Dynamics and fragmentation of van der Waals clusters: (H2O)n, (CH3OH)n, and (NH3)n upon ionization by a 26.5 eV soft x-ray laser.
A tabletop soft x-ray laser is applied for the first time as a high energy photon source for chemical dynamics experiments in the study of water, methanol, and ammonia clusters through time of flight mass spectroscopy. The 26.5 eV/photon laser (pulse time duration of approximately 1 ns) is employed as a single photon ionization source for the detection of these clusters. Only a small fraction of the photon energy is deposited in the cluster for metastable dissociation of cluster ions, and most of it is removed by the ejected electron. Protonated water, methanol, and ammonia clusters dominate the cluster mass spectra. Unprotonated ammonia clusters are observed in the protonated cluster ion size range 2< or =n< or =22. The unimolecular dissociation rate constants for reactions involving loss of one neutral molecule are calculated to be (0.6-2.7)x10(4), (3.6-6.0)x10(3), and (0.8-2.0)x10(4) s(-1) for the protonated water (9< or =n< or =24), methanol (5< or =n< or =10), and ammonia (5< or =n< or =18) clusters, respectively. The temperatures of the neutral clusters are estimated to be between 40 and 200 K for water clusters (10< or =n< or =21), and 50-100 K for methanol clusters (6< or =n< or =10). Products with losses of up to five H atoms are observed in the mass spectrum of the neutral ammonia dimer. Large ammonia clusters (NH(3))(n) (n>3) do not lose more than three H atoms in the photoionization/photodissociation process. For all three cluster systems studied, single photon ionization with a 26.5 eV photon yields near threshold ionization. The temperature of these three cluster systems increases with increasing cluster size over the above-indicated ranges.


Determining the prevalence of SCCmec polymorphism, virulence and antibiotic resistance genes among methicillin-resistant Staphylococcus aureus (MRSA) isolates collected from selected hospitals in west of Iran.
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important pathogens worldwide and compared to other staphylococcal species that are associated with higher mortality rate. A total of 500 Staphylococcus spp. was collected from selected hospitals in Ilam, Kermanshah, Khorram Abad and Hamadan cities and, via phenotypic and genotypic methods, was assessed to find MRSA. The presence or absence of prevalent antibiotic resistance genes and virulence genes was evaluated among MRSA isolates, using polymerase chain reaction (PCR) method, and then the SCCmec typing of these isolates was assayed by multiplex PCR. A total of 372 (74.4%) Stapylococcus spp. isolates were identified as S. aureus, among which 200 (53.8%) possessed the mecA gene and were distinguished as MRSA. All of MRSA isolates contained blaZ gene. The frequency of ermA and ermC genes among erythromycin-resistant MRSA isolates was 21.6% and 66.7%, respectively. The frequency of the virulence genes eta, hla and sea among MRSA isolates was 10%, 80.5% and 100%, respectively. SCCmec type IV accounted for 30.6% of the MRSA isolates and SCCmec type III, SCCmec type II and SCCmec type I accounted for 30%, 22% and 17.5% of the isolates, respectively. The antibiotic resistance genes and the virulence genes of blaZ, hla, sea, eta and ermC had high frequencies among the MRSA isolates. This study showed that the antibiotic resistance genes had higher frequencies among SCCmec types I and IV, which confirms the previous reports in this field.


Deciphering β-tubulin gene of carbendazim resistant Fusarium solani isolate and its comparison with other Fusarium species.
Exploration of molecular structure of β-tubulin is key to understand mechanism of action of carbendazim since its activity depends on strong binding to β-tubulin. Resistance against the fungicide is often associated with mutation in β-tubulin gene. A full-length (1619 bp) β-tubulin gene has been cloned and sequenced from a carbendazim resistant and a sensitive isolates of F. solani isolated from agricultural fields of Murshidabad (24.23 °N, 88.25 °E), West Bengal, India. Phylogenetic position of the isolates was confirmed using internal transcribed spacer and β-tubulin gene sequences. In the β-tubulin based phylogenetic tree, Fusarium species with available data were clustered in nine species complexes and members of both F. solani species complex and F. fujikuroi species complex were distributed into three clades each. The β-tubulin gene of F. solani was found to be shortest due to least number of non-coding sequences indicating its primitiveness among the Fusarium species. The coding region (G + C 58.54%) was organized into five exons. The protein has 446 amino acid, 49.834 KD molecular weight and 4.64 isoelectric point. Amino acid sequence of the resistant and the sensitive isolates were identical, suggesting that the mechanism of carbendazim resistance in the F. solani isolate was not due to point mutation in β-tubulin gene. The secondary and tertiary structure of β-tubulin were similar in all the species except F. oxysporum f.sp. cubense. The identification of binding sites for GDP, carbendazim and α-tubulin would resolve how carbendazim prevents tubulin polymerization. All the data are useful to design tubulin-targeted fungicide with better performance.


Dichlorido(2,3-di-2-pyridyl-pyrazine-κN,N)platinum(II).
The Pt(II) ion in the title complex, [PtCl(2)(C(14)H(10)N(4))], is four-coordinated in a distorted square-planar environment by two N atoms of a chelating 2,3-di-2-pyridyl-pyrazine ligand and two chloride anions. The pyridyl ring coordinated to the Pt(II) atom is inclined slightly to its carrier pyrazine ring [dihedral angle = 13.5 (1)°], whereas the uncoordinated pyridyl ring is inclined considerably to the pyrazine ring [dihedral angle = 54.3 (2)°]. The dihedral angle between the two pyridyl rings is 59.2 (2)°. In the crystal, the complexes are assembled through inter-molecular C-H⋯N and C-H⋯Cl hydrogen bonds, forming a three-dimensional network. Intra-molecular C-H⋯N and C-H⋯Cl hydrogen bonds are also present.


Biosensor analysis of beta2-glycoprotein I-reactive autoantibodies: evidence for isotype-specific binding and differentiation of pathogenic from infection-induced antibodies.
For the laboratory diagnosis of the antiphospholipid syndrome (APS) we developed a biosensor with the ability to distinguish between disease-relevant anti-beta2-glycoprotein I (beta2GPI) autoantibodies (anti-beta2GPI) and pathogen-specific beta2GPI cross-reactive antibodies that occur transiently during infections. We used a surface plasmon resonance (SPR) biosensor device. For the detection of anti-beta2GPI in serum samples, affinity-purified human beta2GPI was covalently attached to a functionalized n-alkanethiol self-assembling monolayer on the biosensor chip. After verifying the specificity of the biosensor system with a panel of monoclonal antibodies to beta2GPI, we analyzed sera from healthy donors and patients suffering from APS, systemic lupus erythematosus (SLE), syphilis, or parvovirus B19 infections. The SPR results were compared with beta2GPI-specific ELISA. Using the SPR biosensor, we recorded antigen binding curves with response levels in the range of 50-500, resonance units (RU) for anti-beta2GPI ELISA-positive APS patient sera. The amplitudes of the antiphospholipid antibody (APL) responses in the biosensor correlated with the overall IgG and IgM anti-beta2GPI ELISA titers with a correlation coefficient of 0.87. Moreover, we observed immunoglobulin isotype-specific association and dissociation profiles for APL binding of different APS patient sera to the biosensor-immobilized beta2GPI. In contrast to APS patient samples, no significant anti-beta2GPI binding (response levels <35 RU) was observed in samples from healthy individuals or from patients suffering from SLE, syphilis, or parvovirus B19 infection. The SPR biosensor system enables specific detection of APS-associated beta2GPI-reactive APL and differentiation from beta2GPI cross-reactive antibodies that occur frequently during acute infections. The established association/dissociation plot for anti-beta2GPI responses in APS patient sera gives additional information regarding the influence of anti-beta2GPI IgG and IgM isotype distribution.


Hearing the voices of service user researchers in collaborative qualitative data analysis: the case for multiple coding.
Health research is frequently conducted in multi-disciplinary teams, with these teams increasingly including service user researchers. Whilst it is common for service user researchers to be involved in data collection--most typically interviewing other service users--it is less common for service user researchers to be involved in data analysis and interpretation. This means that a unique and significant perspective on the data is absent. This study aims to use an empirical report of a study on Cognitive Behavioural Therapy for psychosis (CBTp) to demonstrate the value of multiple coding in enabling service users voices to be heard in team-based qualitative data analysis. The CBTp study employed multiple coding to analyse service users' discussions of CBT for psychosis (CBTp) from the perspectives of a service user researcher, clinical researcher and psychology assistant. Multiple coding was selected to enable multiple perspectives to analyse and interpret data, to understand and explore differences and to build multi-disciplinary consensus. Multiple coding enabled the team to understand where our views were commensurate and incommensurate and to discuss and debate differences. Through the process of multiple coding, we were able to build strong consensus about the data from multiple perspectives, including that of the service user researcher. Multiple coding is an important method for understanding and exploring multiple perspectives on data and building team consensus. This can be contrasted with inter-rater reliability which is only appropriate in limited circumstances. We conclude that multiple coding is an appropriate and important means of hearing service users' voices in qualitative data analysis.


Blunt innominate artery trauma requiring repair and carotid ligation.
Traumatic dissection of the innominate artery is a rare clinical entity. Management of a patient with motorsensory compromise and dissection extending to the subclavian and right common carotid arteries is quite rare and can be quite involved. Here we present such a case and discuss the unique peri-operative decision-making in the context of what is reported in the literature. Restoration of motorsensory function is critical and in this case, requiring a multi-disciplinary team.


[Axial length of the ocular globe and hypotensive effect in glaucoma therapy with prostaglandin analogs].
To observe the possible correlations between the hypotensive effect of the prostaglandin analogs and the axial length of the ocular globe. A prospective, observational and randomized study (one year) on 27 patients with POAG treated by prostaglandin analogs monotherapy. The patients have been divided in two groups according to the type of the prostaglandin analogs used: group A - 12 patients - travoprost 0,004 % (Travatan) and group B - 15 patients - latanoprost 0,005 % (Xalatan). The IOP and the axial length have been evaluated at the beginning of the study and at 1, 3, 6, 9, 12 months using Goldmann aplanotonometry and echo-biometry. The results have been statistically analyzed using the Wilcoxon test. The mean IOP reduction was similar in both groups, without statistically significant differences. Between the IOP reductions and the axial length of the ocular globe were demonstrated significant correlations according to the patients distribution on the echo-biometry results. The IOP reduction with prostaglandin analogs monotherapy may also depend of the axial length of the ocular globe.


