Unique Features of Gastric Cancer in Young Patients: Experience from a General Hospital in Nepal.
Gastric cancer, the fifth most common malignancy in the world, usually affects older individuals but can occur in younger age groups. In this study we compared the clinicopathological profile of young patients of gastric cancer with that of older patients. It is a prospective study of gastric cancer patients treated over three year period (January 2012 to December 2014). Data of patients were obtained from the medical record. Clinical and pathological characters of younger patients (age 40 years or less) were compared with older patients (age more than 40 years). There were total of 152 patients treated during the study period. Twenty patients (13.2%) were less than 40 years of age and 132 (86.8%) were older. The male to female ratio in younger patients was 1:1.5 whereas in older patients it was 1:0.6. In the younger age group 14 patients (70%) had poorly differentiated adenocarcinoma in contrast to 45% in the older age group (<0.01). Some 55% of younger and 42% of older patients had stage IV disease at presentation and curative surgery was not possible. Palliative surgery for gastric outlet obstruction or bleeding from the tumor was performed on 25% and 21% respectively. Gastric cancer in young people aged less than 40 years has unique characters like female predominance, unfavorable tumor biology, and advanced stage at presentation. There should be a high index of suspicion of gastric cancer even in young patients.


Incidence and Risk of Concussions in Youth Athletes: Comparisons of Age, Sex, Concussion History, Sport, and Football Position.
This study was designed to determine concussion incidence, risk, and relative risk among middle and high school athletes participating in various sports. Data were retrospectively obtained from 10,334 athletes of 12 different sports in Hawaii. In addition to determining the overall concussion incidence, comparisons of incidence, risk, and relative risk were made according to age, sex, concussion history, sport, and football position. The overall incidence of concussion among youth athletes was 1,250 (12.1%). The relative risk for a concussion was almost two times greater in 18-year olds than in 13-year-old athletes. In comparable sports, girls had a 1.5 times higher concussion risk than boys. Athletes with a prior concussion had 3-5 times greater risk to sustain a concussion than those with no history of a concussion. Among varied sports, wrestling and martial arts had the highest relative risk of a concussion, followed by cheerleading, football, and track and field. No differences in concussion risks were found among the football players in different positions. Older youths, females, those with a history of concussion, and those participating in high contact sports were found to have higher risks of sustaining a concussion. The findings increase awareness of concussion patterns in young athletes and raise concerns regarding protective strategies and concussion management in youth sports.


Identification and characterization of artists' red dyes and their mixtures by surface-enhanced Raman spectroscopy.
Silver film over nanospheres (AgFONs) were successfully employed as surface-enhanced Raman spectroscopy (SERS) substrates to characterize several artists' red dyes including: alizarin, purpurin, carminic acid, cochineal, and lac dye. Spectra were collected on sample volumes (1 x 10(-6) M or 15 ng/microL) similar to those that would be found in a museum setting and were found to be higher in resolution and consistency than those collected on silver island films (AgIFs). In fact, to the best of the authors' knowledge, this work presents the highest resolution spectrum of the artists' material cochineal to date. In order to determine an optimized SERS system for dye identification, experiments were conducted in which laser excitation wavelengths were matched with correlating AgFON localized surface plasmon resonance (LSPR) maxima. Enhancements of approximately two orders of magnitude were seen when resonance SERS conditions were met in comparison to non-resonance SERS conditions. Finally, because most samples collected in a museum contain multiple dyestuffs, AgFONs were employed to simultaneously identify individual dyes within several dye mixtures. These results indicate that AgFONs have great potential to be used to identify not only real artwork samples containing a single dye but also samples containing dyes mixtures.


A population-based study of urinary symptoms and incontinence: the Canadian Urinary Bladder Survey.
To ascertain the prevalence of lower urinary tract symptoms (LUTS) and urinary incontinence (UI) in Canada, using a cross-Canada telephone survey, as there is a wide discrepancy in the reported prevalence of these conditions. A random survey with a standardized questionnaire was conducted to elicit responses from 1000 adults, aged >or= 18 years; the sample was intended to reflect the population census. Data on age, level of education and household income were obtained from all respondents. All participants were questioned about urinary symptoms and daytime and night-time voids. For those who reported more symptoms than one episode of nocturia a more detailed questionnaire was used to ascertain symptom severity and duration. Data were analysed from 1000 respondents (482 men, mean age 44 years; 518 women, mean age 45 years). Half the respondents (43% of men and 57% of women) reported one or more LUTS, with nocturia the most common, at 36%. Overactive bladder (OAB) symptoms (urgency, with or with no urgency UI, usually with frequency and nocturia) were reported by 13.9% of respondents (13.1% of men and 14.7% of women). UI was reported by 28.8% of women with the 68% of these having stress UI (SUI), followed by mixed UI (MUI) in 21%, and urgency UI (UUI) in 11%. Of the 5.4% of men with UI, 27% had SUI, 15% had MUI, and 58% had UUI. Overall, the prevalence of LUTS increased with age. Respondents reported that symptoms were present for a median of 5 years. LUTS and UI are common in the Canadian population and increase with age. The prevalence in Canada of these conditions is similar to that seen in other countries.


Different roles for thiol and aspartyl proteases in antigen presentation of ovalbumin.
By using the model Ag, chicken OVA, the proteolytic events required for effective presentation of the antigenic epitope, OVA323-339 to H-2d-restricted Th cells were investigated. First, the ability of aspartyl and thiol proteases to generate antigenic fragments of Ova in vitro was determined. It was found that cathepsin D, an aspartyl protease, digested OVA to fragments that could be recognized by Th cells without further processing by APC. Cathepsin B, a thiol protease, was unable to generate antigenic fragments of OVA in vitro. These results provide evidence that APC do not require thiol protease activity for processing OVA. In contrast, APC were unable to present OVA to Th cells when thiol protease inhibitors were added to the incubation. Taken together, these observations indicate that thiol proteases may be important, not for processing, OVA, but for presentation of processed fragments by APC. This conclusion is supported by evidence obtained from experiments in which APC were treated with thiol protease inhibitors before addition of the antigenic peptide, OVA323-339. Under these conditions, the capacity of I-Ad at the cell surface to present OVA323-339 to Th cells was reduced. The results of these experiments provide evidence that Ag presentation of OVA may be achieved through the action of two different classes of proteases: aspartyl proteases such as cathepsin D, which process OVA to antigenic fragments, and thiol proteases such as cathepsin B, which are important for expression of functional MHC II molecules by APC.


Adenotonsillar Hypertrophy in Pre-School Children with Sickle Cell Disease and Diagnostic Accuracy of the Sleep Disturbance Scale for Children.
Introduction Adenotonsillar hypertrophy is more common in children with sickle cell disease, and can lead to sleep-disordered breathing. Objectives To determine the frequency of adenotonsillar hypertrophy in pre-school children with sickle cell disease and assess the diagnostic accuracy of the sleep-disordered breathing subscale in the Sleep Disturbance Scale for Children. Method Observational study with a group of 48 children with sickle cell disease and a control group of 35 children without the disease. The children underwent oropharingoscopy and video nasal endoscopy. The parents and/or guardians answered the questions of the subscale. Results Adenotonsillar hypertrophy was observed in 25% of the children in the study group, and in 20% of the children in the control group, with no statistical difference between the groups. The subscale score ranged from 3 to 11 in both groups. There was a statistical significance in the study group. The average was 4.79 (standard deviation [SD] ± 2.50), with 4.19 (SD ± 1.72) among the children without adenotonsillar hypertrophy, and 6.5 (SD ± 3.40) among the children with adenotonsillar hypertrophy. There was also a statistical significance in the control group. The average was 5.23 (SD ± 2.81), with 4.44 (SD ± 2.2) among the children without adenotonsillar hypertrophy, and 7.87 (SD ± 2.89) among the children with adenotonsillar hypertrophy. Conclusion Adenotonsillar hypertrophy was not associated with sickle cell disease in pre-school children. The subscale of sleep-disordered breathing in the Sleep Disturbance Scale for Children was a useful tool for the diagnostic suspicion of adenotonsillar hypertrophy in children in this age group.


Resistance to the antibiotics viomycin and capreomycin in the Streptomyces species which produce them.
Viomycin capreomycin, antibiotics produced by Streptomyces vinaceus and S. capreolus respectively, are potent inhibitors of bacterial protein synthesis. Although these organisms are highly tolerant of their own products in vivo, their ribosomes are fully sensitive to the action of the drugs in vitro. However, they processes novel, antibiotic-inactivating enzymes (viomycin phosphotransferase, capreomycin phosphotransferase, capreomycin acetyltransferase) which, in addition to possible biosynthetic roles, may contribute to the resistances observed in vivo.


Atypical polypoid adenomyoma treated by hysteroscopy with photodynamic diagnosis using 5-aminolevulinic acid: A case report.
Surgical resection for atypical polypoid adenomyoma (APA) is an option for fertility preservation. Due to the high recurrence rate of APA, studies have been conducted to improve total resection of tumors. Photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) improves tumor resection, but this has not been applied for APA. The patient was 35-year-old. After initial treatment, the APA lesion did not disappear. We performed hysteroscopic tumor resection using 5-ALA-PDD. Only one PDD-positive lesion was found and histopathologically diagnosed as APA. Other areas were PDD-negative and showed no histopathologic APA or malignant findings. This is the first report of hysteroscopic 5-ALA-PDD for APA. This method makes it easy to identify morbid lesions, and may lead to improved total resection and decreased recurrence.


The Effect of Physicians' Treatment Recommendations on Their Epistemic Authority: The Medical Expertise Bias.
This study examines the hypothesis that patients perceive physicians who recommend more active and major treatment as having greater epistemic authority. The hypothesis is based on the assumption that patients expect that their physicians should advocate for an active treatment rather than abstention from treatment. The sample included 631 participants. Data were collected using a between-subjects design and scenarios that described a person who suffers from a medical problem and visits a physician (surgeon, orthopedist, or dentist). The physician gives a passive or active recommendation regarding treatment. Different levels of passive recommendation (against or wait on treatment) and active recommendation (minor, moderate, or major procedures) were used. The experience of the physician was also manipulated. The dependent measure was the patient's rating of the physician's epistemic authority. Physicians who prescribed an active mode of treatment were perceived as having a higher epistemic authority than physicians who gave a passive recommendation. We named this phenomenon the medical expertise bias, as people might be biased when judging the level of expertise of their physicians such that those physicians who recommend an active treatment are considered to have greater medical epistemic authority in general.


