[Metformin: one of the possible options to reduce the mortality of severe coronavirus disease 2019?]
According to the world epidemic report, the mortality of patients with severe coronavirus disease 2019 (COVID-19) is high. Diabetic patients are more susceptible to COVID-19. Since the mortality of COVID-19 patients with diabetes is on the top of list, hyperglycemia is considered an independent risk factor for severe COVID-19. Up to now, there is few effective treatment for severe patients infected with 2019 novel coronavirus (2019-nCoV). Clinical studies observed that cytokine storms existed in patients with severe COVID-19. Sustained high levels of cytokines cause diffuse damage to pulmonary capillary endothelial cells and alveolar epithelial cells, resulting in acute respiratory distress syndrome (ARDS). ARDS is the main cause of death in COVID-19 patients. Host-directed therapy (HDT) is an emerging therapeutic method in the field of anti-infection, which can activate the self-protective immune response, suppress excessive inflammatory response, and be used to assist the treatment of traditional drugs to shorten the course of disease. Metformin has been shown to be effective in HDT and can assist in the treatment of the viral and bacterial infectious disease. This paper discusses the rationality and potential therapeutic mechanism of metformin in the treatment of severe COVID-19. It was speculated that the use of metformin for controlling blood glucose in severe COVID-19 patients with diabetes may prevent or inhibit the occurrence of ARDS, thereby reducing the mortality of COVID-19 patients. The possible mechanism is that metformin could inhibit cytokine storm via suppressing interleukin-6 (IL-6) signaling, prevent the process of lung fibrosis, suppress endocytosis, thereby elevating angiotensin converting enzyme 2 (ACE2) expression.


Three-dimensional structure of rat acid phosphatase in complex with L(+)-tartrate.
The crystal structure of recombinant rat prostatic acid phosphatase in complex with the inhibitor L(+)-tartrate was determined to 3-A resolution with protein crystallographic methods. The inhibitor binds at the carboxyl end of the parallel strands of the alpha/beta domain. One of the carboxyl groups of the tartrate molecule interacts with the conserved residues Arg-11, His-12, and Arg-15, which form part of the phosphate binding site. Furthermore, the C2 and C3 hydroxyl groups interact with His-257 and Arg-79. The second carboxyl group is close to Arg-79 but makes no direct hydrogen bonds to the protein. A sequence comparison between tartrate-sensitive and -resistant acid phosphatases suggests that these enzymes have different three-dimensional structures.


Yellow-to-brown and yellow-to-green electrochromic devices based on complexes of transition metal ions with a triphenylamine-based ligand.
Transmissive-to-colored electrochromism has been achieved by combination of MLCT of transition metal complexes with the electrochromic properties of ligand molecules. The color transitions were from yellow to dark brown for the Fe(ii) complex, yellow to orange to bluish-green for the Co(ii) complex and yellow to green for the Zn(ii) complex. By using a metal ion-ligand coordination approach, the self-assembly of hydrazone-based ligands containing a triphenylamine group with appropriate metal salts (FeCl2, Co(ClO4)2 and Zn(BF4)2) produced novel complexes of the general formula [ML2]X2. The isolated complexes were characterized by spectroscopic methods, and the Co(ii) complex also by X-ray diffraction analysis. Thin films of the complexes have been obtained by a spray-coating method and they were used in the construction of electrochromic devices, which showed good electrochromic stability, a high color contrast of 47.5% for Fe(ii), 37.2% for Co(ii) and 33.7% for Zn(ii) complexes and fast coloring and bleaching times.


Hypoxia-inducible factor 1-regulated lysyl oxidase is involved in Staphylococcus aureus abscess formation.
Hypoxia-inducible factor 1 (HIF-1) is the key transcription factor involved in the adaptation of mammals to hypoxia and plays a crucial role in cancer angiogenesis. Recent evidence suggests a leading role for HIF-1 in various inflammatory and infectious diseases. Here we describe the role of HIF-1 in Staphylococcus aureus infections by investigating the HIF-1-dependent host cell response. For this purpose, transcriptional profiling of HIF-1α-deficient HepG2 and control cells, both infected with Staphylococcus aureus, was performed. Four hours after infection, the expression of 190 genes, 24 of which were regulated via HIF-1, was influenced. LOX (encoding lysyl oxidase) was one of the upregulated genes with a potential impact on the course of S. aureus infection. LOX is an amine oxidase required for biosynthetic cross-linking of extracellular matrix components. LOX was upregulated in vitro in different cell cultures infected with S. aureus and also in vivo, in kidney abscesses of mice intravenously infected with S. aureus and in clinical skin samples from patients with S. aureus infections. Inhibition of LOX by β-aminopropionitrile (BAPN) did not affect the bacterial load in kidneys or blood but significantly influenced abscess morphology and collagenization. Our data provide evidence for a crucial role of HIF-1-regulated LOX in abscess formation.


Understanding the nutrigenomic definitions and concepts at the food-genome junction.
The marked differences in individual response to dietary factors have led to major controversies in nutrition and puzzled nutrition scientists over the last century. The emerging field of nutrigenomics helps us to understand the basis for some of these differences and also promises us the ability to tailor diet based on individual genetic makeup. Great advances in Human Genome Project, documentation of single nucleotide polymorphisms (SNPs) in candidate genes and their association with metabolic imbalances have gradually added new tests to the nutrigenomic panel. Studies based on ethnopharmacology and phytotherapy concepts showed that nutrients and botanicals can interact with the genome causing marked changes in gene expression. This has led to the commercial development of nutraceuticals and functional foods that can modify negative health effects of individual genetic profile bringing the field to the "food/genome" junction. Despite the promise of nutrigenomics to personalize diet, there is skepticism whether it can truly bring about meaningful modification of the risk factors connected to chronic diseases, due to the lack of large scale nutrition intervention studies. Several intervention studies currently underway in the United States and abroad (Israel, Spain, and France) will further help validate nutrigenomic concepts. France has already introduced a National Nutrition and Health Program to assess nutritional status and risk of major metabolic diseases. As the field(s) related to nutritional genomics advance in their scope, it is essential that: (a) strict guidelines be followed in the nomenclature and definition of the subdisciplines; and (b) the state/federal regulatory guidelines be updated for diagnostic laboratories, especially for those offering tests directly to the public (without a physician's request) to help protect the consumer.


Profile of hemophagocytic lymphohistiocytosis in children in a tertiary care hospital in India.
To describe the epidemiology, clinical features, laboratory findings, outcome and the difficulties in diagnosis and management of children with Hemo-phagocytic Lymphohistiocytosis (HLH) in a tertiary children's hospital in India. Retrospective analysis of case records of all the children with a diagnosis of HLH from December 2006 to December 2008. Tertiary care children's teaching hospital in Chennai, India. 43 children had a diagnosis of hemo-phagocytosis, of who only 33 (19 male, mean age 46 months, range 50 days-14 years) met the inclusion criteria based on the HLH 2004 protocol of the Histiocyte Society. The predominant presenting features included prolonged fever and hepatosplenomegaly. CNS symptoms were present in 36%. Anemia (Hb <9 gm/dL), and thrombocytopenia (platelets <1,00,000/mm3) were present in 97% and 72%, respectively. Among the biochemical markers, hyperferritinemia was present in 97%, and hypofibrinogenemia and high LDH in 92%. Bone marrow examination showed hemophagocytosis in 84%. Infectious agents were identified in 42% children, with viruses accounting for 2/3 of them (5 Dengue virus, 3 EBV, 1 CMV, 1 TB and 5 bacterial agents). The mean duration between the onset of symptoms and the diagnosis was 16 days. Corticosteroids were the most commonly used immunomodulatory agents (67%), followed by IVI g (64%). Cyclosporine was used in 33% and Etoposide in 15%. Improvement of laboratory parameters was noticed within 5-7 days of starting treatment. Overall survival rate was 76%. HLH should be considered in the differential diagnosis of children with prolonged fever, hepatosplenomegaly and cytopenia. Prompt recognition and appropriate therapy may result in good outcome, particularly in Infection associated HLH.


Gracilioethers A-C, antimalarial metabolites from the marine sponge Agelas gracilis.
Three new antiprotozoan compounds, gracilioethers A-C (1-3), have been isolated from the marine sponge Agelas gracilis. Their structures were elucidated on the basis of spectroscopic and chemical methods. Gracilioethers A-C showed antimalarial activity against Plasmodium falciparum with IC(50) values of 0.5-10 microg/mL, whereas gracilioether B (2) also showed antileishmanial activity.


Involvement of alphavbeta5 integrin in the establishment of autocrine TGF-beta signaling in dermal fibroblasts derived from localized scleroderma.
Localized scleroderma (LSc) is a connective tissue disorder limited to skin and subcutaneous tissue, which may share pathogenic processes with systemic sclerosis (SSc). We previously demonstrated that upregulated expression of integrin alphavbeta5 might contribute to autocrine TGF-beta signaling in SSc fibroblasts. Based on these data, we presently focused on alphavbeta5 and assessed its involvement in pathogenesis of LSc. We initially demonstrated that LSc fibroblasts might be activated by the stimulation of autocrine TGF-beta. Consistent with SSc fibroblasts, expression levels of alphavbeta5 were elevated in LSc fibroblasts in vitro and in vivo. Anti-alphavbeta5 antibody partially reversed expression levels of type I procollagen and MMP-1 and constitutive DNA-Smad3 binding in LSc fibroblasts. In LSc fibroblasts pretreated with antisense TGF-beta1, exogenous latent TGF-beta1 stimulation increased expression of type I procollagen in an alphavbeta5-dependent manner. The luciferase activities of TMLC cells, Mv1Lu cells stably expressing a portion of the plasminogen activator inhibitor 1 promoter, co-cultured with LSc fibroblasts were significantly elevated compared with those co-cultured with normal fibroblasts and were significantly reduced in the presence of anti-alphavbeta5 antibody. Anti-alphavbeta5 antibody reversed the myofibroblastic features of LSc fibroblasts. These results indicate that upregulated expression of alphavbeta5 contributes to autocrine TGF-beta signaling in LSc fibroblasts.


Probing protein interactions in the membrane-containing virus PRD1.
PRD1 is a Gram-negative bacteria infecting complex tailless icosahedral virus with an inner membrane. This type virus of the family Tectiviridae contains at least 18 structural protein species, of which several are membrane associated. Vertices of the PRD1 virion consist of complexes recognizing the host cell, except for one special vertex through which the genome is packaged. Despite extensive knowledge of the overall structure of the PRD1 virion and several individual proteins at the atomic level, the locations and interactions of various integral membrane proteins and membrane-associated proteins still remain a mystery. Here, we demonstrated that blue native PAGE can be used to probe protein-protein interactions in complex membrane-containing viruses. Using this technique and PRD1 as a model, we identified the known PRD1 multiprotein vertex structure composed of penton protein P31, spike protein P5, receptor-binding protein P2 and stabilizing protein P16 linking the vertex to the internal membrane. Our results also indicated that two transmembrane proteins, P7 and P14, involved in viral nucleic acid delivery, make a complex. In addition, we performed a zymogram analysis using mutant particles devoid of the special vertex that indicated that the lytic enzyme P15 of PRD1 was not part of the packaging vertex, thus contradicting previously published results.


