Cytokine profile and nitric oxide levels in sera from patients with brucellosis.
The aims of this study were to investigate the serum levels of some cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), IL-2R, IL-6, and IL-8] and nitric oxide (NO) levels in patients with untreated brucellosis and to test the correlation of these parameters with each other. The study was conducted on 67 subjects, 37 patients with brucellosis and 30 healthy individuals with no history of Brucella infection. Brucellosis was identified by a positive blood culture and/or increased Brucella antibodies in serological tests in addition to compatible clinical symptoms. Cytokine profile analysis was performed by the immulite chemiluminescent enzyme immunometric assay whose inter- and intra-assay coefficients of variance were 2.6-3.6 and 4.4-8.5%, respectively. The levels of nitrites/nitrates, which are representative of NO levels, were measured by the Griess method. Patients with brucellosis had significantly elevated serum levels of nitrites/nitrates, IL-2R, IL-6 and IL-8 (mean +/- SD, 102.8 +/- 23.8 micromol/l, 806.1 +/- 58.5 U/ml, 21.1 +/- 2.3 pg/ml, and 8.8 +/- 1.6 pg/ml, respectively) compared to healthy controls, whereas TNF-alpha and IL-1beta levels were unchanged. No statistically significant correlation was detected between any of the studied cytokine levels and nitrate/nitrite concentrations according to Pearson's linear correlation test. We conclude that only IL-6, IL-8 and IL-2R are elevated in brucellosis and the extent of elevation depends on the severity and clinical pattern of the disease. Moderate elevation in serum NO was comparable to that observed in previous studies. This explains the absence or very rare occurrence of septic shock in brucellosis.


Translational immunology: Applying fundamental discoveries to human health and autoimmune diseases.
Studying the human immune system is challenging. These challenges stem from the complexity of the immune system itself, the heterogeneity of the immune system between individuals, and the many factors that lead to this heterogeneity including the influence of genetics, environment, and immune experience. Studies of the human immune system in the context of disease are increased in complexity as multiple combinations and variations in immune pathways can lead to a single disease. Thus, although individuals with a disease may share clinical features, the underlying disease mechanisms and resulting pathophysiology can be diverse among individuals with the same disease diagnosis. This has consequences for the treatment of diseases, as no single therapy will work for everyone, therapeutic efficacy varies among patients, and targeting a single immune pathway is rarely 100% effective. This review discusses how to address these challenges by identifying and managing the sources of variation, improving access to high-quality, well-curated biological samples by building cohorts, applying new technologies such as single-cell omics and imaging technologies to interrogate samples, and bringing to bear computational expertise in conjunction with immunologists and clinicians to interpret those results. The review has a focus on autoimmune diseases, including rheumatoid arthritis, MS, systemic lupus erythematosus, and type 1 diabetes, but its recommendations are also applicable to studies of other immune-mediated diseases.


Review and recommendations for zero-inflated count regression modeling of dental caries indices in epidemiological studies.
Over the past 5-10 years, zero-inflated (ZI) count regression models have been increasingly applied to the analysis of dental caries indices (e.g. DMFT, dfms). The main reason for that is linked to the broad decline in children's caries experience, such that dmf and DMF indices more frequently generate low or even zero counts. This article specifically reviews the application of ZI Poisson and ZI negative binomial regression models to dental caries, with emphasis on the description of the models and the interpretation of fitted model results given the study goals. The review finds that interpretations provided in the published caries research are often imprecise or inadvertently misleading, particularly with respect to failing to discriminate between inference for the class of susceptible persons defined by such models and inference for the sampled population in terms of overall exposure effects. Recommendations are provided to enhance the use as well as the interpretation and reporting of results of count regression models when applied to epidemiological studies of dental caries.


Two Decades of Mercury Concentrations in Barents Sea Polar Bears (Ursus maritimus) in Relation to Dietary Carbon, Sulfur, and Nitrogen.
Temporal trends of total mercury (THg) were examined in female polar bear (Ursus maritimus) hair (n = 199) from the Barents Sea in 1995-2016. In addition, hair values of stable isotopes (n = 190-197) of carbon (δ13C), sulfur (δ34S), and nitrogen (δ15N) and information on breeding status, body condition, and age were obtained. Stable isotope values of carbon and sulfur reflect dietary source (e.g., marine vs terrestrial) and the nitrogen trophic level. Values for δ13C and δ34S declined by -1.62 and -1.18‰ over the time of the study period, respectively, while values for δ15N showed no trend. Total Hg concentrations were positively related to both δ13C and δ34S. Yearly median THg concentrations ranged from 1.61 to 2.75 μg/g and increased nonlinearly by 0.86 μg/g in total over the study. Correcting THg concentrations for stable isotope values of carbon and sulfur and additionally breeding status and age slightly accelerated the increase in THg concentrations; however, confidence intervals of the raw THg trend and the corrected THg trend had substantial overlap. The rise in THg concentrations in the polar bear food web was possibly related to climate-related re-emissions of previously stored Hg from thawing sea-ice, glaciers, and permafrost.


Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity.
Heterotrimers composed of B cell CLL/lymphoma 10 (BCL10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and caspase recruitment domain-containing (CARD) family adaptors play a role in NF-κB activation and have been shown to be involved in both the innate and the adaptive arms of immunity in murine models. Moreover, individuals with inherited defects of MALT1, CARD9, and CARD11 present with immunological and clinical phenotypes. Here, we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation. The effect of BCL10 deficiency was dependent on the signaling pathway, and, for some pathways, the cell type affected. Despite the noted similarities to BCL10 deficiency in mice, including a deficient adaptive immune response, human BCL10 deficiency in this patient resulted in a number of specific features within cell populations. Treatment of the patient's myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB-mediated fibroblast functions were dramatically impaired. The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects.


Vertebroplasty and Return to Work for Thoracolumbar Fractures Within the Workers' Compensation Population.
Retrospective cohort study. Analyze efficacy of vertebroplasty and its affect on return to work (RTW) in a workers' compensation (WC) population SUMMARY OF BACKGROUND DATA.: Vertebroplasty remains a controversial treatment modality for vertebral compression fractures (VCFs). No studies have analyzed use of vertebroplasty in the clinically distinct WC population. A total of 371 Ohio WC subjects were identified who sustained VCFs and were treated with either vertebroplasty or conservative medical therapy between 1993 and 2013 using Current Procedural Terminology procedural and International Classification of Diseases, Ninth Revision diagnosis codes. Subjects with a prior smoking history, prior thoracolumbar surgery or comorbidities, or underwent decompression and/or fusion within 3 months after injury were excluded. Forty-six subjects had undergone vertebroplasty within 1 year of injury and were therefore included in the vertebroplasty group. The remaining 325 subjects received spinal orthosis and formed the control group. The primary outcomes were whether subjects returned to work at early and late time points. Early RTW was defined as returning to work within 3 months and remaining at work for more than 6 months of the following year. Late RTW was defined as returning to work within 2 years and remaining at work for more than 6 months of the following year. Secondary outcomes included opioid use, all-cause mortality, and additional VCFs. Approximately 37% (17/46) of vertebroplasty group made an early RTW, compared with 35.4% (115/325) of control group (P = 0.835). Regarding late RTW, only 54.3% (25/46) of vertebroplasty group made a sustainable RTW, compared with 70.8% (230/325) of subjects in control group (P = 0.025). In addition, the vertebroplasty group was associated with significantly higher postoperative opioid use. Vertebroplasty may not be an effective treatment modality for VCFs in the WC population when RTW is the primary goal. 3.


Probability distribution of enantiomorphous forms in spontaneous generation of optically active substances.
The crystallization of 1, l'-binaphthyl from its racemic melt is an example of spontaneous generation of optical activity. The distribution of specific rotations in 200 individual samples varied from [alpha](D) = -218 degrees to [alpha](D) = +206 degrees with a mean of +0.14 degree and standard deviation of 86.4 degrees. This resolution into enantiomers is determined by chance development, with equal probability, of right- or left-handed crystallites; it can be controlled and made stereospecific by addition of dissymmetric compounds at low concentrations.


Candidiasis: the isomorphic response.
Two uncontrolled insulin dependent diabetic patients had Candida albicans infection with the unique manifestation of erythematous scaling papulopustules at the sites of excoriation. In one patient, the clinical presentation suggested herpes zoster. Recognition of this picture and the contributing factors, i.e. Candida infected finger nails and elevated blood sugar will permit early use of appropriate antifungal therapy.


Maturation and persistence of the anti-SARS-CoV-2 memory B cell response.
Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.


Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery.
Predatory cone snails (genus Conus) produce a rich array of venoms that collectively contain an estimated 100,000 small, disulfide-rich peptides (i.e., conotoxins, or conopeptides). Over the last few decades, the conopeptides have revealed a remarkable diversity of pharmacological function and utility. An evolutionary rationale for the existence of such a large and pharmacologically diverse set of gene products can be premised on the complexity of intra- and interspecies interactions that define the ecology of Conus snails. Insights into these evolutionary trends, moreover, have been exploited with great neuropharmacological success, so that research into the Conus snails effectively recapitulates a new concerted discovery approach, which we discuss here, for developing unique ligands for both laboratory and therapeutic applications. The Conus peptides thus serve as a model system for reaping the pharmacological potential of biodiverse animal lineages.