Current major advances in the regulation of milk protein gene expression.
During lactation, functionally differentiated mammary epithelial cells convert circulating nutrients into various milk components, providing all essential nutrients for the growth and development of mammal neonates. One of the major milk components is milk protein, which includes the casein and whey proteins. Regulation of milk protein gene expression is dependent on hormonal and developmental cues that modulate the activity of specific transcription factors and change the chromatin structure in mammary epithelial cells. Understanding the underlying mechanisms involved in mammary-specific milk protein gene regulation will help improve the yield, quality, and efficiency of milk production and identify important signaling factors and pathways involved in mammary development, differentiation, lactation, and disease. In this review we first review advances in the understanding of the regulatory mechanisms of milk protein genes by hormones, growth factors, and the extracellular matrix, with a focus on transcriptional regulation. We then discuss the relationship between chromatin structure and milk protein gene expression from an epigenetic perspective. Finally, we summarize recent achievements using the mammary gland as a bioreactor for producing pharmaceutical proteins for human use.


Quantum support vector machine for big data classification.
Supervised machine learning is the classification of new data based on already classified training examples. In this work, we show that the support vector machine, an optimized binary classifier, can be implemented on a quantum computer, with complexity logarithmic in the size of the vectors and the number of training examples. In cases where classical sampling algorithms require polynomial time, an exponential speedup is obtained. At the core of this quantum big data algorithm is a nonsparse matrix exponentiation technique for efficiently performing a matrix inversion of the training data inner-product (kernel) matrix.


Heterogeneity of DNA deletion in gamma delta beta-thalassemia.
By restriction endonuclease mapping, gene cloning, and DNA sequencing we have determined the region of DNA that is deleted in a family with gamma delta beta-thalassemia. The deletion removes the linked epsilon, gamma-, and delta-globin structural genes and terminates within the coding portion of the beta-globin gene. Since the extent of DNA deletion in this family differs from that reported in another family, we conclude that gamma delta beta-thalassemia is heterogeneous at the molecular level.


Re-establishment of species from synonymies based on DNA barcoding and phylogenetic analysis using Diplopterygium simulans (Gleicheniaceae) as an example.
Because synonymy treatment traditionally relies on morphological judgments, it usually causes many problems in species delimitation and in the biodiversity catalogue. For example, Diplopterygium simulans, which belongs to the Gleicheniaceae family, has been considered to be synonymous with D. glaucum or D. giganteum based mainly on the morphology of its pinna rachis and blade. In the absence of molecular evidence, these revisions remain doubtful. DNA barcoding, which is considered to be a powerful method for species-level identification, was employed to assess the genetic distance among 9 members of the Diplopterygium genus. The results indicate that D. simulans is an independent species rather than a synonymy of D. glaucum or D. giganteum. Moreover, phylogenetic analysis uncovered the sisterhood of D. simulans and D. cantonense, which is supported by their geographical distributions and morphological traits. Incorrect synonymy treatment is prevalent in the characterization of biological diversity, and our study proposes a convenient and effective method for validating synonym treatments and discovering cryptic species.


Glucosamine Suppresses Osteoclast Differentiation through the Modulation of Glycosylation Including O-GlcNAcylation.
Osteoclasts represent the only bone resorbing cells in an organism. In this study, we investigated the effect of glucosamine (GlcN), a nutrient used to prevent joint pain and bone loss, on the osteoclastogenesis of murine macrophage-like RAW264 cells. GlcN supplementation suppressed the upregulation of osteoclast-specific genes (tartrate-resistant acid phosphatase (TRAP), cathepsin K, matrix metallopeptidase 9, and nuclear factor of activated T cell c1 (NFATc1)), receptor activator of nuclear factor-κB ligand (RANKL)-dependent upregulation of TRAP enzyme activity, and the formation of TRAP-positive multinuclear cells more effectively than N-acetylglucosamine (GlcNAc), which we have previously shown to inhibit osteoclast differentiation. To clarify the mechanism by which GlcN suppresses osteoclastogenesis, we further investigated the effect of GlcN on O-GlcNAcylation by Western blotting and on other types of glycosylation by lectin blotting. We found that, upon addition of GlcN, the O-GlcNAcylation of cellular proteins was increased whereas α2,6-linked sialic acid modification was decreased. Therefore, these glycan modifications in cellular proteins may contribute to the suppression of osteoclastogenesis.


Endoscopic submucosal dissection vs endoscopic mucosal resection for early gastric cancer: A meta-analysis.
To compare endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for early gastric cancer (EGC). Computerized bibliographic search was performed on PubMed/Medline, Embase, Google Scholar and Cochrane library databases. Quality of each included study was assessed according to current Cochrane guidelines. Primary endpoints were en bloc resection rate and histologically complete resection rate. Secondary endpoints were length of procedure, post-treatment bleeding, post-procedural perforation and recurrence rate. Comparisons between the two treatment groups across all the included studies were performed by using Mantel-Haenszel test for fixed-effects models (in case of low heterogeneity) or DerSimonian and Laird test for random-effects models (in case of high heterogeneity). Ten retrospective studies (8 full text and 2 abstracts) were included in the meta-analysis. Overall data on 4328 lesions, 1916 in the ESD and 2412 in the EMR group were pooled and analyzed. The mean operation time was longer for ESD than for EMR (standardized mean difference 1.73, 95%CI: 0.52-2.95, P = 0.005) and the "en bloc" and histological complete resection rates were significantly higher in the ESD group [OR = 9.69 (95%CI: 7.74-12.13), P < 0.001 and OR = 5.66, (95%CI: 2.92-10.96), P < 0.001, respectively]. As a consequence of its greater radicality, ESD provided lower recurrence rate [OR = 0.09, (95%CI: 0.05-0.17), P < 0.001]. Among complications, perforation rate was significantly higher after ESD [OR = 4.67, (95%CI, 2.77-7.87), P < 0.001] whereas the bleeding incidences did not differ between the two techniques [OR = 1.49 (0.6-3.71), P = 0.39]. In the endoscopic therapy of EGC, ESD showed a superior efficacy but higher complication rate with respect to EMR.


Achieving equity and inclusion in pediatric dermatology research: Priorities and considerations.
As we increase our focus and energy on equity, diversity, and inclusion (EDI)-relevant research, we must consider the "what, why, and how" of our work. The goals of this paper are to highlight unique issues pediatric dermatologists face in providing equitable care, pose considerations when reporting data on race and ethnicity, and advocate for standardized classification of race and ethnicity in research.


Dissecting the interaction of photosynthetic electron transfer with mitochondrial signalling and hypoxic response in the Arabidopsis rcd1 mutant.
The Arabidopsis mutant rcd1 is tolerant to methyl viologen (MV). MV enhances the Mehler reaction, i.e. electron transfer from Photosystem I (PSI) to O2, generating reactive oxygen species (ROS) in the chloroplast. To study the MV tolerance of rcd1, we first addressed chloroplast thiol redox enzymes potentially implicated in ROS scavenging. NADPH-thioredoxin oxidoreductase type C (NTRC) was more reduced in rcd1. NTRC contributed to the photosynthetic and metabolic phenotypes of rcd1, but did not determine its MV tolerance. We next tested rcd1 for alterations in the Mehler reaction. In rcd1, but not in the wild type, the PSI-to-MV electron transfer was abolished by hypoxic atmosphere. A characteristic feature of rcd1 is constitutive expression of mitochondrial dysfunction stimulon (MDS) genes that affect mitochondrial respiration. Similarly to rcd1, in other MDS-overexpressing plants hypoxia also inhibited the PSI-to-MV electron transfer. One possible explanation is that the MDS gene products may affect the Mehler reaction by altering the availability of O2. In green tissues, this putative effect is masked by photosynthetic O2 evolution. However, O2 evolution was rapidly suppressed in MV-treated plants. Transcriptomic meta-analysis indicated that MDS gene expression is linked to hypoxic response not only under MV, but also in standard growth conditions. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.


Zero ventilation: a transient episode.
A 65-year-old man with known ischemic heart disease and previous coronary artery bypass grafts was admitted having been found collapsed in the street. He was a smoker with a history of alcohol abuse. On clinical examination he was unkempt, febrile, hemodynamically stable, and had no systemic deficits. The O2 saturation on air was 99%, with a po2 of 9.2, and pco2 of 4.0. Ventilation perfusion (VQ) scan was performed to rule out a pulmonary embolism. While in the department he was noted to be dyspneic and generally unwell. The perfusion images showed reduced perfusion to both lower zones more marked on the right. The ventilation study was markedly abnormal on the initial views with no ventilation to the right lung. However, the patient had recurrent episodes of cough with expectoration of sputum before the anterior view was imaged, which subsequently demonstrated ventilation defects in the right mid and lower zones. A repeat ventilation sequence was performed which confirmed these findings in all views. Chest x-ray performed prior to the lung scan was normal.


Update on the clinical utility and optimal use of cefditoren.
This article reviews and updates published data on cefditoren. The in vitro activity of cefditoren and its potential pharmacokinetic/pharmacodynamic adequacy to cover emerging resistance phenotypes in the present decade is reviewed. Cefditoren's in vitro activity against most prevalent bacterial respiratory pathogens in the community and its pharmacokinetic/pharmacodynamic profile suggests a significant role for cefditoren in the treatment of respiratory tract infections. Clinical trials (in acute exacerbations of chronic bronchitis, community-acquired pneumonia, pharyngotonsillitis, and sinusitis) performed during clinical development outside Japan, mainly in adults, are reviewed, together with new clinical studies in the treatment of pharyngotonsillitis, sinusitis, and otitis media in children, mainly in Japan, for efficacy and safety assessment. The results of these studies support the adequacy of cefditoren for the treatment of community-acquired respiratory tract infections with a safety profile similar to previous oral antibiotics. From the data reviewed, it is concluded that cefditoren is an adequate option for the treatment of mild-to-moderate community-acquired respiratory infections, especially in geographical areas with a reported prevalence of phenotypes exhibiting nonsusceptibility to common oral antibiotics.