Near-Infrared II Nanoadjuvant-Mediated Chemodynamic, Photodynamic, and Photothermal Therapy Combines Immunogenic Cell Death with PD-L1 Blockade to Enhance Antitumor Immunity.
The efficacy of immune checkpoint inhibition in inducing death of cancer cells is affected by the immunosuppressive "cold" tumor microenvironment, which results in a poor response by the patient's antitumor immune system. However, the immunomodulatory effects of immunogenic cell death in response to irritation by heat energy and reactive oxygen species (ROS) can switch the tumor microenvironment from "cold" to "hot." This study has developed a nanoadjuvant for immune therapy using iron tungsten oxide (FeWOx)-based nanosheets with surface PEGylation (FeWOx-PEG). This FeWOx-PEG nanoadjuvant serves as a chemodynamic reagent via the Fenton reaction and acts as a photosensitizer for photodynamic and photothermal therapy under near-infrared II laser irradiation; however, it could also be used to augment tumor-infiltrating T-cells and provoke a systemic antitumor immune response by combining the immunogenic cell death triggered by ROS and photothermal therapy with the immune checkpoint blockade. This research demonstrates that application of the FeWOx-PEG nanoadjuvant under the guidance of magnetic resonance/computed tomography/photoacoustic imaging can eliminate the primary tumor and suppress the growth of distant tumors.


An ongoing measles outbreak in Bulgaria, 2009.
After seven years without indigenous transmission of measles in Bulgaria, an increasing number of cases have been reported since 15 April 2009. By 19 June, the total number of notifications reached 84. To date, 64 were confirmed as measles cases and 15 cases, for whom laboratory results are pending, have been classified as probable. The present measles outbreak affects mostly the Roma population living in the north-eastern part of the country. The most affected age groups are young children below 1 year of age and children 1 to 9 years of age. An immunisation campaign was started in the affected administrative regions, targeting all persons from 13 months to 30 years of age who had not received the complete two-dose MMR vaccination.


Mechanical properties of temporomandibular joint disc on the basis of porcine preparation investigations.
The paper presents the results of a study on mechanical properties of porcine temporomandibular joint discs. Taking into account anatomical properties, three typical spots were selected for the investigation: the posterior, anterior and central parts of the disc. The main focus was on the influence of samples' preparation on the changes in mechanical properties. Complete undamaged discs, cylindrically cut disc samples of 5 mm in diameter as well as discs of locally broken continuity in the upper layer around the measuring zone were prepared. Periodic compression was applied during testing, by varying the force in a sawtooth control signal. The rate of increasing the force applied equalled 1 N/s with a maximum value of 3 N. Based on the stress and strain characteristics obtained, the object's rigidity, Young's modulus of the samples, and effective Young's modulus of joint discs were calculated. Results showed that the stress and strain characteristics of the discs' substance depend on sample preparation, measurement location and load history within a given number of cycles. Only the fifth load cycle may be considered as stabilized. The most rigid proved to be the posterior part of the disc, as the rigidity of the samples, of an incised disc and of a complete disc in the fifth loading cycle amounted to 117.9 N/mm, 88.8 N/mm and 87.1 N/mm, respectively. A central part of the disc exhibited the lowest rigidity, whose values for the samples, for an incised disc and for a complete disc reached 87.9 N/mm, 70.6 N/mm, and 38.7 N/mm, respectively. Excision of the samples resulted in their dehydration, which led to increased rigidity, as reflected by Young's modulus values. In the posterior part of the disc, the modulus value was 12.56 MPa, while in the anterior part and in the center, these values reached 7.25 MPa and 6.99 MPa, respectively. Excised discs also exhibited dehydration effects during examination. While loading complete discs, the lowest effective values of Young's modulus were obtained, despite the influence of the tissues adjacent to the loaded zone, counteracting deformation. The values were 4.44 MPa, 1.97 MPa and 2.99 MPa for the posterior, central and anterior parts, respectively. Present data allow the conclusion that the error introduced due to breaking the tissue continuity is greater than the error resulting from ignoring substance continuity when applying local loads to an undamaged disc. Therefore, it seems more sensible to adopt the effective Young's modulus values in numerical analyses rather than to apply the results obtained for the samples cut out of discs.


Self-efficacy beliefs as shapers of children's aspirations and career trajectories.
This prospective study tested with 272 children a structural model of the network of sociocognitive influences that shape children's career aspirations and trajectories. Familial socioeconomic status is linked to children's career trajectories only indirectly through its effects on parents' perceived efficacy and academic aspirations. The impact of parental self-efficacy and aspirations on their children's perceived career efficacy and choice is, in turn, entirely mediated through the children's perceived efficacy and academic aspirations. Children's perceived academic, social, and self-regulatory efficacy influence the types of occupational activities for which they judge themselves to be efficacious both directly and through their impact on academic aspirations. Perceived occupational self-efficacy gives direction to the kinds of career pursuits children seriously consider for their life's work and those they disfavor. Children's perceived efficacy rather than their actual academic achievement is the key determinant of their perceived occupational self-efficacy and preferred choice of worklife. Analyses of gender differences reveal that perceived occupational self-efficacy predicts traditionality of career choice.


How to objectively classify residents based on their psychomotor laparoscopic skills?
In minimally invasive surgery (MIS), a surgeon needs to acquire a certain level of basic psychomotor MIS skills to perform surgery safely. Evaluation of those skills is a major impediment. Although various assessment methods have been introduced, none of them came as a superior. Three aspects of assessing psychomotor MIS skills are discussed here: (i) advantages and disadvantages of currently available assessment methods, (ii) methods to objectively classify residents according to their level of psychomotor skills, and (iii) factors that influence psychomotor MIS skills. Motion analysis has a potential to be the means to deal with assessment of psychomotor skills. Together with classification methods (e.g. linear discriminant analysis), motion analysis provides an aid in deciding whether a resident is ready to move to the next level of training. Presence of factors that influence psychomotor MIS skills results in a high need for standardisation of valid tasks and setups used for the assessment of MIS skills.


Palatoradicular groove: The hidden predator and etiological factor - Advanced proposed classification and literature review.
Palatoradicular grooves are usually found on the palatal or lateral roots of maxillary central and lateral incisors. Since clinical identification of these grooves are inaccessible and arduous in routine oral hygiene practices and are susceptible alcoves for microorganism habituation and plaque accumulation, it may result in acute to severe periodontitis and, if untreated, periapical pathosis also. This paper discusses about a female patient who reported pus discharge in left upper lateral incisor. Based on history, clinical examination and IOPA (intra-oral periapical radiograph), a deep pocket of about 10-14 mm was noticed in the left upper lateral incisor. A timely investigation was made and was treated surgically with advanced modified procedures which include odontoplasty and restoration of the defect with Platelet Rich Fibrin. After follow up of 6 months, the patient reported no signs of disease progression, had good oral hygiene and the tooth remained to be vital.


Coronary Artery Disease in Patients Presenting With Acute Ischemic Stroke or Transient Ischemic Attack and Elevated Troponin Levels.
Background: There is little information concerning the invasive coronary angiography (ICA) findings of patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) with elevated troponin levels and suspected myocardial infarction (MI). This study analyzed patient characteristics associated with ICA outcomes. Methods: A total of 8,322 patients with AIS or TIA, treated between March 2010 and May 2020, were retrospectively screened for elevated serum troponin I at hospital admission. Patients in whom ICA was performed, due to suspected type 1 MI based on symptoms, echocardiography, and ECG, were categorized according to ICA results (non-obstructive coronary artery disease (CAD): ≥1 stenosis ≥50% but no stenosis ≥80%; obstructive CAD: any stenosis ≥80% or hemodynamically relevant stenosis assessed by FFR/iwFR). Results: Elevated troponin levels were detected in 2,205 (22.5%) patients, of whom 123 (5.6%) underwent ICA (mean age 71 ± 12 years; 67% male). CAD was present in 98 (80%) patients, of whom 51 (41%) were diagnosed with obstructive CAD. Thus, ICA findings of obstructive CAD accounted for 2.3% of patients with troponin elevation and 0.6% of all stroke patients. The clinical hallmarks of myocardial ischemia, including angina pectoris (31 vs. 15%, p < 0.05) and regional wall motion abnormalities (49 vs. 32%, p = 0.07), and increased cardiovascular risk indicated obstructive CAD. While there was no association between lesion site or stroke severity and ICA findings, causal large-artery atherosclerosis was significantly more common in patients with obstructive coronary disease (p < 0.05). Conclusion: The rate of obstructive CAD in patients with stroke or TIA and elevated troponin levels with suspected concomitant type I MI is low. The cumulation of several cardiovascular risk factors and clinical signs of MI were predictive. AIS patients with large-artery atherosclerosis and elevated troponin may represent an especially vulnerable subgroup of stroke patients with risk for obstructive CAD.


Combretastatin A4-β-Galactosyl Conjugates for Ovarian Cancer Prodrug Monotherapy.
Chemotherapy for ovarian cancer often causes severe side effects. As candidates for combretastatin A4 (CA4) prodrug for ovarian cancer prodrug monotherapy (PMT), we designed and synthesized two β-galactose-conjugated CA4s (CA4-βGals), CA4-βGal-1 and CA4-βGal-2. CA4 was liberated from CA4-βGals by β-galactosidase, an enzyme more strongly expressed in ovarian cancer cells than normal cells. CA4-βGal-2, which has a self-immolative benzyl linker between CA4 and the β-galactose moiety, was more cytotoxic to ovarian cancer cell lines than CA4-βGal-1 without a linker. Therefore, CA4-βGal-2 can serve as a platform for the design and manufacture of prodrugs for ovarian cancer PMT.


Clinical pathways and case management in anesthesia practice: new tools and systems for the evolving healthcare environment.
Clinical care pathways and case management are strategies utilized by increasing numbers of hospitals to meet the challenges of capitated reimbursement and managed care. A clinical pathway is an outcome-focused tool used to define a multidisciplinary plan of care. A case manager coordinates patient care across an episode of illness or hospitalization. These tools and systems have great potential for use by nurse anesthetists in ensuring that high-quality anesthesia care is delivered in a cost-effective manner.


