The meaning and impact on well-being of bespoke dancing sessions for those living with Parkinson's.
This paper presents qualitative research findings from the evaluation of a Parkinson's Dance well-being venture in the UK. Qualitative data was gathered to see how bespoke dancing sessions helped people with Parkinson's (PwP) to manage their conditions and improve their lives and prospects. Principles of a participatory approach were incorporated and methods included semi-structured interviewing, researchers participant observation and an elicitation-based activity. Nineteen PwP, six carers, four dance artists and seven helpers participated in the study. Participating in Parkinson's Dance sessions meant that PwP could experience the possibilities to dance, develop a "can do" attitude, experience fun, enjoyment, social connection, exercise, movement to music, improvement and/or maintenance of their balance, suppleness, coordination and confidence with movement, symptoms being pushed back and ability to learn new things. Our findings add to the evidence-base about the benefits of dance for people experiencing Parkinson's and through novel application of the Life-world based well-being framework of K. T. Galvin and Todres (2011) we propose a theoretical basis for Parkinson's Dance as a resource for well-being. There is scope to consider application of the well-being framework to other arts activities and as the basis of an arts and well-being evaluation tool.


Remote Leptomeningeal Dissemination in Olfactory Neuroblastoma Mimicking Multiple Parasagittal Meningiomas: Diagnostic and Therapeutic Challenge.
Olfactory neuroblastoma (ON) is a highly aggressive and locally recurrent neoplasm. Distant systemic metastases are not uncommon, but remote leptomeningeal dissemination is extremely rare. We report 2 cases of ON previously treated with endoscopic endonasal radical surgical resection and radiotherapy. After a relatively long period of disease-free survival, multiple leptomeningeal lesions were seen around the sagittal sinus giving a radiologic appearance of parasagittal meningiomas. Both patients underwent surgery and multimodal treatment with radiotherapy and chemotherapy for the disseminated disease. Pathologic examination confirmed the parasagittal lesions as metastatic ON. A high suspicion of secondary disease should be maintained in patients with previous history of ON and parasagittal leptomeningeal enhancing lesion, particularly when multiple lesions are detected around the sagittal sinus. Radical resection and multimodal treatment are warranted to improve long-term outcome. Understanding the venous drainage route as a potential pathway for remote seeding from the primary site of disease has therapeutic implications. We postulate that en-bloc tumor resection and proximal sagittal sinus ligation might reduce potential for leptomeningeal metastasis.


Transporters and drug therapy: implications for drug disposition and disease.
The efficacy of drug therapy results from the complex interplay of multiple processes that govern drug disposition and response. Most studies to date have focused on the contribution of drug-metabolizing enzymes to the drug disposition process. However, over the past decade, it has become increasingly apparent that carrier-mediated processes, or transporters, also play critical roles in the overall disposition of numerous drugs in clinical use. In addition to their roles in xenobiotic transport, drug transporters often mediate important physiologic functions via transport of endogenous substrates such as amino acids, bile acids, and hormones that are critical for maintenance of normal homeostasis. In this review we focus on the emerging field of transporter proteins in relation to the drug disposition process, with particular emphasis on clinical implications of transporters to drug-drug interactions and subsequent development of adverse effects, interindividual variability in drug response, and human disease.


Downregulation of cytokine release by heat preconditioning of livers used for transplantation in rats.
We evaluated the changes in the levels of released cytokines following heat preconditioning of the livers used in rat liver transplantation. The donor rats in the heat preconditioning (HP) group were subjected to heat preconditioning 48 h before graft harvesting. The liver isografts were preserved in Euro-Collins solution for 8 h, and then transplanted orthotopically. The one-week survival rate of the HP group was significantly better than that of the control (C) group. The serum levels of interleukin-6 and interleukin-10 were significantly lower in the HP group than in the C group. Histological staining revealed that the stagnation of red blood cells and infiltration of neutrocytes were reduced in the HP group. The expression of intercellular adhesion molecule-1 was decreased around the central vein in the HP group, as revealed by immunohistochemistry. These results indicate that heat preconditioning downregulates cytokine release and reduces the frequency of microcirculation disorders.


Correlation between different levels and patterns of dyslipidemia and glomerular filtration rate in patients with type 2 diabetes: A cross-sectional survey of a regional cohort.
Due to the high cardiovascular risk in patients with diabetic nephropathy, more attention should be paid to lipid levels and dyslipidemia in these patients. The current study investigated the association between single and mixed dyslipidemia patterns, estimated glomerular filtration rate (eGFR), and different chronic kidney disease (CKD) stages. This cross-sectional study evaluated 4059 patients with type 2 diabetes (T2D). TG, TC, LDL-C, and HDL-C were measured. Non-HDL-C and AIP were calculated. We estimated eGFR using the CKD-EPI equation. With the progression of the kidney failure stage, mean levels of TG, LDL-C, non-HDL-C, and AIP decreased. HDL-C levels decreased with the advance of the CKD stage in men but did not change significantly in women. The prevalence of single dyslipidemia, including high LDL-C and high non-HDL-C, decreased with the advancing CKD stage. The prevalence of mixed dyslipidemia patterns, including high AIP and high LDL-C, high AIP and high non-HDL-C, showed a significant downward tendency. TG and AIP levels were negatively, and HDL-C levels were positively correlated with eGFR after adjusting for the risk factors. Also, CKD stage 3 was positively related to the risk of high TG and low HDL-C. This study shows that blood lipids decreased with the progression of renal failure in patients with T2D. However, after adjustment, TG and AIP levels had negative, and HDL-C levels had a positive correlation with eGFR, which could be consistent with the hypothesis that eGFR decreases with increasing TG or AIP levels or decreasing HDL-C levels.


Structural basis of metabolite transport by the chloroplast outer envelope channel OEP21.
Triose phosphates (TPs) are the primary products of photosynthetic CO2 fixation in chloroplasts, which need to be exported into the cytosol across the chloroplast inner envelope (IE) and outer envelope (OE) membranes to sustain plant growth. While transport across the IE is well understood, the mode of action of the transporters in the OE remains unclear. Here we present the high-resolution nuclear magnetic resonance (NMR) structure of the outer envelope protein 21 (OEP21) from garden pea, the main exit pore for TPs in C3 plants. OEP21 is a cone-shaped β-barrel pore with a highly positively charged interior that enables binding and translocation of negatively charged metabolites in a competitive manner, up to a size of ~1 kDa. ATP stabilizes the channel and keeps it in an open state. Despite the broad substrate selectivity of OEP21, these results suggest that control of metabolite transport across the OE might be possible.


Factors associated with cytomegalovirus serostatus in young people in England: a cross-sectional study.
Human cytomegalovirus (CMV) is a common herpesvirus which is estimated to infect 83% of the global population. Whilst many infections are asymptomatic, it is an important cause of morbidity and mortality, particularly for immunocompromised people and for infants who are congenitally infected. A vaccine against CMV has been stated as a public health priority, but there are gaps in our understanding of CMV epidemiology. To guide potential future vaccination strategies, our aim was to examine risk factors for CMV seropositivity in young people in England. The Health Survey for England (HSE) is an annual, cross-sectional representative survey of households in England during which data are collected through questionnaires, and blood samples are taken. We randomly selected individuals who participated in the HSE 2002, aiming for 25 participants of each sex in each single year age group from 11 to 24 years. Stored samples were tested for CMV antibodies. We undertook descriptive and regression analyses of CMV seroprevalence and risk factors for infection. Demographic data and serostatus were available for 732 individuals, of whom 175 (23.7%) were CMV-seropositive. CMV seroprevalence was associated with age, with 18.3% seropositive at 11-14 years compared to 28.3% at 22-24 years. CMV serostatus was also higher in people of non-white ethnicity (adjusted odds ratio [aOR] 6.22, 95% confidence interval [CI] 3.47-11.14), and in adults who were seropositive for EBV (aOR 2.08 [1.06-4.09]). There was no evidence that smoking status, occupation, body mass index and region of England were associated with CMV serostatus. CMV seroprevalence is strongly associated with ethnicity, and modestly increases with age in 11-24-year-olds. A greater understanding of the transmission dynamics of CMV, and the impact of this on CMV-associated morbidity and mortality, is necessary to inform effective vaccination strategies when a vaccine for CMV becomes available.


Subjective social status and psychosocial and metabolic risk factors for cardiovascular disease among African Americans in the Jackson Heart Study.
Subjective social status has been shown to be inversely associated with multiple cardiovascular risk factors, independent of objective social status. However, few studies have examined this association among African Americans and the results have been mixed. Additionally, the influence of discrimination on this relationship has not been explored. Using baseline data (2000-2004) from the Jackson Heart Study, an African American cohort from the U.S. South (N=5301), we quantified the association of subjective social status with selected cardiovascular risk factors: depressive symptoms, perceived stress, waist circumference, insulin resistance and prevalence of diabetes. We contrasted the strength of the associations of these outcomes with subjective versus objective social status and examined whether perceived discrimination confounded or modified these associations. Subjective social status was measured using two 10-rung "ladders," using the U.S. and the community as referent groups. Objective social status was measured using annual family income and years of schooling completed. Gender-specific multivariable linear and logistic regression models were fit to examine associations. Subjective and objective measures were weakly positively correlated. Independent of objective measures, subjective social status was significantly inversely associated with depressive symptoms (men and women) and insulin resistance (women). The associations of subjective social status with the outcomes were modest and generally similar to the objective measures. We did not find evidence that perceived racial discrimination strongly confounded or modified the association of subjective social status with the outcomes. Subjective social status was related to depressive symptoms but not consistently to stress or metabolic risk factors in African Americans.


Acclimatization to chronic hypobaric hypoxia is associated with a differential transcriptional profile between the right and left ventricle.
Acute hypobaric hypoxia induces a transient reactivation of the fetal-metabolic gene program in the rat heart. Although chronic hypobaric hypoxia causes alterations in metabolism and cardiac function, little is known about the transcriptional profile associated with acclimatization to chronic hypoxia. Because in chronic hypoxia only the right ventricle is exposed to pressure overload (pulmonary hypertension), we hypothesized that chronic hypobaric hypoxia induces a differential transcriptional profile in the right and left ventricle. Male Wistar rats were exposed to a hypobaric environment (11% O2) for 4, 10, and 12 weeks. Right and left ventricular tissue was isolated for histology and candidate gene expression. Chronic hypobaric hypoxia induced right ventricular hypertrophy without fibrosis. In the right ventricle, changes in metabolic gene expression suggested a downregulation of fatty acid metabolism and an increase in glucose metabolism, while left ventricular metabolic gene expression suggested restoration of fatty acid metabolism. While myosin heavy chain isoform transcript levels in the right ventricle indicated a progressive reactivation of the fetal iso-gene pattern, there was normalization of myosin iso-gene expression in the left ventricle. Similarly, sarcoendoplasmic reticulum ATPase 2a (SERCA2a) transcript levels in the right ventricle decreased by 12 weeks of chronic hypoxia exposure, whereas, left ventricular SERCA2a expression was unchanged. In conclusion, acclimatization to chronic hypobaric hypoxia induced a differential transcriptional response between the right and left ventricle. We speculate that reactivation of the fetal-metabolic program in the right ventricle is adaptive to pressure overload.