NAD(P)H oxidases regulate HIF-2alpha protein expression.
Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene (VHL) is linked to the development of hereditary and sporadic renal cell carcinoma (RCC). In the absence of VHL, the alpha subunits of heterodimeric hypoxia-inducible transcription factors (HIF-1alpha and HIF-2alpha) are stabilized. Reactive oxygen species, generated by NAD(P)H oxidases, are involved in signaling cascades of malignant growth. We show that in VHL-deficient cells p22phox, Nox4 protein levels and NADPH-dependent superoxide generation are increased. Reintroduction of VHL into the VHL-deficient cells down-regulates the expression of p22phox and NADPH-dependent superoxide generation. Inhibition of the 26 S proteasome in VHL-expressing cells increased p22phox protein levels, which correlated with an increase of NADPH-dependent superoxide generation. We also show that p22phox co-immunoprecipitates with VHL in vivo. Moreover, p22phox is a target of ubiquitination. Importantly, in VHL-deficient cells, diphenyleneiodonium chloride (DPI), an inhibitor of Nox oxidases, decreased the expression of HIF-2alpha. Down-regulation of Nox1, Nox4, and p22phox expression by small interfering RNA also decreased HIF-2alpha protein expression and inhibited Akt and 4E-BP1 phosphorylation, suggesting that a translational mechanism is involved in maintaining HIF-2alpha in VHL-deficient cells. Colony formation by RCC 786-O in soft agar was markedly inhibited by DPI. Moreover, DPI significantly inhibited RCC 786-O tumor formation in athymic mice. Collectively, the data demonstrate that VHL protein exerts its tumor suppressor action, at least partially, via inhibition of p22phox-based Nox4/Nox1 NADPH oxidase-dependent reactive oxygen species generation.


Current levels of heavy metal pollution in Africa.
Studies of environmental pollution in Africa indicate that toxic metal pollution has reached unprecedented levels over the past decade. Human exposure to toxic metals has become a major health risk on the continent and is the subject of increasing attention from national and international environmentalists. This paper reviews data from the past decade on environmental pollution in Africa and highlights countries where most heavy metal pollutions have been reported. Characteristics of heavy metal pollution in North, West, East and Southern regions of Africa have been described, as have major sources of pollution in the different regions. This review summarizes the sites where most of the heavy metal pollution has been reported in Africa and, where applicable, presents reported levels of pollution in different environmental compartments in the context of internationally acceptable limits. Contaminations in fish and food animals as well as impacts of heavy metal pollution on humans are also described.


[Study of rat control by using bait box].
This study examines the feasibility of using bait boxes for permanent rat control in Taiwan. During the test period between October 1988 and March 1989, 37 bait boxes made of PVC pipes were placed at various baiting sites in public markets, near restaurants and food stands in several communities known to be infested by rats. Each of the 37 boxes was baited with non-toxic rice powder to determine how well these boxes were accepted, the time needed for rats to use the boxes and eat the bait, and to do preliminary census on the relative densities of rat populations at these different places. The results showed that 27 of 29 (93.1%) bait boxes that had not been vandalized, disturbed or moved away and could be monitored continuously were used by rats. Of these 27 bait boxes, 13 (48.1%) were used the day after the boxes were set, and 25 (92.6%) were used within a week after the boxes were set. The amount of bait eaten per day for each bait box varied greatly, from less than 5 g to more than 300 g. After the bait in each bait box was taken regularly, half of the bait boxes with good bait acceptance were pulse-baited with 0.005% brodifacoum coated rice powder, and the other half of the bait boxes with good bait acceptance were baited with non toxic rice powder for comparison. The result of treatment indicated that rat control by using bait boxes is effective. However, the cooperation of the local people and the location of bait boxes have a great influence over the success of this control method.


Interictal myoclonus with paroxysmal kinesigenic dyskinesia.
We report a new association between interictal myoclonus and paroxysmal kinesigenic dyskinesia (PKD) in 2 patients. By definition, PKD is transient, but the overexcitability of the neuronal system that induces these attacks may be permanent. Interictal myoclonus could be a manifestation of permanent overexcitability.


Extranodal diffuse large B-cell lymphomas: A retrospective case series and review of the literature.
Non-Hodgkin lymphomas commonly show extranodal involvement (25-30%) but primary diffuse large B-cell lymphomas (DLBCL) with extranodal localization represent clinically and molecularly distinct entities. The present study involved retrospective analysis of case records of 4 patients who were diagnosed with extranodal DLBCL between 2010 and 2016 at the Medical Oncology and Hematology Departments of the Ioannina University Hospital, Greece. Median age of presentation was 69 years (range 60-77 years). There were 2 males and 2 females. The sites of DLBCL involvement included adrenal gland, mandible, cervix uteri, and ileum. Two patients had B symptoms while none had bone marrow involvement. After staging workup, all the patients fell into IE stage. The treatment approach included chemotherapy combined with rituximab (R), whereas one patient received additionally irradiation therapy. Post-treatment positron emission tomography-computed tomography scan was performed in 3 patients. In terms of the outcome, 3 patients are alive in complete response, whereas one was lost in follow-up. Further prospective data analyses are required so as to better elucidate the biology and course of extranodal DLBCL.


Evaluation of the efficacy and safety of percutaneous biopsy of lung.
Percutanous needle biopsy of the lung (PNBL), under image guidance, has established itself as a safe and effective minimally-invasive method of obtaining a tissue diagnosis of pulmonary lesions, for selected patients with suspected pathologic processes. The purpose of this study was to evaluate the diagnostic yield and safety of percutaneous core biopsy of the lung (PCBL) without Fine Needle Aspiration Biopsy (FNAB), with specific attention to potential risk factors that may predict post-biopsy pneumothorax. A retrospective analysis of 75 consecutive PCBL procedures between January 2006 to March 2008 involving 72 patients with a documented pulmonary nodule or mass lesion on CT scan of Thorax. The study population included 38 males (52.8%) and 34 females (47.2%) aged 20-85 years (mean age 63.6 years). A co-axial cutting system with a 19-gauge outer needle and a 20-gauge inner automated cutting needle (Temno, Allegiance Healthcare Corporation, Ohio, USA) was used in all patients. Lesions varied in size from 0.7cm to 10.7cm (mean maximum trans-axial diameter 3.1cm). The mean number of core biopsy samples obtained was 3.1 (range 1-5). Of the 75 PCBL procedures, 71 yielded specimens adequate for histopathologic evaluation, consistent with a technical success rate of 95%. Malignancy was detected in 48 specimens (64%) and benign diagnoses were identified in 23 specimens (31%). As mentioned, 4 specimens (5%) were nondiagnostic. The most common biopsy-induced complication was pneumothorax, occurring in 15 patients (20%), with 4 (5.3%) requiring thoracostomy tube placement. PCBL without FNAB, under CT fluoroscopy guidance, has an excellent diagnostic accuracy in obtaining a conclusive histologic diagnosis of thoracic lesions and is comparable to FNAB in terms of safety and rates of occurence of complications.


Homocysteine exposure affects early hemodynamic parameters of embryonic chicken heart function.
Maternal hyperhomocysteinemia has been associated with an increased risk of newborns with a congenital heart defect. This has been substantiated in the chicken embryo, as congenital heart defects have been induced after homocysteine treatment. Comparable heart defects are observed in venous clipping studies, a model of altered embryonic blood flow. Because of this overlap in heart defects, our aim was to test the hypothesis that homocysteine would cause alterations in embryonic heart function that precede the structural malformations previously described. Therefore, Doppler flow velocity waveforms were recorded in both primitive ventricles and the outflow tract of the embryonic heart of homocysteine treated and control chicken embryos at embryonic day 3.5. Homocysteine treatment consisted of 50 μL 0.05 M L-homocysteine thiolactone at 24, 48, and 72 hr. Homocysteine-treated embryos displayed significantly lower mean heart rates of 134 (SD 22) bpm, compared to 150 (14) bpm in control embryos. Homocysteine treatment caused an inhibiting effect on hemodynamic parameters, and altered heart function was presented by a shift in the proportions of the different wave times in percentage of total cycle time. Homocysteine induces changes in hemodynamic parameters of early embryonic chicken heart function. These changes may precede morphological changes and contribute to the development of CHD defects through alterations in shear stress and shear stress related genes, as seen before in venous clipping studies.


Respiratory muscle injury, fatigue and serum skeletal troponin I in rat.
To evaluate injury to respiratory muscles of rats breathing against an inspiratory resistive load, we measured the release into blood of a myofilament protein, skeletal troponin I (sTnI), and related this release to the time course of changes in arterial blood gases, respiratory drive (phrenic activity), and pressure generation. After approximately 1.5 h of loading, hypercapnic ventilatory failure occurred, coincident with a decrease in the ratio of transdiaphragmatic pressure to integrated phrenic activity (P(di)/ integral Phr) during sighs. This was followed at approximately 1.9 h by a decrease in the P(di)/ integral Phr ratio during normal loaded breaths (diaphragmatic fatigue). Loading was terminated at pump failure (a decline of P(di) to half of steady-state loaded values), approximately 2.4 h after load onset. During 30 s occlusions post loading, rats generated pressure profiles similar to those during occlusions before loading, with comparable blood gases, but at a higher neural drive. In a second series of rats, we tested for sTnI release using Western blot-direct serum analysis of blood samples taken before and during loading to pump failure. We detected only the fast isoform of sTnI, release beginning midway through loading. Differential detection with various monoclonal antibodies indicated the presence of modified forms of fast sTnI. The release of fast sTnI is consistent with load-induced injury of fast glycolytic fibres of inspiratory muscles, probably the diaphragm. Characterization of released fast sTnI may provide insights into the molecular basis of respiratory muscle dysfunction; fast sTnI may also prove useful as a marker of impending respiratory muscle fatigue.


