Laparoscopic radical cystectomy for muscle-invasive bladder cancer: pathological and oncological outcomes.
Open radical cystectomy (ORC) has been the mainstay of treatment for invasive bladder cancer for decades and remains the standard by which new treatments are judged. Despite improvements in technique and perioperative care, the development of effective perioperative chemotherapy, continent urinary diversion, and extending the limits of pelvic lymphadenectomy, an estimated 35-50% of patients will die from progressive cancer. Likewise, the impact of RC on the patient in terms of treatment-related morbidity and health-related quality of life is substantial. Laparoscopic RC (LRC) offers patients the potential of decreased morbidity and quicker convalescence, while maintaining oncological efficacy by recapitulating the open technique. We and others have investigated this procedure in selected patients with invasive bladder cancer, with slow and measured progress. We favour an open-assisted approach, performing the urinary diversion through a small midline incision. Preliminary comparative data suggest that open-assisted LRC is associated with reduced blood loss and transfusion requirements and it might improve convalescence. These results are achieved while being comparable with ORC for postoperative complications, positive soft-tissue margin rates, and lymph node counts. This procedure is difficult to learn, and ideally it should be restricted to patients with clinically organ-confined cancers, and carried out by surgeons with extensive experience in pelvic laparoscopic procedures. Randomized trials are necessary to determine if the results achieved with LRC are equivalent to those of ORC.


[Simultaneous determination of cellular DNA and proteins by cytofluorimetry. Application to acute leukemia in adults].
DNA and proteins of ethanol fixed cells are simultaneously analysed by cytofluorimetry in 35 cases of adult acute leukemias. DNA is coloured by propidium iodide and proteins by FITC. These technics allow to know the GO/G1, S, G2 + M cell-cycle phases and the protein cell content for each phase. We also can evaluate the fraction of low protein content cells (LPC fraction) that seems to be the GO and early G1 fraction. A good correlation exists between the percentage of S phase cells and the LPC fraction. This parameter, because of its important dispersion, must have a better discriminating value than S phase, especially for the prognosis analysis. Furthermore acute myeloid leukemias have a protein content that varies with the cytological maturation. Therefore, P1 + FITC colorations would give quantitative criteria for the acute leukemias cytological analysis and their prognostic valuation.


Risk of Febuxostat-Associated Myopathy in Patients with CKD.
Febuxostat, a nonpurine xanthine oxidase inhibitor, is widely used to treat hyperuricemia. Although febuxostat-associated rhabdomyolysis was reported in some patients with CKD, the association between CKD and febuxostat-associated myopathy remains uncertain. Our retrospective cohort study included 1332 patients using febuxostat in Taipei Medical University-Wanfang Hospital from February of 2014 to January of 2016. The primary predictor was time-averaged eGFR as calculated by the equation proposed by the 2009 Chronic Kidney Disease Epidemiology Collaboration. The outcome was febuxostat-associated myopathy defined as elevated creatine kinase levels during febuxostat use that were not attributed to other muscular injuries. The median duration of febuxostat use was 224 days (25th, 75th percentiles: 86, 441.5 days). Of 1332 study participants, 1222 (91.7%) had CKD; the median eGFR was 20.8 ml/min per 1.73 m2 (25th, 75th percentiles: 9.0, 35.4 ml/min per 1.73 m2). Forty-one of the participants had febuxostat-associated myopathy (3.2%). All patients with myopathy had CKD, and the incident rate was 0.013 (95% confidence interval, 0.01 to 0.02) events per 100 patient-days in patients with CKD. Of 41 patients with myopathy, 37 had myositis, and four had rhabdomyolysis. Myopathy resolved in 17 patients who withdrew from treatment and eight patients who continued febuxostat treatment. Among the evaluated predictors, multivariate analysis showed that only the lowest eGFR tertile was significantly associated with myopathy in febuxostat users. The odds ratio of the lowest eGFR tertile to the highest tertile was 4.21 (95% confidence interval, 1.7 to 10.43). This finding remained consistent among subgroups stratified by age, sex, diabetes status, coronary artery disease, and statin or fibrate use. Patients with severely reduced eGFR had higher risk of myopathy with treatment of febuxostat. Regular monitoring of creatine kinase level is suggested for early detection of febuxostat-associated myopathy, particularly in patients with CKD.


Common Occupational Disability Tests and Case Law References: An Ontario MVA perspective on interpretation and best practice methodology supporting a holistic model, Part I of III (Pre-104 IRB).
This three-part paper presents practical holistic models of determining impairment and occupational disability with respect to common "own occupation" and "any occupation" definitions. The models consider physical, emotional and cognitive impairments in unison, and draw upon case law support for empirically based functional assessment of secondary cognitive symptoms arising from psychological conditions, including chronic pain disorders. Case law is presented, primarily in the context of Ontario motor vehicle accident legislation, to demonstrate how triers of fact have addressed occupational disability in the context of chronic pain; and interpreted the "own occupation" and "any occupation" definitions. In interpreting the definitions of "own occupation" and "any occupation", courts have considered various concepts, such as: work as an integrated whole, competitive productivity, demonstrated job performance vs. employment, work adaptation relative to impairment stability, suitable work, retraining considerations, self-employment, and remuneration/socio-economic status. The first segment of the paper reviews the above concepts largely in the context of pre-104 Income Replacement Benefit (IRB) entitlement, while the second segment focuses on post-104 IRB entitlement. In the final segment, the paper presents a critical evaluation of computerized transferable skills analysis (TSAs) in the occupational disability context. By contrast, support is offered for the notion that (neuro) psychovocational assessments and situational work assessments should play a key role in "own occupation" disability determination, even where specific vocational rehabilitation/retraining recommendations are not requested by the referral source (e.g., insurer disability examination).


Metabolic inhibition of Peptostreptococcus anaerobius decreases the bactericidal effect of hydrogen peroxide.
Peptostreptococcus anaerobius VPI 4330-1 was tested under various conditions for examination of the bactericidal effect of hydrogen peroxide. The cells were most rapidly killed by hydrogen peroxide when they were in the exponential-growth phase. Cooling or starving the cells decreased the bactericidal effect of hydrogen peroxide. The ionophore nigericin and the metal ion chelating agent 2,2'-bipyridine stopped macromolecular syntheses and greatly decreased the bactericidal effect of hydrogen peroxide. The ionophore valinomycin and the glycolytic inhibitor iodoacetate also stopped the syntheses of the macromolecules but only slightly decreased the bactericidal effect of hydrogen peroxide. Novobiocin, an inhibitor of deoxyribonucleic acid gyrase, and chloramphenicol, an inhibitor of protein synthesis, were not able to decrease the bactericidal effect of hydrogen peroxide. These findings implicate metal ions and an active metabolism of the organism in the bactericidal effect of hydrogen peroxide.


Induction by cholera toxin of synchronous divisions in vivo in the epidermis resulting in hyperplasia.
Intracutaneous injection of cholera toxin, exotoxin of Vibrio cholerae, into the dorsal skin of mice, rats, and hamsters at doses of greater than 0.1 ng evoked an acute reaction at the site of injection, which was characterized histologically by an edematous reaction in the dermis and mitotic stimulation in the epidermis. Mitotic and labeling induces of basal cells of the mouse epidermis showed two peaks at 24 and 48 hr after injection, thereby producing epidermal hyperplasia. The thickness of the intrafollicular epidermis increased progressively from 32 hr after toxin injection, being greatest on day 4 and decreasing to normal on day 7. The epidermis on day 4 after injection of 1.0 ng of toxin was about 4- to 6-fold thicker than normal or phosphate buffer-treated control skin. This sequence of events indicated that cholera toxin induced two successive synchronous divisions of the epidermal cells and produced temporary hyperplasia without interfering with epidermal differentiation. The complete structure and function of the cholera toxin are required for induction of epidermal hyperplasia: no mitotic stimulation was induced by injection of the A and B units of the cholera toxin molecule or by preincubation of the toxin with anti-cholera toxin antibody and with the membrane receptor, GM1 ganglioside. Five other agents known to increase the level of intracellular cyclic AMP by different means (dibutyryl cyclic AMP, 3-isobutyl-1-methylxanthine, theophylline, isoproterenol, and prostaglandin E1) did not produce a skin reaction.


A novel full-angle scanning light scattering profiler to quantitatively evaluate forward and backward light scattering from intraocular lenses.
Glare, glistenings, optical defects, dysphotopsia, and poor image quality are a few of the known deficiencies of intraocular lenses (IOLs). All of these optical phenomena are related to light scatter. However, the specific direction that light scatters makes a critical difference between debilitating glare and a slightly noticeable decrease in image quality. Consequently, quantifying the magnitude and direction of scattered light is essential to appropriately evaluate the safety and efficacy of IOLs. In this study, we introduce a full-angle scanning light scattering profiler (SLSP) as a novel approach capable of quantitatively evaluating the light scattering from IOLs with a nearly 360° view. The SLSP method can simulate in situ conditions by controlling the parameters of the light source including angle of incidence. This testing strategy will provide a more effective nonclinical approach for the evaluation of IOL light scatter.


Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer's Disease.
Oxidative stress is implicated in the pathogenesis and progression of Alzheimer's disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42, but not in Aβ1-42-poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This "Quadrilateral of Neuronal Death" includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research.


Effect of orally administered hydralazine on neurohumoral factors and hemodynamic response in aged patients with chronic congestive heart failure.
We studied the hemodynamic response to orally administered hydralazine (30 mg) and examined the changes in neurohumoral factors in 16 aged patients with chronic congestive heart failure. After a single 30 mg dose, 9 patients (Group I) demonstrated a greater than 30% decrease in systemic vascular resistance (SVR) and a significant increase in the cardiac index (CI); 7 patients, whose SVR was decreased by less than 30% (Group II), showed a less marked increase in CI. After 3 days of drug administration (90 mg/day), the CI decreased in Group I (p less than 0.05) while it tended to increase further in Group II. Pretreatment plasma norepinephrine was lower in Group I than Group II (p less than 0.05). However, in Group I, it increased after 3 days of therapy, with a concomitant increase in plasma renin activity (p less than 0.01) and total plasma volume (P less than 0.025). We conclude that the higher pretreatment plasma norepinephrine level in Group II, suggestive of more severe derangement of left ventricular function, may be associated with a less pronounced dilatory response of the peripheral vasculature after a single dose of hydralazine, and that the increase in norepinephrine in Group I after 3 days of treatment may limit these patients' late hemodynamic responses to the drug.