Allopurinol attenuates left ventricular dysfunction in rats with early stages of streptozotocin-induced diabetes.
Xanthine oxidase-derived superoxide production and oxidative stress contribute to the development of diabetic complications including diabetic cardiomyopathy. We hypothesized that xanthine oxidase-inhibitor allopurinol (ALP) may decrease hyperglycemia-induced oxidative stress, ameliorate cardiomyocyte hypertrophy and fibrosis, and attenuate the development of left ventricle (LV) diastolic dysfunction in rats with streptozotocin (STZ)-induced diabetes. Control Sprague Dawley (C) or streptozotocin-induced diabetic (D) rats were either untreated or treated with allopurinol (100 mg/kg/day) for 4 weeks starting at 1 week after streptozotocin injection. Free 15-F2t-isoprostane, a specific indicator of oxidative stress was measured by enzymatic immunoassay. The cardiomyocyte cross-sectional area was assessed by hematoxylin and eosin-stained paraffin-embedded sections of LVs. Myocardial collagens I and III were assessed by immunol histochemistry and Western blotting. Echocardiography was performed to characterize cardiac structure and function. In diabetic rats, both plasma and cardiac tissue levels of free 15-F2t-isoprostane were increased (p < 0.05 vs. control), accompanied with significant increase (p < 0.05 vs. control) in cross-section area and myocardial collagen deposition of LV cardiomyocyte. Echocardiography in diabetic rats showed that LV weight/body weight ratio was significantly higher than in control rats, whereas the levels of LV end-diastolic volume and stroke volume were decreased (all p < 0.05 diabetic vs. control). All these changes were either attenuated or prevented by allopurinol. In addition, LV ejection fraction in diabetic rats treated with allopurinol was higher than that in untreated diabetic rats (p < 0.05). Allopurinol can attenuate hyperglycemia-induced oxidative stress, ameliorate cardiomyocyte hypertrophy and fibrosis and subsequently prevent left ventricular dysfunction in early diabetes.


Fip1--an essential component of the Saccharomyces cerevisiae polyadenylation machinery is phosophorylated by protein kinase CK2.
Since Fip1 is phosphoprotein we investigated whether it is a substrate for protein kinase CK2. According to the amino acid sequence Fip1 harbours twenty putative CK2 phosphorylation sites. Here we have report characterization of Fip1 as a substrate for both forms of CK2. Fip1 serves as a substrate for both the recombinant CK2alpha ' (Km 1.28 microM) and holoenzyme (Km 1.4 microM) but not for CK1. By MALDI-MS we identified the two serine residues at positions 73 and 77 as the possible in vitro phosphorylation sites. These data may help to elucidate the role of Fip1 in the mRNA 3'-OH polyadenylation process and the involvement of CK2 mediated phosphorylation in regulation of interactions and activity members of cleavage/polyadenylation factor (CPF) complex.


Impact of protein conformational diversity on AlphaFold predictions.
After the outstanding breakthrough of AlphaFold in predicting protein 3D models, new questions appeared and remain unanswered. The ensemble nature of proteins, for example, challenges the structural prediction methods because the models should represent a set of conformers instead of single structures. The evolutionary and structural features captured by effective deep learning techniques may unveil the information to generate several diverse conformations from a single sequence. Here, we address the performance of AlphaFold2 predictions obtained through ColabFold under this ensemble paradigm. Using a curated collection of apo-holo pairs of conformers, we found that AlphaFold2 predicts the holo form of a protein in ∼70% of the cases, being unable to reproduce the observed conformational diversity with the same error for both conformers. More importantly, we found that AlphaFold2's performance worsens with the increasing conformational diversity of the studied protein. This impairment is related to the heterogeneity in the degree of conformational diversity found between different members of the homologous family of the protein under study. Finally, we found that main-chain flexibility associated with apo-holo pairs of conformers negatively correlates with the predicted local model quality score plDDT, indicating that plDDT values in a single 3D model could be used to infer local conformational changes linked to ligand binding transitions. Data and code used in this manuscript are publicly available at https://gitlab.com/sbgunq/publications/af2confdiv-oct2021. Supplementary data are available at Bioinformatics online.


Seeing the Forest in Lieu of the Trees: Continuum Simulations of Cell Membranes at Large Length Scales.
Biological membranes exhibit long-range spatial structure in both chemical composition and geometric shape, which gives rise to remarkable physical phenomena and important biological functions. Continuum models that describe these effects play an important role in our understanding of membrane biophysics at large length scales. We review the mathematical framework used to describe both composition and shape degrees of freedom, and present best practices to implement such models in a computer simulation. We discuss in detail two applications of continuum models of cell membranes: the formation of microemulsion and modulated phases, and the effect of membrane-mediated interactions on the assembly of membrane proteins.


Increased extracellular glutamate evoked by 1-methyl-4-phenylpyridinium [MPP(+)] in the rat striatum is not essential for dopaminergic neurotoxicity and is not derived from released glutathione.
A number of studies have implicated the interactions of the excitatory amino acid L-glutamate (Glu) with its ionotropic and metabotropic receptors as important components of the mechanism underlying the dopaminergic neurotoxicity of 1-methyl-4-phenylpyridinium [MPP(+)]. Furthermore, microdialysis experiments have demonstrated that perfusion of relatively high concentrations of MPP(+) into the rat striatum evoke a delayed, massive release of Glu. Interestingly, perfusion of MPP(+) also mediates a similar release of glutathione (GSH). Together, these observations raise the possibility that the rise of extracellular Glu mediated by MPP(+) may be the result of hydrolysis of released GSH by gamma-glutamyl transpeptidase (gamma-GT). In the present investigation it is demonstrated that perfusions of solutions of 0.7 and 1.3 mM MPP(+) dissolved in artificial cerebrospinal fluid into the rat striatum evoke neurotoxic damage to dopaminergic terminals, assessed by both a two-day test/challenge procedure and tyrosine hydroxylase immunoreactivity, but without the release of Glu. Perfusions of 2.5 mM MPP(+) cause more extensive dopaminergic neurotoxicity and a dose-dependent release of Glu. However, neither this release of Glu nor MPP(+)-induced dopaminergic neurotoxicity are blocked by the irreversible gamma-GT inhibitor acivicin. Together, these observations indicate that a rise of extracellular levels of Glu is not essential for the dopaminergic neurotoxicity of MPP(+). Furthermore, the rise of extracellular Glu caused by perfusion of 2.5 mM MPP(+) is not the result of the gamma-GT-mediated hydrolysis of released GSH. It is possible that the rise of extracellular levels of Glu, L-aspartate, L-glycine and L-taurine evoked by perfusions of 2.5 mM MPP(+) into the rat striatum may reflect, at least in part, the release of these amino acids from astrocytes.


Radiation therapy of the pelvic and paraaortic lymph nodes in cervical carcinoma: a prospective three-dimensional analysis of patient positioning and treatment technique.
Pelvic box fields in prone position are the standard treatment for patients with cervical carcinomas. The issue investigated in this report is whether this technique should also be used when extending the planning target volume to the paraaortic region. In a prospective study of eight consecutive patients with cervical carcinomas, two patient positions (prone and supine) and three radiation techniques (A, anteroposterior/posteroanterior opposed fields; B, four-field box; and C, three-field technique) were examined concerning the dose to critical organs. The analysis was based on three-dimensional planning, dose-volume histograms and normal tissue complication probabilities (NTCP). Compared to the prone position, the supine position led to improved organ sparing in four of seven organs (liver, both kidneys, spinal canal). In two of seven organs (rectum and bladder) no difference between prone and supine position was observed. The best sparing of small bowel was achieved in prone position. Technique B followed by technique C in the supine position resulted in the best overall sparing of critical organs concerning the volumes receiving the respective TD(5/5) doses or more. Mean NTCP values for liver, rectum and bladder were below 1.0%. The highest values of up to 12% were found for both kidneys in prone position with C and for the spinal canal with A in the prone and supine position. According to this analysis, for the treatment of the pelvic and paraaortic lymph node regions together, supine position and technique B (alternatively C) should be preferred despite the advantages of prone position on belly boards for pelvic irradiation alone.


Reduction in purchases of sugar-sweetened beverages among low-income Black adolescents after exposure to caloric information.
We examined the effect of an intervention to provide caloric information about sugar-sweetened beverages (SSBs) on the number of SSB purchases. We used a case-crossover design with 4 corner stores located in low-income, predominately Black neighborhoods in Baltimore, Maryland. The intervention randomly posted 1 of 3 signs with the following caloric information: (1) absolute caloric count, (2) percentage of total recommended daily intake, and (3) physical activity equivalent. We collected data for 1600 beverage sales by Black adolescents, aged 12-18 years, including 400 during a baseline period and 400 for each of the 3 caloric condition interventions. Providing Black adolescents with any caloric information significantly reduced the odds of SSB purchases relative to the baseline (odds ratio [OR] = 0.56; 95% confidence interval [CI] = 0.36, 0.89). When examining the 3 caloric conditions separately, the significant effect was observed when caloric information was provided as a physical activity equivalent (OR = 0.51; 95% CI = 0.31, 0.85). Providing easily understandable caloric information--particularly a physical activity equivalent--may reduce calorie intake from SSBs among low-income, Black adolescents.


