Exercise training in patients after heart transplantation.
The post-cardiac transplantation patient is frequently debilitated as a result of "end-stage" heart disease and typically demonstrates muscle wasting, with a reduced work capacity, maximum heart rate and peak oxygen uptake. At submaximal effort perceived exertion and ventilation are higher, and the absolute ventilatory threshold lower, than in normals. A number of published studies have now shown that an exercise rehabilitation programme can induce a good training effect, although possibly not complete restoration of physiological function. The prescription of exercise must take into account the denervated heart's peculiar response to effort, and rely more on perceived exertion and metabolic measurements for defining intensity of training rather than target training heart rates. Changes in mood and personality have also been noted in these patients, and while these may improve spontaneously with the passage of time, there is some evidence that a rehabilitation programme can help in this regard.


[Carotid surgery, indications, results and perspectives].
A series of 215 patients who had undergone 250 carotid artery operations were followed up for a mean of 30 months. Perioperative mortality was 2%, neurologic morbidity was 7% but with permanent sequelae in 1.39% of cases. Recurrence of stenosis was detected in 0.8% of patients but there were no cases of postoperative thrombosis. Indications for surgery were based on the existence of hemispheric ischemic accidents corresponding to the territory supplied by the artery operated upon, and on anatomic and evolutive arguments drawn from results of non-invasive review examinations: ultrasonography and Doppler. Results obtained: 81.9% of patients were asymptomatic after 30 months, appear to be superior to those of the natural history of carotid artery lesions.


A comparative study on the u.v. resistance of double-stranded and single-stranded encephalomyocarditis virus RNAs: evaluation of the possible contribution of host-mediated repair.
To reveal previously suggested host-mediated repair of u.v.-induced lesions in dsRNA of encephalomyocarditis (EMC) virus, two sets of experiments have been carried out: (i) samples of dsRNA of EMC virus were irradiated with different doses of u.v. light and their infectivity was assayed in krebs II cells, before and after conversion of dsRNA into a ss form: (ii) samples of ssRNA of EMS virus were similarly irradiated and their infectivity was assayed before and after conversion of ssRNA into a ds form. No evidence for a significant host-mediated repair of dsRNA in this virus-cell system has been obtained.


Chemoradiotherapy with a radiation boost for anal cancer decreases the risk for salvage abdominoperineal resection: analysis from the national cancer data base.
Chemoradiotherapy (CRT), the primary treatment for anal cancer, achieves complete tumor regression in most patients. Abdominoperineal resection (APR) is reserved for persistent or recurrent disease. An additional boost dose of radiation after CRT often is used to improve the response rate for advanced local disease (T3, 4, and N+). This study examines the need for salvage APR after radiation boost. Patients with de novo anal cancer in the National Cancer Data Base from the years 2004-2010 were analyzed. Patients with missing data points or who did not receive standard CRT were excluded. Variables included age, gender, race, primary tumor size, clinical nodal status, TNM stage, radiation boost, and APR. A logistic regression model assessing the relationship between boost radiation and APR was developed. Of 1,025 patients meeting inclusion criteria, 450 patients received CRT without a radiation boost and 575 patients received CRT with a radiation boost. The two groups were similar in age, gender, race, tumor size, nodal status, and TNM stage (p values all >0.05). Significant multivariate predictors of salvage APR were tumor size, negative nodal status, and boost RT (all p < 0.05), whereas gender, age, race, and TNM stage were not significant (all p > 0.05). When controlling for age, tumor size, and nodal status, salvage APR is less likely to occur after boost RT (odds ratio 0.63; 95 % confidence interval 0.47, 0.85; p = 0.003). When controlling for age, tumor size, and nodal status, those who received boost radiation for anal cancer were less likely to require salvage APR.


Cone beam computed tomography in veterinary dentistry.
The purpose of this study was to assess the feasibility of cone beam computed tomography (CBCT) in imaging dogs and cats for diagnostic dental veterinary applications. CBCT scans of heads of six dogs and two cats were made. Dental panoramic and multi-planar reformatted (MPR) para-sagittal reconstructions were created using specialized software. Image quality and visibility of anatomical landmarks were subjectively assessed by two observers. Good image quality was obtained for the MPR para-sagittal reconstructions through multiple teeth. The image quality of the panoramic reconstructions of dogs was moderate while the panoramic reconstructions of cats were poor since the images were associated with an increased noise level. Segmental panoramic reconstructions of the mouth seem to be useful for studying the dental anatomy especially in dogs. The results of this study using human dental CBCT technology demonstrate the potential of this scanning technology in veterinary medicine. Unfortunately, the moderate image quality obtained with the CBCT technique reported here seems to be inferior to the diagnostic image quality obtained from 2-dimensional dental radiographs. Further research is required to optimize scanning and reconstruction protocols for veterinary applications.


OTX1 and OTX2 as possible molecular markers of sinonasal carcinomas and olfactory neuroblastomas.
OTX Homeobox genes are involved in embryonic morphogenesis and in the development of olfactory epithelium in adult. Mutations occurring in the OTX genes are reported to be associated to tumorigenisis in human. No reports correlate the expression of OTX genes and neoplasms of the nasal cavity. Thus, through immunohistochemical and Real-time PCR analysis we investigated OTX1 and OTX2 expression in the more frequent types of nasal and sinonasal tumours. Variable expression of both genes were found in normal sinonasal mucosa and in tumours. Interestingly, no expression of both OTX genes were detected in sinonasal intestinal-type adenocarcinomas; only OTX1 was found in non-intestinal-type adenocarcinomas and OTX2 was selectively expressed in olfactory neuroblastomas. In conclusion, OTX1 and OTX2 genes might have a role in the pathogenesis of different types of sinonasal neoplasms.


Head and Neck Acinic Cell Carcinoma: A New Grading System Proposal and Diagnostic Utility of NR4A3 Immunohistochemistry.
Acinic cell carcinoma (AciCC) is traditionally considered as a low-grade salivary gland carcinoma. However, a subset demonstrates high-grade features with a higher mortality rate and distant metastasis. In this large retrospective study of 117 cases, we aimed to establish a histologic grading scheme for AciCC. Adverse independent prognostic factors identified on the multivariate analysis included older age, tumor necrosis, nuclear anaplasia, lymphovascular invasion, absence of tumor-associated lymphoid stroma, and high American Joint Committee on Cancer (AJCC) pT and pN stages. A 3-tiered grading scheme using 4 pathologic parameters (mitotic index, necrosis, tumor border, and fibrosis at the frankly invasive front) was subsequently applied. Compared with low/intermediate-grade, high-grade AciCC defined as a mitotic index ≥5/10 HPFs and/or necrosis was an independently adverse prognostic factor. The 5-year overall survival was 50% in high-grade AciCCs, and 100% in low-grade or intermediate-grade AciCCs. Compared with low-grade or intermediate-grade AciCC, high-grade tumors were associated with older age, larger tumor size, focal rather than diffuse zymogen granules, solid architecture, infiltrative tumor border, fibrosis at the frankly invasive front, lymphovascular invasion, perineural invasion, positive margin, high pT, and pN stages. NR4A3 was a highly sensitive and specific immunohistochemical stain for diagnosing AciCC with a sensitivity and specificity of 96% and 93%, respectively. In conclusion, although we proposed a 2-tiered grading system for AciCC with high-grade tumors defined by a mitotic count ≥5/10 HPFs and/or necrosis, more studies are needed to assess the prognostic value of intermediate grade. NR4A3 immunohistochemical stain is a useful diagnostic marker for AciCC.


Friend or Foe? Venoarterial ECMO via Carotid Artery "Jump Graft": A Case Series.
Extracorporeal life support is used in adult and pediatric patients for refractory cardiac and respiratory failure. The great arteries and veins of the neck and groin are often used for cannulation to extracorporeal membrane oxygenation (ECMO). Newer cannulation techniques use the subclavian or axillary arteries, in addition to synthetic grafts anastomosed in end-to-side fashion, from which the cannula is positioned. These newer techniques can prevent need for ligation and sacrifice of important major vessels that is often undertaken in "traditional" direct surgical cannulation strategies. To our knowledge this graft technique has not been performed in pediatric ECMO patients. We describe a case series of nine patients from 2012 to 2017 supported with venoarterial (V-A) ECMO utilizing a synthetic Gore-Tex® "jump graft" sewn in an end-to-side fashion to the right carotid artery, for the arterial cannula insertion. Each patient's hospital course was reviewed with particular consideration given to disease process, site of cannulation, neurologic examination abnormalities noted during ECMO, computed tomography (CT) or magnetic resonance imaging (MRI) evidence of intracranial hemorrhage, and outcomes. Eight of nine patients were successfully cannulated utilizing this technique without neurologic complication. One suffered catastrophic intracerebral hemorrhage. This series is limited by small sample size and single center experience. Further work is needed to determine the advantages and disadvantages of utilizing a synthetic graft in pediatric V-A ECMO.


Optimizing Autotrophic Sulfide Oxidation in the Oxygen-Based Membrane Biofilm Reactor to Recover Elemental Sulfur.
Biological sulfide oxidation is an efficient means to recover elemental sulfur (S0) as a valuable resource from sulfide-bearing wastewater. This work evaluated the autotrophic sulfide oxidation to S0 in the O2-based membrane biofilm reactor (O2-MBfR). High recovery of S0 (80-90% of influent S) and high sulfide oxidation (∼100%) were simultaneously achieved when the ratio of O2-delivery capacity to sulfide-to S0 surface loading (SL) (O2/S2- → S0 ratio) was around 1.5 (g O2/m2-day/g O2/m2-day). On average, most of the produced S0 was recovered in the MBfR effluent, although the biofilm could be a source or sink for S0. Shallow metagenomic analysis of the biofilm showed that the top sulfide-oxidizing genera present in all stages were Thauera, Thiomonas, Thauera_A, and Pseudomonas. Thiomonas or Pseudomonas was the most important genus in stages that produced almost only S0 (i.e., the O2/S2- → S0 ratio around 1.5 g of the O2/m2-day/g O2/m2-day). With a lower sulfide SL, the S0-producing genes were sqr and fccAB in Thiomonas. With a higher sulfide SL, the S0-producing genes were in the soxABDXYZ system in Pseudomonas. Thus, the biofilm community of the O2-MBfR adapted to different sulfide-to-S0 SLs and corresponding O2-delivery capacities. The results illustrate the potential for S0 recovery using the O2-MBfR.


