M2-related cytokines. Additionally, miR-148a expression level was negatively associated with macrophage recruitment by colorectal cancer cells. Furthermore, in miR-148a over-expression, the number of macrophages recruited by SW480 cells was reduced. Meanwhile, cancer cell apoptosis induced by macrophages was enhanced. Thus, miR-148a expression was beneficial for the transformation of macrophages, from an immune-suppressive status to an immune-promoting status. These anti-cancer effects of miR-148a were related to the down-regulation of SIRPα in macrophages, directly targeted by miR-148a. A xenograft assay showed that the co-inoculation of macrophages over-expressing miR-148a reduced subcutaneous tumorigenesis and M2 macrophage infiltration. miR-148a promoted the differentiation of M0 macrophages into anti-tumor classical activation type M1, and reduced TAM recruitment by targeting SIRPα to inhibit colorectal cancer cell viability.


Formulaic Language in Parkinson's Disease and Alzheimer's Disease: Complementary Effects of Subcortical and Cortical Dysfunction.
The production of formulaic expressions (conversational speech formulas, pause fillers, idioms, and other fixed expressions) is excessive in the left hemisphere and deficient in the right hemisphere and in subcortical stroke. Speakers with Alzheimer's disease (AD), having functional basal ganglia, reveal abnormally high proportions of formulaic language. Persons with Parkinson's disease (PD), having dysfunctional basal ganglia, were predicted to show impoverished formulaic expressions in contrast to speakers with AD. This study compared participants with PD, participants with AD, and healthy control (HC) participants on protocols probing production and comprehension of formulaic expressions. Spontaneous speech samples were recorded from 16 individuals with PD, 12 individuals with AD, and 18 HC speakers. Structured tests were then administered as probes of comprehension. The PD group had lower proportions of formulaic expressions compared with the AD and HC groups. Comprehension testing yielded opposite contrasts: participants with PD showed significantly higher performance compared with participants with AD and did not differ from HC participants. The finding that PD produced lower proportions of formulaic expressions compared with AD and HC supports the view that subcortical nuclei modulate the production of formulaic expressions. Contrasting results on formal testing of comprehension, whereby participants with AD performed significantly worse than participants with PD and HC participants, indicate differential effects on procedural and declarative knowledge associated with these neurological conditions.


Patient-reported experiences of consultation with an advanced nurse practitioner: Factor structure and reliability analysis of the patient enablement and satisfaction survey.
The aim was to analyse the psychometric properties of a patient-reported-experience measure, the Patient Enablement and Satisfaction Survey (PESS), when used to evaluate the care provided by Advanced Nurse Practitioners (ANPs) in terms of factor structure and internal consistency. The PESS is a 20-item, patient-completed data collection tool that was originally developed to measure patient experience and enablement following consultation with nurses in general practice. Cross-sectional survey; validity and reliability analysis. The sample in this study consisted of 178 patients who consulted with 26 ANPs working in four different specialities. Data were collected between June and December 2019. An exploratory factor analysis of the PESS was conducted to determine convergent validity which was supported by parallel analysis and the traditional Kaiser criterion. The internal consistency of individual PESS items was determined via Cronbach's alpha, McDonald's omega, the Average Variance Extracted tests and item-subscale/total score correlations. A three-factor structure (PESS-ANP) was found through exploratory factor analysis and this was supported by parallel analysis, the traditional Kaiser criterion and the percentage of variance explained criterion. A high degree of internal consistency was reported across all factors. One question was omitted from the analysis ('Overall Satisfaction') following the identification of problematic cross-loadings. The three factor solution was identified as: patient satisfaction, quality of care provision and patient enablement. The findings of this study propose a three-factor model that is sufficiently reliable for analysing the experience and enablement of patients following consultation with an ANP. Increasingly, patient-reported experience measures are being used to evaluate patients' experience of receiving care from a healthcare professional. The PESS was identified to be reliable in evaluating the experience of patients who receive care from an ANP while a three-factor structure was proposed that can capture specific attributes of this care.


Birth plans: tickets to the OR?
Although some nurses and physicians might suggest that women who write birth plans are at greater risk of a cesarean birth, research has not supported this myth. The research studies on this topic have suggested, actually, that women who write birth plans do not have higher cesarean rates or worse obstetric outcomes. Birth plans have been shown to inform and empower women, and lead to more satisfaction with their birth experiences. The purpose of this article is to present the existing evidence on perinatal outcomes in women with birth plans and to explore the phenomenon of divergent perceptions among care givers.


Performance of a Nomogram Based on the Integration of Inflammation Markers with Tumor Staging in Prognosis Prediction of Stage III Colorectal Cancer.
The aim of the present study was to evaluate a nomogram model for predicting the 5-year overall survival (OS) in lymph node-metastatic colorectal cancer (CRC) patients by combining inflammation markers with some traditional prognostic factors. A total of 399 patients with stage III (pTXN1-3M0) CRC operated from January 2007 to December 2012 were enrolled in this retrospective study. All patients underwent D2 lymphadenectomy in the hospital. A prognostic nomogram based on the integration of traditional prognostic factors and NLR (neutrophil-to-lymphocyte ratio) and PLR (platelet-to-lymphocyte ratio) was established and compared with the nomogram based on the traditional prognostic factors alone. ROC curves were further applied to verify the predictive accuracy of the established model. Both NLR (P=0.00) and PLR (P=0.01) predicted the 5-year OS. In multivariate analysis, age, T3 category, T4 category, N2 category, N3 category, Pgp (P-glycoprotein), NLR and PLR are proven to be independent (all P≤0.05). The established nomogram showed better predictive power than that of traditional profile (c-index: 0.66 versus 0.63) in both training and validation cohorts. External assessment by ROC curve analysis demonstrated that the established model had a good prediction accuracy of 5-year OS in stage III CRC patients, with area under curve values of 0.657 and 0.629 in training and validating sets, respectively. A nomogram based on the integration of traditional prognostic factors and inflammatory markers (NLR and PLR) could provide more precise long-term prognosis information for lymph node-metastatic CRC patients than the model based on traditional profile alone. This model might be useful for clinical application in personalized evaluation.


p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway.
Macrophages are a major target cell for HIV-1, and their infection contributes to HIV pathogenesis. We have previously shown that the cyclin-dependent kinase inhibitor p21 inhibits the replication of HIV-1 and other primate lentiviruses in human monocyte-derived macrophages by impairing reverse transcription of the viral genome. In the attempt to understand the p21-mediated restriction mechanisms, we found that p21 impairs HIV-1 and simian immunodeficiency virus (SIV)mac reverse transcription in macrophages by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis by a SAM domain and HD domain-containing protein 1 (SAMHD1)-independent pathway. We found that p21 blocks dNTP biosynthesis by down-regulating the expression of the RNR2 subunit of ribonucleotide reductase, an enzyme essential for the reduction of ribonucleotides to dNTP. p21 inhibits RNR2 transcription by repressing E2F1 transcription factor, its transcriptional activator. Our findings unravel a cellular pathway that restricts HIV-1 and other primate lentiviruses by affecting dNTP synthesis, thereby pointing to new potential cellular targets for anti-HIV therapeutic strategies.