Effect of slope and footwear on running economy and kinematics.
Lower energy cost of running (Cr) has been reported when wearing minimal (MS) vs traditional shoes (TS) on level terrain, but the effect of slope on this difference is unknown. The aim of this study was to compare Cr, physiological, and kinematic variables from running in MS and TS on different slope conditions. Fourteen men (23.4 ± 4.4 years; 177.5 ± 5.2 cm; 69.5 ± 5.3 kg) ran 14 5-min trials in a randomized sequence at 10 km/h on a treadmill. Subjects ran once wearing MS and once wearing TS on seven slopes, from -8% to +8%. We found that Cr increased with slope gradient (P < 0.01) and was on average 1.3% lower in MS than TS (P < 0.01). However, slope did not influence the Cr difference between MS and TS. In MS, contact times were lower (P < 0.01), flight times (P = 0.01) and step frequencies (P = 0.02) were greater at most slope gradients, and plantar-foot angles - and often ankle plantar-flexion (P = 0.01) - were greater (P < 0.01). The 1.3% difference between footwear identified here most likely stemmed from the difference in shoe mass considering that the Cr difference was independent of slope gradient and that the between-footwear kinematic alterations with slope provided limited explanations.


Generation of a human iPSC line, INMi004-A, with a point mutation in CRX associated with autosomal dominant Leber congenital amaurosis.
The human induced pluripotent stem cell (iPSC) line, INMi004-A, was generated using dermal fibroblasts from a 6 year-old patient with autosomal dominant Leber Congenital Amaurosis (LCA) caused by the point mutation c.695delC (p.Pro232Argfs*139) in the CRX gene. We used non-integrative Sendai virus vectors containing the human OSKM transcription factor cocktail to reprogram patient fibroblasts. The generated iPSC line contained the congenital deletion c.695delC in exon 4 of CRX, had a normal karyotype, and was capable of differentiation into all three germ layers. This cell line represents an important tool to study the pathophysiology of CRX-associated LCA.


A simple FCM method to avoid misinterpretation in Saccharomyces cerevisiae cell cycle assessment between G0 and sub-G1.
Extensively developed for medical and clinical applications, flow cytometry is now being used for diverse applications in food microbiology. Most uses of flow cytometry for yeast cells are derived from methods for mammalian cells, but yeast cells can present specificities that must be taken into account for rigorous analysis of the data output to avoid any misinterpretation. We report an analysis of Saccharomyces cerevisiae cell cycle progression that highlights possible errors. The cell cycle was analyzed using an intercalating fluorochrome to assess cell DNA content. In analyses of yeast cultures, the presence of a sub-G1 peak in the fluorescent signal is often interpreted as a loss of DNA due to its fragmentation associated with apoptosis. However, the cell wall and its stucture may interfere with the fluorescent signal recorded. These observations indicate that misinterpretation of yeast DNA profiles is possible in analyses based on some of the most common probes: cells in G0 appeared to have a lower DNA content and may have been mistaken as a sub-G1 population. However, careful selection of the fluorochrome for DNA quantification allowed a direct discrimination between G0 and G1 yeast cell cycle steps, without additional labeling. We present and discuss results obtained with five current fluorochromes. These observations led us to recommend to use SYTOX Green for cycle analysis of living cells and SYBR Green I for the identification of the apoptosis sub-G1 population identification or the DNA ploidy application.


Molecular cloning and characterization of an NADPH quinone oxidoreductase from Kluyveromyces marxianus.
NAD(P)H quinone oxidoreductase is a ubiquitous enzyme that is known to directly reduce quinone substrates to hydroquinones by a two-electron reaction. We report the identification of NADPH quinone oxidoreductase from Kluyveromyces marxianus (KmQOR), which reduces quinone substrates directly to hydroquinones. The KmQOR gene was sequenced, expressed in Escherichia coli, purified, and characterized. The open-reading frame of the KmQOR gene consists of 1143 nucleotides, encoding a 380 amino acid polypeptide. The nucleotide sequence of the KmQOR gene was assigned to EMBL under accession number AY040868. The M(r) that was determined by SDS-PAGE for the protein subunit was about 42 kDa, and the molecular mass of the native KmQOR was 84 kDa, as determined by column calibration, indicating that the native protein is a homodimer. The KmQOR protein efficiently reduced 1,4-benzoquinone, whereas no activities were found for menadiones and methoxyquinones. These observations, and the result of an extended sequence analysis of known NADPH quinone oxidoreductase, suggest that KmQOR possesses a different action mechanism.


Docetaxel rechallenge in metastatic castration-resistant prostate cancer: any place in the modern treatment scenario? An intention to treat evaluation.
We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing.


TNF-alpha, soluble TNF receptor and interleukin-6 plasma levels in the general population.
The cytokines tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, and interleukin 6 (IL-6) are involved in host defense against several microbiological agents, in the process of inflammation and also in body weight regulation. In the present study, we sought to assess the influence of age, gender, smoking, and body mass index on plasma levels of TNF-alpha, TNF receptors, and IL-6 in more than 550 adult subjects randomly selected from the Bavarian population. None of the cytokine parameters had a normal distribution and all distributions were significantly skewed. The cytokine plasma levels investigated increased significantly with age, while gender had a relatively weaker influence on the plasma levels. Plasma levels of TNF-alpha, TNF receptors, and IL-6 correlated significantly with the BMI. The study provides insights into factors influencing the cytokine levels investigated in a randomly chosen study sample.


Nanovoid-Enhanced Thin-Film Composite Reverse Osmosis Membranes Using ZIF-67 Nanoparticles as a Sacrificial Template.
In this work, nanovoid-enhanced thin-film composite (TFC) membranes have been successfully fabricated using ZIF-67 nanoparticles as the sacrificial template. By incorporating different amounts of ZIF-67 during interfacial polymerization, the resultant TFC membranes can have different degrees of nanovoids after self-degradation of ZIF-67 in water, consequently influencing their physiochemical properties and separation performance. Nanovoid structures endow the membranes with additional passages for water molecules. Thus, all the newly developed TFC membranes exhibit better separation performance for brackish water reverse osmosis (BWRO) desalination than the pristine TFC membrane. The membrane made from 0.1 wt % ZIF-67 shows a water permeance of 2.94 LMH bar-1 and a salt rejection of 99.28% when being tested under BWRO at 20 bar. This water permeance is 53% higher than that of the pristine TFC membrane with the salt rejection well maintained.


Socioeconomic Condition and Anaemia among the Mahishya Population of Southern West Bengal, India.
A cross-sectional study was conducted among the Mahishya population of Chakpota village in Southern West Bengal to determine the relationship between socio-economic conditions and certain haematological parameters, haemoglobin level and haemotocrit. Households were divided into high, middle and low socioeconomic groups on the basis of per capita income per year. The demographic data were collected from all the 255 households comprising 404 adult males and 383 adult females (above 20 years of age). Higher values in the parameters were observed among the males in all the three socioeconomic sub-groups. Significant differences in haemoglobin level and haemotocrit of males were observed between the three socioeconomic groups (p= <.01). On the contrary, insignificant differences in haemoglobin level and haemocrit were observed between the three socioeconomic groups among the females. Higher nutritional intake and lower parasitic infections may be responsible for the higher levels of the haematological parameters in the higher socioeconomic groups. Our study reveals that sex discrimination in food sharing seems to be the major cause for the gender difference in haemoglobin status in all the three economic groups. It is apparent from the study that cultural factors play an important role in determining the haemoglobin status at micro-level, even in high-income households.


Mechanical Properties and Wear Susceptibility Determined by Nanoindentation Technique of Ti13Nb13Zr Titanium Alloy after "Direct Laser Writing".
Laser treatment has often been applied to rebuild the surface layer of titanium and its alloys destined for long-term implants. Such treatment has always been associated with forming melted and re-solidified thin surface layers. The process parameters of such laser treatment can be different, including the patterning of a surface by so-called direct writing. In this research, pulse laser treatment was performed on the Ti13Nb13Zr alloy surface, with the distance between adjacent laser paths ranging between 20 and 50 µm. The obtained periodic structures were tested to examine the effects of the scan distance on the microstructure using SEM, the roughness and chemical and phase composition using EDS and XRD, and the mechanical properties using the nanoindentation technique. After direct laser writing, the thickness of the melted layers was between 547 and 123 µm, and the surface roughness varied between 1.74 and 0.69 µm. An increase in hardness was observed after laser treatment. The highest hardness, 5.44 GPa, was obtained for the sample modified with a laser beam spacing of 50 µm. The value of the distance has been shown to be important for several properties and related to a complex microstructure of the thin surface layer close to and far from the laser path.


[Hyponatremia: diagnostic approach].
Hyponatremia is the most common electrolyte disorder in hospitalized patients and may be associated with non negligible morbidity and mortality. Here we summerize its diagnostic approach based on the physiopathology. Assessment of volume status, measurement of plasma and urinary osmolality remain key steps in the management of this electrolyte disorder.


Clinical treatment options for peristomal pyoderma gangrenosum.
Pyoderma gangrenosum is a rare debilitating skin disease of unknown aetiology that manifests itself as painful lesions and is often associated with inflammatory bowel disease. Stoma care nurses will encounter it directly around the stoma as peristomal pyoderma gangrenosum (PPG). There are many case reports of varying methods of treatment for PPG, although none have proven to be efficacious in all circumstances. When these lesions develop in the peristomal area, treatment must be balanced with the need to maintain an intact stoma appliance.


Ubiquitous p63 expression in human esophageal squamous cell carcinoma.
p63, a recently identified member of the p53 gene family, plays an important role in human tissue functions. We examined the pattern of p63 expression in human esophageal squamous cell carcinomas including early-stage cancers, and its clinicopathological significance. Immunoreactivity for p63 was detected in 96.9% (63/65) esophageal squamous cell carcinomas. Diffuse p63 expression was seen in 75.4% (49/65). p63 was detected not only in the in situ carcinomatous components or intramucosal carcinomas, but also in the invasive carcinomatous parts of the p63-positive cases. There were no significant correlations between p63 expression and clinicopathological features, such as depth of tumor invasion, tumor differentiation, lymph node metastasis and venous/lymphatic invasion. We also analyzed the relationship between p63 and p53 expression in esophageal squamous cell carcinomas. These results suggest that the p63 gene, as well as the p53 gene, play a major role in the carcinogenesis of human esophageal squamous cells and in the growth of the carcinoma.