Analysis of B-cell epitopes from the allergen Hev b 6.02 revealed by using blocking antibodies.
Hev b 6.02 (hevein), identified as a major allergen from natural rubber latex (NRL), is involved in the latex-fruit syndrome and also acts as a pathogenesis defense-related protein. Its 3D structure has been solved at high resolution, and its linear epitopes have already been reported. However, information about conformational epitopes is still controversial, even though it is relevant for an accurate diagnosis and treatment, as well as for the study of allergen-antibody molecular interactions. We sought to analyze the B-cell epitopes of Hev b 6.02 at a molecular and structural level, using specific recombinant antibodies. We obtained a murine monoclonal antibody (mAb 6E7) and three human single chain fragments (scFvs A6, H8, and G7) anti-Hev b 6.02 that were able to compete for hevein binding with serum IgEs from latex allergic patients. In vitro assays showed that the mAb 6E7 and scFv H8 recognized the area of Hev b 6.02 where the aromatic residues are exposed; while the scFv G7 defined the amino and carboxy-terminal regions that lie close to each other, as a different epitope. The structural modeling of the Hev b 6.02-scFv H8 and Hev b 6.02-scFv G7 complexes revealed the putative regions of two conformational epitopes. In one of these, the aromatic residues, as well as polar side chains are important for the interaction, suggesting that they are part of a dominant conformational epitope also presented on the Hev b 6.02-IgE interactions. Antibodies recognizing this important allergen have potential to be used to diagnose and ultimately treat latex allergy.


Perceived risk factors and preventive practices of Hepatitis B viral infection among pregnant women in Nigerian hospitals: A cross-sectional study.
The study assessed the perceived risk factors and prevention practices of HBV infection among pregnant women in Nigerian hospitals. A descriptive cross-sectional study was conducted among 343 pregnant women attending antenatal clinics at two purposefully selected primary health care centers in Ile-Ife. Women were included in the study using systematic sampling. A structured researcher-administered questionnaire was used for data collection. Descriptive and inferential (Chi-square test and Logistic regression) statistical analysis were carried out. More than half (53%) of the respondents had a low perceived risk for hepatitis. Majority (73.5%) had been screened for HBV during the index pregnancy but only 30% received complete doses of HBV vaccine. Respondents who underwent HBV screening during pregnancy (OR = 2.06, 95% CI = 0.94 - 4.5), who had completed Hepatitis B vaccination had reduced odds ratios for perceiving risk factors for Hepatitis B Viral Infection (OR = 0.224, 95% CI = 0.94 - 4.5). Pregnant women had a low-risk perception of HBV infection. The low level of risk perception can serve as a basis for developing preventive interventions aimed at educating and empowering expectant mothers in order to prevent HBV infection and its transmission to their children.


POT1-TPP1 differentially regulates telomerase via POT1 His266 and as a function of single-stranded telomere DNA length.
Telomeres cap the ends of linear chromosomes and terminate in a single-stranded DNA (ssDNA) overhang recognized by POT1-TPP1 heterodimers to help regulate telomere length homeostasis. Here hydroxyl radical footprinting coupled with mass spectrometry was employed to probe protein-protein interactions and conformational changes involved in the assembly of telomere ssDNA substrates of differing lengths bound by POT1-TPP1 heterodimers. Our data identified environmental changes surrounding residue histidine 266 of POT1 that were dependent on telomere ssDNA substrate length. We further determined that the chronic lymphocytic leukemia-associated H266L substitution significantly reduced POT1-TPP1 binding to short ssDNA substrates; however, it only moderately impaired the heterodimer binding to long ssDNA substrates containing multiple protein binding sites. Additionally, we identified a telomerase inhibitory role when several native POT1-TPP1 proteins coat physiologically relevant lengths of telomere ssDNA. This POT1-TPP1 complex-mediated inhibition of telomerase is abrogated in the context of the POT1 H266L mutation, which leads to telomere overextension in a malignant cellular environment.


Prognostic impact of cytoreductive surgery conducted with primary intent, versus cytoreductive surgery after neoadjuvant chemotherapy, in the management of patients with advanced epithelial ovarian cancers: a multicentre, propensity score-matched study from the FRANCOGYN group.
To compare survival and morbidity rates between primary cytoreductive surgery (pCRS) and interval cytoreductive surgery (iCRS) for epithelial ovarian cancer (EOC), using a propensity score. We conducted a propensity score-matched cohort study, using data from the FRANCOGYN cohort. Retrospective, multicentre study of data from patients followed in 15 French department specialized in the treatment of ovarian cancer. Patients included were those with International Federation of Gynaecology and Obstetrics (FIGO) stage III or IV EOC, with peritoneal carcinomatosis, having undergone CRS. The propensity score was designed using pre-therapeutic variables associated with both treatment allocation and overall survival (OS). The primary outcome was OS. Secondary outcomes included recurrence-free survival (RFS), quality of CRS and other variables related to surgical morbidity. A total of 513 patients were included. Among these, 334 could be matched, forming 167 pairs. No difference in OS was found (hazard ratio, HR = 0.8, p = 0.32). There was also no difference in RFS (median = 26 months in both groups) nor in the rate of CRS leaving no macroscopic residual disease (pCRS 85%, iCRS 81.4%, p = 0.76). The rates of gastrointestinal tract resections, stoma, postoperative complications and hospital stay were significantly higher in the pCRS group. Analysis of groups of patients made comparable by propensity score matching showed no difference in survival, but lower postoperative morbidity in patients treated with iCRS.


The Impact of Mitochondrial Dysfunction on Dopaminergic Neurons in the Olfactory Bulb and Odor Detection.
Understanding non-motor symptoms of Parkinson's disease is important in order to unravel the underlying molecular mechanisms of the disease. Olfactory dysfunction is an early stage, non-motor symptom which occurs in 95% of Parkinson's disease patients. Mitochondrial dysfunction is a key feature in Parkinson's disease and importantly contributes to the selective loss of dopaminergic neurons the substantia nigra pars compacta. The olfactory bulb, the first olfactory processing station, also contains dopaminergic neurons, which modulate odor information and thereby enable odor detection as well as odor discrimination. MitoPark mice are a genetic model for Parkinson's disease with severe mitochondrial dysfunction, reproducing the differential vulnerability of dopaminergic neurons in the midbrain. These animals were used to investigate the impact of mitochondrial dysfunction on olfactory-related behavior and olfactory bulb dopaminergic neuron survival. Odor detection was severely impaired in MitoPark mice. Interestingly, only the small anaxonic dopaminergic subpopulation, which is continuously replenished by neurogenesis, was moderately reduced in number, much less compared with dopaminergic neurons in the midbrain. As a potential compensatory response, an enhanced mobilization of progenitor cells was found in the subventricular zone. These results reveal a high robustness of dopaminergic neurons located in the olfactory bulb towards mitochondrial impairment, in striking contrast to their midbrain counterparts.


Disturbance of DNA-Synthesis in early psoriasis.
In earlier studies we have shown that there is a significant prolongation of DNA-synthesis time (ts) in the epidermal cells of fully developed psoriatic lesions. The present study shows that this prolongation is to be observed even in very early plaques. The prolongation of ts precedes the development of acanthosis. A dermal infiltrate with increased proliferative activity seems to be a stimulus, in the sense of a Koebner-phenomenon. There is no pronounced prolongation of ts in other acute or chronic inflammatory processes of the skin. The behaviour of the infiltrate in psoriasis is similar to that in allergic patch test reaction. However, the abnormal psoriatic epidermis, with disturbed DNA-synthesis, does not react to the above mentioned infiltrate with a limited hyperproliferation but with the development of a psoriatic plaque. There is obviously congenital disturbances of metabolism within the epidermal cells in psoriasis.


Long-term characteristics of idiopathic persistent corpus luteum in the mare.
Persistent CL (PCL; n = 10) in mares was studied daily from Day 20 (Day 0 = ovulation) to the ending ovulation. In addition, the 10 days before ovulation at the end of a PCL were compared with the end of an interovulatory interval (IOI; n = 28) during the same months. Concentration of P4, cross-sectional area of CL, and percentage of CL with Doppler signals of blood flow during PCLs remained constant from 64 to about 33 days before the end of luteolysis and then decreased linearly. Concentration of LH between Day 20 and beginning of the ovulatory LH surge increased linearly. A dominant follicle developed on average every 15 days throughout each PCL. Novel transient P4 depressions were detected with the P4 nadir at a day of maximal diameter of a dominant follicle. At the apparent beginning of luteolysis before the ending ovulation, P4 concentration in PCLs (5.0 ± 0.5 ng/mL) was less (P < 0.0001) than that in IOIs (9.3 ± 0.6 ng/mL). Concentration of LH began to increase 2 days before the end of luteolysis in each group, but concentration on the day of the ending ovulation in PCLs (3.7 ± 0.3 ng/mL) was less (P < 0.005) than that in IOIs (8.9 ± 1.8 ng/mL). In a separate survey of PCLs (n = 23) and IOIs (n = 352), frequency of PCL (6.1%) differed significantly among mares indicating repeatability. These original and critical comparisons between PCLs and IOIs should provide hypotheses for further study.


Age-related declines to serum prestin levels in humans.
Measurement of the motor protein prestin offers a novel approach to assessing outer hair cell (OHC) status using serological techniques. Motivated by our prior work showing reduced serum prestin levels in healthy young adults at-risk for noise damage, the current study examined serum prestin levels, measured from circulating blood, across the age span from 18 to 82 years old. Results suggest that serum prestin levels negatively correlate with age, with young adults having higher levels of circulating serum in the blood than older adults. Group-level analyses showed minimal differences in prestin levels between 18 and 29, 30-39, and 40-49 year olds, but significant reductions in the 50+ years-old age group compared to the three younger groups, even though all groups significantly differed from each other in audiometric thresholds and distortion product otoacoustic emissions signal-to-noise ratio. Serum prestin levels declined with increasing levels of hearing loss, with a statistically significant relationship emerging between prestin and low-frequency hearing thresholds (0.25-2 kHz) but a weaker non-significant relationship for high-frequency hearing thresholds (3-8 kHz). This differential pattern between low- and high- frequency thresholds is consistent with the basal-to-apical progression of OHC loss with age. Findings support the idea that serum prestin is the product of residual OHCs in the less age-affected apical regions. Moreover, when entered in a regression model with audiometric thresholds, age was a stronger predictor than pure tone hearing threshold level for predicting serum prestin levels.