[The peculiar hydrogeochemical features of the hydrosphere in the regions of salt-dome tectonics (as exemplified by the giant salt domes of the Peri-Caspian Lowland megabasin)].
The Peri-Caspian Lowland megabasin is a vast region of ancient salt accumulation that occurred during the Permian period. The territory over which the salt domes were formed gave rise to and accumulated huge resources of subterranean brackish and salted waters within the hypergenesis zone that also included brine and mineral mud lakes containing chemical elements of great therapeutic value. Nowadays, the subterranean waters (leaches, pools, and springs) provide the sources of the mineral-rich materials of balneological significance, such as sulfide, bromine, and boron-containing mineral waters the ion and mineral composition of which together with the high degree of mineralization makes them highly valuable for medicinal applications. Both leaches and peloids are extensively used in chemical industry and cosmetology. Brine lakes of the Peri-Caspian Depression are hypersaline lake water bodies with waters of the chlorine-magnesium type having marine origin. These lakes are fed by ground waters (especially those coming from the salt springs) in the combination with atmospheric precipitation. The chemical composition of brine and peloids of lakes Inder and Baskunchak is characterized by the high degree of mineralization with sodium chloride the concentration of which amounts to 264 и 325 g/dm3 respectively. The natural brine of the lake Inder contains the following biologically active components: Br - 460 mg/dm3 and H3BO3 - 100 mg/dm3. The territories surrounding the lakes Inder, Baskunchak, and El'ton are the sources of salt-saturated sulfide-silty muds characterized by a high degree of mineralization (250-306 mg/dm3) due to the presence of 0,15-0,50% of FeS. In addition, they contain biologically active bromine and borates, besides hydrogen sulphide. The ground-water discharge sites at the territories around lakes Inder and Baskunchak are located largely in the vicinity of the Permian sulphate-halogen deposits. The springs bring mostly water with the enhanced content of sodium chloride and the high degree of mineralization ranging from 20-30 g/dm3 to 150 g/dm3. They can be considered to be the analogues of waters of the Usol'skiy, Staroruskiy, ands Vologodskiy types and are highly suitable for the application for the purpose of balneotherapy.


Use of a chemical genetic technique to identify myosin IIb as a substrate of the Abl-related gene (Arg) tyrosine kinase.
Abl family kinases have been implicated in the regulation of cell morphogenesis and migration, but the molecular mechanisms through which they operate are not fully elucidated. We applied the bump-hole technique, pioneered by Shokat and colleagues, to identify direct substrates of Abl and the Abl-related gene (Arg) kinases. This technique required the engineering of Abl/Arg to utilize an unnatural ATP analogue as a phospho-donor. Mutation of T334A and T361A in Abl and Arg, respectively, altered their nucleotide specificity and allowed them to utilize N6-benzyl-ATP as a phospho-donor. These mutations did not affect the catalytic activity or protein substrate specificity of Abl and Arg. An unexpected high level of background labeling necessitated further optimization of this approach. Dialysis, pretreatment with a broad-spectrum Ser/Thr kinase inhibitor, K-252a, and purification of phosphotyrosine-containing proteins allowed for definitive identification of putative substrates. Using mass spectrometry, we identified eight putative substrates. One of these putative substrates, myosin IIB, can be phosphorylated in vivo by Arg. Our results indicate that the bump-hole technique can be used to identify Abl family kinase substrates and suggests that myosin IIB may be regulated by tyrosine phosphorylation.


Efficacy of combined therapy with plasmapheresis and immunosuppressants in rheumatoid vasculitis.
The combined effects of plasmapheresis and immunosuppressive therapy in the treatment of rheumatoid vasculitis was evaluated in 8 patients. These modalities, in combination, proved to promote rapid healing of cutaneous ulcers. In addition, it appeared that this aggressive therapy can occasionally reverse early gangrenous lesions involving extremities. By contrast, little change occurred in longstanding neuropathic manifestations. Our preliminary results suggest that plasmapheresis, used as an acute treatment modality, and combined with prolonged therapy with immunosuppressive drugs, may reduce the morbidity associated with certain manifestations of rheumatoid vasculitis.


Determination of Total Sulfur, Sulfate, Sulfite, Thiosulfate, and Sulfolipids in Plants.
In response to oxidative stress the biosynthesis of the ROS scavenger, glutathione is induced. This requires the induction of the sulfate reduction pathway for an adequate supply of cysteine, the precursor for glutathione. Cysteine also acts as the sulfur donor for the sulfuration of the molybdenum cofactor, crucial for the last step of ABA biosynthesis. Sulfate and sulfite are, respectively, the precursor and intermediate for cysteine biosynthesis and there is evidence for stress-induced sulfate uptake and further downstream, enhanced sulfite generation by 5'-phosphosulfate (APS) reductase (APR, EC 22.214.171.124) activity. Sulfite reductase (SiR, E.C.188.8.131.52) protects the chloroplast against toxic levels of sulfite by reducing it to sulfide. In case of sulfite accumulation as a result of air pollution or stress-induced premature senescence, such as in extended darkness, sulfite can be oxidized to sulfate by sulfite oxidase. Additionally sulfite can be catalyzed to thiosulfate by sulfurtransferases or to UDP-sulfoquinovose by SQD1, being the first step toward sulfolipid biosynthesis.Determination of total sulfur in plants can be accomplished using many techniques such as ICP-AES, high-frequency induction furnace, high performance ion chromatography, sulfur combustion analysis, and colorimetric titration. Here we describe a total sulfur detection method in plants by elemental analyzer (EA). The used EA method is simple, sensitive, and accurate, and can be applied for the determination of total S content in plants.Sulfate anions in the soil are the main source of sulfur, required for normal growth and development, of plants. Plants take up sulfate ions from the soil, which are then reduced and incorporated into organic matter. Plant sulfate content can be determined by ion chromatography with carbonate eluents.Sulfite is an intermediate in the reductive assimilation of sulfate to the essential amino acids cysteine and methionine, and is cytotoxic above a certain threshold if not rapidly metabolized and can wreak havoc at the cellular and whole plant levels. Plant sulfite content affects carbon and nitrogen homeostasis Therefore, methods capable of determining sulfite levels in plants are of major importance. Here we present two robust laboratory protocols which can be used for sulfite detection in plants.Thiosulfate is an essential sulfur intermediate less toxic than sulfite which is accumulating in plants in response to sulfite accumulation. The complexity of thiosulfate detection is linked to its chemical properties. Here we present a rapid, sensitive, and accurate colorimetric method based on the enzymatic conversion of thiosulfate to thiocyanate.The plant sulfolipid sulfoquinovosyldiacylglycerol (SQDG) accounts for a large fraction of organic sulfur in the biosphere. Aside from sulfur amino acids, SQDG represents a considerable sink for sulfate in plants and is the only sulfur-containing anionic glycerolipid that is found in the photosynthetic membranes of plastids. We present the separation of sulfolipids from other fatty acids in two simple ways: by one- and two-dimensional thin-layer chromatography.


Replication/Assembly Defective Avian Flavivirus With Internal Deletions in the Capsid Can Be Used as an Approach for Living Attenuated Vaccine.
Avian Tembusu virus (TMUV) is a novel flavivirus causing severe egg drop and fatal encephalitis in avian in Asia. In the present study, we screened the structural and functional requirements of TMUV capsid protein (CP) for viral morphogenesis using reverse genetics methods in combination with replicon packaging assays. TMUV-CP showed dramatic functional and structural flexibility, and even though 44 residues were removed from the N-terminus, it was still capable of packaging replicon RNA; in addition, 33 residues were deleted from the C-terminus (containing nearly the entire α4-helix), and infectious particles were still produced, although α4-α4' is supposedly vital for CP dimerization and nucleocapsid formation. We further analyzed two mutants (ΔC20-43 and ΔC64-96 viruses) with relatively large deletions that still replicated well in BHK-21 cells. Our data indicate that internal deletions within CP impaired viral replication or assembly, resulting in attenuated virus proliferation in cells and attenuated virulence in duck embryos, and these deletion mutations are quite stable in cell culture. An in vivo assay indicated that both ΔC20-43 virus and ΔC64-96 virus were highly attenuated in ducklings but still immunogenic. Single-dose immunization with ΔC20-43 virus or ΔC64-96 virus could protect ducklings from a lethal challenge with good antigen clearance. Together, our data shed light on replication/assembly defective TMUV with internal deletions in CP and provide an effective approach to attenuate viral virulence in live vaccines without changing the antigen composition.


Procedure for monitoring exposure to sulfur mustard based on modified edman degradation of globin.
A procedure for the modified Edman degradation of globin for determination of sulfur mustard adducts to the N-terminal valine residue in human hemoglobin has been developed for use under field laboratory conditions. The minimum detectable exposure level of human blood (in vitro) to sulfur mustard using this procedure is 100 nM. The interindividual and intraindividual variabilities of the procedure were acceptable (standard deviation < 10% and < 20%, respectively). The procedure could be properly set up and carried out in another laboratory within one working day, demonstrating its robustness.


VEGF, bFGF, and their receptors in the endometrium of rhesus monkey during menstrual cycle and early pregnancy.
A number of cytokines and growth factors are known to modulate proliferation and differentiation of human endometrium. In this study, the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and VEGF receptors, fms-like tyrosine kinase (Flt1) and kinase insert domain-containing region (KDR), and bFGF receptor 1 (Flg) were examined in the endometrium of rhesus monkey on Day 5, 10, 16, 20, 25 of menstrual cycle and on Day 19 of early pregnancy. Western blot analysis showed the specificity of the anti-human antibodies with the monkey tissue. The expression of mRNA and protein of VEGF was correlated with that of its receptor KDR, which was detected in epithelial, vascular, and myometrial cells. The localization of bFGF and its receptor Flg was similar to that of VEGF, except that the Flg was absent in the endothelial cells. Strong expression of VEGF and bFGF in the glandular epithelial cells was observed in the proliferative phase, declined in the secretory phase during the cycle. Stronger staining of these factors was also observed in the decidual cells of the pregnant uterus, as compared with the stromal cells of cycling uterus. No expression of Flt1 was detected in the tissue examined in this study. These data suggest that VEGF, bFGF, and their receptors play important roles in epithelial and stromal development, angiogenesis, and blood vessel function in the endometrium during the menstrual cycle and early pregnancy of the rhesus monkey.


