Protective role of melatonin in cardiac ischemia-reperfusion injury: From pathogenesis to targeted therapy.
Acute myocardial infarction (MI) is a major cause of mortality and disability worldwide. In patients with MI, the treatment option for reducing acute myocardial ischemic injury and limiting MI size is timely and effective myocardial reperfusion using either thombolytic therapy or primary percutaneous coronary intervention (PCI). However, the procedure of reperfusion itself induces cardiomyocyte death, known as myocardial reperfusion injury, for which there is still no effective therapy. Recent evidence has depicted a promising role of melatonin, which possesses powerful antioxidative and anti-inflammatory properties, in the prevention of ischemia-reperfusion (IR) injury and the protection against cardiomyocyte death. A number of reports explored the mechanism of action behind melatonin-induced beneficial effects against myocardial IR injury. In this review, we summarize the research progress related to IR injury and discuss the unique actions of melatonin as a protective agent. Furthermore, the possible mechanisms responsible for the myocardial benefits of melatonin against reperfusion injury are listed with the prospect of the use of melatonin in clinical application.


Erratic absorption of intramuscular antimicrobial delivery in infants and children.
In the absence of intravenous or enteral access, an intramuscular (IM) injection of medications is a viable alternative. Vaccines, antibiotics and analgesics are commonly administered by this route in pediatric medicine to enhance adherence to regimens. Although it is expected that the entire dose be administered by the IM route, the absorption (rate and extent) of the medication from the muscle tissue into systemic circulation can be erratic and depends on the drug's physicochemical factors and patient-specific factors. Despite the variability in absorption, administration of medications by the IM route may be considered when medications do not need to attain maximal concentrations rapidly. IM injections are generally well-tolerated, but potential injury to the injected muscle and the proximal nerves should be recognized.


Gas-chromatographic quantification of methylphenidate in plasma with use of solid-phase extraction and nitrogen-sensitive detection.
The gas-chromatographic assay for methylphenidate described here involves isolation by solid-phase extraction and quantification by thermionic nitrogen-phosphorus detection. Methylphenidate and the internal standard, ethylphenidate, are extracted from plasma by partition onto C2 reversed-phase packing. Methylphenidate and ethylphenidate are eluted, dried, derivatized with trifluoroacetic anhydride, and gas-chromatographed, with nitrogen-sensitive detection. The standard curve for the assay is linear in the range 5-100 micrograms/L. The within-run CV is less than 4%, the between-run CV less than 6%. Mean analytical recovery of methylphenidate was greater than 90%. The smallest measurable concentration is 2 micrograms/L. The sensitivity, reproducibility, and economy of this assay make it suitable for clinical monitoring and pharmacokinetic studies.


Diminished erythropoietin-induced erythroid growth in patients with renal anemia is restored by recombinant human erythroid differentiation factor.
An examination of the in vitro sensitivity of marrow burst-forming units for erythroid (BFU-E) to various concentrations of human recombinant erythropoietin (rEpo) and interleukin-3 (IL-3, 20 ng/mL) in serum-deprived methylcellulose cultures revealed that cells obtained from patients with chronic renal failure showed a defective response to rEpo, particularly at lower concentrations. This poor response was not corrected by the addition of neutralizing antibodies to antitumor necrosis factor-alpha or antiinterleukin-1 alpha/beta. When purified CD34+ cells from these patients were tested for dose-dependent growth to rEpo, the curve resembled that of normal donors, indicating that there was an intrinsic defect in the patients' progenitor/accessory cell interactions. Using unseparated cells from the patients, we then tested whether the interaction between erythroid differentiation factor (EDF) and rEpo affected BFU-E growth. Although EDF, either alone or in combination with IL-3, did not affect the growth of BFU-E in the absence of rEpo, the reduced sensitivity to rEpo in the patients was brought closer to normal limits by the addition of 10 ng/mL EDF to the cultures. The present results may suggest the possibility that, in patients with renal anemia, concomitant administration of EDF may increase the therapeutic ratio of rEpo therapy by enhancing the sensitivity of progenitor cells to rEpo, thereby decreasing the therapeutic dose of costly rEpo.


Low-Volume Reaction Monitoring of Carbon Dot Light Absorbers in Optofluidic Microreactors.
Optical monitoring and screening of photocatalytic batch reactions using cuvettes ex situ is time-consuming, requires substantial amounts of samples, and does not allow the analysis of species with low extinction coefficients. Hollow-core photonic crystal fibers (HC-PCFs) provide an innovative approach for in situ reaction detection using ultraviolet-visible absorption spectroscopy, with the potential for high-throughput automation using extremely low sample volumes with high sensitivity for monitoring of the analyte. HC-PCFs use interference effects to guide light at the center of a microfluidic channel and use this to enhance detection sensitivity. They open the possibility of comprehensively studying photocatalysts to extract structure-activity relationships, which is unfeasible with similar reaction volume, time, and sensitivity in cuvettes. Here, we demonstrate the use of HC-PCF microreactors for the screening of the electron transfer properties of carbon dots (CDs), a nanometer-sized material that is emerging as a homogeneous light absorber in photocatalysis. The CD-driven photoreduction reaction of viologens (XV2+) to the corresponding radical monocation XV•+ is monitored in situ as a model reaction, using a sample volume of 1 μL per measurement and with a detectability of <1 μM. A range of different reaction conditions have been systematically studied, including different types of CDs (i.e., amorphous, graphitic, and graphitic nitrogen-doped CDs), surface chemistry, viologens, and electron donors. Furthermore, the excitation irradiance was varied to study its effect on the photoreduction rate. The findings are correlated with the electron transfer properties of CDs based on their electronic structure characterized by soft X-ray absorption spectroscopy. Optofluidic microreactors with real-time optical detection provide unique insight into the reaction dynamics of photocatalytic systems and could form the basis of future automated catalyst screening platforms, where samples are only available on small scales or at a high cost.


The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins.
Early in programmed cell death (apoptosis), mitochondrial membrane permeability increases. This is at least in part due to opening of the permeability transition (PT) pore, a multiprotein complex built up at the contact site between the inner and the outer mitochondrial membranes. The PT pore has been previously implicated in clinically relevant massive cell death induced by toxins, anoxia, reactive oxygen species, and calcium overload. Here we show that PT pore complexes reconstituted in liposomes exhibit a functional behavior comparable with that of the natural PT pore present in intact mitochondria. The PT pore complex is regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2-like proteins. Although calcium, prooxidants, and several recombinant caspases (caspases 1, 2, 3, 4, and 6) enhance the permeability of PT pore-containing liposomes, recombinant Bcl-2 or Bcl-XL augment the resistance of the reconstituted PT pore complex to pore opening. Mutated Bcl-2 proteins that have lost their cytoprotective potential also lose their PT modulatory capacity. In conclusion, the PT pore complex may constitute a crossroad of apoptosis regulation by caspases and members of the Bcl-2 family.


[Application of chromatography and related techniques in quality evaluation of traditional Chinese medicine].
Chemomics, the methodology for the study of traditional Chinese medicines (TCMs) on the substance basis, and chromatographic fingerprinting, the crucial technology of quality evaluation of TCMs, are introduced. The applications of chromatography as well as some related techniques in the information acquisition of TCMs are summarized. Guided by chemomics, with the results of chromatography and multi-component quantification, this research mode is of great significance to the establishment of the quality evaluation system of TCMs.


Omidenepag Isopropyl in Latanoprost Low/Non-Responders with Primary Open-Angle Glaucoma or Ocular Hypertension: A Phase 3, Non-Randomized, Two-Phase, Open-Label Study.
This study demonstrates the efficacy and safety of once-daily 0.002% omidenepag isopropyl (OMDI) in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) who do not respond or respond poorly to latanoprost. To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of OMDI in latanoprost low/non-responders with POAG or OHT. Phase 3, non-randomized, two-phase, open-label, multicenter study (NCT03697811) in the United States. Key inclusion criteria included individuals aged ≥18 years, POAG or OHT diagnosis in both eyes, IOP ≥22 mm Hg in ≥1 eye and ≤34 mm Hg in both eyes at all time points. Overall, 107 patients were enrolled; 104 completed treatment. Included a screening period (≤35-day washout period and 8-week latanoprost run-in period) and a 3-month treatment period comprising one drop of OMDI 0.002% once daily in both eyes. Primary study endpoint was change from baseline in mean diurnal (MD) IOP at month 3. Safety endpoints included incidence of adverse events (AEs), serious AEs, and adverse drug reactions. At baseline (visit 4), 75 (70.1%) patients had POAG, 32 (29.9%) had OHT, and 68 (63.6%) had prior use of prostaglandin/prostaglandin analogs (37.4% of whom used latanoprost). Mean (standard deviation [SD]) baseline MD IOP was 23.34 mm Hg (2.12). Mean (SD) 3-month (visit 7) MD IOP change from baseline (following latanoprost run-in period and OMDI treatment period) was an additional decrease of 2.96 mm Hg (2.83) (P<0.0001). No significant safety issues were reported during OMDI treatment. These data demonstrate OMDI efficacy and safety in latanoprost low/non-responders with POAG or OHT, suggesting OMDI is a treatment option in the patient population in this study.


Abundance-occupancy dynamics in a human dominated environment: linking interspecific and intraspecific trends in British farmland and woodland birds.
1. Range size, population size and body size, the key macroecological variables, vary temporally both within and across species in response to anthropogenic and natural environmental change. However, resulting temporal trends in the relationships between these variables (i.e. macroecological patterns) have received little attention. 2. Positive relationships between the local abundance and regional occupancy of species (abundance-occupancy relationships) are among the most pervasive of all macroecological patterns. In the absence of formal predictions of how abundance-occupancy relationships may vary temporally, we outline several scenarios of how changes in abundance within species might affect interspecific patterns. 3. We use data on the distribution and abundance of 73 farmland and 55 woodland bird species in Britain over a 32-year period encompassing substantial habitat modification to assess the likelihood of these scenarios. 4. In both farmland and woodland habitats, the interspecific abundance-occupancy relationship changed markedly over the period 1968-99, with a significant decline in the strength of the relationship. 5. Consideration of intraspecific dynamics shows that this has been due to a decoupling of abundance and occupancy particularly in rare and declining species. Insights into the intraspecific processes responsible for the interspecific trend are obtained by analysis of temporal trends in the distribution of individuals between sites, which show patterns consistent with habitat quality declines. 6. This study shows that a profitable approach to ascertaining the nature of human impacts is to link intra- and interspecific processes. In the case of British farmland and woodland birds, changes to the environment lead to species-specific responses in large-scale distributions. These species-specific changes are the driver of the observed changes in the form and strength of the interspecific relationship.