Effects of the antimicrobial tylosin on the microbial community structure of an anaerobic sequencing batch reactor.
The effects of the antimicrobial tylosin on a methanogenic microbial community were studied in a glucose-fed laboratory-scale anaerobic sequencing batch reactor (ASBR) exposed to stepwise increases of tylosin (0, 1.67, and 167 mg/L). The microbial community structure was determined using quantitative fluorescence in situ hybridization (FISH) and phylogenetic analyses of bacterial 16S ribosomal RNA (rRNA) gene clone libraries of biomass samples. During the periods without tylosin addition and with an influent tylosin concentration of 1.67 mg/L, 16S rRNA gene sequences related to Syntrophobacter were detected and the relative abundance of Methanosaeta species was high. During the highest tylosin dose of 167 mg/L, 16S rRNA gene sequences related to Syntrophobacter species were not detected and the relative abundance of Methanosaeta decreased considerably. Throughout the experimental period, Propionibacteriaceae and high GC Gram-positive bacteria were present, based on 16S rRNA gene sequences and FISH analyses, respectively. The accumulation of propionate and subsequent reactor failure after long-term exposure to tylosin are attributed to the direct inhibition of propionate-oxidizing syntrophic bacteria closely related to Syntrophobacter and the indirect inhibition of Methanosaeta by high propionate concentrations and low pH.


Alpha 2-macroglobulin-proteinase complexes as correlated with alpha 1-proteinase inhibitor-elastase complexes in synovial fluids of rheumatoid arthritis patients.
The levels of alpha1-proteinase inhibitor-elastase and alpha 2-macroglobulin (alpha 2M)-proteinase complexes were measured in synovial fluids from arthritis patients by use of specific immunosorbent assays. Both types of proteinase inhibitor-proteinase complexes were significantly correlated with each other as well as with the total neutrophil count in synovial fluids of rheumatoid arthritis patients but were discordant in synovial fluids of patients with osteoarthritis. One synovial fluid sample showed active (inhibitory) alpha 2M as well as active collagenase. We purified alpha 2M from pooled synovial fluids obtained from patients with rheumatoid arthritis. This alpha 2M retained approximately 90% of its proteinase binding (inhibiting) capacity, compared with that of normal plasma alpha 2M. We found no evidence that alpha 2M was inactivated by means other than proteinases.


1st EFORT European Consensus "Medical & Scientific Research Requirements for the Clinical Introduction of Artificial Joint Arthroplasty Devices": Background, Delphi Methodology & Consensus process.
The objectives of the 1st EFORT European Consensus on 'Medical and Scientific Research Requirements for the Clinical Introduction of Artificial Joint Arthroplasty Devices' were foremost to focus on patient safety by establishing performance requirements for medical devices. The 1st EFORT European Consensus applied an a priori-defined, modified Delphi methodology to produce unbiased, high-quality recommendation statements, confirmed by consensus voting of a European expert panel. Intended key outcomes are practical guidelines justified by the current stage of knowledge and based on a broad European Expert Consensus, to maintain innovation and optimisation of orthopaedic devices within the boundaries of MDR 2017/745. Twenty-one main research areas of relevance were defined relying on input from the EFORT IPSI WG1 'Introduction of Innovation' recommendations and a related survey. A modified Delphi approach with a preparatory literature review and work in small groups were used to prepare answers to the research questions in the form of 32 draft Consensus statements. A Consensus Conference in a hybrid format, on-site in the Carl Gustav Carus University of Dresden was organised to further refine the draft statements and define consensus within the complete group of participants by final voting, intended to further quantify expert opinion knowledge. The modified Delphi approach provides practical guidelines for hands-on orientation for orthopaedic surgeons, research institutes and laboratories, orthopaedic device manufacturers, patient representatives, Notified Bodies, National Institutes and authorities. For the first time, initiated by the EFORT IPSI (WG1 'Introduction of Innovation'), knowledge of all related stakeholders was combined in the 1st EFORT European Consensus to develop guidelines and result in a comprehensive set of recommendations.


Adenocarcinoma of the alimentary tract: peritoneal distribution scintigraphy.
Effective intraperitoneal (IP) chemotherapy and colloidal radiation therapy depend on contact of the drugs with the entire peritoneal surface. Using technetium-99m sulfur colloid, one can evaluate the completeness of peritoneal fluid distribution. Forty-eight planar IP scans from 26 patients with gastrointestinal malignancies were reviewed and scan findings were correlated with the site of primary tumor, surgical findings, and the location of any residual disease. Of the 26 patients, 22 had undergone resection of the primary lesion prior to scanning. Scans typically demonstrated more activity in the upper and lower portions of the abdomen than in the midabdomen. Diminished uptake in the pelvis, right lower quadrant, and right upper quadrant was generally due to metastases. A tumor mass was identified as responsible in only one of eight patients with diminished or absent left upper quadrant activity. Knowledge of variability in patterns seen on IP scans is essential to rational guidance of IP chemotherapy and radiation therapy.


The site of action of lidocaine in intravenous regional anesthesia.
Despite vast clinical experience and success with intravenous regional anaesthesia (IVRA), the site and mode of action of the local anesthetic agents remains controversial. Many investigations have been published, but conclusions are variable. The principal site of action of lidocaine in IVRA was studied using 15 ASA I-II patients receiving surgical operation on the hands and forearms. A 22 gauge plastic cannula was inserted into the median cubital vein at the elbow. A double cuff tourniquet was secured on the upper arm, as described by Bier and modified by Homes. Another single tourniquet was then applied on the forearm as near the plastic catheter as possible. Two different concentrations of lidocaine (0.5% and 2%) in a total dose of 3 mg kg-1 was slowly injected into the vein via the catheter after the limb was exsanguinated and the tourniquets were inflated. The results showed that 0.5% lidocaine produced analgesia only on the intercuff area; there was no analgesic response noted on the forearm distal to the third tourniquet after a 15 minutes observation. However patients who received 2% lidocaine experienced in analgesia rapidly on the intercuff area and also slowly on the forearm and hand. The anesthesia developed from the fingertips upward. Based on this evidence, we concluded that the principal site of action of lidocaine in IVRA depends on concentration. The lower concentration acts on the sensory nerve endings and the small nerves. Whereas, the higher concentration acts on both nerve trunks and nerve endings.


Identification of an ectopic periorbital lymph node in two horses.
To describe the clinical presentation and treatment of an ectopic periorbital lymph node in two young horses. Two warm-blood horses were presented at the equine clinic of the University of Liège with a periorbital non-painful mass. Differential diagnosis included neoplasm (lymphoma), (sterile) abscess, cyst, ectopic lacrimal gland tissue, hematoma, adipose tissue, or ectopic lymphoid tissue. Information collected included physical and ophthalmic examination findings, results of the ocular and periocular ultrasound, surgical procedure, histopathology, and follow-up. Masses of 2 × 2 cm and 3 × 2 cm subcutaneous, ovoid, smooth, and firm mass were observed in the zygomatic region of the head. On ultrasound, the mass appeared as a hypoechoic subcutaneous structure. Cytology showed a mixed lymphocytic cell population. No abnormal mitotic activity was observed. Histopathology revealed a chronic markedly reactive lymph node. To the authors' knowledge, this is the first description of periorbital ectopic lymph nodes in veterinary medicine. Ectopic lymph nodes should therefore be included in the differential diagnosis of periocular masses in animals. Surgery was easily performed and was curative.


[Myopathy caused by hypothyroidism].
The authors report a case of primary hypothyroidism where the main symptoms were caused by muscular lesions and disappeared after treatment with L-thyroxine. Based on this case study the authors then review both the clinical aspects and the diagnostical methods of hypothyroidism myopathy, noting its frequency, be it in terms of isolated laboratory changes or in terms of functional changes.


Inhaled Biologicals for the Treatment of Cystic Fibrosis.
Cystic Fibrosis (CF), one of the most frequent genetic diseases, is characterized by the production of viscous mucus in several organs. In the lungs, mucus clogs the airways and traps bacteria, leading to recurrent/resistant infections and lung damage. For cystic fibrosis patients, respiratory failure is still lethal in early adulthood since available treatments display incomplete efficacy. The objective of this review is to extend the current knowledge in the field of available treatments for cystic fibrosis. A special focus has been given to inhaled peptide-based drugs. The current review is based on recent and/or relevant literature and patents already available in various scientific databases, which include PubMed, PubMed Central, Patentscope and Science Direct. The information obtained through these diverse databases is compiled, critically interpreted and presented in the current study. An in-depth but not systematic approach to the specific research question has been adopted. Recently, peptides have been proposed as possible pharmacologic agents for the treatment of respiratory diseases. Of note, peptides are suitable to be administered by inhalation to maximize efficacy and reduce systemic side effects. Moreover, innovative delivery carriers have been developed for drug administration through inhalation, allowing not only protection against proteolysis, but also a prolonged and controlled release. Here, we summarize newly patented peptides that have been developed in the last few years and advanced technologies for inhaled drug delivery to treat cystic fibrosis.


Exploring the impact of an automated prescription-filling device on community pharmacy technician workflow.
To explore community pharmacy technician workflow change after implementation of an automated robotic prescription-filling device. At an independent community pharmacy in rural Mayville, WI, pharmacy technicians were observed before and 3 months after installation of an automated robotic prescription-filling device. The main outcome measures were sequences and timing of technician workflow steps, workflow interruptions, automation surprises, and workarounds. Of the 77 and 80 observations made before and 3 months after robot installation, respectively, 17 different workflow sequences were observed before installation and 38 after installation. Average prescription filling time was reduced by 40 seconds per prescription with use of the robot. Workflow interruptions per observation increased from 1.49 to 1.79 (P = 0.11), and workarounds increased from 10% to 36% after robot use. Although automated prescription-filling devices can increase efficiency, workflow interruptions and workarounds may negate that efficiency. Assessing changes in workflow and sequencing of tasks that may result from the use of automation can help uncover opportunities for workflow policy and procedure redesign.