Performance of ChatGPT in French language Parcours d'Accès Spécifique Santé test and in OBGYN.
To evaluate the performance of ChatGPT in a French medical school entrance examination. A cross-sectional study using a consecutive sample of text-based multiple-choice practice questions for the Parcours d'Accès Spécifique Santé. ChatGPT answered questions in French. We compared performance of ChatGPT in obstetrics and gynecology (OBGYN) and in the whole test. Overall, 885 questions were evaluated. The mean test score was 34.0% (306; maximal score of 900). The performance of ChatGPT was 33.0% (292 correct answers, 885 questions). The performance of ChatGPT was lower in biostatistics (13.3% ± 19.7%) than in anatomy (34.2% ± 17.9%; P = 0.037) and also lower than in histology and embryology (40.0% ± 18.5%; P = 0.004). The OBGYN part had 290 questions. There was no difference in the test scores and the performance of ChatGPT in OBGYN versus the whole entrance test (P = 0.76 vs P = 0.10, respectively). ChatGPT answered one-third of questions correctly in the French test preparation. The performance in OBGYN was similar.


Formin-related protein 1 facilitates proliferation and aggressive phenotype of clear cell renal cell carcinoma through MAPK/MMP2 pathway.
Formin-related protein-1(FRL1) has reportedly been overexpressed in a variety of malignancies, such as clear cell renal cell carcinoma (ccRCC). However, the clinical value and molecular mechanisms underlying ccRCC tumorigenesis and progression in association with FRL1 remain poorly understood. Immunohistochemical analysis was performed on 119 paraffin-embedded RCC tissue samples to detect FRL1 expression and analyze its prognostic value. Colony formation, the CCK-8 assay, flow cytometry, and in vivo nude mice subcutaneous experiments were used to identify the effects of FRL1 on growth and proliferation. In vitro tests for wound healing, migration, and invasion were used to assess the involvement of FRL1 in invasion and metastatic potential. The process of epithelial-mesenchymal transition process (EMT) and the MMP2 expression were detected in stably transfected RCC cells via western blotting, as well as in tumor tissue paraffin sections from xenograft model. Both FRL1 mRNA and protein levels were noticeably elevated in ccRCC cell lines and samples. Aberrant overexpression of FRL1 was associated with unfavorable clinicopathological features of ccRCC and indicated poor prognosis. Ectopic overexpression of FRL1 increased the growth-promoting traits of ccRCC cells as well as the migratory and invasive capacity of RCC cells, whereas FRL1-silencing caused the opposite results. In addition, FRL1 promoted epithelial-mesenchymal transition (EMT) and upregulated the expression of matrix metalloproteinase 2 (MMP2). Finally, overexpression of FRL1 upregulated phosphorylation level of ERK1/2 with no effect on total level of ERK1/2 in the RCC cells. MAPK/ERK inhibitor reversed the promotional effects of FRL1. FRL1 was overexpressed in ccRCC tissues and predicted poor prognosis. FRL1 contributes to invasion and aggressive phenotype of ccRCC by facilitating EMT through MAPK/MMP2 axis.


Clinical application of monitoring mycophenolic acid trough concentration in heart transplant recipients--single center's experience.
The purpose of this study was to assess the clinical utility of mycophenolic acid (MPA) trough concentration monitoring in heart transplant recipients. We reviewed 456 MPA plasma level measurements (EMIT/Dade-Behring) which were performed in 76 pts. after orthotopic heart transplantation (OHT): 57 M and 21 F, age 41.9 +/- 16, time after OHT (months) 17.6 +/- 24. Daily dose of mycophenolate mofetil (MMF) was 2-3 g before MPA measurement introduction, then it was adjusted to achieve MPA trough levels (TL) of 2-4 microg/ml. Additionally pts. received either cyclosporine-A (CyA) or tacrolimus and prednisone. We analyzed first MPA levels obtained in pts. without previous monitoring, then we looked for a relation between CyA or tacrolimus and MPA level, and finally we checked for a relation between MPA level and the side-effects of MMF RESULTS: In a group of 59 pts. without earlier MPA level monitoring we found that 36 pts. (61%) had MPA level below, 19 pts. (32%) within, and 4 pts. (7%) above target TL. We identified a group of 11 pts. (characterized by unstable CyA TLs and liver impairment) with a significant positive correlation between CyA and MPA level. For the remaining group of pts. we found a non-significant negative correlation between CyA and MPA concentrations. Target MPA TL was achieved in 40% of cases in pts. with CyA TL below 200 ng/ml (Axsym/Abbott), in 40% of cases in pts. with CyA TL 200-300 ng/ml, and in 27% of cases in pts. with CyA TL over 300 ng/ml. There was no correlation between tacrolimus and MPA level. MPA TL over 4 microg/ml occurred in 22% of results from pts. receiving tacrolimus (n=6) and 11% of pts. on CyA (n=17, p = 0.011). 90% of these pts. had symptoms of GI irritation, 33%--leucopoenia, and 14%--anemia. It is uncommon to achieve MPA TL of 2-4 microg/ml with typical doses of MMF, especially with concomitant high CyA TL. Typical side effects of MMF should be an indication to check MPA TL.


Conjoined twins in a triplet pregnancy. A rare obstetrical dilemma.
Conjoined twins are derived from division of a single fertilized ovum after the twelfth day of fertilization. Triplet conjoined twin is considered as a unique phenomenon that is accompanied with a wide variety of congenital abnormalities and also hazardous consequences for both fetuses and parents. We present an extremely rare case of conjoined twins in a triplet pregnancy with symmetric thoracoomphalopagus that was diagnosed in prenatal period by using ultrasound scanning and MRI. In triplet pregnancies, we should be aware about the possibility of conjoined twins. If there are severe congenital malformations, termination of pregnancy should be recommended immediately after the diagnosis regardless of gestational age, particularly in early gestational age.


The recurrence risks for mild idiopathic mental retardation.
A genetic study of children attending ESN(M) schools in Coventry has shown a recurrence risk of idiopathic mental retardation in sibs lying between 1 in 4 and 1 in 5. There was also a prevalence of mental retardation in other relatives that was greater than the population prevalence, and was less for second degree relatives than for first degree, and less still for third degree relatives. Recurrence in sibs was greater if more than one first degree relative was affected. There was no suggestion of a contribution by X linked genes, once the fragile X syndrome had been excluded. The presence of perinatal and other environmental factors in the index children did not alter the recurrence risk for sibs except for very low birth weight. There was a low recurrence rate of mental retardation in Asian families, suggesting that they had a different distribution of intelligence from non-Asian families.


Using clinical risk models to predict outcomes: what are we predicting and why?
Clinical risk prediction models can support decision making in emergency medicine, but directing intervention towards high-risk patients may involve a flawed assumption. This concepts paper examines prognostic clinical risk prediction and specifically describes the potential impact of treatment effects in model development studies. Treatment effects may lead to models failing to achieve the aim of identifying the patients most likely to benefit from intervention, and may instead identify patients who are unlikely to benefit from intervention. The paper provides practical advice to help clinicians who wish to use clinical prediction scores to assist clinical judgement rather than dictate clinical decision making.


Molecular subtypes based on DNA sensors predict prognosis and tumor immunophenotype in hepatocellular carcinoma.
DNA sensors play crucial roles in inflammation and have been indicated to be involved in antitumor or tumorigenesis, while it is still unclear whether DNA sensors have potential roles in the prognosis and immunotherapy of hepatocellular carcinoma (HCC). Herein, The Cancer Genome Atlas and Gene Expression Omnibus databases were used to analyze RNA sequencing data and clinical information. A total of 14 DNA sensors were collected and performed consensus clustering to determine their molecular mechanisms in HCC. Two distinct molecular subtypes (Clusters C1 and C2) were identified and were associated with different overall survival (OS). Immune subtype analysis revealed that C1 was mainly characterized by inflammation, while C2 was characterized by lymphocyte depletion. Immune scoring and immunomodulatory function analysis confirmed the different immune microenvironment of C1 and C2. Notably, significant differences in "Hot Tumor" Immunophenotype were observed between the two subtypes. Moreover, the prognostic model based on DNA sensors is capable of effectively predicting the OS of HCC patients. Besides, the chemotherapeutic drug analysis showed the different sensitivity of two subtypes. Taken together, our study shows that the proposed DNA sensors were a reliable signature to predict the prognosis and immunotherapy response with potential application in the clinical decision and treatment of HCC.


Visual Working Memory of Chinese Characters and Expertise: The Expert's Memory Advantage Is Based on Long-Term Knowledge of Visual Word Forms.
People unfamiliar with Chinese characters show poorer visual working memory (VWM) performance for Chinese characters than do literates in Chinese. In a series of experiments, we investigated the reasons for this expertise advantage. Experiments 1 and 2 showed that the advantage of Chinese literates does not transfer to novel material. Experts had similar resolution as novices for material outside of their field of expertise, and the memory of novices and experts did not differ when detecting a big change, e.g., when a character's color was changed. Memorizing appears to function as a rather abstract representation of word forms because memory for characters' fonts was poor independently of expertise (Experiment 3), though still visual. Distractors that were highly similar conceptually did not increase memory errors, but visually similar distractors impaired memory (Experiment 4). We hypothesized that literates in Chinese represent characters in VWM as tokens of visual word forms made available by long-term memory. In Experiment 5, we provided novices with visual word form knowledge. Participants subsequently performed a change detection task with trained and novel characters in a functional magnetic resonance experiment. We analyzed set size- and training-dependent effects in the intraparietal sulcus (IPS) and the visual word form area. VWM for trained characters was better than for novel characters. Neural activity increased with set size and at a slower rate for trained than for novel characters. All conditions approached the same maximum, but novel characters reached the maximum at a smaller set size than trained characters. The time course of the bold response depended on set size and knowledge status. Starting from the same initial maximum, neural activity at small set sizes returned to baseline more quickly for trained characters than for novel characters. Additionally, high performers showed generally more neural activity in the IPS than low performers. We conclude that experts' better performance in working memory (WM) is caused by the availability of visual long-term representations (word form types) that allow a sparse representation of the perceived stimuli and make even small changes big because they cause a type change that is easily detected.


The criteria and analysis of good multiple choice questions in a health professional setting.
Assessment of health workers as students and professionals has a profound impact on their learning and is an essential safety valve before certification. It is used for their training, their placement, their certification, and their promotion. The multiple choice question MCQ type of tests represents one of the most important examination tools that is commonly used in this assessment. The MCQs can be reliable, valid, and cost-effective in assessing medical knowledge. This paper portrays the different purposes of assessment in the medical field. The paper discusses in detail the criteria of a good assessment tool. Interpretation of MCQ test results is the final section of the paper.