Role of circulating complement and polymorphonuclear leukocyte transfusion in treatment and outcome in critically ill neonates with sepsis.
We examined the effects of early administration of polymorphonuclear leukocyte (PMN) transfusions in neonates with sepsis by prospectively randomizing 35 consecutive critically ill infants with sepsis, 21 of whom received PMN transfusions in addition to supportive care, one transfusion every 12 hours for a total of five transfusions. Each transfusion consisted of 15 mL/kg containing 0.5 to 1.0 X 10(9) PMN with less than 10% lymphocytes, and was subjected to 1500 rads. PMNs were obtained by continuous-flow centrifugation leukopheresis. Pretreatment values that did not significantly affect survival included weight, gestational age, sex, prematurity, C-reactive protein, initial hematocrit, platelet count and absolute granulocyte count (AGC less than or equal to 1500/mm3), IgM, IgG, IgA, neutrophil supply pool depletion, hypoxia, acidosis, and hypotension. Postnatal age was significantly lower in the nontransfused group than in the transfused group; 2.3 +/- 0.6 vs 6.1 +/- 2.2, (P less than 0.001). Positive blood cultures were obtained in 80% of both groups. Low circulating levels of total hemolytic complement were associated with a poor outcome and higher mortality: 56 +/- 4.0 IU in survivors vs 31 +/- 4.4 IU in nonsurvivors (P less than 0.01). Survival was significantly greater in the PMN transfused group than in the nontransfused group: 20 (95%) of 21 vs nine (64%) of 14 (P less than or equal to 0.05). No untoward effects were attributable to PMN transfusions, either during the study or on subsequent follow-up visits. These preliminary data suggest that early treatment with PMN transfusions improves survival in neonates with overwhelming sepsis. In addition, depleted or low circulating levels of complement may influence prognosis and thus future treatment strategies for neonatal sepsis.


The exchangeable splenic platelet pool in response to selective adrenergic beta-i-receptor blockade.
The aim of the present work was to investigate the effect of selective beta-I-blockade on the exchangeable splenic platelet pool (ESPP). Therefore, 50 mg of metoprolol (a selective beta-I-receptor blocking agent) was given by mouth to three groups of subjects: (1) 15 healthy volunteers, (2) five asplenic subjects, and (3) 10 patients with different myeloproliferative disorders (MPD) with and without splenomegaly. The platelet count was determined 90, 150, 210, 270 and 330 min after the ingestion of the drug. In the group of healthy controls a significant increase (P less than 0.005) in the platelet count occurred and amounted to about 10% over baseline. The average peak value was reached at 150 min and the elevation in platelet count was maintained more than 4 h. An increase in the platelet count was also induced in patients with MPD, but the mean for the peak value only reached borderline significance (0.10 greater than P greater than 0.05). In the group of asplenic subjects no change in the platelet count occurred. It is concluded that acute oral administration of metoprolol causes a significant release of platelets from the ESPP. This platelet release is, however, no enhanced if the ESPP is enlarged.


Uncouplers of oxidative phosphorylation. A structure-activity study of their inhibitor effect on passive chloride permeability.
Uncoupling agents inhibit chloride transport in red blood cells, which is a metabolism-independent process. An analysis of the molecular requirements shows that this inhibitory activity is closely correlated with the electronic and the hydrophobic bonding properties of phenols: the more lipophilic and the more electron-attracting the substituent groups are, the greater the activity they confer on the parent molecule. A recent structure-activity study concerning various classes of reversible inhibitors of chloride transport led to the same conclusion (Motais, R. and Cousin, J.L. (1977) in International Conference on Biological Membranes: Drugs, Hormones and Membranes (Bolis, L., Hoffman, J.F. and Straub, R.W., eds.), Raven Press, New York, in the press). The effects of substituents on the activity of phenols as uncouplers have been recently examined (Stockdale, M. and Selwyn, M.J. (1971) Eur. J. Biochem. 21, 565). The comparison of these results with our data shows that uncoupling depends more on electronic properties of phenols than does choloride inhibition.


[Scientifically based patient education exemplified by patients with primary systemic vasculitis. The vasculitis patient education program--development, contents and initial results of evaluation].
Referring to the literature, it is known that structured standardized patient education represents an effective additional treatment in patients with chronic diseases. Most programs are based on cognitive behavioral interventions. Within the last few years, an interdisciplinary approach for providing information on disease, therapies, side effects, coping strategies, nutrition and physiotherapy has been developed for patients with primary systemic vasculitides (PSV) in the vasculitis center of the Medical University of Lübeck/Bad Bramstedt. The contents of the seminars were revised and condensed into five modules. New slides and handouts for patients were developed. To evaluate the new form of the program, a documentation system consisting of patient and physician-administered questionnaires assessing socioeconomic, knowledge and disease-related outcome-parameters was designed. Patients are trained in closed groups (n = 10-15) and asked to complete questionnaires at baseline, 4 weeks and 6 months after training. First results show statistically significant improvement of knowledge and health-related quality of life.


NOVEL RETINAL IMAGING ABNORMALITIES IN ALPORT SYNDROME.
The purpose of this study was to report a novel observation during retinal screening of a child with Alport syndrome. This was a review of case record and imaging files. Clinical examination of the retina and standard color fundus photography revealed no abnormality. However, distinct and identical wrinkling of the temporal macula (fingerprint sign) in both eyes was noted on Optos pseudocolor images of the retina. On optical coherence tomography, there were corresponding "saw-tooth" corrugations in the middle layers of the retina. En face images further highlighted the characteristic nature of this unusual observation. Fingerprint sign in the retina, a heretofore undescribed feature, is reported in a child with biopsy confirmed Alport syndrome.


Deletions of the hypervariable region (HVR) in open reading frame 1 of hepatitis E virus do not abolish virus infectivity: evidence for attenuation of HVR deletion mutants in vivo.
Hepatitis E virus (HEV) is an important human pathogen, although little is known about its biology and replication. Comparative sequence analysis revealed a hypervariable region (HVR) with extensive sequence variations in open reading frame 1 of HEV. To elucidate the role of the HVR in HEV replication, we first constructed two HVR deletion mutants, hHVRd1 and hHVRd2, with in-frame deletion of amino acids (aa) 711 to 777 and 747 to 761 in the HVR of a genotype 1 human HEV replicon. Evidence of HEV replication was detected in Huh7 cells transfected with RNA transcripts from mutant hHVRd2, as evidenced by expression of enhanced green fluorescent protein. To confirm the in vitro results, we constructed three avian HEV mutants with various HVR deletions: mutants aHVRd1, with deletion of aa 557 to 585 (Delta557-585); aHVRd2 (Delta612-641); and aHVRd3 (Delta557-641). Chickens intrahepatically inoculated with capped RNA transcripts from mutants aHVRd1 and aHVRd2 developed active viral infection, as evidenced by seroconversion, viremia, and fecal virus shedding, although mutant aHVRd3, with complete HVR deletion, was apparently attenuated in chickens. To further verify the results, we constructed four additional HVR deletion mutants using the genotype 3 swine HEV as the backbone. Mutants sHVRd2 (Delta722-781), sHVRd3 (Delta735-765), and sHVRd4 (Delta712-765) were shown to tolerate deletions and were infectious in pigs intrahepatically inoculated with capped RNA transcripts from the mutants, whereas mutant sHVRd1 (Delta712-790), with a nearly complete HVR deletion, exhibited an attenuation phenotype in infected pigs. The data from these studies indicate that deletions in HVR do not abolish HEV infectivity in vitro or in vivo, although evidence for attenuation was observed for HEV mutants with a larger or nearly complete HVR deletion.


Myosin isozyme transitions occurring during the postnatal development of the rat soleus muscle.
The myosin isozymes present in the developing rat soleus muscle from 1 week to 6 weeks after birth were investigated using biochemical and immunological methods. Electrophoresis of native myosin reveals that adult slow myosin is present in the soleus as early as 1 week after birth. At this time, embryonic and neonatal myosin can also be demonstrated. Using an immunotransfer technique, the presence of slow myosin heavy chain can be demonstrated at all time points examined whereas neonatal myosin heavy chain diminishes in quantity between 2 and 3 weeks, and is undetectable in the adult soleus. Specific polyclonal antibodies were prepared to embryonic, neonatal, and adult fast and slow myosins. Immunocytochemistry reveals a cellular heterogeneity at all stages examined. Different combinations of myosin isozymes can be found in the soleus fibers depending on the stage of development; these results suggest therefore that myosin isozyme transitions are occurring. Approximately half the fibers contain embryonic and slow myosin at 1 week after birth; these fibers subsequently contain only slow myosin. A second group of fibers contains embryonic and neonatal myosin at 1 week and most of them subsequently accumulate adult fast myosin. A portion of this latter group begins to acquire slow myosin from 4 weeks of age. These data are interpreted to suggest that a preprogrammed sequence of myosin isozymes is embryonic----neonatal----adult fast. At any time during development of an individual fiber, induction of slow myosin accumulation and repression of other types can occur.


KIT as a therapeutic target in neuroendocrine prostate cancer.
Understanding lineage plasticity in prostate cancer cells is crucial to overcoming disease progression and therapeutic resistance. In this issue of Cancer Cell, Han et al. demonstrate that Foxa2 promotes luminal-to-neuroendocrine differentiation and that it also upregulates Kit expression in neuroendocrine cells. KIT signaling inhibition represents a promising therapeutic strategy in neuroendocrine prostate cancer.


Immunogold staining: an alternative method for lymphocyte subset enumeration. Comparison with immunofluorescence microscopy and flow cytometry.
An immunogold staining procedure for light microscopic enumeration of peripheral blood lymphocyte subsets defined by monoclonal antibodies (OKT3, OKT4, OKT8, OKIa1, Leu 1, Leu 4, Leu 2a, Leu 3a, Leu 10, Leu 12, B1) is described. It uses colloidal gold-labeled goat anti-mouse Ig (GAM G40 and GAM G30) as second layer and a methyl-green pyronin counterstain. Performed on small volumes of blood without sophisticated laboratory equipment, this method allows accurate cell type recognition and permanent records, essential for longitudinal observations. By enumerating the gold particles on positively labeled cells, it was shown that the staining reactivity depended on the monoclonal antibody used. Lymphocytes reacting with OKT8 or OKIa1 or B1 exhibited the strongest labeling whereas OKT4+ cells were weakly labeled. When compared with flow cytometry analysis in healthy subjects, the accuracy, precision and sensitivity of both methods were very similar. Similarly, a close correlation (97%) was found between immunogold staining and immunofluorescence microscopy in 35 patients with various diseases suggesting that immunogold staining may be useful in a clinical context.