New approaches to lymphatic imaging.
Accurate imaging of the lymphatic system can aid in cancer staging, optimize surgical procedures to reduce lymphedema, and may one day be a means of delivering intralymphatic therapy. The Sentinel Lymph Node (SLN) concept has been pivotal in driving new imaging techniques. Metastasis to a SLN is a critical indicator of advanced disease. However, presently, few tools are available for imaging the lymphatics, and even fewer are available for locating the SLN for biopsy. Recently, new macromolecular agents, including gadolinium-labeled dendrimers, fluorescent quantum dots, and fluorescently-labeled immunoglobins, have been used to image the lymphatics and SLN with MRI and optical techniques, and new fluorescent nanoparticles such as upconverting nanocrystals are potential future agents. Additionally, multi-modality probes combining two modalities such as optical/MR dendrimers have been designed to provide both preoperative imaging, and intraoperative guidance during lymph node resections. These probes can map the lymphatic system for maximal therapeutic benefit while minimizing complications such as lymphedema. Advances in the understanding of the molecular mechanisms of lymphangiogenesis and lymphatic spread of tumors offer the opportunity for more targeted imaging of the lymphatic system. Additionally, these imaging agents could be used as powerful research tools for tracking immunological cells and monitoring the immune response as well as providing the means to deliver lymphatic-targeted therapies. The future holds great promise for the translation of these methods to the clinic.


Co-localization of neural cell adhesion molecule and fibroblast growth factor receptor 2 in early embryo development.
During development there is a multitude of signaling events governing the assembly of the developing organism. Receptors for signaling molecules such as fibroblast growth factor receptor 2 (FGFR2) enable the embryo to communicate with the surrounding environment and activate downstream pathways. The neural cell adhesion molecule (NCAM) was first characterized as a cell adhesion molecule highly expressed in the nervous system, but recent studies have shown that it is also a signaling receptor. Using a novel single oocyte adaptation of the proximity ligation assay, we here show a close association between NCAM and FGFR2 in mouse oocytes and 2-cell embryos. Real-time PCR analyses revealed the presence of messenger RNA encoding key proteins in downstream signaling pathways in oocytes and early mouse embryos. In summary these findings show a co-localization of NCAM and FGFR2 in early vertebrate development with intracellular signaling pathways present to enable a cellular response.


Tackle and ruck technique proficiency within academy and senior club rugby union.
This study examined the validity of a tool that assesses tackle and ruck technique in training and established reference data for tackle, ball-carry and ruck technique at different levels of play in rugby union. One hundred and thirty-one amateur rugby union players; 37 senior, 51 first-grade academy and 43 second-grade academy players, participated in a two-on-two contact drill. The drill was filmed and the players' tackle, ball-carry and ruck technique were assessed using standardized technical criteria. Senior level players scored significantly higher in all three assessments; tackle technique senior vs academy 1st (p < 0.01, effect size (ES) = 0.7, moderate), senior vs academy 2nd (p < 0.01, ES = 0.7, moderate); ball-carry technique senior vs academy 1st (p < 0.01, ES = 0.6, moderate), senior vs academy 2nd (p < 0.01, ES = 0.8, moderate); ruck technique senior vs academy 1st (p < 0.01, ES = 0.7, moderate), senior vs academy 2nd (p < 0.01, ES = 0.4, small). These findings emphasize the importance of developing contact technique to allow players to progress to higher levels, and provide validity to an assessment tool which can facilitate this process.


Guided bone regeneration using nonexpanded polytetrafluoroethylene membranes in preparation for dental implant placements--a report of 420 cases.
The biologic principle of guided bone regeneration has been successfully used to prevent bone loss in extraction sites. This study comprises 420 cases of alveolar ridge maintenance in preparation for dental implant placements. Nonexpanded polytetrafluoroethylene membranes were positioned over all extraction sites and left intentionally exposed. Lyophilized mineralized bone allografts were used to prevent membrane collapse when buccal bone walls were lost. Membranes were removed at week 4. At the time of implant placements, all sites presented soft tissue compatibility with keratinized gingiva. The mucogingival junction position seemed to be preserved. Exposed nonexpanded polytetrafluoroethylene membranes associated, or not, with bone graft provide tissue formation suitable for implant placement.


Hydrogen sulfide adsorption on MOFs and MOF/graphite oxide composites.
Composites of a copper-based metal-organic framework (MOF) and graphite oxide (GO) were tested for hydrogen sulfide removal at ambient conditions. In order to understand the mechanisms of adsorption, the initial and exhausted samples were analyzed by various techniques including X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analyses, and sorption of nitrogen. Compared to the parent materials, an enhancement in hydrogen sulfide adsorption was found. It was the result of physical adsorption of water and H(2)S in the pore space formed at the interface between the MOF units and the graphene layers where the dispersive forces are the strongest. Besides physisorption, reactive adsorption was found as the main mechanism of retention. H(2)S molecules bind to the copper centers of the MOF. They progressively react with the MOF units resulting in the formation of copper sulfide. This leads to the collapse of the MOF structure. Water enhances adsorption in the composites as it allows the dissolution of hydrogen sulfide.


Helicobacter Pylori Associated Gastritis Increases Risk of Colorectal Polyps: a Hospital Based-Cross-Sectional Study in Nakhon Ratchasima Province, Northeastern Thailand.
Colorectal polyps are common in Thailand, particularly in the northeastern region. The present study aimed to determine any correlation between Helicobacter pylori-associated gastritis and colorectal polyps in the Thai population. A total of 303 patients undergoing esophagogastroduodenoscopy with colonoscopy for investigation of chronic abdominal pain participated in this study from November 2014 to October 2015. A diagnosis of Helicobacter pylori associated gastritis was made if the bacteria were seen on histopathological examination and a rapid urease test was positive. Colorectal polyps were confirmed by histological examination of colorectal biopsies. Patient demographic data were analyzed for correlations. The prevalence of colorectal polyps was 77 (25.4%), lesions being found more frequently in Helicobacter pylori infected patients than non-infected subjects [38.4% vs. 12.5%; Odds Ratio (OR) (95% CI): 2.26 (1.32 - 3.86), p < 0.01]. Patients with Helicobacter pylori - associated gastritis were at high risk of having adenomas featuring dysplasia [OR (95% CI): 1.15 (1.16 - 7.99); P = 0.02]. There was no varaition in location of polyps, age group, sex and gastric lesions with respect to Helicobacter pylori status. This study showed that Helicobacter pylori associated gastritis is associated with an increased risk of colorectal polyps, especially adenomas with dysplasia in the Thai population. Patients with Helicobacter pylori-associated gastritis may benefit from concurrent colonoscopy for diagnosis of colorectal polyps as a preventive and early treatment for colorectal cancer.


Progress on aptamer-based SERS sensors for food safety and quality assessment: methodology, current applications and future trends.
It is well known that food safety has aroused extensive attentions from governments to researchers and to food industries. As a versatile technology based on molecular interactions, aptamer sensors which could specifically identify a wide range of food contaminants have been extensively studied in recent years. Surface-enhanced Raman spectroscopy integrated aptamer combines the advantages of both technologies, not only in the ability to specifically identify a wide range of food contaminants, but also in the ultra-high sensitivity, simplicity, portable and speed. To provide beneficial insights into the evaluation techniques in the field of food safety, we offer a comprehensive review on the design strategies for aptamer-SERS sensors in different scenarios, including non-nucleic acid amplification methods ("on/off" mode, sandwich mode, competition model and catalytic model) and nucleic acid amplification methods (hybridization chain reaction, rolling circle amplification, catalytic hairpin assembly). Meanwhile, a special attention is paid to the application of aptamer-SERS sensors in biological (foodborne pathogenic, bacteria and mycotoxins) and chemical contamination (drug residues, metal ions, and food additives) of food matrix. Finally, the challenges and prospects of developing reliable aptamer-SERS sensors for food safety were discussed, which are expected to offer a strong guidance for further development and extended applications.


Fiber-type transitions and satellite cell activation in low-frequency-stimulated muscles of young and aging rats.
We examined satellite cell content and the activity of satellite cell progeny in tibialis anterior muscles of young (15 weeks) and aging (101 weeks) Brown Norway (BN) rats, after they were exposed for 50 days to a standardized and highly reproducible regime of chronic low-frequency electrical stimulation. Chronic low-frequency electrical stimulation was successful in inducing fast-to-slow fiber-type transformation, characterized by a 2.3-fold increase in the proportion of IIA fibers and fourfold and sevenfold decreases in the proportion of IID/X and IIB fibers in both young and aging BN rats. These changes were accompanied by a twofold increase in the satellite cell content in both the young and aging groups; satellite cell content reached a level that was significantly higher in the young group (p <.04). The total muscle precursor cell content (i.e., satellite cells plus progeny), however, did not differ between groups, because there was a greater number of satellite cell progeny passing through the proliferative and differentiative compartments of the aging group. The resulting 1.5-fold increase in myonuclear content was similar in the young and aging groups. We conclude that satellite cells and satellite cell progeny of aging BN rats possess an unaltered capacity to contribute to the adaptive response.


Extraction of a Fully Deployed Coronary Stent during Retrieval of Another Dislodged Stent.
Coronary stent dislodgement is a rare and serious complication of percutaneous coronary intervention and is associated with major adverse cardiac events. Successful retrieval of the stent is recommended in this situation because it is important for the prognosis. Recently, a patient was referred to our hospital with a dislodged coronary stent. When attempting to percutaneously extract the dislodged stent, a challenging situation was encountered, as the stent was entrapped and tightly entangled with another fully deployed coronary stent. Extraction of a fully deployed stent is generally prohibited as it may result in severe complications. Nevertheless, we extracted both the dislodged stent and the fully deployed stent, as a last resort. Herein, we report about this case. Our case highlights if the operator had a thorough understanding of the surrounding circumstances regarding the fully deployed coronary stent, successful extraction of the fully deployed coronary stent without any complications could be possible.