Cavitary Choroidal Metastasis from Clear Cell Renal Cell Carcinoma.
To report the clinical, funduscopic, and echographic features of a choroidal metastatic tumor from a clear cell renal cell carcinoma presenting with intralesional cavitation. An 81-year-old man with history of clear cell renal cell carcinoma presented with blurred vision. A clinical examination including standardized ultrasound was performed, which revealed a choroidal mass with cystic-like cavitation. The patient underwent brachytherapy with regression of the tumor. We report the features of a cavitary choroidal metastasis from clear cell renal cell carcinoma. Occurrence of features usually associated with uveal melanoma in a patient with a metastatic choroidal tumor may lead to misdiagnosis.


Routine visualization of the left internal mammary artery before bypass surgery: is it necessary?
The left internal mammary (LIMA) is an ideal conduit for bypassing the left anterior descending artery (LAD) during coronary artery bypass surgery (CABG). In this study, we evaluate the frequency of significant disease in the LIMA prior to CABG and describe associated significant lateral costal branches (> 1.5 mm), subclavian disease and vertebral disease. In 115 consecutive patients referred to CABG, 101 patients met the inclusion criteria. All patients who underwent routine visualization of the LIMA vessels were reviewed and quantitatively analyzed by an independent reader. Disease in the LIMA, left subclavian and vertebral arteries were graded and considered significant if lesions were > 50%. Lateral costal branches of the LIMA were also noted for their presence and size. Of the 101 patients, 87.1% of the LIMAs prior to surgery were without any disease. One LIMA had a 25-50% narrowing and the remaining LIMAs showed 0-25% disease. Of the LIMAs, 48.5% had lateral costal branches with diameters > 1.5 mm. The incidence of significant left vertebral disease and proximal subclavian disease was 37.6% and 5%, respectively. Cardiolite stress imaging post-CABG (n = 75) showed that when ischemia persisted in the anterior wall in patients with a LIMA to the LAD, this was not associated with the presence of significant LIMA disease, lateral costal branches, or subclavian disease identified pre-operatively. We conclude that the LIMA rarely shows significant disease on routine visualization prior to CABG. Asymptomatic subclavian artery disease and the presence of lateral costal branches pre-operatively did not correlate with post-CABG ischemia in the LAD territory.


Sample test array and recovery (STAR) platform at the National Ignition Facility.
We have developed the Sample Test Array and Recovery (STAR) platform for the National Ignition Facility (NIF) for studying the thermal and hydrodynamic responses of materials in extreme environments. The STAR platform expands the range of obtainable fluences and quadruples the rate that materials experiments can be conducted at the NIF. Example configurations are demonstrated for fluences spanning 0.56-34 J/cm2 with environmental isolation for post-shot material recovery and inspection and up to 1740 J/cm2 without isolation, with surface heating rates of up to 2 × 1014 K/s. An example experiment involving thermally driven shock and spallation of aluminum alloy 7075 is briefly discussed.


Distinguishing between cooperative and unimodal downhill protein folding.
Conventional cooperative protein folding invokes discrete ensembles of native and denatured state structures in separate free-energy wells. Unimodal noncooperative ("downhill") folding, however, proposes an ensemble of states occupying a single free-energy well for proteins folding at >/=4 x 10(4) s(-1) at 298 K. It is difficult to falsify unimodal mechanisms for such fast folding proteins by standard equilibrium experiments because both cooperative and unimodal mechanisms can present the same time-averaged structural, spectroscopic, and thermodynamic properties when the time scale used for observation is longer than for equilibration. However, kinetics can provide the necessary evidence. Chevron plots with strongly sloping linear refolding arms are very difficult to explain by downhill folding and are a signature for cooperative folding via a transition state ensemble. The folding kinetics of the peripheral subunit binding domain POB and its mutants fit to strongly sloping chevrons at observed rate constants of >6 x 10(4) s(-1) in denaturant solution, extrapolating to 2 x 10(5) s(-1) in water. Protein A, which folds at 10(5) s(-1) at 298 K, also has a well-defined chevron. Single-molecule fluorescence energy transfer experiments on labeled Protein A in the presence of denaturant demonstrated directly bimodal distributions of native and denatured states.


Analysis of full-text publication and publishing predictors of abstracts presented at an Italian public health meeting (2005-2007).
In Public Health, a thorough review of abstract quality evaluations and the publication history of studies presented at scientific meetings has never been conducted. To analyse the long-term outcome of quality abstracts submitted to conferences of Italian Society of Hygiene and Public Health (SItI) from 2005 to 2007, we conducted a second analysis of previously published material aiming to estimate full-text publication rate of high quality abstract presented at Italian public health meetings, and to identify predictors of full-text publication. The search was undertaken through scientific databases and search engines and through the web sites of the major Italian journals of Public Health. For each publication confirmed as a full text paper, the journal name, impact factor, year of publication, gender of the first author, type of study design, characteristics of the results and sample size were collected. The overall publication rate of the abstracts presented is 23.5%; most of the papers were published in Public Health journals (average impact factor: 3.007). Non universitary affiliation had resulted in a lower probability of publication, while some of the Conference topics had predisposed the studies to an increased likelihood of publication as well as poster form presentation. The method presented in this study provides a good framework for the evaluation of the scientific evidence. The findings achieved should be taken into consideration by the Scientific Societies during the contributions selection phase, with the aim of achieving a continuous improvement of work quality. In the future, it would be interesting to survey the abstract authors to identify reasons for unpublished data.


Reduced penetrance of the Huntington's disease mutation.
Controversy persists concerning the significance of Huntington disease (HD) alleles in the 36-39 repeat range. Although some clinically affected persons have been documented with repeats in this range, elderly unaffected individuals have also been reported. We examined 10 paternal transmissions of HD alleles of 37-39 repeats in collateral branches of families with de novo HD. All 10 descendants, including many who are elderly, are without symptoms of HD. Forty percent of the transmissions were unstable, although none varied by more than one repeat. The observation that individuals with alleles of 37-39 repeats may survive unaffected beyond common life expectancy supports the presence of reduced penetrance for HD among some persons with repeat sizes which overlap the clinical range. Non-penetrance may be increased in the collateral branches of de novo mutation families when compared to penetrance estimates from patient series. There was no CAA-->CAG mutation for the penultimate glutamine in either a de novo expanded 42 repeat allele or the corresponding non-penetrant 38 repeat allele in a family with fresh mutation to HD.


Enzymology of bacterial lysine biosynthesis.
Bacteria have evolved three strategies for the synthesis of lysine from aspartate via formation of the intermediate diaminopimelate (DAP), a metabolite that is also involved in peptidoglycan formation. The objectives of this chapter are descriptions of mechanistic studies on the reactions catalyzed by dihydrodipicolinate synthase, dihydrodopicolinate reductase, tetrahydrodipicolinate N-succinyl-transferase, N-succinyl-L,L-DAP aminotransferase, N-succinyl-L,L-DAP desuccinylase, L,L-DAP epimerase, L,L-DAP decarboxylase, and DAP dehydrogenase. These enzymes are discussed in terms of kinetic, isotopic, and X-ray crystallographic data that allow one to infer the nature of interactions of each of these enzymes with its substrate(s), coenzymes, and inhibitors.


Duplex nanoporous alumina and polyelectrolyte adsorption: more insights from a combined neutron reflectivity and electron microscopy study.
Neutron reflectivity (NR) is a powerful technique to investigate the incorporation of nanomaterials (polymers, nanoparticles, etc) into multilayer porous systems. Here we propose an experimental approach combining NR and scanning electron microscopy (SEM) to successfully characterize duplex nanoporous anodic aluminum oxides (nAAO) and to extract quantitative information about the entering and adsorption of polyelectrolytes (PEs) in nanopores. Duplex nAAO are promising systems to study the influence of geometrical constriction, i.e. the reduction of pore diameters along the pore channel, on the confinement of condensed matters.


Treatment of a radial artery pseudoaneurysm with ultrasound-guided percutaneous thrombin injection in a patient with Behçet's syndrome.
A 57-year-old man with Behçet's syndrome and recurrent deep vein thrombosis of the lower limbs presented with a painful, pulsating mass on the volar aspect of the radial edge of his left wrist. One month before this visit, he had had venous blood drawn from the same site. Using color Doppler sonography, we diagnosed an iatrogenic pseudoaneurysm of the left radial artery, which was then treated with an ultrasound-guided percutaneous injection of thrombin. A follow-up examination 6 months after the treatment revealed complete resolution of the pseudoaneurysm. To our knowledge, this is the first case report to demonstrate the use of this technique for thrombosis of a pseudoaneurysm in a patient with Behçet's syndrome. We believe that the safety, efficiency, speed, and minimal invasiveness of this procedure make it feasible for use as a treatment for peripheral pseudoaneurysms in such patients.


The biosimilar insulin landscape: current developments.
Biosimilar insulins have the potential to increase access to treatment among patients with diabetes mellitus, reduce treatment costs, and expand market competition. The patents for several insulins are soon to expire, meaning there is room for copies of these products--or 'biosimilars'--to join the marketplace. It is vital that similar safety and efficacy to the innovator product is demonstrated for biosimilars. This presents many possible manufacturing and regulatory challenges. Complex manufacturing processes mean that even small differences between manufacturers can have a potential impact on the final product. Several companies are currently developing biosimilar insulins or are already producing these products in emerging markets with different regulatory requirements. For insulin biosimilars to be licensed in more established markets, manufacturers will need to meet the rigid criteria set out by agencies such as the European Medicines Agency and US Food and Drug Administration, and fulfill several pre-clinical, clinical, and pharmacovigilance surveillance criteria. As a result of differing regulatory requirements, there are possible gaps in the publically available clinical data to support the safety and efficacy of biosimilar insulins from around the world current as of July 2014. This review summarizes the current biosimilar insulin landscape.


Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription.
The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7-stimulated pro-B cell cultures revealed a reduced differentiation from large pre-B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2-deficient B cells. Moreover, expression of IL7Rα and Rag 1/2, downstream targets of Irf4 and Foxo1, were also reduced in the absence of Fra-2. Pro-B cell proliferation and small pre-B cell differentiation were fully rescued by expression of Foxo1 and Irf4 in Fra-2-deficient pro-B cells. Hence, Fra-2 is a key upstream regulator of Foxo1 and Irf4 expression and influences proliferation and differentiation of B cells at multiple stages.


Assessment of sexual behavior and neuromodulation of Cyperus esculentus L. and Tetracarpidium conophorum Müll. Arg dietary supplementation regulating the purinergic system in the cerebral cortex of L-NAME-challenged rats.
This study examined the behavioral responses, purinergic receptor densities, ectonucleotidases (E-NTPDase), adenosine deaminase (ADA) activity, and nitric oxide (NO) levels along with the parameters of oxidative stress-related to erectile function in the cerebral cortex (CC) of L-NAME-challenged rats pretreated with tigernut (TN) and walnut (WN) dietary supplementation. Wistar rats (male) of 70 total animals (250-300 g) were used in this research and hence separated into seven groups (n = 10): Group I: normal control-fed basal diet; Group II: positive control-fed basal diet/L-NAME/Sildenafil citrate (5 mg kg-1 day-1 ); Group III: ED-induced (placed on a basal diet/L-NAME); Group IV: diet supplemented with processed TN (20%)/L-NAME; Group V: diet supplemented with raw TN (20%)/L-NAME; Group VI: diet supplemented with processed WN (20%)/L-NAME; and Group VII placed on a diet supplemented with raw WN (20%)/L-NAME. The rats were pretreated for 2 weeks before the L-NAME (40 mg kg-1 day-1 ) challenge on their respective diet. L-NAME brought about a decrease in the sexual behaviors evaluated while the effect was significantly reversed by supplemented diets containing TN and WN. L-NAME increased the levels of reactive oxygen species and malondialdehyde, E-NTPDase as well as ADA activities, and caused the level of NO in the CC as well as the purinoreceptor densities to be downregulated. Treatments with enriched diets, however, greatly reverse these effects. The behavioral responses and neuromodulatory capacity of the nuts displayed on the CC can, therefore, further support their aphrodisiac property. PRACTICAL APPLICATIONS: The results revealed the ability of tigernut (TN; Cyperus esculentus L.) and walnut (WN; Tetracarpidium conophorum Müll. Arg.) to enhance behavioral responses; modulate purinergic receptor densities, E-NTPDase, and ADA activities; increase NO levels; and prevent oxidative stress related to erectile function in the CC of L-NAME-challenged Wistar rats. The results show that these nuts are useful feeds for both animal and human nutrition.


Sinus grafting related to implantology. Statistical analysis of 15 years of surgical experience (1979-1994).
Sinus cavities are often a major obstacle to the placement of dental implants in the posterior maxilla, especially when early tooth loss has occurred. Several grafting procedures aimed at reducing the expanded volume of these pneumatic cavities have been routinely utilized since 1979. Essentially, these techniques have consisted of recreating the necessary viable bone volume at the floor of sinus cavities by placing different bone substitute materials to allow for the insertion of endosseous implant devices. The progress achieved in the refinement of the surgical procedures and the knowledge acquired in the field of patient screening and selection, choice of biomaterials, management of complications, etc., have made sinus graft surgery highly codified and predictable. A comprehensive statistical study by multifactorial procedures was carried out to establish a Burt Contingency Chart. This chart visualizes the frequencies of all the "modality combinations" among the selected "qualitative parameters" and, by a " factorial analysis", the "multiple correlations", so that the "statistical affinities" that may exist among the same variables can be determined. This critical study endeavors to search for and reveal the favorable clinical, biologic and scientific parameters necessary for the success of sinus graft surgery on short-, medium-, and long-term bases (more than nine years). It is a particularly homogenous study, since all the operative procedures have been carried out exclusively by the author under standardized conditions. The wide variety of biomaterials utilized by the author since 1979 shows the development of bone substitute biomaterials as they have been introduced into the market during the past 15 years. The large number of patients treated, the variety of grafting materials, the important success rate obtained, and the long duration of patient follow-up have been instrumental in enabling us to establish scientifically significant results. Autogenous bone and its combinations with calcium- and phosphorus-containing biomaterials remain undoubtedly the best all-purpose biomaterials. The synthetic biomaterials have their own specific indications according to their stable (non-resorbable) or unstable (resorbable) nature and their rates of metabolic "turnover". Differently treated bones from the tissue bank (if not contaminated or immunologically questionable) behave in a fashion not unlike autogenous bone. Root-form implants are by far the best implants in the reconstructed sinus sites, while other implant types (subperiosteal implants, etc.) inserted beneath the reinforced osseous sinus floor, buccal wall, and pyramidal process, also have their indications.


Expansion of the Genetic Code Through the Use of Modified Bacterial Ribosomes.
Biological protein synthesis is mediated by the ribosome, and employs ~20 proteinogenic amino acids as building blocks. Through the use of misacylated tRNAs, presently accessible by any of several strategies, it is now possible to employ in vitro and in vivo protein biosynthesis to elaborate proteins containing a much larger variety of amino acid building blocks. However, the incorporation of this broader variety of amino acids is limited to those species utilized by the ribosome. As a consequence, virtually all of the substrates utilized over time have been L-α-amino acids. In recent years, a variety of structural and biochemical studies have provided important insights into those regions of the 23S ribosomal RNA that are involved in peptide bond formation. Subsequent experiments, involving the randomization of key regions of 23S rRNA required for peptide bond formation, have afforded libraries of E. coli harboring plasmids with the rrnB gene modified in the key regions. Selections based on the use of modified puromycin derivatives with altered amino acids then identified clones uniquely sensitive to individual puromycin derivatives. These clones often recognized misacylated tRNAs containing altered amino acids similar to those in the modified puromycins, and incorporated the amino acid analogues into proteins. In this fashion, it has been possible to realize the synthesis of proteins containing D-amino acids, β-amino acids, phosphorylated amino acids, as well as long chain and cyclic amino acids in which the nucleophilic amino group is not in the α-position. Of special interest have been dipeptides and dipeptidomimetics of diverse utility.


[Thoracoscopy in pulmonary histiocytosis X].
We report 4 cases of recurrent multiple pneumothorax in patients with diffuse interstitial lung disease diagnosed as histiocytosis X. These cases demonstrate the dual value of thoracoscopy in that disease: (1) it facilitates the diagnosis by showing the characteristic macroscopic aspect of the lung with multiple blebs and by enabling pulmonary biopsies to be performed; (2) it contributes to the treatment and prevention of pneumothorax by diffuse pleural poudrage. Immediate thoracoscopy should therefore be contemplated in special conditions, such as pulmonary interstitial lung disease with pneumothorax as first presentation.


Response of lymphocytes from multiple sclerosis patients to murine brain extract.
Forty-seven patients with multiple sclerosis (MS), 21 subjects with neurological diseases other than MS (OND), 7 with miscellaneous disease (MD) and 21 healthy individuals (HI) were examined by the standard procedure of blast transformation for the in vitro response to mouse brain (MB), mouse kidney (MK) and mouse lung (ML) tissue extracts. Increased cellular response to MB was limited to the MS and OND groups, whereas high and low values of stimulation index to MK and ML were similarly observed in all groups of individuals examined. No correlation was found between the clinical activity of the MS patients and the in vitro response to MG. The possibility that low sensitivity of the technique and complexity of the antigenic composition of MS are determining factors in the results obtained in these studies is discussed.


Azithromycin-induced rash in a patient of infectious mononucleosis - a case report with review of literature.
Antibiotic induced skin rash in setting of infectious mononucleosis is often encountered in clinical practice. However, macrolides like azithromycin are considered relatively safe and till date only two cases of azithromycin induced rash in setting of infectious mononucleosis have been reported. The following report illustrates the case of a 23-year-old man suffering from infectious mononucleosis who exhibited a generalized cutaneous rash following treatment with azithromycin. Using the Naranjo ADR probability scale, this case of acute onset rash following azithromycin administration was found to be in 'probable' category. The mechanism of antibiotic-induced rash in patients suffering from infectious mononucleosis is incompletely understood. It has been suggested that the rash could result from virus mediated immunomodulation or due to altered drug metabolism. The report calls for cautious use of antibiotics in the setting of suspected viral infections like infectious mononucleosis as injudicious use might increase the risk of deleterious skin reactions and increase the cost of healthcare.


Dual-energy computed tomography: is there a penalty in image quality and radiation dose compared with single-energy computed tomography?
To assess dose and image quality of dual-energy (DE) mixed images in comparison to single-energy (SE) images. A phantom containing iodine contrast inserts was scanned using SE and DE protocols. Dual-energy mixed images were reconstructed with varying composition ratios (ratio describing the contribution of 80 and 140 data in the mixed images). Image noise, iodine contrast, and contrast-to-noise ratios (CNRs) were assessed inside and outside the central field of view (FoV). With the default composition ratio (0.3), noise and contrast were comparable between both protocols in the central FoV. Peripherally, DE image noise exceeded noise in SE images; CNR in the periphery was lower in the DE images. The highest CNR was found for a composition ratio of 0.5 to 0.9, exceeding the CNR of SE images. Dual-energy mixed images offer an image quality comparable to SE images within the central FoV at comparable dose levels. In the peripheral FoV, image quality is decreased. By optimizing the composition ratio in the DE mixed images, higher CNRs than in the SE images can be achieved, leading to a dose reduction potential.


Treatments for hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is not easily treated. Although not uncommon, HS is often misdiagnosed outside specialized clinics and inappropriately treated as a simple boil or abscess. In recent years, guidelines have been developed on the basis of expert opinion and the available literature. A multifaceted approach is necessary as HS lesions include both inflammation (amenable to medical treatment) as well as fibrosis (amenable to surgery only). The recommended antiinflammatory therapies encompass both antimicrobials and regular anti-inflammatory drugs. We have, therefore, reviewed treatments with the following agents: clindamycin, tetracycline, rifampicin, ertapenem, dapsone, triamcinolone, infliximab, adalimumab, and anakinra. The development of new medical treatments, however, is an ongoing effort, and important new data have been presented since the publication of the guideline. The current approach to the management of fibrotic lesions is surgery. It is important, as manifest fibrosis is generally not susceptible to medical treatment. Here minor excision, carbon dioxide-laser, and major surgery are discussed, and current evidence supporting their use is provided. A comprehensive three-pronged approach with adjuvant therapy, medical therapy, and surgery is recommended. The importance of adjuvant therapy, that is, pain management, wound care, and attention, is stressed. Adjuvant therapy not only plays a major role in patients' perception of a successful treatment but also is of practical importance to their coping and self-management. HS presents a significant unmet need, and this review provides a mechanistic update on the current real-world therapeutic option for the management of this distressing disease.