Prolonged increased concentrations of 17beta-estradiol associated with development of persistent ovarian follicles do not influence conception rates in beef cattle.
Objectives were to evaluate conception rates and time to estrus following cessation of treatments designed to either cause prolonged elevated concentrations of 17beta-estradiol associated with development of persistent ovarian follicles or to inhibit elevated concentrations of 17beta-estradiol and development of persistent ovarian follicles. Beef heifers (n = 80) and 2-yr-old nonlactating cows (n = 39) were stratified by age, blocked by estrual status (previously exhibited estrus or anestrus) and assigned to receive either 1) four norgestomet implants (4 Norg; n = 59) for 9 d (d 0 = treatment initiation) or 2) one norgestomet implant from d 0 to 7 and three additional norgestomet implants from d 7 to 9 (1 + 3 Norg; n = 60). All animals received PGF2alpha on d 0 to lyse corpora lutea. All implants were removed on d 9 followed by estrus detection every 6 h for 7 d following implant removal. Females exhibiting estrus were artificially inseminated 6 to 12 h after detection of estrus. A treatment x day interaction (P < .01) for concentrations of 17beta-estradiol from d 0 to 9 of the experiment with elevated 17beta-estradiol occurring in females treated with 1 + 3 Norg implants. The interval from treatment withdrawal to estrus was longer (P < .01) in females treated with 1 + 3 Norg (105 h) than in those treated with 4 Norg (61 h). Synchrony of estrus among anestrous females was greater (P < .10) in females treated with 4 Norg (97%) than in females treated with 1 + 3 Norg (67%) but was similar in estrual females. Conception rates (number conceiving to AI/number bred by AI) did not differ (4 Norg = 67%; 1 + 3 Norg = 72%; P > .10). Pregnancy rates (number conceiving to AI/number in treatment group) also did not differ between treatment groups of either estrual or anestrous females. Conception rates are not compromised in females that develop persistent ovarian follicles and have prolonged elevated concentrations of 17beta-estradiol when persistent ovarian follicles are not allowed to ovulate.


Interpreting genotype × environment interaction in tropical maize using linked molecular markers and environmental covariables.
An understanding of the genetic and environmental basis of genotype×environment interaction (GEI) is of fundamental importance in plant breeding. In mapping quantitative trait loci (QTLs), suitable genetic populations are grown in different environments causing QTLs×environment interaction (QEI). The main objective of the present study is to show how Partial Least Squares (PLS) regression and Factorial Regression (FR) models using genetic markers and environmental covariables can be used for studying QEI related to GEI. Biomass data were analyzed from a multi-environment trial consisting of 161 lines from a F(3:4) maize segregating population originally created with the purpose of mapping QTLs loci and investigating adaptation differences between highland and lowland tropical maize. PLS and FR methods detected 30 genetic markers (out of 86) that explained a sizeable proportion of the interaction of maize lines over four contrasting environments involving two low-altitude sites, one intermediate-altitude site, and one high-altitude site for biomass production. Based on a previous study, most of the 30 markers were associated with QTLs for biomass and exhibited significant QEI. It was found that marker loci in lines with positive GEI for the highland environments contained more highland alleles, whereas marker loci in lines with positive GEI for intermediate and lowland environments contained more lowland alleles. In addition, PLS and FR models identified maximum temperature as the most-important environmental covariable for GEI. Using a stepwise variable selection procedure, a FR model was constructed for GEI and QEI that exclusively included cross products between genetic markers and environmental covariables. Higher maximum temperature in low- and intermediate-altitude sites affected the expression of some QTLs, while minimum temperature affected the expression of other QTLs.


Electroconvulsive therapy for the elderly: a review.
Treatment of psychiatric disorders among the elderly is complicated by such factors as high incidence of medical illness and changes in drug metabolism; electroconvulsive therapy (ECT) is considered a reasonable treatment alternative for the elderly for several psychiatric syndromes. The authors review indications, complications, and precautions related to ECT for older patients. The primary indication is major depression; about 80 percent of elderly patients respond favorably. ECT appears less effective for depression secondary to dementia or somatization disorder. Although ECT is relatively safe for the elderly, up to one-third may experience a complication that interferes with treatment. Careful pre-ECT medical evaluation is essential, with special attention to cardiovascular factors and to concurrent medications.


Disruptive Innovation Can Prevent the Next Pandemic.
Public health surveillance (PHS) is at a tipping point, where the application of novel processes, technologies, and tools promise to vastly improve efficiency and effectiveness. Yet twentieth century, entrenched ideology and lack of training results in slow uptake and resistance to change. The term disruptive innovation - used to describe advances in technology and processes that change existing markets - is useful to describe the transformation of PHS. Past disruptive innovations used in PHS, such as distance learning, the smart phone, and field-based laboratory testing have outpaced older services, practices, and technologies used in the traditional classroom, governmental offices, and personal communication, respectively. Arguably, the greatest of these is the Internet - an infrastructural innovation that continues to enable exponential benefits in seemingly limitless ways. Considering the Global Health Security Agenda and facing emerging and reemerging infectious disease threats, evolving environmental and behavioral risks, and ever changing epidemiologic trends, PHS must transform. Embracing disruptive innovation in the structures and processes of PHS can be unpredictable. However, it is necessary to strengthen and unlock the potential to prevent, detect, and respond.


[Immunoscintigraphy results in the comparison of ocular with cutaneous melanoma].
For several years, immunoscintigraphy (IS) using a 99mTc-labeled monoclonal antibody for tumor localization has been used as an additional tool in the diagnosis of malignant melanoma. The aim of our study was to verify previously published data with respect to our own patients and to correlate immunoscintigraphic results with histological findings. In particular, we wanted to compare the outcome of IS in ocular melanoma with that in cutaneous melanoma. We examined 28 patients (15 females, 13 males, average age 64 years) with clinically suspected ocular melanoma. IS was performed using the monoclonal antibody 225.28S (Tecnemab-K-1, Fa. Sorin/Solco), and images were obtained in a standard fashion (planar) as well as with the SPECT technique. In 16 patients, the tumor was examined afterwards histologically. The control group consisted of 102 patients with histologically proven metastasizing cutaneous melanoma who were investigated by IS in an identical fashion. In contrast to the literature published so far, we demonstrated a positive IS reaction in only 42% (and 56% in histologically proven cases, respectively) in our patients with ocular melanoma, while in patients with cutaneous melanoma, we found a sensitivity of more than 80%. In the 3 patients who turned out not to have ocular melanoma, we found one false-positive reaction (subretinal hemorrhage). No correlation was found between the various histological features of ocular melanoma and the immunoscintigraphic results. We conclude that IS using the antibody 25.28S is of limited value in patients with ocular melanoma and should only be recommended in selected cases.(ABSTRACT TRUNCATED AT 250 WORDS)


Targeting of doxorubicin to the urinary bladder of the rat shows increased cytotoxicity in the bladder urine combined with an absence of renal toxicity.
Targeting of anti-tumor drugs to the urinary bladder for the treatment of bladder carcinoma may be useful, since these agents generally have a low degree of urinary excretion and are highly toxic elsewhere in the body. The anti-tumor drug doxorubicin was coupled to the low-molecular weight protein lysozyme via the acid-sensitive cis-aconityl linker. All free amino groups of the lysozyme were used for drug attachment to achieve intact excretion of the doxorubicin-aconityl-lysozyme conjugate into the bladder. In the bladder, the cytotoxic drug should be regenerated through acidification of the urine. First, the doxorubicin-aconityl-lysozyme conjugate was tested in rats for its target specificity and general toxicity. Wistar rats were injected intravenously with 2 mg/kg free doxorubicin or 10 mg/kg lysozyme-conjugated doxorubicin. Total urinary excretion of doxorubicin was about 10 times higher if the drug was coupled to lysozyme (39 +/- 3% versus 4.4 +/- 0.4%). Free doxorubicin had no detectable toxic effects on heart, liver and lung but caused severe renal damage (proteinuria, N-acetylglucosaminidase excretion and glomerulosclerosis). None of the rats injected with doxorubicin-lysozyme conjugate showed such renal toxicity. Second, we tested whether doxorubicin could be released from the conjugate in the bladder through acidification of the urine and if the released doxorubicin could still exert a cytotoxic effect. Doxorubicin-aconityl-lysozyme (2 mg/kg conjugated doxorubicin, i.v.) was administered in rats with acidified urine (pH 6.1 +/- 0.1) and in rats with a high urinary pH (8.2 +/- 0.4). Ten times more doxorubicin was released from the conjugate in the group with acidified urine (15 +/- 7% versus 1.7 +/- 0.1%). In agreement with this, cytotoxicity was also higher in the low pH group (IC50 of 255 +/- 47 nM versus 684 +/- 84 nM doxorubicin). In conclusion, a specific delivery of doxorubicin to the urinary bladder combined with a reduced toxicity of doxorubicin in the kidneys can be achieved by coupling this anti-tumor drug to the low-molecular weight protein lysozyme via an acid-labile linker. A release of cytotoxic doxorubicin in the urinary bladder can be achieved by acidification of the urine. This technology, after further optimization, may provide an interesting tool for the treatment of bladder carcinoma.


Flow and mass transfer around a core-shell reservoir.
I have developed an alternative numerical approach to study mass transfer from a stationary core-shell reservoir under channel flow conditions. I use the lattice Boltzmann method to compute both the solvent fluid flow and the diffusion and advection of the solute. I have investigated the impact of the flow by reporting mass transfer quantities such as the instantaneous solute concentration and the local Sherwood number at the surface of the reservoir. The flow is found to enhance the release of the encapsulated material, but it prevents the released material from reaching the channel walls.


Chemical synaptic and gap junctional interactions between principal neurons: partners in epileptogenesis.
Field potential signals, corresponding to electrographic seizures in cortical structures, often contain two components, which sometimes appear to be separable and other times to be superimposed. The first component consists of low-amplitude very fast oscillations (VFO, >70-80 Hz); the second component consists of larger amplitude transients, lasting tens to hundreds of ms, and variously called population spikes, EEG spikes, or bursts--terms chosen in part because of the cellular correlates of the field events. To first approximation, the two components arise because of distinctive types of cellular interactions: gap junctions for VFO (a model of which is reviewed in the following), and recurrent synaptic excitation and/or inhibition for the transients. With in vitro studies of epileptic human neocortical tissue, it is possible to elicit VFO alone, or VFO superimposed on a large transient, but not a large transient without the VFO. If such observations prove to be general, they would imply that gap junction-mediated interactions are the primary factor in epileptogenesis. It appears to be the case then, that in the setting of seizure initiation (but not necessarily under physiological conditions), the gain of gap junction-mediated circuits can actually be larger than the gain in excitatory synaptic circuits.