Dopamine agonists and their role in Parkinson's disease treatment.
Dopamine agonists directly activate dopamine receptors, bypassing the presynaptic synthesis of dopamine. There are two main classes of dopamine receptors: the D1 class linked to the enzyme adenyl cyclase and the D2 coupled to G-proteins that inhibit adenyl cyclase. Dopamine agonists are effective as monotherapy in early Parkinson's disease and as an adjunctive treatment to levodopa in the advanced stages of the disease. Dopamine agonists are increasingly used early, particularly in young-onset Parkinson's disease due to their levodopa-sparing effects and putative role as neuroprotective agents. The potential neuroprotective property of agonists has been the focus of research and debate in recent years. This review summarizes the use of dopamine agonists in Parkinson's disease and reviews the laboratory, clinical and functional imaging evidence of neuroprotection in this class of drug and discusses the clinical implications of their use in Parkinson's disease management.


The threat of avian influenza A (H5N1). Part III: Antiviral therapy.
Among emerging and re-emerging infectious diseases, influenza constitutes one of the major threats to mankind. In this review series epidemiologic, virologic and pathologic concerns raised by infections of humans with avian influenza virus A/H5N1 as well as treatment options are discussed. The third part discusses therapeutic options. Neuraminidase (NA) inhibitors are the most promising agents despite uncertainty about efficacy. Dosage increase, prolonged treatment or combination therapies may increase treatment efficacy and/or inhibit resistance formation. Immune system dysregulation contributes to H5N1 disease. Although current evidence does not support the use of anti-inflammatory drugs beneficial effects cannot be excluded at later disease stages.


The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in psoriasis.
Psoriasis is a common chronic skin disease. Recent studies demonstrated that IL-20 and IL-22, cytokines produced by keratinocytes and T cells, respectively, both inhibit keratinocyte terminal differentiation and induce psoriasis-like epidermis alterations. Here, we investigated the relationship between these mediators. Although IL-20 was not able to regulate IL-22 production, IL-22 induced IL-20 mRNA and protein in human keratinocytes. However, IL-22 had only a minimal effect, if any, on IL-19 and IL-26. Cutaneous IL-20 was also elevated in mice following IL-22 application. Accordingly, some of IL-22's effects on differentiation-regulating genes were partially mediated by an endogenous, secreted protein and attenuated by anti-IL-20 Ab. Like IL-22, IL-17A and TNF-alpha induced IL-20 in keratinocytes, whereas IFN-gamma and IL-20 itself did not. Furthermore, IL-17A and TNF-alpha individually strengthened the IL-22-induced IL-20 production. In lesional skin of psoriasis patients, highly elevated IL-20 levels strongly correlated with IL-22, and to a lesser extent, with IL-17A and TNF-alpha. As previously shown for IL-22, IL-20 blood levels correlated with the disease severity, although with a lower significance. This study demonstrates that a T-cell mediator induces a tissue cell mediator with similar effects to its own and therefore suggests the existence of a novel type of pathogenetic cascade.


A chemical-specific adjustment factor for human interindividual differences in kinetics for glutamates (E620-625).
Use of a default methodology for establishment of a health-based guidance value (HBGV) resulted in a group acceptable daily intake (ADI) for glutamates (E620-625) below the normal dietary glutamate intake, and also lower than the intake of free glutamate by breast fed babies. Use of a chemical-specific adjustment factor (CSAF) may overcome this problem. The present study investigates the interindividual human variability in glutamate plasma and brain levels in order to define a CSAF for the interindividual variation in kinetics, a HKAF, for glutamates. Human clinical data on plasma glutamate levels available from different groups of subjects at Mitsui Memorial Hospital as well as literature data on plasma and brain-related glutamate levels were collected and analysed. The median HKAF value obtained amounted to 2.62-2.74 to 2.33-2.52 for plasma derived values and to 1.68-1.81 for brain derived values. Combining these values with the CSAF for the interspecies differences in kinetics of 1 and the default factors for interspecies and interindividual differences in dynamics of 2.5 and 3.16 results in an overall CSAF of 16-20. Using this CSAF will result in a HBGV for glutamate that is no longer below the acceptable range of oral intake (AROI).


Oesophageal intubation can be undetected by auscultation of the chest.
Prompt detection of oesophageal intubation is a primary concern in anaesthetic practice. This blind, randomised study evaluates three widely used tests of intubation. Forty patients had both their trachea and oesophagus intubated, each patient was studied twice. Auscultation of the epigastrium, right and left axilla is more reliable than auscultation of the chest, and the anaesthetist's feeling when he squeezes the bag. P = 0.001 and P = 0.048, respectively. The tests were carried out after gastric distension with gas had occurred. We conclude that auscultation of epigastrium, right and left axilla, are recommended.


A novel approach to restore lung immunity during systemic immunosuppression.
Systemic immunosuppression accounts for significant morbidity and mortality worldwide. Pulmonary infections represent the most common cause of death in these patients. The resident inflammatory cell in the lung is the alveolar macrophage (AM) and its function is markedly diminished by immunosuppression. We hypothesized that AMs from normal mice with or without gene transfer of the gamma interferon gene inside the macrophages, can restore alveolar immunity in immunosuppressed mice with severe combined immunodeficiency syndrome (SCID). To test this hypothesis we intratracheally instilled normal and IFN-gamma activated macrophages to the lungs of SCID mice. We demonstrated that airway delivery of macrophages results in widespread alveolar distribution, improved phagocytic function and ability to clear opportunistic infections such as Pneumocystis carinii. Airway delivery of IFN-gamma expressing macrophages further increased the function of alveolar macrophages. Reconstitution of the lungs of immunosuppressed mice with normal or activated AMs can restore alveolar immunity despite ongoing systemic immunosuppression.


Oil/water droplet formation by temperature change in the water/c(16)e(6)/mineral oil system.
Droplet sizes of oil/water (O/W) nanoemulsions prepared by the phase inversion temperature (PIT) method, in the water/C16E6/mineral oil system, have been compared with those given by a theoretical droplet model, which predicts a minimum droplet size. The results show that, when the phase inversion was started from either a single-phase microemulsion (D) or a two-phase W+D equilibrium, the resulting droplet sizes were close to those predicted by the model, whereas, when emulsification was started from W+D+O or from W+D+Lalpha (Lalpha = lamellar liquid crystal) equilibria, the difference between the measured and predicted values was much higher. The structural changes produced during the phase inversion process have been investigated by the 1H-PFGSE-NMR technique, monitoring the self-diffusion coefficients for each component as a function of temperature. The results have confirmed the transition from a bicontinuous D microemulsion at the hydrophile-lipophile balance (HLB) temperature to oil nanodroplet dispersion in water when it is cooled to lower temperatures.


Virus-induced asthma.
Clinical and experimental investigations indicate that respiratory viral infections are important triggers for asthma attacks. Viral upper respiratory infections have been associated with 80% of asthma exacerbations in children and 50% of all asthma episodes in adults. Human Rhinovirus (HRV) has been implicated as the most common virus associated with asthma episodes. The observation that the great majority of wheezing lower respiratory tract illnesses in early life are associated with acute viral infections suggests that viruses may also alter the development of the lungs or of the immune system, acting as co-factors for the inception of asthma. Whilst there is no doubt that viruses are important asthma exacerbation factors, the role of viral infections in the development of asthma still remains controversial.


Brønsted base-catalyzed one-pot three-component Biginelli-type reaction: an efficient synthesis of 4,5,6-triaryl-3,4-dihydropyrimidin-2(1H)-one and mechanistic study.
An efficient one-pot synthesis of 4,5,6-triaryl-3,4-dihydropyrimidin-2(1H)-ones via a three-component Biginelli-type condensation of aldehyde, 2-phenylacetophenone, and urea/thiourea in the presence of a catalytic amount of t-BuOK (20 mol %) is described. The reactions proceeded efficiently at 70 degrees C to afford the desired products in moderate to good yields. Detailed mechanistic study shows that the Biginelli-type reaction using urea and thiourea proceeds through two totally different pathways. Enone 5 and bis-urea 8 were highly suggested as respective reaction intermediates for reactions involving thiourea and urea as substrates.


Tetraiodothyroacetic acid (tetrac) and nanoparticulate tetrac arrest growth of medullary carcinoma of the thyroid.
Tetraiodothyroacetic acid (tetrac) blocks angiogenic and tumor cell proliferation actions of thyroid hormone initiated at the cell surface hormone receptor on integrin alphavbeta3. Tetrac also inhibits angiogenesis initiated by vascular endothelial growth factor and basic fibroblast growth factor. We tested antiangiogenic and antiproliferative efficacy of tetrac and tetrac nanoparticles (tetrac NP) against human medullary thyroid carcinoma (h-MTC) implants in the chick chorioallantoic membrane (CAM) and h-MTC xenografts in the nude mouse. h-MTC cells were implanted in the CAM model (n = 8 per group); effects of tetrac and tetrac NP at 1 microg/CAM were determined on tumor angiogenesis and tumor growth after 8 d. h-MTC cells were also implanted sc in nude mice (n = 6 animals per group), and actions on established tumor growth of unmodified tetrac and tetrac NP ip were determined. In the CAM, tetrac and tetrac NP inhibited tumor growth and tumor-associated angiogenesis. In the nude mouse xenograft model, established 450-500 mm(3) h-MTC tumors were reduced in size over 21 d by both tetrac formulations to less than the initial cell mass (100 mm(3)). Tumor tissue hemoglobin content of xenografts decreased by 66% over the course of administration of each drug. RNA microarray and quantitative real-time PCR of tumor cell mRNAs revealed that both tetrac formulations significantly induced antiangiogenic thrombospondin 1 and apoptosis activator gene expression. Acting via a cell surface receptor, tetrac and tetrac NP inhibit growth of h-MTC cells and associated angiogenesis in CAM and mouse xenograft models.