Anti-plasminogen antibodies compromise fibrinolysis and associate with renal histology in ANCA-associated vasculitis.
Antibodies recognizing plasminogen, a key component of the fibrinolytic system, associate with venous thrombotic events in PR3-ANCA vasculitis. Here, we investigated the prevalence and function of anti-plasminogen antibodies in independent UK and Dutch cohorts of patients with ANCA-associated vasculitis (AAV). We screened Ig isolated from patients (AAV-IgG) and healthy controls by ELISA. Eighteen of 74 (24%) UK and 10/38 (26%) Dutch patients with AAV had anti-plasminogen antibodies compared with 0/50 and 1/61 (2%) of controls. We detected anti-plasminogen antibodies in both PR3-ANCA- and MPO-ANCA-positive patients. In addition, we identified anti-tissue plasminogen activator (tPA) antibodies in 13/74 (18%) patients, and these antibodies were more common among patients with anti-plasminogen antibodies (P = 0.011). Eighteen of 74 AAV-IgG (but no control IgG) retarded fibrinolysis in vitro, and this associated with anti-plasminogen and/or anti-tPA antibody positivity. Only 4/18 AAV-IgG retarded fibrinolysis without harboring these antibodies; dual-positive samples retarded fibrinolysis to the greatest extent. Patients with anti-plasminogen antibodies had significantly higher percentages of glomeruli with fibrinoid necrosis (P < 0.05) and cellular crescents (P < 0.001) and had more severely reduced renal function than patients without these antibodies. In conclusion, anti-plasminogen and anti-tPA antibodies occur in AAV and associate with functional inhibition of fibrinolysis in vitro. Seropositivity for anti-plasminogen antibodies correlates with hallmark renal histologic lesions and reduced renal function. Conceivably, therapies that enhance fibrinolysis might benefit a subset of AAV patients.


Prediction of Plasma Concentration-time Profiles of Drugs in Humans from Animals Following Oral Administration: An Allometric Approach.
Allometric scaling is regularly used for the prediction of human pharmacokinetic (PK) parameters from animal PK studies. The predicted human PK parameters can also be used for the prediction of plasma concentration-time profiles in humans. The main objective of this work is to predict human concentration-time profiles of drugs (one-compartment model) following oral administration using animal oral pharmacokinetic parameters. Six drugs from the literature were chosen that were described by one-compartment model in both humans and animals following oral administration. Pharmacokinetic parameters such as oral clearance, oral volume of distribution of the central compartment, time to reach maximum plasma concentration, absorption rate constant, and half-life in humans were predicted from animals using allometric scaling. These predicted human pharmacokinetic parameters were then used to predict human plasma concentrations-time profiles of drugs. The results of this study indicate that the proposed method can be used to predict human plasma concentrations- time profiles of drugs with reasonable accuracy (≤50% prediction error). Given the complexity in the pharmacokinetics of oral drugs there remains some uncertainty in this entire exercise. One can minimize the prediction error by experience in allometric scaling, scientific judgment, and unconventional or innovative thinking.


Absolute determination of the wavelength and spectrum of an extreme-ultraviolet beam by a Young's double-slit measurement.
The interference pattern produced by irradiation of a pair of pinholes with a beam contains information on both the spatial and the temporal coherence properties of the beam, as well as its power spectrum. We demonstrate experimentally for what is believed to be the first time that the spectrum of an extreme-ultraviolet (EUV) beam can be obtained from a measurement of the interference pattern produced by a pinhole pair. This approach offers a convenient method of making absolute wavelength and relative spectral intensity calibrations in the EUV.


Comparisons of transient evoked otoacoustic emissions using chirp and click stimuli.
Transient-evoked otoacoustic emission (TEOAE) responses (0.7-8 kHz) were measured in normal-hearing adult ears using click stimuli and chirps whose local frequency increased or decreased linearly with time over the stimulus duration. Chirp stimuli were created by allpass filtering a click with relatively constant incident pressure level over frequency. Chirp TEOAEs were analyzed as a nonlinear residual signal by inverse allpass filtering each chirp response into an equivalent click response. Multi-window spectral and temporal averaging reduced noise levels compared to a single-window average. Mean TEOAE levels using click and chirp stimuli were similar with respect to their standard errors in adult ears. TEOAE group delay, group spread, instantaneous frequency, and instantaneous bandwidth were similar overall for chirp and click conditions, except for small differences showing nonlinear interactions differing across stimulus conditions. These results support the theory of a similar generation mechanism on the basilar membrane for both click and chirp conditions based on coherent reflection within the tonotopic region. TEOAE temporal fine structure was invariant across changes in stimulus level, which is analogous to the intensity invariance of click-evoked basilar-membrane displacement data.


Epidemiology and etiology of blood stream infections in a Belgian burn wound center.
Infections are a major cause of morbidity in burn patients. We aimed to investigate the epidemiology and antibiotic susceptibility of blood stream infections in order to gain a better understanding of their role and burden in our Burn Wound Center. This retrospective epidemiological investigation analyzed data derived from medical files of patients admitted to our Burn Wound Center having had at least one positive blood culture between 1 January and 31 December 2018. We focused on the prevalence of causative agents in blood stream infections in function of the time after injury and on their drug sensitivity. Among the 363 patients admitted to our Burn Wound Center during the study period, 29 had at least one episode of blood stream infection. Gram-negative organisms accounted for 56,36% of the pathogens in blood stream infections, Gram-positives for 38,17%, and yeasts for 5,45%. Pseudomonas aeruginosa was the most common bacterium (20%), followed by Staphylococcus epidermidis (16.36%), Escherichia coli and Klebsiella pneumoniae (9,09% each). A third of the Gram-negative isolates were multidrug resistant. Gram-positive cocci were isolated from blood cultures at a median of 9 days after the injury, earlier than Gram-negative rods (median 15 days). The main sources of blood stream infections were the burn wounds, followed by infected catheters. Multidrug resistant bacteria must be considered when selecting empirical antibiotic therapy in septic burn patients. In our center, we need to update our antibiotic guidelines, to review the hospital infection control measures and to introduce routine typing technology.


A case of ovarian serous cystadenofibroma with scattered lesions in pelvic cavity, like malignant disseminations.
Ovarian serous cystadenofibroma is a relatively rare subtype of serous cystadenoma classified as ovarian benign epithelial tumor. We report a rare case of ovarian serous cystadenofibroma with scattered lesions in pelvic cavity, like malignant disseminations. The patient was 22 years old, gravida 0, para 0. In the laparoscopic surgery, numerous hard yellowish-white solid masses of various sizes were present in the bilateral ovaries. Grossly similar masses were scattered in the fimbria of the fallopian tubes, peritoneum, and great omentum. Because the intraoperative rapid histological diagnosis was benign tumor, surgery was completed for only tumor excision. Postoperative histopathological diagnosis is serous cystadenofibroma. Similar pathological findings were noted in the scattered lesions in the peritoneum and great omentum. No malignant or borderline malignant finding was observed. Because of a benign disease, careful treatment taking fertility preservation into consideration is necessary, especially for young patients.


Using continuous improvement to obtain and document informed consent.
This article describes a continuous improvement team's activities to improve the process of obtaining and documenting informed consent and to decrease the incidence of communication errors during the surgical scheduling process. Integrating surgeons' informed consent process at their office sites with hospital records was the key to success.


New antimycobacterial agents.
Development of new antimycobacterial agents has gained impetus from the frequent occurrence of disseminated M. avium complex infections associated with the AIDS epidemic and the resurgence of tuberculosis. Promising new agents are being developed by modification of existing antimycobacterial agents (for example, aminoglycosides, macrolides, beta-lactams, and rifamycins) and by development of new therapeutic classes of drugs (for example, 4-quinolones). In addition, new drug delivery systems (liposome encapsulation) and immunomodulators may prove to be clinically useful in the treatment of some mycobacterial infections. New antimycobacterial agents will likely have their greatest impact on nontuberculous mycobacterial diseases because this is the area in which improved therapy is most needed. The specific role for new agents will be established only after more extensive study in animal models of mycobacterial infection is followed by controlled, randomized clinical trials.


Variations in signal intensity with periodical temperature changes in vivo in rat brain: analysis using wide-field optical coherence tomography.
In a previous study, we reported measurements of three-dimensional (3D) optical coherence tomography (OCT) images through a thinned skull by reducing temperatures from 28 °C to 18 °C in vivo in the rat brain to show negative correlation coefficients (CCs) between ratios of signal intensity (RSI) and temperature for applications to monitoring brain viability. In this study, using the same OCT system, we measured 3D OCT images of the rat brain by periodically changing tissue temperatures from 20 °C to 32 °C in vivo. In the evaluation of CCs among RSI, temperature, and heart rate, the largest number of periods was four, and the longest measurement time was 570 min. Averaged CCs between RSI and temperature, and between RSI and heart rate, were -0.42 to -0.50 and -0.48 to -0.64, respectively. RSI reversibly changed subsequent variations of temperatures and finally increased rapidly just before cardiac arrest. These results indicate that RSI could correspond to decreases in viability because of local ischemia and recovery.