Gender and suicide in India: a multiperspective approach.
The gap between male and female suicide rates in India is relatively small. However, society's views on female and male motives are quite different. In order to investigate the perceptions of male and female suicide, we interviewed a focus group of university professors as well as police inspectors, crime reporters, and hospital nurses in Bangalore. We also obtained four narratives of suicide. Women tended to be blamed for their own or their husband's suicide, although they were also viewed more often as victims of life adversities than men. A historical review illustrates that both men and women have been associated with culturally sanctioned suicides. One known form is sati, and we discuss the recent case of sati-murder of Roop Kanwar in 1987. The social sciences and the media also pay a lot of attention to the typical female suicides, symbolizing their role as martyrs of society, which seems to compensate for attribution of blame.


Schistura alboguttata, a new loach species of the family Nemacheilidae (Pisces: Cypriniformes) from the Pearl River basin in Guangxi, South China.
Schistura alboguttata, a new species of nemacheilid loach, is herein described from the Leli-He, a tributary flowing to the You-Jiang of the Pearl River basin (Zhu-Jiang in Chinese) at Tianlin County, Guangxi, South China. This new species can be readily distinguished from all other Chinese species of Schistura by its striking body coloration consisting of irregular white spots scattered over the dorsal and lateral regions of the body, with occasional irregular bars with narrow interspaces on the predorsal region.


Comparison of health-related quality of life between American and Taiwanese heart failure patients.
Few investigators have compared health-related quality of life (HRQOL) in heart failure (HF) patients from different countries.The purposes of this study were to compare HRQOL between American (n = 87) and Taiwanese (n = 88) HF patients and to determine factors associated with HRQOL in both groups. In this cross-sectional survey, HRQOL was measured using the Minnesota Living with Heart Failure Questionnaire. American patients rated their HRQOL worse than Taiwanese patients did. Sociodemographics, disease severity, and symptom severity were associated with HRQOL, accounting for 42.4% of the variance in HRQOL in Americans and 57.3% in Taiwanese. Symptom severity was the most important predictor of HRQOL in both groups. Interventions targeting symptom severity could improve HF patients' HRQOL.


Recruitment into psychiatry: quantitative myths and qualitative challenges.
Recruitment into psychiatry is perceived as problematic in the UK but the paper by Goldacre and colleagues in this issue of the Journal shows that recruitment of new UK graduates has altered little over 35 years. Sources of psychiatry's malaise should be sought in its changing focus and the quality, rather than quantity, of its recruits.


Herd-level factors associated with detection of calves persistently infected with bovine viral diarrhoea virus (BVDV) in Irish cattle herds with negative herd status (NHS) during 2017.
A compulsory national BVD eradication programme commenced in Ireland in 2013. Since then considerable progress has been made, with the animal-level prevalence of calves born persistently infected (PI) falling from 0.67 % in 2013 to 0.06 % in 2018. The herd-level prevalence fell from 11.3 % in 2013 to 1.1 % in 2018. In the Irish programme, herds in which all animals have a known negative status and which have not contained any PI animals for 12 months or more are assigned a negative herd status (NHS). While considerable progress towards eradication has been made, PI calves have been identified in a small proportion of herds that had previously been assigned NHS. Given this context, a case-control study was conducted to investigate potential risk factors associated with loss of NHS in 2017. 546 herds which had NHS on 1 January 2017 and lost that status during 2017 (case herds) were matched with 2191 herds (control herds) that retained their NHS status throughout 2017. Previous history of BVD infection, herd size, herd expansion, the purchase of cattle including potential Trojan cattle and the density of BVD infection within 10 km of the herd emerged as significant factors in a multivariable logistic regression model. This work adds to the evidence base in support of the BVD eradication programme, particularly establishing why BVD re-emerged in herds which had been free of BVD for at least the previous 12 months prior to the identification of a BVD positive calf. This information will be especially important in the context of identifying herds which may be more likely to contain BVD positive animals once the programme moves to herd-based serology status for trading purposes in the post-eradication phase.


RSF1 regulates the proliferation and paclitaxel resistance via modulating NF-κB signaling pathway in nasopharyngeal carcinoma.
Purpose: Aberrant expression and dysfunction of RSF1 has been reported in diverse human malignancies. However, its exact role in nasopharyngeal carcinoma (NPC) remains unclear. Methods: The expression of RSF1 mRNA and protein were assayed by qRT-PCR and western blotting, and their correlations with clinicopathological parameters of patients with NPC were further analysed. Lentivirus mediated RSF1 shRNA and RSF1 cDNA were used to knockdown and upregulate the expression of RSF1. CCK8 assays and flow cytometry were applied to monitor the changes of proliferation and paclitaxel sensitivity caused by RSF1 modulation, inhibition of NF-κB pathway by inhibitor Bay 11-7082 and Survivin knockdown. Western blotting was used to detect protein alterations in NF-κB signaling pathway. Results: Our present study demonstrated that both mRNA and protein expressions of RSF1 were increased and correlated with advanced NPC clinical stage. Functional analyses revealed that RSF1 inhibition or overexpression induced changes in cell cycle, apoptosis, and then led to altered proliferation and paclitaxel sensitivity in diverse NPC cells in vitro. Further mechanism investigation hinted that RSF1 overexpression in NPC CNE-2 cells activated NF-κB pathway and promoted the expression NF-κB dependent genes involved in cell cycle and apoptosis including Survivin. Importantly, inhibition of NF-κB pathway by Bay 11-7082 and knockdown its downstream Survivin reversed the paclitaxel resistance caused by RSF1 overexpression. Conclusions: Taken together, our data indicate that RSF1 regulates the proliferation and paclitaxel resistance via activating NF-κB signaling pathway and NF-κB-dependent Survivin upregulation, suggesting that RSF1 may be used as a potential therapeutic target in NPC.


[Diagnostic imaging in the evaluation of heart transplant recipients].
Cardiac transplantation has become an important treatment option in terminal cardiac disease since the introduction of cyclosporin A for immunosuppression. Imaging methods play an important role in the diagnosis of all complications occurring after heart transplantation except for the transplant rejection reaction; endomyocardial biopsy is in continued use as none of the diagnostic imaging methods is able at present to diagnose rejection with sufficient accuracy. However, new imaging modalities that are only just starting to be widely used may change this in the foreseeable future.


Papillary muscle dynamics: in situ function and responses of the papillary muscle.
Experiments were designed to 1) study in situ changes in papillary muscle length and force during the cardiac cycle, 2) investigate the relationship between papillary muscle length and maximal ventricular pressure, 3) study the effect of both positive and negative inotropic intervention on this relationship. A mercury gauge transduceror Walton-Brodie strain-gauge arch was sutured to the anterior papillary muscleand used to measure the extent of shortening or lengthening (deltaL) or force (APMF),.respectively. The anterior papillary muscle showed rapid increase of length and forcewhile contracting during isovolumic contraction and reached peak systolic length at end-isovolumic contraction or during the early injection phase. The papillary muscle was observed to shorten during the phases of ejection and isovolumic relaxation. It was concluded that changes in ventricular pressure during the cardiac cycle are associated with changes in papillary muscle length and force such that the resulting "lengthening contraction force" is appropiate for maintenance of normal atrioventricular valve function during isovolumic contraction. There was an inverse relationship between deltaL and maximal ventricular pressure such that for each increment in peak ventricular pressure there was a decrease in deltaL. The deltaL-force relationship was shifted upward and to the right by norepinephrine (NE) and isoproterenol and downward and to the left by occlusion of the posterior vena cava. Phenylephrine had little or no effect on this relationship.


Integration of somatic and visceral inputs by the brainstem: functional considerations.
Studies of the brainstem have traditionally either focused on mechanisms for the control of limb or axial muscles or for the maintenance of homeostasis (e.g., the circuitry for the regulation of respiration or blood pressure). However, recent studies have demonstrated that movement and changes in cardiorespiratory activity often are coordinated, indicating a linkage between the pathways that control somatic motor activity and those that regulate respiration or circulation. Neurons in regions such as nucleus tractus solitarius and the lateral medullary reticular formation that regulate circulation and respiration have been shown to receive somatic sensory signals (including those from the vestibular system) indicating body position in space. In addition, somatic motor control may be influenced by signals from visceral receptors that provide cues regarding body position in space. Some areas of the brainstem may also participate directly in both motor control and regulation of blood pressure and respiration. Thus, a simple division of the brainstem into "somatic" and "autonomic" regions is no longer possible.


Robust Quantum Memory in a Trapped-Ion Quantum Network Node.
We integrate a long-lived memory qubit into a mixed-species trapped-ion quantum network node. Ion-photon entanglement first generated with a network qubit in ^{88}Sr^{+} is transferred to ^{43}Ca^{+} with 0.977(7) fidelity, and mapped to a robust memory qubit. We then entangle the network qubit with a second photon, without affecting the memory qubit. We perform quantum state tomography to show that the fidelity of ion-photon entanglement decays ∼70 times slower on the memory qubit. Dynamical decoupling further extends the storage duration; we measure an ion-photon entanglement fidelity of 0.81(4) after 10 s.


Influence of ABO Locus on PFA-100 Collagen-ADP Closure Time Is Not Totally Dependent on the Von Willebrand Factor. Results of a GWAS on GAIT-2 Project Phenotypes.
(1) Background: In a previous study, we found that two phenotypes related to platelet reactivity, measured with the PFA-100 system, were highly heritable. The aim of the present study was to identify genetic determinants that influence the variability of these phenotypes: closure time of collagen-ADP (Col-ADP) and of collagen-epinephrine (Col-Epi). (2) Methods: As part of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia (2) Project, 935 individuals from 35 large Spanish families were studied. A genome-wide association study (GWAS) with ≈ 10 M single nucleotide polymorphisms (SNPs) was carried out with Col-ADP and Col-Epi phenotypes. (3) Results: The study yielded significant genetic signals that mapped to the ABO locus. After adjusting both phenotypes for the ABO genotype, these signals disappeared. After adjusting for von Willebrand factor (VWF) or for coagulation factor VIII (FVIII), the significant signals disappeared totally for Col-Epi phenotype but only partially for Col-ADP phenotype. (4) Conclusion: Our results suggest that the ABO locus exerts the main genetic influence on PFA-100 phenotypes. However, while the effect of the ABO locus on Col-Epi phenotype is mediated through VWF and/or FVIII, the effect of the ABO locus on Col-ADP phenotype is partly produced through VWF and/or FVIII, and partly through other mechanisms.


