Improving Martini 3 for Disordered and Multidomain Proteins.
Coarse-grained molecular dynamics simulations are a useful tool to determine conformational ensembles of proteins. Here, we show that the coarse-grained force field Martini 3 underestimates the global dimensions of intrinsically disordered proteins (IDPs) and multidomain proteins when compared with small-angle X-ray scattering (SAXS) data and that increasing the strength of protein-water interactions favors more expanded conformations. We find that increasing the strength of interactions between protein and water by ca. 10% results in improved agreement with the SAXS data for IDPs and multidomain proteins. We also show that this correction results in a more accurate description of self-association of IDPs and folded proteins and better agreement with paramagnetic relaxation enhancement data for most IDPs. While simulations with this revised force field still show deviations to experiments for some systems, our results suggest that it is overall a substantial improvement for coarse-grained simulations of soluble proteins.


Combined inoculation with Glomus intraradices and Rhizobium tropici CIAT899 increases phosphorus use efficiency for symbiotic nitrogen fixation in common bean (Phaseolus vulgaris L.).
This study compared the response of common bean (Phaseolus vulgaris L.) to arbuscular mycorrhizal fungi (AMF) and rhizobia strain inoculation. Two common bean genotypes i.e. CocoT and Flamingo varying in their effectiveness for nitrogen fixation were inoculated with Glomus intraradices and Rhizobium tropici CIAT899, and grown for 50 days in soil-sand substrate in glasshouse conditions. Inoculation of common bean plants with the AM fungi resulted in a significant increase in nodulation compared to plants without inoculation. The combined inoculation of AM fungi and rhizobia significantly increased various plant growth parameters compared to simple inoculated plants. In addition, the combined inoculation of AM fungi and rhizobia resulted in significantly higher nitrogen and phosphorus accumulation in the shoots of common bean plants and improved phosphorus use efficiency compared with their controls, which were not dually inoculated. It is concluded that inoculation with rhizobia and arbuscular mycorrhizal fungi could improve the efficiency in phosphorus use for symbiotic nitrogen fixation especially under phosphorus deficiency.


Browning and pigmentation in food through the Maillard reaction.
The Maillard reaction was discovered in 1912 by Louis C. Maillard when he observed the browning phenomena with aroma formation in a heated solution containing a sugar and an amino acid. The Maillard reaction starts from the reactions between carbonyl groups of various sugars and amino groups of amino acids/ proteins, following the formation of intermediate compounds or poly-carbonyl compounds, which further react with each other and amino acids/proteins. Through various chemical reactions such as condensation, polymerization, degradation, cyclization etc., color and aroma are formed. The imparting of brown color is mainly attributed to melanoidins. However, the chemical structure of melanoidins remains unclear because melanoidins are complex and heterogeneous polymers. On the other hand, various kinds of low-molecular-weight pigments formed through the Maillard reaction have been isolated and their structures have been identified. Even though the contribution of each pigment is small, the recognition of color is cumulative. In some case, these pigments form brown polymers or significantly contribute to the total color of a model solution. These chemically clear information gives us a novel aspect for an overview of browning or pigmentation through the Maillard reaction. Graphical abstract.


Effect of autoanalgesia on CNS enkephalin receptors.
Fear conditioning to foot shock (15 sec/day, 12 days) elicited autoanalgesia in 10 male (Sprague-Dawley) rats, while 17 non-shock control rats exhibited no analgesia as measured by the tail-flick assay. The binding of 3H-leu-enkephalin to synaptosomal preparations isolated from fear conditioned (experimental) and control animals was analyzed. At leu-enkephalin concentrations of 10(-9) M or less, both synaptosomal preparations demonstrated high affinity binding with dissociation constants on the order of 10(-10). Binding of leu-enkephalin could not be displaced by a hundred-fold excess of naloxone at leu-enkephalin concentrations less than 10(-9) M. However, the ability of naloxone to compete with leu-enkephalin for binding sites progressively increased at concentrations greater than 10(-9) M leu-enkephalin. At these ligand concentrations, the competition of naloxone for leu-enkephalin binding sites was more dramatic in the control than in the experimental animals. These data support the existence of two classes of receptors for leu-enkephalin, one of which is not blocked by opiate antagonists. Furthermore, changes in binding capacity associated with autoanalgesia produced by conditioned fear are consistent with the hypothesis of endogenous release of opiate-like peptides in response to stress.


Enhanced mitochondrial genome analysis: bioinformatic and long-read sequencing advances and their diagnostic implications.
Primary mitochondrial diseases (PMDs) comprise a large and heterogeneous group of genetic diseases that result from pathogenic variants in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Widespread adoption of next-generation sequencing (NGS) has improved the efficiency and accuracy of mtDNA diagnoses; however, several challenges remain. In this review, we briefly summarize the current state of the art in molecular diagnostics for mtDNA and consider the implications of improved whole genome sequencing (WGS), bioinformatic techniques, and the adoption of long-read sequencing, for PMD diagnostics. We anticipate that the application of PCR-free WGS from blood DNA will increase in diagnostic laboratories, while for adults with myopathic presentations, WGS from muscle DNA may become more widespread. Improved bioinformatic strategies will enhance WGS data interrogation, with more accurate delineation of mtDNA and NUMTs (nuclear mitochondrial DNA segments) in WGS data, superior coverage uniformity, indirect measurement of mtDNA copy number, and more accurate interpretation of heteroplasmic large-scale rearrangements (LSRs). Separately, the adoption of diagnostic long-read sequencing could offer greater resolution of complex LSRs and the opportunity to phase heteroplasmic variants.