Stability changes of miniscrew implants over time.
To quantify in vivo changes in miniscrew implant (MSI) stability over time using resonance frequency analysis, and to determine if pilot holes and placement sites affect changes in MSI stability. Twenty-two self-tapping MSIs (1.6 mm wide and 9 mm long) were placed in the maxillae of 2 adult beagle dogs (20 months old). The Osstell Mentor was used to measure the implant stability quotient (ISQ) weekly for 8 weeks. A split-mouth design was used to evaluate the effects of 1.1-mm wide, 3-mm deep pilot holes. The MSIs that failed showed significantly (P < .05) greater decreases in ISQ values during the first 3 weeks than the MSIs that remained stable. All of the MSIs that failed (41%) had been placed in nonkeratinized tissue. MSIs that remained stable throughout the study also showed significant decreases in ISQ values during the first 3 weeks, followed by increases during the fourth and fifth weeks. Changes in ISQ values of MSIs inserted into bone with and without pilot holes were comparable (P > .05). Stability of unloaded MSIs decreased during the first 3 weeks and increased thereafter. Although the effects of pilot holes on stability could not be confirmed, placement of MSIs into nonkeratinized tissue negatively affected their stability and increased the likelihood of failures.


Clearing the Air: A Qualitative Investigation of Genetic Counselors' Experiences of Counselor-Focused Patient Anger.
Patient anger is challenging for healthcare professionals to manage, particularly when it is directed at them. This study comprises the first in-depth investigation of genetic counselors' experiences with patient anger. Using a brief survey and interview methods, this study explored prevalence and context of patient anger directed at the genetic counselor, how genetic counselors manage patient anger directed at them, and possible thematic differences due to genetic counseling experience. Individuals enrolled in the National Society of Genetic Counselors (NSGC) listserv were invited to participate in a study of their experiences with patient anger directed at them. A majority of survey respondents (95.7 %, 243/254) reported experiencing patient anger directed at them, and 19.4 % reported having feared for their safety because of patient anger. Twenty-two survey respondents were purposively selected to participate in individual interviews. Inductive and cross case analysis yielded prevalent themes concerning patient triggers for anger, including bad news, logistical mishaps, and perceived counselor characteristics. Interview results further suggest unaddressed patient anger negatively affected patient and counselor emotional well-being and hindered genetic counseling goals. Prevalent challenges included genetic counselor attempts to accurately recognize, understand, and effectively manage patient anger without taking it personally. Commonly recommended strategies for addressing anger were empathy (i.e., understanding origins of patient anger), anticipating and acknowledging anger, maintaining personal, professional and legal protection, and debriefing with colleagues. Themes were quite similar across counselor experience levels. The findings underscore the importance of training and continuing education regarding patient anger. Additional findings, practice implications, and research recommendations are presented.


Identification of two novel RanGTP-binding proteins belonging to the importin beta superfamily.
Nucleo-cytoplasmic transport comprises a large number of distinct pathways, many of which are defined by members of the importin beta superfamily of nuclear transport receptors. These transport receptors all directly interact with RanGTP to modulate the compartment-specific binding of their transport substrates. To identify new members of the importin beta family, we used affinity chromatography on immobilized RanGTP and isolated Ran-binding protein (RanBP) 16 from HeLa cell extracts. RanBP16 and its close human homologue, RanBP17, are distant members of the importin beta family. Like the other members of the transport receptor superfamily, RanBP16 interacts with the nuclear pore complex and is able to enter the nucleus independent of energy and additional nuclear transport receptors.


Immunomodulatory effects of polysaccharides produced by Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1.
The extracellular polysaccharides (EPS) produced by lactic acid bacteria (LAB) are associated with the rheology, texture, and mouthfeel of fermented milk products, including yogurt. This study investigated the immunomodulatory effects of EPS purified from the culture supernatant of Lactobacillus delbrueckii ssp. bulgaricus (L. bulgaricus) OLL1073R-1. The crude EPS were prepared from the culture supernatant of L. bulgaricus OLL1073R-1 by standard chromatographic methods, and were fractionated into neutral EPS and acidic EPS (APS). Acidic EPS were further fractionated into high molecular weight APS (H-APS) and low molecular weight APS (L-APS). High molecular weight APS were shown to be phosphopolysaccharides containing D-glucose, D-galactose, and phosphorus. Stimulation of mouse splenocytes by H-APS significantly increased interferon-gamma production, and, moreover, orally administered H-APS augmented natural killer cell activity. Oral administration of yogurt fermented with L. bulgaricus OLL1073R-1 and Streptococcus thermophilus OLS3059 to mice showed a similar level of immunomodulation as H-APS. However, these effects were not detected following administration of yogurt fermented with the starter combination of L. bulgaricus OLL1256 and S. thermophilus OLS3295. We conclude from these findings that yogurt fermented with L. bulgaricus OLL1073R-1, containing immunostimulative EPS, would have an immunomodulatory effect on the human body.


Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.
Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer.


A new conceptual model of asymmetry in motor performance for bidimensional fast-oscillating movements in selected variants of performance.
Spatial characteristics and lateral differences between two upper extremities were investigated in unilateral graphical tasks involving fast oscillating movements in the vertical plane based on the model of restricted (less than 10 degrees) horizontal abduction adduction in the shoulder joint. The spatial locations of reversal points were used to identify two groups of motor performance: with big angles and gross vertical vectors (stretched accordion group), and small projectile angles with small vertical vectors (compressed accordion group). Both groups appeared in right and left arm performance. The former group had a strong pattern of distribution of big and small projectile angles which reflects a particular variant of execution with a significant difference between angles and intermittent big and small angles (BB). Two other variants of execution relating to specific angular patterns of performance were identified in the compressed accordion group: one (Bs) showed a big difference between big and small angles but without intermittance; the other (ss) had only small differences between magnitudes of angles. The Bs variant of execution was observed only in left-handed performance, whilst ss was typical of both extremities. The performances affiliated to the stretched accordion group with the BB variant of execution mostly operated with reciprocal cooperation between alterations of X and Y vectors for the right arm. Performance related to the same group with the Bs variant of execution used concurrent collaboration involving alteration of these vectors for the left arm. The compressed accordion group which deployed the ss variant of execution mostly displayed concurrent alteration of vectors irrespective of the side of performance. It is suggested that the spatial movement strategies might reflect several different schemes of motor control wherein coupling of oscillators controls vertical and horizontal movements. It is also proposed that specific subunits of the functional system of nervous elements responsible for the expression of spatial derivatives of motor programmes may exist at lower levels of the CNS and might be initiated by the left brain or by the cooperative activity of the left and right hemispheres.


CT of neonatal herpes encephalitis.
Seven neonates with proven herpes (HSV type 2) encephalitis exhibited a characteristic sequence of findings on cranial computed tomography (CT). The initial CT abnormalities in all infants were fingerlike areas of cortical increased attenuation noted on unenhanced scans obtained 2-30 days after presentation. These usually were accentuated by increased white-matter lucency. Subsequently (more than 30 days after presentation), extensive cerebral destruction, multicystic encephalomalacia, and calcification were seen on follow-up CT scans obtained in five infants.


Effect of synthetic ANP on renal and loop of Henle functions in the young rat.
The present studies were undertaken to determine, by recollection micropuncture, the effect of a synthetic atrial natriuretic peptide (ANP) on the absolute and fractional deliveries of water and sodium to the juxtamedullary end-descending limb. Two groups of young female Munich-Wistar rats were studied: control (n = 8) received the vehicle only; and ANP (n = 12) received a prime followed by the constant infusion of a synthetic rat atrial peptide (28 amino acids). With the infusion of ANP, clearance of p-[14C]aminohippurate [( 14C]PAH) and glomerular filtration rate (GFR) fell significantly. Despite this fall in GFR and renal plasma flow, ANP produced a 2-fold increase in urine volume and a 10-fold increase in sodium excretion. Absolute and fractional sodium deliveries to the end-descending limb increased by approximately 30% in the ANP group, whereas mean juxtamedullary single-nephron glomerular filtration rate (SNGFR) remained stable. In three additional rats prepared for micropuncture of the superficial end-accessible proximal tubule, ANP reduced cortical SNGFR by approximately 15%. By contrast, GFR did not decline in response to ANP in larger rats, when treated identically. We conclude that in young rats ANP can produce a natriuresis in the absence of a rise in GFR; the fall in GFR observed following ANP is due presumably to the immaturity of the animals used in these studies; and ANP produces a rise in absolute and fractional water and sodium deliveries to the end-descending limb that cannot be attributed to a change in SNGFR.(ABSTRACT TRUNCATED AT 250 WORDS)


A SoxB gene acts as an anterior gap gene and regulates posterior segment addition in a spider.
Sox genes encode a set of highly conserved transcription factors that regulate many developmental processes. In insects, the SoxB gene Dichaete is the only Sox gene known to be involved in segmentation. To determine if similar mechanisms are used in other arthropods, we investigated the role of Sox genes during segmentation in the spider Parasteatoda tepidariorum. While Dichaete does not appear to be involved in spider segmentation, we found that the closely related Sox21b-1 gene acts as a gap gene during formation of anterior segments and is also part of the segmentation clock for development of the segment addition zone and sequential addition of opisthosomal segments. Thus, we have found that two different mechanisms of segmentation in a non-mandibulate arthropod are regulated by a SoxB gene. Our work provides new insights into the function of an important and conserved gene family, and the evolution of the regulation of segmentation in arthropods.


Fundamentals of Cellular Calcium Signaling: A Primer.
Ionized calcium (Ca2+) is the most versatile cellular messenger. All cells use Ca2+ signals to regulate their activities in response to extrinsic and intrinsic stimuli. Alterations in cellular Ca2+ signaling and/or Ca2+ homeostasis can subvert physiological processes into driving pathological outcomes. Imaging of living cells over the past decades has demonstrated that Ca2+ signals encode information in their frequency, kinetics, amplitude, and spatial extent. These parameters alter depending on the type and intensity of stimulation, and cellular context. Moreover, it is evident that different cell types produce widely varying Ca2+ signals, with properties that suit their physiological functions. This primer discusses basic principles and mechanisms underlying cellular Ca2+ signaling and Ca2+ homeostasis. Consequently, we have cited some historical articles in addition to more recent findings. A brief summary of the core features of cellular Ca2+ signaling is provided, with particular focus on Ca2+ stores and Ca2+ transport across cellular membranes, as well as mechanisms by which Ca2+ signals activate downstream effector systems.