The B cell response to both protein and nucleic acid antigens displayed on apoptotic cells are dependent on endosomal pattern recognition receptors.
In systemic autoimmune diseases such as systemic lupus erythematosus (SLE), B cell tolerance is lost and there is a production of autoantibodies that drive pathology. The specificities of these antibodies are towards a wide range of autoantigens including proteins such as serum factors including cytokines as well as towards nucleic acids and modified glycolipids. It is known that endosomal pattern recognition receptors are involved in specific responses but if they drive specificity towards a specific group of autoantigens is not known. Here, we used syngeneic apoptotic cells alone to break B cell tolerance and investigated the antibody response in Unc93b1 mutant mice that lack signalling from the TLR3, TLR7 and TLR9 receptors. We found that specific B cell responses known from patients with SLE including antibodies towards Ro-52/60, La, cardiolipin as well as DNA were all significantly lower in the knockout mice. Thus, we found that endosomal TLR receptors were involved in break of tolerance and drive B cell responses for protein, nucleic acid and modified lipid antigens. This pinpoints these receptors as key drivers for the full range of antibody driven pathology in SLE and suggests that targeting of endosomal TLR driven responses will quench all B cell driven autoreactivity.


Cross-Country Individual Participant Analysis of 4.1 Million Singleton Births in 5 Countries with Very High Human Development Index Confirms Known Associations but Provides No Biologic Explanation for 2/3 of All Preterm Births.
Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice. We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and one comparator U.S. state (California) to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors. Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6-6.0 and 2.8-5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25-50% and 11-16% of excess population attributable risk, respectively (p<0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted. We have quantified the causes of variation in preterm birth rates among countries with very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions.


Selective suppression of an early step in human B cell activation by cyclosporin A.
The effect of cyclosporin A (CsA), a fungal metabolite with immunosuppressive properties, on the induction of human B cell proliferation and differentiation, has been described. CsA had a selective inhibitory effect on the activation phase of the cell cycle vs. the proliferation phase following preactivation of the cells. Cell enlargement and RNA synthesis of small resting B cells triggered by anti-mu were inhibited by addition of CsA (5-500 ng/ml). The inhibitory effect of CsA was found only when the drug was added within 24 h of initiation of culture. In marked contrast, once small B cells were activated by anti-mu, the resulting large, activated B cells could be induced to initiate DNA synthesis by incubation with B cell growth factor (BCGF), and addition of CsA (1-1,000 ng/ml) to the culture did not suppress this BCGF-induced B cell proliferation. Addition of CsA to cultures of B cells which had been preactivated with Staphylococcus aureus Cowan strain I (SAC) and were already proliferating did not suppress B cell differentiation factor (BCDF)-induced differentiation of these cells. Thus, these data indicate that CsA can be used as a pharmacologic tool to dissect out human B cell responses into two distinct steps: (a) the initial activation step induced by anti-Ig, which is characterized by cell enlargement, RNA synthesis, and expression of receptors for BCGF; and (b) the proliferative step induced by BCGF in these preactivated B cells that undergo DNA synthesis and can then go on to differentiate in the presence of BCDF. In this regard, CsA selectively suppresses an early step of human B cell activation and has little inhibitory effect on the subsequent factor-dependent proliferation and differentiation.


R124C mutation of the betaIGH3 gene leads to remarkable phenotypic variability in a Greek four-generation family with lattice corneal dystrophy type 1.
Five autosomal dominantly inherited corneal dystrophies are caused by missense mutations in the betaIGH3 gene on chromosome 5q31. Here we describe the clinical features and the analysis of the betaIGH3 gene in a Greek four-generation family with lattice corneal dystrophy type 1 (CDL1). Sequencing of the betaIGH3 cDNA from an affected family member revealed the R124C mutation. More recent data indicate that this is probably a mutation hot spot in CDL1. We could not find a common haplotype with another CDL1 family with the R124C mutation demonstrating that this mutation occurs independently in different families. The clinical course of the disease showed a remarkable variability between the affected family members. To investigate a possible role between the phenotypic variability and apolipoprotein E (ApoE), which co-localises with amyloid deposits in CDL1, we determined the ApoE genotype of all family members. The resulting data revealed no association with the variable clinical course.


Mycoplasma hominis infection of the central nervous system in newborn infants.
The incidence of infections of the central nervous system caused by Mycoplasma hominis in newborn infants is not known. However, such infections occur in both full-term and premature infants, either with or without malformations such as myelomeningocele. M. hominis has also been recovered from brain abscesses. Infected infants usually present with signs of meningitis or meningoencephalitis. Hydrocephalus may develop. The cerebrospinal fluid characteristically has a reduced glucose content and an elevated protein concentration. The white blood cell count is high, with a predominance of either mono- or polymorphonuclear leukocytes. Cerebrospinal fluid yields M. hominis but not other bacteria. Some newborn infants with M. hominis infection of the central nervous system die, whereas others survive and become healthy. In spite of adequate antibiotic therapy, some of those infected develop sequelae such as hemiplegia. Therapy with tetracycline or lincomycin can rapidly eradicate the organism from cerebrospinal fluid.


A systematic review of cross-cultural measures of resilience and its promotive and protective factors.
As psychological resilience has been increasingly recognized as contextually constructed, mixed methods studies that map out local ecologies of resilience have become increasingly common. However, the direct adaptation of quantitative tools for cross-cultural use based on qualitative findings has been relatively lacking. The current review aims to provide an overview of existing measures of resilience used cross-culturally and to synthesize the protective and promotive factors and processes (PPFP) of resilience identified within these measures into a single resource. A January 2021 search of PubMed for studies of the development of psychological resilience measures that excluded studies of non-psychological resilience yielded 58 unique measures. These measures contain 54 unique PPFP of resilience, ranging from individual to communal-level characteristics. This review is intended to serve as a complementary tool for adapting standardized measures for stakeholders requiring an assessment tool that is attuned to their context for mental health risk assessment and intervention evaluation.


Hamartoma of the urinary bladder in a 15-year-old boy.
Hamartoma of the bladder is an unusual entity described in only eleven patients to date. It may present as painless hematuria, irritative urinary tract symptoms, or inability to void or it may be diagnosed incidentally. Hamartoma of the bladder may be isolated or occur as part of a syndrome. No isolated bladder hamartoma to date has shown malignant potential. We describe here a bladder hamartoma in a 15-year-old boy.


Diagnostic Accuracy and Prognostic Significance of Point-Of-Care Ultrasound (POCUS) for Traumatic Cervical Spine in Emergency care setting: A Comparison of clinical outcomes between POCUS and Computed Tomography on a Cohort of 284 Cases and Review of Literature.
The cervical spine is injured in approximately 3% of major trauma patients, and 10% of patients with serious head injury. Therefore, clearance of the cervical spine in multitrauma patients is a critically important task. This is particularly important, considering that there is a positive correlation between a Glasgow Coma Scale of <14 and cervical spine injury. Radiography is not sensitive enough to rule out cervical spine injury, especially as radiography done in the trauma setting is usually technically unsatisfactory. The current study aims to assess the diagnostic accuracy and prognostic significance of using bedside point-of-care ultrasound (POCUS) in traumatic cervical spine injuries compared to computed tomography (CT) as the reference standard. This comparative study enrolled 284 patients with severe multiple trauma at a tertiary care center between July 2017 and March 2020. The inclusion criteria included an indication of cervical spine CT scan, satisfaction of patients with participation in the study, and the lack of history of injury and severe traumatic events. The exclusion criteria were the history of a previous cervical spinal trauma, spondylosis, scoliosis, spinal tuberculosis, degenerative vertebral changes, and patients who refused to give consent to participate in research or CT scanning. The data were analyzed by SPSS software, and sensitivity, specificity, and positive predictive value (PPV)/negative predictive value (NPV) were determined based on CT findings. The best window for the cervical spine was through the anterior triangle using the linear array probe (6-13 MHz). POCUS had a sensitivity of 78.5%, specificity of 98.4%, PPV of 93.2%, NPV of 92.8%, and accuracy of 93.2% in detecting all types of spinal injuries in comparison with CT scan as the standard modality. POCUS had a sensitivity of 100%, specificity of 92.3%, PPV of 62.3%, NPV of 100%, and accuracy of 91.7% in cases with the movement of injured particles. POCUS had a sensitivity of 32.2%, specificity of 100%, PPV of 100%, NPV of 91.4%, and accuracy of 90.8% in detecting the fracture of transverse process. POCUS had a sensitivity of 36.1%, specificity of 100%, PPV of 100%, NPV of 98.1%, and accuracy of 98.4% in ≤14-year age multitrauma patients. In comparison, the current study achieved a sensitivity of 79.4%, specificity of 95.7%, PPV of 92.1%, NPV of 86.3%, and accuracy of 88.6% in >14-year age multitrauma patients. POCUS for cervical spine is feasible using portable ultrasound machine and by neurosurgeons/radiologists/emergency physicians with basic training. It holds great potential in resource-starved settings and in unstable patients for ruling out unstable cervical spine injuries and injuries associated with the movement of fractured or dislocated particles. POCUS examination of the cervical spine was possible in the emergency setting and even in unstable patients and could be done without moving the neck. Future studies, ideally conducted as randomized control trials, are required to establish training and education standards, and to assess the feasibility and safety of POCUS as an alternative to radiography.


Glycoconjugates prevent B. anthracis toxin-induced cell death through binding while activating macrophages.
Bacillus anthracis toxins may be attenuated if macrophages could neutralize toxins upon contact or exposure. Glycoconjugate-bearing polymers, which have been shown to bind to Bacillus spores, were tested for recognition and binding of protective antigen (PA), lethal factor (LF), and edema factor (EF) toxins. We have demonstrated modulation of macrophage activity following exposure to these toxins. Without glycoconjugate (GC) activation, murine macrophages were killed by Bacillus toxins. GCs were shown to have a protective influence, sparing macrophages from toxin-induced cell death, as shown by increased macrophage cell viability based on trypan blue assay. Increased levels of inducible nitric oxide (NO) production by macrophages in presence of GCs suggest that GCs provide an activation signal for macrophages and stimulate their function. Results hint to GCs that promote neutralization of Bacillus toxins, block toxin-induced macrophage death, while increasing macrophage activation. Polymeric GCs may suggest novel approaches to improve existing or develop new vaccines as well as immunotherapeutics.