Inhibition of p53 by pifithrin-alpha reduces myocyte apoptosis and leukocyte transmigration in aged rat hearts following 24 hours of reperfusion.
Ischemic heart disease is a common age-related disease. Apoptotic cell death and inflammation are the major contributors to I/R injury. The mechanisms that trigger myocyte apoptosis and inflammation during myocardial I/R (MI/R) remain to be elucidated. Published data from our laboratory demonstrated that pretreatment of MI/R rats with pifithrin-alpha (PFT), a specific p53 inhibitor, reduced myocyte apoptosis and improved cardiac function compared with MI/R rats pretreated with saline at 4 h of reperfusion. In the present study, we investigated the effects of PFT on the occurrence of myocyte apoptosis and leukocyte transmigration in the later period of reperfusion. Aged (20-month-old) male F344 rats were subjected to 30 min of myocardial ischemia via ligature of the LCA, followed by 24 h of reperfusion. Pifithrin-alpha (2.2 mg/kg, intraperitoneally) or saline was administered to rats before ischemia. The results indicate that pretreatment of MI/R rats with PFT significantly decreased the percentage of infarct area to ischemic area (33 +/- 8 vs. 54 +/- 9, P < 0.05) and improved cardiac output (79 +/- 11 vs. 38 +/- 9 mL/min per 100 g body weight, P < 0.05) when compared with rats pretreated with saline at 24 h of reperfusion. The protective effects of PFT may involve the p53/Bax-mediated apoptosis because treatment of MI/R rats with PFT attenuated the ratio of Bax to Bcl2 (0.97 +/- 0.1 vs. 2.1 +/- 0.2, P < 0.05) and reduced myocyte apoptosis. Interestingly, inhibition of p53 transcriptional function by PFT alleviated leukocyte infiltration into the ischemic area of the heart (339 +/- 37 vs. 498 +/- 75 cells/10 high-power fields, P < 0.05). These data suggest that inhibition of p53 transcriptional function by PFT attenuates myocyte apoptosis and alleviates leukocyte transmigration at 24 h of reperfusion. The mechanisms by which p53 modulates leukocyte transmigration require further investigation.


Immunolocalization of RANKL is increased and OPG decreased during dietary magnesium deficiency in the rat.
Epidemiological studies have linked low dietary magnesium (Mg) to low bone mineral density and osteoporosis. Mg deficiency in animal models has demonstrated a reduction in bone mass and increase in skeletal fragility. One major mechanism appears to be an increase in osteoclast number and bone resorption. The final pathway of osteoclastogenesis involves three constituents of a cytokine system: receptor activator of nuclear factor kB ligand (RANKL); its receptor, receptor activator of nuclear factor kB (RANK); and its soluble decoy receptor, osteoprotegerin (OPG). The relative presence of RANKL and OPG dictates osteoclastogenesis. The objective of this study was to assess the presence of RANKL and OPG in rats on a low Mg diet. RANKL and OPG were assessed by immunocytochemistry staining in the tibia for up to 6 months in control rats on regular Mg intake (0.5 g/kg) and experimental rats on reduction of dietary Mg (.04%, 25% and 50% of this Nutrient Requirement). At all dietary Mg intakes, alteration in the presence of immunocytochemical staining of RANKL and OPG was observed. In general, OPG was decreased and RANKL increased, reflecting an alteration in the RANKL/OPG ratio toward increased osteoclastogenesis. We have, for the first time demonstrated that a reduction in dietary Mg in the rat alters the presence of RANKL and OPG and may explain the increase in osteoclast number and decrease in bone mass in this animal model. As some of these dietary intake reductions in terms of the RDA are present in a large segment of or population, Mg deficiency may be another risk factor for osteoporosis.


Characterization of allergens secreted by Anisakis simplex parasite: clinical relevance in comparison with somatic allergens.
Diagnostic methods for the study of allergic reactions to Anisakis simplex (A.s.) based on whole-body extracts of the larva are clearly insufficient. To study the allergenicity of the proteins secreted by the parasite. Comparison with somatic antigens and determination of their clinical importance in allergic patients were also addressed. An excretory/secretory (E/S) extract was produced by culturing third-stage A.s. larvae. It was used to perform immediate skin tests and to determine specific IgE in 10 patients diagnosed with allergy to A.s. Both tests were compared with the results obtained with the whole-body extract (somatic (S)). The molecular weight (MW) of their allergens was determined by immunoblotting, and a single-blind placebo-controlled oral challenge with E/S proteins was performed. Finally, allergens' resistance to gastric pepsin and acid pH was explored. A.s. larvae secreted allergens more potent than those present in the S extract. The skin prick test wheal area produced by E/S molecules and the absorbance obtained in the determination of specific IgE with these allergens (ELISA) were 5.8 times bigger than those obtained with S extract. MW allergens of 72 and 56 kDa in E/S extracts and those of 56, 48 and 43 kDa in S extract were recognized by more than 50% of the patients. Partial cross-reactivity between them was revealed by immunoblotting inhibition studies. Oral challenge with E/S extract (up to 479 microg) was negative in all the patients. Treatment of E/S proteins with gastric pepsin inhibited the binding of the E/S allergens for specific IgE. The acid pH did not affect the overall binding of IgE to E/S extract. It decreased by 15.23% and 19.96% at pH 4 and 2, but the difference was not statistically significant. A.s. secretes allergens more potent than somatic antigens and should be used in the diagnostic procedures. These allergens are inactivated by the pepsin, which supports the theory that live larva is necessary to induce an allergic reaction in most of the patients.


Exploring new catechin derivatives as SARS-CoV-2 Mpro inhibitors from tea by molecular networking, surface plasma resonance, enzyme inhibition, induced fit docking, and metadynamics simulations.
SARS-CoV-2 Mpro (Mpro) is the critical cysteine protease in coronavirus viral replication. Tea polyphenols are effective Mpro inhibitors. Therefore, we aim to isolate and synthesize more novel tea polyphenols from Zhenghedabai (ZHDB) white tea methanol-water (MW) extracts that might inhibit COVID-19. Through molecular networking, 33 compounds were identified and divided into 5 clusters. Further, natural products molecular network (MN) analysis showed that MN1 has new phenylpropanoid-substituted ester-catechin (PSEC), and MN5 has the important basic compound type hydroxycinnamoylcatechins (HCCs). Thus, a new PSEC (1, PSEC636) was isolated, which can be further detected in 14 green tea samples. A series of HCCs were synthesized (2-6), including three new acetylated HCCs (3-5). Then we used surface plasmon resonance (SPR) to analyze the equilibrium dissociation constants (KD) for the interaction of 12 catechins and Mpro. The KD values of PSEC636 (1), EGC-C (2), and EC-CDA (3) were 2.25, 2.81, and 2.44 μM, respectively. Moreover, compounds 1, 2, and 3 showed the potential Mpro inhibition with IC50 5.95 ± 0.17, 9.09 ± 0.22, and 23.10 ± 0.69 μM, respectively. Further, we used induced fit docking (IFD), binding pose metadynamics (BPMD), and molecular dynamics (MD) to explore the stable binding pose of Mpro-1, showing that 1 could tightly bond with the amino acid residues THR26, HIS41, CYS44, TYR54, GLU166, and ASP187. The computer modeling studies reveal that the ester, acetyl, and pyrogallol groups could improve inhibitory activity. Our research suggests that these catechins are effective Mpro inhibitors, and might be developed as therapeutics against COVID-19.