[Immunocompromised HIV patient with lymphadenopathy and fever].
The case of a immunocompromised HIV patient with fever and lymphadenopathy discussed in an anatomo-pathological round. This complex clinical case was used as an opportunity to discuss the broad differential diagnosis of fever in an immunocompromized individual with multiples lymphadenopathies. Clinical reasoning leading to the probable diagnosis based on clinical, biological and radiological informations is not only a difficult task for the speaker but also a rich source of learning opportunities for our medical community.


Plasma exchange for primary autoimmune autonomic failure.
We report on a patient with long-standing severe autonomic failure that affected his sympathetic and parasympathetic nervous systems. Antibodies against the ganglionic acetylcholine receptors were detected in the serum. Removal of the antibodies by means of plasma exchange resulted in a dramatic clinical improvement.


Facile synthesis of phosphorus and nitrogen co-doped carbon dots with excellent fluorescence emission towards cellular imaging.
Fluorescent carbon nanomaterials have attracted increasing attention owing to their unique photoluminescence properties, good biocompatibility and low toxicity in bioimaging as well as biosensing. Heteroatom doping is usually used to improve photoluminescence properties by tuning the functional groups and the particle size domain effect, thus leading to redshifted emission. Here, we report a straightforward strategy for the fabrication of a mixture of fluorescent phosphorus and nitrogen carbon nanodots (P,N-CDs) followed by separating two kinds of fluorescent fractions based on their different negative charges. Such a one-pot hydrothermal method using formamide, urea and hydroxyethylidene diphosphonic acid as the precursor yields fluorescent P,N-CDs. Specifically, blue-emitting CDs (bCDs) and green-emitting CDs (gCDs) were separated by using column chromatography. The quantum yields of bCDs and gCDs were 20.33% and 1.92%, respectively. And the fluorescence lifetimes of bCDs and gCDs were 6.194 ns and 2.09 ns, respectively. What is more, the resultant P,N-CDs exhibited low toxicity and excellent biocompatibility. Confocal fluorescence microscopy images were obtained successfully, suggesting that P,N-CDs have excellent cell membrane permeability and cellular imaging. This work provides a promising fluorescent carbon nanomaterial with tunable emission as a probe for versatile applications in bioimaging, sensing and drug delivery.


Effect of treatment with human chorionic gonadotropin on day 5 after timed artificial insemination on fertility of lactating dairy cows.
Reproductive management programs that synchronize ovulation can ovulate a smaller than normal follicle, potentially resulting in inadequate progesterone (P4) concentrations after artificial insemination (AI). Ovulation of the dominant follicle of the first follicular wave with human chorionic gonadotropin (hCG) treatment can produce an accessory corpus luteum and increase circulating P4 concentrations. This manuscript reports the results of 2 separate analyses that evaluated the effect of hCG treatment post-AI on fertility in lactating dairy cows. The first study used meta-analysis to combine the results from 10 different published studies that used hCG treatment on d 4 to 9 post-AI in lactating dairy cows. Overall, pregnancies per artificial insemination (P/AI) were increased 3.0% by hCG treatment post-AI [34% (752/2,213) vs. 37% (808/2,184); Control vs. hCG-treated, respectively]. The second study was a field research trial in which lactating Holstein cows (n=2,979) from 6 commercial dairy herds were stratified by parity and breeding number and then randomly assigned to one of 2 groups: control (no further treatment, n=1,519) or hCG [Chorulon i.m.: 2,000 IU (in 3 of the herds) or 3,300 IU (in 3 herds); n=1,460] on d 5 after a timed AI (ovulation synchronized with Ovsynch, Presynch-Ovsynch, or Double-Ovsynch). In a subset of cows, the hCG profile and P4 changes were determined. Treatment with hCG increased P4 (4.3 vs. 5.3 ng/mL on d 12). Pregnancies per AI were greater in cows treated with hCG (40.8%; 596/1,460) than control (37.3%; 566/1,519) cows. Interestingly, an interaction among treatment and parity was observed; primiparous cows had greater P/AI after hCG (49.7%; 266/535) than controls (39.5%; 215/544). In contrast, older cows receiving hCG (35.7%; 330/925) had similar P/AI to controls (36.0%; 351/975).Thus, targeted use of hCG on d 5 after TAI enhances fertility about 3.0% (based on meta-analysis) to 3.5% (based on our field trial). Surprisingly, this fertility-enhancing effect of hCG was very large in first-lactation cows but not observed in older cows in the field study. Future research is needed to confirm these intriguing results and to determine why older cows did not have improved fertility after hCG treatment.


Definitions of intradialytic hypotension.
Intradialytic hypotension (IDH) is a common and often distressful complication of hemodialysis. However, despite its clinical significance, there is no consensus, evidence-based medical definition for the condition. Over the years, numerous definitions have been implemented in both the clinical and research settings. Definition inconsistencies have hindered data synthesis and the development of evidence-based guidelines for the prevention and treatment of IDH, as well as prevented accurate estimation of the population burden of IDH and patient risk assessment. Most existing IDH definitions are comprised of one or more of the following components: (1) intradialytic BP criteria (requisite BP declines or minimum BP thresholds), (2) the provision of interventions aimed at restoring effective arterial volume, and/or (3) patient-reported symptoms. Remarkably, there are insufficient data to inform IDH definition construction, and it remains unknown if a single, universal definition can adequately capture the condition across patient subgroups, and in clinical and research settings.


Periodontal pathogens are a risk factor of oral cavity squamous cell carcinoma, independent of tobacco and alcohol and human papillomavirus.
Over the past decade, there has been a change in the epidemiology of oral cavity squamous cell cancer (OC-SCC). Many new cases of OC-SCC lack the recognized risk factors of smoking, alcohol and human papilloma virus. The aim of this study was to determine if the oral microbiome may be associated with OC-SCC in nonsmoking HPV negative patients. We compared the oral microbiome of HPV-negative nonsmoker OC-SCC(n = 18), premalignant lesions(PML) (n = 8) and normal control patients (n = 12). Their oral microbiome was sampled by oral wash and defined by 16S rRNA gene sequencing. We report that the periodontal pathogens Fusobacterium, Prevotella, Alloprevotella were enriched while commensal Streptococcus depleted in OC-SCC. Based on the four genera plus a marker genus Veillonella for PML, we classified the oral microbiome into two types. Gene/pathway analysis revealed a progressive increase of genes encoding HSP90 and ligands for TLRs 1, 2 and 4 along the controls→PML → OC-SCC progression sequence. Our findings suggest an association between periodontal pathogens and OC-SCC in non smoking HPV negative patients.


Spontaneous adenocarcinomas of the ventral prostate of aged A X C rats.
Spontaneous adenocarcinomas of the ventral prostate were present in 7 of 41 aged (34- to 37-month-old), virgin, untreated male A X C rats. The only consistent gross evidence of possible neoplastic involvement was intraprostate hemorrhage. The principally intraglandular neoplasms were composed of markedly anaplastic epithelial cells which retained a moderate propensity to form glandular patterns. The nuclei of the neoplastic cells were pleomorphic, vesiculated, enlarged, and hyperchromatic. Mitotic figures were frequent. Interglandular connective tissue was invaded in one rat; however, metastases were not demonstrated.


Gelatin-glucosamine hydrochloride/crosslinked-cyclodextrin metal-organic frameworks@IBU composite hydrogel long-term sustained drug delivery system for osteoarthritis treatment.
Osteoarthritis (OA) is a disease of articular cartilage degradation and inflammation of the joint capsule. Combining anti-inflammatory therapy with nutritional supplement is an effective means for the treatment of OA. In this study, we prepared gelatin (Gel)-glucosamine hydrochloride (GH) mixed crosslinked-cyclodextrin metal-organic framework (G-GH/CL-CD-MOF) composite hydrogel. Polyethylene glycol diglycidyl ether was the crosslinking agent of GH and Gel to solve the problem of poor mechanical properties and water solubility at 37 °C. CL-CD-MOF was fabricated through a simple one-step chemical reaction to crosslink the hydrophilic hydroxyl groups in CD-MOF with diphenyl carbonate. Electron microscopy and x-ray diffraction analysis of CL-CD-MOF showed perfect porous morphology with a chaotic internal structure. CL-CD-MOF@IBU was prepared by immersing CL-CD-MOF in high-concentration ibuprofen (IBU) solution. CL-CD-MOF@IBU was uniformly dispersed in Gel and GH mixed solution to prepare G-GH/CL-CD-MOF@IBU composite hydrogel long-term sustained drug delivery system. The compression curve of G-GH/CL-CD-MOF composite hydrogel showed a non-linear elastic behavior. The cyclic loading-unloading compression showed that the shape of the G-GH/CL-CD-MOF composite hydrogel can be kept intact under 50% strain. On the day 14, the G-GH/CL-CD-MOF@IBU composite hydrogel was degraded by 87.1%, 61% of IBU was released. G-GH/CL-CD-MOF@IBU exhibited good biocompatibility during co-culture with MC3T3-E1 cells. Briefly, the certain mechanical properties, sustained drug release behavior, and good biocompatibility of G-GH/CL-CD-MOF@IBU composite hydrogel showed that it has potential application in OA treatment of long-term sustained nutritional supplement and anti-inflammatory synchronously.


Homelessness and mental illness in a professional- and peer-led cocaine treatment clinic.
The combined problems of substance abuse, mental illness, and homelessness among the urban poor represent a major public health issue. The study evaluated 340 patients attending a cocaine day treatment program that integrates peer leadership and professional supervision. Thirty-six percent of the sample had a major mental illness, and 39 percent were homeless. Sixty-nine percent achieved an acceptable final urine toxicology status, and the median number of program visits was 46. Homelessness, a longer history of cocaine use, and a diagnosis of schizophrenia were associated with positive treatment outcomes. The results support the feasibility of a cocaine abuse treatment model combining professional and peer leadership.