[Impact of the response of primary tumor to preoperative chemotherapy and anti-HER2 therapy on survival of HER2-positive breast cancer patients].
To study the impact of anti-HER2 therapy and response of primary tumor on distant disease free survival (DDFS) of the patients with HER2-positive breast cancer. The clinical data of the patients with HER2-positive breast cancer treated with neoadjuvant systemic therapy were analyzed retrospectively. Patients treated with preoperative anti-HER2 therapy and chemotherapy had a significant improved pathological complete response (pCR) rate (48.4%) compared with those treated with preoperative chemotherapy (17.2%) (P=0.000). The median follow-up period was 62(6-160) months. The 5-year DDFS in patients with anti-HER2 therapy and patients without anti-HER2 therapy was 93.5% and 83.3% respectively (P=0.006). The 5-year DDFS in patients achieving a pCR and patients not achieving a pCR was 94.7% and 82.6% respectively(P=0.001). Among patients achieving a pCR, anti-HER2 therapy did not improve DDFS significantly (P=0.960). Benefits of anti-HER2 therapy in DDFS among patients without a pCR achieved statistical significance (P=0.028). Combination of neoadjuvant anti-HER2 therapy and chemotherapy resulted in a higher pCR rate in HER2-overexpressing primary breast cancer. Patients treated with neoadjuvant systemic therapy who achieved a pCR have excellent outcome regardless of whether they received anti-HER2 therapy.


Skeletal muscle evaluation by MRI in a rabbit model of acute ischaemia.
To assess rhabdomyolysis-associated skeletal muscle changes induced by complete ischaemia in rabbits using MRI. Acute ischaemia was induced in the right hind limb of 34 New Zealand white rabbits by arterial ligation. MRI of vastus lateralis was carried out pre-operatively and every hour post-operatively up to 7 h. T1 weighted images, T2 weighted images with fat suppression, T2 maps and diffusion tensor scans were obtained. The correlation of MRI findings with histopathological changes in biopsies of vastus lateralis was examined. Histopathology demonstrated early cellular oedema 1 h post ischaemia and irreversible injuries by 7 h, including loss of striation and broken muscle fibres. T2 weighted images with fat suppression showed inhomogeneous high signal intensity of vastus lateralis, which progressively increased from 2 h following ischaemia. The T2 relaxation rate of ischaemic vastus lateralis was significantly greater than normal muscle (p<0.001) and demonstrated a linear increase with time following ischaemia. A similar linear increase was also found in the ischaemic vastus lateralis apparent diffusion coefficient (ADC) 1-5 h post ischaemia (p=0.006). Both the T2 ADC and fractional anisotropy (FA) were significantly higher on the ischaemic side 7 h post ischaemia (for T2, p=0.02; for ADC, p=0.004). Muscle oedema is detectable on MR images and is reflected well by T2, ADC and FA values. MRI may have value in clinical evaluation of rhabdomyolysis. Ischaemic changes detected by MRI may have value in the diagnosis of rhabdomyolysis.


Synthesis of the trisaccharide repeating unit of the atypical O-antigen polysaccharide from Danish Helicobacter pylori strains employing the 2'-carboxybenzyl glycoside.
[reaction: see text] Synthesis of the unique trisaccharide repeating unit of the O-polysaccharide of the lipopolysaccharide from Danish Helicobacter pylori strains has been accomplished. Key steps include the coupling of three monosaccharide moieties by glycosylations employing the 2'-carboxybenzyl glycoside method. Also presented is a method for the synthesis of the novel branched sugar, 3-C-methyl-D-mannose, which is one of three monosaccharide components.


Clonal T cell-mediated cyclic thrombocytopenia.
Cyclic thrombocytopenia is a rare disorder characterized by periodic platelet count fluctuations of unknown aetiology. We report on a female patient with cyclic changes of platelet counts ranging from 6 x 10(9)/l to 753 x 10(9)/l in 4-week intervals. Platelet counts were inversely correlated to thrombopoietin levels suggesting production failure. Reticulocyte counts and neutrophil counts showed similar, but less prominent, fluctuations. Clonal T-cell receptor rearrangement was detected in bone marrow samples as well as in peripheral blood. Cell typing of blood lymphocytes revealed a relative increase in CD3+ T cells. Treatment with cyclosporine A resulted in a substantial improvement of platelet counts. Taken together, we provide evidence for clonal T-cell mediated bone marrow failure with cyclic impairment of thrombopoiesis responsive to cyclosporine therapy.


Improvement of stress tolerance and riboflavin production of Bacillus subtilis by introduction of heat shock proteins from thermophilic bacillus strains.
In this study, stress tolerance devices consisting of heat shock protein (HSP) genes from thermophiles Geobacillus and Parageobacillus were introduced into riboflavin-producing strain Bacillus subtilis 446 to improve its stress tolerance and riboflavin production. The 12 HSP homologs were selected from 28 Geobacillus and Parageobacillus genomes according to their sequence clustering and phylogenetically analysis which represents the diversity of HSPs from thermophilic bacillus. The 12 HSP genes and 2 combinations of them (PtdnaK-PtdnaJ-PtgrpE and PtgroeL-PtgroeS) were heterologously expressed in B. subtilis 446 under the control of a strong constitutive promoter P43. Most of the 14 engineered strains showed increased cell density at 44 to 48 °C and less cell death at 50 °C compared with the control strains. Among them, strains B.s446-HSP20-3, B.s446-HSP20-2, and B.s446-PtDnaK-PtDnaJ-PtGrpE increased their cell densities over 25% at 44 to 48 °C. They also showed 5-, 4-, and 4-fold improved cell survivals after the 10-h heat shock treatment at 50 °C, respectively. These three strains also showed reduced cell death rates under osmotic stress of 10% NaCl, indicating that the introduction of HSPs improved not only the heat tolerance of B. subtilis 446 but also its osmotic tolerance. Fermentation of these three strains at higher temperatures of 39 and 43 °C showed 23-66% improved riboflavin titers, as well as 24-h shortened fermentation period. These results indicated that implanting HSPs from thermophiles to B. subtilis 446 would be an efficient approach to improve its stress tolerance and riboflavin production.


Molecular basis of the selectivity of the immunoproteasome catalytic subunit LMP2-specific inhibitor revealed by molecular modeling and dynamics simulations.
Given that immunoproteasome inhibitors are currently being developed for a variety of potent therapeutic purposes, the unique specificity of an α',β'-epoxyketone peptide (UK101) toward the LMP2 subunit of the immunoproteasome (analogous to β5 subunit of the constitutive proteasome) has been investigated in this study for the first time by employing homology modeling, molecular docking, molecular dynamics simulation, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. On the basis of the simulated binding structures, the calculated binding free energies are in qualitative agreement with the corresponding experimental data, and the selectivity of UK101 is explained reasonably. The observed selectivity of UK101 for the LMP2 subunit is rationalized by the requirement for both a linear hydrocarbon chain at the N terminus and a bulky group at the C terminus of the inhibitor, because the LMP2 subunit has a much more favorable hydrophobic pocket interacting with the linear hydrocarbon chain, and the bulky group at the C terminus has a steric clash with the Tyr 169 in β5 subunit. Finally, our results help to clarify why UK101 is specific to the LMP2 subunit of immunoproteasome, and this investigation should be valuable for rational design of more potent LMP2-specific inhibitors.


Comparison of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing proposed standard and the E-test with the NCCLS broth microdilution method for voriconazole and caspofungin susceptibility testing of yeast species.
The proposed standard of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing (AFST-EUCAST) and the E-test procedures were compared with the NCCLS reference broth microdilution method for voriconazole and caspofungin susceptibility testing of 102 clinical Candida species and Saccharomyces cerevisiae isolates. The voriconazole MIC at which 50% of strains were inhibited (MIC(50)) was < or =0.125 mg/liter for all yeast species except for Candida glabrata and Candida krusei, which yielded MIC(50) values of 0.25 to 1 mg/liter depending on the method. Caspofungin exhibited in vitro activity (MIC(50) of < or =0.125 to 2 mg/liter) against all yeast species except for Candida guilliermondii. The agreements between MICs within +/-2 dilutions obtained by the NCCLS method and the EUCAST standard were 97% for voriconazole and 96% for caspofungin. Intraclass correlation coefficients were statistically significant (P < 0.05). The agreements between voriconazole MICs provided by the E-test and the NCCLS and between the E-test and the AFST-EUCAST method were 100 and 90%, respectively. Because of lower caspofungin MICs provided by the E-test, the agreement was slightly poorer with the NCCLS method (89%) than with the AFST-EUCAST procedure (94%). Both the EUCAST and the E-test procedures can be reliable techniques for susceptibility testing of yeasts to voriconazole and caspofungin.


Function of Light in the Light-induced Geotropic Response in Zea Roots.
The light doses just above the threshold energy value for inducing the geotropic responsiveness in the roots of Zea mays L., cv. Golden Cross Bantam 70, caused a drastic rise in the NADPH level and a drop in the NADP level in 2-millimeter root tips. Some reducing agents lowered the threshold energy value up to about one-third of the control. From these results, we deduce that light may exert two functions in the geotropic response of Zea primary roots, one being the photochemical transformation of a photoreceptor and the other being the induction of a reduction state in the tissue.


Identification of immune-related ferroptosis prognostic marker and in-depth bioinformatics exploration of multi-omics mechanisms in thyroid cancer.
Background: Factors such as variations in thyroid carcinoma (THCA) gene characteristics could influence the clinical outcome. Ferroptosis and immunity have been verified to play an essential role in various cancers, and could affect the cancer patients' prognosis. However, their relationship to the progression and prognosis of many types of THCA remains unclear. Methods: First, we extracted prognosis-related immune-related genes and ferroptosis-related genes from 2 databases for co-expression analysis to obtain prognosis-related differentially expressed immune-related ferroptosis genes (PR-DE-IRFeGs), and screened BID and CDKN2A for building a prognostic model. Subsequently, multiple validation methods were used to test the model's performance and compare its performance with other 4 external models. Then, we explored the mechanism of immunity and ferroptosis in the occurrence, development and prognosis of THCA from the perspectives of anti-tumor immunity, CDKN2A-related competitive endogenous RNA regulatory, copy number variations and high frequency gene mutation. Finally, we evaluated this model's clinical practice value. Results: BID and CDKN2A were identified as prognostic risk and protective factors, respectively. External data and qRT-PCR experiment also validated their differential expression. The model's excellent performance has been repeatedly verified and outperformed other models. Risk scores were significantly associated with most immune cells/functions. Risk score/2 PR-DE-IRFeGs expression was strongly associated with BRAF/NRAS/HRAS mutation. Single copy number deletion of CDKN2A is associated with upregulation of CDKN2A expression and worse prognosis. The predicted regulatory network consisting of CYTOR, hsa-miRNA-873-5p and CDKN2A was shown to significantly affect prognosis. The model and corresponding nomogram have been shown to have excellent clinical practice value. Conclusion: The model can effectively predict the THCA patients' prognosis and guide clinical treatment. Ferroptosis and immunity may be involved in the THCA's progression through antitumor immunity and BRAF/NRAS/HRAS mutation. CYTOR-hsa-miRNA-873-5p-CDKN2A regulatory networks and single copy number deletion of CDKN2A may also affect THCA' progression and prognosis.