Methylene Blue Reduces Fluid Loading and Norepinephrine Requirements for Post-Resuscitation Syndrome in a Pig Model of Refractory Cardiac Arrest Resuscitated with Veno-Arterial ECMO.
Refractory cardiac arrest management relies on extracorporeal cardiopulmonary resuscitation (ECPR), requiring the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Circulatory flow recovery can be associated with an ischemia-reperfusion injury, leading to vasoplegia and vasopressor requirement. The aim of this work was to evaluate the impact on hemodynamics of a methylene blue bolus infusion in a porcine model of ischemic refractory cardiac arrest. Ischemic refractory cardiac arrest was induced in 20 pigs. After a low flow period of 30 min, VA-ECMO was initiated and the pigs were randomly assigned to the standard care group (norepinephrine + crystalloids) or methylene blue group (IV 2 mg·kg-1 bolus of methylene blue over 30 min + norepinephrine and crystalloids). Macrocirculatory parameters and lactate clearance were measured. Sublingual microcirculation was evaluated with sidestream dark field (SDF) imaging. The severity of the ischemic digestive lesions was assessed according to the histologic Chiu/Park scale. Eighteen pigs were included. The total crystalloid load (5000 (6000-8000) mL vs. 17,000 (10,000-19,000) mL, p = 0.007, methylene blue vs. standard care group) and catecholamine requirements (0.31 (0.14-0.44) μg·kg-1·min-1 vs. 2.32 (1.17-5.55) μg·kg-1·min-1, methylene blue vs. standard care group, p = 0.004) were significantly reduced in the methylene blue group. There were no significant between-group differences in lactate clearance, sublingual capillary microvascular parameters assessed by SDF or histologic Chiu/Park scale. In our refractory cardiac arrest porcine model treated with ECPR, methylene blue markedly reduced fluid loading and norepinephrine requirements in comparison to standard care during the first 6 h of VA-ECMO.


How many COVID-19 PCR positive individuals do we expect to see on the Diamond Princess cruise ship?
The coronavirus disease 2019 (COVID-19) has become a global epidemic crisis with tens of thousands confirmed cases surfacing everyday. The infection rates in households, offices and public places are quite different from those in encompassed spaces such as airplanes, trains and cruise ships. Studying the behavior of COVID-19 in confined spaces like Diamond Princess cruise is of great importance to understand the disease progression and to manage the epidemic. We propose a novel mixture model to estimate the infection distribution and total infected number after 14 days of quarantine based on PCR test data performed on the Diamond Princess cruise. In contrast to the officially reported 634 individuals with PCR-positive results after the 14 day quarantine, which as of April 27, 2020 had increased to 712, we conclude that this number should be at least 1000. The discrepancy might be caused by the false-negative result of the PCR test or the occurrence of infection after the test.


The effects of mineralocorticoid receptor antagonists on cardiovascular outcomes in patients with end-stage renal disease and heart failure.
Mineralocorticoid receptor antagonists (MRAs) have been shown to provide survival benefits in patients with heart failure; however, MRA use in patients with chronic kidney disease has been limited by safety concerns. The effects of MRAs on outcomes in patients with end-stage renal disease (ESRD) and heart failure remain unknown. The aim of this study was to evaluate the effects of MRAs on cardiovascular outcomes in patients with heart failure under maintenance dialysis in a real-world setting. A retrospective cohort study was conducted by collecting data from the Taiwan National Health Insurance Research Database (NHIRD). Patients diagnosed with heart failure and ESRD and who started maintenance dialysis between 1 January 2001 and 31 December 2013 were identified. Patients were grouped according to MRA prescription. The outcomes of interest included cardiovascular (CV) death, hospitalization for heart failure (HHF), all-cause mortality, acute myocardial infarction (AMI), ischaemic stroke, any coronary revascularization procedures, and new-onset hyperkalaemia. Propensity score matching was performed at a 1:3 ratio between MRA users and non-users to minimize selection bias. A total of 50 872 patients who satisfied our inclusion and exclusion criteria were identified. After 1:3 matching, 2176 patients were included in the MRA group, and 6528 patients were included in the non-MRA group. The risk of CV death was significantly lower among patients who received MRAs than those who did not (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.80-0.95), as was the risk of all-cause mortality (HR 0.88, 95% CI 0.83-0.94). Reductions in the risks of CV death and all-cause mortality were more prominent among patients undergoing haemodialysis and those with coronary artery disease. In patients undergoing regular dialysis who are diagnosed with heart failure, the use of MRAs is associated with lower risks of all-cause mortality and CV death. The benefits of MRA treatment in heart failure may persist in patients with ESRD. Further investigations through randomized controlled trials are needed to assess the efficacy and safety of MRAs in this high-risk population.


Biphasic calcium response of platelet-derived growth factor stimulated glioblastoma cells is a function of cell confluence.
Previous reports have linked the spiking or two-phased character of calcium transients evoked by platelet-derived growth factor (PDGF) to the position of cells in the cell cycle without regard to cell-cell contact and communication. Because cell confluence can regulate growth factor receptor expression and dephosphorylation, we investigated the effect of cell culture confluence and cell cycle on calcium responses of PDGF-BB-stimulated A172 glioblastoma cells. Digital imaging cytometry was used to correlate the peak and duration of calcium response with bromodeoxyuridine positivity and DNA content and with culture confluence on a cell-by-cell basis. In serum-starved cultures, complete two-phase calcium signals and shorter, lower spikes occurred independent of cell cycle phase. However, the confluence of cell culture seemed essential for inducing a complete response because cells in sparse cultures exhibited mostly short spikes with lower peaks or no transients at all. Because cell confluence, by virtue of cell-cell contacts, is assumed to be an important regulator of proliferation, one is tempted to speculate that in transformed cells the ability to produce stronger growth signals upon reaching confluence and facing contact inhibition could provide a proliferative advantage.


Somatic Embryogenesis in Two Orchid Genera (Cymbidium, Dendrobium).
The protocorm-like body (PLB) is the de facto somatic embryo in orchids. Here we describe detailed protocols for two orchid genera (hybrid Cymbidium Twilight Moon 'Day Light' and Dendrobium 'Jayakarta', D. 'Gradita 31', and D. 'Zahra FR 62') for generating PLBs. These protocols will most likely have to be tweaked for different cultivars as the response of orchids in vitro tends to be dependent on genotype. In addition to primary somatic embryogenesis, secondary (or repetitive) somatic embryogenesis is also described for both genera. The use of thin cell layers as a sensitive tissue assay is outlined for hybrid Cymbidium while the protocol outlined is suitable for bioreactor culture of D. 'Zahra FR 62'.


Peak distortion in reversed-phase liquid chromatography separation of active carbonyl-containing compounds: Mechanism and solution for this overlooked phenomenon.
Peak distortion is frequently encountered for compounds containing active carbonyl groups during reversed-phase (RP) LC separation. However, as being commonly overlooked or misdiagnosed, this problem is rarely reported in the literature and lacks an effective solution. In the present study, six pharmaceutical-related compounds containing keto or aldehyde groups, that exhibited severe peak distortion in early method development, were selected as the model compounds for further investigation. Systematic pH-screening experiments and a series of LC quadrupole-time of flight (Q-TOF) MS and NMR experiments were conducted on each model compound. The underlying chemical behavior of this type of compound during RP-LC separation was explicitly revealed. The formation of gem-diol/hemiketal/hemiacetal species via nucleophilic addition with H2O/MeOH will occur in a low pH eluent, but will be completely suppressed when the pH is higher than an analyte-specific value. As further validated by twelve other pharmaceutical-related compounds belonging to this type, we confirmed that increasing the eluent pH using buffers without nucleophilicity is a simple and effective method to solve this peak distortion problem.


Prospects for monolithic nano-LC columns in shotgun proteomics.
We report a premier side-by-side comparison of two leading types of monolithic nano-LC column (silica-C(18), polystyrene) in shotgun proteomics experiments. Besides comparing the columns in terms of the number of peptides from a real-life sample (Arabidopsis thaliana chloroplast) that they identified, we compared the monoliths in terms of peak capacity and retention behavior for standard peptides. For proteomics applications where the mobile phase composition is constrained by electrospray ionization considerations (i.e., there is a restricted choice of ion-pairing modifiers), the polystyrene nano-LC column exhibited reduced identification power. The silica monolith column was superior in all measured values and compared very favorably with traditional packed columns. Finally, we investigated the performances of the monoliths at high flow rates in an attempt to demonstrate their advantages for high-throughput identification.


The passivity breakdown of zinc antimony alloy as an anode in the alkaline batteries.
Zn is utilized as an anode in alkaline batteries because of its propensity to produce a passive colloidal layer on its surface. Then the surface should be reactivated in the passive region. Therefore, the passive state on the surface can be significantly hindered by utilizing a tiny percentage of Sb alloyed with Zn. Accordingly, the effect of minor Sb alloying with Zn on the performance of anodic dissolution and passivation in concentrated alkaline media (6 M KOH, which is used in the batteries) was studied using potentiodynamic and potentiostatic techniques. Besides, the passive layers formed at various anodic potentials were characterized utilizing scanning electron microscopy (SEM) and X-ray diffraction (XRD). The data of potentiodynamic measurements exhibited the active-passive transition curve of all studied specimens. All obtained results revealed that passivation is gradually hindered with increasing Sb content in the alloy, and less passivity was obtained at 1% Sb. Along this, a dramatic rise in current density at a particular positive potential (+ 2.0 V vs. SCE) to markedly higher values only of the electrodes containing Sb is observed.


Morphology of geniculo-striate afferents in a prosimian primate.
In order to analyze the arborization pattern of single axons innervating layer IV of striate cortex in Galago (a prosimian primate), injections of horseradish peroxidase were made into the white matter below visual cortex. Two distinct fiber types were identified which ramify within different subdivisions of layer IV. Fibers with large axons (type I) have relatively wide terminal arbors which ramify in layer IVa and lower layer III, while those with small axons (type II) arborize in restricted zones of layer IVb. Evidence from previous investigations suggests that terminals of these two fiber types represent the axon terminals of X-like and Y-like geniculate relay cells.