Cross-cultural adaptation of the VISA-P questionnaire for Greek-speaking patients with patellar tendinopathy.
To cross-culturally adapt the VISA-P questionnaire for Greek-speaking patients and evaluate its psychometric properties. The VISA-P was developed in the English language to evaluate patients with patellar tendinopathy. The validity and use of self-administered questionnaires in different language and cultural populations require a specific procedure in order to maintain their content validity. The VISA-P questionnaire was translated and cross-culturally adapted according to specific guidelines. The validity and reliability were tested in 61 healthy recreational athletes, 64 athletes at risk from different sports, 32 patellar tendinopathy patients and 30 patients with other knee injuries. Participants completed the questionnaire at baseline and after 15-17 days. The questionnaire's face and content validity were judged as good by the expert committee, and the participants. Concurrent validity was almost perfect (ρ=-0.839, p<0.001). Also, factorial validity testing revealed a two-factor solution, which explained 85.6% of the total variance. A one-factor solution explained 80.8% of the variance when the other knee injury group was excluded. Known group validity was demonstrated by significant differences between patients compared with the asymptomatic groups (p<0.001). The VISA-P-GR exhibited very good test-retest reliability (ICC=0.818, p<0.001; 95% CI 0.758 to 0.864) and internal consistency since Cronbach's α analysis ranged from α=0.785 to 0.784 following a 15-17 days interval. The translated VISA-P-GR is a valid and reliable questionnaire and its psychometric properties are comparable with the original and adapted versions.


Ethical, social, and cultural considerations for site selection for research with genetically modified mosquitoes.
Recent advances in technology have made strategies for disease control using genetically modified (GM) vectors more plausible. Selecting an appropriate field site for research with GM mosquitoes may be one of the most complex and significant aspects of the research process. Among the key considerations of the process is the need to address ethical, legal, and cultural (ESC) issues. No guidelines have been developed to date for this complicated and sensitive process. In this paper, we describe a site selection process and a set of preliminary considerations for addressing the ESC aspects of a research program involving genetic strategies for the control of mosquitoes as vectors for dengue viruses. These considerations reflect some of the key ESC issues for site selection decisions for research with GM vectors.


Fine-needle aspiration of the prostate.
Fine-needle aspiration biopsy of the prostate has been used for over 20 years as the prostate biopsy technique of choice throughout much of Europe. However, this technique has only recently gained acceptance in the United States. There is now an enlarging body of data confirming that fine-needle aspiration can be viewed as a safe, accurate, and reliable means for detection and diagnosis of prostate cancer. This review summarizes the European and United States experience with fine-needle aspiration and supports the utility of this biopsy technique as an important addition to the urologist's diagnostic armamentarium.


Chemical and physical carcinogenesis: advances and perspectives for the 1990s.
Carcinogenesis is a multistage process driven by carcinogen-induced genetic and epigenetic damage in susceptible cells that gain a selective growth advantage and undergo clonal expansion as the result of activation of protooncogenes and/or inactivation of tumor suppressor genes. Therefore, the mutational spectra of chemical and physical carcinogens in these critical genes are of interest to define endogenous and exogenous mutational mechanisms. The p53 tumor suppressor gene is ideally suited for analysis of the mutational spectrum. Such an analysis has revealed evidence for both exogenous and endogenous molecular mechanisms of carcinogenesis. For example, an informative p53 mutational spectrum of frequent G----T transversions in codon 249 is found in hepatocellular carcinomas from either Qidong, People's Republic of China, or southern Africa. This observation links exposure to aflatoxin B1, a known cancer risk factor in these geographic regions, with a specific mutation in a cancer-related gene. Other studies indicate that abnormalities in genes controlling the cell cycle may cause genomic instability and increase the probability of neoplastic transformation. Finally, mechanistic understanding of carcinogenesis is leading to improved cancer risk assessment and to the identification of individuals at high cancer risk.


The Role of Atypical Cannabinoid Ligands O-1602 and O-1918 on Skeletal Muscle Homeostasis with a Focus on Obesity.
O-1602 and O-1918 are atypical cannabinoid ligands for GPR55 and GPR18, which may be novel pharmaceuticals for the treatment of obesity by targeting energy homeostasis regulation in skeletal muscle. This study aimed to determine the effect of O-1602 or O-1918 on markers of oxidative capacity and fatty acid metabolism in the skeletal muscle. Diet-induced obese (DIO) male Sprague Dawley rats were administered a daily intraperitoneal injection of O-1602, O-1918 or vehicle for 6 weeks. C2C12 myotubes were treated with O-1602 or O-1918 and human primary myotubes were treated with O-1918. GPR18 mRNA was expressed in the skeletal muscle of DIO rats and was up-regulated in red gastrocnemius when compared with white gastrocnemius. O-1602 had no effect on mRNA expression on selected markers for oxidative capacity, fatty acid metabolism or adiponectin signalling in gastrocnemius from DIO rats or in C2C12 myotubes, while APPL2 mRNA was up-regulated in white gastrocnemius in DIO rats treated with O-1918. In C2C12 myotubes treated with O-1918, PGC1α, NFATc1 and PDK4 mRNA were up-regulated. There were no effects of O-1918 on mRNA expression in human primary myotubes derived from obese and obese T2DM individuals. In conclusion, O-1602 does not alter mRNA expression of key pathways important for skeletal muscle energy homeostasis in obesity. In contrast, O-1918 appears to alter markers of oxidative capacity and fatty acid metabolism in C2C12 myotubes only. GPR18 is expressed in DIO rat skeletal muscle and future work could focus on selectively modulating GPR18 in a tissue-specific manner, which may be beneficial for obesity-targeted therapies.


Exercise responses before and after physical conditioning in patients with severely depressed left ventricular function.
The ability of patients with severely impaired left ventricle function to perform short-term exercise and to participate in a cardiac rehabilitation program and attain physical training effects was evaluated. Treadmill exercise tests were performed before and after physical conditioning in 10 patients with a prior myocardial infarction and a left ventricular ejection fraction at rest of less than 27 percent (range 13 to 26) determined by radionuclide angiography. All patients participated in a supervised exercise program with a follow-up period of 4 to 37 (mean 12.7) months. Baseline exercise capacity showed marked variability, ranging from 4.5 to 9.4 (mean 7.0 +/- 1.9) METS, and improved to 5.5 to 14 (mean 8.5 +/- 2.9) METS after conditioning (p = 0.05). The oxygen pulse (maximal oxygen uptake/maximal heart rate) before and after conditioning was used to assess a training effect and increased significantly from 12.8 +/- 2.0 to 15.7 +/- 3.2 ml/beta (p less than 0.01). There was no exercise-related morbidity or mortality, although two patients died during the study period. It is concluded that selected patients with severely imparied left ventricular function can safely participate in a conditioning program and achieve cardiovascular training effects.


[Tissue microcirculation in patients with reflex neurodystrophic syndromes of cervical osteochondrosis].
In 62 normals and 70 patients with reflex vertebrogenic syndromes the authors studied tissue clearance (the time of resorbtion--50% and 80% isotope, the mean rate of elimination in percentage) by radioisotope indications. The study determined as well the informative value of radiogramm indices. The data reveal distinct disorders of tissue microcirculation in the affected areas. It was also possible to establish a correlation between the capillarotissue metabolism and the duration of the disease, duration of the exacerbation, stage of the disease and some other factors. The authors followed the development of microcirculation in the process of treatment. The obtained results indicate the diagnostical significance of the method of radioisotope indication and the possibility of its application for the prognosis of the disease and evaluation of treatment methods of reflex neurodystrophical syndromes of cervical osteochondrosis.


Uncovering allosteric pathways in caspase-1 using Markov transient analysis and multiscale community detection.
Allosteric regulation at distant sites is central to many cellular processes. In particular, allosteric sites in proteins are major targets to increase the range and selectivity of new drugs, and there is a need for methods capable of identifying intra-molecular signalling pathways leading to allosteric effects. Here, we use an atomistic graph-theoretical approach that exploits Markov transients to extract such pathways and exemplify our results in an important allosteric protein, caspase-1. Firstly, we use Markov stability community detection to perform a multiscale analysis of the structure of caspase-1 which reveals that the active conformation has a weaker, less compartmentalised large-scale structure compared to the inactive conformation, resulting in greater intra-protein coherence and signal propagation. We also carry out a full computational point mutagenesis and identify that only a few residues are critical to such structural coherence. Secondly, we characterise explicitly the transients of random walks originating at the active site and predict the location of a known allosteric site in this protein quantifying the contribution of individual bonds to the communication pathway between the active and allosteric sites. Several of the bonds we identify have been shown experimentally to be functionally critical, but we also predict a number of as yet unidentified bonds which may contribute to the pathway. Our approach offers a computationally inexpensive method for the identification of allosteric sites and communication pathways in proteins using a fully atomistic description.


A comparison of the academic outcome of chiropractic students on full-time and full-time equivalent chiropractic education routes.
To compare the academic equivalence of full-time (FT) and full-time equivalent (FTE) delivery routes for chiropractic training and to assess nontraditional education delivery as a viable method for training chiropractors. A retrospective analysis of student summative assessment data was undertaken on a total of 196 FT and FTE students studying for the master's in chiropractic degree at a UK chiropractic college between 2009 and graduating by 2017. The analysis consisted of within-group comparison and between-group comparisons using the Kruskal-Wallis test and the Mann-Whitney U test. The demographics of the 2 student groups varied in terms of gender and age distribution. The analysis of summative data indicated no differences between the 2 routes of delivery. There was also no difference in the distribution of final degree classification outcome between the 2 routes. While it is possible that demographic differences influence the outcomes in each training route, this preliminary study indicates that, based only on analysis of overall achievement, there is no difference in either FT or FTE programs in training chiropractors, allowing them to register with the UK regulatory body. It suggests that a nontraditional mode of delivery is an achievable route to qualification as a chiropractor, enabling a greater number of students to consider chiropractic as a career choice while managing other life commitments.