Radioprotective action of curcumin extracted from Curcuma longa LINN: inhibitory effect on formation of urinary 8-hydroxy-2'-deoxyguanosine, tumorigenesis, but not mortality, induced by gamma-ray irradiation.
We evaluated the radioprotective action of curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] extracted from Curcuma longa LINN against the acute and chronic effects and the mortality induced by exposure to radiation using female rats. For the assay of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine, a marker for acute effects, Wistar-MS virgin rats were fed the basal diet with exposure at 0 or 3 Gy to gamma-rays from a 60Co source as the control. Rats in the experimental groups received whole-body irradiation with 3 Gy and were fed a diet containing 1% (wt/wt) curcumin for 3 days before and/or 2 days after irradiation. The urine was collected for a 24-h period between 1 and 2 days after irradiation. Urine samples were used to determine the 8-OHdG level using an enzyme-linked immunosorbent assay and the creatinine level by a modified Jaffé reaction. For long-term effects, rats at Day 17 of pregnancy were fed a diet containing curcumin for 3 days before and/or 3 days after irradiation with 1.5 Gy, and received a pellet of diethylstilbestrol as the promoter. The rats were examined for mammary and pituitary tumors for 1 year. To determine survival, virgin rats received whole-body irradiation with 9.6 Gy and were fed a diet containing curcumin for 3 days before and/or 3 days after irradiation. After irradiation, all rats were assessed daily for survival for 30 days. Acutely in virgin rats irradiated with 3 Gy, the creatinine-corrected concentration and total amount of 8-OHdG in the 24-h urine samples were higher (approximately 1.3-fold) than the corresponding values in the nonirradiated controls. Adding curcumin to the diet for 3 days before and/or 2 days after irradiation reduced the elevated 8-OHdG levels by 50-70%. The evaluation of the protective action of curcumin against the long-term effects revealed that curcumin significantly decreased the incidence of mammary and pituitary tumors. However, the experiments on survival revealed that curcumin was not effective when administered for 3 days before and/or 3 days after irradiation (9.6 Gy). These findings demonstrate that curcumin can be used as an effective radioprotective agent to inhibit acute and chronic effects, but not mortality, after irradiation.


[Combination of celiprolol and amiodarone in the treatment of recurrent ventricular tachycardia].
The combination of beta-blockers and amiodarone has been shown to be affective in the treatment of refractory chronic ventricular tachycardia. However, the possible induction of excessive sinus bradycardia can constitute a limitation to the use of this treatment. Celiprolol is a cardioselective beta-blocker with a partial beta-2 agonist activity and an alpha-2 blocking activity, with a minimal depressant effect on heart rate. It therefore seemed useful to evaluate this drug in combination with amiodarone in patients with chronic ventricular tachycardia refractory to amiodarone alone. Twelve men with age of 57 +/- 16 years (9 with a history of myocardial infarction) received 200 mg of celiprolol per day associated with an average of 2 grams of amiodarone per week. Failure of oral amiodarone alone was confirmed by "reloading" (1,200 mg per day for 4 days) in 11 patients. The mean left ventricular ejection fraction was 36 +/- 19%, and was < or = 30% in 5 patients. Three patients were classified as stage 3-4 of the NYHA functional classification. Episodes of tachycardia were paroxysmal in 10 patients and diurnal in 10 cases. The effects of treatment were evaluated by clinical examination, continuous electrocardiographic monitoring, stress test and endocavitary electrophysiological investigation. No patient developed cardiac decompensation or collapse during beta-blocker treatment. In one case, the dose of celiprolol had to be decreased to 100 mg per day because of hypotension. No proarrhythmic effect was observed. The sinus rate remained unchanged after addition of celiprolol to amiodarone (57 +/- 3 bpm before versus 56 +/- 4 bpm after). On the stress test, the exercise capacity was maintained and no tachyarrhythmia was induced. Right ventricular refractory periods were not modified by celiprolol (mean effective period 289 +/- 20 ms before versus 294 +/- 20 ms after). Following a hospital stay of 17 +/- 7 days, the beta-blocker was discontinued in 5 patients because of persistence of permanent tachycardia in 1 case, and because of inducibility of a tachycardia with the same frequency as before treatment in the other 4 cases. No sudden death or haemodynamically unstable recurrence of ventricular tachycardia were observed during follow-up over a period of 38 +/- 24 months (range: 2-55) of the 7 patients in whom treatment was considered to be effective. Only one patient presented a temporary and reversible deterioration of heart failure. The absence of excessive bradycardia was also observed during follow-up. In one patient, celiprolol was replaced by another antiarrhythmic due to the recrudescence of inducibility to programmed stimulation. Three patients developed a spontaneous recurrence of sustained monomorphie ventricular tachycardia, which was well tolerated. In conclusion, these results suggest that celiprolol in combination with amiodarone in the treatment of refractory chronic ventricular tachycardia is a valuable therapeutic option because of its good inotropic and particularly chronotropic safety. However, the efficacy of treatment must be evaluated by a stress test and by endocavitary electrophysiological investigation including programmed ventricular stimulation in every case.


Long term inhibition of neointima formation in balloon-injured rat arteries by intraluminal instillation of a matrix-targeted retroviral vector bearing a cytocidal mutant cyclin G1 construct.
Restenosis from neointimal proliferation is a frequent complication of intracoronary stenting and catheter-based revascularization procedures. Currently, there is no known therapeutic strategy that has been sufficiently effective to warrant its widespread use. In the present study, the anti-proliferative properties of a matrix (collagen)-targeted retroviral vector bearing a mutant cyclin G1 (DNT 41-249) construct was evaluated in vitro and in vivo. In controlled one-month efficacy studies, the intraluminal instillation of the mutant cyclin G1 vector significantly inhibited neointima lesion formation in balloon-injured rat arteries without neointimal growth, associated necrosis or intense inflammatory reaction. Taken together, these data extend the potential utility of the matrix-targeted mutant cyclin G1 retroviral vector for management of vascular restenosis.


Indicators of deprivation predict diurnal cortisol regulation during infancy.
Dysregulation of diurnal cortisol rhythms is often seen among children exposed to early adversity and has been associated with a variety of negative physical and mental health outcomes. The present study examined whether two indicators of deprivation, sociodemographic burden and observed parental insensitivity, were associated with child diurnal cortisol rhythms among a diverse community sample of 250 infants ages 5 to 22 months (M = 12.68 months, 47.2% male). The sample was diverse in terms of socioeconomic status as assessed by household income (M = $59,163, SD = $57,775, range = $0-230,000) and infant race/ethnicity (41.6% African American, 19.2% White, 17.2% multiracial, 14.0% Hispanic/Latin, 2.8% Caribbean, 2.8% other, 1.2% American Indian/Alaska Native, and 1.2% Asian). Sociodemographic burden indicators were assessed through questionnaires completed by the parent. Parental sensitivity was assessed through observations of parents' interactions with their infants during a play interaction task. Cortisol was assayed from infant saliva samples collected at waking and bedtime across 3 days. Structural equation modeling revealed that higher sociodemographic burden, but not parental insensitivity, was associated with blunted diurnal cortisol slopes. Neither sociodemographic burden nor parental insensitivity were associated with the cortisol awakening response. These findings suggest that sociodemographic burden may be an important early predictor of diurnal cortisol slope dysregulation, highlighting the importance of interventions providing support to individuals who experience sociodemographic burden and promoting reduction of these early stressors. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Modulation of ventricular fibrillation in the isolated heart: the role of slow calcium channel activity under continuous perfusion.
The individual activities of sodium versus calcium channels in the initiation and maintenance of ventricular fibrillation (VF) have not been fully elucidated. Therefore we studied in isolated heart under nonischemic conditions (a) VF characteristics in untreated hearts, (b) initiation and maintenance of VF during attenuation and blockade of slow calcium channel activity by verapamil, (c) the effect of these interventions on the characteristics of the induced arrhythmia, and (d) the impact of heart weight on the observed results. Measurements were carried out in both ventricles of isolated feline hearts during ventricular pacing and 8 min of electrically induced tachyarrhythmias. Measurements during ventricular pacing included epicardial conduction time (CON), refractoriness (VRP), and all tissue resistivity (ATR; an indirect measure of changes in intercellular electrical coupling). Measurements during arrhythmia included ATR, peak frequency [PKF; a measure of the prevailing frequency based on Fast Fourier Transform (FFT) analysis], and normalized entropy (ENTROP; a measure of the degree of arrhythmia organization). Measurements during sinus rhythm and arrhythmia were repeated after blocking of calcium channel activity by verapamil at a high concentration (1.8x10(-4) M; n = 8) and at two low concentrations (1.5 and 3.0x10(-7) M; n = 8). In untreated hearts, mainly VF episodes were induced, exhibiting a low degree of organization with no significant change in this parameter throughout the arrhythmia (8 min). In the left ventricle (LV; and to a much smaller extent in the right ventricle; RV), a gradual increase in PKF was observed throughout the arrhythmia, with no significant change in ATR. Verapamil at a high concentration increased CON, but did not affect VRP. These findings were similar in both ventricles. In lower verapamil concentrations, CON was not affected, and VRP was slightly shortened. After treatment with a high verapamil concentration, VF could not be induced in small hearts but was always inducible in large hearts. Transient arrhythmia episodes appeared in 9% of untreated hearts, in 25% with "high" verapamil, and in 25-37% with "low" verapamil. With all verapamil concentrations, the induced arrhythmia was modulated from a predominantly VF to PVT or MVT type, manifested by a decrease in ENTROP. This effect was less pronounced with increasing heart weight. No significant change in PKF and in ATR was obtained with verapamil throughout the arrhythmia. It is suggested that verapamil modulation of arrhythmia organization is associated mainly with a direct blockade of calcium channel activity (perhaps by causing reduction in the safety factor for conduction), rather than with indirect modulation of electrophysiological parameters.