T-cell lymphocytosis associated with invasive thymomas.
Peripheral T-cell lymphocytosis and bone marrow infiltration is a rarely associated feature of invasive thymomas. Hypotheses for the origin of the circulating lymphocytes include a spillover of tumor lymphocytes into the circulation, a neoplastic lymphoid proliferation, and a reactive proliferation of peripheral lymphocytes resulting from a thymoma-induced immunoregulatory disorder. The authors describe two cases of peripheral T-cell lymphocytosis associated with invasive thymomas with a predominantly lymphocyte-rich, cortical type histologic appearance. In both cases T cells constituted as much as 99% of the circulating lymphoid cell population, according to flow-cytometric analysis before and after treatment, and expressed a mature phenotype consistent with medullary thymic or peripheral T cells (CD2+, CD3+, CD4+ or CD8+, CD5+, CD7+) with predominant expression of the alpha/beta T-cell receptor heterodimer. Bone marrow biopsy specimens showed nodular and interstitial infiltrates of small T cells. No monoclonal rearrangement of the T-cell receptor beta gene was observed. Both cases had a normal female karyotype. Our findings confirm those of previous studies supporting a reactive origin for the peripheral lymphocytosis. Although an immunoregulatory disorder is probably involved in lymphocyte proliferation in situ, we postulate that peripheral lymphocytosis results from augmented release of the more mature thymoma-associated lymphocytes into the circulation through tumor invasiveness. A thymic origin is supported by the presence of a subset of peripheral T cells with low-intensity CD5 expression.


[Changes of dendritic cells and its subsets in peripheral blood of patients with Mycobacterium tuberculosis].
To analyze the changes of dendritic cells and its subsets in peripheral blood of patients with mycobacterium tuberculosis, and to explore its immune mechanism. 32 patients with mycobacterium tuberculosis and 11 healthy controls were selected, who were diagnosed in our hospital from Nov. 2008 to Aug. 2009. The patients included 19 initial-treatment cases and 13 retreatment cases, and 19 lung tuberculosis patients with different sputum tests. Dendritic cells and its subsets in peripheral blood were detected by using flow cytometry. DC1 subset and Total DCs in experimental group were (0.28+/-0.13)%, (0.42+/-0.19)% respectively, which were significant lower than they were in control group (0.47+/-0.23)%, (0.65+/-0.22)% respectively (P<0.01); DC1 subset and Total DCs in sputum positive group were (0.16+/-0.04)%, (0.24+/-0.06)% respectively, which were significant lower than they were in sputum negative group(0.28+/-0.14)%, (0.43+/-0.12)% (P<0.05); There was no significance in Total DCs and its subsets between initial-treatment group and retreatment group (P>0.05). As its reflection of immune response to mycobacterium tuberculosis, DCs may be regarded as the indicator for screening reservoirs of MTB and evaluating anti-tuberculosis therapy.


Ambulatory care classification systems.
This article describes several methods of classifying resources used in ambulatory care into isoresource consumption groups. These methods are based on resources used by patients during a year, rather than on resources used in a single visit. Variables used to partition patient-year charges into isoresource consumption groups are age, race, number of health problems or major diagnostic categories addressed, number of medications or categories of medications prescribed, and indexes developed to reflect resources used by diagnostic categories during a patient-year. Confirmation in other settings of the findings of this study would have important implications for the design of prospective payment plans for ambulatory care.


Secondary plastic closure of gastroschisis is associated with a lower incidence of mechanical ventilation.
Nonsurgical closure after primary silo placement, secondary plastic closure (SPC), has been used as an alternative to secondary surgical closure (SSC) in gastroschisis. The benefits described were closure without formal surgical procedure, cosmetic aspect, and minimization of intra-abdominal pressures. This study compared requirements for mechanical ventilation and general anesthesia, nutritional care, and outcomes between SPC and SSC. We included patients with primary staged-silo reduction with a 1-year minimum follow-up. SPC was performed at bedside with sedation using a nonadherent dressing. SSC was performed in operating room under general anesthesia using standard surgical techniques. This retrospective study included 64 patients, 23 SPC and 41 SSC. The characteristics of the two groups were comparable. Mechanical ventilation was used for 15 SPC and 41 SSC (p=0.0001) with a comparable median duration (5.5 and 6.0 days, not significant [NS]). General anesthesia was required for 9 SPC and 41 SSC (p<0.0001). Complications included one SPC and six SSC with necrotizing enterocolitis, zero SPC and four SSC with intestinal atresia, two SPC and four SSC with small bowel obstruction, zero SPC and one SSC with abdominal compartment syndrome resulting in a short bowel syndrome (NS). Median duration of parenteral nutrition (30 and 27 days), time to first feeds (14 and 14 days), time at or above minimal enteral feeding (22 and 17 days), time to full feeds (31 and 28 days), length of stay (LOS) in neonatal intensive care unit (24 and 23.5 days) and overall hospital LOS (37 and 36 days) were not statistically different between SPC and SSC patients without complications, respectively. These data were comparable for SPC and SSC patients with complications. Five SPC and six SSC developed an umbilical hernia (NS); two patients in each group required a surgical repair (NS). Plastic closure of gastroschisis after primary silo reduction is simple, safe, reproducible, and associated with a significant lower incidence of mechanical ventilation. Nutritional management and length of hospital stay were similar to conventional surgical closure for patients. Plastic closure allows nonoperative management without general anesthesia at patient's bedside, in comparison with surgical closure that must be performed under general anesthesia in the operating room. Plastic closure does not appear to be associated with more umbilical hernias in this retrospective study.


[Biomarkers of acute hypoxia-reoxygenation injury to nercycites during laparoscopic resection of renal parenchyma].
Intraoperative occlusion of the renal artery during laparoscopic partial nephrectomy results in warm ischemia and nonspecific hypoxia-reoxygenation alteration of the renal parenchyma cells with a predominant injury to epitheliocytes of the proximal segments of the tubular nephron system. The onset and development of acute kidney injury (AKI) syndrome, which requires immediate correction, is due to the typical pathological process of cell injury. In this regard, the issue of timely diagnosis of AKI remains highly relevant. In patients at high risk of developing acute renal failure, detection of AKI biomarkers enables early diagnosis. In cases with hypoxia-reoxygenation mediated destruction of epithelial cells of tt. renales, related to warm ischemia, the quality of diagnosis is significantly improved if the standard work-up is supplemented by measurements of the concentration and/or activity of cystatin C, interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, liver fatty acid binding protein, N-acetyl --glucosaminidase, glutathione S-transferase -isoform, -glutamyl transpeptidase and lactate dehydrogenase. This article provides an overview of published evidence on the properties and diagnostic capabilities of biomarkers of warm ischemia related AKI.


Long-term follow-up of empirical treatment or prompt endoscopy for patients with persistent dyspeptic symptoms?
There are concerns about the safety and possible high costs of ongoing proton pump inhibitor therapy of empirical management strategies for patients with persistent dyspeptic symptoms. To compare the long-term results of two treatment strategies: empirical treatment followed by the Helicobacter pylori test and treat strategy (treat and test group) and prompt upper gastrointestinal endoscopy followed by directed medical treatment (endoscopy group). In this study we describe the long-term follow-up data from a previously published randomized clinical trial. At least 6 years after randomization all participating general practitioners and patients were asked to give information about medication use, diagnostic testing, symptoms and quality of life by questionnaire. Information about a total of 77 out of the 80 patients initially included (96%) was retrieved. Overall, 16 patients from the treat and test group (41%) underwent 18 diagnostic investigations. The 34 patients (100%) from the endoscopy group underwent 38 investigations (P < 0.01). The number of patients of the treat and test group and endoscopy group using acid inhibition therapy was 15 (38%) and 19 (56%), respectively (P = 0.14). There were also no differences in symptom prevalence and quality of life between the groups. Treat and test management for patients with dyspeptic symptoms is safe and does not lead to additional diagnostic testing or use of medication when compared to prompt endoscopy.


Vascular response to stress in health and disease.
The body's vasculature plays a critical role in the development of functional and structural alterations responsible for tissue and organ damage in laboratory animals and human subjects during illness and senescence, and in response to stress. Components of the vasculature, namely, major arteries such as the aorta, smaller arteries, arterioles, capillaries, post-capillary venules, and collecting central veins, all serve as conduits through which vital substrates are delivered to cellular masses and/or waste products are removed. A number of physical and neurohumoral agents known to be responsive to stress stimuli exert functional control over the vasculature. Both physical and emotional stress have been found to cause significant hemodynamic alterations. Large artery rigidity, for instance, develops rapidly following stress-induced activation of the autonomic nervous system. Associated with this process is increased release into the circulation of catecholamines and angiotensin-II. At the same time, insulin resistance develops, accompanied by nitric oxide release and changes in the immune system. The response of large arterial conduits to stress is characterized by increased pulse pressure, which in turn affects the endothelium of the arterial vessels responsible for determining total peripheral resistance. Microcirculation networks, where a large fraction of the blood volume is contained, are affected as well, and the blood in them is subject to redistribution into adjacent interstitial fluid compartments. Changes in endothelial permeability, secondary to variations in pulse pressure, can lead to interstitial edema and changes in the physicochemical properties of interstitial compartments. These changes give rise to alterations in the traffic of substrates and waste products between blood and cells. This sequence of events also takes place in the vasa vasorum microcirculation that nourishes large arteries, and likely contributes to remodeling of the vascular wall and to atherogenesis. The contribution of large artery rigidity to the morbidity and mortality associated with arterial hypertension, diabetes mellitus, heart failure, and terminal uremia, is relatively well established in human populations. In addition, it appears that aortic rigidity precedes the development of arterial hypertension in the spontaneously hypertensive rat (SHR) model, as well as in individuals with borderline hypertension. The fact that some of the functional and structural vascular alterations produced by stress are reversible reinforces the importance of developing behavioral techniques and pharmacologic agents that can successfully interrupt this pathological sequence of events.