Ultra-highly selective trapping of perrhenate/pertechnetate by a flexible cationic coordination framework.
The selective binding and trapping of perrhenate/pertechnetate is of great interest in the contamination remediation of nuclear waste. Herein, we report a cationic metal-organic framework (TJNU-216, TJNU = Tianjin Normal University), with ultra-high selectivity in trapping perrhenate/pertechnetate in the presence of a large excess of SO42- (20 000 times) or NO3- (300 times), and the highest exchange capacity of 417 mg g-1 (1 mol mol-1). The exchange mechanism can be confirmed by the crystal structure of TJNU-216(Re) via single-crystal-to-single-crystal transformation.


Types of Glaucoma and recent trends applied in treatment: Observations from a Glaucoma Training Workshop in the Gambia.
To determine types of glaucoma seen and the recent trends applied in treatment, a retrospective non-comparative case-series study was conducted in the Eye Unit of the Royal Victoria Hospital, Banjul, The Gambia. The records of the 88 patients(145 eyes) seen during the glaucoma training workshop(organised by Prof.James Standefer, a clinical ophthalmologist from Minneapolis, U.S.A.) which held between 3rd and 14th of September, 2001, were analysed for types of glaucoma and treatment given. All but one patient who was a baby underwent the following tests: visual acuity measurement using the illiterate E-Chart with multiple optotypes; tonometry using the Schiotz tonometer with the 5.5g weight; oblique flashlight test; Van Herrick's estimation of the angle depth; pupillary reactions to light; Slitlamp biomicroscopy; gonioscopy using the 4-mirror pressure gonioprism; fundoscopy using the +78D Volk lens and confrontational visual field analysis. 27 eyes did not have definite glaucoma. Out of the remaining 118 eyes, 65(55.08%) had POAG;17(14.41%)ACG out of which 8 were CACG and 2 acute ACG. 8 eyes had pseudoexfoliation of the lens capsule with or without glaucoma. In the frail and elderly, guttae Timoptol 0.5% was given once daily. 27 eyes had trabeculectomy; all were with releasable sutures and intraoperative application of 5-Fluorouracil. 3 eyes had laser trabeculoplasty and 5, diode laser transscleral cyclophotocoagulation. POAG was the commonest type of glaucoma seen. Pseudoexfoliation of the lens capsule with or without glaucoma and ACG are not very rare in The Gambia. In the frail and elderly, guttae Timoptol 0.5% was given once daily and none at all in painless glaucoma-blind eyes. Trabeculectomy with releasable sutures and intraoperative application of 5-FU has a very satisfactory pressure-lowering effect. glaucoma; treatment; the Gambia.


Coding SNPs analysis highlights genetic relationships and evolution pattern in eggplant complexes.
Brinjal (Solanum melongena), scarlet (S. aethiopicum) and gboma (S. macrocarpon) eggplants are three Old World domesticates. The genomic DNA of a collection of accessions belonging to the three cultivated species, along with a representation of various wild relatives, was characterized for the presence of single nucleotide polymorphisms (SNPs) using a genotype-by-sequencing approach. A total of 210 million useful reads were produced and were successfully aligned to the reference eggplant genome sequence. Out of the 75,399 polymorphic sites identified among the 76 entries in study, 12,859 were associated with coding sequence. A genetic relationships analysis, supported by the output of the FastSTRUCTURE software, identified four major sub-groups as present in the germplasm panel. The first of these clustered S. aethiopicum with its wild ancestor S. anguivi; the second, S. melongena, its wild progenitor S. insanum, and its relatives S. incanum, S. lichtensteinii and S. linneanum; the third, S. macrocarpon and its wild ancestor S. dasyphyllum; and the fourth, the New World species S. sisymbriifolium, S. torvum and S. elaeagnifolium. By applying a hierarchical FastSTRUCTURE analysis on partitioned data, it was also possible to resolve the ambiguous membership of the accessions of S. campylacanthum, S. violaceum, S. lidii, S. vespertilio and S. tomentsum, as well as to genetically differentiate the three species of New World Origin. A principal coordinates analysis performed both on the entire germplasm panel and also separately on the entries belonging to sub-groups revealed a clear separation among species, although not between each of the domesticates and their respective wild ancestors. There was no clear differentiation between either distinct cultivar groups or different geographical provenance. Adopting various approaches to analyze SNP variation provided support for interpretation of results. The genotyping-by-sequencing approach showed to be highly efficient for both quantifying genetic diversity and establishing genetic relationships among and within cultivated eggplants and their wild relatives. The relevance of these results to the evolution of eggplants, as well as to their genetic improvement, is discussed.


Investigation of Poly(MM-EM-BM) as Nanosealing Materials in Oil-Based Drilling Fluids: Synthesis and Evaluation.
Nanosealing technology has become the key to overcoming the wellbore instability problem in deep and ultradeep shale formations. In this Article, the terpolymer poly(MM-EM-BM) was synthesized from methyl methacrylate, ethyl methacrylate, and butyl methacrylate by a Michael addition reaction. The poly(MM-EM-BM) nanoparticles were investigated by Fourier transform infrared spectroscopy, laser scattering analysis, and thermogravimetric analysis. The results imply that the particle size range of poly(MM-EM-BM) is between 33.90 and 135.62 nm and the average diameter is about 85.95 nm at room temperature, which can maintain excellent stability at 382.75 °C. The effects of poly(MM-EM-BM) on the properties of oil-based drilling fluids (OBDFs) were ascertained through experiments on the rheological performance, electrical stability, and high-temperature and high-pressure (HTHP) filtration loss. The results suggested that when the amount of added poly(MM-EM-BM) increases, the apparent viscosity, plastic viscosity, dynamic shear force, and demulsification voltage of the drilling fluids will increase correspondingly; in contrast, the HTHP filtration loss gradually decreased. When poly(MM-EM-BM) is added at 0.75%, the kinetic-to-plastic ratio of the drilling fluids is 0.24 and the filtration loss is 0.6 mL, showing excellent overall performance. The drilling fluids have a good rock-carrying ability and water loss wall-building property. The sealing performance and mechanism of poly(MM-EM-BM) were researched by the method of a sealing performance test under high temperature. The results indicated that the more poly(MM-EM-BM) used, the higher the sealing efficiency of the mud cake and the core as the sealing medium. When poly(MM-EM-BM) was added at 0.75%, the sealing rates of the mud cake and the core as the sealing medium reached the maximum sealing rates of 40.30% and 91.48%, respectively. When poly(MM-EM-BM) enters the core nanopore joint for a certain distance under formation pressure, a tight sealing layer will be formed to effectively prevent the entry of filtrate. Poly(MM-EM-BM) as a potential oil-based nanosealing agent is expected to solve the problem caused by wellbore instability in shale horizontal wells.


Apurinic/apyrimidinic endonuclease 1, the sensitive marker for DNA deterioration in dextran sulfate sodium-induced acute colitis.
Mutations in mismatch repair (MMR) genes are commonly associated with the development of colorectal cancer. Additionally, base excision repair, which involves apurinic/apyrimidinic endonuclease 1 (APE1), recognizes and eliminates oxidative DNA damage. Here, we investigated the possible roles of APE1 in dextran sulfate sodium (DSS)-induced acute colitis using the young rat model. Four-week-old Sprague-Dawley rats were administered 2% DSS in drinking water for 1 week. MMR and APE1 expression levels were assessed by western blotting and immunohistochemistry. Following DSS treatment, growth of young rats failed and the animals had loose stools. Together with the histological changes associated with acute colitis, APE1 and MSH2 levels increased significantly at 3 and 5 days after DSS treatment, respectively. The difference between APE1 and MSH2 expression was significant. DSS-induced DNA damage and subsequent repair activity were evaluated by staining for 8-hydroxy-deoxyguanosine (8-OHdG) and APE1, respectively; 8-OHdG immunoreactivity increased throughout the colonic mucosa, while APE1 levels in the surface epithelium increased at an earlier timepoint. Taken together, our data suggest that changes in APE1 expression after DSS treatment occurred earlier and were more widespread than changes in MMR expression, suggesting that APE1 is more sensitive for prediction of DNA deterioration in DSS-induced colitis.


The use of natural and synthetic phospholipids as pharmaceutical excipients.
In pharmaceutical formulations, phospholipids obtained from plant or animal sources and synthetic phospholipids are used. Natural phospholipids are purified from, e.g., soybeans or egg yolk using non-toxic solvent extraction and chromatographic procedures with low consumption of energy and minimum possible waste. Because of the use of validated purification procedures and sourcing of raw materials with consistent quality, the resulting products differing in phosphatidylcholine content possess an excellent batch to batch reproducibility with respect to phospholipid and fatty acid composition. The natural phospholipids are described in pharmacopeias and relevant regulatory guidance documentation of the Food and Drug Administration (FDA) and European Medicines Agency (EMA). Synthetic phospholipids with specific polar head group, fatty acid composition can be manufactured using various synthesis routes. Synthetic phospholipids with the natural stereochemical configuration are preferably synthesized from glycerophosphocholine (GPC), which is obtained from natural phospholipids, using acylation and enzyme catalyzed reactions. Synthetic phospholipids play compared to natural phospholipid (including hydrogenated phospholipids), as derived from the number of drug products containing synthetic phospholipids, a minor role. Only in a few pharmaceutical products synthetic phospholipids are used. Natural phospholipids are used in oral, dermal, and parenteral products including liposomes. Natural phospholipids instead of synthetic phospholipids should be selected as phospholipid excipients for formulation development, whenever possible, because natural phospholipids are derived from renewable sources and produced with more ecologically friendly processes and are available in larger scale at relatively low costs compared to synthetic phospholipids. Practical applications: For selection of phospholipid excipients for pharmaceutical formulations, natural phospholipids are preferred compared to synthetic phospholipids because they are available at large scale with reproducible quality at lower costs of goods. They are well accepted by regulatory authorities and are produced using less chemicals and solvents at higher yields. In order to avoid scale up problems during pharmaceutical development and production, natural phospholipid excipients instead of synthetic phospholipids should be selected whenever possible.