Soccer related sudden deaths in Turkey.
Regular physical exercise is recommended by the medical community, because it offers the potential to reduce the incidence of coronary events. On the other hand, vigorous exertion may act as a trigger of acute myocardial infarction and sudden cardiac death in susceptible individuals. Death during sports activities differs among sports disciplines and countries. In Turkey, soccer attracts more spectators than any other sports activity and the attention of the press and media, and is preferred over other sports by many young and middle-aged individuals. As autopsy-based studies are infrequent in literature and there is a lack of data detailing sudden death during physical activity in Turkey, we present a Turkish series of sudden deaths that occurred during soccer games based on data provided by the Morgue Specialization Department of the Council of Forensic Medicine. We identified 15 male cases of soccer-related sudden death aged from 10 to 48 years. Coronary artery disease was identified as the cause of sudden death in 11 cases. Key pointsThis study is one of the largest series of soccer related SD with reported 15 cases.In our series, CAD is the most common cause of SCD also in very young athletes in contrast with international literature.In autopsy, detailed cardio-vascular system evaluation and toxicological analysis including doping agents are essential to determine precise cause of exercise induced SD.Medical screening is important for all people interested in sport, not only for athletes, as a powerful means of prevention.


A case of right atrial myxoma--effect of large myxoma in the right atrium studied by M-mode and Doppler echocardiography.
Doppler profiles are rarely used to assess cardiac function that has been partially impaired by a sizeable myxoma in the right atrium or to evaluate the improvement caused by extirpation of the tumor. In a 54-year-old man with a large right atrial myxoma (6.5 x 5.5 x 4.0 cm) along with first-degree atrioventricular (AV) block, M-mode and pulsed Doppler echocardiography were used to evaluate the left ventricular systolic and diastolic function before and 1 month after surgical removal of the myxoma. End-diastolic left ventricular (LV) and left atrial diameters increased postsurgically from 47 to 51 mm and from 38 to 41 mm, respectively, while end-systolic LV remained unchanged. In the LV inflow pattern, peak early filling velocity (E) increased substantially (preoperative 31, postoperative 58 cm/sec), with no change in peak late filling velocity (A) (53 cm/sec), which gave a favorable E/A ratio (from 0.58 to 1.09). First-degree AV block resolved after tumor resection (PR interval: 0.23 vs 0.20 sec). Improved LV diastolic function associated with natural recovery from the myxoma was ascribed to the restoration of preload and recovery of systolic function. The results of this study show that removal of a large myxoma in the right atrium is important not only for preventing possible obstruction of the tricuspid orifice, eliminating pulmonary emboli, and maintaining systolic function, but also for restoring LV diastolic function.


Hormetic Effect of H2O2 in Saccharomyces cerevisiae: Involvement of TOR and Glutathione Reductase.
In this study, we investigated the relationship between target of rapamycin (TOR) and H2O2-induced hormetic response in the budding yeast Saccharomyces cerevisiae grown on glucose or fructose. In general, our data suggest that: (1) hydrogen peroxide (H2O2) induces hormesis in a TOR-dependent manner; (2) the H2O2-induced hormetic dose-response in yeast depends on the type of carbohydrate in growth medium; (3) the concentration-dependent effect of H2O2 on yeast colony growth positively correlates with the activity of glutathione reductase that suggests the enzyme involvement in the H2O2-induced hormetic response; and (4) both TOR1 and TOR2 are involved in the reciprocal regulation of the activity of glucose-6-phosphate dehydrogenase and glyoxalase 1.


Synthesis of Benzoisoselenazolone Derivatives by Nickel-Catalyzed Dehydrogenative Direct Selenation of C(sp2)-H Bonds with Elemental Selenium in Air.
Nickel-catalyzed direct selenation of benzamides bearing an 8-quinolyl auxiliary with elemental selenium provides benzoisoselenazolones in good yield via carbon-selenium and nitrogen-selenium bond formation under aerobic conditions. In addition to aryl C-H bonds, the method can also be applied to alkenyl C-H bonds, constructing an isoselenazolone skeleton. Simple mechanistic analysis shows that the reaction proceeds through a rate-determining C-H bond cleavage. The obtained benzoisoselenazolones are transformed into various organoselenium compounds and utilized as the catalyst for bromolactonization of alkenoic acids.


Veterans Living with HIV: A High-Risk Group for Cigarette Smoking.
The Veterans Health Administration is the largest U.S. medical provider for persons living with HIV (PLHIV). Although HIV and veteran status are known risk factors for smoking, there are no population estimates of smoking prevalence among veteran PLHIV. Using data from a national random sample (National Survey on Drug Use and Health; 2005-2014), smoking prevalence was estimated by self-reported veteran and HIV status (N = 376,620). Results indicated 42% of veteran PLHIV smoked daily, compared to 18% of veterans without HIV and 30% of non-veteran PLHIV. Findings suggest that veteran PLHIV have high risk for smoking and consequent poor health.


Occurrence, management and outcome of immune-complex glomerulonephritis in dogs with suspected glomerulopathy in the UK.
To determine the proportion of dogs diagnosed with immune-complex glomerulonephritis in a large cohort of UK dogs with clinical suspicion of glomerular disease in which renal histopathology, including routine light microscopy, transmission electron microscopy and immunofluorescence, had been performed. The second objective was to describe treatment and long-term clinical outcome of dogs diagnosed with immune-complex glomerulonephritis. Sixty-two UK dogs that underwent renal biopsies for investigation of suspected glomerulopathy (urine protein-to-creatinine ratio persistently >0.5) were included in this retrospective multicentre study. Signalment, clinico-pathological abnormalities, histopathological diagnosis, treatment following diagnosis and survival were recorded. Seventeen (27%) of the dogs with suspected glomerular disease were diagnosed with immune-complex glomerulonephritis and nine (53%) of these were still alive at the study end point, with a median follow-up of 366 days (range 52 to 1299). Six dogs diagnosed with immune-complex glomerulonephritis were treated with mycophenolate. Four received mycophenolate alone for immunosuppression and two received mycophenolate and chlorambucil; all these six dogs were alive at data collection [median follow-up time 712.5 days (range 73 to 1299)]. Seven dogs diagnosed with immune-complex glomerulonephritis did not receive immunosuppressive treatment; only one of these dogs was alive at study end point [median survival time 302 days (range 52 to 723)]. Immune-complex glomerulonephritis may be less common in the UK than previously reported in North America and mainland Europe, reducing the likelihood of treatment modification following renal biopsy. Mycophenolate was the most commonly used immunosuppressant for cases of immune-complex glomerulonephritis.


Nicotinamide inhibits inducible nitric oxide synthase enzyme activity in macrophages by allowing nitric oxide to inhibit its own formation.
Nitric oxide (NO) production by macrophages is mainly regulated by induction of nitric oxide synthase (iNOS) by cytokines and microbial products. Nicotinamide (NIC) inhibits NO production by activated macrophages in a dose dependent manner. NIC also inhibits NOS enzyme activity in extracts from activated macrophages. The inhibition was noncompetitive with L-arginine (Ki 13.37 +/- 4.40 mM, n=3), uncompetitive versus NADPH (Ki 3.06 +/- 0.17 mM, n=3) and tetrahydrobiopterin. Finally, the inhibition by nicotinamide was fully reversed by scavenging NO with hemoglobin. We suggest that NIC acts by allowing NO to inhibit its own formation.


Various conditioning methods for root canals influencing the tensile strength of titanium posts.
Conditioning the root canal is frequently advised to achieve high post-retention when resin composite luting cements are used. However, manufacturers' instructions for this purpose differ widely from one another. The aim of this study was to compare the tensile bond strengths of passive, tapered, titanium root posts that were luted with four different resin composite cements (Compolute Aplicap, Flexi-Flow cem, Panavia 21 EX, Twinlook) in the root canals at three conditions, namely (i) no conditioning, (ii) etching with 37% phosphoric acid, and (iii) etching + bonding agent application. Panavia 21 EX was further tested after using the primer for the post-surface according to the manufacturer's recommendations. The posts luted with zinc phosphate cement (Tenet) acted as the control group. Following endodontic preparation of 140 intact anterior teeth with hand instruments, the post-spaces were prepared using the opening drills of the corresponding size of the posts. The samples were first stored in water at 37 degrees C for 24 h and then thermocycled (5000 cycles, 5-55 degrees C, 30 s). The tensile strength values were measured with the universal testing machine at a crosshead speed of 0.5 mm min(-1). The data were analysed statistically using anova and corrected with Scheffé test due to the significance levels (P < 0.05). The tensile bond strengths of the titanium posts after luting with various cements and thermocycling were affected by the conditioning systems used for the root canals. Tensile bond strengths were the highest with Flexi-Flow (475 +/- 78 N) followed in descending order by Panavia 21 EX (442 +/- 97 N), Twinlook (430 +/- 78 N) and Compolute Aplicap (352 +/- 76 N) after conditioning the root canal. The use of primer on the post improved the tensile bond strength compared with the non-conditioned group for the Panavia 21 EX group (375 +/- 77 N) (P < 0.001). Tensile bond strengths obtained after luting the posts with zinc phosphate cement (414 +/- 102 N) were not significantly different (P < 0.05) than those of resin composite cements. Although the importance of conditioning the root canal was evident for Panavia 21 EX, it was not the case for the other luting cements tested.


Lethal effect of butylated hydroxyanisole as related to bacterial fatty acid composition.
Bacillus cereus, Clostridium perfringens, Staphylococcus aureus, Pseudomonas fluorescens, Pseudomonas fragi, Escherichia coli, and Salmonella "anatum" were challenged with butylated hydroxyanisole (BHA). Susceptibility was measured as the concentration of BHA required to cause a 90% reduction in bacterial survivors. Staphylococcus aureus LP and P. fragi were two of the most resistant species examined; C. perfringens and P. fluorescens were the most susceptible. Gram stain reaction was found not to be a strict indicator of bacterial susceptibility to BHA. There was no obvious relationship between individual fatty acids and susceptibility. The ratio of saturated to unsaturated fatty acids in the total lipid fraction of only the gram-positive species was related to susceptibility. The ratios of saturated to unsaturated fatty acids of other fractions were not related to susceptibility.


Emesis-related biochemical and histopathological changes induced by cisplatin in the ferret.
Cisplatin is an effective antineoplastic agent that causes severe vomiting due to unknown mechanism. The ferret, an animal model useful in the determination of emetic activity, was used to clarify the emesis-related biochemical and histopathological changes that were induced by cisplatin. Cisplatin (5 to 10 mg/kg) was administered intraperitoneally and a 7-10 mg/kg i.p. dose evoked dose-dependent emesis in the ferret. Almost all cisplatin-vomiting episodes occurred within a 6 hour observation period. All ferrets receiving cisplatin in this study died within 3-5 days. Significant increases in ileal mucosal levels of serotonin and norepinephrine were observed in cisplatin-treated ferrets. There were no significant changes in the levels of serotonin and dopamine in the gastric mucosa. Also, karyorrhexis was observed in the epithelial cells of the ileum and in the lymph follicles of the spleen of cisplatin-treated ferrets. These significant biochemical and pathological changes in the ileum may play an important role in cisplatin-induced emesis.