Age-specific prevalence and risk associations for impaired glucose tolerance in urban southern Indian population.
A national survey of diabetes and impaired glucose tolerance (IGT) conducted in 2000 AD in six major cities of India showed a high prevalence of diabetes (12.1%) and IGT (14%). Prevalence of IGT was higher than that of diabetes in subjects with less than 40 years when compared with older subjects. This analysis was done to look for differences in the risk factors associated with IGT in the younger and older subjects. Associations of body mass index (BMI), waist : hip ratio, physical activity, family history of diabetes and monthly income with IGT and with diabetes were tested in the age groups of < 40 and > or = 40 years separately. Multiple logistic regression analyses were done to test the associations. Prevalence of IGT was higher than diabetes in the younger group (13.1% Vs 5%, P < 0.001). Prevalence of obesity was higher in the older IGT subjects (38% Vs 30.5%, p < 0.003). Presence of positive family history of diabetes was similar in both the groups. In the > or = 40 year group age, BMI and family history of diabetes were common risk factors for diabetes and IGT. In the younger group, only BMI showed an association with IGT. The association of family history of diabetes with IGT was weaker than for diabetes even in the older subjects (Odds Ratio (OR) = 3.5 for diabetes, 1.33 for IGT). Prevalence of IGT was higher than diabetes in the age group < 40 years. Only BMI showed an association with IGT in them while the risk associations were similar to diabetes in the older group. Prospective studies will throw more light on the implications of these findings.


Population structure promotes the evolution of costly sex in artificial gene networks.
We build on previous observations that Hill-Robertson interference generates an advantage of sex that, in structured populations, can be large enough to explain the evolutionary maintenance of costly sex. We employed a gene network model that explicitly incorporates interactions between genes. Mutations in the gene networks have variable effects that depend on the genetic background in which they appear. Consequently, our simulations include two costs of sex-recombination and migration loads-that were missing from previous studies of the evolution of costly sex. Our results suggest a critical role for population structure that lies in its ability to align the long- and short-term advantages of sex. We show that the addition of population structure favored the evolution of sex by disproportionately decreasing the equilibrium mean fitness of asexual populations, primarily by increasing the strength of Muller's Ratchet. Population structure also increased the ability of the short-term advantage of sex to counter the primary limit to the evolution of sex in the gene network model-recombination load. On the other hand, highly structured populations experienced migration load in the form of Dobzhansky-Muller incompatibilities, decreasing the effective rate of migration between demes and, consequently, accelerating the accumulation of drift load in the sexual populations.


Japanese encephalitis following liver transplantation: A rare case report.
Japanese encephalitis (JE) is a serious public health concern with a high mortality rate in many Asian countries. For many years, JE virus (JEV) was considered the major cause of viral encephalitis in Asia. Although most JE cases are asymptomatic, the case fatality rate approaches 30%, and approximately 30%-50% of survivors have long-term neurological sequelae. To the best of our knowledge, JEV infection has never been reported following liver transplantation. We report a case of a woman who underwent liver transplantation for autoimmune liver disease but presented with fever and neurological symptoms 13 d after transplantation. Magnetic resonance imaging revealed JEV infection, and positive immunoglobulin M antibody to JEV in blood and cerebrospinal fluid confirmed JE. The patient was treated with antiviral agents, immune regulation, and organ function support. No neurological sequelae were present after 1 year of follow-up. Imaging and lumbar puncture examination should be performed as soon as possible in patients with fever and central nervous system symptoms after liver transplantation, and the possibility of atypical infection should be considered, which is helpful for early diagnosis and improved prognosis.


[Liver transplantation--from experiment to routine care. Experiences from the first 500 liver transplantations in Gothenburg].
During a fifteen-year period, 500 liver transplantations have been performed at Sahlgrenska University Hospital in Göteborg. The results have improved, and factors influencing outcome are discussed. A one-year survival rate over 90% and a 5-year survival rate close to 80% can now be expected for most indications. Long-term complications as well as special problems occurring in different groups of recipients are discussed. New indications for liver transplantation such as liver metastasis of endocrine tumors are described. This article also describes our experience of in situ splitting and living-related liver transplantation as well as other innovations such as cavoportal hemitransposition and multivisceral transplantation.


[A case of melioidosis occurring after a long-term stay in Vietnam that developed pulmonary cavitation and relapsed with multiple pulmonary nodules].
A 69-year-old man complained of fever in September 2009, after returning from Vietnam where he has been working for 20 years. He had diabetes mellitus and was on diabetic oral medication. He was examined at a nearby hospital, and found out to have pneumonia with cavity formation in the right upper lobe which was found out to be not due to tuberculosis. Although the patient once recovered with antibacterial medicine, after a few months, in January 2010, he was admitted to our hospital because of recurrent fever. Computed tomography revealed multiple pulmonary nodules which were thought to be pulmonary emboli, as well as subcutaneous abscess, spleen abscess, and kidney abscess. Blood test showed that he also had DIC. As Burkholderia pseudomallei was cultured from the subcutaneous abscess and blood, was diagnosed as melioidosis. The patient was treated with meropenem for 8 weeks, and then a maintenance oral antibacterial medicine was continued for the next 6 months. The patient fully recovered after those treatments and has not relapsed since then. This is the ninth case report of melioidosis in Japan which is an imported infectious disease.


State v. Yepez: Admissibility and Relevance of Behavioral Genetic Evidence in a Criminal Trial.
The New Mexico Supreme Court recently considered whether a trial court had erred in excluding behavioral genetic evidence of a murder defendant's low-activity monoamine oxidase A (MAOA) gene, which the defendant argued had predisposed him-along with his history of childhood maltreatment-to "maladaptive or violent behavior." After an extensive analysis of the underlying science and its relevance to the case, the supreme court held unanimously that the trial judge had the discretion to exclude the MAOA evidence. The court's analysis provides insights into how other courts are likely to rule on the relevance of behavioral genetic evidence.


Increased endosomal sorting of ligand to recycling enhances potency of an interleukin-2 analog.
An interleukin-2 (IL-2) variant containing adjacent point mutations (L18M/L19S, termed 2D1) displaying binding affinity to the heterotrimeric IL-2 receptor similar to that of wild-type IL-2 (WT) had been previously found to surprisingly exhibit increased bioactivity in a peripheral blood lymphocyte proliferation assay. In order to provide an explanatory mechanism for this unexpected potency enhancement, we hypothesize that altered endocytic trafficking of the 2D1 variant might be responsible by increasing the number of ligand-receptor complexes. We demonstrate here that the internalization kinetics of 2D1 via the high affinity IL-2 receptor are equivalent to those of WT but that a significantly increased fraction of internalized 2D1 is sorted to recycling instead of to lysosomal degradation. We further find a reduced pH sensitivity of binding to IL-2 receptor alpha relative to IL-2 receptor beta compared with WT, which could be responsible for the altered sorting behavior of 2D1 in the acidic endosomal compartment. Accordingly, the 2D1 variant displays a half-life 36 h longer than that of IL-2 in T-lymphocyte culture at concentrations equal to the K(D) of the IL-2 receptor. The extended half-life of intact 2D1 provides enhanced mitogenesis as compared with IL-2. In addition, 2D1 stimulates natural killer cells to a lesser degree than IL-2 at equal concentrations. We conclude that this IL-2 variant provides increased mitogenic stimulation that could not be easily predicted from its cell surface receptor binding affinity while minimizing undesired stimulation of natural killer cells. This concept of altering trafficking dynamics may offer a generalizable approach to generating improvements in the pharmacological efficacy of therapeutic cytokines.


Paracellular permeability of extracellular space markers across rat jejunum in vitro. Indication of a transepithelial fluid circuit.
1. The characteristics of [51Cr]EDTA, [3H]methoxyinulin ([3H]MI), [14C]polyethylene glycol-4000 ([14C]PEG), and [3H]mannitol as markers of the extracellular space (e.c.s.) of isolated mucosa from the rat small intestine have been examined. 2. Unidirectional transmural fluxes across the rat jejunum of [3H]MI, [14C]PEG and [3H]mannitol have been measured in the absence of glucose or in the presence of 28 mM glucose. 3. Assuming that [14C]PEG does not enter the cells, [51Cr]EDTA and [3H]mannitol seem to have access to approximately 50 and 90% of the intracellular water respectively. 4. The commercially availabel [3H]MI had access to a space which exceeded th [14C]PEG space by 10%. Upon purification by gel filtration the high molecular weight fraction of the [3H]MI provided estimates of the e.c.s. identical with the estimates obtained with [14C]PEG. 5. For all the markers used the e.c.s. estimates remained constant between the 40th and 80th min of incubation. 6. In the absence of glucose the transepithelial net fluxes of each of the different markers were zero. In the presence of 28 mM glucose the serosato-mucosa fluxes of all markers were dramatically increased. The ratio between the serosa-to-mucosa and the mucosa-to-serosa fluxes increased in the order [3H]mannitol greater than [3H]MI greater than [14C]PEG. 7. The effect of glucose on the flux ratio of the marker substances suggests that glucose-induced net water transport to the serosa side of the gut wall represents the difference between a transcellular net water transport to the serosal side and a significant paracellular net water transport through the lateral intercellular spaces to the mucosal solution.


Computed tomography and magnetic resonance imaging in children with rare movement disorders.
Both CT and MR can aid in the differentiation between benign and less favorable pediatric movement disorders. However, MR is the more sensitive imaging modality and thus preferable. This was demonstrated in 18 patients with conditions ranging from idiopathic dystonias to aminoacidopathies, Leigh's disease, and Hallervorden-Spatz disease. In the latter three entities characteristic lesions were shown in the basal ganglia, although not consistently. A specific diagnosis seems possible in Leigh's disease, provided the clinical setting is appropriate.


Four new tri-forked species of the Australian genus Abantiades Herrich-Schäffer (Lepidoptera: Hepialidae) from the "dark obscura clade".
A distinct group of Abantiades Herrich-Schäffer species is here confirmed as a valid clade that we refer to as the "dark obscura clade" supported by morphological and mtDNA evidence. The clade is the sister group of A. obscura Simonsen of north-western Australia and comprises four new species: Abantiades centralia sp. nov., A. kayi sp. nov., A. zonatriticum sp. nov., and A. hutchinsoni sp. nov. These species together with A. obscura, are reciprocally allopatric and have a combined distribution spanning much of the western half of Australia and this distribution is consistent with their each differentiating locally from a widespread ancestor. The four new species raise the diversity of Abantiades to 42 species. [Zoobank urn:lsid:zoobank.org:pub:C05458D1-0D34-4432-8EC4-D031ED6B7BEF].