Short term dynamic psychotherapy goes to Hollywood: the treatment of performance anxiety in cinema.
This article uses characters in popular films to demonstrate the theory and application of short term dynamic psychotherapy (STDP) in the treatment of performance anxiety. The reader is taught to identify affect phobias that are hypothesized to underlie performance anxiety. Similar in function to external phobias, affect phobias or internal phobias involve the avoidance of feelings (e.g., fear about feeling anger, shame about showing grief, pain about closeness), which thwarts adaptive responding and generates numerous behavioral problems. STDP treatment focuses on the restructuring of defenses, conflicted affects, and attachments. The resolution of the affect phobia requires systematic desensitization of affective responses (i.e., exposure and desensitization of underlying conflicted feelings). When patients learn to access adaptive forms of feelings, performance anxiety can often be resolved.


In vitro production of estradiol by bovine granulosa cells: evaluation of culture condition, stage of follicular development, and location of cells within follicles.
In vitro estradiol (E2) production by bovine granulosa cells was evaluated under several culture conditions, which included the presence or absence of fetal bovine serum (FBS; 2.5 and 10%), serum substitutes (1% Nutridoma [Boehringer-Mannheim, Indianapolis, IN], 2% UltroSer G [IBF Biotechnics, Villenue-la Garenne, France]), selenium (Se; 10 ng/ml), lipoprotein (0.25% Excyte/ml), O2 concentration (5 and 20%), and two attachment factors (Pronectin F and PepTite-2000). Dulbecco's Modified Eagle's medium:Ham's F-12 medium (1:1 mixture) containing 1 microM androstenedione, 1 microgram/ml insulin, and 0.1% BSA was the basal medium evaluated. The optimum conditions determined were the basal medium in 5% O2. These conditions were then used to ascertain whether or not E2 production by granulosa cells varied with respect to location of cells within a follicle. Follicular fluid was aspirated and centrifuged to obtain granulosa cells expected to be primarily luminal and cumulus cells. Follicles were then bisected, and remaining mural granulosa cells were removed by scraping the follicle wall with a fine plastic loop. Aspirated granulosa cells secreted more (p < 0.01) E2 than scraped cells. Production of E2 during Days 0 to 2 of culture by aspirated (0.15 +/- 0.05 ng/microgram DNA) and scraped (0.02 +/- 0.01 ng/microgram DNA) granulosa cells from small follicles (< 8 mm) was less than that by aspirated (6.30 +/- 2.20 ng/micrograms DNA) and scraped cells (1.90 +/- 1.00 ng/microgram DNA) from large follicles (> or = 8 mm). During Days 2 to 4 of culture when compared to Days 0 to 2, E2 production increased for aspirated (but not scraped) granulosa cells from small follicles (0.66 +/- 0.23 ng/microgram DNA)). In contrast, E2 production decreased (p < 0.05) over time in culture for aspirated (2.10 +/- 0.50 ng/microgram DNA) and scraped (0.16 +/- 0.07 ng/microgram DNA) granulosa cells from large follicles. Thus, granulosa cells proximal to the basement membrane may be less differentiated with regard to E2 production than cells distal to the basement membrane. In addition, aspirated granulosa cells from small follicles appear to continue to differentiate toward E2-producing cells during culture, a characteristic difficult to obtain with bovine granulosa cells.


Induction of fetal malformations after treatment of mouse embryos with methylnitrosourea at the preimplantation stages.
The effects of methylnitrosourea (MNU) on the development of preimplantation mouse embryos were investigated in this study. ICR mice were treated intraperitoneally with single doses of 10, 20, and 30 mg MNU/kg body wt on day 0, 1, 2, or 3 of pregnancy. The uterine contents were examined on day 18 of pregnancy. The fetuses were examined for external and skeletal abnormalities. No significant differences were observed in the number of implantation sites between all the MNU-treated groups and controls. MNU treatment on day 2 or 3 of pregnancy caused dose-dependent significant increases in the incidence of abnormal fetuses over the control level, while treatment on day 0 or 1 failed to cause an increase of abnormalities. Cleft palate, exencephalus, and malformed vertebrae were the most common types of abnormalities. In the embryo transfer experiments, the frequency of fetal abnormalities induced when embryos were transferred from MNU-treated females to untreated pseudopregnant females was significantly higher than that induced when embryos were transferred from untreated females to MNU-treated or untreated pseudopregnant females. The results in the present study confirm and extend the previously proposed hypothesis that the direct effects of MNU on preimplantation embryos make a significant contribution to the induction of fetal malformations.


Cysteine-Rich Whey Protein Isolate (CR-WPI) Ameliorates Erectile Dysfunction by Diminishing Oxidative Stress via DDAH/ADMA/NOS Pathway.
Nitric oxide synthase- (NOS-) dependent endothelial dysfunction induced by oxidative stress (OS) is assumed to play a pivotal role in the pathogenesis and progression of diabetes mellitus-related erectile dysfunction (DMED). Cysteine-rich whey protein isolate (CR-WPI) is a widely used protein supplement and has been confirmed to reduce reactive oxygen species (ROS) by increasing cellular antioxidant glutathione (GSH). However, it is currently unknown whether CR-WPI elicits therapeutic effects in DMED. Here, we provide diabetic rats with CR-WPI to determine its effect on DMED and the underlying mechanisms. The results suggest that CR-WPI supplementation increased GSH biosynthesis and reduced ROS content and simultaneously upregulated the dimethylarginine dimethylaminohydrolase (DDAH)/asymmetrical dimethylarginine (ADMA)/nitric oxide synthase (NOS) metabolic pathway. Evaluation of intracavernous pressure (ICP) also showed an improvement of penile erectile function in CR-WPI-treated rats. The results of the vitro cell culture showed that glutathione pretreatment protected corpus cavernosum smooth muscle cells (CCSMC) from H2O2-induced apoptosis by decreasing Caspase 9 and Caspase 3 expressions. These results augur well for the potential therapeutic application of dietary CR-WPI supplementation for treating diabetic erectile dysfunction.


Percutanous closure of left ventricular aneurysms in a patient with Loeys-Dietz syndrome.
We report a case of percutaneous closure of multiple left ventricular aneurysms in a patient with inherited aortic-aneurysm syndrome-the Loeys-Dietz syndrome. One aneurysm was a true aneurysm in the subaortic region and the second one was a pseudoaneurysm at the left ventricular apex. The patient was a high-risk candidate for repeated operations. Both aneurysms were closed successfully percutaneously in staged procedures. There were no complications. The patient remained clinically well with stable echocardiographic results upon reassessment. This case illustrated that catheter-based closure of left ventricular aneurysms is a feasible approach in the context of connective tissue abnormalities related to the Loeys-Dietz syndrome.


The CCR5-antagonist Maraviroc reverses HIV-1 latency in vitro alone or in combination with the PKC-agonist Bryostatin-1.
A potential strategy to cure HIV-1 infection is to use latency reversing agents (LRAs) to eliminate latent reservoirs established in resting CD4+ T (rCD4+) cells. As no drug has been shown to be completely effective, finding new drugs and combinations are of increasing importance. We studied the effect of Maraviroc (MVC), a CCR5 antagonist that activates NF-κB, on HIV-1 replication from latency. HIV-1-latency models based on CCL19 or IL7 treatment, before HIV-1 infection were used. Latently infected primary rCD4+ or central memory T cells were stimulated with MVC alone or in combination with Bryostatin-1, a PKC agonist known to reverse HIV-1 latency. MVC 5 μM and 0.31 μM were chosen for further studies although other concentrations of MVC also increased HIV-1 replication. MVC was as efficient as Bryostatin-1 in reactivating X4 and R5-tropic HIV-1. However, the combination of MVC and Bryostatin-1 was antagonistic, probably because Bryostatin-1 reduced CCR5 expression levels. Although HIV-1 reactivation had the same tendency in both latency models, statistical significance was only achieved in IL7-treated cells. These data suggest that MVC should be regarded as a new LRA with potency similar as Bryostatin-1. Further studies are required to describe the synergistic effect of MVC with other LRAs.


Exacerbations and healthcare resource utilization among COPD patients in a Swedish registry-based nation-wide study.
Exacerbations of chronic obstructive pulmonary disease (COPD) are an important measure of disease severity in terms of impaired disease progression, increased recovery time, healthcare resource utilization, overall morbidity and mortality. We aimed to quantify exacerbation and healthcare resource utilization rates among COPD patients in Sweden with respect to baseline treatments, exacerbation history, and comorbidities. Patients with a COPD or chronic bronchitis (CB) diagnosis in secondary care at age of ≥40 years on 1.7.2009 were identified and followed until 1.7.2010 or death. Severe exacerbations were defined as hospitalizations due to respiratory disease, and healthcare resource utilization was measured by all-cause hospitalizations and secondary care visits. Poisson regression was used adjusting for age, gender, time since COPD/CB diagnosis, and Charlson comorbidity index. In 88,548 patients (54% females, mean age 72 years), previous respiratory hospitalizations and current high use of COPD medication (double or triple therapy) predicted an 8.3-fold increase in severe exacerbation rates and 1.8-fold increase in healthcare resource utilization rates in the following year, compared to patients without combination treatment and/or history of severe exacerbations. COPD/CB patients with history of severe exacerbations and high use of COPD medication experienced a significantly increased rate of severe exacerbations and healthcare resource utilization during the one-year follow-up.


Intramuscular myxoma.
Myxomas of the skeletal muscle are uncommon mesenchymal tumours. About one hundred such tumours have been reported in the world literature so far. In the present paper, we report a case of myxoma which occurred in the thigh muscles, with brief review of pertinent literature.


Travel times to health care and survival from cancers in Northern England.
The aim was to assess the effect of geographical accessibility on the stage of cancer at diagnosis and survival. Records of 117,097 cases of breast, colorectal, lung, ovary and prostate cancer diagnosed in Northern England between 1994 and 2002 were supplemented with estimates of travel times to the patients' general practitioners (GPs) and hospitals attended, together with measures of access to public transport. Logistic regression and Cox proportional hazards models were used, adjusting for age, sex, whether the first hospital visited was a cancer centre and deprivation of area of residence. Late stage at diagnosis was associated with increasing travel time to GP for breast and colorectal cancers and risk of death was associated with travel time to GP for prostate cancer. Travel times to hospital and other accessibility measures showed no consistent associations with stage at diagnosis or survival, so travel to GP was the only influential factor.