[Identification of caries risk patients 1. An overview of predictive models].
The ability of dentists to select caries risk patients on the basis of what they see and know, varies considerably. There is a need for objective methods. Methods using bacterial counts and salivary tests appeared to be inferior compared to methods based on the caries experience of the patient. There are two models, Nexø and Dentoprog, using the caries experience as caries predictor. The well documented Nexø method does not predict caries increment, but gives the provider a tool to target preventive intervention to those patients in need. The Dentoprog method is accurate, but has only one level of caries risk, which is considered by most providers as too low and thus unpractical.


Structure based drug design and fragment based approach to identify potential methotrexate analogues as dual inhibitors for management of psoriasis.
Psoriasis is characterized as chronic inflammatory disorder of skin having unregulated hyperproliferation and shedding of plaques. As per first line treatment methotrexate is the most widely used cytotoxic drug for psoriasis. It shows anti-proliferative effect with hDHFR while anti-inflammatory and immunosuppressive action is due to AICART. Serious hepatotoxic effects are recognized with long-term treatment of methotrexate. In this study, in silico technique is used in this work to find Dual-Acting Methotrexate-like molecules with increased efficacy and decreased toxicity. Structure-based virtual screening assisted by a fragment-based method against a library of chemicals that are similar to methotrexate revealing 36 and 27 potential inhibitors of hDHFR and AICART respectively. Further, based on dock score, binding energy, molecular interactions, and ADME/T analysis compound 135565151 was chosen for dynamic stability evaluation. Overall, these findings provided information on possible methotrexate analogues for the treatment of psoriasis that had lower hepatotoxicity.Communicated by Ramaswamy H. Sarma.


Metastasectomy and surgical resection of the primary tumor in patients with stage IV breast cancer: time for a second look?
Patients with metastatic or stage IV breast cancer have limited therapeutic options, and the mainstay of treatment remains systemic chemotherapy. Traditionally, the role of surgery has been confined to strict palliation. Improvements in the efficacy of chemotherapeutic regimens, coupled with the use of hormonal and targeted therapy, have resulted in an expansion of surgical resection beyond simple palliation. Several single-institution studies have reported improved survival and even long-term cures after surgical resection for oligometastatic stage IV breast cancer. Similarly, provocative new data suggest that removal of the primary tumor in some patients may confer a survival advantage. The aim of this review is to summarize studies in the medical literature pertaining to the use of surgical resection in patients with stage IV breast cancer. We believe there is enough evidence to challenge conventional thinking about the role of surgery in stage IV breast cancer and to consider a new multimodality treatment paradigm to optimize patient outcomes. It is time to conduct a carefully designed randomized trial to see whether surgery in stage IV breast cancer does indeed warrant a second look.


ProGMap: an integrated annotation resource for protein orthology.
Current protein sequence databases employ different classification schemes that often provide conflicting annotations, especially for poorly characterized proteins. ProGMap (Protein Group Mappings, http://www.bioinformatics.nl/progmap) is a web-tool designed to help researchers and database annotators to assess the coherence of protein groups defined in various databases and thereby facilitate the annotation of newly sequenced proteins. ProGMap is based on a non-redundant dataset of over 6.6 million protein sequences which is mapped to 240,000 protein group descriptions collected from UniProt, RefSeq, Ensembl, COG, KOG, OrthoMCL-DB, HomoloGene, TRIBES and PIRSF. ProGMap combines the underlying classification schemes via a network of links constructed by a fast and fully automated mapping approach originally developed for document classification. The web interface enables queries to be made using sequence identifiers, gene symbols, protein functions or amino acid and nucleotide sequences. For the latter query type BLAST similarity search and QuickMatch identity search services have been incorporated, for finding sequences similar (or identical) to a query sequence. ProGMap is meant to help users of high throughput methodologies who deal with partially annotated genomic data.


Early mucosal healing and chronic changes in pony jejunum after various types of strangulation obstruction.
Strangulation obstruction was induced in anesthetized ponies for periods of 2 and 3 hours by clamping 45-cm segments of jejunum and their veins only (venous strangulation obstruction, VSO) and arteries and veins (arterial and venous strangulation obstruction, AVSO). These types of strangulation obstruction were studied in 4 segments in each of 4 ponies allowed to survive 12 hours (group 1) and in a single segment in each of 10 ponies allowed to survive 42 days (group 2) after the strangulation period ended. On visual inspection, segments subjected to VSO had hemorrhage and edema in the bowel wall and mesentery and were dark purple after all time intervals. They improved slowly after clamps were removed, but remained hemorrhagic and edematous. Segments subjected to AVSO were purple and had mild edema and scattered petechiae in the bowel wall and mesentery. They improved rapidly and closely resembled normal bowel after 5 minutes of reperfusion. On light and scanning electron microscopy, the mucosa of intestine subjected to VSO and AVSO had necrotic, denuded villi 1 hour after the strangulation periods ended. Twelve hours after removal of occlusion devices in group-1 ponies, 4 (25%) segments were unchanged, 4 (25%) had deteriorated, and 8 (50%) had stunted villus remnants partly or completely lined with regenerating epithelium. Separation and detachment of villus tip mucosal cells were seen in 3 of 4 control segments, 1 and 12 hours after the strangulation periods ended.(ABSTRACT TRUNCATED AT 250 WORDS)


Childhood trauma and auditory verbal hallucinations.
Hallucinations have consistently been associated with traumatic experiences during childhood. This association appears strongest between physical and sexual abuse and auditory verbal hallucinations (AVH). It remains unclear whether traumatic experiences mainly colour the content of AVH or whether childhood trauma triggers the vulnerability to experience hallucinations in general. In order to investigate the association between hallucinations, childhood trauma and the emotional content of hallucinations, experienced trauma and phenomenology of AVH were investigated in non-psychotic individuals and in patients with a psychotic disorder who hear voices. A total of 127 non-psychotic individuals with frequent AVH, 124 healthy controls and 100 psychotic patients with AVH were assessed for childhood trauma. Prevalence of childhood trauma was compared between groups and the relation between characteristics of voices, especially emotional valence of content, and childhood trauma was investigated. Both non-psychotic individuals with AVH and patients with a psychotic disorder and AVH experienced more sexual and emotional abuse compared with the healthy controls. No difference in the prevalence of traumatic experiences could be observed between the two groups experiencing AVH. In addition, no type of childhood trauma could distinguish between positive or negative emotional valence of the voices and associated distress. No correlations were found between sexual abuse and emotional abuse and other AVH characteristics. These results suggest that sexual and emotional trauma during childhood render a person more vulnerable to experience AVH in general, which can be either positive voices without associated distress or negative voices as part of a psychotic disorder.


Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis.
Estrogenic and inflammatory components play key roles in a broad range of diseases including endometriosis, a common estrogen-dependent gynecological disorder in which endometrial tissue creates inflammatory lesions at extrauterine sites, causing pelvic pain and reduced fertility. Current medical therapies focus primarily on reducing systemic levels of estrogens, but these are of limited effectiveness and have considerable side effects. We developed estrogen receptor (ER) ligands, chloroindazole (CLI) and oxabicycloheptene sulfonate (OBHS), which showed strong ER-dependent anti-inflammatory activity in a preclinical model of endometriosis that recapitulates the estrogen dependence and inflammatory responses of the disease in immunocompetent mice and in primary human endometriotic stromal cells in culture. Estrogen-dependent phenomena, including cell proliferation, cyst formation, vascularization, and lesion growth, were all arrested by CLI or OBHS, which prevented lesion expansion and also elicited regression of established lesions, suppressed inflammation, angiogenesis, and neurogenesis in the lesions, and interrupted crosstalk between lesion cells and infiltrating macrophages. Studies in ERα or ERβ knockout mice indicated that ERα is the major mediator of OBHS effectiveness and ERβ is dominant in CLI actions, implying involvement of both ERs in endometriosis. Neither ligand altered estrous cycling or fertility at doses that were effective for suppression of endometriosis. Hence, CLI and OBHS are able to restrain endometriosis by dual suppression of the estrogen-inflammatory axis. Our findings suggest that these compounds have the desired characteristics of preventive and therapeutic agents for clinical endometriosis and possibly other estrogen-driven and inflammation-promoted disorders.


Electrical stimulation of the thigh muscles after reconstruction of the anterior cruciate ligament. Effects of electrically elicited contraction of the quadriceps femoris and hamstring muscles on gait and on strength of the thigh muscles.
The effects of neuromuscular electrical stimulation on the strength of the thigh muscles and on gait were examined in ten patients after reconstruction of the anterior cruciate ligament. The patients were randomly assigned to one of two treatment groups: neuromuscular electrical stimulation and volitional exercise, or volitional exercise alone. A four-week course of electrically elicited co-contraction of the thigh muscles resulted in significant attenuation of the characteristic loss of strength of the quadriceps as compared with volitional exercise. There was no significant difference between groups in any measure of performance of the hamstring muscles. In the group that received neuromuscular electrical stimulation, the values for cadence, walking velocity, stance time of the involved limb, and flexion-excursion of the knee during stance were significantly different from those of the volitional exercise group. Flexion-excursion of the knee during stance was directly and significantly correlated with strength of the quadriceps femoris muscle. Flexion of the knee during stance was qualitatively different in the involved extremity as compared with the uninvolved extremity in all patients. There is a rapid flexion of the knee at weight acceptance that is maintained throughout stance and probably reflects stabilization of the joint by muscular coactivation to compensate for weakness of the quadriceps. The patients who received neuromuscular electrical stimulation had stronger quadriceps muscles and more normal gait patterns than those in the volitional exercise group.