Humanization in the Intensive Care: perception of family and healthcare professionals.
Understanding perceptions of family members and healthcare professionals about humanization at the Intensive Care Unit (ICU) to direct it to an educational action. Exploratory descriptive and qualitative study conducted in an ICU level 3 of a public hospital in Porto Alegre, RS, Brazil, with fourteen subjects, eight family members and six healthcare professionals. Data collection carried out through semi-structured interviews and focus group. Content Analysis was used. Emerged categories were: welcoming; communication; ethical and sensible professionalism; unfavorable aspects; perception on humanization; and religiosity/spirituality. Although the subjects have expressed their perceptions about humanization in different ways, both groups pointed out the same needs and priorities to improve humanization in Intensive Care. From the results, we created a reflective manual of humanizing assistance practices for professionals, a board to facilitate communication of these professionals with patients and a guideline book for family members. Compreender as percepções de familiares e profissionais de saúde sobre humanização na Unidade Terapia Intensiva (UTI) para direcionar a uma ação educativa. Estudo exploratório-descritivo qualitativo, realizado em uma UTI nível III de um hospital público de Porto Alegre/RS com 14 sujeitos, sendo oito familiares e seis profissionais de saúde. Coleta de dados realizada por meio de: entrevistas semiestruturadas e grupo focal. Utilizou-se Análise de Conteúdo. As categorias emergidas foram: acolhida; comunicação; profissionalismo ético e sensível; aspectos desfavoráveis; percepção sobre humanização; e religiosidade/espiritualidade. Apesar dos sujeitos expressarem de maneiras distintas suas percepções sobre humanização, os dois grupos comparados elencaram iguais necessidades e prioridades para o aprimoramento da humanização na Terapia Intensiva. A partir dos resultados, criou-se um Manual Reflexivo de práticas assistenciais humanizadoras para os profissionais, um tabuleiro para facilitar a comunicação destes profissionais com os usuários e um guia de orientações aos familiares.


Small scale spatial gradients of outdoor and indoor benzene in proximity of an integrated steel plant.
Benzene is known as a human carcinogen, whose annual mean concentration exceeded the EU limit value (5 μg/m(3)) only in very few locations in Europe during 2012. Nevertheless 10% to 12% of the EU-28 urban population was still exposed to benzene concentrations above the WHO reference level of 1.7 μg/m(3). WHO recommended a wise choice of monitoring stations positioning in proximity of "hot spots" to define and assess the representativeness of each site paying attention to micro-scale conditions. In this context benzene and other VOCs of health concern (toluene, ethylbenzene, xylenes) concentrations have been investigated, with weekly passive sampling for one year, both in outdoor and indoor air in inhabited buildings in close proximity (180 m far up to 1100 m) of an integrated steel plant in NE of Italy. Even though the outdoor mean annual benzene concentration was below the EU limit in every site, in the site closest to the works the benzene concentration was above 5 μg/m(3) in 14 weeks. These events were related to a benzene over toluene ratio above one, which is diagnostic for the presence of an industrial source, and to meteorological factors. These information pointed at the identification of the coke ovens of the plant as the dominant outdoor source of benzene. Benzene gradients with the increasing distance from coke ovens have been found for both outdoor and indoor air. Linear models linking outdoor to indoor benzene concentrations have been then identified, allowing to estimate indoor exposure from ambient air benzene data. In the considered period, a narrow area of about 250 m appeared impacted at a higher degree than the other sites both considering outdoor and indoor air. Passive BTEX sampling permits to collect information on both ambient air and daily life settings, allowing to assemble a valuable data support for further environmental cost-benefit analyses.


The effects of opioid drugs and of lithium on steroidogenesis in rat adrenal cell suspensions.
1. The effects of opioid drugs and of Na+ replacement on steroidogenesis in rat adrenal cell suspensions were investigated. 2. In medium containing normal Na+ (156 mM), opioid antagonists but not opioid agonists reduced the steroidogenic response to adrenocorticotrophic hormone1-24 (ACTH1-24) but not to dibutyryl adenosine 3',5' cyclic monophosphate (db cyclic AMP). 3. Replacement of 50% Na+ in the medium by choline had no effect on steroidogenesis, but further reductions in Na+ content reduced the steroidogenic activity of both ACTH1-24 and db cyclic AMP. 4. In 50% Na+ medium both opioid agonists and antagonists inhibited ACTH1-24 induced steroidogenesis. 5. Addition of therapeutic concentrations of lithium to otherwise normal medium inhibited the steroidogenic response to ACTH1--24 but not to db cyclic AMP. 6. The selective inhibition of ACTH1--24-induced steroidogenesis by opioid drugs suggests some similarity between the opioid and ACTH receptors. 7. The relevance of the potent inhibitory effect of lithium to its therapeutic actions is discussed.


Cerebral palsy: orthopedic aspects and rehabilitation.
Cerebral palsy is the most common chronic disability of childhood today. The concept of management rather than cure forms the basis of intervention. Therapy programs should be integrated with summer camps, home activities, and school, enabling the child and the family to live as close to normal as possible. Successful rehabilitation should prevent additional problems, minimize disability, and create a happy child.