Ochratoxin A in artisan salami produced in Veneto (Italy).
Fifty samples of artisan salami purchased in Veneto (Italy) were analysed for the determination of ochratoxin A (OTA). The analytical method, based on a sample preparation procedure with immunoaffinity columns (IACs), together with analysis by high-performance liquid chromatography with fluorescence detection (HPLC-FD), has guaranteed a high rate of recovery (about 97%), limit of detection (LOD) and limit of quantification (LOQ), respectively, of 0.06 µg kg(-1) and 0.20 µg kg(-1). OTA was detected in five samples, but only one exceeded the guideline value (1 µg kg(-1)) established by the Italian Ministry of Health for pork meat and derived products. The results would seem to suggest that salami made with the traditional, non-industrial production method can be considered safe as regards contamination by OTA. However, the very high concentration observed in one sample proves that a high OTA contamination is also possible in this type of product. Thus, the controls of mycotoxin contamination must consider also salami.


[Interactions of 1A2 insulator with promoter of hsp 70 gene in Drosophila melanogaster].
Insulators are regulatory DNA elements that participate in the modulation of the interactions between enhancers and promoters. Depending on the situation, insulators can either stabilize or destroy the contacts between enhancers and promoters. A possible explanation for the activity of insulators is their ability to directly interact with gene promoters. In the present study, it was demonstrated that, in model systems, a 1A2 insulator could interact with the core sequence of an hsp70 promoter. In this case, the insulator protein CP190 is found on the hsp70 promoter, which depends on the presence of an insulator in the transgene. The data obtained are consistent with the model, which implies that direct contacts between insulators and promoters make a considerable contribution to the modulation of the interactions between insulators and promoters.


Individual-specific DNA fingerprinting in man using the oligonucleotide probe (GTG)5/(CAC)5.
Restriction fragment length polymorphisms (RFLPs) associated with interspersed simple repetitive DNA arise from DNA fragment lengths that contain variable numbers of the repeated motifs. Using restriction enzymes with different 4 base pair recognition sites and the simple triplet repeat hybridization probe, (GTG)5/(CAC)5, DNA multilocus fingerprints can be obtained in man. Only the DNAs of monozygous twins show indistinguishable banding patterns. Since the bands are inherited according to Mendelian laws, DNA fingerprints can be used for identification of individuals and paternity analysis. The discriminatory power in the DNA fingerprinting technique in forensic science is demonstrated and examples of paternity testing are given.


Organosilyl/-germyl polyoxotungstate hybrids for covalent grafting onto silicon surfaces: towards molecular memories.
Organosilyl/-germyl polyoxotungstate hybrids [PW(9)O(34)(tBuSiO)(3)Ge(CH(2))(2)CO(2)H](3-) (1a), [PW(9)O(34)(tBuSiO)(3)Ge(CH(2))(2)CONHCH(2)C[triple bond]CH](3-) (2 a), [PW(11)O(39)Ge(CH(2))(2)CO(2)H](4-) (3a), and [PW(11)O(39)Ge(CH(2))(2)CONHCH(2)C[triple bond]CH](4-) (4a) have been prepared as tetrabutylammonium salts and characterized in solution by multinuclear NMR spectroscopy. The crystal structure of (NBu(4))(3)1a.H(2)O has been determined and the electrochemical behavior of 1a and 2a has been investigated by cyclic voltammetry. Covalent grafting of 2a onto an n-type silicon wafer has been achieved and the electrochemical behavior of the grafted clusters has been investigated. This represents the first example of covalent grafting of Keggin-type clusters onto a Si surface and a step towards the realization of POM-based multilevel memory devices.


Hyperbilirubinemia as a Risk Factor for Mortality and Morbidity in Trauma Patients.
Hyperbilirubinemia is frequently reported in trauma patients. However, few studies have investigated the effects of hyperbilirubinemia on patients' clinical trajectories. This study aimed to evaluate the relationship between hyperbilirubinemia and patient outcomes following trauma. Our study included 387 patients who were admitted to the trauma bay with severe trauma between January 2017 and December 2021. We categorized patients into two groups based on their peak bilirubin levels: the low-bilirubin (LB) group, with levels below 3 mg/dL, and the high-bilirubin (HB) group, with levels above 3 mg/dL. We then compared the rates of complications and mortality between these two groups. The incidence of pneumonia (10.8% vs. 32.3%, p < 0.001), acute kidney injury (AKI) (2.8% vs. 19.2%, p < 0.001), sepsis (2.8% vs. 10.1%, p = 0.003), and wound infections (8.3% vs. 30.3%, p < 0.001) was significantly higher in the HB group. Additionally, the mortality rate was significantly higher (4.2% vs. 10.1%, p = 0.028) in the HB group. Multivariate analysis revealed that the higher the bilirubin level, the greater the risk of complications (pneumonia: odds ratio [OR] = 3.238; 95% confidence interval [CI] = 1.68-6.22; p < 0.001, AKI: OR = 4.718; 95% CI = 1.65-13.44; p = 0.004, sepsis: OR = 3.087; 95% CI = 1.00-9.52; p = 0.04, wound infection: OR = 3.995; 95% CI = 2.073-7.700; p < 0.001). In conclusion, hyperbilirubinemia was associated with poorer outcomes in trauma patients.


Purification and partial characterization of two prolactin-like glycoprotein hormone complexes from the midpregnant mouse conceptus.
Two PRL-like glycoprotein hormone complexes were purified from the medium of cultured mouse conceptuses from day 10 of pregnancy: mouse placental lactogen-I (mPL-I) (29-32K), and mPL-I (36.5-42K). Sodium dodecyl sulfate-gel electrophoresis revealed that mPL-I (36.5-42K) is a complex of five proteins with mol wt of 36.5K, 37.5K, 39K, 40.5K, and 42K. Deglycosylation with peptide: N-glycosidase F or trifluoromethanesulfonic acid produced a single 29K protein. mPL-I (36.5-42K) was also sensitive to neuraminidase, but not to endo-beta-N-acetylglucosaminidase H or bacterial alkaline phosphatase. The production of intermediates from partial digestion of mPL-I (36.5-42K) with endo-beta-N-acetylglucosaminidase F indicated the presence of multiple glycosylation sites. mPL-I (29-32K) is a complex of three proteins with mol wt of 29K, 30.5K, and 32K. Treatment with peptide:N-glycosidase F or trifluoromethanesulfonic acid reduced the mol wt of the 30.5K and 32K bands to 28K. The 30.5K band was sensitive to endo-beta-N-acetylglucosaminidase H and endo-beta-N-acetylglucosaminidase F, but the 32K band was not. Neither band was sensitive to neuraminidase or bacterial alkaline phosphatase. The 29K band was resistant to all chemical and enzymatic treatments and is probably not glycosylated or phosphorylated. In the nonreduced state, neither form of mPL-I showed an increase in mobility over that of its reduced counterpart on sodium dodecyl sulfate-gel electrophoresis, indicating that neither form of mPL-I contains the large disulfide loop common to hormones of the PRL family. After iodination, all component proteins of both forms of mPL-I were found to bind to day 17 pregnant mouse liver membranes and were displaceable by excess mPL-II. In a radioreceptor assay, 125I-labeled mPL-I (36.5-42K) was displaced by mPRL or mPL-II, but not by mGH. An antiserum to both forms of mPL-I was generated, and a RIA employing mPL-I (36.5-42K) as the standard and radioligand was developed. Dilutions of day 10 pregnant maternal mouse serum and placental homogenate and a partially purified fraction of mPL-I (29-32K) produced displacement curves parallel to that of mPL-I (36.5-42K) standard curve. Five micrograms of mPRL, mPL-II, or mGH or 10 microliter day 17 pregnant or male mouse serum did not displace the radioligand from the antibody. mPL-I (36.5-42K) was lactogenic, but it did not possess LH-like bioactivity.


Quantitative structure-activity relationship models of clinical pharmacokinetics: clearance and volume of distribution.
Reliable prediction of two fundamental human pharmacokinetic (PK) parameters, systemic clearance (CL) and apparent volume of distribution (Vd), determine the size and frequency of drug dosing and are at the heart of drug discovery and development. Traditionally, estimated CL and Vd are derived from preclinical in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) measurements. In this paper, we report quantitative structure-activity relationship (QSAR) models for prediction of systemic CL and steady-state Vd (Vdss) from intravenous (iv) dosing in humans. These QSAR models avoid uncertainty associated with preclinical-to-clinical extrapolation and require two-dimensional structure drawing as the sole input. The clean, uniform training sets for these models were derived from the compilation published by Obach et al. (Drug Metab. Disp. 2008, 36, 1385-1405). Models for CL and Vdss were developed using both a support vector regression (SVR) method and a multiple linear regression (MLR) method. The SVR models employ a minimum of 2048-bit fingerprints developed in-house as structure quantifiers. The MLR models, on the other hand, are based on information-rich electro-topological states of two-atom fragments as descriptors and afford reverse QSAR (RQSAR) analysis to help model-guided, in silico modulation of structures for desired CL and Vdss. The capability of the models to predict iv CL and Vdss with acceptable accuracy was established by randomly splitting data into training and test sets. On average, for both CL and Vdss, 75% of test compounds were predicted within 2.5-fold of the value observed and 90% of test compounds were within 5.0-fold of the value observed. The performance of the final models developed from 525 compounds for CL and 569 compounds for Vdss was evaluated on an external set of 56 compounds. The predictions were either better or comparable to those predicted by other in silico models reported in the literature. To demonstrate the practical application of the RQSAR approach, the structure of vildagliptin, a high-CL and a high-Vdss compound, is modified based on the atomic contributions to its predicted CL and Vdss to propose compounds with lower CL and lower Vdss.


Optimal initial dose adjustment of warfarin in orthopedic patients.
Warfarin sodium is commonly prescribed for the prophylaxis and treatment of venous thromboembolism. Dosing algorithms have not been widely adopted because they require a fixed initial warfarin dose (eg, 5 mg) and are not tailored to other factors that may affect the international normalized ratio (INR). To develop an algorithm that could predict a therapeutic warfarin dose based on drug interactions, INR response after the initial warfarin doses, and other clinical factors. We used stepwise regression to quantify the relationship between these factors in patients beginning prophylactic warfarin therapy immediately prior to joint replacement. In the derivation cohort (n = 271), we separately modeled the therapeutic dose after 2 and 3 initial doses. We prospectively validated these 2 models in an independent cohort (n = 105). About half of the therapeutic dose variability was predictable after 3 days of therapy: R2 was 53% in the derivation cohort and 42% in the validation cohort. INR response after 3 warfarin doses (INR3) inversely correlated with therapeutic dose (p < 0.001). Intraoperative blood loss transiently, but significantly, elevated the postoperative INR values. Other significant (p < 0.03) predictors were the first and second warfarin doses (+7% and +6%, respectively, per 1 mg), and statin use (-15.0%). The model derived after 2 warfarin doses explained 32% of the variability in therapeutic dose. We developed and validated algorithms that estimate therapeutic warfarin doses based on clinical factors and INR response available after 2-3 days of warfarin therapy. The algorithms are implemented online at www.WarfarinDosing.org.