Mechanisms of in vivo release of triamcinolone acetonide from PLGA microspheres.
Little is known about the underlying effects controlling in vitro-in vivo correlations (IVIVCs) for biodegradable controlled release microspheres. Most reports of IVIVCs that exist are empirical in nature, typically based on a mathematical relationship between in vitro and in vivo drug release, with the latter often estimated by deconvolution of pharmacokinetic data. In order to improve the ability of in vitro release tests to predict microsphere behavior in vivo and develop more meaningful IVIVCs, the in vivo release mechanisms need to be characterized. Here, two poly(lactic-co-glycolic acid) (PLGA) microsphere formulations encapsulating the model steroid triamcinolone acetonide (Tr-A) were implanted subcutaneously in rats by using a validated cage model, allowing for free fluid and cellular exchange and microsphere retrieval during release. Release kinetics, as well as mechanistic indicators of release such as hydrolysis and mass loss, was measured by direct analysis of the recovered microspheres. Release of Tr-A from both formulations was greatly accelerated in vivo compared to in vitro using agitated phosphate buffered saline +0.02% Tween 80 pH7.4, including rate of PLGA hydrolysis, mass loss and water uptake. Both microsphere formulations exhibited erosion-controlled release in vitro, indicated by similar polymer mass loss kinetics, but only one of the formulations (low molecular weight, free acid terminated) exhibited the same mechanism in vivo. The in vivo release of Tr-A from microspheres made of a higher molecular weight, ester end-capped PLGA displayed an osmotically induced/pore diffusion mechanism based on confocal micrographs of percolating pores in the polymer, not previously observed in vitro. This research indicates the need to fully understand the in vivo environment and how it causes drug release from biodegradable microspheres. This understanding can then be applied to develop in vitro release tests which better mimic this environment and cause drug release by the relevant mechanistic processes, ultimately leading to the development of mechanism based IVIVCs.


Minigene-like inhibition of protein synthesis mediated by hungry codons near the start codon.
Rare AGA or AGG codons close to the initiation codon inhibit protein synthesis by a tRNA-sequestering mechanism as toxic minigenes do. To further understand this mechanism, a parallel analysis of protein synthesis and peptidyl-tRNA accumulation was performed using both a set of lacZ constructs where AGAAGA codons were moved codon by codon from +2, +3 up to +7, +8 positions and a series of 3-8 codon minigenes containing AGAAGA codons before the stop codon. Beta-galactosidase synthesis from the AGAAGA lacZ constructs (in a Pth defective in vitro system without exogenous tRNA) diminished as the AGAAGA codons were closer to AUG codon. Likewise, beta-galactosidase expression from the reporter +7 AGA lacZ gene (plus tRNA, 0.25 microg/microl) waned as the AGAAGAUAA minigene shortened. Pth counteracted both the length-dependent minigene effect on the expression of beta-galactosidase from the +7 AGA lacZ reporter gene and the positional effect from the AGAAGA lacZ constructs. The +2, +3 AGAAGA lacZ construct and the shortest +2, +3 AGAAGAUAA minigene accumulated the highest percentage of peptidyl-tRNA(Arg4). These observations lead us to propose that hungry codons at early positions, albeit with less strength, inhibit protein synthesis by a minigene-like mechanism involving accumulation of peptidyl-tRNA.


Design of Protein Segments and Peptides for Binding to Protein Targets.
Recent years have witnessed a rise in methods for accurate prediction of structure and design of novel functional proteins. Design of functional protein fragments and peptides occupy a small, albeit unique, space within the general field of protein design. While the smaller size of these peptides allows for more exhaustive computational methods, flexibility in their structure and sparsity of data compared to proteins, as well as presence of noncanonical building blocks, add additional challenges to their design. This review summarizes the current advances in the design of protein fragments and peptides for binding to targets and discusses the challenges in the field, with an eye toward future directions.


Cytoplasmic expression of c-erb-B2 in endometrial carcinomas.
The aim of this study was to investigate the expression of c-erb-B2 in endometrial cancer with attention to both membranous and cytoplasmic staining, and to elucidate the significance of cytoplasmic signaling. c-erb-B2 reactivity was assessed by immunohistochemistry in 110 patients using a polyclonal antibody, and evaluated semiquantitatively according to the percentage of cells demonstrating membranous or diffuse cytoplasmic staining. Correlation was made with tumor stage, grade, myometrial invasion, histologic type, and disease outcome. c-erb-B2 overexpression, indicated by membranous and cytoplasmic staining of at least 10% of the tumor cells, was found in 47 (42.7%) cases. Cytoplasmic expression of c-erb-B2 was observed more frequently than membranous (69.1 vs. 5.5%). Synchronous cytoplasmic and membranous signaling was noticed in 7.9% of cases. Interestingly, patients with cytoplasmic c-erb-B2-positive tumors had a significantly shorter survival (p = 0.047). These results indicate that c-erb-B2 is a specific marker of endometrial cancer. It is also an independent prognostic indicator of poor outcome. Cytoplasmic staining is as important as membranous staining, and is also a specific finding.


[Strategies to ensure careers of young academics in plastic surgery - analysis of the current situation and future perspectives].
Recruitment problems in surgical disciplines have become an increasingly debated topic. On the one hand current career prospects appear to be less attractive than those were seen for the previous generation. On the other hand the demands for a so-called "work-life balance" have changed and the proportion of female students and colleagues in medicine has risen and will continue to increase. Although Plastic Surgery currently seems to be less affected by these problems than other surgical disciplines, securing a qualified supply of young academics in Plastic Surgery is a prerequisite for the further development of this discipline. The traditional model of mentoring is discussed and the role of coaching in a sense of helping the mentorees examine what they are doing in the light of their intentions and goals is reflected. The present article tries to analyze the current status of academic Plastic Surgery from the viewpoint of German university senior surgeons in academic plastic surgery, and aims to highlight the specific prospects for young academics against the backdrop of an often one-sided and superficial perception of this profession.


The cytotoxic activity of carfilzomib together with nelfinavir is superior to the bortezomib/nelfinavir combination in non-small cell lung carcinoma.
Chemotherapy resistance is still a major problem in the treatment of patients with non-small-cell-lung carcinoma (NSCLC), and novel concepts for the induction of cytotoxicity in NSCLC are highly warranted. Proteotoxicity, the induction of cytotoxicity by targeting the ubiquitin proteasome system, represents an appealing innovative strategy. The combination of the proteasome inhibitor bortezomib (BTZ) and the proteotoxic stress-inducing HIV drug nelfinavir (NFV) synergistically induces proteotoxicity and shows encouraging preclinical efficacy in NSCLC. The second-generation proteasome inhibitor carfilzomib (CFZ) is superior to BTZ and overcomes BTZ resistance in multiple myeloma patients. Here, we show that CFZ together with NFV is superior to the BTZ + NFV combination in inducing endoplasmic reticulum stress and proteotoxicity through the accumulation of excess proteasomal substrate protein in NSCLC in vitro and ex vivo. Interestingly, NFV increases the intracellular availability of CFZ through inhibition of CFZ export from NSCLC cells that express multidrug resistance (MDR) protein. Combining CFZ with NFV may therefore represent a future treatment option for NSCLC, which warrants further investigation.


Shifts in the diversity of root endophytic microorganisms across the life cycle of the ratooning rice Jiafuzhan.
The diversity of root endophytic microorganisms, which is closely related to plant life activities, is known to vary with the plant growth stage. This study on the ratooning rice Jiafuzhan explored the diversity of the root endophytic bacteria and fungi and their dynamics during the plant life cycle. By sequencing the 16S ribosomal ribonucleic acid (16S rRNA) and internal transcribed spacer (ITS) genes, 12,154 operational taxonomic units (OTUs) and 497 amplicon sequence variants (ASVs) were obtained, respectively. The root endophytic microorganisms of rice in the seedling, tillering, jointing, heading, and mature stages of the first crop and at 13, 25, and 60 days after regeneration (at the heading, full heading, and mature stages of the second crop, respectively) were analyzed using diversity and correlation analyses. There were significant differences in the α-diversity and β-diversity of root endophytic bacteria and fungi in the growth stage. Additionally, linear discriminant analysis (LDA) effect size (LEfSe) analysis revealed biomarker bacteria for each growth stage, but biomarker fungi did not exist in every stage. Moreover, the correlation analysis showed that the bacterial and fungal biomarkers interacted with each other. Furthermore, the nitrogen-fixing genus Bradyrhizobium existed in all growth stages. These findings indicate the pattern of root endophytic microorganisms of ratooning rice at different growth stages, and they provide new insights into the high yield of the second crop of ratooning rice (in light of the abundance of various bacteria and fungi).


Synthesis and pharmacological evaluation of some dual-acting amino-alcohol ester derivatives of flurbiprofen and 2-[1,1'-biphenyl-4-yl]acetic acid: a potential approach to reduce local gastrointestinal toxicity.
The search for safer non-steroidal anti-inflammatory drugs (NSAIDs) continues with the failure of anticipated 'ideal' anti-inflammatory agents, the coxibs, on long-term usage. Increased gastric motility and acidity due to the free carboxy group are involved in the etiology of gastric toxicity, common to conventional NSAIDs. Keeping this fact in mind, it was planned to modify some of the conventional NSAIDs to amino-alcohol ester derivatives, which satisfied the structural requirements for these compounds to possess anticholinergic activity in the intact form. Besides blocking the acidic carboxylic group, incorporation of anticholinergic acivity in these molecules was expected to reduce the gastric toxicity by decreasing gastric acid secretion and motility. Synthesis and pharmacological evaluation of six different N,N-disubstituted amino-ethyl ester derivatives, structurally resembling the amino-alcohol ester class of anticholinergic agents, each for [1,1'-biphenyl]-4-acetic acid (3) and flurbiprofen (10), have been reported as potential substitutes for these NSAIDs, with improved therapeutic profile. All the ester derivatives were found to have sufficient chemical stability in buffers (pH 2.0 and 7.4), ensuring them to be absorbed as intact moieties from the gastrointestinal tract. A significant reduction in ulcerogenic potency in comparison to the parent drugs with a slightly higher anti-inflammatory potency suggests that the majority of these candidates have an improved therapeutic profile over their parent drugs. Hence, a promising novel approach, different from the conventional prodrug concept, has been successfully worked out to overcome the local gastric toxicity, yielding therapeutically better compounds for long-term oral anti-inflammatory therapy.


Proteomics in antiphospholipid syndrome: a review.
The presence of antiphospholipid antibodies (aPL) has been closely related to the development of thrombosis and complications in pregnancy. However, not all patients with aPL will develop those clinical features. The exact pathogenic mechanisms leading to thrombosis and/or pregnancy morbidity are poorly understood. Currently, biomarkers which enable one to predict the prognosis of patients with positive aPL are not readily available. Current advances in genomics and proteomics provide the opportunity to discover novel biomarkers based on changes in concentration levels or post-translational modifications of proteins and peptides. These techniques are now being applied in various areas of medicine with very promising results. This review covers recent studies that have used this approach for a better understanding of the pathogenic mechanisms involved in the development of thrombosis in patients with antiphospholipid syndrome (APS). Although, there are very few qualified biomarkers that have arisen as a result of efforts in proteomics, it is expected that these techniques will deliver biomarkers that might ultimately identify different subgroups of APS patients with various prognoses that might have implications with respect to management and prognosis.