Public Perceptions of Resuming Elective Surgery During the COVID-19 Pandemic.
Many U.S. health systems are grappling with how to safely resume elective surgery amid the COVID-19 pandemic. We used online crowdsourcing to explore public perceptions and concerns toward resuming elective surgery during the pandemic, and to determine factors associated with the preferred timing of surgery after health systems reopen. A 21-question survey was completed by 722 members of the public using Amazon Mechanical Turk. Multivariable logistic regression analysis was performed to determine factors associated with the timing of preferred surgery after health systems reopen. Most (61%) participants were concerned with contracting COVID-19 during the surgical process, primarily during check-in and in waiting room areas, as well as through excessive interactions with staff. Overall, 57% would choose to have their surgery at a hospital over an outpatient surgery center. About 1 in 4 (27%) would feel comfortable undergoing elective surgery in the first month of health systems reopening. After multivariable adjustment, native English speaking (OR, 2.6; 95% CI, 1.04-6.4; P = .042), male sex (OR, 1.9; 95% CI, 1.3-2.7; P < .001), and Veterans Affairs insurance (OR, 4.5; 95% CI, 1.1-18.7; P = .036) were independent predictors of preferring earlier surgery. Women and non-native English speakers may be more hesitant to undergo elective surgery amid the COVID-19 pandemic. Despite concerns of contagion, more than half of the public favors a hospital setting over an outpatient surgery center for their elective surgery. Concerted efforts to minimize patient congestion and unnecessary face-to-face interactions may prove most effective in reducing public anxiety and concerns over the safety of resuming elective care.


A fatty meal aggravates apnea and increases sleep in patients with obstructive sleep apnea.
The purpose of this study was to investigate the role of a fatty meal before bedtime, on sleep characteristics and blood pressure in patients with obstructive sleep apnea (OSA). Recently diagnosed, by full polysomnography (PSG), patients with OSA (n=19) were included. These underwent PSG for additional two consecutive nights. Two hours before the PSG examination, a ham and cheese sandwich of 360 kcal was served to all patients, at first night, while a fatty meal of 1,800 kcal was served before the second PSG examination. Comparisons were performed between the last two examinations in terms of PSG data and morning and night blood pressure measurements. After the fatty meal, a significant increase was observed in total sleep time (p=0.026) in the Apnea-Hypopnea Index (AHI) (p=0.015), as well as in the absolute number of obstructive and central apneas (p=0.032 and p=0.042, respectively) compared to the previous night. Conversely, distribution of sleep stages and indices of nocturnal hypoxia (average and minimum SpO2 and sleep time with SpO2<90 %) did not change significantly. Likewise, no significant change was observed in blood pressure measurements. Fatty meal intake before sleep can increase AHI in OSA patients, although it does not affect sleep architecture or indices of hypoxia.


Synthesis of solid-supported mirror-image sugars: a novel method for selecting receptors for cellular-surface carbohydrates.
We introduced a novel method, through mirror-image phage display, for the identification of high-affinity D-peptides to target specific cell-surface carbohydrates. Both 3-deoxy-alpha-L-manno-2-octulosonic acid (L-KDO) and L-sialic acid and an L-sialo-disaccharide have been synthesized and attached to a solid support for selection of high-affinity peptide binders displayed on phages. Our initial studies in this effort produce single-chain Fab sequences and dodecapeptides that bind to sialic acid and KDO with nanomolar and high micromolar affinity.


Cellular responses elicited by insulin mimickers in cells lacking detectable plasma membrane insulin receptors.
Madin-Darby canine kidney (MDCK) cells were previously shown to have few or no plasma membrane insulin binding sites (Hofmann et al: J Biol Chem 258:11774, 1983]. Accordingly, neither insulin-stimulated incorporation of [14C]glucose into glycogen, nor insulin-induced uptake of radiolabeled alpha-aminoisobutyrate ([3H]AIB) could be demonstrated. To probe for receptors, MDCK cultures were surface-labeled with Na125I or were labeled with [35S]methionine. When solubilized cells were immunoprecipitated with sera containing antibodies to the insulin receptor, and immunoprecipitates were analyzed on SDS-gel electrophoresis, no evidence for insulin receptor components was found. Also, when intact MDCK cells wee incubated first with serum containing antibodies to the insulin receptor and then with 125I-protein A, no radiolabeling of insulin receptors occurred. Various agents reported to have insulin-like activity were tested on MDCK cells. The insulinomimetic lectins concanavalin A and wheat germ agglutinin as well as hydrogen peroxide enhanced incorporation of [14C]glucose into glycogen and induced stimulated [3H]AIB uptake, whereas trypsin, vanadate, and serum containing antibodies to the insulin receptor were without effects. Altogether, these results showed that MDCK cells had few or no insulin receptors and were correspondingly insulin-insensitive. However, since insulin-associated responses could be elicited by some insulin mimickers, the post-receptor limb of response in MDCK cells was apparently intact.


Protection against reactive oxygen species by NAD(P)H: quinone reductase induced by the dietary antioxidant butylated hydroxyanisole (BHA). Decreased hepatic low-level chemiluminescence during quinone redox cycling.
Menadione elicits low-level chemiluminescence (lambda greater than 620 nm) associated with redox cycling of the quinone in mouse hepatic postmitochondrial fractions. This photoemission is suppressed when the animals are fed a diet containing the anticarcinogenic antioxidant, 2[3]-(tert-butyl)-4-hydroxyanisole (BHA), which leads to a 13-fold increase in NAD(P)H: quinone reductase (EC 22.214.171.124). Inhibition of the enzyme by dicoumarol completely abolishes the protective effect of BHA treatment and leads to higher chemiluminescence, reaching similar photoemission for BHA-treated and control animals. These findings indicate that the two-electron reduction promoted by quinone reductase prevents redox cycling and that BHA protects against reactive oxygen species by elevating the activity of this enzyme.


[cDNA microarray and cluster analysis to identify the significance of immune genes associated with benzene poisoning].
To delineate the immune regulatory pathway of benzene poisoning by using gene expression profile analysis. Peripheral white blood cell gene expression profile of 7 benzene poisoning patients, including one aplastic anemia, was determined by microarray. Seven chips from normal workers were served as controls. Cluster analysis of gene expression profile was performed. Differentially expressed immune genes associated with benzene poisoning were determined. Among the 2 779 target genes, 38 genes differentially expressed were identified, including 10 up-regulated genes such as CD59, TRA@, MCP etc, and 14 down-regulated genes such as HLA-DMB, HLA-DQA1, HLA-DPB1, ITGB2, PFC etc. Cluster analysis showed that the expression profiles of 38 genes were associated with benzene poisoning. Differentially expressed immune genes may play an important role in the pathogenesis of benzene poisoning.