Cardiac sarcoplasmic reticulum function in insulin- or carnitine-treated diabetic rats.
Cardiac sarcoplasmic reticulum (SR) function and SR levels of long-chain (LC) acylcarnitines were determined in streptozotocin-induced diabetic rats treated with insulin or D,L-carnitine. ATP-dependent calcium transport was significantly depressed in cardiac SR isolated from untreated diabetic rats compared with control rats. Diabetic rat cardiac SR levels of LC acylcarnitines were also significantly elevated. Various parameters of heart function (left ventricular developed pressure, +dP/dT, and -dP/dT), as determined on an isolated working heart apparatus, were found to be depressed in untreated diabetic rats. Cardiac SR isolated from diabetic rats treated throughout the study period with insulin or D,L-carnitine did not have elevated levels of LC acylcarnitines associated with SR membrane nor was SR calcium transport activity depressed. Heart function in the diabetic rats treated with insulin was similar to control rat hearts but heart function remained depressed in diabetic rats treated with D,L-carnitine. The data suggest that the LC acylcarnitines are involved in the observed impairment of cardiac SR function in diabetic rats. Other factors, however, must be contributing to the depression in heart function noted in these animals.


Genetic Variant of PAX1 Gene Is Functionally Associated With Adolescent Idiopathic Scoliosis in the Chinese Population.
A genetic association study. To investigate the association between PAX1 gene and the susceptibility of adolescent idiopathic scoliosis (AIS) in the Chinese population and to further determine the functional variant regulating PAX1 expression in patients with AIS. In a previous study an enhancer locus of PAX1 was reported to be associated with the development of AIS in the Caucasian and the Japanese population. However, there is a paucity of knowledge concerning the functional role of PAX1 in the Chinese AIS population. The single-nucleotide polymorphisms rs6137473 and rs169311 were genotyped in 2914 patients and 3924 controls. The differences of genotype and allele distributions between patients and controls were calculated using chi-square test. Paraspinal muscles were collected from 84 patients with AIS. The one-way analysis of variance test was used to compare the mRNA expression of PAX1 among different genotypes. Both rs6137473 and rs169311 were significantly associated with the susceptibility of AIS. Allele G of rs6137473 and allele A of rs169311 can significantly add to the risk of AIS with an odds ratio of 1.17 and 1.22, respectively. Moreover, there was significant difference regarding the expression of the PAX1 between the concave side and convex side of the patients. Patients with genotype AA of rs169311 had significantly decreased expression of PAX1 than those with genotype CC. As for rs6137473, no remarkable difference of PAX1 expression was found among the three genotypes. The association between PAX1 and the susceptibility of AIS was successfully replicated in the Chinese population. Moreover, rs169311 could be a functional variant regulating the expression of PAX1 in the paraspinal muscles of AIS. Further functional analysis is warranted for a comprehensive knowledge on the contribution of this variant to the development of AIS. 3.


Acute administration of natural honey protects isolated heart in normothermic ischemia.
This study intended to assess the efficacy of acute administration of natural honey on cardiac arrhythmias and infarct size when it is used during the normothermic ischemia in isolated rat heart. During 30 min of regional normothermic ischemia followed by 120 min of reperfusion, the isolated hearts were perfused by a modified drug free Krebs-Henseleit solution (control) or the solution containing 0.125, 0.25, 0.5 and 1% of freshly prepared natural honey (test groups), respectively. Cardiac arrhythmias were analyzed and determined through the recorded ECGs. The infarct size was measured using computerized planimetry package. At the ischemic phase, honey (0.25 and 0.5%) decreased the number and duration of ventricular tachycardia (VT), total number of ventricular ectopic beats (VEBs), duration and incidence of reversible ventricular fibrillation (VF) and total VF (p < 0.05 for all). During the reperfusion, concentrations of 0.125, 0.25 and 0.5% lowered the number of VT (p < 0.05), duration of reversible VF (p < 0.01) and total number of VEBs (p < 0.05). In addition, VT duration was reduced significantly with honey 0.125 and 0.25%. Moreover, the infarct size was 45.6 ± 3.4% in the control group, while the perfusion of honey (0.125, 0.25 and 0.5%) reduced it to 14.8 ± 5.1 (p < 0.001), 24.6 ± 7.3 (p < 0.01) and 31.4 ± 7.3% (p < 0.05), respectively. Regarding the results, it is concluded that the acute administration of natural honey in normothermic ischemia conditions can protect the rat heart as the reduction of infarct size and arrhythmias. Conceivably, the antioxidant and free radical scavenging activity, the reduction of necrotized tissue and the providence of rich energy source are more important mechanisms in cardioprotective effects of natural honey.


Herpes simplex virus-mediated gene delivery to the rodent visual system.
To determine the types of cells in the visual system of the mouse and rat that can express a transgene delivered by an attenuated replication competent Herpes simplex virus-1 (HSV-1) vector. C57/BL6 x BALB/C mice and Albino rats were treated with 1 x 10(7) pfu of the HSV-1 ribonucleotide reductase mutant (hrR3) expressing the Escherichia coli lacZ gene. The hrR3 virus was delivered by topical application to the cornea, intravitreal (IV) injection, intracameral injection (IC), or stereotactic injection into the visual cortex (VC). At specified times postinfection, animals were killed and tissues were removed, fixed, sectioned, and stained with X-gal or hematoxylin and eosin for histochemical and histopathologic examination. Topical delivery after corneal scarification in both mouse and rat resulted in lacZ expression in 25% of the corneal epithelial cells and 25% of the retinal pigment epithelium (RPE) cells. Topical application without concurrent scarification also resulted in transgene delivery to 20% of the RPE cells of the rat but not the mouse. IV injection resulted in expression primarily in RPE cells, with up to 100% of the cells expressing lacZ in the mouse and rat. Other cells expressing the transgene included ciliary body (CB) and optic nerve cells. Up to 25% of the retinal ganglion cells in the rat expressed lacZ, but only rarely in mice. IC delivery in rats resulted in expression in trabecular meshwork, CB cells, RPE, and iris epithelium. Injection into area 17 of the rat VC resulted in efficient labeling of the VC neurons and neurons in the lateral geniculate nucleus without any evident pathology or inflammation. Neither inflammation nor disease pathology was observed in either the mouse or rat after any route of delivery. It was demonstrated that the hrR3 HSV-1 virus can deliver a functioning gene to several cell types in the eye and neurons in the VC and that the virus can move via retrograde transport to nuclei that project to the VC.


Biochemical and pharmacological activities of SR 26831, a potent and selective elastase inhibitor.
SR 26831 ([[5-(2-chloro-benzyl-2-(terbutyloxycarbonyl)]-4,5,6,7- tetrahydrothieno(3,2-c)pyridine]N-oxide) is the first member of a new class of human leukocyte elastase inhibitors. SR 26831 inhibited in a dose-dependent manner elastases from human leukocytes or pancreas with IC50 values of 80 +/- 2.6 nM and 4.8 +/- 0.12 microM, respectively. Steady-state studies revealed that SR 26831 behaved like a noncompetitive, irreversible inhibitor of both types of enzymes. SR 26831 inhibited in a dose-dependent manner degradation of [3H]elastin and [3H]collagens (types I and IV) by human leukocyte elastase (IC50 values were between 1.2 and 1.8 microM). In this respect, SR 26831 was 3- to 20-fold more active than alpha-1-antitrypsin. SR 26831 was also highly selective for elastases inasmuch as it did not inhibit pepsin, collagenase, trypsin, alpha-chymotrypsin, factor Xa, plasmin, kallikrein, cathepsins B, C, D and G and thrombin. In the rabbit, SR 26831 was cleared rapidly from blood after i.v. injection, but affected intracellular leukocyte elastase activity shortly after either i.v. or p.o. administration. In the rat, i.v. or p.o. administration of SR 26831 prevented in a dose-dependent manner acute lung injury induced by intratracheal instillation of human leukocyte elastase. SR 26831 (1 mg/kg) was still efficient when it was administered 90 min before elastase instillation and was also able to limit further hemorrhage development in response to elastase, after it had begun. SR 26831 may therefore be of therapeutic value in the treatment of diseases such as rheumatoid arthritis or pulmonary emphysema thought to be due to the destructive action of leukocyte elastase.


Subliminal stimuli in the near absence of attention influence top-down cognitive control.
Recent research has shown that visual stimuli can influence cognitive control functions, even if subjects are unaware of the identity of the stimuli. However, in those previous studies, subjects actively attended to the location of the subliminal stimuli. Here we assessed the role of endogenous spatial attention in such paradigms. We required subjects to quickly prepare for one of two numerical judgment tasks on the basis of the direction of motion in patches of moving dots presented in cued spatial locations. We found that irrelevant motion patches presented in the uncued spatial locations also influenced task performance. Motion in the uncued patches was weak and did not affect the perception of the cued patches. Further analyses suggested that the effect of priming by the uncued stimuli was present even for subjects who could only discriminate such stimuli at chance level. Three additional experiments confirmed that subjects paid minimal attention to the uncued locations, in that the subjects could not perform simple discriminations of conjunctions of features in those locations.


THE GENUS VEILLONELLA. 3. HYDROGEN SULFIDE PRODUCTION BY GROWING CULTURES.
Rogosa, Morrison (National Institute of Dental Research, Bethesda, Md.), and Ferial S. Bishop. The genus Veillonella. III. Hydrogen sulfide production by growing cultures. J. Bacteriol. 88:37-41. 1964.-The conditions necessary for H(2)S production by 105 strains of Veillonella, from a variety of sources and comprising seven anti-genic groups, are presented and discussed. All strains, during 1 to 2 days of growth, produced H(2)S in a defined medium supplemented with proper amounts of l-cysteine, l-cystine, reduced glutathione, thiosulfate, thiocyanate, or thioglycolate. Erratic or negative results were obtained with some commonly used media containing yeast extract and casein digest, but which were not supplemented with appropriate substrates for H(2)S production. Previous literature descriptions of V. alcalescens as not producing H(2)S are incorrect; H(2)S production, or the previously presumed lack of it, cannot be used as a criterion differentiating V. alcalescens from V. parvula.