Mathematical modeling of microscale biology: Ion pairing, spatially varying permittivity, and Born energy in glycosaminoglycan brushes.
Biological macromolecules including nucleic acids, proteins, and glycosaminoglycans are typically anionic and can span domains of up to hundreds of nanometers and even micron length scales. The structures exist in crowded environments that are dominated by multivalent electrostatic interactions that can be modeled using mean-field continuum approaches that represent underlying molecular nanoscale biophysics. We develop such models for glycosaminoglycan brushes using steady state modified Poisson-Boltzmann models that incorporate important ion-specific (Hofmeister) effects. The results quantify how electroneutrality is attained through ion electrophoresis, spatially-varying permittivity hydration forces, and ion-specific pairing. Brush-salt interfacial profiles of the electrostatic potential as well as bound and unbound ions are characterized for imposed jump conditions across the interface. The models should be applicable to many intrinsically-disordered biophysical environments and are anticipated to provide insight into the design and development of therapeutics and drug-delivery vehicles to improve human health.


Neuronal ceroid-lipofuscin storage in Siamese cats.
The clinico-pathological findings of a nervous disease in two mature Siamese cats are described. In one animal intermittent convulsions and mania over a period of three weeks terminated in death, while in the other irritability and hind leg weakness were the main clinical features. Neuronal cytoplasmic inclusions composed of a complex lipid material were detected microscopically. The ultrastructure and staining reactions of these inclusions in one cat were similar to the curvilinear bodies described in neurovisceral storage disease in humans and in a neuronal lipodystrophy of cattle. The deposit was considered likely to be related to ceroid-lipofuscin. No differences in brain lipid quantity or quality could be detected when compared to two control cats.


Using a personality inventory to identify risk of distress and burnout among early stage medical students.
Distress and burnout are common among medical students and negatively impact students' physical, mental, and emotional health. Personality inventories such as the Myers-Briggs Type Indicator (MBTI), used in medical education, may have a role in identifying burnout risk early. The authors conducted a cross-sectional survey study among 185 1st year medical students with the MBTI, the general well-being schedule (GWB), and Maslach Burnout Inventory-Student Survey (MBI-SS). Descriptive statistics and one-way MANOVAs were used to identify the prevalence and differences in MBTI preferences and distress/burnout risk. Response rate was 185/185 (100%). Distress (GWB) was reported by 84/185 (45.4%). High scores on exhaustion were reported by 118/182 (64.8%), cynicism by 76/182 (41.8%), and decreased professional efficacy by 38/182 (20.9%) for the three dimensions of the MBI-SS. Only 21/182 (11.5%) of respondents had high scores on all three dimensions of burnout. Students with MBTI preferences for extraversion reported greater positive well-being (P < 0.05), self-control (P < 0.05), professional efficacy (P < 0.01), and lower levels of depression (P < 0.01) compared with those with introversion preference. Distress and burnout are prevalent early in medical training. The significant difference between extraversion and introversion in relation to distress and burnout deserves further study. Use of a personality inventory may help identify students at risk of burnout and allow appropriate early stress management.


An Extended Multireference Study of the Singlet and Triplet States of the 9,10-didehydroanthracene Diradical.
The 9,10-didehydroanthracene is an aromatic diradical produced by the Bergman cyclization of a benzannulated 10-membered enediyne. It is a 1,4 diradical, similar to p-benzyne. Here we study the spin state occupancy of the ground state of 9,10-didehydroanthracene by employing multireference methods (MR-CISD and MR-AQCC) with different basis sets (cc-pVDZ and cc-pVTZ) and active space sizes (CAS (2,2) through CAS (8,8)). At the CAS (8,8) MR-AQCC/cc-pVDZ level of theory, we find a two-configurational singlet ground state with an adiabatic Δ EST of 6.13 kcal/mol. Unpaired electron density populations and dominant electronic configuration interactions were used to analyze the features of the 9,10-didehydroanthracene diradical.


Intermediate Band Material of Titanium-Doped Tin Disulfide for Wide Spectrum Solar Absorption.
Intermediate band (IB) materials are of great significance due to their superior solar absorption properties. Here, two IBs peaking at 0.88 and 1.33 eV are reported to be present in the forbidden gap of semiconducting SnS2 ( Eg = 2.21 eV) by doping titanium up to 6 atom % into the Sn site via a solid-state reaction at 923 K. The solid solution of Sn1- xTi xS2 is able to be formed, which is attributed to the isostructural structure of SnS2 and TiS2. These two IBs were detected in the UV-vis-NIR absorption spectra with the appearance of two additional absorption responses at the respective regions, which in good agreement with the conclusion of first-principles calculations. The valence band maximum (VBM) consists mostly of the S 3p state, and the conduction band minimum (CBM) is the hybrid state composing of Ti 3d (eg), S 3p, and Sn 5s, and the IBs are mainly the nondegenerate t2g states of Ti 3d orbitals. The electronic states of Ti 3d reveal a good ability to transfer electrons between metal and S atoms. These wide-spectrum absorption IBs bring about more solar energy utilization to enhance solar thermal collection and photocatalytic degradation of methyl orange.


Measuring and predicting maximal aerobic power in international-level intermittent sport athletes.
The purpose of this study was to measure actual VO2max during the multi-stage fitness test (MSFT) and to compare this with predicted values obtained using previously established, commonly used methods. We also wanted to determine a new and more accurate regression equation for the prediction of VO2max in intermittent sport athletes. Twenty-six, elite, male, intermittent sport athletes performed the MSFT with oxygen uptake (VO2) and heart rate (HR) measured throughout. Paired t-tests were used to compare measured VO2max with predicted VO2max. Linear regression was used to determine the equation for the prediction of VO2max from the total number of shuttles completed. There were no differences between the two methods of predicting VO2max, however, both predicted values (53.6+/-3.9 and 51.3+/-4 mL x kg(-1) x min(-1)) were significantly lower (9.3% and 13.2%, respectively) than measured VO2max (59.1+/-6.6 mL x kg(-1) x min(-1), P < 0.001). Correlations between measured and predicted VO2max were similar for both prediction methods (r = 0.61, P = 0.013 and r = 0.68 and P = 0.004). We present a new prediction equation [Y (VO2max, mL x kg(-1) x min(-1)) = 0.38 x total number of shuttles completed +25.98] (where R = 0.69; R2 = 0.48; SEE = 4.9 mL x kg(-1) x min(-1); SEE% = 8.3) which provides a more valid method of predicting actual max in intermittent sport athletes. A new regression equation to predict VO2max in intermittent sport athletes has been established. Whilst some error in predicting VO2max still exists, the new equation will provide coaches and sport-scientists with a more suitable equation with which to predict VO2max in intermittent sport athletes.


First report of Fusarium concentricum causing wilt on Podocarpus macrophyllus in China.
Podocarpus macrophyllus (Thunb.) D. Don is used in many fields, including landscape, medicine, and forest interplanting. In July 2019, shoot blight was observed on P. macrophyllus at three nurseries in Harbin, China. Approximately 15% of plants had symptoms of the disease, which included rapid, synchronized death of leaves on individual branches. Eventually the whole plant wilted. Leaves and stems turned dark blue to brown. Ten infected vascular tissue samples from 10 individual plants were surface-disinfested in 0.5% NaOCl for 5 min, rinsed 3 times in sterile distilled water, and cultured on potato dextrose agar (PDA) amended with 50 µg/ml streptomycin at 26°C. Six similar fungal isolates from ten samples were isolated and subcultured. Single-conidium isolates were generated with methods reported previously (Leslie and Summerell 2006). Colonies on PDA consisted of densely floccose aerial hyphae with light yellow and pinkish pigments. Microconidia were oval to obovoid or allantoid, 3.8 to 11.8 μm in length and 2.8 to 4.6 μm in width, mostly non-septate on carnation leaf agar (CLA). Macroconidia were naviculate-to-fusiform slender, 24.9 to 57.2 μm in length and 2.8 to 4.5 μm in width with 3- to 5- septate, with a beaked apical cell and a foot-shaped basal cell. According to these morphological characteristics, all isolates were identified as Fusarium spp. (Aoki et al. 2001 ). Genomic DNA was extracted from a representative isolate LHS1. The internal transcribed spacer regions (ITS), translation elongation factor 1-alpha gene (TEF-1ɑ) and β-tubulin (TUB2) gene were amplified using the primers ITS1 and ITS4 (Yin et al. 2012),EF1-728F/EF1-986R (Carbone and Kohn 1999) and T1/Bt2b (Glass and Donaldson 1995), respectively. DNA sequences of LHS1 were deposited in GenBank (accession nos. MT914496 for ITS, MT920920 for TEF-1ɑ and MT920921 for TUB2, respectively). MegaBLAST analysis of the ITS, TEF-1a, and TUB2 sequences indicated 100%, 97.7% and 100% similarity with Fusarium concentricum isolate CBS 450.97 (accession no. MH862659.1 for ITS, MT010992.1 for TEF-1a, and MT011040.1 for TUB2, respectively). To determine pathogenicity, P. macrophyllus plants were grown in 10-cm pots containing a commercial potting mix (five plants/pot). At the 10 to 12 leaf stage, 10 healthy plants (2 pots) were inoculated by spraying 5 ml of a conidial suspension (4×106 spores/ml) onto every plant. Ten plants treated with sterile distilled water served as a control. The test was repeated twice. All plants were placed in a humidity chamber (>95% RH, 26℃) for 48 h after inoculation and then transferred to a greenhouse at 22/28°C (night/day). All inoculated wilted with leaves and stems turning dark blue to brown 15 days after inoculation. No symptoms were observed on the control plants. The fungus was re-isolated and confirmed to be F. concentricum according to morphological characteristics and molecular identification. To our knowledge, this is the first report of F. concentricum on P. macrophyllus in world. The disease caused a large number of plants to wilt and die, seriously impacting the ability of the horticulture industry to produce P. macrophyllus. Although this pathogen causes leaf and shoot blight symptoms, it is not clear if the pathogen is also a vascular wilt disease. The occurrence of the new disease caused by F. concentricum highlights the importance of developing management strategies to protect P. macrophyllus.