Gender differences in bone mineral density in patients with sporadic primary hyperparathyroidism.
Primary hyperparathyroidism reduces bone mineral density, which increases the risk of fracture. To investigate differences in bone mineral density and clinical characteristics after parathyroidectomy between men and women (premenopausal and postmenopausal) with sporadic primary hyperparathyroidism. This is a retrospective study of adult patients who underwent parathyroidectomy in a tertiary referral center from 1990 to 2013. A total of 1529 patients underwent parathyroidectomy during the study period; 80 patients met the inclusion criteria. Of these, 24 were men and 56 were women (10 premenopausal and 46 postmenopausal). Demographics, preoperative and postoperative biochemical analysis, preoperative and postoperative T-scores, preoperative Z-scores, preoperative and postoperative absolute bone mineral density values, and percentage change in bone mineral density from baseline to 12 ± 6 months after parathyroidectomy in the lumbar spine, femoral neck, total hip and distal one-third of the nondominant radius. Preoperative 24-hour urinary calcium levels were significantly higher in men than in women overall (P = 0.02) and postmenopausal women (P = 0.01). Men had significantly lower preoperative Z-scores than women overall, premenopausal women and postmenopausal women. Men had greater percentage change of increase in bone mineral density in the femoral neck than did women overall (2.77%; P = 0.04) and postmenopausal women (2.98%; P = 0.03) 1 year after parathyroidectomy. From this study, men demonstrated a greater improvement of bone mineral density in the femoral neck from baseline after parathyroidectomy compared with women.


Soft Rot on Cucumis melo var. makuwa Caused by Rhizopus oryzae.
Rhizopus oryzae is reported for the first time on Cucumis melo L. var. makuwa Makino. A detailed description of this Korean specimen is given, along with its rDNA internal transcribed spacer sequence. On the basis of mycological characteristics and molecular data, the fungus was identified as R. oryzae Went & Prinsen Geerligs.


An analysis of the influences of maternal age, gestational age, contraceptive method, and the mode of primary treatment of patients with hydatidiform moles on the incidence of subsequent chemotherapy.
In relation to the total number of births in the United Kingdom there was an excess of hydatidiform moles arising in women over 34 years of age and possibly also under 15. The incidence of trophoblastic tumour requiring chemotherapy after hydatidiform mole was greatest in the 30 to 34 years age group and it was also high in the 20 to 24 years age group. This distribution appears to be influenced by the morphology of the moles, the mode of their removal and the use of oestrogens and progestogens in the post-evacuation period. The need for chemotherapy for trophoblastic tumour after evacuation of a hydatidiform mole was found to be two- to three-fold greater in patients who had undergone a medical induction, hysterectomy or hysterotomy compared with those whose hydatidiform moles had been evacuated by vacuum or surgical curettage, or who had aborted spontaneously. The increased risk of chemotherapy was most marked in the earlier weeks of gestation.


Residual dormant cancer stem-cell foci are responsible for tumor relapse after antiangiogenic metronomic therapy in hepatocellular carcinoma xenografts.
Hepatocellular carcinoma (HCC) is the fifth most common solid tumor and the third leading cause of cancer-related deaths. Currently available chemotherapeutic options are not curative due in part to tumor resistance to conventional therapies. We generated orthotopic HCC mouse models in immunodeficient NOD/SCID/IL2rγ null mice by injection of human alpha-feto protein (hAFP)- and/or luciferase-expressing HCC cell lines and primary cells from patients, where tumor growth and spread can be accurately monitored in a non-invasive way. In this model, low-dose metronomic administration of cyclophosphamide (LDM-CTX) caused complete regression of the tumor mass. A significant increase in survival (P<0.0001), reduced aberrant angiogenesis and hyperproliferation, and decrease in the number of circulating tumor cells were found in LDM-CTX-treated animals, in comparison with untreated mice. Co-administration of LDM-CTX with anti-VEGF therapy further improved the therapeutic efficacy. However, the presence of residual circulating hAFP levels suggested that some tumor cells were still present in livers of treated mice. Immunohistochemistry revealed that those cells had a hAFP+/CD13+/PCNA- phenotype, suggesting that they were dormant cancer stem cells (CSC). Indeed, discontinuation of therapy resulted in tumor regrowth. Moreover, in-vitro LDM-CTX treatment reduced hepatosphere formation in both number and size, and the resulting spheres were enriched in CD13+ cells indicating that these cells were particularly resistant to therapy. Co-treatment of the CD13-targeting drug, bestatin, with LDM-CTX leads to slower tumor growth and a decreased tumor volume. Therefore, combining a CD13 inhibitor, which targets the CSC-like population, with LDM-CTX chemotherapy may be used to eradicate minimal residual disease and improve the treatment of liver cancer.


Current trends in U.S. general surgery practice consolidation.
Consolidation of physician practices is well-documented in recent years, yet minimal data exist regarding consolidation in general surgery. This study evaluates current trends in general surgery practice consolidation. Data were obtained through the CMS Physician Compare database. Surgeons and practices were categorized by size, and trends were analyzed using the Cochran-Armitage test. Data were stratified by US region. From 2012 to 2020, practicing general surgeons increased from 20,044 to 20,637 (+3%). Unique general surgery practices declined from 8178 to 6489 (-21%). The percentage of surgeons in practices of 1 or 2 declined from 19% to 12%, while surgeons in groups of 500 or more grew from 20% to 31%. Tests for trends towards consolidation at both the individual surgeon and unique practice levels were significant (p < .001). The Midwest region demonstrated the highest degree of consolidation. Consistent with trends in medicine overall, general surgery is experiencing substantial practice consolidation.


Transcription factor STAT1 gene polymorphism is associated with the development of severe forms of periodontal disease.
Periodontal disease (PD) is one of the most common inflammatory diseases, affecting about 10 % of the world population. The establishment of PD is influenced by polymorphisms in genes involved with the inflammatory response. Signal Transducer and Activator of Transcription (STAT)-1 is a transcription factor that plays a key role in the intracellular signaling triggered by cytokines and, thus, its activation is critical in inflammatory diseases. We aim to evaluate the occurrence of association between STAT-1 (rs3771300) polymorphism and distinct clinical forms and severity of PD; we genotyped 180 subjects using realtime PCR. We observed that the presence of the G allele for STAT-1 was associated with twice as high of a chance to develop aggressive periodontitis, and the most severe form of the disease.