Cytotoxic T lymphocyte responses by chimeric thymocytes. Self-recognition is determined early in T cell development.
In this study the cytotoxic T lymphocyte (CTL) recognition pattern of thymocytes from recently reconstituted parent leads to F1 and F1 leads to parent radiation bone marrow chimeras was investigated. Chimeric thymocytes were entirely of donor origin approximately 4 wk after irradiation and reconstitution but were not capable of autonomously generating either alloreactive or trinitrophenyl (TNP)-modified-self-reactive CTL responses. However, in the presence of interleukin-2 (I1-2), the the putative T helper cell product, CTL could be generated in vitro by thymocytes from recently reconstituted chimeras. Experiments with thymocytes from A leads to A X B and A X B leads to A chimeras revealed the following: (a) thymocytes from both types of chimeras were nonreactive to either A or B parental major-histocompatibility complex (MHC) determinants even though they were alloreactive to third-party stimulator cells; and (b) thymocytes from these chimeras were restricted to the recognition of TNP in association with MHC determinants syngeneic to the chimeric host. Thus, these experiments demonstrate that even at the earliest time CTL effectors of donor origin from the thymuses of chimeras can be studied, their self-receptor repertoire has already been restricted to recognition of host MHC determinants. These results support the concept that the host environment influences the self-recognition capacity of T cells at the pre- or intrathymic stage of differentiation.


Paternalism in healthcare decision making.
Paternalism is described as a dominant attitude of one over another. It was widely practiced years ago because clinicians were usually expected to make the best decision for the patient. Modern healthcare, with its many technically advanced diagnostic and treatment modalities complicates decision making. The trend legally and morally is to include the patient in the decision making process because patients are increasingly informed and able to participate in the decision making process. However, the risks of paternalism continue to be a debatable issue in healthcare. The purpose of this article is to describe types of paternalism, to present justification for paternalism, and to offer a case study to illustrate the struggle that occurs when decisions made by clinicians collide with decisions made by patients.


A comparison between mometasone furoate nasal spray and intranasal glycyrrhetic acid in patients with allergic rhinitis: a preliminary study in clinical practice.
Allergic rhinitis (AR) is caused by an IgE-mediated inflammatory reaction consequent to the exposure to the causal allergen. Glycyrrhetic acid (GlyAc) is a natural compound extracted from the liquorice that exerts anti-inflammatory activity. This real-life study compared intranasal GlyAc, present in a medical device containing also glycerol and mannitol, with mometasone furoate nasal spray (MFNS) in 50 adult outpatients with AR. Both treatments lasted 2 months. Endoscopic signs, perception of symptom severity, assessed by VAS, and nasal function measured by rhinomanometry were evaluated at baseline (T0), after one (T1) and two (T2) months. The intergroup analysis showed that at T1 there was no significant difference between groups about the use of decongestants and antihistamines, turbinate hypertrophy and pale mucosa, perception of olfaction and snoring. At T2 there was no significant difference between groups about use of relievers, all endoscopic signs, and perception of nasal discomfort, nasal obstruction, olfaction, and snoring. The intragroup analysis showed that in MFNS group there was a significant change during the entire period of treatment for all parameters except watery rhinorrhea (sign) and ocular discomfort; in GlyAc group there was a significant change during the entire period of treatment for all parameters. In conclusion, this preliminary study, conducted in clinical practice, evidenced that intranasal CysAC plus mannitol was able to significantly improve nasal endoscopic signs, perception of symptoms, and nasal function in patients with AR. Therefore, GlyAc could be a reasonable therapeutic option to control allergic inflammation.


Tannic acid synergistically enhances the anticancer efficacy of cisplatin on liver cancer cells through mitochondria‑mediated apoptosis.
Cisplatin (cis‑dichlorodiamine platinum, CDDP) is a potent antitumor agent. However, its clinical application is limited by its side effects and the development of drug resistance. Tannic acid (TA) has previously been reported to suppress tumor growth in different types of cancer. The present study evaluated the anticancer efficacy of TA in combination with CDDP on the liver cancer cell line HepG2, and investigated the associated underlying molecular mechanisms. The results revealed that treatment with TA or CDDP alone inhibited HepG2 cell growth, with a half maximal inhibitory concentration of 360 µM and 1.8 µg/ml, respectively. The combination of TA and CDDP induced mitochondria‑mediated apoptosis in HepG2 cells and significantly enhanced the growth inhibitory effect compared with TA or CDDP treatment alone. The results obtained from the present study suggest that the combination of TA and CDDP may exert synergistic anticancer effects and may be a novel adjuvant treatment for liver cancer.


An innovative method for human height estimation combining video images and 3D laser scanning.
Digitalization has increased the number of video surveillance systems that sometimes capture crime images. Traditional methods of human height estimation use projective geometry. However, sometimes they cannot be used because the video camera surveillance system is not available or has been moved and there are no reference lines on the frame. Scientific studies have developed a new method for human height estimation using 3D laser scanning. This model necessarily requires a series of approximations, which increase the final measurement error. To overcome this problem, in the present study, images of a subject are projected directly on the 3D model, estimating the height of the subject. This article describes the methodological approach adopted through the analysis of a real case study in a controlled environment executed by Carabinieri Forensic Investigation Department (Italy). The aim is to obtain a human anthropometric measure derived from frames extracted from the videos associated with the digital survey of the framed area obtained with 3D laser scanning and point cloud analysis. The result is the height estimation of five subjects filmed by a camera obtained through the combination of 2D images extracted by a DVR/surveillance systems with 3D laser scanning. Results show that most estimated measurements are less than the real measurement of the subject; it also depends on the posture of the subject while walking. Furthermore, results shows the differences between the real height and the estimated height with a statistical approach.


Role of Additives in Electrochemical Deposition of Ternary Metal Oxide Microspheres for Supercapacitor Applications.
A simple two-step approach has been employed to synthesize a cobalt-nickel-copper ternary metal oxide, involving electrochemical precipitation/deposition followed by calcination. The ternary metal hydroxide gets precipitated/deposited from a nitrate bath at the cathode in the catholyte chamber of a two-compartment diaphragm cell at room temperature having a pH ≈ 3. The microstructure of the ternary hydroxides was modified in situ by two different surfactants such as cetyltrimethylammonium bromide and dodecyltrimethylammonium bromide in the bath aiming for enhanced storage performance in the electrochemical devices. The effect of the surfactant produces a transition from microspheres to nanosheets, and the effect of micelle concentration produces nanospheres at a higher ion concentration. The ternary hydroxides were calcined at 300 °C to obtain the desired ternary mixed oxide materials as the electrode for hybrid supercapacitors. X-ray diffraction analysis confirmed the formation of the ternary metal oxide product. The scanning electron microscopy images associated with energy-dispersive analysis suggest the formation of a nanostructured porous composite. Ternary metal oxide in the absence and presence of a surfactant served as the cathode and activated carbon served as the anode for supercapacitor application. DTAB-added metal oxide showed 95.1% capacitance retention after 1000 cycles, achieving 188 F/g at a current density of 0.1 A/g, and thereafter stable until 5000 cycles, inferring that more transition metals in the oxide along with suitable surfactants at an appropriate micellar concentration may be better for redox reactions and achieving higher electrical conductivity and smaller charge transfer resistance. The role of various metal cations and surfactants as additives in the electrolytic bath has been discussed.


Variation in hematologic and serum biochemical values of belugas (Delphinapterus leucas) under managed care.
Blood analytes are critical for evaluating the general health of cetacean populations, so it is important to understand the intrinsic variability of hematology and serum chemistry values. Previous studies have reported data for follow-up periods of several years in managed and wild populations, but studies over long periods of time (> 20 yr) have not been reported. The study objective was to identify the influences of partitioning characteristics on hematology and serum chemistry analytes of apparently healthy managed beluga (Delphinapterus leucas). Blood values from 31 managed belugas, at three facilities, collected over 22 yr, were assessed for seasonal variation and aging trends, and evaluated for biologic variation among and within individuals. Linear mixed effects models assessed the relationship between the analytes and sex, age, season, facility location, ambient air temperature, and photoperiod. Sex differences in analytes and associations with increasing age were observed. Seasonal variation was observed for hemoglobin, hematocrit, mean corpuscular volume, monocytes, alkaline phosphatase, total bilirubin, cholesterol, and triglycerides. Facilities were associated with larger effects on analyte values compared to other covariates, whereas age, sex, and ambient temperature had smaller effects compared to facility and season. Present findings provide important baseline information for future health monitoring efforts. Interpretation of blood analytes and animal health in managed and wild populations over time is aided by having available typical levels for the species and reference intervals for the degree to which individual animals vary from the species average and from their own baseline levels during long-term monitoring.


Comparison of motor competence in children aged 6-9 years across northern, central, and southern European regions.
The present study aimed to examine differences in motor competence (MC) in children aged 6-9 years old in northern, central, and southern European regions using the Körperkoordinationstest für Kinder (KTK). The secondary aim of the study was to examine interactions between region and children's age, sex, and weight status (determined as healthy weight or overweight/obese). Data were pooled from independent studies conducted in Finland (mean age 7.81 ± 1.19 years, n = 690), Belgium (mean age 8.25 ± 1.09 years, n = 1896), and Portugal (mean age 8.31 ± 1.02 years, n = 758) between 2008 and 2016. Cross-cultural differences in MC and interaction effects were tested using ANOVAs and ANCOVAs. Age, sex, and BMI percentile were used as covariates. Geographical region significantly explained 19% of the variance in MC, while BMI (5%), sex (3%), and age (0.3%) were significant covariates. The interaction effect of region and age (5%), region and sex (0.6%), and region and BMI (0.2%) on MC was also significant. Cross-cultural differences in children's MC increased substantially across age, independent of weight status. Girls slightly underperformed in MC compared to boys in regions where the overall level of MC was lower. Interestingly, the association between body weight status and MC was relatively consistent across the regions. Future cross-cultural studies should further explore the influence of individual (eg, physical activity) and environmental (eg, physical activity and sport policy) factors on MC development.