Carbonic anhydrase, ultrastructural localization in the mouse gastric mucosa and improvements in the technique.
The ultrastructural localization of carbonic anhydrase activity in mouse gastric mucosal cells as revealed by the cobalt bicarbonate histochemical method of Hansson has been made. In addition the effects of fixatives used for ultrastructural studies have been evaluated for reduction of carbonic anhydrase activity; exogenous erythrocyte carbonic anhydrase has been localized in tissues; acetazolamide and potassium cyanate inhibition of activity demonstrated; and an improved method for the osmication of reacted tissues for electron microscopy has been developed. The results indicate that the glutaraldehyde, formaldehyde, picric acid fixative, which retains about 5% of the original carbonic anhydrase activity, is distinctly better for histochemical studies than formaldehyde fixation, which retains about 32% activity. Acetazolamide at 10(-5) M consistently inhibits histochemical reaction, as does 20 mM KCNO, in the incubation medium. Exogenous carbonic anhydrase is readily visualized by the histochemical technique. Electron microscopy of gastric mucosa reacted for carbonic anhydrase activity indicates the focal deposition of the cobalt sulfide reaction product in the cores of microvilli lining the intracellular canaliculi, in the basal and lateral cell folds of parietal cells, and in the microvilli as well as the cytoplasm between mucous granules in the surface mucous cells. In addition, some reaction product was found in the mitochondrial cristae and in some nuclei and intercellular spaces.


Activation of dynamin GTPase by acidic phospholipids and endogenous rat brain vesicles.
Dynamin is a GTPase thought to play a role in endocytosis based on genetic analysis of its homolog in Drosophila melanogaster shibire. Previous studies have stressed an in vitro association with microtubules, though additional evidence suggests that dynamin associates with membranous organelles. In an analysis of the enzymatic and membrane binding properties of dynamin, we have found that the acidic phospholipids, phosphatidylserine, phosphatidylglycerol, and phosphatidylinositol, are able to stimulate GTP hydrolysis in a manner similar to activation previously shown with microtubules. A neutral phospholipid, phosphatidylcholine, had no effect on dynamin GTPase. Activation of dynamin was biphasic, with a decrease in activity back to basal levels with increased concentrations of either microtubules or liposomes. A comparison between GTPase stimulation induced by microtubules and that by phospholipids suggests that ionic interactions between the basic C-terminal domain of dynamin and the negatively charged microtubule or phospholipid head group are important. In support of this, GTPase stimulation by these agents in combination was not additive. A salt-extracted membrane fraction from brain tissue also activated dynamin GTPase, though to a lower extent than pure phospholipids. These results suggest that membrane components could be responsible for some aspects of the regulation of dynamin function in vivo.


Positional assembly of hemin and gold nanoparticles in graphene-mesoporous silica nanohybrids for tandem catalysis.
Here, for the first time, a hybrid catalyst in which hemin and gold nanoparticles are positioned in spatially separate domains within a graphene-mesoporous silica support is presented. Specifically, monomeric hemin can be anchored on the inner exposed graphene surface of a graphene-mesoporous silica hybrid (GS) via π-π stacking interactions. After the assembly, such nanocomposites can function as a peroxidase mimic. Next, gold nanoparticles, which act as artificial glucose oxidase, can be conjugated to the functional NH2 groups present on the outer coated silica surface. As a result, the integrated catalysts containing multiple catalytic sites can be used to catalyze sequential reactions, without the aid of true enzymes. This work is an important step forward in positional assembly of biomimetic catalysts for artificially mimicking natural organelles or important chemical transformations in the future.


Lupeol Alleviates Cerebral Ischemia-Reperfusion Injury in Correlation with Modulation of PI3K/Akt Pathway.
This study aimed to investigate the effect and mechanism of lupeol on cerebral ischemia-reperfusion injury in rats. The effects of lupeol on cerebral infarction, cerebral water content, neurological symptoms and cerebral blood flow in rats were evaluated. Nissl staining was carried out to assess the neuronal damage of ischemic brain after I/R in rats. Apoptosis of ischemic brain neurons after I/R was detected by TUNEL staining. Western blotting was carried out to detect the effects of lupeol on the expression of p-PDK1, p-Akt, pc-Raf, p-BAD, cleaved caspase-3 and p-PTEN. Lupeol significantly increased cerebral blood flow after I/R in rats, reduced brain water content and infarct volume, and decreased neurological function scores. It significantly reduced neuronal damage after I/R in rats, and significantly reduced neuronal cell loss. PI3K inhibitor (LY294002) can eliminate the effect of lupeol on I/R in rats. In addition, lupeol significantly increased the protein expression of p-PDK1, p-Akt, pc-Raf, p-BAD, and down-regulated the expression of cleaved caspase-3. LY294002 reversed the effects of lupeol on the expression of PI3K/Akt signaling pathway-related proteins and cleaved caspase-3 after I/R in rats. Lupeol had significant neuroprotective effects on brain I/R injury and neuronal apoptosis, and its mechanism may be related to the activation of PI3K/Akt signaling pathway.


[Expert consensus on diagnosis and treatment of end-stage liver disease complicated infection (2021 version)].
End-stage liver disease (ESLD) is a life-threatening clinical syndrome with significantly increased mortality when the patients are complicated with infections. For patients with ESLD, infections can induce or aggravate the liver decompensation. In turn, infections are among the most common complication with the disease progression. Experts from Society of Infectious Diseases, Chinese Medical Association firstly formulated "Expert Consensus on Diagnosis and Treatment of End-Stage Liver Disease Complicated with Infection" in July 2018, which is extensively revised based on clinical evidence of recent three years. This consensus summarizes the up-to-date knowledge and experiences across Chinese colleagues, intending to provide principles and wording procedures for clinicians to diagnose and treat ESLD patient complicated with infections.


Strategies for gastric cancer in the modern era.
Gastric cancer is one of the most common neoplasms in Japan, and it is also the second leading cause of cancer-related deaths worldwide. Nowadays, infection with Helicobacter pylori (H. pylori) is a known risk factor for the development of gastric cancer. Therefore, gastric cancer should be considered as an infectious disease, and in fact, prophylactic eradication of H. pylori may prevent the development of metachronous gastric carcinoma. Before the role of H. pylori was understood, a different approach was used. Recently even after the cancer has developed, some newer therapeutic approaches have been pursued. These newer treatments have been summarized as "minimally invasive therapies" and use endoscopic or laparoscopic techniques. In addition, robotic approaches are being developed that seem to hold a great potential to change the surgical approach. Since basic understanding and treatment of the disease have both changed significantly over the last decade, we present a review of current advances in gastric cancer research and therapy.


Use of forensic analysis to better understand shark attack behaviour.
Shark attacks have primarily been analyzed from wound patterns, with little knowledge of a shark's approach, behaviour and intention leading to such wounds. For the first time, during a shark-human interaction project in South Africa, a white shark, Carcharodon carcharias, was filmed biting a vertically positioned person at the water surface, and exhibiting distinct approach patterns leading to the bite. This bite was compared to ten white shark attacks that occurred (i) in the same geographical area of South Africa, and (ii) where the same body parts were bitten. Close similarity of some of these wound patterns to the bite imprint of the videotaped case indicate that the observed behaviour of the white shark may represent a common pattern of approaching and biting humans.


Sandimmun (cyclosporin A): mode of action and clinical results in rheumatoid arthritis.
Cyclosporin A (Sandimmun) has gained wide acceptance by most transplant physicians as the immunosuppressant of choice for preventing rejection of solid organ grafts and graft-versus-host disease. The drug has a specific effect on T-lymphocytes in which it seems to prevent the transcription of genes for several lymphokines. The reduction in IL-2 prevents the clonal expansion of T-lymphocytes and their differentiation into effector T-cells. The reduction in IFN-tau interrupts the feedback mechanism between T-cells and macrophages and the aberrant expression of MHC class II molecules. Through these mechanisms Sandimmun exerts an immunosuppressive and anti-inflammatory effect. Considerable evidence has accumulated to suggest that rheumatoid arthritis (RA) is an auto-immune disease. Activated T-lymphocytes interrelate with macrophages, other inflammatory cells and effector cells in joint tissue, leading to symptoms of inflammation accompanied by joint destruction. Immunosuppressive treatment is already well established in this disease and several trials have already taken place using Sandimmun. A total of 224 patients with RA refractory to conventional disease-modifying drugs have participated in 11 published clinical studies. A review of these studies concludes that Sandimmun is efficacious in controlling inflammatory and functional symptoms, although this improvement is no generally accompanied by reductions in ESR and rheumatoid factor. The frequency of adverse events is comparable to that of other treatments but nephropathy remains the principal factor limiting the use of Sandimmun. Recent evidence suggests that with a strict dosage strategy and good monitoring this problem is controllable and reversible. Further studies are under way to confirm these claims.


High ANKZF1 expression is associated with poor overall survival and recurrence-free survival in colon cancer.
Aim: To investigate the association and prognostic value of ANKZF1 gene for survival in colorectal cancer, the mechanism of ANKZF1 level alteration and correlated signaling pathways ANKZF1 is involved. Patients & methods: The Cancer Genome Atlas COREAD dataset was analyzed by bioinformatical investigation. Results: High ANKZF1 expression is associated with poor overall survival (hazard ratio [HR]: 2.094; 95% CI: 1.188-3.689; p = 0.011) and recurrence-free survival (HR: 1.762; 95% CI: 1.021-3.042; p = 0.042) in colon cancer. Bioinformatical analysis showed ANKZF1 was upregulated by amplification and exon expression. ANKZF1 was associated with angiogenesis and cancer signaling pathways. Conclusion: High ANKZF1 is an independent factor of poor survival (overall survival and recurrence-free survival) in colon cancer by taking part in angiogenesis and some cancer signaling pathways.