[RÉALITÉ LT, a pharmacoepidemiological study of semiology and therapeutic strategy of patients with schizophrenia treated by antipsychotic loxapine in routine clinical practice].
Data concerning the clinical and therapeutic characteristics of patients with schizophrenia treated by antipsychotic in naturalistic conditions are useful. Two national pharmacoepidemiological studies were conducted in France, a retrospective survey RÉALITÉ and a prospective study RÉALITÉ LT, to examine the use of loxapine, first in acute and chronic psychotic states and second in long-term treatment prescribed for patients with schizophrenia. The aim of RÉALITÉ LT is to specify the clinical characteristics of schizophrenic patients treated by loxapine for at least 4 months and the description of the methods of use of this antipsychotic medication during a 6-month follow-up in "real life" conditions. RÉALITÉ LT is an epidemiologic, observational, longitudinal, prospective (during a half-year period), multicenter and national study of the prescription of loxapine in routine clinical practice. For this study, 645 patients with schizophrenia treated by loxapine were recruited, assessed by PANSS, CGI, GAF, MeDra-SOC-PT for side effects and Girerd questionnaire for compliance; statistical analysis used SAS 9.2. Six hundred and forty-five adult patients were included and assessed at inclusion, month 3 and 6. These patients were mostly male (69%), with an average age of 41, inactive (68%), lonely with no child (79%), under psychiatric care for more than 5 years (81%), less than one third were inpatients. The subtypes of schizophrenia were paranoid (59%), disorganised (21%), undifferentiated or residual (10%), the outcome of psychotic illness was episodic (50%) or continuous (33%). The daily mean dosage of loxapine was 168,4 mg/d, in antipsychotic loxapine monotherapy (27%) or in combination with other antipsychotics (63%); it was often associated with psychotropic medications (anxiolytic [72%], antidepressant [21%], normothymic [19%]). The stability of the dosage of loxapine during the 6 months follow-up (60%) was associated with strict loxapine monotherapy or antipsychotic monotherapy (loxapine associated with other psychotropic medication). Safety, side effects and compliance were compared with previous studies. These results are discussed, comparing the two pharmacoepidemiological studies RÉALITÉ and RÉALITÉ LT, loxapine is used in compliance with the two indications (smpc) and French guidelines (HAS, Haute Autorité de santé).


Chemical modification of arglabin and biological activity of its new derivatives.
This review summarizes the results of own research on chemical modification of the molecule of sesquiterpene lactone arglabin from Artemisia glabella Kar. et Kir. Over 70 new arglabin derivatives were obtained which are polyfunctional compounds with oxy functions, atoms of haloids, phosphorus, nitrogen, and cyclopropane fragments. For the first time the results of bioscreening of new arglabin derivatives are reported.


[The role of electrocardiotopography in evaluation of a graded exercise test during rehabilitation of patients who had myocardial infarction].
A total of 217 male survivors of myocardial infarction with resumed working capacity were monitored. Their electrocardiotopography, with ECG recordings from 36 leads on anterolateral surface of the chest, was examined in order to assess tolerance to rationed exercise by bicycle ergometry. The multiple lead recording techniques is shown to give more objective results, as compared to the conventional routine procedure, in analyzing causes of test discontinuation and evaluating changes in exercise tolerance during prolonged monitoring. Chest electrode placed in the 4th and 5th positions was not shown to possess any preferential informative value with respect to effects of exercise tests.


Duodenal somatostatinoma: a case report and review of the literature.
About 70% of well-differentiated endocrine tumors arise from the gastrointestinal tract. Duodenal well-differentiated endocrine tumors account for only 2.6% of all neuroendocrine tumors. Following the first two case reports of somatostatin-secreting tumors in 1977, fewer than 200 cases of somatostatinoma have been reported. These tumors of the duodenum are usually silent and asymptomatic, but can cause gastrointestinal symptoms. Depending on the localization of the tumor, multiple surgical procedures can be performed, ranging from local resection to pancreaticoduodenectomy. Here, we report a case of a submucosal duodenal mass in a 42-year-old Turkish White man presenting with nausea, vomiting, fatigue and abdominal pain. The treatment decision of pancreaticoduodenectomy made preoperatively was later altered to intraoperative removal via local resection with sphincteroplasty. Tumors of the periampullary region are considered highly malignant, and the Whipple operation is usually the only procedural treatment. In the current case, we decided not to perform pancreaticoduodenectomy but to excise the mass intraoperatively, and consequently avoided unnecessary resection of the pancreas and anastomosis to undilated hepatic and pancreatic ducts. This protective strategy prevented duodenum- and pancreas-related morbidity.


Classification of sugarcane genotypes susceptible and resistant to the initial attack of sugarcane borer Diatraea saccharalis using epicuticular wax composition.
Identifying compounds present in the sugarcane epicuticular wax and using these compounds to classify the genotypes susceptible and resistant to the initial attack of sugarcane borer (Diatraea saccharalis) was the aim of this study. A greenhouse experiment was performed in a factorial scheme with and without borer infestation using genotypes previously characterized as resistant or susceptible in field-based experiments. Sugarcane whorls of six-month-old plants were collected before (BI) and after (AI) 72 h of sugarcane borer infestation. The sugarcane epicuticular wax was extracted in both times, i.e., BI and AI and its chemical composition was assessed by gas chromatography coupled to mass spectrometry (GC-MS). Twenty-five compounds were identified for both BI and AI. Classification models were built using partial least squares for discriminant analysis (PLS-DA) and linear discriminant analysis (LDA). Variable selection methods were used to improve the classification models. Ordered predictors selection for discriminant analysis (OPSDA) selected compounds that correctly classified all the test samples before borer infestation (Error = 0.000), and exhibited the most suitable classification parameters for the test set after borer infestation (Error = 0.111). The C30 pentacyclic triterpene friedelin and a high alcohol/aldehyde ratio were associated with the classification of resistant genotypes. Our findings have applicability in developing a screening methodology for breeding programs interested in identifying genotypes resistant to the initial feeding of sugarcane borer.


Platelet-Activating Factor Acetylhydrolase and Brain Development.
The heterotrimeric brain platelet-activating factor acetylhydrolase (PAFAH1B1) contains two catalytic subunits and a regulatory subunit. This complex plays important, surprising roles in brain development and in spermatogenesis. The regulatory subunit, PAFAH1B1 (LIS1 protein), is critically regulated and when deficient leads to the devastating human neurological disorder Lissencephaly, or smooth brain. The role of the protein in brain development is not the catalysis of platelet-activating factor, rather the entire brain platelet-activating factor acetylhydrolase complex serves a signaling role, coordinating important pathways in brain development. The role of this complex in spermatogenesis was not foreseen, but appears to function to regulate a critical level of the PAFAH1B1 protein, such that too much of this protein or too little of this protein can lead to a disruption of spermatogenesis. Brain platelet-activating factor is thus a signaling complex, important for brain development and for spermatogenesis.


Intestinal calcium absorption is enhanced by D-glucose in diabetic and control rats.
The effect of glucose on intestinal absorption of calcium was studied in the jejunum and ileum of control, diabetic (streptozotocin-induced), and insulin-treated diabetic rats. Intestinal absorption was determined in vivo using an in situ one-pass perfusion technique. In the jejunum of control and diabetic rats, net absorption and unidirectional lumen to mucosa flux of calcium and net absorption of water were significantly greater during perfusion of an isotonic NaCl solution, containing 15 mmol/L of glucose, than during perfusion of the same solution containing 15 mmol/L of mannitol instead of glucose. To determine if net absorption of calcium and water were related, the jejunum was perfused with a hypotonic solution (260 mosmol/kg) in separate groups of rats. Although net absorption of water was equivalent during perfusion of the hypotonic solution to that noted during perfusion of the isotonic glucose-containing solution, rate of absorption of calcium was not enhanced. Thus, it appeared that, if the enhancement in absorption of calcium by glucose was an effect on the passive absorption of calcium, it was through a mechanism not related to passive absorption of water. As expected, jejunal absorption of calcium was lower in diabetic than in control rats. Because in diabetic rats the metabolism of vitamin D to its active metabolite, 1,25-dihydroxy vitamin D, is defective, the enhancement in absorption of calcium by glucose did not appear to be due to a mechanism influenced by vitamin D metabolism. In the ileum, rate of absorption of calcium was lower than in the corresponding jejunum and was not significantly altered by the presence of glucose in the perfusion solution, by perfusion of a hypotonic solution, or by the diabetic state. The mechanism of action of glucose on calcium absorption in the jejunum needs to be studied further.


Whole Genome Amplification in Genomic Analysis of Single Circulating Tumor Cells.
Investigation of the genome of organisms is one of the major basics in molecular biology to understand the complex organization of cells. While genomic DNA can easily be isolated from tissues or cell cultures of plant, animal or human origin, DNA extraction from single cells is still challenging. Here, we describe three techniques for the amplification of genomic DNA of fixed single circulating tumor cells (CTC) isolated from blood of cancer patients. This amplification is aimed to increase DNA amounts from those of one cell to yields sufficient for different DNA analyses such as mutational analysis including next-generation sequencing, array-comparative genome hybridization (CGH), and quantitative measurement of gene amplifications. Molecular analysis of CTC as liquid biopsy can be used to identify therapeutic targets in personalized medicine directed, e.g. against human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR) and to stratify the patients to those therapies.


Involvement of calcium in phosphoinositide metabolism in the blood-brain barrier.
The Ca2+ effect on phosphoinositide metabolism in the blood-brain barrier was studied by using rat cerebral microvessels prelabelled with either [32P]orthophosphate or myo-[3H]inositol and stimulated with Ca2+ ionophore A23187. In radioactivity steady-state conditions, addition of ionophore caused a rapid and marked loss of labelling in both phosphatidylinositol-4-phosphate (PIP) and phosphatidylinositol-4,5-bisphosphate (PIP2), without significant alterations in phosphatidylinositol (PI) and phosphatidic acid (PA) labelling. These facts were accompanied by a rise in labelling of both inositol 1-monophosphate (IP) and inositol 1,4-bisphosphate (IP2), but not in inositol 1,4,5-trisphosphate (IP3). In addition, a Ca(2+)-dependent inhibition of phosphoinositide kinase activities from isolated membranes was also found. These data suggest that elevated intracellular Ca2+ level evokes a PIP and PIP2 hydrolysis by phosphodiesterasic and phosphomonoesterasic activities respectively, and also partially inhibits the synthesis of these phosphoinositides. Our results constitute evidence that a reciprocal control mechanism between polyphosphoinositide metabolism and mobilization of Ca2+ exists in the blood-brain barrier.


Blepharoptosis after traumatic third-nerve palsies.
We evaluated the clinical records of 16 patients with blepharoptosis secondary to direct traumatic third-nerve palsies. Most patients were involved in auto accidents, and had associated skull fractures. Of 12 patients who were followed up for at least one year, ten recovered completely. Over half of the patients had evidence of aberrant regeneration, which could be seen clinically as early as nine weeks after the trauma. Orbital localization of the third-nerve dysfunction carries an excellent prognosis for prompt, spontaneous recovery without aberrant regeneration. Surgical intervention in these cases should be delayed at least one year after the traumatic event, and longer if continued slow but progressive recovery is demonstrated.


Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene.
Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding and pulmonary fibrosis result from defects of melanosomes, platelet dense granules and lysosomes. HPS is common in Puerto Rico, where it is caused by mutations in the genes HPS1 and, less often, HPS3 (ref. 8). In contrast, only half of non-Puerto Rican individuals with HPS have mutations in HPS1 (ref. 9), and very few in HPS3 (ref. 10). In the mouse, more than 15 loci manifest mutant phenotypes similar to human HPS, including pale ear (ep), the mouse homolog of HPS1 (refs 13,14). Mouse ep has a phenotype identical to another mutant, light ear (le), which suggests that the human homolog of le is a possible human HPS locus. We have identified and found mutations of the human le homolog, HPS4, in a number of non-Puerto Rican individuals with HPS, establishing HPS4 as an important HPS locus in humans. In addition to their identical phenotypes, le and ep mutant mice have identical abnormalities of melanosomes, and in transfected melanoma cells the HPS4 and HPS1 proteins partially co-localize in vesicles of the cell body. In addition, the HPS1 protein is absent in tissues of le mutant mice. These results suggest that the HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis.


The impact of waist-to-hip ratio on clinical outcomes in metastatic breast cancer patients treated with aromatase inhibitors.
We aimed to identify whether abdominal fat distribution could affect the outcome in metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs) or not. A total of 42 MBC patients treated with first line hormonal therapy were enrolled in this study. Factors associated with overall survival in the univariate analysis were age, c-erb-B2 expression intensity (+++ versus others by immunohistochemistry), and WHR, whereas only WHR retained significance in the multivariate analysis. Median overall survival figures were 472 days versus unreached for patients with a WHR of <0.92 and >or=0.92 (Log rank statistic=9.76, P=0.002). Similarly, the corresponding progression free survival figures for patients with a WHR of <0.92 and >or=0.92 were 423 versus 1004 days (Log rank statistic=6.37, P=0.012). This study suggests that WHR may serve as a potential predictive marker in MBC patients treated with AIs.


Aquatic predicted no-effect concentration for three polycyclic aromatic hydrocarbons and probabilistic ecological risk assessment in Liaodong Bay of the Bohai Sea, China.
Predicted no-effect concentration (PNEC) is often used in ecological risk assessment to determine low-risk concentrations for chemicals. In the present study, native marine species were selected for toxicity testing. The PNECs for three polycyclic aromatic hydrocarbons (PAHs), specifically phenanthrene (Phe), pyrene (Pyr), and benzo[a]pyrene (BaP), were derived from chronic and acute toxicity data with log-normal statistical methods. The achieved PNECs for Phe, Pyr, and BaP were 2.33, 1.09, and 0.011 μg/L, respectively. In Jinzhou Bay and the Shuangtaizi River Estuary of Liaodong Bay in the Bohai Sea, China, the surface water concentrations of the three PAHs were analyzed by gas chromatography-mass spectrometry. Based on two probabilistic ecological risk assessment (PERA) methods, namely probabilistic risk quotient and joint probability curve, the potential risk of Phe, Pyr, and BaP in Jinzhou Bay and Shuangtaizi River Estuary was assessed. The same order of ecological risk (BaP > Phe > Pyr) was found by both models. Our study considered regional characteristics of marine biota during the calculation of PNECs, and the PERA methods provided probabilities of potential ecological risks of chemicals. Within the study area, further research on BaP is required due to its high potential ecological risk.


Effect of co-administration of a serotonin-noradrenaline reuptake inhibitor and a dopamine agonist on extracellular monoamine concentrations in rats.
Recent studies have shown that dopamine agonists are useful for the treatment of not only Parkinson's disease, but also major depressive disorders. However, while these dopamine agonists provide a new treatment strategy for major depressive disorders, such as treatment-resistant cases, the antidepressant effect of dopamine agonists has yet to be investigated. To examine the mechanism of the antidepressive effect of dopamine agonists, we investigated the acute effect of the dopamine receptor agonist, cabergoline, and the serotonin-noradrenaline reuptake inhibitor, milnacipran, on extracellular noradrenaline, dopamine and serotonin concentrations in the rat medial prefrontal cortex. There was a greater increase in extracellular noradrenaline concentrations when acute milnacipran (30 mg/kg intraperitoneally) was administered after acute high-dose cabergoline (1 and 2 mg/kg subcutaneously) than when acute milnacipran was administered following acute vehicle or low-dose cabergoline (0.25 mg/kg subcutaneously). There were no significant differences noted in the dopamine or serotonin concentrations. These results suggest that the addition of cabergoline has the potential to strengthen the antidepressant effects of milnacipran and that the mechanism of action of the antidepressive effect of dopamine agonists might be due to enhancement of induced increases of extracellular noradrenaline.


Crystallographic analysis of the three-dimensional structure of baboon alpha-lactalbumin at low resolution. Homology with lysozyme.
The crystal structure of baboon alpha-lactalbumin has been determined at 6 A and at 4.5 A (0.6 nm and 0.45 nm) resolution by the method of isomorphous replacement. The principal derivative was prepared by reducing a disulphide bridge in the crystals and inserting a mercury atom. Detailed comparison of the electron-density maps with corresponding maps of hen egg-white lysozyme shows that they are closely similar, with correlation coefficients of 0.57 and 0.44 at 6 A and 4.5 A resolution respectively. This result, in accordance with earlier predictions based upon comparisons of amino-acid sequences, provides further evidence that class C lysozymes and alpha-lactalbumins are homologous proteins and it is in keeping with the hypothesis that the alpha-lactalbumins evolved from a lysozyme precursor.


Comparison of SARS-CoV-2 viral load in asymptomatic and symptomatic children attended in a referral public pediatric hospital in Argentina.
At present, different reports have shown that children reach similar SARS-CoV-2 viral load (VL) levels compared to adults; however, the impact of VL on children remains ambiguous when asymptomatic versus symptomatic cases are compared. Thus, the aim of this study was to assess VL at the time of diagnosis in asymptomatic and symptomatic SARS-CoV-2 infected children. VL analysis was retrospectively carried out from nasopharyngeal swabs on 82 SARS-CoV-2 infected children, from March to October 2020. Of the 82 children, 31 were asymptomatic. Symptomatic patients had significantly higher VL values compared to asymptomatic ones (median=7.41 vs 4.35log10 copies/ml, respectively). Notwithstanding, 8 out of 31 asymptomatic children had high VL levels, overlapping levels observed above the first quartile in the symptomatic group. Analysis of different age groups revealed that median VL values were higher in the symptomatic groups, although there was only a significant difference in children younger than 5 years of age. On the other hand, there was no significant difference between the VL values from the 82 SARS-CoV-2 infected children according to age, sex, underlying disease, symptoms or severity of COVID-19 related disease. This study emphasizes the importance of VL analysis in SARS-CoV-2 infected children, who could contribute to viral spread in the community. This concern could be extended to healthcare workers, who are in contact with children.


A comparison of photosynthesis in two thalloid liverworts.
Standard infra-red gas analysis techniques were used to compare the photosynthesis of the liverworts Marchantia foliacea Mitt. and Monoclea forsteri Hook. Parameters measured include net photosynthetic rates, light response curves, quantum efficiencies, diffusive resistances to CO2 and water, apparent photorespiration and chlorophyll content. A series of morphological measurements were also made to determine resistance of pores and the 'mesophyll' to dorsal surface ratio, A mes/A. Marchantia has a cuticularised thallus with the photosynthetic tissues arranged in air chambers giving an A mes/A of 9 whilst Monoclea has a solid thallus, A mes/A of 1. Both species are shade adapted and it was found that whilst the air chambers were advantageous for water relations they increased maximum photosynthesis only slightly. Calculations showed that the solid thallus would be photosynthetically superior in very moist environments. The results are discussed with reference to existing ideas on the evolution of the structure of land plants.


CircLARP1B promotes pyroptosis of high glucose-induced renal mesangial cells by regulating the miR-578/TLR4 axis.
Diabetic nephropathy (DN) is a main cause of end-stage renal disease with high mortality. Circular RNAs (circRNAs) are associated with the pathogenesis of DN. This study aimed to explore the role of circLARP1B in DN. The levels of circLARP1B, miR-578, TLR4 in DN and high glucose (HG)-treated cells using quantitative real-time PCR. Their relationship was analyzed using dual-luciferase reporter assay. The biological behaviors were assessed by MTT assay, EDU assay, flow cytometry, ELISA, and western blot. The results indicated that circLARP1B and TLR4 were highly expressed, and miR-578 was low expressed in patients with DN and HG-induced cells. Knockdown of circLARP1B promoted the proliferation and cell cycle, and inhibited pyroptosis and inflammation of HG-induced cells. CircLARP1B is a sponge of miR-578, which targets TLR4. Rescue experiments showed that inhibition of miR-578 reversed the effects of circLARP1B knockdown, while TLR4 reversed the effects of miR-578. CircLARP1B/miR-578/TLR4 axis suppressed the proliferation, blocked cell cycle at the G0-G1 phase, promoted pyroptosis, and inflammatory factor release of renal mesangial cells induced by HG. The findings suggested that circLARP1B may be a target for the treatment of DN.


Exploring progressive mental model representation of core physiology concepts in physician assistant students through word frequency and association analyses.
A well-developed mental model is crucial for effectively studying physiology core concepts. However, mental models can be difficult for students to represent and for instructors to evaluate and correct. Systems modeling as a visualization cognitive tool may facilitate mental model development. On the other hand, evidence of mental model development may also be represented verbally, in writing, and therefore, be evaluated. In this study, analysis of writing prompt completions illustrated progress in physician assistant student mental model formation of physiology core concepts, such as homeostasis and cell-cell communication, over time. Two cohorts of physician assistant students were invited to voluntarily submit completions of writing prompts five times over 16 months. Sessions included submissions pre- and post-small group systems modeling participation. Word frequency and word association cluster dendrogram analyses were conducted on submissions using the tm text mining package in R to provide insight into progressive changes in core concepts of word use and associations. Students demonstrated expanded core concepts systems thinking over time. This was apparent through the increased use of systems process terms, such as homeostasis, in submissions immediately following systems modeling activities. Students also increasingly included terms and associations emphasizing cell-cell communication and systems integration. The inclusion of these concepts within student mental models was demonstrably enhanced by participation in systems modeling activities.NEW & NOTEWORTHY This study applies text mining, an artificial intelligence form of natural language processing, to evaluate a series of physiology student-written prompt completions. Text mining of student writing in physiology has not yet been reported in the literature. Through the application of this technique, longitudinal trends in student development of mental models of core concepts were identified and visualized through word frequency distributions and cluster dendrograms.