Alpha-methyldopa-induced autoimmune hemolytic anemia in the third trimester of pregnancy.
Alpha-methyldopa has been demonstrated to be safe for use during pregnancy and is now used to treat gestational hypertension. In pregnancy, alpha-methyldopa-induced autoimmune hemolytic anemia does not have typical features and the severity of symptoms ranges from mild fatigue to dyspnea, respiratory failure, and death if left untreated. A case of alpha-methyldopa-induced autoimmune hemolytic anemia in a 36-year-old gravida 2, para 1 woman at 37(+6) weeks of gestation is reported herein along with the differential diagnostic procedure and the potential risks to the mother and the fetus.


Ultrasonography-Based Thyroidal and Perithyroidal Anatomy and Its Clinical Significance.
Ultrasonography (US)-guided procedures such as ethanol ablation, radiofrequency ablation, laser ablation, selective nerve block, and core needle biopsy have been widely applied in the diagnosis and management of thyroid and neck lesions. For a safe and effective US-guided procedure, knowledge of neck anatomy, particularly that of the nerves, vessels, and other critical structures, is essential. However, most previous reports evaluated neck anatomy based on cadavers, computed tomography, or magnetic resonance imaging rather than US. Therefore, the aim of this article was to elucidate US-based thyroidal and perithyroidal anatomy, as well as its clinical significance in the use of prevention techniques for complications during the US-guided procedures. Knowledge of these areas may be helpful for maximizing the efficacy and minimizing the complications of US-guided procedures for the thyroid and other neck lesions.


Factors influencing long-term adherence to two previously implemented hospital guidelines.
After successful implementation, adherence to hospital guidelines should be sustained. Long-term adherence to two hospital guidelines was audited. The overall aim was to explore factors accounting for their long-term adherence or non-adherence. A fluid balance guideline (FBG) and body temperature guideline (BTG) were developed and implemented in our hospital in 2000. Long-term adherence was determined retrospectively based on data from patient files. Focus groups were launched to explore nurses' perceptions of barriers and facilitators regarding long-term adherence. The predominant themes from the nurses' focus groups were posed to clinicians in questionnaires. Nurses involved in the FBG (overall adherence 100%) stated that adherence has immediate advantages in terms of safety and a gain in time. Nurses and oncologists acted unanimously which was thought to enhance adherence. On the other hand, opinions differed on the BTG within the nursing teams and medical staff (overall adherence 50%). Although the guideline discourages routine postoperative body temperature measurements, temperature should be measured according to the guideline in a considerable number of cases due to changes in patient characteristics since the year 2000. Therefore, adherence was judged to be rather complex. To secure adherence to hospital guidelines after their successful implementation, guidelines should preferably be comprehensive in terms of being applicable to the majority of the patients in that particular setting and to the most common clinical situations. All healthcare professionals involved should be aware of its immediate benefits for themselves or to their patients.


[The well-being of dentists following a complaint procedure].
It is known that a patient's complaint can have a serious impact on the well-being of dentists. But little is known on the nature and the extent of this impact. That's why in 2013 an anonymous survey was conducted among 955 dentists and dental specialists, for whom in the period mid-2008 to mid-2013 a complaint was handled through the Complaint Committee of the Royal Dutch Dental Association (KNMT). Altogether, 413 (43%) of them participated in the study. 71% of the respondents reported that the complaint had influenced their professional practice. 52% reported that it had (also) influenced their attitude towards colleagues and patients, and 60% (also) experienced an impact on their mental and/or physical condition. Altogether, 68% reported that they had unpleasant feelings and 75% stated that the treatment relationship with the patient was terminated as a result of the complaint.


Effect of gene conversion on polymorphic patterns at major histocompatibility complex loci.
The pattern of polymorphisms at MHC loci was studied by computer simulations and by DNA sequence analyses, with special reference to synonymous and non-synonymous divergence among alleles. A model of overdominance plus short-term selection was simulated for a gene family with allelic and non-allelic gene conversion. It was found that the ratio of non-synonymous-to-synonymous divergence among alleles decreases as the non-allelic conversion becomes more frequent. On the other hand, the ratio of synonymous divergence at the antigen recognition site to that at non-coding region increases by non-allelic conversion. By comparing such a pattern with the observed values of mammalian genes, it is suggested that non-allelic conversion is less frequent in human genes than in genes of other mammals. A quantitative analysis on the patchwork pattern was attempted by using identity excess among nucleotide sites of a gene. Comparison of simulation results with DNA data analysis shows that the rate of allelic conversion is high.


Construction and Validation of a Newly Prognostic Signature for CRISPR-Cas9-Based Cancer Dependency Map Genes in Breast Cancer.
Cancer Dependency Map (CDM) genes comprise an extensive series of genome-scale RNAi-based loss-of-function tests; hence, it served as a method based on the CRISPR-Cas9 technique that could assist scientists in investigating potential gene functions. These CDM genes have a role in tumor cell survival and proliferation, suggesting that they may be used as new therapeutic targets for some malignant tumors. So far, there have been less research on the involvement of CDM genes in breast cancer, and only a tiny percentage of CDM genes have been studied. In this study, information of patients with breast cancer was extracted from The Cancer Genome Atlas (TCGA), from which differentially expressed CDM genes in breast cancer were determined. A variety of bioinformatics techniques were used to assess the functions and prognostic relevance of these confirmed CDM genes. In all, 290 CDM genes were found differentially expressed. Six CDM genes (SRF, RAD51, PMF1, EXOSC3, EXOC1, and TSEN54) were found to be associated with the prognosis of breast cancer samples. Based on the expression of the identified CDM genes and their coefficients, a prognosis model was constructed for prediction, according to which patients with breast cancer were separated into two risk groups. Those with high risk had substantially poorer overall survival (OS) than patients in the other risk group in the TCGA training set, TCGA testing set, and an external cohort from Gene Expression Omnibus (GEO) database. The area under the receiver operating characteristic (ROC) curve for this prognostic signature was, respectively, 0.717 and 0.635 for TCGA training and testing sets, demonstrating its reliability in predicting the prognosis of patients with breast cancer. We next created a nomogram using the six CDM genes discovered to create a therapeutically useful model. The Human Protein Atlas database was used to acquire all immunohistochemistry staining images of the discovered CDM genes. The proportions of tumor-infiltrating immune cells, as well as the expression levels of checkpoint genes, varied substantially between the two risk groups, according to the analyses of immune response. In conclusion, the findings of this research may aid in the understanding of the prognostic value and biological roles of CDM genes in breast cancer.


Nucleon Matrix Elements of the Antisymmetric Quark Tensor.
If physics beyond the standard model enters well above the electroweak scale, its low-energy effects are described by standard model effective field theory. Already, at dimension 6, many operators involve the antisymmetric quark tensor q[over ¯]σ^{μν}q, whose matrix elements are difficult to constrain from experiment, Ward identities, or low-energy theorems, in contrast to the corresponding vector and axial-vector or even scalar and pseudoscalar currents. However, with normalizations determined from lattice QCD, analyticity and unitarity often allow one to predict the momentum dependence in a large kinematic range. Starting from recent results in the meson sector, we extend this method to the nucleon case and, in combination with pole dominance, provide a comprehensive assessment of the current status of the nucleon form factors of the quark tensor.


Irreversible desensitization of ATP responses in developing chick skeletal muscle.
1. In developing chick skeletal muscle, extracellular adenosine 5'-triphosphate (ATP) elicits an early excitatory conductance increase followed by a late potassium conductance increase. Both of these responses desensitize profoundly. Intracellular recordings and whole-cell voltage-clamp recordings were made in order to examine the time course and mechanism of desensitization and the recovery from desensitization. 2. Most of the loss of responsiveness to ATP occurred during the first minute of exposure to ATP. For the excitatory conductance, the loss of responsiveness to ATP resulted in part from long-lasting activation of the ATP-sensitive channels and in part from entrance into an inactive (non-conducting) state. In contrast, desensitization of the potassium conductance was entirely the result of a relatively fast transition to an inactive state. 3. Recovery from desensitization took many hours for both responses and was quite sensitive to temperature. 4. Recovery from desensitization for both responses was prevented by preincubation with the glycosylation inhibitor, tunicamycin. Several lines of evidence suggest that tunicamycin treatment blocked the delivery of new ATP receptors to the cell surface. 5. The recovery of the early response to ATP following exposure to two non-competitive inhibitors of the ATP response was also examined. These two compounds are thought to covalently modify the receptor. After exposure to either of these inhibitors, responsiveness to ATP returned over a time course that was similar to the time course of recovery from desensitization. 6. These results indicate that, following activation, ATP receptors do not become available for reactivation, and that recovery from desensitization is due to the insertion of newly synthesized receptors into the plasma membrane.


Enhanced Extracellular Matrix Deposition on Titanium Implant Surfaces: Cellular and Molecular Evidences.
The surface structure of the titanium dental implants can modulate the activity of mesenchymal stem cells in order to promote the upregulation of osteoblastic related genes and the release of extracellular matrix (ECM) components. The present work was focused on the in vitro evaluation of the interaction of human periodontal ligament stem cells (hPDLSCs) and two different implant titanium surfaces topography (CTRL and TEST). This study was aimed at analyzing the cytotoxicity of the dental implant surfaces, the cellular adhesion capacity, and the improvement in the release of ECM molecules in an in vitro model. These parameters were carried out by means of the microscopic evaluation, viability assays, immunofluorescence, Western blot and RT-PCR investigations. The knowledge of the cell/implant interaction is essential for implant healing in order to obtain a more performing surfaces that promote the ECM release and provide the starting point to initiate the osseointegration process.


PEO-PPO-PEO-based poly(ether ester urethane)s as degradable reverse thermo-responsive multiblock copolymers.
Aiming at developing biodegradable thermo-responsive polymers that display enhanced rheological properties, a family of PEO-PPO-PEO based poly(ether ester urethane)s, was developed. The materials were produced following a two-step synthetic pathway. The PEO-PPO-PEO triblocks were first end-capped with LA or CL oligo(ester)s whereby pentablocks were produced. Then, the different precursors were chain extended using hexamethylene diisocyanate to create the respective polymers. The length and type of the ester block influenced the behavior of the molecules in water, especially their viscosity versus temperature response. The gelation temperature increased from 23 degrees C for a 20wt% F127 solution to 26 and 31 degrees C for pentablocks with 4.4 and 7.5 lactoyl units, respectively. Materials containing longer LA units failed to show any reverse thermo-responsiveness. The presence of the oligo(ester) blocks also reduced the viscosity of the gel at 37 degrees C. While F127 displayed a viscosity of around 28,000Pas, pentablocks containing 4.4 and 7.5 LA units showed values of 15,400 and 12,600Pas. Also, the viscosity at 37 degrees C as well as the gelation temperature decreased as the molecular weight of the oligo(ester)s increased. Finally, the degradation process of the gels was studied by monitoring their viscosity at body temperature and determining the molecular weight of the polymers, over time. Polymers were tailored so to combine high initial viscosity values with diverse degradation rates, as a function of the length and type of the oligo(ester) present along the polymeric backbone.