Selection of viral variants during persistent infection of insectivorous bat cells with Middle East respiratory syndrome coronavirus.
Coronaviruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are speculated to have originated in bats. The mechanisms by which these viruses are maintained in individuals or populations of reservoir bats remain an enigma. Mathematical models have predicted long-term persistent infection with low levels of periodic shedding as a likely route for virus maintenance and spillover from bats. In this study, we tested the hypothesis that bat cells and MERS coronavirus (CoV) can co-exist in vitro. To test our hypothesis, we established a long-term coronavirus infection model of bat cells that are persistently infected with MERS-CoV. We infected cells from Eptesicus fuscus with MERS-CoV and maintained them in culture for at least 126 days. We characterized the persistently infected cells by detecting virus particles, protein and transcripts. Basal levels of type I interferon in the long-term infected bat cells were higher, relative to uninfected cells, and disrupting the interferon response in persistently infected bat cells increased virus replication. By sequencing the whole genome of MERS-CoV from persistently infected bat cells, we identified that bat cells repeatedly selected for viral variants that contained mutations in the viral open reading frame 5 (ORF5) protein. Furthermore, bat cells that were persistently infected with ΔORF5 MERS-CoV were resistant to superinfection by wildtype virus, likely due to reduced levels of the virus receptor, dipeptidyl peptidase 4 (DPP4) and higher basal levels of interferon in these cells. In summary, our study provides evidence for a model of coronavirus persistence in bats, along with the establishment of a unique persistently infected cell culture model to study MERS-CoV-bat interactions.


Mobile intensive care in myocardial infarction.
In the first six months of its existence a mobile intensive care unit was used to admit 95 patients with definite or probable myocardial infarction to the local district hospital. Though the area served was a rural one, with a radius of about 25 miles from the hospital, the average interval between receiving a call and starting intensive care was less than 30 minutes. Five patients with ventricular fibrillation were successfully resuscitated by the mobile team outside hospital. The mobile unit has made it possible to admit many more patients with myocardial infarction to hospital than before, and we believe its cost and use of skilled staff are justified by the results. The unit reduces the delay between the onset of symptoms and initiation of intensive care and thus diminishes the risk of primary ventricular fibrillation, which is maximal soon after the onset of symptoms. Since mobile intensive care removes the risk of transport it allows concentration of cases of acute myocardial infarction in the larger hospitals.


Small ventricular septal defect associated with severe pulmonary hypertension.
A small ventricular septal defect in an 18 year old man was shown by serial cardiac catheterisation to be associated with a progressive increase in pulmonary arterial pressure. Surgical closure of the defect had no effect on the increased pulmonary arterial pressure. Whether pulmonary hypertension occurred secondary to the haemodynamics of the ventricular septal defect or as an independent event is uncertain.


Tomato derived polysaccharides for biotechnological applications: chemical and biological approaches.
Recent studies concerning the isolation and purification of exopolysaccharides from suspension-cultured tomato (Lycopersicon esculentum L. var. San Marzano) cells and the description of a simple, rapid and low environmental impact method with for obtaining polysaccharides from solid tomato-processing industry wastes are reported. Their chemical composition, rheological properties and partial primary structure were determined on the basis of spectroscopic analyses (UV, IR, GC-MS, (1)H-, (13)C-NMR). Moreover, the anticytotoxic activities of exopolysaccharides obtained from cultured tomato cells were tested in a brine shrimp bioassay and the preparation of biodegradable film by chemical processing of polysaccharides from solid tomato industry waste was also reported.


Decreased expression and release of dipeptidyl peptidase IV (CD26) in cultured peripheral blood T lymphocytes of oral cancer patients.
To investigate the mechanism whereby serum dipeptidyl peptidase (DPP) IV activity in oral cancer patients is decreased, we examined the expression of cell surface DPP IV, also known as CD26, in cultured peripheral blood T lymphocytes of these patients and the amounts of DPP IV released into culture medium; values were compared with those found in healthy subjects. When peripheral blood T lymphocytes were cultured in the presence of phytohemagglutinin, concanavalin A and/or interleukin-2, the proliferative response and expression of CD26 (DPP IV) in their plasma membranes were greatly diminished in oral cancer patients as compared with those in healthy subjects. In addition, DPP IV activity in lymphocyte culture medium was reduced more in oral cancer patients than in healthy subjects, indicating decreased shedding of DPP IV from activated T lymphocytes in the patients. Based on these findings, it is suggested that suppression of DPP IV expression in peripheral blood T lymphocytes is one of the important factors involved in the mechanism of decrease of serum DPP IV activity in oral cancer patients.


Resident Esophageal Microbiota Dysbiosis Correlates with Cancer Risk in Barrett's Esophagus Patients and Is Linked to Low Adherence to WCRF/AICR Lifestyle Recommendations.
Esophageal adenocarcinoma (EAC) is the consequence of longstanding gastroesophageal reflux, which leads to inflammation and could cause Barrett's esophagus (BE), the main risk factor for EAC development. The 5 year survival rate of EAC is poor since the diagnosis occurs at the late stage of the disease. To improve patient management, a better comprehension of the mechanism undergoing the evolution through to adenocarcinoma is needed. Within this scenario, the resident microbiome investigation was studied. This study aimed to explore the esophageal microbial profile in patients affected by non-dysplastic BE, low- and high-grade dysplastic BE, and EAC to identify parameters characterizing cancer progression and to develop a score suitable for clinical practice to stratify cancer risk. The microbiota was investigated through the 16S rRNA gene sequencing of esophageal biopsies. The microbial composition was evaluated at each different taxonomic level along the disease progression. To further investigate bacteria potentially associated with cancer development, non-dysplastic and dysplastic/cancer patients were compared. The presence of the six significant microbial features with multivariate analysis was used to develop a multiparametric score (Resident Esophageal Microbial Dysbiosis Test) to predict the risk of progression toward EAC. Finally, the diagnostic ability of the test and its discrimination threshold for its ability to identify dysplastic/cancer patients were demonstrated. Since EAC has been related to obesity, the relationship between these microbial parameters and patients' diet/lifestyle habits was also investigated. Developing microbiome-based risk prediction models for esophageal adenocarcinoma onset could open new research avenues, demonstrating that the resident microbiome may be a valid cancer risk biomarker.


Few-Layer Antimonene: Anisotropic Expansion and Reversible Crystalline-Phase Evolution Enable Large-Capacity and Long-Life Na-Ion Batteries.
Two-dimensional (2D) antimonene is a promising anode material in sodium-ion batteries (SIBs) because of its high theoretical capacity of 660 mAh g-1 and enlarged surface active sites. However, its Na storage properties and sodiation/desodiation mechanism have not been fully explored. Herein, we propose the sodiation/desodiation reaction mechanism of 2D few-layer antimonene (FLA) based on results acquired by in situ synchrotron X-ray diffraction, ex situ selected-area electron diffraction, and theoretical simulations. Our study shows that the FLA undergoes anisotropic volume expansion along the a/b plane and exhibits reversible crystalline phase evolution (Sb ⇋ NaSb ⇋ Na3Sb) during cycling. Density-functional theory calculations demonstrate that the FLA has a small Na-ion diffusion barrier of 0.14 eV. The FLA delivers a larger capacity of 642 mAh g-1 at 0.1 C (1 C = 660 mA g-1) and a high rate capability of 429 mAh g-1 at 5 C and maintains a stable capacity of 620 mA g-1 at 0.5 C with 99.7% capacity retention from the 10th to the 150th cycle. Considering the 660 mAh g-1 theoretical capacity of Sb, the electrochemical utilization of Sb atoms of FLA is as high as 93.9% at a rate of 0.5 C for over 150 cycles, which is the highest capacity and Sb utilization ratio reported so far. Our study discloses the Na storage mechanism of 2D FLA, boosting promising applications of 2D materials for advanced SIBs.


Glycine Polymerization on Oxide Minerals.
It has long been suggested that mineral surfaces played an important role in peptide bond formation on the primitive Earth. However, it remains unclear which mineral species was key to the prebiotic processes. This is because great discrepancies exist among the reported catalytic efficiencies of minerals for amino acid polymerizations, owing to mutually different experimental conditions. This study examined polymerization of glycine (Gly) on nine oxide minerals (amorphous silica, quartz, α-alumina and γ-alumina, anatase, rutile, hematite, magnetite, and forsterite) using identical preparation, heating, and analytical procedures. Results showed that a rutile surface is the most effective site for Gly polymerization in terms of both amounts and lengths of Gly polymers synthesized. The catalytic efficiency decreased as rutile > anatase > γ-alumina > forsterite > α- alumina > magnetite > hematite > quartz > amorphous silica. Based on reported molecular-level information for adsorption of Gly on these minerals, polymerization activation was inferred to have arisen from deprotonation of the NH3+ group of adsorbed Gly to the nucleophilic NH2 group, and from withdrawal of electron density from the carboxyl carbon to the surface metal ions. The orientation of adsorbed Gly on minerals is also a factor influencing the Gly reactivity. The examination of Gly-mineral interactions under identical experimental conditions has enabled the direct comparison of various minerals' catalytic efficiencies and has made discussion of polymerization mechanisms and their relative influences possible Further systematic investigations using the approach reported herein (which are expected to be fruitful) combined with future microscopic surface analyses will elucidate the role of minerals in the process of abiotic peptide bond formation.


Diagnosis of trichomoniasis in 'virgin' bulls by culture and polymerase chain reaction.
The diagnostic test for Tritrichomonas foetus in bulls is microscopic examination of cultured preputial samples. Trichomonads other than T. foetus can be present in a preputial sample. Both a staining technique and a polymerase chain reaction assay were useful in differentiating between T. foetus and another trichomonad observed in samples from virgin bulls.


Reproductive Diapause in North American Populations of the Introduced Lady Beetle Hippodamia variegata (Coleoptera: Coccinellidae).
The Palearctic lady beetle species, Hippodamia variegata (Coleoptera: Coccinellidae), first collected in 1984 near Montreal, Quebec, Canada, is expanding its distribution into northeastern and north central portions of North America. Examination of responses to abiotic factors that influence the seasonal biology of H. variegata may provide insights into its potential range expansion in North America. The induction and duration of adult hibernal diapause in three North American populations of H. variegata, collected between 40°N and 44°N latitude, was determined at four constant photoperiods (L:D 16:8, 14:10, 12:12, and 10:14) at 22°C. Thirteen to twenty-one percent of females reared at L:D 16:8 entered diapause, whereas shorter photoperiods (L:D 12:12 and 10:14) induced diapause in 100% of females. Variation in the response to L:D 14:10 was observed among the three populations, 27-100% of females exhibited reproductive diapause. Pupae and young adults were sensitive to changes in constant photoperiods (L:D 16:8 ⇆ 10:14). Individuals reared at L:D 10:14 that were moved to L:D 16:8 on the day of pupation or the day of adult eclosion produced ovipositing females. Individuals reared at L:D 16:8 and transferred to L:D 10:14 on the day of pupation or the day of adult eclosion produced females that did not oviposit within 30 d of eclosion.