Synthesis and biological evaluation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines: synthetic methodology, enantioselective total synthesis of epicoccin G, 8,8'-epi-ent-rostratin B, gliotoxin, gliotoxin G, emethallicin E, and haematocin and discovery of new antiviral and antimalarial agents.
An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis[bis(trimethylsilyl)amino]trisulfide (23) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (1), 8,8'-epi-ent-rostratin B (2), gliotoxin (3), gliotoxin G (4), emethallicin E (5), and haematocin (6). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., 46, 2,2'-epi-46, and 61) and several low-micromolar anti- Plasmodium falciparum lead compounds (i.e., 46, 2,2'-epi-46, 58, 61, and 1).


[Estimation of postoperative morphological changes in the area of a potential formation of colorectal anastomosis in experiment].
In experiment on 50 white mongrel male rats there were investigated postoperative morphological changes in the area of a potential formation of colorectal anastomosis, occurring after total rectal mobilization performance. There was established, that rectal mobilization, even while securing a blood flow along the main vessels, causes nonreversible ischemic disorders in its wall. The investigation results witness the enhanced risk of the sutures insufficiency occurrence in low colorectal anastomoses and substantiate the expediency of application of prophylactic methods for this complication in a clinical practice.


Synthesis of the cyanobacterial halometabolite Chlorosphaerolactylate B and demonstration of its antimicrobial effect in vitro and in vivo.
Chlorosphaerolactylate B, a newly discovered antimicrobial halometabolite from the cyanobacterium Sphaerospermopsis sp. LEGE 00249 has been synthesized in three steps by using 12-bromododecanoic acid as starting material. A total of 0.5 g was produced for in vitro and in vivo antimicrobial efficacy testing. In vitro, the minimal inhibitory concentration (MIC) was estimated to be 256 mg/L for Staphylococcus aureus, while the minimal biofilm inhibitory concentration (MBIC) was estimated to be 74 mg/L. The in vivo study utilized a porcine model of implant-associated osteomyelitis. In total, 12 female pigs were allocated into 3 groups based on inoculum (n = 4 in each group). An implant cavity (IC) was drilled in the right tibia and followed by inoculation and insertion of a steel implant. All pigs were inoculated with 10 μL containing either: 11.79 mg synthetic Chlorosphaerolactylate B + 104 CFU of S. aureus (Group A), 104 CFU of S. aureus (Group B), or pure saline (Group C), respectively. Pigs were euthanized five days after inoculation. All Group B animals showed macroscopic and microscopic signs of bone infection and both tissue and implant harbored S. aureus bacteria (mean CFU on implants = 1.9 × 105). In contrast, S. aureus could not be isolated from animals inoculated with saline. In Group A, two animals had a low number of S. aureus (CFU = 6.7 × 101 and 3.8 × 101, respectively) on the implants, otherwise all Group A animals were similar to Group C animals. In conclusion, synthetic Chlorosphaerolactylate B holds potential to be a novel antimicrobial and antibiofilm compound.


A biomechanical comparison of superior and anterior positioning of precontoured plates for midshaft clavicle fractures.
With recent studies suggesting improved outcomes in displaced midshaft clavicle fractures treated with open reduction and internal fixation, debate has increased over the preferred plate positioning. Biomechanical studies have yielded conflicting results and have been limited by the almost exclusive use of a simple transverse fracture model. We conducted a study to biomechanically compare superior and anterior plate positioning for clinically relevant midshaft clavicle fracture patterns. Oblique, bending wedge, and complex comminuted fracture patterns were created sequentially in 12 synthetic clavicles. Half were plated with precontoured superior plates and half with precontoured anterior plates. Constructs were loaded in axial compression, torsion, and cantilever bending to determine construct stiffness for comparison of plate positioning. Results showed that, for all fracture patterns, more construct stiffness was achieved in axial compression and torsion (except for the oblique fracture pattern in clockwise torsion) with a superior plate, whereas more construct stiffness was achieved in cantilever bending with an anterior plate. Oblique fractures were significantly stiffer than bending wedge and complex comminuted fractures. Given the unknown relative importance of loading conditions, absolute recommendations for either superior or anterior plates cannot be made.


111In-pentetreotide scintigraphy in the detection of insulinomas: importance of SPECT imaging.
The aim of this study was to determine whether the systematic use of SPECT can increase the reported low sensitivity of somatostatin receptor scintigraphy (SRS) in detecting insulinomas. Fourteen patients were evaluated. After 111In-pentetreotide injection (approximately 250 MBq intravenously), abdominal SPECT images were obtained at 4 h and multiple planar images were obtained at 4 and 24 h. MRI and CT were performed within 1 mo of SRS. Sixteen tumors were histologically verified after surgery in 14 patients. SPECT revealed 14 lesions in 12 patients (sensitivity, 87.5%), both planar SRS and MRI revealed 7 tumors in 7 patients (sensitivity, 43.8%), and CT revealed only 5 lesions in 4 patients (sensitivity, 31.3%). Moreover, in 4 patients SPECT was the only examination with positive findings. SPECT at 4 h is mandatory for preoperative detection of insulinomas using SRS because the images are more sensitive than planar images and are superior to images from other conventional methods.


[Introduction to LGBT: definitions, some historical facts, and evolution of thinking in the era of HIV/AIDS--hopes and challenges].
This article deals with the subject matter of LGBT (lesbians, gays, bisexuals, transgenders), i.e. individuals who are not heterosexual, presenting definitions, some historical facts, and evolution of thinking in 2010. Attention is drawn to discrimination and stigmatization of members of the LGBT community. Problems related to the prevention of HIV/AIDS among men having sexual contacts with other men are discussed. A concise presentation of the functioning of the LGBT community in the heterosexual society is included. Emphasis is placed on equality of non-heterosexual orientations with reference to important ideas such as homo- and binormativity.


The antinociceptive effect of intrathecal escin in the rat formalin test.
This study investigated the antinociceptive effect of intrathecal escin and examined its effect on the formalin-induced activation of c-Fos and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) in the rat spinal cord. Rats were chronically implanted with lumbar intrathecal catheters, and the ability of intrathecal escin to alter nociceptive behaviours in the rat formalin test was examined. The expression of c-Fos and p-p38 MAPK in the dorsal horn of the spinal cord was detected in the control and escin (40μg) groups using immunohistochemical techniques. Intrathecal escin produced a dose-dependent reduction in formalin-evoked flinching behaviour in rats during the second phase; however, no effect was observed in the first phase. In addition, immunohistochemical experiments showed that the expression of c-Fos and p-p38 MAPK in the spinal cord dorsal horn increased after an injection of formalin into the paw. Interestingly, the 40μg dose of intrathecal escin, which was the larger of the two doses that blocked formalin-induced hyperalgaesia, attenuated the formalin-induced increases in c-Fos and p-p38 MAPK in the dorsal horn of the spinal cord. The decrease in pain-related behaviours and c-Fos expression indicated that escin produced antinociceptive effects in the rat formalin test. Although the specific mechanisms of these effects were not investigated, the reduction in p-p38 MAPK in the dorsal horn of the spinal cord may be involved.


Effect of a single breath of 100% oxygen on respiration in neonates during sleep.
To determine the effect of a single breath of 100% O2 on ventilation, 10 full-term [body wt 3,360 +/- 110 (SE) g, gestational age 39 +/- 0.4 wk, postnatal age 3 +/- 0.6 days] and 10 preterm neonates (body wt 2,020 +/- 60 g, gestational age 34 +/- 2 wk, postnatal age 9 +/- 2 days) were studied during active and quiet sleep states. The single-breath method was used to measure peripheral chemoreceptor response. To enhance response and standardize the control period for all infants, fractional inspired O2 concentration was adjusted to 16 +/- 0.6% for a control O2 saturation of 83 +/- 1%. After 1 min of control in each sleep state, each infant was given a single breath of O2 followed by 21% O2. Minute ventilation (VE), tidal volume (VT), breathing frequency (f), alveolar O2 and CO2 tension, O2 saturation (ear oximeter), and transcutaneous O2 tension were measured. VE always decreased with inhalation of O2 (P less than 0.01). In quiet sleep, the decrease in VE was less in full-term (14%) than in preterm (40%) infants (P less than 0.001). Decrease in VE was due primarily to a drop in VT in full-term infants as opposed to a fall in f and VT in preterm infants (P less than 0.05). Apnea, as part of the response, was more prevalent in preterm than in full-term infants. In active sleep the decrease in VE was similar both among full-term (19%) and preterm (21%) infants (P greater than 0.5). These results suggest greater peripheral chemoreceptor response in preterm than in full-term infants, reflected by a more pronounced decrease in VE with O2. The results are compatible with a more powerful peripheral chemoreceptor contribution to breathing in preterm than in full-term infants.


Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus.
Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1 → 3)-β-D-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1 → 3)-β-D-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1 → 3)-β-D-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1 → 3)-β-D-glucan levels in the majority of patients.


Chlamydia trachomatis enters a viable but non-cultivable (persistent) state within herpes simplex virus type 2 (HSV-2) co-infected host cells.
Epidemiological and clinical studies have shown that double infection with herpes simplex virus type 2 (HSV-2) and Chlamydia trachomatis occurs in vivo. We hypothesized that co-infection would alter replication of these agents. To test this hypothesis, HeLa cells were infected with C. trachomatis serovar E, followed 24 h later by HSV-2 strain 333. Transmission electron microscopic (TEM) analyses indicated that, by 10 h after HSV addition, reticulate bodies (RBs) in co-infected cells were swollen, aberrantly shaped and electron-lucent. In infectious titre assays, HSV-2 co-infection abrogated production of infectious chlamydial progeny. Western blot analyses indicated that accumulation of chlamydial major outer membrane protein (MOMP) was decreased by HSV co-infection while accumulation of chlamydial heat-shock protein 60-1 (HSP60-1) was increased. Polymerase chain reaction (PCR) experiments indicated that chlamydial genome copy number was unaltered by HSV-2 superinfection. Semi-quantitative, reverse transcription PCR (RT-PCR) experiments demonstrated that levels of chlamydial groEL, ftsK, ftsW, dnaA and unprocessed 16S rRNA transcripts were not changed by HSV-2 super-infection. These data indicate that HSV-2 superinfection drives chlamydia into a viable but non-cultivable state, which is the hallmark of persistence. Because chlamydial HSP60-1 has been associated with immunopathology in vivo, these results also suggest that disease severity might be increased in co-infected individuals.