Neuronal differentiation requires a biphasic modulation of gap junctional intercellular communication caused by dynamic changes of connexin43 expression.
It was suggested that gap junctional intercellular communication (GJIC) and connexin (Cx) proteins play a crucial role in cell proliferation and differentiation. However, the mechanisms of cell coupling in regulating cell fate during embryonic development are poorly understood. To study the role of GJIC in proliferation and differentiation, we used a human neural progenitor cell line derived from the ventral mesencephalon. Fluorescence recovery after photobleaching (FRAP) showed that dye coupling was extensive in proliferating cells but diminished after the induction of differentiation, as indicated by a 2.5-fold increase of the half-time of fluorescence recovery. Notably, recovery half-time decreased strongly (five-fold) in the later stage of differentiation. Western blot analysis revealed a similar time-dependent expression profile of Cx43, acting as the main gap junction-forming protein. Interestingly, large amounts of cytoplasmic Cx43 were retained mainly in the Golgi network during proliferation but decreased when differentiation was induced. Furthermore, down-regulation of Cx43 by small interfering RNA reduced functional cell coupling, which in turn resulted in a 50% decrease of both the proliferation rate and neuronal differentiation. Our findings suggest a dual function of Cx43 and GJIC in the neural development of ReNcell VM197 human progenitor cells. GJIC accompanied by high Cx43 expression is necessary (1) to maintain cells in a proliferative state and (2) to complete neuronal differentiation, including the establishment of a neural network. However, uncoupling of cells is crucial in the early stage of differentiation during cell fate commitment.


Three-dimensional sub-100 nm resolution fluorescence microscopy of thick samples.
Imaging volumes as thick as whole cells at three-dimensional (3D) super-resolution is required to reveal unknown features of cellular organization. We report a light microscope that generates images with translationally invariant 30 x 30 x 75 nm resolution over a depth of several micrometers. This method, named biplane (BP) FPALM, combines a double-plane detection scheme with fluorescence photoactivation localization microscopy (FPALM) enabling 3D sub-diffraction resolution without compromising speed or sensitivity.


Dose-Response Relationship in Selective Serotonin and Norepinephrine Reuptake Inhibitors in the Treatment of Major Depressive Disorder: A Meta-Analysis and Network Meta-Analysis of Randomized Controlled Trials.
Selective serotonin and norepinephrine reuptake inhibitors (SNRI) are among the most prescribed antidepressants, and dose escalation is a frequently applied strategy after non-response to an initially prescribed dose. This meta-analysis aimed to find evidence of a dose-response relationship or to the contrary in direct comparisons of different SNRI doses in patients with major depressive disorder. A systematic literature search for RCTs comparing at least two doses of SNRIs was carried out in CENTRAL, PubMed, PsycINFO, and EMBASE. Doses were classified as high, medium, and low according to manufacturers' product monographs and analyses at the level of SNRIs as a group and for single substances, accompanied by sensitivity network meta-analyses (Prospero CRD42018081031). From 2,070 studies screened, we included 26 studies with a total of 10,242 patients. Comparisons of medium versus low and high versus medium doses resulted in clinically and statistically non-significant standardized mean differences of -0.06 (-0.16 to 0.04) and -0.06 (-0.16 to 0.03) in favor of higher doses. In the analyses of single substances, no statistically significant results emerged, and many contrasts yielded very small effect sizes. Dropouts due to side effects tended to be more frequent with higher doses. Heterogeneity was low. Network meta-analyses of direct comparisons supported the findings, as did a risk of bias analysis. Based on the lack of positive evidence for a dose-response relationship in SNRIs as a group and in single SNRIs, we recommend prescribing medium doses. In case of insufficient response, we do not recommend increasing the dose of SNRIs.


[Expression of HBV preS2/S gene in mammalian cells transferred with adenoviral vector].
To study HBV preS2/S gene expression effects in mammalian cells transferred with recombinant adenoviral vector. The replication-deficient recombinant adenoviral vector (Ad-HBs) carrying HBV preS2/S gene were constructed by homologous recombination in bacteria. The 293 cells, Vero cells, HepG2 cells and mesenchymal stem cells (MSCs) were infected with adenoviruses. The expressions of enhanced green fluorescent protein (EGFP) were observed with fluorescence microscope and the expressions of HBsAg were detected by RT-PCR and ELISA in vitro. More than 90% of 293 cells, Vero cells, HepG2 cells or MSCs expressed EGFP after transfection at the MOI of 20 and the titers of HBsAg were more than 3.229 (A value) in culture supernatant. The HBV preS2/S gene was not only expressed efficiently in immortalized cells, but also expressed efficiently in stem cells with the recombinant adenoviruses vector.


Addressing desaturation in a tracheal stenosis patient using the transnasal humidified rapid-insufflation ventilatory exchange technique during tracheostomy: A case report.
Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) is used in tracheostomy but not in cases of airway obstruction. This case report explores the use of THRIVE for managing airway obstruction during tracheostomy in patients with subglottic and tracheal stenosis, thereby addressing the current knowledge gap and exploring its potential for airway management. A 63-year-old female with subglottic and tracheal stenoses underwent tracheostomy. Multiple attempts to establish a patent airway were unsuccessful, and oxygen saturation dropped to 56%. Endotracheal tube was directed toward the tracheal wall, causing airway obstruction. THRIVE was administered to the patient. Subsequently, the tube position was adjusted to enhance ventilation. The patient's oxygen saturation increased to 99%. The postoperative complications, including subcutaneous emphysema, pneumothorax, pneumomediastinum and pneumopericardium, resolved. The patient was discharged on postoperative day 9. THRIVE could be considered a temporary measure to enhance oxygenation before initiating a definitive treatment strategy.