Antiplatelet therapy in non-ST-segment elevation acute coronary syndromes.
Acute coronary syndromes are a frequent cause of hospital admission for patients with coronary artery disease. The pathophysiology of acute coronary syndromes often involves plaque rupture or fissure with platelet aggregation. Recognition of the importance of platelet aggregation resulted in several large randomized trials testing 3 types of platelet antagonists, aspirin, glycoprotein IIb/IIIa inhibitors, and adenosine diphosphate inhibitors. A thorough understanding of the data, risks, and benefits of these therapies is important to optimize treatment of the patient with an acute coronary syndrome. Recognition that there is a great deal of interpatient variability in response to these antiplatelet therapies highlights the need for future research in this area.


Signatures of charge inhomogeneities in the infrared spectra of topological insulators Bi2Se3, Bi2Te3 and Sb2Te3.
We present the results of an infrared spectroscopy study of topological insulators Bi(2)Se(3), Bi(2)Te(3) and Sb(2)Te(3). Reflectance spectra of all three materials look similar, with a well defined plasma edge. However, there are some important differences. Most notably, as temperature decreases the plasma edge shifts to lower frequencies in Bi(2)Se(3), whereas in Bi(2)Te(3) and Sb(2)Te(3) it shifts to higher frequencies. In the loss function spectra we identify asymmetric broadening of the plasmon, and assign it to the presence of charge inhomogeneities. It remains to be seen if charge inhomogeneities are characteristic of all topological insulators, and whether they are of intrinsic or extrinsic nature.


Autosomal dominant von Willebrand disease type 2M.
von Willebrand disease (VWD) type 2M is a distinct entity and clearly differs from type 1. The genotype-phenotype correlation for cases with ristocetin cofactor activity (RCo)/antigen (Ag) ratios <0.60 is clear, whereas the von Willebrand factor (VWF):collagen binding (CB)/VWF:Ag ratio is normal in VWD 2M. Typical laboratory features of VWD type 2 M are decreased ristocetin-induced platelet aggregation in the presence of a normal or near normal VWF multimeric pattern on a low-resolution agarose gel, a poor response to desmopressin (DDAVP) of VWF:RCo, and a good response of both VWF:CB and VWF:Ag to DDAVP. The phenotypic definition of VWD type 2M may need to be more stringent and should be the subject of an international standardization initiative.


Changes in the subcellular distribution of free carnitine and its acyl derivatives in diabetic rat hearts following treatment with L-carnitine.
Carnitine deficiency has been demonstrated in diabetic hearts, and it is also well known that L-carnitine administration has a beneficial effect on cardiac function. Carnitine treatment would be expected to reduce the accumulation of long-chain acylcarnitine. However, many reports have shown that myocardial long-chain acylcarnitine levels were increased following treatment with L-carnitine in whole-heart studies. Since acylcarnitine exists in both the mitochondrial and cytosolic compartments, it is difficult to investigate changes in subcellular distribution by studying whole-heart preparations. The present study investigated the myocardial subcellular distribution of carnitine and its acyl derivatives in diabetic rats with or without L-carnitine treatment. Approximately 90% of total cellular carnitine was located in the cytosol in the diabetic hearts. Both mitochondrial and cytosolic levels of free carnitine and short-chain acylcarnitine were significantly decreased in the diabetic heart. However, the mitochondrial level of long-chain acylcarnitine was significantly increased. L-carnitine treatment reduced the mitochondrial level of long-chain acylcarnitine, but the cytosolic level of long-chain acylcarnitine was significantly increased. These results show that L-carnitine treatment prevents the accumulation of long-chain acylcarnitine in the mitochondrial space and then reduces the detergent effect of long-chain acylcarnitine on the mitochondrial membrane. We suggest that it is a possible mechanism of the beneficial effect of L-carnitine treatment on the diabetic heart.


Bromotyrosine Alkaloids with Acetylcholinesterase Inhibitory Activity from the Thai Sponge Acanthodendrilla sp.
Twenty bromotyrosine alkaloids, including a new compound, 13-oxosubereamolline D (5), were isolated from the Thai sponge Acanthodendrilla sp. Their structures were determined by analyses of 1D- and 2D-NMR, high-resolution mass, and circular dichroism data. The complete 1H and 13C NMR assignments of 5,7β-dichlorocavernicolin (19) and 5,7α-dichlorocavernicolin (20) are described herein for the first time. The acetylcholinesterase (AChE) inhibitory activity of all isolated compounds was evaluated. Only homoaerothionin (7) and fistularin 1 (10) exhibited inhibitory activity against human recombinant AChE (hrAChE) with IC50s of 4.5 and 47.5 µM, respectively. The hrAChE inhibition kinetics of 7, the most potent alkaloid, showed increased Km and unchanged Vmaxvalues, suggesting its competitive mode of inhibition. The spirocyclohexadienylisoxazole and the length of the alkyl diamine linkage were proposed as the crucial parts for its strong inhibitory activity. This finding indicates a therapeutic potential for 7 in acetylcholine-related diseases, most importantly Alzheimer's disease.


Strategies to convert organic fluorophores into red/near-infrared emitting analogues and their utilization in bioimaging probes.
Organic fluorophores aided by current microscopy imaging modalities are essential for studying biological systems. Recently, red/near-infrared emitting fluorophores have attracted great research efforts, as they enable bioimaging applications with reduced autofluorescence interference and light scattering, two significant obstacles for deep-tissue imaging, as well as reduced photodamage and photobleaching. Herein, we analyzed the current strategies to convert key organic fluorophores bearing xanthene, coumarin, and naphthalene cores into longer wavelength-emitting derivatives by focussing on their effectiveness and limitations. Together, we introduced typical examples of how such fluorophores can be used to develop molecular probes for biological analytes, along with key sensing features. Finally, we listed several critical issues to be considered in developing new fluorophores.


Evaluation of Mycoplasma inactivation during production of biologics: egg-based viral vaccines as a model.
Although mycoplasmas are generally considered to be harmless commensals, some mycoplasma species are able to cause infections in pediatric, geriatric, or immunocompromised patients. Thus, accidental contamination of biologics with mycoplasmas represents a potential risk for the health of individuals who receive cell-derived biological and pharmaceutical products. To assess the efficiency of inactivation of mycoplasmas by the agents used in the manufacture of egg-derived influenza vaccines, we carried out a series of experiments aimed at monitoring the viability of mycoplasmas spiked into both chicken allantoic fluid and protein-rich microbiological media and then treated with beta-propiolactone, formalin, cetyltrimethylammonium bromide, Triton X-100, and sodium deoxycholate, which are agents that are commonly used for virus inactivation and disruption of viral particles during influenza vaccine production. Twenty-two mycoplasma species (with one to four strains of each species) were exposed to these inactivating agents at different concentrations. The most efficient inactivation of the mycoplasmas evaluated was observed with either 0.5% Triton X-100 or 0.5% sodium deoxycholate. Cetyltrimethylammonium bromide at concentrations of >or=0.08% was also able to rapidly inactivate (in less than 30 min) all mycoplasmas tested. In contrast, negligible reductions in mycoplasma titers were observed with 0.0125 to 0.025% formaldehyde. However, increasing the concentration of formaldehyde to 0.1 to 0.2% improved the mycoplasmacidal effect. Incubation of mycoplasmas with 0.1% beta-propiolactone for 1 to 24 h had a marked mycoplasmacidal effect. A comparison of the mycoplasma inactivation profiles showed that strains of selected species (Mycoplasma synoviae, Mycoplasma gallisepticum, Mycoplasma orale, Mycoplasma pneumoniae, and Acholeplasma laidlawii) represent a set of strains that can be utilized to validate the effectiveness of mycoplasma clearance obtained by inactivation and viral purification processes used for the manufacture of an inactivated egg-based vaccine.


Alterations in EGFR and related genes following neo-adjuvant chemotherapy in Chinese patients with non-small cell lung cancer.
Genetic aberrancies within epidermal growth factor receptor (EGFR) pathway are associated with therapeutic outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, the impact of chemotherapy on EGFR-related genes alterations has not been defined in NSCLC. Our study aims to investigate the impact of neoadjuvant chemotherapy (Neoadj-Chemo) on EGFR activating mutations and associated EGFR-TKIs resistance-related genes. Matched tumor samples were obtained retrospectively from 66 NSCLC patients (stages IIb-IIIb) corresponding to pre- and post- Neoadj-Chemo. EGFR mutations were detected by denaturing high performance liquid chromatography (DHPLC) and confirmed by Amplification Refractory Mutation System technology (ARMS), KRAS mutations, T790M mutation and c-MET amplification were identified using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), ARMS, and real-time PCR, respectively. Before Neoadj-Chemo, EGFR mutations were identified in 33.3% (22/66) of NSCLC patients. Only 18.2% (12/66) of patients carried EGFR mutations after Neoadj-Chemo (p = 0.013). The median peak value of EGFR 19 exon mutations decreased non-significantly after Neoadj-Chemo. KRAS mutation rate decreased from 4.6% (3/66) to 3.0% (2/66) with Neoadj-Chemo. Although the overall percentage of patients exhibiting c-MET amplifications (6.1% [4/66]) did not change with Neoadj-Chemo, two patients transitioned from negative to positive c-MET amplification, and two patients reversed these changes post-Neoadj-Chemo. T790M mutations were absent from all samples. Neoadjuvant chemotherapy tends to decrease the mutation frequency of EGFR mutation and downstream genes, which suggests that real-time samples analysis for genetic aberrancies within EGFR pathways have important value to delineate specific patient populations and facilitate individualized treatment.