Subretinal neovascularization following metallic intraocular foreign-body trauma.
Two patients developed subretinal neovascularization after chorioretinal injury from a metallic intraocular foreign body. In the first patient, a metallic foreign body struck the retina temporal to the macula and settled inferiorly. Eight months later, subretinal neovascularization developed at the initial impact site. In the second patient, a piece of silver wire became embedded in the retina and choroid near the macula, and subretinal neovascularization occurred six months later at the nasal end of the wire. In both patients, the subretinal neovascularization was confirmed with fluorescein angiography and successfully obliterated with argon laser photocoagulation.


[Periprosthetic joint infections - a review for general practitioners].
The number of prosthetic joint implantation is continuously increasing. Periprosthetic joint infection is a rare but serious complication. The correct diagnosis is essential for successful treatment. It requires the close collaboration between general practitioners, orthopaedic surgeons and infectious disease specialists. A delayed diagnosis sets hurdles to the medical and surgical treatment. Also, antimicrobial treatment without proper microbiological sampling must be avoided. Swabs from wounds are not helpful, because the results represent the skin flora, but not the causative pathogen of infection. The general practitioner is the first physician that patients contact and has, therefore, a central role in diagnosing and managing periprosthetic joint infections. In this review, classification, diagnostic means and treatment concepts of periprosthetic joint infections are presented.


Analysis of MTHFR 1298A>C in addition to MTHFR 677C>T polymorphism as a risk factor for neural tube defects in the Turkish population.
Maternal folic acid intake in the periconceptional period is strongly related to reduction in recurrence and occurrence of birth defects involving the neural tube. Among the single nucleotide polymorphisms (SNPs) influencing the folate metabolism, the methylenetetrahydrofolate reductase (MTHFR) gene has been the one most exclusively studied. Many studies have reported significant association between MTHFR 677C>T and increased risk of neural tube defects (NTDs). Our previous study did not support this observation. The present study aimed to determine the prevalence of 1298A>C polymorphism in addition to 677C>T in the same Turkish population as a risk factor for NTDs. We genotyped case (95 offspring with NTDs, 80 mothers, 72 fathers) and control (93 healthy children) populations for MTHFR 677C>T and MTHFR 1298 A>C polymorphisms. The comparison demonstrated a significant increase in the 1298AA/677TT genotype frequency among mothers of offspring with NTDs (OR 5.23 [1.06-25.9]; p=0.067). The 677CT genotype was only 1.35 times higher than controls among mothers when 677C>T polymorphism was evaluated alone, while 677CT/1298AC in the current study demonstrated a 3.8 times increase in this risk. These observations led us to conclude that although not statistically significant, MTHFR 1298AC polymorphism might be a risk factor for the occurrence of NTDs in the Turkish population.


Novel aspects of heat shock factors: DNA recognition, chromatin modulation and gene expression.
Heat shock factor (HSF) is an evolutionarily conserved stress-response regulator that activates the transcription of heat shock protein genes, whose products maintain protein homeostasis under normal physiological conditions, as well as under conditions of stress. The promoter regions of the target genes contain a heat shock element consisting of multiple inverted repeats of the pentanucleotide sequence nGAAn. A single HSF of yeast can bind to heat shock elements that differ in the configuration of the nGAAn units and can regulate the transcription of various genes that function not only in stress resistance, but also in a broad range of biological processes. Mammalian cells have four HSF family members involved in different, but in some cases similar, biological functions, including stress resistance, cell differentiation and development. Mammalian HSF family members exhibit differential specificity for different types of heat shock elements, which, together with cell type-specific expression of HSFs is important in determining the target genes of each HSF. This minireview focuses on the molecular mechanisms of DNA recognition, chromatin modulation and gene expression by yeast and mammalian HSFs.


Antibiotic prophylaxis for transrectal ultrasound biopsy of the prostate in Ireland.
Prostate cancer is the most common solid cancer affecting men in Ireland. Transrectal ultrasound (TRUS) biopsies of the prostate are routinely performed to diagnose prostate cancer. They are, in general, a safe procedure but are associated with a significant risk of infective complications ranging from fever, urinary tract infection to severe urosepsis. At present, there are no recommended national guidelines on the use of antibiotic prophylaxis to minimise the risk of infective complications post-TRUS biopsy. To review the antibiotic prophylaxis for TRUS biopsy used in Irish hospitals. We used a standard telephone questionnaire to establish what antibiotic protocol is in use in each hospital. 40 hospitals were contacted, of which 29 perform TRUS biopsies. In the majority of hospitals, TRUS biopsies are carried out in the radiology department. All hospitals administer antibiotic prophylaxis but there is wide variation in the protocols used. There are five different antibiotics prescribed, ciprofloxacin being the most common. Treatment protocols vary from 1 to 10 days antibiotic cover post procedure. There is a lack of standardisation of antibiotic prophylaxis in Irish hospitals. There is a need for guidelines to clarify the most appropriate antibiotic, route of administration and duration of treatment.


Indole Functionalization via Photoredox Gold Catalysis.
The use of photoredox catalyst [Au2(dppm)2]Cl2 to initiate free-radical cyclizations onto indoles is reported. Excitation of the dimeric Au(I) photocatalyst for the reduction of unactivated bromoalkanes and bromoarenes is used for the generation of carbon-centered radicals. Previous to this work, reduction processes leading to indole functionalization utilizing photoredox catalysts were limited to activated benzylic or α-carbonyl-positioned bromoalkanes. This method offers a mild and safe alternative to organostannanes and pyrophoric initiators for access to high energy radicals that were previously inaccessible through catalytic or stoichiometric means.


[Estimation of atherogenic immune complexes containing modified lipoproteins in complement fixation tests].
A method for determining atherogenicity of the immune complexes containing multiple modified low-density lipoprotein (mmLDL) in complement fixation test has been found. In the proposed method, the precipitate immune complexes containing mmLDL (IC mmLDL) was prepared from human serum by treating it with buffer (8.3% of th PEG 3350 and 3.3% PVP 12600 th in the ratio 1: 1.2) for 10 min at 23 °C. IC mmLDL aggregates were separated by centrifugation at 3100g for 10 min at 23 °C. The precipitate IC mmLDL was dissolved in buffer without PEG and PVP, cholesterol content and the degree of binding of guinea pig complement were measured. Atherogenicity of the IC mmLDL was registered as the ratio of the degree of complement binding to cholesterol in the the immune complexes.


Reproducibility of retinal nerve fiber layer and macular thickness measurement with the RTVue-100 optical coherence tomograph.
To evaluate the reproducibility of peripapillary retinal nerve fiber layer thickness (RNFLT) and ganglion cell complex (GCC) measurements made with the RTVue-100 Fourier-domain optical coherence tomography (OCT) device (Optovue, Inc., Fremont, CA) and to determine the influence of 4 factors: pupil dilation, subject age, experience in imaging examinations, and glaucoma severity. Prospective study for evaluation of a diagnostic test. Thirty-seven hospital-based participants (14 normal and ocular hypertensive subjects, 11 patients with moderate and 12 with severe glaucoma), all experienced in imaging examinations, and 40 consecutive screening trial participants lacking such experience. One eye of all participants was imaged 5 times. For the hospital-based participants, on the same day the measurement series was repeated after pupil dilation. For determination of intersession reproducibility, measurements were performed again 3 months later. Intrasession and intersession coefficient of variation (CV), intraclass correlation coefficient (ICC), intratest variability, and test-retest variability. For the average and quadrant RNFLT parameters and the GCC parameters, intrasession ICC varied between 93.9% and 99.0%, intrasession CV between 1.95% and 5.69%, and intratest variability varied between 3.11 and 9.13 microm. Most thickness values, all intrasession CV and intratest variability values, and the signal strength index were not changed significantly after pupil dilation. Intrasession CV of the 16 peripapillary RNFLT sectors varied between 4.90% and 11.66%. Most intrasession CV values increased significantly with increased disease severity, but intratest variability for average RNFLT and the quadrant RNFLT parameters, which are used for statistical comparison with the normative database, were unaffected by the severity of glaucoma. Patient age and experience in imaging examinations had no influence on intrasession CV. Intratest variability and intrasession CV represented 79.1% to 98.6% and 77.1% to 95.0% of test-retest variability and intervisit CV, respectively, for the average and quadrant RNFLT and the GCC parameters. Intrasession and intersession reproducibility of RNFLT and GCC measurements with the RTVue-100 OCT are satisfactory for diagnostic purposes, both in normals and in patients with different glaucoma severity. Pupil dilation, age, and experience in imaging examinations did not influence reproducibility in a clinically significant manner. Proprietary or commercial disclosure may be found after the references.


Development of a flow amperometric enzymatic method for the determination of total glucosinolates in real samples.
The first amperometric flow analyzer, based on the biosensor concept, capable of determining total glucosinolates in real samples, is described. Myrosinase was immobilized on aminopropyl-modified controlled pore glass, which was then used for the construction of a packed-bed reactor. Myrosinase catalyzes the hydrolysis of glucosinolates (sinigrin) to glucose (among the other products), which is then oxidized by the action of glucose oxidase to produce hydrogen peroxide. The glucose enzyme electrode is based on a multimembrane architecture and was mounted on an amperometric flow cell (hydrogen peroxide detection at a platinum anode poised at +0.65 V vs Ag/AgCl/3M KCl). Different membrane types and different activation procedures were tested. The system was optimized to various working parameters, either as a glucose electrode or as a glucosinolate analyzer. The interference effect of various compounds was also investigated. Application of the method to real samples was carried out using glucose/glucose, hydrolyzed sinigrin and glucose/sinigrin solution as calibrators of the glucose electrode and the glucosinolate analyzer. Deviations due to the enantioselectivity of glucose oxidase to the beta-glucose anomer were observed, and a data elaboration protocol is proposed. The possibility of the simultaneous determination of glucose and glucosinolates is also demonstrated.