Analysis of intestinal cell proliferation after guanethidine-induced sympathectomy. I. Stathmokinetic, labelling index, mitotic index, and cellular migration studies.
Guanethidine-induced sympathectomy in the rat during the neonatal period (injection of 20 microgram/g body weight every 48 h from day of birth until day 14) produces an absolute reduction in the number of sympathetic ganglion cells, but no significant alteration of body weight. Superior cervical ganglia show 79.8% fewer cell bodies at 15 days and 92.3% at 45 days; coeliac ganglia exhibit an 81.0% reduction at 15 days and 89.6% at 45 days in guanethidine-treated rats as compared to normal controls. The sympathetic ganglion cells that remain after treatment have an abnormal morphological appearance with distended mitochondria and depletion of endoplasmic reticulum. Sympathectomy produces a prolongation of the generation cycle time (Tc) as measured by the colchicine-induced mitotic arrest technique, and a decrease in labelling, mitotic, and migration indices. In addition, sympathectomy suppresses the amplitude of the circadian rhythm in mitotic activity. The general suppression of this activity in the intestinal epithelium is more pronounced in the jejunum and ileum than in the duodenum. Variation in the effectiveness of sympathectomy on the inhibition of intestinal cell proliferation may be related to segmental differences in cell proliferation, to segmental differences in innervation, and/or to segmental variation in the effectiveness of guanethidine.


More refined superbag: Distantly supervised relation extraction with deep clustering.
Distant supervision (DS) can automatically generate annotated data for relation extraction (RE) with knowledge bases and corpora. The existing DS methods that train on bags selected by attention mechanism are susceptible to noisy bags and neglect useful information in noisy bags. In this paper, we propose DCSR, a novel DS method which utilizes deep clustering to obtain refined superbag representations for solving the wrong labeling problem. we substitute deep clustering for selective attention to construct superbags, capturing helpful information between spatially-close bags, including noisy bags. Moreover, we implement data augmentation on the input sentences to handle the long-tail problem. Experiments on the NYT2010 and NYT-H datasets show that our method can effectively improve RE and significantly outperforms state-of-the-art methods.


Use of osteoporosis drugs in patients with recent-onset rheumatoid arthritis in Finland.
We investigated the implementation of pharmaceutical osteoporosis (OP) prevention in early rheumatoid arthritis (RA) in Finland. All incident RA cases from 2000 to 2007 were identified using the national register of the Social Insurance Institution (SII) as the sole source. The use of calcium and vitamin D preparations and OP drugs during the first year was evaluated. A total of 14,878 incident RA patients were found. They had a mean age of 56 (SD 15) and 68% were female. Nine per cent of the total number, which equated to 11% for women and to 5% men, had purchased OP drugs. The use of OP drugs increased over time: in the 2006-2007 period, relative risk (RR) for purchase was 1.62 (95% CI 1.38-1.92) for women and 2.1 (1.34-3.30) for men compared to the 2000-2001 period. Over the 2000-2005 period, 49% of females and 52% of males used glucocorticoids (GCs) during the first year. Among the GC-users, 38% of women and 24% of men also received calcium and vitamin D preparations by prescription, and 14% of women and 6% of men also used OP drugs. For GC users, the female sex, and older age increased the risk for OP use: the respective RRs were 1.45 (95% CI 1.31-1.61), 2.54 (95% CI 2.21-2.91), and 1.060 (95% CI 1.057-1.065). Patients with early RA are increasingly receiving OP drugs, and the use is more frequent among patients with known risk factors.


Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder.
SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease. Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher. Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present. We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.


A glimpse of the ERS International Congress 2022.
An overview of what to expect from the European Respiratory Society (ERS) International Congress 2022, including the top picks of the International Congress Programme Committee and a summary of the Early Career Member session. https://bit.ly/3tNTlgY.


Study of the Efficacy of Probiotic Bacteria to Reduce Acrylamide in Food and In Vitro Digestion.
In this study, probiotic bacteria as a new post-processing approach to reduce acrylamide (AA) was investigated. The AA reduction ability of selected Lactobacillus strains and Bifidobacterium strains was demonstrated in (a) AA chemical solutions; (b) food matrices (biscuits and chips) and (c) in vitro digestion. The findings showed tested bacteria exhibited AA reduction ability which was probiotic strain-, AA concentration-, probiotic concentration-, incubation time- and pH-dependent. L. acidophilus LA 45 and B. longum ATCC 15707 (109 CFU/mL) showed the highest AA reduction (86.85 and 88.85%, respectively) when exposed to 350 ng/mL AA solution for 8 h. The findings also demonstrated that AA reduction ability of selected probiotic strains was pH- and food matrix-dependent in both food matrices (9.45-22.15%) and in vitro digestion model (10.91-21.29%). This study showed probiotic bacteria can lower AA bioaccessibility under simulated digestion.


Intensive care diaries and relatives' symptoms of posttraumatic stress disorder after critical illness: a pilot study.
Relatives of patients recovering from critical illness are at risk of developing posttraumatic stress disorder. To test whether providing a diary to intensive care patients and their relatives reduces the level of symptoms related to posttraumatic stress disorder in the relatives. Observational study of close family members of patients who stayed more than 72 hours in an intensive care unit, recruited in 2 centers of a 12-center randomized controlled trial examining the effect of a diary outlining the details of the patients' stay in the intensive care unit on the development of new-onset posttraumatic stress disorder in patients. The close family members of the patients were recruited to examine the additional effect of the provision of the patient's diary on the family members' symptoms related to posttraumatic stress syndrome. Thirty-six family members were recruited, and 30 completed the study. Family members of patients who received their diary at 1 month had lower levels of symptoms related to posttraumatic stress disorder (P = .03) at the 3-month follow-up than did the control family members. Provision of a diary may help psychological recovery in patients' families after critical illness.


Carotid space involvement is a prognostic factor and marker for induction chemotherapy in patients with nasopharyngeal carcinoma.
The carotid space is an integral part of the parapharyngeal space, with ambiguous prognostic value for patients with nasopharyngeal carcinoma (NPC). This study aimed to investigate the prognostic significance of carotid space involvement (CSI) and propose a treatment strategy. This retrospective study enrolled 792 patients with biopsy-confirmed, non-distant metastatic NPC staged by magnetic resonance imaging before treatment. We used multivariable Cox regression models and Kaplan-Meier methods to assess the association between the variables and survival outcomes. A matched-pair method (1:1) was used to compare the survival differences between the patients with CSI treated with induction chemotherapy (ICT)and that of those who were not. The incidence rate of CSI was 21.7 % (172/792). Multivariate analysis revealed that CSI was not an independent prognostic factor for survival outcomes in the 792 patients with NPC; however, the Chi-square test showed a different distribution of treatment strategies with ICT for patients with and without CSI. After stratification by ICT, CSI was an independent prognostic factor for overall survival (OS) (p = 0.049) in patients without ICT, but not for distant metastasis-free, local recurrence-free, or progression-free survival (p˃0.05). Additionally, ICT improved OS in patients with CSI (hazard ratio, 0.42; p = 0.019). Matched pair analysis showed that patients with CSI gained prolonged OS from ICT compared with the non-ICT group (88.4 % vs 69.4 %, p = 0.028). CSI was an independent negative prognostic factor for OS in patients with NPC without ICT and might be an imaging marker for identifying eligible candidates for ICT.