Exciton dynamics in amide-I [Formula: see text] -helix protein chains with long-range intermolecular interactions.
The amide-I [Formula: see text] -helix protein is a long molecular chain made up of regularly spaced peptide groups interacting via C=O bonds. According to the current theory the energy released by hydrolyzed adenosine triphosphate is carried across the protein via vibration modes, caused by C=O bond stretchings which, in the presence of anharmonic molecular vibrations, can promote nonlinear localized excitations called excitons. In this work the effects of long-range interactions between amide-I molecules on the modulational instability of small-amplitude excitons, and on characteristic parameters of soliton wavetrain-type excitons, are investigated with emphasis on long-range interactions saturating at finite intermolecular interaction ranges. It is found that long-range interactions strongly affect the dispersion of vibration modes of the protein chain, causing a narrowing of the modulational-instability regions for small-amplitude excitons. Characteristic parameters of the exciton soliton wavetrain, including its velocity, tail and average width (i.e., the exciton width at half tail), are drastically enhanced with respect to their values when only the short-range interaction is considered. The results suggest a sizable increase of the energy carried by excitons along the protein chain above predictions based on short-range considerations.


Tubulocystic carcinoma of the kidney: a case report of natural history and long-term follow-up.
Tubulocystic carcinoma (TC) is a rare primary renal tumor that has been recently described in the pathology literature. Formerly termed low-grade collecting duct carcinoma, further molecular analysis has shown TC to be a distinct entity that is separate from the more aggressive collecting duct carcinoma. Previous series have described the microscopic and immunohistochemical features of this tumor. We describe the natural history of this tumor in a patient who was followed with active surveillance for several years and then underwent partial nephrectomy. Long-term follow-up has shown no evidence of disease. A review of the pertinent literature is performed.


Coal Mine Dust Desquamative Chronic Interstitial Pneumonia: A Precursor of Dust-Related Diffuse Fibrosis and of Emphysema.
Diseases associated with coal mine dust continue to affect coal miners. Elucidation of initial pathological changes as a precursor of coal dust-related diffuse fibrosis and emphysema, may have a role in treatment and prevention. To identify the precursor of dust-related diffuse fibrosis and emphysema. Birefringent silica/silicate particles were counted by standard microscope under polarized light in the alveolar macrophages and fibrous tissue in 25 consecutive autopsy cases of complicated coal worker's pneumoconiosis and in 21 patients with tobacco-related respiratory bronchiolitis. Coal miners had 331 birefringent particles/high power field while smokers had 4 (p<0.001). Every coal miner had intra-alveolar macrophages with silica/silicate particles and interstitial fibrosis ranging from minimal to extreme. All coal miners, including those who never smoked, had emphysema. Fibrotic septa of centrilobular emphysema contained numerous silica/silicate particles while only a few were present in adjacent normal lung tissue. In coal miners who smoked, tobacco-associated interstitial fibrosis was replaced by fibrosis caused by silica/silicate particles. The presence of silica/silicate particles and anthracotic pigment-laden macrophages inside the alveoli with various degrees of interstitial fibrosis indicated a new disease: coal mine dust desquamative chronic interstitial pneumonia, a precursor of both dust-related diffuse fibrosis and emphysema. In studied coal miners, fibrosis caused by smoking is insignificant in comparison with fibrosis caused by silica/silicate particles. Counting birefringent particles in the macrophages from bronchioalveolar lavage may help detect coal mine dust desquamative chronic interstitial pneumonia, and may initiate early therapy and preventive measures.


A comparison of molecular markers and morphology for Neidium taxa (Bacillariophyta) from eastern North America.
Historically, a morphological species concept has applied shape subjectively in the delimitation of diatom species. This has led to confusion between taxa within the benthic diatom genus Neidium. Samples from Ontario, Quebec, Nova Scotia, Newfoundland (Canada) and New York (USA) were examined for Neidium taxa under LM and SEM. Fourier shape analysis showed that shape as a taxonomic character was not able to discern all species. Isolated individuals from the samples were amplified and sequenced for three chloroplast molecular markers (rbcL, psbC, and psbA) and one nuclear ribosomal molecular marker (18S). Phylogenetic reconstructions were completed with the concatenated chloroplast and 18S dataset using Maximum Likelihood and Bayesian analyses. The concatenated chloroplast dataset exhibited a species-level resolution phylogeny of Neidium taxa. The 18S dataset had a lower level of sequence divergence and was unable to differentiate between Neidium taxa. We present emended species descriptions and sequence data for four previously described species: Neidium sacoense, N. longiceps, N. fossum, and N. affine. We describe three novel species (Neidium lowei, N. promontorium, and N. potapovae) and identify two forms with unique molecular signatures. The distinguishing features of N. lowei are its size, valve shape, and longitudinal canal structure. Distinguishing features of N. promontorium are its valve shape, longitudinal canal and apex formation, and surface depression along the axial area. Neidium potapovae is distinguished by its size, formation of valve and apices and single longitudinal canal. This paper demonstrates how future phylogenetic treatments using single cell multigene sequencing can help resolve taxonomic confusion within diatoms.


Presence of Metallic Microfragments on Dentinal Walls and Instrument Defects following Root Canal Preparation.
To determine the presence of metallic microfragments and their elemental composition in the dentinal walls of root canals following preparation using different endodontic instruments and to assess the active cutting edges of instruments with regard to structural defects. A total of 108 molar teeth were selected and prepared using different endodontic instruments. Teeth were randomly divided into nine groups of 12 teeth each, according to the instruments employed: Manual systems -K-FlexoFile, K-File, and Hedstroem; rotary systems - ProTaper Next, Mtwo, BioRaCe; and reciprocating systems - Reciproc, Unicone, and WaveOne. Both root canals and instruments were assessed using scanning electron microscopy, and the elemental composition of metallic microfragments was determined using energy-dispersive X-ray spectroscopy. Metallic microfragments were found in the groups prepared with both manual and reciprocating instruments, with no statistically significant differences between groups, thirds, or presence of metallic microfragments (p ≥ 0.05). Moreover, all groups presented structural defects in both new and used instruments; however, rotary instruments (ProTaper Next, Mtwo 702, BioRaCe) were the ones with the lowest number of defects, at statistically significant differences in comparison with other instruments (p < 0.05). The presence of metallic microfragments on dentinal walls following root canal preparation was associated with manual and reciprocating instrumentation. Furthermore, rotary instruments were the ones with the lowest number of defects. Considering the outcomes measured in this study, rotary instruments performed better than the other two groups, as they were associated with the lowest number of metallic microfragments and structural defects. During root canal preparation, operative procedures may induce changes to the root canal shape, as well as the release of metallic fragments resulting from the action of instruments on dentinal walls. Therefore, it is important to determine, among the different techniques used for this purpose, which ones are least susceptible to this occurrence.


Neoral: a microemulsion cyclosporine.
Cyclosporine (Sandimmune), introduced in the 1980s, improved patient and graft survival rates primarily by decreasing the frequency and severity of early, acute rejection. Today, the challenge for coordinators and clinicians is to promote long-term clinical stability in transplant recipients. This requires maintaining the cyclosporine blood level within a relatively narrow therapeutic range to ensure adequate and stable immunosuppression, thus reducing the risk of rejection caused by a suboptimal drug level or drug-related toxicity because of a level above the therapeutic range. However, the clinical use of Sandimmune is complicated by low bioavailability and highly variable pharmacokinetics that provide management challenges and can affect clinical outcomes adversely. Neoral, a new oral microemulsion formulation (in capsules and oral solution) of cyclosporine, improves the bioavailability and pharmacokinetics of cyclosporine and reduces inter- and intraindividual pharmacokinetic variability with a safety profile comparable to that of Sandimmune.


Dexmedetomidine Directs T Helper Cells toward Th1 Cell Differentiation via the STAT1-T-Bet Pathway.
Dexmedetomidine is an α2 adrenergic receptor agonist that has been reported to modulate the polarization of CD4+ T cells. However, the underlying mechanisms by which dexmedetomidine induces T-helper 1 (Th1) cell differentiation remain poorly understood. The aim of this study was to explore the potential mechanisms through which dexmedetomidine can induce Th1 cell differentiation. Purified CD4+ T cells were stimulated with anti-CD3/anti-CD28 and then treated with dexmedetomidine. Flow cytometry analysis was adopted to measure the concentration of Th1 cells. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qPCR) were performed to detect protein levels and mRNA expression, respectively, of IFN-γ and IL-4. Western blotting was used to determine the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and T-bet expression. The Th1 cell subset and IFN-γ levels were elevated in the dexmedetomidine-induced CD4+ T cells. Dexmedetomidine enhanced the phosphorylation of STAT1 and the expression of T-bet in the CD4+ T cells. Atipamezole (an α2 adrenergic antagonist) and fludarabine (a STAT1 inhibitor) reversed the dexmedetomidine-induced Th1 cell differentiation. These results suggested that dexmedetomidine induced Th1 cell differentiation via the STAT1-T-bet signaling pathway.


Discovery of an ergosterol-signaling factor that regulates Trypanosoma brucei growth.
Ergosterol biosynthesis and homeostasis in the parasitic protozoan Trypanosoma brucei was analyzed by RNAi silencing and inhibition of sterol C24β-methyltransferase (TbSMT) and sterol 14α-demethylase [TbSDM (TbCYP51)] to explore the functions of sterols in T. brucei growth. Inhibition of the amount or activity of these enzymes depletes ergosterol from cells at <6 fg/cell for procyclic form (PCF) cells or <0.01 fg/cell for bloodstream form (BSF) cells and reduces infectivity in a mouse model of infection. Silencing of TbSMT expression by RNAi in PCF or BSF in combination with 25-azalanosterol (AZA) inhibited parasite growth and this inhibition was restored completely by adding synergistic cholesterol (7.8 μM from lipid-depleted media) with small amounts of ergosterol (1.2 μM) to the medium. These observations are consistent with the proposed requirement for ergosterol as a signaling factor to spark cell proliferation while imported cholesterol or the endogenously formed cholesta-5,7,24-trienol act as bulk membrane components. To test the potential chemotherapeutic importance of disrupting ergosterol biosynthesis using pairs of mechanism-based inhibitors that block two enzymes in the post-squalene segment, parasites were treated with AZA and itraconazole at 1 μM each (ED50 values) resulting in parasite death. Taken together, our results demonstrate that the ergosterol pathway is a prime drug target for intervention in T. brucei infection.