Deletion of Alu sequences in the fifth c-sis intron in individuals with meningiomas.
An abnormality in the c-sis protooncogene was identified in leukocyte DNA from members of a family predisposed to the development of meningioma, and was found to be associated with the development of the tumor in those individuals. Molecular analysis of this abnormality demonstrated a deletion within the fifth intron of the c-sis gene. The normal c-sis gene has an Alu sequence in this region which includes two perfect 130 nucleotide repeated sequences separated by 5 bp. The deleted c-sis allele is missing precisely one copy of the 130 bp repeat and the intervening 5 bp. An identical deletion was also found in DNA from 1 of 13 sporadic meningiomas.


[Congenital intrapulmonary lymphangioma and pulmonary hemangioma in 5 infants and young children].
To analyze the clinical, imaging and pathological findings of congenital intrapulmonary lymphangioma and hemangioma in 5 infants and young children. Data of 3 cases with congenital intrapulmonary lymphangioma and 2 cases with haemangioma were analyzed. All the 5 cases had cough, difficulty in breathing, cyanosis of lips, and shortness of breath. Imaging study indicated cystic and space occupying changes of partial lung. In the two cases of hemangioma, the blood vessels passing through the hemangioma were observed on CT films. Histochemical studies showed that the cystic pockets from removed tissues were different in size and there was a line of flat endothelial tissue around these pockets. Immunochemical studies indicated D2-40 positive, factor VIII weak positive for lymphangioma cases; while in hemangioma cases, factor VIII was positive, D2-40 was negative or weakly positive, and both of cytokeratin was negative. It is very important to consider and identify congenital intrapulmonary lymphangioma or hemangioma when a patient has cystic pockets and space occupying change in their lung by imaging and pathological studies.


Clinico-pathologic function of cerebral ABC transporters - implications for the pathogenesis of Alzheimer's disease.
In recent years it has become evident that ABC transporters fulfill important barrier functions in normal organs and during disease processes. Most importantly, resistance to drugs in cancer cells led to intense oncological and pharmacological investigations in which researchers were able to highlight important pharmacological interactions of chemotherapeuticals with ABC transporter function. Recently, the development of neurodegenerative diseases and the maintenance of neuronal stem cells have been linked to the activity of ABC transporters. Here, we summarize findings from cell culture experiments, animal models and studies of patients with Alzheimer's disease. Furthermore, we discuss pharmacological interactions and computational methods for risk assessment.


Dealing With Brain MRI Findings in Pediatric Patients With Endocrinological Conditions: Less Is More?
Neuroimaging is a key tool in the diagnostic process of various clinical conditions, especially in pediatric endocrinology. Thanks to continuous and remarkable technological developments, magnetic resonance imaging can precisely characterize numerous structural brain anomalies, including the pituitary gland and hypothalamus. Sometimes the use of radiological exams might become excessive and even disproportionate to the patients' medical needs, especially regarding the incidental findings, the so-called "incidentalomas". This unclarity is due to the absence of well-defined pediatric guidelines for managing and following these radiological findings. We review and summarize some indications on how to, and even if to, monitor these anomalies over time to avoid unnecessary, expensive, and time-consuming investigations and to encourage a more appropriate follow-up of brain MRI anomalies in the pediatric population with endocrinological conditions.


Integrative medicine consultation service in a comprehensive cancer center: findings and outcomes.
This study portrays the characteristics of patients who attended an integrative oncology clinic at a large comprehensive cancer center and evaluated whether this service addressed patients' concerns about complementary and integrative medicine (CIM). Patient information was collected prior to an integrative consultation, including demographics, previous use of CIM, and primary reason for requesting the consultation. Concerns and outcomes were measured using the Measure Yourself Concerns and Well-being (MYCaW) Scale at the consultation and then again at follow-up (6-12 weeks later). Patients met with a physician for an integrative consultation that included a discussion of nutrition, supplements, physical activity, useful complementary therapies, and the mind-body-spirit connection. A total of 238 patients were referred for consultation regarding the integration of CIM into their care. The majority of participants were female (60%, n = 143), and the mean age was 56 years (range, 21-90 years), with all major cancer types represented. Patients' leading concerns were related to "What else can I do?" and "How can I better cope?" Although distressed over these concerns at the initial consultation, intense distress (5-6 out of 6 on the MYCaW scale) was reduced to less than half (31%) by the follow-up visit. Additional qualitative data revealed that patients value the process of obtaining reliable information that empowers them to be more involved in managing their care. Integrative medicine consultations at a large comprehensive cancer center appear to provide some benefit in addressing patients' concerns about CIM use.


α1-adrenergic receptor antagonists versus placebo for female lower urinary tract symptoms: A meta-analysis.
The aim of the present study was to evaluate the effectiveness of α1-adrenergic receptor antagonists (α1ARAs) versus placebo for female patients with lower urinary tract symptoms (LUTS). A meta-analysis of randomized controlled trials was conducted. The main outcome indices used to measure the effectiveness were the total International Prostate Symptom Score (I-PSS) and maximum urinary flow rate of female patients receiving treatment for LUTS. The I-PSS quality of life (QOL) and average urinary flow rate (AFR) were also observed and analyzed. Two randomized controlled trials with a total of 213 patients were included. Meta-analysis results were as follows: Following 4 weeks of treatment, patients taking α1ARAs presented a significant advantage over patients under placebo in terms of total I-PSS [standardized mean difference (SMD), -0.67; 95% confidence interval (CI), -0.94 to -0.39] but no difference was observed in maximum urinary flow rate (SMD, -0.05; 95% CI, -0.32 to 0.22) between the experimental and control groups. The I-PSS QOL post-treatment was lower in the α1ARA group compared with that in the placebo group (SMD, -0.86; 95% CI, -1.32 to -0.40) according to one study, and in the other study the improvement of AFR was not significant (SMD, 0.09; 95% CI, -0.25 to 0.43). It was concluded that α1ARAs are more effective than placebo in female patients with LUTS.


Ablation Versus Antiarrhythmic Drugs as First-Line Therapy for Treatment-Naive Atrial Fibrillation: Systematic Review and Meta-Analysis.
Evidence on the relative safety and efficacy of atrial fibrillation catheter ablation and antiarrhythmic drugs (AADs) as the first-line therapy for patients with treatment-naive atrial fibrillation (AF) remains disputed. Digital databases were queried to identify relevant randomized controlled trials. The incidence of recurrent AF, major adverse cardiovascular events, and its components (all-cause death, nonfatal stroke, and bleeding) were compared using the DerSimonian and Laird method under the random-effects model to calculate pooled unadjusted risk ratio (RR) with 95% confidence intervals (CIs). A total of 6 randomized controlled trials consisting of 1,120 patients (574 ablation and 549 AADs) were included in the final analysis. Over a median follow-up of 1 year, the risk of any AF recurrence (RR 0.54, 95% CI 0.39 to 0.75) was significantly lower in patients receiving ablation than in patients receiving AADs. However, there was similar risk of major adverse cardiovascular events (RR 2.65, 95% CI 0.61 to 11.46), trial-defined composite end point of adverse events (RR 0.71, 95% CI 0.28 to 1.80), stroke (RR 2.42, 95% CI 0.22 to 26.51), all-cause mortality (RR 1.98, 95% CI 0.28 to 13.90), and procedure/medication failure (RR 2.65, 95% CI 0.61 to 11.46) with both therapies. In conclusion, in patients presenting with treatment-naive AF, ablation as a first-line therapy lowers the risk of AF recurrence with no associated increase in major adverse events, stroke, and mortality compared with AADs.


A comparison of applanation tonometry using conventional reusable goldmann prisms and disposable prisms.
To determine the agreement between intraocular pressure (IOP) measurements using conventional Goldmann applanation tonometry (GAT) and Tonosafe disposable prisms, and also to provide a comprehensive cost analysis of the use of both types of prisms : In this prospective observational study, 198 eyes of 100 glaucoma patients had their IOPs measured by 5 consultant ophthalmologists. Data were analyzed using the Bland-Altman method of differences, and correlation was measured using the Pearson coefficient. An analysis of the cost incurred using the 2 methods over a 6-month period was performed. The majority were Chinese (82%), with a male preponderance (57%). The range of IOPs as measured by GAT was 4 to 34 mm Hg. Using the Bland-Altman method to compare GAT and disposable prisms, the bias was 0.2 mm Hg. Tonosafe overestimated the IOP by 0.2 mm Hg in the right eye and underestimated it by 0.2 mm Hg in the left eye. The Tonosafe IOP correlated well with GAT, with a Pearson coefficient of correlation(r) of 0.91 (P<0.0005) for the right eye and 0.92 (P<0.0005) for the left eye, respectively. For those with GAT IOP≥21 mm Hg (n=26), Tonosafe underestimated the IOP by 0.35 mm Hg. The cost incurred by Tonosafe prisms was approximately 8 times that of GAT, but the cost differential reverses when GAT had to be replaced after every 100 cycles of disinfection. We found a good correlation between Tonosafe prisms and conventional GAT in measuring the IOP. Tonosafe prisms may be of use, especially if the risk of transmission of infection is high. However, cost may limit its more widespread use.


On the structure and physical origin of the interaction in H(2) ... Cl(-) and H(2) ... Br(-) van der Waals anion complexes.
The ab initio three-dimensional potential energy surface (PES) for the weak interaction of hydrogen molecule with bromine anion is presented. The surface was obtained by the supermolecular method at the coupled cluster with single and double excitations and noniterative correction to triple excitations (CCSD(T)) level of theory. Our calculations indicate the van der Waals (vdW) system for the linear orientation at R=3.37 A with a well depth of D(e)=660.1 cm(-1). The presented PES reveals also transition state for the perpendicular orientation at R=4.22 A with a barrier of 607.1 cm(-1). The physical origin of the stability of vdW H(2) ... Br(-) structure with respect to the H(2) ... Cl(-) one was analyzed by the symmetry adapted perturbation theory based on the single determinant Hartree-Fock (HF) wave function. The separation of the interaction energy shows that the dispersion forces play slightly more important role in the stabilization of the vdW system with Br(-) than with Cl(-).