PDCD10 gene mutations in multiple cerebral cavernous malformations.
Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.


B-Pred, a structure based B-cell epitopes prediction server.
The ability to predict immunogenic regions in selected proteins by in-silico methods has broad implications, such as allowing a quick selection of potential reagents to be used as diagnostics, vaccines, immunotherapeutics, or research tools in several branches of biological and biotechnological research. However, the prediction of antibody target sites in proteins using computational methodologies has proven to be a highly challenging task, which is likely due to the somewhat elusive nature of B-cell epitopes. This paper proposes a web-based platform for scoring potential immunological reagents based on the structures or 3D models of the proteins of interest. The method scores a protein's peptides set, which is derived from a sliding window, based on the average solvent exposure, with a filter on the average local model quality for each peptide. The platform was validated on a custom-assembled database of 1336 experimentally determined epitopes from 106 proteins for which a reliable 3D model could be obtained through standard modeling techniques. Despite showing poor sensitivity, this method can achieve a specificity of 0.70 and a positive predictive value of 0.29 by combining these two simple parameters. These values are slightly higher than those obtained with other established sequence-based or structure-based methods that have been evaluated using the same epitopes dataset. This method is implemented in a web server called B-Pred, which is accessible at http://immuno.bio.uniroma2.it/bpred. The server contains a number of original features that allow users to perform personalized reagent searches by manipulating the sliding window's width and sliding step, changing the exposure and model quality thresholds, and running sequential queries with different parameters. The B-Pred server should assist experimentalists in the rational selection of epitope antigens for a wide range of applications.


Accelerated evolution of sex chromosomes in aphids, an x0 system.
Sex chromosomes play a role in many important biological processes, including sex determination, genomic conflicts, imprinting, and speciation. In particular, they exhibit several unusual properties such as inheritance pattern, hemizygosity, and reduced recombination, which influence their response to evolutionary factors (e.g., drift, selection, and demography). Here, we examine the evolutionary forces driving X chromosome evolution in aphids, an XO system where females are homozygous (XX) and males are hemizygous (X0) at sex chromosomes. We show by simulations that the unusual mode of transmission of the X chromosome in aphids, coupled with cyclical parthenogenesis, results in similar effective population sizes and predicted levels of genetic diversity for X chromosomes and autosomes under neutral evolution. These results contrast with expectations from standard XX/XY or XX/X0 systems (where the effective population size of the X is three-fourths that of autosomes) and have deep consequences for aphid X chromosome evolution. We then localized 52 microsatellite markers on the X and 351 on autosomes. We genotyped 167 individuals with 356 of these loci and found similar levels of allelic richness on the X and on the autosomes, as predicted by our simulations. In contrast, we detected higher dN and dN/dS ratio for X-linked genes compared with autosomal genes, a pattern compatible with either positive or relaxed selection. Given that both types of chromosomes have similar effective population sizes and that the single copy of the X chromosome of male aphids exposes its recessive genes to selection, some degree of positive selection seems to best explain the higher rates of evolution of X-linked genes. Overall, this study highlights the particular relevance of aphids to study the evolutionary factors driving sex chromosomes and genome evolution.


Design of a head coil for high resolution mouse brain perfusion imaging using magnetic particle imaging.
Magnetic particle imaging (MPI) is a novel and versatile imaging modality developing toward human application. When up-scaling to human size, the sensitivity of the systems naturally drops as the coil sensitivity depends on the bore diameter. Thus, new methods to push the sensitivity limit further have to be investigated to cope for this loss. In this paper a dedicated surface coil for mice is developed, improving the sensitivity in cerebral imaging applications. Similar to magnetic resonance imaging the developed surface coil improves the sensitivity due to the closer vicinity to the region of interest. With the developed surface coil presented in this work, it is possible to image tracer samples containing only 896 pg[Formula: see text] and detect even small vessels and anatomical structures within a wild type mouse model. As current sensitivity measures require a tracer system a new method for determining a sensitivity measure without this requirement is presented and verified to enable comparison between MPI receiver systems.


In vivo optical imaging of LacZ expression using lacZ transgenic mice.
beta-Galactosidase (beta-gal) (encoded by the lacZ gene) has been widely used as a transgene reporter enzyme. The ability to image lacZ expression in living transgenic animals would further extend the use of this reporter. It has been reported that 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one)-beta-d-galactopyranoside (DDAOG), a conjugate of beta-galactose and 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one), is not only a chromogenic lacZ substrate but that the cleavage product has far-red fluorescence properties detectable by in vivo imaging. In an attempt to noninvasively image lacZ expression in vivo, we applied fluorescence imaging to a G protein-coupled receptor (GPR56), knockout (KO) mouse model, in which the lacZ gene is introduced in the GPR56 locus. Compared to wild-type (WT) mice, GPR56KO/LacZ mice showed three- to fourfold higher fluorescence intensity in the head area 5 min after tail-vein injection of DDAOG. beta-Gal staining in sections of whole brain showed strong lacZ expression in homozygotes, but not in WT mice, consistent with lacZ activity detected by in vivo imaging. The kidneys were also visualized with fluorescence imaging both in vivo and ex vivo, consistent with beta-gal staining findings. Our results demonstrate that fluorescence imaging can be used for in vivo real-time detection of lacZ activity by fluorescence imaging in lacZ transgenic mice. Thus, this technology can potentially be used to noninvasively image changes of certain endogenous molecules and/or molecular pathways in transgenic animals.


Dose-response relationship of robot-assisted stroke motor rehabilitation: the impact of initial motor status.
The increasing availability of robot-assisted therapy (RT), which provides quantifiable, reproducible, interactive, and intensive practice, holds promise for stroke rehabilitation, but data on its dose-response relation are scanty. This study used 2 different intensities of RT to examine the treatment effects of RT and the effect on outcomes of the severity of initial motor deficits. Fifty-four patients with stroke were randomized to a 4-week intervention of higher-intensity RT, lower-intensity RT, or control treatment. The primary outcome, the Fugl-Meyer Assessment, was administered at baseline, midterm, and posttreatment. Secondary outcomes included the Medical Research Council scale, the Motor Activity Log, and the physical domains of the Stroke Impact Scale. The higher-intensity RT group showed significantly greater improvements on the Fugl-Meyer Assessment than the lower-intensity RT and control treatment groups at midterm (P=0.003 and P=0.02) and at posttreatment (P=0.04 and P=0.02). Within-group gains on the secondary outcomes were significant, but the differences among the 3 groups did not reach significance. Recovery rates of the higher-intensity RT group were higher than those of the lower-intensity RT group, particularly on the Fugl-Meyer Assessment. Scatterplots with curve fitting showed that patients with moderate motor deficits gained more improvements than those with severe or mild deficits after the higher-intensity RT. This study demonstrated the higher treatment intensity provided by RT was associated with better motor outcome for patients with stroke, which may shape further stroke rehabilitation. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00917605.


Tricuspid valve involvement in combined mitral and aortic valve surgery.
Combined mitral and aortic valve disease requiring surgery may involve the tricuspid valve as well. Our treatment policy is conservative especially for tricuspid regurgitation which is operated on when severe only. A retrospective study was performed at a tertiary and secondary referral center for cardiovascular disease. Over a 15-year period, 65 consecutive patients underwent aortic and mitral surgery with concomitant tricuspid regurgitation and/or stenosis. Fifty-five/65 (85%) patients were in NYHA class III-IV. Fifty-eight/65 (89%) patients had tricuspid regurgitation secondary to right chamber dilatation and 7/65 (11%) had tricuspid stenosis and/or regurgitation because of previous endocarditis. Twenty-two/65 (34%) tricuspid valves were operated on: 18/22 (82%) de Vega annuloplasty, 2/22 (9%) commissurotomies and 2/22 (9%) prosthetic valves. Mortality and complications were recorded during a mean follow-up of 5.3 yrs (range, 6 months-15.3 yrs). Event-free survivals were determined using the Kaplan-Meier method. Hospital mortality was 6.2% (4/65) and the complication rate was 18.5% (12/65). The freedom from late valve related mortality and morbidity at 5, 10 and 15 years was 86+/-5.5%, 81.9+/-6.8%, and 81.9+/-6.8% respectively. One valve related complication was due to the tricuspid valve. At last follow-up, 87% (47/54) of the survivors were in NYHA class I-II. With a conservative policy of tricuspid valve intervention, functional results of this patient population are good and long-term valve related morbidity and mortality are mainly related to the mitral and aortic valve procedures.


Adrenal stress hormone action in skeletal muscle during exercise training: An old dog with new tricks?
Exercise is a key component of a healthy lifestyle as it helps maintain a healthy body weight and reduces the risk of various morbidities and co-morbidities. Exercise is an acute physiological stress that initiates a multitude of processes that attempt to restore physiological homeostasis and promote adaptation. A component of the stress response to exercise is the rapid release of hormones from the adrenal gland including glucocorticoids, the catecholamines and aldosterone. While each hormone targets several tissues throughout the body, skeletal muscle is of interest as it is central to physical function and various metabolic processes. Indeed, adrenal stress hormones have been shown to elicit specific performance benefits on the muscle. However, how the acute, short-lived release of these stress hormones during exercise influences adaptations of skeletal muscle to long-term training remains largely unknown. Thus, the objective of this review was to briefly highlight the known impact of adrenal stress hormones on skeletal muscle metabolism and function (Old Dog), and critically examine the current evidence supporting a role for these endogenous hormones in mediating long-term training adaptations in skeletal muscle (New Tricks).