The presence of kynurenine aminotransferases in the human cornea: Evidence from bioinformatics analysis of gene expression and immunohistochemical staining.
Kynurenine aminotransferases (KATs) catalyze the synthesis of kynurenic acid (KYNA), a compound of significant biological activity. The aim of this study is to investigate the presence and distribution of KAT immunoreactivity in the healthy human cornea. Data on gene expression in human eye structures were extracted from public microarray experiments using Genevestigator software. Immunohistochemistry was conducted using polyclonal antibodies against KAT I, II, and III on sections of eight enucleated eyes from patients with choroidal melanoma. Bioinformatics analysis showed that all four KAT isoforms were actively transcribed in the cornea and the conjunctiva. Immunohistochemical analysis revealed the presence of KAT I, II, and III in all examined corneal sections. The corneal endothelium showed the strongest reactivity for all three KAT isoforms. There was a slight positive staining of the corneal stroma for KAT I and II. KAT III immunoreactivity was found only in the stroma of the limbal region. In the corneal epithelium, the expression of all three KAT isoforms showed a specific pattern of the stain with fine squatter granules throughout the cytoplasm. This reactivity was more pronounced in the basal cell layers. The intermediate cell layers showed only faint immunoreactivity, and occasionally, there was no staining. KAT I, II, and III were also present in the adjacent limbal conjunctiva. The results indicate that kynurenine can be metabolized to KYNA in the corneal epithelium, stroma, and endothelium.


Neuroimmune interactions and pain: focus on glial-modulating targets.
Chronic pain is the most difficult type of pain to treat. Previously, the development of analgesics has focused on neuronal targets; however, current analgesics are only modestly effective, have significant side effects and do not provide universal efficacy. New strategies are needed for the development of more effective analgesics. Glial cells have integral roles in CNS homeostasis, and chronic pain etiology and progression. In this review, the role of glia in neuropathic pain and opioid administration is described, as well as the potential superior efficacy and wider therapeutic indices provided by drugs that modulate specific glial function via novel targets.


Diverging trends in the incidence of occupational and nonoccupational injury in Ontario, 2004-2011.
We describe trends in occupational and nonoccupational injury among working-age adults in Ontario. We conducted an observational study of adults aged 15 to 64 over the period 2004 through 2011, estimating the incidence of occupational and nonoccupational injury from emergency department (ED) records and, separately, from survey responses to 5 waves of a national health interview survey. Over the observation period, the annual percentage change (APC) in the incidence of work-related injury was -5.9% (95% confidence interval [CI] = -7.3, -4.6) in ED records and -7.4% (95% CI=-11.1, -3.5) among survey participants. In contrast, the APC in the incidence of nonoccupational injury was -0.3% (95% CI=-0.4, 0.0) in ED records and 1.0% (95% CI=0.4, 1.6) among survey participants. Among working-age adults, the percentage of all injuries attributed to work exposures declined from 20.0% in 2004 to 15.2% in 2011 in ED records and from 27.7% in 2001 to 16.9% in 2010 among survey participants. Among working-age adults in Ontario, nearly all of the observed decline in injury incidence over the period 2004 through 2011 is attributed to reductions in occupational injury.


Itraconazole in the treatment of two young brothers with chronic mucocutaneous candidiasis.
We report on two children affected by chronic mucocutaneous candidiasis involving the mouth and all the nails who were successfully treated with itraconazole at 200 mg/day for 2 months. This therapy produced a rapid cure of both candidal nail and mouth infections. The drug was very well tolerated, and routine laboratory monitoring during treatment did not reveal any abnormalities.


Prevalence of hepatitis C virus (HCV) infection in Mumbai.
A study was carried out to determine the prevalence of Hepatitis C virus (HCV) in Mumbai among certain high risk groups such as renal transplant recipients, multitransfused and haemodialysis patients; professional and voluntary blood donors and viral hepatitis cases for comparison. Repeated testing of 602 subjects for antibodies to HCV using a second generation ELISA assay (Abbott, USA) showed an overall prevalence of 16.9%. We found 36.4% of multitransfused patients, 27.8% of renal failure cases and 26.2% of renal transplant recipients to be seropositive. Voluntary blood donors in our series showed a surprisingly high prevalence of 15.9%, and this group needs further investigation. Fifty-six of these sera (of which 45 were anti-HCV positive) were tested for HCV RNA by PCR and 14(31.1%) of the seropositive samples were also HCV RNA positive. The present investigation not only shows a high prevalence of HCV in the study groups but also proves the presence of HCV genomes in a significant proportion.


Discontinuation, suboptimal adherence, and reinitiation of oral HIV pre-exposure prophylaxis: a global systematic review and meta-analysis.
Poor adherence to oral HIV pre-exposure prophylaxis (PrEP) diminishes its clinical and public health benefits. This study synthesises evidence regarding discontinuation, adherence, and reinitiation of PrEP among geographically diverse PrEP users. We did a systematic review and meta-analysis evaluating studies published in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to Dec 18, 2020. We included longitudinal studies that presented data for PrEP discontinuation, defined as investigator-reported loss to follow-up or participant self-reported PrEP stoppage. Data were extracted from published reports and assessed for risk of bias. We used a random-effects meta-analysis to pool estimates of discontinuation and I2 and τ2 to evaluate heterogeneity. This study is registered with PROSPERO, CRD42020155675. We identified 4129 records, of which 59 articles were included (n=43 917 participants). 41·0% (95% CI 18·8-63·5) of participants discontinued PrEP within 6 months, with the highest rates in observational studies. The discontinuation rate in sub-Saharan Africa (47·5%, 95% CI: 29·4-66·4%) was higher than in other regions (p<0·001). Discontinuation rates were lower in studies with adherence interventions than in those without (24·7% vs 36·7%, p=0·015). Gay or bisexual men who have sex with men and transgender women offered daily or non-daily dosing options had lower discontinuation rates than those offered daily dosing alone (21·6% vs 31·5%; p<0·001). The pooled suboptimal adherence within 6 months was 37·7% (95% CI 8·4-66·9). Among people who discontinued PrEP, 47·3% (95% CI 31·5-63·2) reinitiated PrEP within 1 year of PrEP initiation. The included studies had poor quality in terms of study design, with a moderate risk of bias. Strategies to encourage reinitiating PrEP for new or persistent risk should be a focus of future PrEP implementation strategies. National Institutes of Health and Nature Science Foundation of China.


Ionic basis of tonic firing in spinal substantia gelatinosa neurons of rat.
Ionic conductances underlying excitability in tonically firing neurons (TFNs) from substantia gelatinosa (SG) were studied by the patch-clamp method in rat spinal cord slices. Ca(2+)-dependent K(+) (K(CA)) conductance sensitive to apamin was found to prolong the interspike intervals and stabilize firing evoked by a sustained membrane depolarization. Suppression of Ca(2+) and K(CA) currents, however, did not abolish the basic pattern of tonic firing, indicating that it was generated by voltage-gated Na(+) and K(+) currents. Na(+) and K(+) channels were further analyzed in somatic nucleated patches. Na(+) channels exhibited fast activation and inactivation kinetics and followed two-exponential time course of recovery from inactivation. The major K(+) current was carried through tetraethylammonium (TEA)-sensitive rapidly activating delayed-rectifier (K(DR)) channels with a slow inactivation. The TEA-insensitive transient A-type K(+) (K(A)) current was very small in patches and was strongly inactivated at resting potential. Block of K(DR) rather than K(A) conductance by 1 mM TEA lowered the frequency and stability of firing. Intracellular staining with biocytin revealed at least three morphological groups of TFNs. Finally, on the basis of present data, we created a model of TFN and showed that Na(+) and K(DR) currents are sufficient to generate a basic pattern of tonic firing. It is concluded that the balanced contribution of all ionic conductances described here is important for generation and modulation of tonic firing in SG neurons.


Levels of myosin heavy chain mRNA transcripts and protein isoforms in the fast extensor digitorum longus muscle of 7-month-old rats with chronic thyroid status alterations.
We have studied the effect of chronic thyroid status alterations on the myosin heavy chain (MyHC) isoform composition (by SDS-PAGE) and on MyHC mRNA levels (by RT-PCR) in the fast extensor digitorum longus (EDL) muscle of 7-month-old inbred Lewis strain female rats and compared this with corresponding results of the previously studied slow soleus muscle. Our findings show that in the EDL muscle, all four types 1, 2a, 2x/d and 2b of MyHC mRNA transcripts and protein isoforms are present in euthyroid, hypothyroid and hyperthyroid rats, i.e. after chronic treatment with methimazole and T(3), respectively. This is in contrast with the soleus, where only MyHC1 and 2a protein isoforms are expressed under similar conditions. Except for 2x/d MyHC mRNA transcripts in the EDL muscles, there was always significant difference between hypothyroid and hyperthyroid rats both at mRNA and protein levels. From our results we can conclude that extended alteration of the thyroid status leads to typical changes in the expression of MyHC mRNA transcripts and MyHC protein isoforms in the fast EDL and the slow soleus muscles. These changes correspond to those described after shorter periods of altered thyroid status. The characteristic phenotype differences between soleus and EDL muscles remain, however, preserved even after 7 months of thyroid hormone status alteration.


Incidence and aetiology of renal phosphate loss in patients with hypophosphatemia in the intensive care unit.
Hypophosphatemia is a common finding in patients in the intensive care unit (ICU). Its cause is often poorly understood. The aim of this study was to understand the incidence of renal phosphate loss in ICU-related hypophosphatemia, and to examine the role of phosphaturic hormones in its etiology. Plasma phosphate levels were measured on day 1, 3, 5 and 7 in 290 consecutive patients admitted to the ICU. Renal phosphate handling and phosphaturic hormones were studied in a subset of patients with phosphate levels <0.6 mmol/L. Renal phosphate loss was defined as a TmP/gfr < 0.6 mmol/L. Hypophosphatemia developed in 24% of all patients. This mainly occurred within the first 3 days of stay and in patients with serum creatinine levels <150 μmol/L. Renal phosphate loss was present in 80% of patients who developed hypophosphatemia, and was not related to serum levels of parathyroid hormone (PTH), PTH-related protein (PTH-rp), fibroblast growth factor 23 (FGF-23), or calcitonin. Hypophosphatemia in the ICU is commonly associated with renal phosphate loss. It mainly occurs within the first 3 days of admission, in particular in patients with preserved renal function. Renal phosphate loss is not explained by elevated PTH, PTH-rp, FGF-23 or calcitonin levels.