No effect of prenatal vitamin D deficiency on autism-relevant behaviours in multiple inbred strains of mice.
Autism Spectrum Disorders (ASD) is a group of neurodevelopmental disorders commonly characterised by verbal and non-verbal communication deficits, impaired social interaction and repetitive, stereotypic behaviours. The aetiology of ASD is most likely a combination of genetic and environmental factors. Epidemiological evidence suggests that prenatal vitamin D deficiency is associated with an increased incidence of ASD. The overall aim of this study was to investigate prenatal vitamin D deficiency on ASD-related behavioural phenotypes in multiple inbred strains of mice. We included two commonly used inbred mouse strains (C57BL/6J and BALB/c) as well as inbred BTBR mice, which show ASD-related behaviours, such as excessive self-grooming, hyperlocomotion, social interaction deficits and altered communication. We also studied the effect of prenatal vitamin D deficiency in a fourth strain; an F1 cross of C57BL/6J x BTBR mice, which have a partial BTBR phenotype. To implement prenatal vitamin D deficiency, female mice were placed on vitamin D deplete diets for ten weeks, including mating and gestation, until littering, when all dams were switched to the control diet. Behavioural symptoms related to ASD were measured, including isolation-induced ultrasonic vocalisations to measure communication, the three-chambered social interaction task to observe social interaction, the open field test to examine hyperlocomotion, assessment of grooming and rearing behaviour and finally the active place avoidance task to observe spatial learning and memory in response to a mild foot shock. Prenatal vitamin D deficiency had a negative impact on preference for social novelty in C57BL/6J mice, despite similar vocalisation phenotypes, and prenatal vitamin D-deficient F1 mice were found to be hypolocomotive in the open field test yet performed better on the active place avoidance task. Despite clear differences between strains, there were no other consistent significant main effects of maternal diet on the behaviour of the offspring. Vitamin D deficiency has been implicated as a risk factor for ASD and these data show that there is greater variation between different inbred strains in ASD-related behaviour, suggesting that prenatal vitamin D deficiency is not sufficient to recapitulate an ASD phenotype in multiple inbred strains of mice.


Molecular mechanisms regulating the pharmacological actions of icariin with special focus on PI3K-AKT and Nrf-2 signaling pathways.
Icariin is a primary active component of the traditional Chinese medicinal plant Epimedium grandiflorum. A range of pharmacological effects of icariin has been researched by modern science to explain its traditional medicinal uses. Attributing to the wide range of pharmacological properties like anti-osteoporosis, anti-inflammation, anti-oxidative stress, anti-depression, and anti-tumor property possessed by icariin, it is now being considered a potential therapeutic agent for a wide variety of disorders ranging from neoplasm, neurodegenerative disorders, osteoporosis, and cardiovascular diseases. Various signaling pathways including NFκB/NALP3, IGF-1, MiR-223-3p/ NALP3, TLR4/ NFκB, and WNT1/β-catenin are involved in the different biological actions exerted by icariin. Apart from these pathways, PI3K-AKT (Phosphoinositide 3 kinase-Protein kinase B) and Nrf-2 (nuclear erythroid 2-related factor 2) signaling pathways are two important pathways that form the fundamental basis for the pharmaceutical efficacy of icariin. This review gives an overview of previous in vitro and in vivo studies that investigated the potential role of icariin via PI3K-AKT and Nrf-2 signaling pathways to provide greater insights into its potential clinical use in a variety of disorders.


Effect of Interfacial Schemes on the Optical and Structural Properties of InAs/GaSb Type-II Superlattices.
Incorporating an intentional strain compensating InSb interface (IF) layer in InAs/GaSb type-II superlattices (T2SLs) enhances device performance. But there is a lack of studies that correlate this approach's optical and structural quality, so the mechanisms by which this improvement is achieved remain unclear. One critical issue in increasing the performance of InAs/GaSb T2SLs arises from the lattice mismatch between InAs and GaSb, leading to interfacial strain in the structure. Not only that but also, since each side of the InAs/GaSb heterosystem does not have common atoms, there is a possibility of atomic intermixing at the IFs. To address such issues, an intentional InSb interfacial layer is commonly introduced at the InAs-on-GaSb and GaSb-on-InAs IFs to compensate for the strain and the chemical mismatches. In this report, we investigate InAs/GaSb T2SLs with (Sample A) and without (Sample B) InSb IF layers emitting in the mid-wavelength infrared (MWIR) through photoluminescence (PL) and band structure simulations. The PL studies indicate that the maximum PL intensity of Sample A is 1.6 times stronger than that of Sample B. This could be attributed to the effect of migration-enhanced epitaxy (MEE) growth mode. Band structure simulations understand the impact of atomic intermixing and segregation at T2SL IFs on the bandgap energy and PL intensity. It is observed that atomic intermixing at the IFs changes the bandgap energy and significantly affects the wave function overlap and the optical property of the samples. Transmission electron microscopy (TEM) measurements reveal that the T2SL IFs in Sample A are very rough compared to sharp IFs in Sample B, indicating a high possibility of atomic intermixing and segregation. Based on these results, it is believed that high-quality heterostructure could be achieved by controlling the IFs to enhance its structural and compositional homogeneities and the optical properties of the T2SLs.


Rapid differentiation of the major causative agents of bacterial meningitis by use of frequency-pulsed electron capture gas-liquid chromatograph: analysis of acids.
The major causative agents of bacterial meningitis, Haemophilus influenzae serogroup B, Neisseria meningitidis serogroups B and C, Klebsiella pneumoniae, Streptococcus pneumoniae, and two types of Escherichia coli, were cultured in a modified chemically defined Catlin medium and in a commercial version of the unmodified Catlin medium. The spent media were extracted under acidic conditions, and electron-capturing derivatives were prepared by derivatization with trichloroethanol or haptafluorobutyric anhydride. The derivatives were analyzed on a gas chromatograph equipped with a frequency-pulsed electron capture detector and a PEP-2 computer. The data obtained from the study show that these organisms can be easily distinguished from each other on the basis of metabolic products detected in either type of medium. Three different metabolic groups were detected within two serogroups of N. meningitidis. The methods are practical, and the new technique should offer clinical laboratories and hospitals a better method for rapid identification of this important group of pathogens.


[Spinal and epidural anaesthesia for caesarean section in patients with pre-eclampsia].
Neuraxial regional anaesthesia is now widely used in obstetric anaesthesia. Specifically, the rate of spinal anaesthesia increased considerably and is favoured for scheduled caesarean section. Former concerns to use regional anaesthetic techniques in non scheduled cases, e.g. spinal anaesthesia for pre-eclampsia are not supported by recent study data. Spinal and epidural anaesthesia are both safe in patients presenting with pre-eclampsia, if contraindications for neuraxial anaesthesia are taken into account.


Two new lactones and one new aryl-8-oxa-bicyclo[3,2,1]oct-3-en-2-one from Descurainia sophia.
Two new lactones (1, 2), descurainolide A and B, and one new aryl-8-oxa-bicyclo[3,2,1]-oct-3-en-2-one (3), descurainin, together with five known compounds (4-8), were isolated from the seeds of Descurainia sophia (L.) WEBB ex PRANTL. The structures of the new compounds were elucidated by extensive studies of their 1D, 2D NMR and HR-MS. Compounds 4 and 5 showed cytotoxicity.


Postoperative Portal Hypertension Enhances Alloimmune Responses after Living-Donor Liver Transplantation in Patients and in a Mouse Model.
Controlling portal vein pressure in living-donor liver transplantation has received increased attention owing to its potential importance for graft survival. Portal hypertension may lead to the activation of liver-resident APCs, including liver sinusoidal endothelial cells (LSECs), which have immunological tolerogenic capacity. We investigated the effects of portal hypertension on graft survival and the antidonor immune response using clinical data and a mouse model. We categorized patients (n = 136) according to their portal vein pressure values at the end of surgery. Using propensity score-matching analyses, we found that portal hypertension was significantly associated with a higher antidonor immune response and incidence of acute rejection. To investigate the mechanism, we performed an allogeneic coculture assay using a 70% hepatectomized (HTx) mouse model with or without a portosystemic shunt. Liver cells from HTx mice without a shunt exhibited a significantly greater anti-BALB/c B6 T cell response than those from sham-operated mice or HTx mice with a shunt. LSECs from sham-operated mice, but not from HTx mice, suppressed the B6 T cell alloresponse in a dose-dependent manner. Furthermore, LSECs from HTx mice without a shunt showed significantly downregulated MHC class I/II and programmed death-ligand 1 expression, and those from mice with a shunt showed recovered expression of these molecules. Postoperative portal hypertension enhances alloimmune responses in recipients after living-donor liver transplantation, likely due, in part, to the impaired immune-suppression capacity of LSECs.


Productive Infection of Human Breast Cancer Cell Lines with Human Cytomegalovirus (HCMV).
Breast cancer is the leading cause of cancer deaths among women worldwide. There are many known risk factors for breast cancer, but the role of infectious disease remains unclear. Human cytomegalovirus (HCMV) is a widespread herpesvirus that usually causes little disease. Because HCMV has been detected in breast tumor biopsy samples and is frequently transmitted via human breast milk, we investigated HCMV replication in breast tumor cells. Four human breast cancer cell lines with different expression profiles for the key diagnostic markers of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), were infected with a bacterial artificial chromosome-derived HCMV clinical strain TB40/E tagged with green fluorescent protein (GFP). Fluorescence microscopy confirmed that all four breast cancer cell lines supported virus entry. RNA was isolated from infected cells and the expression of immediate early (UL123), early (UL54), and late (UL111A) genes was confirmed using PCR. Viral proteins were detected by immunoblotting, and viral progeny were produced during the infection of breast tumor cells, as evidenced by subsequent infection of fibroblasts with culture supernatants. These results demonstrate that breast tumor cells support productive HCMV infection and could indicate that HCMV replication may play a role in breast cancer progression.