The correlation between 1H MRS choline concentrations and MR diffusion trace values in human brain tumors.
The aim of this study was to develop a method for evaluating the spatial distribution of human brain gliomas in individual subjects by evaluating the correlation between the Choline (Cho) signal intensity and the diffusion trace (Tr(ADC)) values. Eleven patients with different histopathologic diagnoses and five healthy subjects were examined with diffusion-weighted EPI-trace sequence and (1)H MR spectroscopic imaging. The calculation of the correlation between choline and Tr(ADC) values on a pixel-by-pixel basis and simulations estimating the influence of partial volume effects on the result were performed. Statistical evaluation of the data in the patients with a glioblastoma showed that pixels corresponding to different tissue states are situated in different areas in the Cho-Tr(ADC) correlation graph. Namely, points forming an inverse linear dependence interpreted as an area of an active tumor were observed. Different types of correlations were found in grade II and III gliomas. No statistically significant correlation was found in healthy subjects. Simulations proved that the observed linear dependence cannot be attributed solely to partial volume effects. The analysis of the correlation between Cho concentrations and Tr(ADC) values on a pixel-by-pixel basis should help the regional identification of the pathological state of a tissue in patients with a glioblastoma.


ORF50-dependent and ORF50-independent activation of the ORF45 gene of Kaposi's sarcoma-associated herpesvirus.
The ORF45 gene of Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a multifunctional tegument protein. Here, we characterize the transcriptional control of the ORF45 gene and show that its promoter can be activated by ORF50 protein, a latent-lytic switch transactivator. The ORF45 promoter can also be induced by sodium butyrate (SB), a histone deacetylase inhibitor, in the absence of ORF50 protein. Although SB induces the ORF45 gene independently of ORF50, its full activation may require the presence of ORF50. Deletion and point mutation analyses revealed that two RBP-Jκ-binding sites in the ORF45 promoter confer the ORF50 responsiveness, whereas NF-Y and Sp1-binding sites mediate the response to SB. Direct binding of NF-Y, Sp1, or RBP-Jκ protein to the ORF45 promoter is required for the promoter activation induced by SB or by ORF50. In conclusion, our study demonstrates both ORF50-dependent and ORF50-independent transcriptional mechanisms operated on the activation of the ORF45 gene.


An easy pill to swallow: oral recombinant vaccines for the 21st century.
Oral vaccines have a distinctive advantage of stimulating immune responses in the mucosa, where numerous pathogens gain entry and cause disease. Although various efforts have been attempted to create recombinant mucosal vaccines that provoke strong immunogenicity, the outcomes in clinical trials have been weak or inconsistent. Therefore, next-generation mucosal vaccines are needed that are more immunogenic. Here, we discuss oral vaccines with an emphasis on a next-generation mucosal vaccine that utilizes a nonreplicating human recombinant adenovirus type-5 (rAd5) vector. Numerous positive clinical results investigating oral rAd5 vaccines are reviewed, with a summary of the immunogenicity and efficacy results for specific vaccine indications of influenza, norovirus, and SARS-CoV-2. The determination of correlates of protection for oral vaccination and the potential impact this novel vaccine formulation may have on disease transmission are also discussed. In summary, successful oral vaccination can be accomplished and would have major public health benefits if approved.


Cervical assessment in women with threatened preterm labor.
The aim of the study was to examine the clinical value of cervical assessment by transvaginal ultrasonography in women with symptoms of preterm labor. We prospectively evaluated 172 women with singleton pregnancies and symptoms of preterm labor. Seventy of them were nulliparas, while 102 were multiparas. Gestational age ranged between 24 and 34 wks. All women underwent cervical assessment with transvaginal ultrasonography and were given intravenous tocolytics. The only parameter evaluated was cervical length. Women with multiple pregnancies, gestational age <24 wks or >34 wks, cervical dilatation >2 cm, placenta praevia, premature rupture of membranes, or cervical cerclage were excluded from the study. The outcome measure was delivery before 34 wks gestation. The preterm delivery rate before 34 wks was 37%. The sensitivity and the specificity of a cervical length of less than 20 mm was 60 and 53.8% and 97.7 and 95.2% for nulliparas and multiparas, respectively. A cervical length <20 mm was also 93.7% predictive of preterm delivery in nulliparas and 87.5% in multiparas, while the corresponding numbers for its negative predictive value (NPV) were 81.4 and 76.9%, respectively. Cervical assessment in women with symptoms of preterm labor can distinguish those at high risk for preterm delivery. Cervical sonography can be a valuable adjunct to the clinical evaluation of these patients.


Trends in the incidence, rate and treatment of miscarriage-nationwide register-study in Finland, 1998-2016.
What changes have occurred in the incidence of miscarriage, its treatment options, and the profile of the women having miscarriages in Finland between 1998 and 2016? The annual incidence of registry-identified miscarriage has declined significantly between 1998 and 2016, and non-surgical management has become the dominant treatment. Miscarriage occurs in 8-15% of clinically recognized pregnancies and in ~30% of all pregnancies. Increasing maternal age is associated with an increasing risk of miscarriage. The treatment of miscarriage has evolved significantly in recent years: previously, surgical evacuation of the uterus was the standard of care, but nowadays medical and expectant management are increasingly used. We conducted a nationwide retrospective cohort study of 128 381 women that had experienced a miscarriage that was managed in public healthcare between 1998 and 2016 in Finland. We used the National Hospital Discharge Registry for the data. Women aged 15-49 years that had experienced their first miscarriage during the follow-up period and had miscarriage-related diagnoses during their admission to public hospital were included in the study. Miscarriages were defined by the 10th Revision of the International Statistical Classification of Diseases and related Medical Problems (ICD-10) diagnostic codes O02*, O03* and O08*. Women with ectopic, molar and continuing pregnancies and induced abortions were excluded. Treatment was divided into surgical and non-surgical treatment using the surgical procedure codes. The annual incidence of registry-identified miscarriage has declined from 6.8/1000 15-49-year-old women in 1998 to 5.0/1000 in 2016 (P < 0.001). Also, the incidence rate of registry-identified miscarriage (i.e. the proportion of miscarriages of registry-identified pregnancies [i.e. deliveries, induced abortions, and miscarriages]) has declined from 112/1000 15-49-year-old pregnant women in 1998 to 83/1000 in 2016 (P < 0.001). The largest decrease in this proportion occurred among women over 40 years of age, among whom 26.5% of registry-identified pregnancies in 1998 ended in miscarriage compared to that of 16.4% in 2016. The proportion of missed abortion has increased (30.3 to 38.8%, P < 0.001) whereas that of blighted ovum has decreased (25.4 to 12.8%, P < 0.001). The proportion of registry-identified miscarriages seen among nulliparous women has increased from 43.7 to 49.6% (P < 0.001). Mean age at the time of miscarriage remained at 31 years throughout the study. Altogether, 29% of all miscarriages were treated surgically and 71% underwent medical or expectant management. The proportion of surgical management has decreased from 38.0 to 1.6% for spontaneous abortion, from 60.7 to 9.4% for blighted ovum and 70.9 to 11.2% for missed abortion between 1998 and 2016. This study includes only women with registry-identified pregnancies, i.e. women who were treated in public hospitals. However, the number of women treated elsewhere is presumed to be small. Neither can this study estimate the number of women having spontaneous miscarriage with no hospital contact. Both the annual incidence and incidence rate of miscarriage of all registry-identified pregnancies has decreased, and non-surgical management has become the standard of care. These findings are of value when planning allocation of healthcare resources and at individual level considering fertility and miscarriage questions. We speculate that improving ultrasound diagnostics explains the increasing proportion of missed abortion relative to other types of miscarriage. More investigation is needed to examine potential risk factors, complications and morbidity associated with miscarriages. This study was funded by the research funds of the Helsinki and Uusimaa hospital system, by a personal grant from Viipurin Tuberkuloosisäätiö to R.L. and by a personal grant from The Finnish Cultural Foundation to N.H. The authors have no conflicts of interest to declare.


The independent impact of newborn hepatitis B vaccination on reducing HBV prevalence in China, 1992-2006: A mathematical model analysis.
To evaluate the independent impact of newborn hepatitis B vaccination on reducing HBV prevalence in China, from its introduction in 1992 to 2006. An age- and time-dependent discrete dynamic model was developed to simulate HBV transmission in China under the assumptions of no any change in interventions and only with newborn vaccination introduction, respectively. The initial conditions of the model were determined according to the national serosurvey in 1992. The simulated results were compared with the observed results of the national serosurvey in 2006, and the contribution rate of newborn vaccination on reducing HBV prevalence was calculated overall and by birth cohort. The total HBV prevalence would remain stable through the 14-year period if no any change in interventions, but decrease year by year if only with newborn vaccination introduction. Newborn vaccination could account for more than 50% of the reduction of the total HBV prevalence, although the full 3-dose and timely birth dose vaccination coverage rates were low in the early years. The results by birth cohort showed that the higher the two coverage rates, the higher contribution rate on reducing HBV prevalence. For the 2005 birth cohort which had high levels in the two coverage rates, the contribution rate could reach more than 95%. Newborn hepatitis B vaccination from 1992 to 2006 in China had played the most important role in reducing HBV prevalence. Newborn vaccination with high full 3-dose and timely birth dose coverage rates is the decisive factor in controlling hepatitis B in China.


Tumour-associated trypsin inhibitor (TATI): comparison with CA125 as a preoperative prognostic indicator in advanced ovarian cancer.
We have evaluated the prognostic value of tumour-associated trypsin inhibitor (TATI) in stage III or IV ovarian cancer. Tumour-associated trypsin inhibitor (TATI) and CA 125 were determined in serum samples from 66 patients taken before primary surgery. TATI was elevated (> 22 micrograms l-1) in 27 patients (41%). These had a 5 year cumulative survival of 8%, whereas survival was 45% in 39 patients with normal preoperative TATI values. By contrast, the preoperative CA 125 level did not predict survival. In multivariate analysis which included age, stage, histological grade and preoperative TATI and CA 125 levels, patients with elevated preoperative TATI levels had a 2.3-fold relative risk of death (95% confidence interval 1.23-4.20; P = 0.002) compared with patients with normal preoperative levels. This result was comparable with the predictive value of primary residual tumour size, since patients with residual tumour larger than 2 cm in diameter had a 5.2-fold relative risk of death (95% confidence interval 2.55-10.68) compared with patients with a smaller or no residual tumour. Thus, preoperative determination of serum TATI may have a place in the pretreatment evaluation of patients with advanced ovarian cancer.