Perceptual Accuracy for Sexual Rejection in Romantic Relationships.
In the current research, we investigated perceptual accuracy in romantic partners' detection of sexual rejection. In two daily diary studies of predominantly cisgender heterosexual couples, we examined patterns of accuracy and bias concerning both the degree of sexual disinterest (Study 1; N = 98 couples) and occurrence of sexual rejection (Study 2; N = 115 couples), as well as how these perceptions were associated with satisfaction. Using a multi-method approach to capture both continuous and categorical operationalizations of sexual rejection (Study 1: truth and bias; Study 2: quasi-signal detection), we found that people were both accurate and biased in their perceptions of partner rejection. Across studies, results showed that people demonstrated general tracking accuracy in detecting a partner's sexual rejection, but they also overestimated the degree and occurrence of this rejection. Additionally, this overestimation bias was associated with lower daily relationship and sexual satisfaction. Overall, our findings highlight the importance of dyadic perceptions of sexual rejection in shaping daily relationship and sexual functioning.


Pentagalloylglucose Inhibits the Replication of Rabies Virus via Mediation of the miR-455/SOCS3/STAT3/IL-6 Pathway.
Our previous study showed that pentagalloylglucose (PGG), a naturally occurring hydrolyzable phenolic tannin, possesses significant anti-rabies virus (RABV) activity. In BHK-21 cells, RABV induced the overactivation of signal transducer and activator of transcription 3 (STAT3) by suppressing the expression of suppressor of cytokine signaling 3 (SOCS3). Inhibition of STAT3 by niclosamide, small interfering RNA, or exogenous expression of SOCS3 all significantly suppressed the replication of RABV. Additionally, RABV-induced upregulation of microRNA 455-5p (miR-455-5p) downregulated SOCS3 by directly binding to the 3' untranslated region (UTR) of SOCS3. Importantly, PGG effectively reversed the expression of miR-455-5p and its following SOCS3/STAT3 signaling pathway. Finally, activated STAT3 elicited the expression of interleukin-6 (IL-6), thereby contributing to RABV-associated encephalomyelitis; however, PGG restored the level of IL-6 in vitro and in vivo in a SOCS3/STAT3-dependent manner. Altogether, these data identify a new miR-455-5p/SOCS3/STAT3 signaling pathway that contributes to viral replication and IL-6 production in RABV-infected cells, with PGG exerting its antiviral effect by inhibiting the production of miR-455-5p and the activation of STAT3.IMPORTANCE Rabies virus causes lethal encephalitis in mammals and poses a serious public health threat in many parts of the world. Numerous strategies have been explored to combat rabies; however, their efficacy has always been unsatisfactory. We previously reported a new drug, PGG, which possesses a potent inhibitory activity on RABV replication. Herein, we describe the underlying mechanisms by which PGG exerts its anti-RABV activity. Our results show that RABV induces overactivation of STAT3 in BHK-21 cells, which facilitates viral replication. Importantly, PGG effectively inhibits the activity of STAT3 by disrupting the expression of miR-455-5p and increases the level of SOCS3 by directly targeting the 3' UTR of SOCS3. Furthermore, the downregulated STAT3 inhibits the production of IL-6, thereby contributing to a reduction in the inflammatory response in vivo Our study indicates that PGG effectively inhibits the replication of RABV by the miR-455-5p/SOCS3/STAT3/IL-6-dependent pathway.


Total and free iodothyronine changes in response to transport of Equidae (Equus asinus and Equus caballus).
In this study the effects of short distance road transport on total and free iodothyronine changes in 12 stallions (Equus asinus and Equus caballus) were evaluated. Donkeys (n = 6) and horses (n = 6) were transported for a distance of 50 km. Blood samples were collected 1 week before transport in basal conditions, 1 week later immediately before loading, and after transport and unloading. After transport, donkeys showed significant increases in circulating T4 (P≤0.01), fT3 (P≤0.001), and fT4 (P≤0.01) levels; while horses had significant increases in circulating T3, fT3 and fT4 (P≤0.01) levels. Compared to donkeys' values, horses showed lower T4 values in basal condition, before and after transport (P≤0.001); higher fT3 values in basal condition and before (P≤0.001), and lower values (P≤0.001) after transport; higher fT4 values (P≤0.001) in basal condition. The results indicate that short road transport of donkeys and horses induces the activation of the thyroid gland, with the same release of fT3 and fT4 iodothyronines, but with different preferential release of T3 in horses and T4 in donkeys after transport.


From the archives of the AFIP. Musculoskeletal malignant fibrous histiocytoma: radiologic-pathologic correlation.
Malignant fibrous histiocytoma (MFH) is a pleomorphic sarcoma, occurring most frequently in the deep soft tissues of the extremities. Primary osseous MFH is less common. MFH is the most common soft-tissue sarcoma of late adult life. Although its imaging appearance is often nonspecific, any deep-seated invasive intramuscular mass in a patient over 50 years of age is most likely an MFH. Cortical involvement by soft-tissue MFH is common, and identification of this finding increases the likelihood of MFH. Prominent fluid components with peripheral nodular enhancement after contrast material administration and lack of adipose elements are suggestive of a specific histologic subtype, myxoid MFH. Osseous MFH shows aggressive bone destruction with cortical involvement and a soft-tissue mass and is located in the diaphysis or metaepiphysis. Lesions in the metaepiphysis may have a less aggressive appearance and do not extend to subchondral bone. Computed tomography and magnetic resonance imaging are vital for preoperative staging and surgical planning and in detecting early recurrence postoperatively.


Genomic cluster and network analysis for predictive screening for hepatotoxicity.
The present study was undertaken to estimate the usefulness of genomic approaches to predict hepatotoxicity. Male rats were treated with acetaminophen (APAP), carbon tetrachloride (CCL), amiodarone (AD) or tetracycline (TC) at toxic doses. Their livers were extracted 6 or 24 hr after the dosings and were used for subsequent examinations. At 6 hr there were no histological changes noted in any of the groups except for the CCL group, but at 24 hr, such changes were noted in all but the AD group. Regarding genomic analysis, we performed hierarchical cluster analysis using S-plus software. The individual microarray data were clearly classified into 5 treatment-related clusters at 24 hr as well as at 6 hr, even though no morphological changes were noted at 6 hr. In the gene expression analysis using GeneSpring, transcription factor and oxidative stress- and lipid metabolism-related genes were markedly affected in all treatment groups at both time points when compared with the corresponding control values. Finally, we investigated gene networks in the above-affected genes by using Ingenuity Pathway Analysis software. Down-regulation of lipid metabolism-related genes regulated by SREBP1 was observed in all treatment groups at both time points, and up-regulation of oxidative stress-related genes regulated by Nrf2 was observed in the APAP and CCL treatment groups. From the above findings, for the application of genomic approaches to predict hepatotoxicity, we considered that cluster analysis for classification and early prediction of hepatotoxicity and network analysis for investigation of toxicological biomarkers would be useful.


Statistical consulting in clinical research: the two-way street.
Clinical research often rests on statistical interpretation of numerical data. Thus, effective collaboration between clinician and statistician can have central importance. Interaction in the planning phases of a project can identify tractable scientific and statistical problems that will need attention and can help avoid intractable ones. The central need is for clear, broad, specific two-way communication on scientific issues and research roles.


An assessment of equity in the distribution of non-financial health care inputs across public primary health care facilities in Tanzania.
There is limited evidence on how health care inputs are distributed from the sub-national level down to health facilities and their potential influence on promoting health equity. To address this gap, this paper assesses equity in the distribution of health care inputs across public primary health facilities at the district level in Tanzania. This is a quantitative assessment of equity in the distribution of health care inputs (staff, drugs, medical supplies and equipment) from district to facility level. The study was carried out in three districts (Kinondoni, Singida Rural and Manyoni district) in Tanzania. These districts were selected because they were implementing primary care reforms. We administered 729 exit surveys with patients seeking out-patient care; and health facility surveys at 69 facilities in early 2014. A total of seventeen indices of input availability were constructed with the collected data. The distribution of inputs was considered in relation to (i) the wealth of patients accessing the facilities, which was taken as a proxy for the wealth of the population in the catchment area; and (ii) facility distance from the district headquarters. We assessed equity in the distribution of inputs through the use of equity ratios, concentration indices and curves. We found a significant pro-rich distribution of clinical staff and nurses per 1000 population. Facilities with the poorest patients (most remote facilities) have fewer staff per 1000 population than those with the least poor patients (least remote facilities): 0.6 staff per 1000 among the poorest, compared to 0.9 among the least poor; 0.7 staff per 1000 among the most remote facilities compared to 0.9 among the least remote. The negative concentration index for support staff suggests a pro-poor distribution of this cadre but the 45 degree dominated the concentration curve. The distribution of vaccines, antibiotics, anti-diarrhoeal, anti-malarials and medical supplies was approximately proportional (non dominance), whereas the distribution of oxytocics, anti-retroviral therapy (ART) and anti-hypertensive drugs was pro-rich, with the 45 degree line dominating the concentration curve for ART. This study has shown there are inequities in the distribution of health care inputs across public primary care facilities. This highlights the need to ensure a better coordinated and equitable distribution of inputs through regular monitoring of the availability of health care inputs and strengthening of reporting systems.


Nonparametric methods for analysing the accuracy of diagnostic tests with multiple readers.
The evaluation of diagnostic agents or imaging procedures is governed by the same scientific and regulatory rules as that of other medical products. Receiver operating characteristic (ROC) curves, and especially the area under these ROC curves, are indices for the accuracy of a diagnostic test for continuous as well as ordinal data. The methodology of multivariate rank statistics for the nonparametric Behrens-Fisher problem is used to evaluate the accuracy of a diagnostic test in a complex factorial design with repeated measurements. Hypotheses are formulated by means of relative treatment effects and are tested by a multivariate extension of the Mann-Whitney statistic in a heteroscedastic model. The application of this method is demonstrated by the analysis of a data set from a diagnostic clinical trial.