Hotspots of Sequence Variability in Gut Microbial Genes Encoding Pro-Inflammatory Factors Revealed by Oligotyping.
The gut microbiota has been implicated in a number of normal and disease biological processes. Recent studies have identified a subset of gut bacterial genes as potentially involved in inflammatory processes. In this work, we explore the sequence variability for some of these bacterial genes using a combination of deep sequencing and oligotyping, a data analysis application that identifies mutational hotspots in short stretches of DNA. The genes for pks island, tcpC and usp, all harbored by certain strains of E. coli and all implicated in inflammation, were amplified by PCR directly from stool samples and subjected to deep amplicon sequencing. For comparison, the same genes were amplified from individual bacterial clones. The amplicons for pks island and tcpC from stool samples showed minimal levels of heterogeneity comparable with the individual clones. The amplicons for usp from stool samples, by contrast, revealed the presence of five distinct oligotypes in two different regions. Of these, the oligotype GT was found to be present in the control uropathogenic clinical isolate and also detected in stool samples from individuals with colorectal cancer (CRC). Mutational hotspots were mapped onto the USP protein, revealing possible substitutions around Leu110, Glu114, and Arg115 in the middle of the pyocin domain (Gln110, Gln114, and Thr115 in most healthy samples), and also Arg218 in the middle of the nuclease domain (His218 in the uropathogenic strain). All of these results suggest that a level of variability within bacterial pro-inflammatory genes could explain differences in bacterial virulence and phenotype.


Extracorporeal support for patients with acute respiratory distress syndrome.
Extracorporeal membrane oxygen (ECMO) has been used for many years in patients with life-threatening hypoxaemia and/or hypercarbia. While early trials demonstrated that it was associated with poor outcomes and extensive haemorrhage, the technique has evolved. It now encompasses new technologies and understanding that the lung protective mechanical ventilation it can facilitate is inextricably linked to improving outcomes for patients. The positive results from the CESAR (Conventional ventilation or ECMO for Severe Adult Respiratory failure) study and excellent outcomes in patients who suffered severe influenza A (H1N1/09) infection have established ECMO in the care of patients with severe acute respiratory distress syndrome. Controversy remains as to at what point in the clinical pathway ECMO should be employed; as a rescue therapy or more pro-actively to enable and ensure high-quality lung protective mechanical ventilation. The primary aims of this article are to discuss: 1) the types of extracorporeal support available; 2) the rationale for its use; 3) the relationship with lung protective ventilation; and 4) the current evidence for its use.


Tumor Recurrence and Graft Survival in Renal Transplant Recipients with a History of Pretransplant Malignancy: A Matched Pair Analysis.
Organ scarcity demands critical decision-making regarding eligible transplant candidates and graft allocation to ensure best benefit from renal transplantation (RTx). Among the controversial relative contraindications is a history of pretransplant malignancy (PTM). While oncological outcomes of PTM-RTx recipients are well described, data on graft-specific outcome are scarce. A retrospective double case control matched pair analysis (60 months follow-up) was carried out and RTx-recipients were stratified for history of PTM. First, PTM-RTx recipients were matched according to age, sex and duration of immunosuppressive therapy. Next, PTM-RTx recipients were matched 1:1 for age, sex and cause of end-stage renal disease. Five-year patient and graft survival as well as oncological outcomes were analyzed. A total of 65 PTM-RTx recipients were identified. Post-RTx recurrence rate was 5%, while 20% developed second de novo malignancy, comparable to 14% in the control group. PTM-RTx recipients had a noticeable lower five-year death-censored as well as overall graft survival and Cox proportional hazard modeling showed a correlation between PTM and inferior graft survival. Although underlying reasons remain not fully understood, this study is the first to show inferior graft survival in PTM-RTx recipients and advocates necessity to focus on more meticulous graft monitoring in PTM recipients in addition to heightened surveillance for cancer recurrence.


Helicobacter pylori immune escape is mediated by dendritic cell-induced Treg skewing and Th17 suppression in mice.
Helicobacter pylori infection increases gastric regulatory T cell (Treg) response, which may contribute to H pylori immune escape. We hypothesize that H pylori directs Treg skewing by way of dendritic cells (DCs) and thus inhibits interleukin-17(+) helper T cells (Th17) immunity. Two-photon microscopy was used to locate DCs in gastric lamina propria of mice. The induction of Th17 and Treg responses by bacteria-pulsed murine bone marrow-derived DCs was analyzed by cytokine production and stimulation of T-cell proliferation. The effect of VacA, CagA, transforming growth factor-beta (TGF-beta), and IL-10 on Th17/Treg balance was assessed. The in vivo significance of Tregs on the H pylori-specific Th17 response and H pylori density was determined by using anti-CD25 neutralizing antibodies to deplete Tregs in mice. We showed that mucosal CD11c(+) DCs are located near the surface of normal gastric epithelium, and their number increased after H pylori infection. Study of the direct interaction of DCs with H pylori showed a Treg-skewed response. The Treg skewing was independent of H pylori VacA and CagA and dependent on TGF-beta and IL-10. In vivo Treg skewing by adoptive transfer of H pylori-pulsed DCs reduces the ratio of gastric IL-17/Foxp3 mRNA expressions. The depletion of CD25(+) Tregs results in early reduction of H pylori density, which is correlated with enhanced peripheral H pylori-specific Th17, but not Th1, response. Overall, our study indicates that H pylori alters the DC-polarized Th17/Treg balance toward a Treg-biased response, which suppresses the effective induction of H pylori-specific Th17 immunity.


Metal-Free Route to Carboxylated 1,4-Disubstituted 1,2,3-Triazoles from Methoxycarbonyl-Modified Vinyl Sulfone.
A metal-free alternative to the regioselective synthesis of carboxylated 1,4-disubstituted 1,2,3-triazoles (1,4-cDTs) has been accomplished. A methoxycarbonyl-substituted vinyl sulfone on reactions with organic azides resulted in the formation of 1,4-cDTs in an operationally simple route. The reaction, carried out with a variety of organic azides containing free alcohol, acid, Boc-protected amine, ester, protected sugars, long-chain alkanes, benzyl, 9-methylanthracenyl, and cholesteryl groups, was found to be general in nature, which afforded a plethora of new chemical entities; reactions of diazides generated mostly the desired and a few unexpected products. This article reports for the first time the targeted metal-free synthesis of any 1,4-disubstituted 1,2,3-triazole using the cycloaddition reactions of an appropriately functionalized vinyl sulfone.


Evaluation of Soft-Tissue Hematomas With Real-Time, Contrast-Enhanced Ultrasound: A Pilot Study With Preliminary Findings.
In this study, we investigated the feasibility of using contrast-enhanced ultrasound (CEUS) to detect active hemorrhage in patients presenting with soft-tissue hematomas. Adult patients with clinically suspected, actively bleeding hematomas were prospectively enrolled. Contrast-enhanced ultrasound was used to assess for contrast extravasation. Ultrasound results were compared with those of multidetector computed tomographic (MDCT) imaging, operative findings, and clinical course. Sixteen patients (9 women, 7 men; mean age, 69 [SD, 13] years) were enrolled. Thirteen patients underwent MDCT imaging during their initial visit, and for 11, CEUS and computed tomography (CT) findings were concordant. The remaining patients had a negative CEUS study that was consistent with their clinical course. In 8 patients, CT imaging showed active extravasation (6 arterial, 1 indeterminate, 1 slow venous). Contrast-enhanced ultrasound and CT findings were concordant for all cases of arterial bleeding. For 1 patient, CEUS provided superior diagnostic information by identifying a pseudoaneurysm. The 2 discrepant patient cases had a ≥3-hour delay between CT and CEUS, and in 1 patient, CEUS was limited by body habitus. The second patient had no active bleeding identified in the operating room. Compared with CT, CEUS had a sensitivity and specificity of 75% and 100%, respectively, and positive and negative predictive values were 100% and 71%, respectively. Diagnostic accuracy was 85% in this limited study. Contrast-enhanced ultrasound is a promising alternative to MDCT in select patients and may sometimes provide superior clinical information. Limiting factors are large hematoma size, unfavorable anatomic location, and body habitus.


Thioredoxin in cancer--role of histone deacetylase inhibitors.
Increased levels of thioredoxin (Trx) occur in a number of human cancers, which may contribute to the resistance of cancers to therapy by scavenging reactive oxygen species (ROS) which are generated by various anti-cancer agents. Many human cancers have low levels of thioredoxin-binding protein (TBP-2). TBP-2 binds to Trx and blocks its reducing activity. Histone deacetylase inhibitors (HDACi) up-regulate TBP-2 in various transformed cells, associated with a decrease in Trx levels. Up-regulation of TBP-2 and decrease of Trx may contribute to the sensitivity of many hematologic and solid tumors to anti-cancer activity of HDACi.


Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.
Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).


An analysis of the platelet and polyploid megakaryocyte response to acute thrombocytopenia and its biological implications.
Thrombocytopenia was induced in rabbit by a single injection of anti-platelet serum. The circulating platelet number and concomitant mean platelet volume were measured 6 h after the injection and daily thereafter. The megakaryocyte nuclear DNA content was measured in control rabbits and after 2 h and 24 h of thrombocytopenia respectively. The observed recovery of circulating platelet number is used to construct the variation of platelet destruction rate and platelet production rate with time during thrombocytopenia. The observed rebound thrombocytosis is explained by using a balance equation of these two rates. Platelet production is linked to the megakaryocyte by physical fragmentation theory and an explanation of the observed variation of mean platelet volume is used to obtain an estimated bleeding time and circulating platelet biomass during recovery from thrombocytopenia. An interpretation is given of the homeostatic control of megakaryocytopoiesis and thrombopoiesis.


Personality Assessment for Employee Development: Ivory Tower or Real World?
The acceptance and popularity of personality assessments in organizational contexts has grown enormously over the last 40 years. Although these are used across many applications, such as executive coaching, team building, and hiring and promotion decisions, the focus of most published research on the use of personality assessments at work is biased toward assessment for employee selection. Reviews have therefore tended to use criteria that are appropriate for selection, neglecting the additional and different criteria that are important in relation to employee development. An illustration of the often-discussed scientist-practitioner divide is that the Myers-Briggs Type Indicator is the most widely known and used personality assessment in organizations, despite harsh criticism by the academic community. This article reviews this debate, and draws implications for the appropriate choice of personality assessments for use in individual and team development, and a new direction for scientific research.