The contribution of podocytes to chronic allograft nephropathy.
Progressive proteinuria and glomerulosclerosis characterize chronic allograft nephropathy. However, the causes are not fully elucidated. Podocytes function to prevent proteinuria; injury to this glomerular cell leads to glomerulosclerosis. The potential role of podocytes in the failing transplanted kidney is unknown. A rat model of kidney transplantation, characterized by proteinuria and glomerulosclerosis, was utilized to examine the potential role of podocytes. Archival tissue was examined from allografts (Dark Agouti kidneys transplanted into operationally tolerant Albino Surgery rats), isografts (Dark Agouti) and controls (Dark Agouti: age-matched or after unilateral nephrectomy). The number of podocytes (by WT-1 staining) as well as the podocyte proteins podocin, nephrin and synaptopodin (by immunostaining) were measured at days 0, 2, 6 and at 6 months after transplantation. Changes in these parameters were compared between groups and correlated with urinary protein excretion. At 6 months, podocyte number was reduced in allografted kidneys, accompanied by a decrease in nephrin and synaptopodin, but not podocin staining. Remnant kidneys in the uninephrectomized rats also showed a decreased podocyte number but no change in podocyte protein staining. Podocyte loss in allografts was established on day 6, whereas a decrease in nephrin and synaptopodin was not evident until 6 months. In contrast, podocyte number and protein staining was decreased but not significantly so in remnant and isografted kidneys. A decrease in the slit diaphragm proteins, nephrin and synaptopodin, is a component of chronic allograft pathology.


Tonic Local Brain Blood Flow Control by Astrocytes Independent of Phasic Neurovascular Coupling.
According to the current model of neurovascular coupling, blood flow is controlled regionally through phasic changes in the activity of neurons and astrocytes that signal to alter arteriole diameter. Absent in this model, however, is how brain blood flow is tonically regulated independent of regional changes in activity. This is important because a large fraction of brain blood flow is required to maintain basal metabolic needs. Using two-photon fluorescence imaging combined with patch-clamp in acute rat brain slices of sensory-motor cortex, we demonstrate that reducing resting Ca(2+) in astrocytes with intracellular BAPTA causes vasoconstriction in adjacent arterioles. BAPTA-induced vasoconstriction was eliminated by a general COX blocker and the effect is mimicked by a COX-1, but not COX-2, antagonist, suggesting that astrocytes provide tonic, steady-state vasodilation by releasing prostaglandin messengers. Tonic vasodilation was insensitive to TTX, as well as a variety of synaptic and extrasynaptic receptor antagonists, indicating that the phenomenon operates largely independent of neural activity. Using in vivo two-photon fluorescence imaging of the barrel cortex in fully awake mice, we reveal that acute COX-1 inhibition reduces resting arteriole diameter but fails to affect vasodilation in response to vibrissae stimulation. Our findings demonstrate that astrocytes provide tonic regulation of arterioles using resting intracellular Ca(2+) in a manner that is independent of phasic, neuronal-evoked vasodilation. Significance statement: The brain requires both phasic and tonic regulation of its blood supply to service energy needs over various temporal windows. While many mechanisms have been described for phasic blood flow regulation, how the brain accomplishes tonic control is largely unknown. Here we describe a way in which astrocytes contribute to the management of basal brain blood flow by providing steady-state vasodilation to arterioles via resting astrocyte Ca(2+) and the continuous release of prostaglandin messengers. This phenomenon may be important for understanding the declines in basal brain blood flow that occur in aging and dementia, as well as for the interpretation of fMRI data.


[Otogenic cerebral abscess: description of 3 cases, clinical and therapeutic considerations].
The authors use the 3 cases of otogenous cerebral abscess which came under observation as starting point for a discussion of the main etiopathogenetic, microbiological, clinical-diagnostic and therapeutic aspects of this disorder. After a brief presentation of the data regarding incidence, preferential localization and age of onset, they discuss the means for intracranial spread of infection and the related symptoms. As regards diagnosis, the authors assert that clinical examination and imaging techniques--CT and especially MRI--enable one to determine the dimension and site of the abscess cavity, differentiating it from other intracranial lesions and to monitor clinical evolution and response to therapy. After mentioning the principle bacteria involved in infection, they deal with the various means of treatment. The authors favor surgical removal of the auricular phlogistic focus and medical treatment of the intracranial abscess. They resort to neurosurgery only in those cases which do not respond to drug treatment or when the size and particular location of the abscess threaten the patient's life. In conclusion, the authors underline the problems seen today in diagnosis and therapy, comparing the quoad vitam and quoad valetudinem prognosis for the affected patients.


Physical and genetic map of the Finegoldia magna (formerly Peptostreptococcus magnus) ATCC 29328 genome.
A physical and genetic map of Finegoldia magna (formerly Peptostreptococcus magnus) ATCC 29328 chromosome was constructed. The order of rare cleavage restriction fragments was determined by double digestion with the restriction enzymes I-CeuI, SgrAI, ApaI and PmeI, cross-hybridization and ApaI-linking clones. The size of the circular chromosome of F. magna was estimated to be 1.9 Mb. This strain also had a 200-kb megaplasmid. The chromosome contained four rrn operons, and the orientation of two rrn operons was opposite to the others. Fragment analysis of Peptostreptococcus anaerobius ATCC 27337(T) chromosome suggested that its size was much smaller than that of F. magna ATCC 29328.


Endocytic Recycling of MHC Class I Molecules in Non-professional Antigen Presenting and Dendritic Cells.
Major histocompatibility complex class I (MHC I) molecules are glycoproteins that display peptide epitopes at the cell surface of nucleated cells for recognition by CD8+ T cells. Like other cell surface receptors, MHC class I molecules are continuously removed from the surface followed by intracellular degradation or recycling to the cell surface, in a process likely involving active quality control the mechanism of which remains unknown. The molecular players and pathways involved in internalization and recycling have previously been studied in model cell lines such as HeLa. However, dendritic cells (DCs), which rely on a specialized endocytic machinery that confers them the unique ability to "cross"-present antigens acquired by internalization, may use distinct MHC I recycling pathways and quality control mechanisms. By providing MHC I molecules cross-presenting antigens, these pathways may play an important role in one of the key functions of DCs, priming of T cell responses against pathogens and tumors. In this review, we will focus on endocytic recycling of MHC I molecules in various experimental conditions and cell types. We discuss the organization of the recycling pathway in model cell lines compared to DCs, highlighting the differences in the recycling rates and pathways of MHC I molecules between various cell types, and their putative functional consequences. Reviewing the literature, we find that conclusive evidence for significant recycling of MHC I molecules in primary DCs has yet to be demonstrated. We conclude that endocytic trafficking of MHC class I in DCs remains poorly understood and should be further studied because of its likely role in antigen cross-presentation.


Misdiagnosis of sebaceous carcinoma.
Sebaceous carcinoma is an aggressive malignant tumour. To prevent mutilating surgery and improve patient outcomes, early diagnosis and prompt treatment are necessary. When the tumour invades surrounding tissues, treatment may become complex. We present a case report illustrating complex resection and reconstruction of a sebaceous carcinoma after initial misdiagnosis. A 74-year-old man with a sebaceous carcinoma to his right upper eyelid had a delay in treatment due to initial misdiagnosis. Upon the correct diagnosis, computed tomography scan showed tumour invasion of the medial rectus muscle and tumour spread to the right parotid gland. An orbital exenteration, partial parotidectomy and selective cervical lymphadenectomy were performed. Frozen section examination showed false-free margins, as additional paraffin embedded sections showed uncomplete tumour resection. Adjuvant radiotherapy was offered to the patient. The treatment was complicated by radio necrosis, necessitating surgical reconstruction by a paramedian forehead flap. Final reconstruction of the right orbit was accomplished by a personalised epithesis. Sebaceous carcinoma is a tumour that is often misdiagnosed. The aim of this case report is to emphasize the possible consequences of its misdiagnosis. An overview of characteristic clinical findings is provided to help reduce the number of misdiagnoses.


Dysgonomonas termitidis sp. nov., isolated from the gut of the subterranean termite Reticulitermes speratus.
A facultatively anaerobic, Gram-stain-negative, non-motile and rod-shaped bacterium, strain N-10(T), was isolated from the gut of the termite Reticulitermes speratus. Strain N-10(T) was closely related to Dysgonomonas gadei JCM 16698(T) according to 16S rRNA gene sequence similarity analysis (98 %) and DNA-DNA relatedness value (≤61.3 %). The optimum growth temperature of strain N-10(T) was 30 °C, which was distinct from that (37 °C) of known species of the genus Dysgonomonas. Growth of strain N-10(T) was inhibited on medium containing 5 or 20 % bile, unlike other species of the genus Dysgonomonas. In addition, acid production in the API 20A system and enzymic reactions in the Rapid ID 32A system of strain N-10(T) differed from those of other species of the genus Dysgonomonas. Based on these characteristics, strain N-10(T) represents a novel species of the genus Dysgonomonas, for which the name Dysgonomonas termitidis sp. nov. is proposed. The type strain is N-10(T) ( = JCM 30204(T) = CCUG 66188(T)).


Oxygen Sensing by Arterial Chemoreceptors Depends on Mitochondrial Complex I Signaling.
O2 sensing is essential for mammalian homeostasis. Peripheral chemoreceptors such as the carotid body (CB) contain cells with O2-sensitive K(+) channels, which are inhibited by hypoxia to trigger fast adaptive cardiorespiratory reflexes. How variations of O2 tension (PO2) are detected and the mechanisms whereby these changes are conveyed to membrane ion channels have remained elusive. We have studied acute O2 sensing in conditional knockout mice lacking mitochondrial complex I (MCI) genes. We inactivated Ndufs2, which encodes a protein that participates in ubiquinone binding. Ndufs2-null mice lose the hyperventilatory response to hypoxia, although they respond to hypercapnia. Ndufs2-deficient CB cells have normal functions and ATP content but are insensitive to changes in PO2. Our data suggest that chemoreceptor cells have a specialized succinate-dependent metabolism that induces an MCI state during hypoxia, characterized by the production of reactive oxygen species and accumulation of reduced pyridine nucleotides, which signal neighboring K(+) channels.