Social determinants of type 2 diabetes and health in the United States.
Diabetes is the sixth leading cause of death in the United States. To date, most research and resulting clinical strategies have focused on the individual with short-term health improvements that have not been maintained over time. Researchers more recently have recognized the need to consider the social determinants of diabetes and health along with individual factors. The purpose of this literature review is to examine current understanding of the social determinants affecting diabetes and health. A search of medical and nursing literature was conducted using PubMed, PsychInfo, CINAHL and MEDLINE databases, selecting articles published between 2000 and 2013. Search terms included: type 2 diabetes, social determinants, and health determinants. Inclusion criteria were: English language, human studies, social determinants of diabetes and health, and research in the United States. Additional search methods included reference chaining of the literature. Twenty research articles met the inclusion criteria for the review and analysis and included quantitative and qualitative methods. All studies selected for this review were descriptive in nature (n = 20). Fifteen studies were quantitative studies and five were qualitative studies. No intervention studies met inclusion criteria. Each study is summarized and critiqued. Study findings indicate that external or upstream factors consistently affect individuals diagnosed with diabetes, influencing self-management. Significant methodological limitations result directly from small sample sizes, convenience or nonprobability sampling, and low statistical power.


Do Older Listeners With Hearing Loss Benefit From Dynamic Pitch for Speech Recognition in Noise?
Dynamic pitch, the variation in the fundamental frequency of speech, aids older listeners' speech perception in noise. It is unclear, however, whether some older listeners with hearing loss benefit from strengthened dynamic pitch cues for recognizing speech in certain noise scenarios and how this relative benefit may be associated with individual factors. We first examined older individuals' relative benefit between natural and strong dynamic pitches for better speech recognition in noise. Further, we reported the individual factors of the 2 groups of listeners who benefit differently from natural and strong dynamic pitches. Speech reception thresholds of 13 older listeners with mild-moderate hearing loss were measured using target speech with 3 levels of dynamic pitch strength. Individuals' ability to benefit from dynamic pitch was defined as the speech reception threshold difference between speeches with and without dynamic pitch cues. The relative benefit of natural versus strong dynamic pitch varied across individuals. However, this relative benefit remained consistent for the same individuals across those background noises with temporal modulation. Those listeners who benefited more from strong dynamic pitch reported better subjective speech perception abilities. Strong dynamic pitch may be more beneficial than natural dynamic pitch for some older listeners to recognize speech better in noise, particularly when the noise has temporal modulation.


The impact of PARP inhibitors in the whole scenario of Ovarian Cancer management: a Systematic Review and Network Meta-Analysis.
Carboplatin is still the cornerstone of the first-line treatment in advanced Epithelial Ovarian Cancer (aEOC) management and the clinical response to platinum-derived agents remains the major predictor of long-term outcomes. We aimed to identify the best treatment of the aEOC in terms of efficacy and safety, considering all treatment phases. A systematic literature search has been done to compare all treatments in aEOC population. Randomized trials with available survival and safety data published in the 2011-2022 timeframe were enclosed. Only trials reporting the BRCA or HRD (Homologous Recombination Deficiency) status were considered. A ranking of treatment schedules on the progression-free survival (PFS) endpoint was performed. The random-effect model was used to elaborate and extract data. The Network Meta-Analysis (NMA) by Bayesian model was performed by STATA v17. Data on PFS were extracted in terms of Hazard ratio with relative confidence intervals. This NMA involved 18 trials for a total of 9105 patients. Within 12 treatment groups, we performed 3 different sensitivity analyses including "all comers" Intention to Treat (ITT) population, BRCA-mutated (BRCAm), and HRD subgroups, respectively. Considering the SUCRA-reported cumulative PFS probabilities, we showed that in the ITT population, the inferred best treatment was niraparib plus bevacizumab with a SUCRA of 96.7. In the BRCAm subgroup, the best SUCRA was for olaparib plus chemotherapy (96,9). The HRD population showed an inferred best treatment for niraparib plus bevacizumab (SUCRA 98,4). Moreover, we reported a cumulative summary of PARPi toxicity, in which different 3-4 grade toxicity profiles were observed, despite the PARPi "class effect" in terms of efficacy. Considering all aEOC subgroups, the best therapeutical option was identified as PARPi plus chemotherapy and/or antiangiogenetic agents, suggesting the relevance of combinatory approaches based on molecular profile. This work underlines the potential value of "chemo-free" regimens to prolong the platinum-free interval (PFI).


Cardiovascular phenotypes and functional parameters in the general population--results of the MONICA/KORA studies.
The MONICA/KORA surveys are characterized by a careful and broad investigation of multiple cardiovascular phenotypes. Particularly, repeated blinded measurements of blood pressure, comprehensive echocardiographic and electrocardiographic evaluations as well as differentiation between fat and fat-free body mass have led to manifold innovative observations. Specifically, genetic and serological markers of the renin angiotensin system could be associated with high blood pressure and left ventricular hypertrophy. The same applies to the importance of parameters of body composition as obesity and muscular mass. Moreover, the prevalence of heart failure in the general population could be determined for the first time in Germany. Additionally, the prevalence of left ventricular systolic and diastolic dysfunction could be obtained in the region of the survey, exemplarily for the Federal Republic of Germany. Finally, the surveys of the population random sample were used to define normal serum levels of natriuretic peptides. In summary, the evaluation of cardiovascular phenotypes in the MONICA/KORA surveys resulted in a -- in the European region unique -- documentation of cardiovascular functional parameters in the general population. Moreover, multiple epidemiological observations as to pathophysiologically relevant topics of heart and vascular diseases could be studied in extraordinary details.


Human immunodeficiency virus serodiscordant couples on highly active antiretroviral therapies with undetectable viral load: conception by unprotected sexual intercourse or by assisted reproduction techniques?
Until recently, only assisted reproduction was proposed to serodiscordant couples wishing to conceive. Nevertheless, recent publications have proposed unprotected sexual intercourse, targeting fertile days, for couples where antiretroviral treatment has lowered blood viral load to an undetectable level. Available data and the arguments for and against conception by safe sex versus the use of a strategy of unprotected sexual intercourse targeting fertile days are reviewed and analyzed. Although the rate of transmission of human immunodeficiency virus in serodiscordant couples in precise conditions (such as an undetectable viral load on treatment by highly active antiretroviral therapies and sexual intercourse limited to the fertile days) is very low, not zero, here we stress the various factors which can increase the risk of seroconversion in this particular population. In this context, it seems less cautious to abandon the recommendations of safe sex in serodiscordant couples desiring a child. The recourse to medically assisted procreation is advised, as long as evidence from further studies does not show that unprotected sexual intercourse, targeted to fertile days, does not have unexpected harmful consequences.


Surface features of human natural killer cells and antibody-dependent cytotoxic cells.
The purpose of the present study was to examine the surface features of purified large granular lymphocytes (LGLs) (natural killer (NK) cells, antibody-dependent cytotoxic lymphoid (ADCL) cells, K-cells, Fc gamma (+) third population (non-T, non-B) lymphoid cells, T gamma cells) by scanning electron microscopy (SEM) and to compare their surface features with granulocytes, monocytes and Fc gamma (-) lymphoid cells that were all fixed for SEM under identical conditions. We have determined that 72-80% of LGLs enriched by rosette formation with sensitized erythrocytes or using Percoll gradients, have a complex microvillous surface (CMS) pattern identical to that of lymphocytes. The LGL fraction appears by SEM to represent a morphologically homogeneous population of cells. Monocytes prepared for SEM under identical conditions had distinct surface folds and granulocytes displayed numerous broad-based ridge-like profiles. The majority of lymphoid cells in an unfractioned population have a CMS pattern when incubated at room temperature (25 degrees C) before fixation, and a sparse microvillous surface (SMS) pattern when incubated at body temperature (37 degrees C). Ficoll-Hypaque (FH) also had a direct effect on the cell surface pattern. Over half of the unfractionated lymphoid cells displayed a CMS pattern after cells were washed free of FH and incubated at 37 degrees C before fixation. The CMS pattern is therefore not unique to LGLs but can be produced by the surface alteration of non-LGLs found in unfractionated buffy coat and mononuclear fractions. The interactions between LGLs and sensitized erythrocytes in an antibody-dependent cytotoxic assay system, and LGLs and K562 target cells in an NK assay system, were also examined. This is the first report that describes the surface features of human LGLs interacting with K562 target cells in an NK assay system. The LGL populations studied by SEM were determined to have a high percentage of Leu-11(+) and Leu-7(+) cells. These same population were also shown to have high antibody-dependent cytotoxicity and NK activity using the 51Cr release assay.


Effect of angiotensin II receptor blockade on proximal tubular fluid reabsorption.
The effect of physiological concentrations of angiotensin II on proximal tubular fluid reabsorption remains controversial. To investigate the effect of blockade of intratubular AT1 receptors on tubular reabsorption, losartan (10(-5) M) was administered by microperfusion into an early proximal convolution of halothane-anesthetized Sprague-Dawley rats. Four parameters that depend on the rate of proximal fluid reabsorption were measured: proximal intratubular pressure (Pprox), early and late proximal flow rate, and early distal NaCl concentration. Pprox decreased by 0.5 +/- 0.1 mmHg, late proximal flow rate decreased by 2.0 +/- 0.8 nl/min, and early distal NaCl concentration decreased by 4.3 +/- 0.8 mM (mean +/- SE). No changes were observed after microperfusion with saline. Because the tubuloglomerular feedback mechanism was operating in the closed-loop mode, the decreased NaCl load to the macula densa will be compensated by an increase in the single-nephron glomerular filtration rate. In agreement with this, the early proximal flow rate, measured proximal to the site of losartan administration, increased by 5.7 +/- 1.3 nl/min. The increase in the rate of proximal reabsorption between the early and late proximal convolutions was estimated to be 7.8 nl/min (approximately 36%). It is concluded that a decrease in local luminal angiotensin II levels and/or AT1 receptor activity under free flow conditions increases the rate of proximal tubular fluid reabsorption.