Surfactant treatment for acute respiratory distress syndrome.
To determine prospectively the efficacy of surfactant in acute respiratory distress syndrome. Twenty patients, 1 month to 16 years of age, diagnosed with an acute pulmonary disease with severe hypoxaemia (PaO2/FiO2 < 100) (13 with systemic or pulmonary disease and seven with cardiac disease) were treated with one to six doses of 50-200 mg/kg of porcine surfactant administered directly into the trachea. The surfactant was considered to be effective when the PaO2/FiO2 improved by > 20%. After initial surfactant administration the PaO2/FiO2 increased significantly in patients with systemic or pulmonary disease from 68 to 111, and the oxygenation index (OI) diminished significantly from 36.9 to 27.1. The PaO2/FiO2 and OI did not improve in children with cardiac disease. The improvement of the patients who survived was greater than that of those who died. Surfactant moderately improves oxygenation in some children with severe acute respiratory distress syndrome secondary to pulmonary or systemic disease.


Evaluating susceptibility of karst dolines (sinkholes) for collapse in Sango, Tennessee, USA.
Dolines or sinkholes are earth depressions that develop in soluble rocks complexes such as limestone, dolomite, gypsum, anhydrite, and halite; dolines appear in a variety of shapes from nearly circular to complex structures with highly curved perimeters. The occurrence of dolines in the studied karst area is not random; they are the results of geomorphic, hydrologic, and chemical processes that have caused partial subsidence, even the total collapse of the land surface when voids and caves are present in the bedrock and the regolith arch overbridging these voids is unstable. In the study area, the majority of collapses occur in the regolith (bedrock cover) that bridges voids in the bedrock. Because these collapsing dolines may result in property damage and even cause the loss of lives, there is a need to develop methods for evaluating karst hazards. These methods can then be used by planners and practitioners for urban and economic development, especially in regions with a growing population. The purpose of this project is threefold: 1) to develop a karst feature database, 2) to investigate critical indicators associated with doline collapse, and 3) to develop a doline susceptibility model for potential doline collapse based on external morphometric data. The study has revealed the presence of short range spatial dependence in the distribution of the dolines' morphometric parameters such as circularity, the geographic orientation of the main doline axes, and the length-to-width doline ratios; therefore, geostatistics can be used to spatially evaluate the susceptibility of the karst area for doline collapse. The partial susceptibility estimates were combined into a final probability map enabling the identification of areas where, until now, undetected dolines may cause significant hazards.


Designing voriconazole treatment for racing pigeons: balancing between hepatic enzyme auto induction and toxicity.
Aspergillosis is a major cause of mortality in captive birds and its prognosis is often poor due to treatment failure. Voriconazole is a novel triazole antifungal agent that may be useful for the treatment of this infection in birds as it has shown promise in other animal models of the disease. We examined the pharmacokinetic behaviour of voriconazole in racing pigeons (Columbia livia forma domestica). Intravenous, oral and aerosol administration were investigated in single (10 mg/kg BW PO; 10, 5, 2.5 mg/kg BW IV), multiple dose (10, 20 mg/kg BW PO q12h, q24h) and nebulization (15 min, 10 mg/ml NaCl 0.9%) experiments. Quantitative measurements of voriconazole in plasma, as well as in lung tissue, collected at several time points, were done with a validated high performance liquid chromatography method using ultraviolet detection. Designing a treatment schedule with voriconazole is complicated by dose-dependent pharmacokinetics and induction of its biotransformation. Moreover, hepatic changes were seen in the oral multiple dose regimen at 10 and 20 mg/kg BW twice a day. Taking all features into account our study suggests that the oral dosage schedules of 10 mg/kg BW twice a day or 20 mg/kg BW once a day could be most appropriate in treating pigeons with aspergillosis.


Compost feedstock characteristics and ratio modelling for organic waste materials co-composting in Malaysia.
In Malaysia, large amounts of organic materials, which lead to disposal problems, are generated from agricultural residues especially from palm oil industries. Increasing landfill costs and regulations, which limit many types of waste accepted at landfills, have increased the interest in composting as a component of waste management. The objectives of this study were to characterize compost feedstock properties of common organic waste materials available in Malaysia. Thus, a ratio modelling of matching ingredients for empty fruit bunches (EFBs) co-composting using different organic materials in Malaysia was done. Organic waste materials with a C/N ratio of < 30 can be applied as a nitrogen source in EFB co-composting. The outcome of this study suggested that the percentage of EFB ranged between 50% and 60%, which is considered as the ideal mixing ratio in EFB co-composting. Conclusively, EFB can be utilized in composting if appropriate feedstock in term of physical and chemical characteristics is coordinated in the co-composting process.


Positron Emission Tomography Imaging of Platelet-Derived Growth Factor Receptor β in Colorectal Tumor Xenograft Using Zirconium-89 Labeled Dimeric Affibody Molecule.
Platelet-derived growth factor receptor β (PDGFRβ) is overexpressed in a variety of malignant cancers, plays a critical role in tumor angiogenesis, and has been proven as a valuable target for cancer treatment. In this pilot study, a dimeric affibody molecule, ZPDGFRβ, was prepared and radiolabeled with positron emission radionuclide zirconium-89 for PET imaging of colorectal tumors by targeting PDGFRβ expression in vivo. The PDGFRβ-binding capability of dimeric affibody was evaluated by flow cytometry, immunofluorescent staining, and whole-body optical imaging. Then, ZPDGFRβ was conjugated with DFO-Bn-NCS and radiolabeled with 89Zr. Targeted binding capability of 89Zr-DFO-ZPDGFRβ to PDGFRβ expressing cells was investigated by cellular assay in vitro and microPET/CT imaging in vivo. Dimeric ZPDGFRβ affibody had specifically higher binding capability with PDGFRβ expressing pericytes rather than LS-174T cancer cells, and well colocalized with tumor neovasculature by flow cytometry and immunofluorescent assay. ZPDGFRβ was successfully labeled with 89Zr by DFO chelating with yield of 94.1 ± 3.53%. 89Zr-DFO-ZPDGFRβ indicated preserved specific binding ability with PDGFRβ expressing cells and effective inhibiting capability to PDGF-β ligands ( P < 0.05) in vitro. Biodistribution indicated that tumor uptake of 89Zr-DFO-ZPDGFRβ reached the peak of 6.93 ± 0.64%ID/g, and the tumor-to-blood ratio was 5.5 ± 0.6 at 2 h post-injection. LS-174T xenografts were clearly visualized by microPET/CT imaging through 1 to 4 h post-injection of 89Zr-DFO-ZPDGFRβ affibody conjugate. In conclusion, the 89Zr-DFO-ZPDGFRβ conjugate demonstrated specific and high binding ability with colorectal tumor, which indicated its use as a potential radiopharmaceutical for diagnostic imaging of tumor associate vasculatures with PET/CT.


Updates and Controversies of Robotic-Assisted Surgery in Gynecologic Surgery.
minimally invasive surgery (MIS) is the standard approach to performance of several gynecologic procedures, including hysterectomy, gynecologic cancer staging procedures, myomectomy, pelvic organ prolapse repair, and select adnexal procedures. Robotic-assisted surgery, a computer-based MIS approach, has been adopted widely in the United States and several other countries. Robotics may offer technological and ergonomic benefits that overcome limitations associated with conventional laparoscopy; however, it is not clear that reported claims of superiority translate into improved gynecologic patient outcomes compared with other MIS approaches. This review critically appraises the evolving role, benefits, limitations, and controversies of robotic-assisted surgery utilization in benign and oncologic gynecology settings.


Histone 2B (H2B) expression is confined to a proper NAD+/NADH redox status.
S-phase transcription of the histone 2B (H2B) gene is dependent on Octamer-binding factor 1 (Oct-1) and Oct-1 Co-Activator in S-phase (OCA-S), a protein complex comprising glyceraldehyde-3-phosphate dehydrogenase and lactate dehydrogenase (p38/GAPDH and p36/LDH) along with other components. H2B transcription in vitro is modulated by NAD(H). This potentially links the cellular redox status to histone expression. Here, we show that H2B transcription requires a proper NAD(+)/NADH redox status in vitro and in vivo. Therefore, perturbing a properly balanced redox impairs H2B transcription. A redox-modulated direct p38/GAPDH-Oct-1 interaction nucleates the occupancy of the H2B promoter by the OCA-S complex, in which p36/LDH plays a critical role in the hierarchical organization of the complex. As for p38/GAPDH, p36/LDH is essential for the OCA-S function in vivo, and OCA-S-associated p36/LDH possesses an LDH enzyme activity that impacts H2B transcription. These studies suggest that the cellular redox status (metabolic states) can directly feedback to gene switching in higher eukaryotes as is commonly observed in prokaryotes.


Structure-based DNA-targeting strategies with small molecule ligands for drug discovery.
Nucleic acids are the molecular targets of many clinical anticancer drugs. However, compared with proteins, nucleic acids have traditionally attracted much less attention as drug targets in structure-based drug design, partially because limited structural information of nucleic acids complexed with potential drugs is available. Over the past several years, enormous progresses in nucleic acid crystallization, heavy-atom derivatization, phasing, and structural biology have been made. Many complicated nucleic acid structures have been determined, providing new insights into the molecular functions and interactions of nucleic acids, especially DNAs complexed with small molecule ligands. Thus, opportunities have been created to further discover nucleic acid-targeting drugs for disease treatments. This review focuses on the structure studies of DNAs complexed with small molecule ligands for discovering lead compounds, drug candidates, and/or therapeutics.


Does Availability of Worksite Supports for Physical Activity Differ by Industry and Occupation?
To explore combinations of worksite supports (WSS) for physical activity (PA) that may assist employees in meeting PA recommendations and to investigate how availability of WSS differs across industries and occupations. Cross-sectional. Several Missouri metropolitan areas. Adults employed >20 h/wk outside the home. Survey utilized existing self-reported measures (eg, presence of WSS for PA) and the International Physical Activity Questionnaire. Logistic regression was conducted for 2 outcome variables: leisure and transportation PA. Independent variables included 16 WSS. Of particular interest were interaction effects between WSS variables. Analyses were stratified by 5 occupation and 7 industry types. Overall, 2013 people completed the survey (46% response rate). Often, availability of 1 WSS did not increase the likelihood of meeting PA recommendations, but several pairs of WSS did. For example, in business occupations, the odds of meeting PA recommendations through transportation PA increased when employees had access to showers and incentives to bike/walk (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.16-2.22); showers and maps (OR = 1.25; 1.02-1.55); maps and incentives to bike/walk (OR = 1.48; 1.04-2.12). Various combinations of WSS may increase the likelihood that employees will meet PA recommendations. Many are of low or no cost, including flexible time for exercise and maps of worksite-adjacent walk/bike routes. Findings may be instructive for employers seeking to improve employee health through worksite PA.