The Efficacy and Safety of Adalimumab in Treating Pediatric Noninfectious Chronic Anterior Uveitis With Peripheral Retinal Vascular Leakage: A Pilot Study.
This study is aimed to assess the efficacy of adalimumab in alleviating peripheral vascular leakage in pediatric chronic anterior uveitis patients, along with its ability to improve best-corrected visual acuity (BCVA) and inflammation parameters, its efficacy in reducing topical glucocorticosteroids (GCs) and systemic immunomodulatory therapy (IMT), and its safety profile. A self-controlled study of pediatric chronic anterior uveitis patients who presented with peripheral retinal vascular leakage on ultra-widefield fluorescein fundus angiography and underwent adalimumab treatment was conducted. The primary outcome was the extent of retinal vascular leakage at the 3- and 6-month follow-up visits. Secondary outcomes included BCVA, inflammation parameters (fresh keratic precipitates, anterior chamber cell, and vitreous cell grades), frequency of topical glucocorticosteroid eye drops, IMT load, and adverse effects at the 3- and 6-month follow-up visits. Twenty patients with a mean age of 9.30 ± 3.26 years old were included. The mean follow-up period was 9.0 ± 3.0 months, with all patients followed up for at least 6 months. At the 3- and 6-month follow-ups, the peripheral vascular leakage score decreased significantly (2.87, 95% CI (2.14, 3.60), p < 0.001 for 3 months, 2.75, 95% CI (1.76, 3.73), p < 0.001 for 6 months). Alongside BCVA (p = 0.013 for 3 months, p = 0.005 for 6 months) was improved significantly, inflammatory parameters represented by fresh keratic precipitates, anterior chamber cell, and vitreous cell grades were improved significantly (p < 0.001, p < 0.001, for all parameters) and topical GC usage was significantly reduced (p < 0.001, p < 0.001) at 3 and 6 months. There was also a statistically significant reduction in systemic IMT load at 6 months (p < 0.001). Adverse events in the observation period included local redness around the injection site and mild upper respiratory symptoms. Adalimumab could effectively alleviate peripheral vascular leakage in pediatric patients with chronic anterior uveitis. It could also be helpful in improving BCVA and inflammation parameters and decreasing topical glucocorticosteroid eye drops and systemic IMT. Adalimumab is generally safe for pediatric uveitis.


Beta-blockade in the primary prevention of coronary heart disease in hypertensive patients. Review of present evidence.
The aim of this review is to present an overview of the results of randomized primary preventive trials with beta-blockers in patients with hypertension. For statistical and biological reasons, any preventive effect on coronary events is hard to demonstrate in women in these primary preventive trials because of the low incidence of coronary events in middle-aged, white women. Therefore, special attention will be focused on the effect in men. Four beta-blockers have been studied: propranolol, oxprenolol, atenolol, and metoprolol. Results from the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) trial showed that the risk for coronary events was 24% lower in patients receiving beta-blockade compared with patients receiving diuretics (p less than 0.001). In men, three beta-blockers (propranolol, oxprenolol, and metoprolol) have shown significantly lower risk for coronary events (fatal and nonfatal) in the nonsmoking subgroup. Results from the MAPHY study also indicated a reduction in total and coronary mortality with the beta-blocker as compared with thiazide diuretics. The observed reduced risk for coronary events with beta-blockers as compared with diuretics is probably independent of the reduction in blood pressure. Mechanisms currently under study include antiatherosclerotic effects, antithrombotic effects, anti-ischemic effects, and antifibrillatory effects. It is not possible to judge, with present evidence, if all beta-blockers are equally effective in preventing sudden death and other coronary events.


Discrimination between 34S and 32S during bacterial metabolism of inorganic sulfur compounds.
Sulfur isotope effects during the oxidation of thiosulfate by Thiobacillus versutus were found to be negligible. This result is considered in relation to other oxidative and reductive processes to assess which reactions are most likely to control the isotopic compositions of sulfur compounds in microbial sulfureta.


Kinetic changes associated with load carriage using two rucksack designs.
This study assessed changes in kinetics from unloaded walking associated with load carriage using both a traditional and a new rucksack design that incorporates front balance pockets (AARN). Nine subjects walked at 3(+/-0.05) km x h(-1) over a force plate unloaded and carrying 25.6 kg in each of the rucksacks. The order of trials was randomized and speed-controlled by use of photoelectric cells and a millisecond timer. Anteroposterior and vertical ground reaction forces were analyzed using repeated measures ANCOVA (speed covariate). There was a trend for the AARN pack to elicit a shorter support time than the traditional pack, 1.025+/-0.049 versus 1.037+/-0.06 s (p = 0.056), while the unloaded condition produced the shortest support time, 1.016+/-0.04 s. Both braking and propulsive forces for the rucksacks were significantly greater than for unloaded walking. While there was no significant difference between the packs for the braking force, the AARN pack produced a significantly lower (p<0.05) propulsive force than the traditional rucksack, 0.79+/-0.2 versus 0.94+/-0.16 N x kg bodyweight(-1). Both rucksacks produced significantly greater (p<0.001) vertical force peaks than unloaded walking, the increases being proportional to the increase in system weight. These findings indicate that there may be some advantage in terms of propulsive force production for the front/back system.


Understanding the Impact of Chronic Rhinosinusitis with Nasal Polyposis on Smell and Taste: An International Patient Experience Survey.
The aim is to understand the patient experience of living with chronic rhinosinusitis with nasal polyposis (CRSwNP), clinician interactions and how symptoms, smell and taste disturbance are managed. An anonymized, online survey was distributed through a UK charity, Fifth Sense, a UK otolaryngology clinic and online support groups to capture qualitative and quantitative data. Data were collected from 1st December 2022 to 1st February 2023. A total of 124 individuals participated. The majority were female (66%) and in the age range of 41-70 years; 74.2% of participants were from the UK with the rest from North America, Europe and Asia. A total of 107 participants declared they had CRSwNP. Rhinologists and general otolaryngology clinicians scored the highest for patient satisfaction whilst general practitioners scored the lowest. Satisfaction with the management of smell and taste disturbance was lower amongst all clinicians compared to overall satisfaction. Ratings correlated with response to therapy and clinician interactions. Respondents reported hyposmia/anosmia to be the most debilitating symptom. Surgery and oral steroids were considered to be effective; however, the benefit lasted less than six months (62%). Hyposmia/anosmia is a key CRSwNP symptom that has limited treatment options and is frequently undervalued by clinicians. There is a need for more effective management options, education and patient support.


Home or children's treatment centre: where should initial therapy assessments of children with disabilities be done?
Following developmental paediatric consultation at a child development clinic, 50 preschool children newly referred for a developmental rehabilitation programme were assigned randomly for initial therapist assessments at home or at the clinic. It was thought that children would perform more typically at home, that therapists would be able to observe more of the children's usual functions, and that parents would feel more satisfied. Despite several minor statistically significant differences between the two venues, there was no obvious advantage of home evaluation over clinic assessment. However, the added cost of home assessments was marginal, and there may still be some value in seeing young disabled children for first assessment in their own homes.


Fast and reliable fabrication of gold tips with sub-50 nm radius of curvature for tip-enhanced Raman spectroscopy.
We have developed a new electrochemical etching procedure to fabricate gold tips with sub-50 nm apical radius of curvature with a production yield of 80% and production time lower than 5 min. The technique is based on a two-step self-terminating process in which a gold wire is first quickly (<1 min) pre-etched in an hydrochloric acid (HCl)∕ethanol solution at high voltage (10 VDC), and then slowly (2-4 min) etched at lower voltages (<2.5 VDC). The first step occurs under intense bubbling conditions and allows us to thin rapidly the wire. This reduces the time required by subsequent low-voltage process during which the tips are formed at the liquid∕air interface. A statistical analysis of the surface morphology has been carried out on a set of 60 tips by scanning electron microscopy. The results show that the surface roughness and the sharpness of the final tip are critically influenced by the intrinsic granularity of the gold wires. Moreover, there is a correlation between the tip quality and the time elapse required to complete the low-voltage etching step. Tips featuring smooth surfaces and radii of curvature <50 nm are produced whenever the etching times are lower than 250 s, while etching times larger than 300 s typically yield rough, blunt tips. Such a correlation can be used as a screening criterion to select sharp tips during production with an 80% yield. The high quality of the gold tips produced with such method is confirmed by the electromagnetic field enhancement measured both in tip-enhanced Raman scattering and surface-enhanced Raman scattering on the tip apex experiments.


[Polyketides--status and perspective].
The increased resistance among pathogenic bacteria is an important reason for research into new drugs and into improved efficiency of the ones already existing. A group of natural products, the polyketides, exhibits a range of antibiotic and other important pharmacological activities. This group of natural products has therefore attracted much attention from researchers world-wide. The biosynthesis of polyketides occurs in a stepwise fashion on gigantic multienzymes. Individual enzymatic entities within these multienzymes are responsible for catalysis of each step in the biosynthetic pathway of the polyketide chain. It has been demonstrated that there is a direct correlation between the DNA-sequence encoding these enzymatic units and the order in which the reactions are catalysed. Polyketide synthases may thus be considered a molecular assembly line, and new polyketides can be designed by changing the modules of the assembly line. An understanding of the rules governing the genetic manipulation of the synthases is of course of the utmost importance for success. The first major steps towards this goal have been taken with the results from a number of new experiments.


Targeted deletion of p53 in the proximal tubule prevents ischemic renal injury.
The contribution of p53 to kidney dysfunction, inflammation, and tubular cell death, hallmark features of ischemic renal injury (IRI), remains undefined. Here, we studied the role of proximal tubule cell (PTC)-specific p53 activation on the short- and long-term consequences of renal ischemia/reperfusion injury in mice. After IRI, mice with PTC-specific deletion of p53 (p53 knockout [KO]) had diminished whole-kidney expression levels of p53 and its target genes, improved renal function, which was shown by decreased plasma levels of creatinine and BUN, and attenuated renal histologic damage, oxidative stress, and infiltration of neutrophils and macrophages compared with wild-type mice. Notably, necrotic cell death was attenuated in p53 KO ischemic kidneys as well as oxidant-injured p53-deficient primary PTCs and pifithrin-α-treated PTC lines. Reduced oxidative stress and diminished expression of PARP1 and Bax in p53 KO ischemic kidneys may account for the decreased necrosis. Apoptosis and expression of proapoptotic p53 targets, including Bid and Siva, were also significantly reduced, and cell cycle arrest at the G2/M phase was attenuated in p53 KO ischemic kidneys. Furthermore, IRI-induced activation of TGF-β and the long-term development of inflammation and interstitial fibrosis were significantly reduced in p53 KO mice. In conclusion, specific deletion of p53 in the PTC protects kidneys from functional and histologic deterioration after IRI by decreasing necrosis, apoptosis, and inflammation and modulates the long-term sequelae of IRI by preventing interstitial fibrogenesis.


Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase.
The molecular mechanism underlying adipogenesis and the physiological functions of adipose tissue are not fully understood. We describe here a unique mouse model of severe lipodystrophy. Ablation of Ptpn11/Shp2 in adipocytes, mediated by aP2-Cre, led to premature death, lack of white fat, low blood pressure, compensatory erythrocytosis, and hepatic steatosis in Shp2(fat-/-) mice. Fat transplantation partially rescued the lifespan and blood pressure in Shp2(fat-/-) mice, and administration of leptin also restored partially the blood pressure of mutant animals with endogenous leptin deficiency. Consistently, homozygous deletion of Shp2 inhibited adipocyte differentiation from embryonic stem (ES) cells. Biochemical analyses suggest a Shp2-TAO2-p38-p300-PPARγ pathway in adipogenesis, in which Shp2 suppresses p38 activation, leading to stabilization of p300 and enhanced PPARγ expression. Inhibition of p38 restored adipocyte differentiation from Shp2(-/-) ES cells, and p38 signaling is also suppressed in obese patients and obese animals. These results illustrate an essential role of adipose tissue in mammalian survival and physiology and also suggest a common signaling mechanism involved in adipogenesis and obesity development.


Presence of antimicrobial resistance in coliform bacteria from hatching broiler eggs with emphasis on ESBL/AmpC-producing bacteria.
Antimicrobial resistance is recognized as one of the most important global health challenges. Broilers are an important reservoir of antimicrobial resistant bacteria in general and, more particularly, extended-spectrum β-lactamases (ESBL)/AmpC-producing Enterobacteriaceae. Since contamination of 1-day-old chicks is a potential risk factor for the introduction of antimicrobial resistant Enterobacteriaceae in the broiler production chain, the presence of antimicrobial resistant coliform bacteria in broiler hatching eggs was explored in the present study. Samples from 186 hatching eggs, collected from 11 broiler breeder farms, were inoculated on MacConkey agar with or without ceftiofur and investigated for the presence of antimicrobial resistant lactose-positive Enterobacteriaceae, particularly, ESBL/AmpC-producers. Escherichia coli and Enterobacter cloacae were obtained from the eggshells in 10 out of 11 (10/11) sampled farms. The majority of the isolates were recovered from crushed eggshells after external decontamination suggesting that these bacteria are concealed from the disinfectants in the egg shell pores. Antimicrobial resistance testing revealed that approximately 30% of the isolates showed resistance to ampicillin, tetracycline, trimethoprim and sulphonamides, while the majority of isolates were susceptible to amoxicillin-clavulanic acid, nitrofurantoin, aminoglycosides, florfenicol, neomycin and apramycin. Resistance to extended-spectrum cephalosporins was detected in eight Enterobacteriaceae isolates from five different broiler breeder farms. The ESBL phenotype was confirmed by the double disk synergy test and blaSHV-12, blaTEM-52 and blaACT-39 resistance genes were detected by PCR. This report is the first to present broiler hatching eggs as carriers and a potential source of ESBL/AmpC-producing Enterobacteriaceae for broiler chicks.


Temperature-Sensitive Mutants in the Influenza A Virus RNA Polymerase: Alterations in the PA Linker Reduce Nuclear Targeting of the PB1-PA Dimer and Result in Viral Attenuation.
The influenza virus RNA-dependent RNA polymerase catalyzes genome replication and transcription within the cell nucleus. Efficient nuclear import and assembly of the polymerase subunits PB1, PB2, and PA are critical steps in the virus life cycle. We investigated the structure and function of the PA linker (residues 197 to 256), located between its N-terminal endonuclease domain and its C-terminal structured domain that binds PB1, the polymerase core. Circular dichroism experiments revealed that the PA linker by itself is structurally disordered. A large series of PA linker mutants exhibited a temperature-sensitive (ts) phenotype (reduced viral growth at 39.5°C versus 37°C/33°C), suggesting an alteration of folding kinetic parameters. The ts phenotype was associated with a reduced efficiency of replication/transcription of a pseudoviral reporter RNA in a minireplicon assay. Using a fluorescent-tagged PB1, we observed that ts and lethal PA mutants did not efficiently recruit PB1 to reach the nucleus at 39.5°C. A protein complementation assay using PA mutants, PB1, and β-importin IPO5 tagged with fragments of the Gaussia princeps luciferase showed that increasing the temperature negatively modulated the PA-PB1 and the PA-PB1-IPO5 interactions or complex stability. The selection of revertant viruses allowed the identification of different types of compensatory mutations located in one or the other of the three polymerase subunits. Two ts mutants were shown to be attenuated and able to induce antibodies in mice. Taken together, our results identify a PA domain critical for PB1-PA nuclear import and that is a "hot spot" to engineer ts mutants that could be used to design novel attenuated vaccines. By targeting a discrete domain of the PA polymerase subunit of influenza virus, we were able to identify a series of 9 amino acid positions that are appropriate to engineer temperature-sensitive (ts) mutants. This is the first time that a large number of ts mutations were engineered in such a short domain, demonstrating that rational design of ts mutants can be achieved. We were able to associate this phenotype with a defect of transport of the PA-PB1 complex into the nucleus. Reversion substitutions restored the ability of the complex to move to the nucleus. Two of these ts mutants were shown to be attenuated and able to produce antibodies in mice. These results are of high interest for the design of novel attenuated vaccines and to develop new antiviral drugs.


Association between Body Composition and Motor Performance in Preschool Children.
Being overweight makes physical movement more difficult. Our aim was to investigate the association between body composition and motor performance in preschool children. A total of 476 predominantly normal-weight preschool children (age 3.9 ± 0.7 years; m/f: 251/225; BMI 16.0 ± 1.4 kg/m2) participated in the Swiss Preschoolers' Health Study (SPLASHY). Body composition assessments included skinfold thickness, waist circumference (WC), and BMI. The Zurich Neuromotor Assessment (ZNA) was used to assess gross and fine motor tasks. After adjustment for age, sex, socioeconomic status, sociocultural characteristics, and physical activity (assessed with accelerometers), skinfold thickness and WC were both inversely correlated with jumping sideward (gross motor task β-coefficient -1.92, p = 0.027; and -3.34, p = 0.014, respectively), while BMI was positively correlated with running performance (gross motor task β-coefficient 9.12, p = 0.001). No significant associations were found between body composition measures and fine motor tasks. The inverse associations between skinfold thickness or WC and jumping sideward indicates that children with high fat mass may be less proficient in certain gross motor tasks. The positive association between BMI and running suggests that BMI might be an indicator of fat-free (i.e., muscle) mass in predominately normal-weight preschool children.


Effect of (-)-epigallocatechin-3-gallate on maintaining the periodontal ligament cell viability of avulsed teeth: a preliminary study.
Avulsed tooth can be completely recovered, if sound periodontal ligament (PDL) of tooth is maintained. Although a lot of storage solutions have been explored for the better storage of avulsed tooth, there is a shortcoming that the preservation time is much short. On the other hand, there has been studies that (-)-epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, which is related to the anti inflammatory, antioxygenic, and antibacterial effects, allows the successful preservations of tissues and cells. This study evaluated the effect of EGCG on avulsed-teeth preservation of Beagle dogs for a period of time. The atraumatically extracted teeth of Beagle dogs were washed and preserved with 0/10/100 µM of EGCG at the time of immediate, period 1 (4 days in EGCG-contained media and additional 1 day in EGCG-free media), period 2 (8 days in EGCG-contained media and additional 2 days in EGCG-free media) and period 3 (12 days in EGCG-contained media and additional 2 days in EGCG-free media). Then, the cell viabilities of preserved teeth was calculated by dividing optical density (OD) of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with OD of eosin assay to eliminate the measurement errors caused by the different tissue volumes. From the results, the immediately analyzed group presented the highest cell viability, and the rate of living cells on teeth surface decreased dependent on the preservation period. However, the 100 µM of EGCG-treated group showed statistically significant positive cell activity than EGCG-free groups throughout preservation periods. Our findings showed that 100 µM EGCG could maintain PDL cell viability of extracted tooth. These results suggest that although EGCG could not be a perfect additive for tooth preservation, it is able to postpone the period of tooth storage. However, further in-depth studies are required for more plausible use of EGCG.


Role of periodontal ligament fibroblasts in osteoclastogenesis: a review.
During the last decade it has become clear that periodontal ligament fibroblasts may contribute to the in vitro differentiation of osteoclasts. We surveyed the current findings regarding their osteoclastogenesis potential. Periodontal ligament fibroblasts have the capacity to select and attract osteoclast precursors and subsequently to retract and enable migration of osteoclast precursors to the bone surface. There, fusion of precursors takes place, giving rise to osteoclasts. The RANKL-RANK-osteoprotegerin (OPG) axis is considered crucial in this process. Periodontal ligament fibroblasts produce primarily OPG, an osteoclastogenesis-inhibitory molecule. However, they may be influenced in vivo by direct or indirect interactions with bacteria or by mechanical loading. Incubation of periodontal ligament fibroblasts with bacteria or bacterial components causes an increased expression of RANKL and other osteoclastogenesis-stimulating molecules, such as tumor necrosis factor-α and macrophage-colony stimulating factor. Similar results are observed after the application of mechanical loading to these fibroblasts. Periodontal ligament fibroblasts may be considered to play an important role in the remodelling of alveolar bone. In vitro experiments have demonstrated that periodontal ligament fibroblasts adapt to bacterial and mechanical stimuli by synthesizing higher levels of osteoclastogenesis-stimulating molecules. Therefore, they probably contribute to the enhanced osteoclast formation observed during periodontitis and to orthodontic tooth movement.