Geographical diversification, firm size and profitability in Malaysia: A quantile regression approach.
The relationship between geographical diversification (GDI) and profitability (ROA) has yielded mixed findings across various developed countries. This study re-examined the relationship using data of public firms listed on the main market of Bursa Malaysia for the period of 2010-2014 using quantile regression approach. The firms are categorised into small firms and large firms based on the firm size median value. The empirical results show that GDI affects ROA heterogeneously in various quantile levels of the ROA for all firms, small firms and large firms. GDI significantly (positive relationship) influences ROA in the middle quantile region (from quantile 0.25 to 0.75) for all firms, in the low quantile region (from quantile 0.1 to 0.5) for the sample of small firms and in the high quantile region (from quantile 0.5 to 0.9) for the sample of large firms. Therefore, GDI activities could benefit firms, provided that the activities are conducted wisely by taking into account the profitability levels of firms as well as the size of firms. This study contributes to literature on geographical diversification by providing empirical support in the context of an emerging market.


De novo cancer incidence after kidney and liver transplantation: Results from a nationwide population based data.
The cancer risk among solid organ transplantation recipients in East-Asia has been insufficiently studied. This study estimated de novo cancer incidence in kidney and liver recipients 2008-2015, compared with the general population in Korea using nationwide data. This is a retrospective cohort study using nationwide health insurance claims data. The study population was comprised of cancer-free 10,085 kidney recipients and 3,822 liver recipients. Standardized incidence ratio (SIR) of cancer using indirect standardization was calculated. Compared with the general population, the cancer risk increased by 3.19-fold in male and 2.56-fold in female kidney recipients. By cancer type, a notably increased SIR was observed for Kaposi sarcoma, renal cancer, skin cancer, and non-Hodgkin's lymphoma in male and for bladder cancer, renal cancer, and non-Hodgkin's lymphoma in female kidney recipients. In liver recipients, the SIR of all cancers was 3.43 in males and 2.30 in females. In male liver recipients, the SIRs for Kaposi sarcoma, non-Hodgkin's lymphoma, myeloid leukemia, and skin cancer and in female recipients those for non-Hodgkin's lymphoma and liver cancer were prominent. A greatly higher SIRs for overall cancer and non-Hodgkin's lymphoma in kidney and liver recipients aged 0-19 were observed, compared with recipients in other age group. The incidence of de novo cancer in kidney and liver recipients was higher than the general population and common types were different. Strategies of cancer prevention and screening after kidney and liver transplantation should be developed in response to the incidence of common types of de novo cancers.


Postcatheterization radial arteriovenous fistula: balloon-assisted direct percutaneous embolization with N-butyl cyanoacrylate and 50 % glucose solution in two sessions.
We report an iatrogenic radial arteriovenous fistula (AVF) in a 74-year-old woman presenting with right radial bruit and pain 8 months after sheath removal for cardiac catheterization. She refused surgical ligation and underwent balloon-assisted direct percutaneous embolization of the draining vein with N-butyl cyanoacrylate (NBCA). Another draining vein that developed immediately after the procedure was conservatively treated with 1 month of continuous band compression. However, its diameter gradually increased and, as the patient desired complete remission, an additional procedure was conducted 2 months after initial treatment. A second balloon-assisted direct percutaneous embolization was performed using a 50 % glucose solution, which resulted in complete resolution. Although surgical repair is considered to be the standard treatment, in patients where surgery is not indicated, endovascular intervention-although complicated-may be an alternative treatment modality.


Pedestrians who required admission to hospital after collisions with motor vehicles in Sweden from 1987 to 1994.
To report the incidence, range of injury, medical consequences, and mortality of pedestrians in collisions with motor vehicles in Sweden. Retrospective case study. The Swedish Hospital Discharge Register (SHDR). 8684 pedestrians in collisions with motor vehicles had a total of 12,036 episodes treated in Swedish hospitals from 1987-1994. Statistical analysis of the Register. Incidence of pedestrians in collisions with motor vehicles in Sweden, mortality, range of injuries, and medical consequences. From 1987 to the end of 1994, a total of 8684 pedestrians were admitted to Swedish hospitals after collisions with motor vehicles. A mean of 17.6 persons were admitted/100,000 population/year. In all there were 12,036 admissions of injured pedestrians. There were 4593 men (53%) and 4091 women (47%), with a median age of 47 (range 1-100) years. The annual incidence of injured pedestrians (both men and women) decreased significantly during this period. Injuries to the extremities were commonest (39% fractures), followed by injuries to the head and neck (34%). The total number of deaths in our series of patients was 444 (5%). Of these, more than half had head injuries, 22% had fractures, and 5% abdominal or thoracic injuries. The number of pedestrians in collisions with motor vehicles is low in Sweden. Injuries to the extremities were commonest, followed by injuries to the head and neck. Old people were most likely to be injured and 5% of the patients treated in hospital died.


Polybase induced lysis of yeast spheroplasts. A new gentle method for preparation of vacuoles.
The polybasic macromolecules DEAE-dextran (diethylaminoethyl-dextran, molecular weight 500000) and poly-DL-lysine (molecular weight 30000-70000) were absorbed with a high affinity by spheroplasts of Candida utilis and subsequently, induced lysis. The extent of lysis of spheroplasts and of the liberated vacuoles was studied under various conditions using alpha-glucosidase activity and soluble arginine as cytoplasmic and vacuolar markers, respectively. Adsorption of polybases was rapidly completed even at 0 degrees C; however, with small doses, lysis was poor at 0-12 degrees C and extensive at temperatures above 12 degrees C. This permitted the completion of adsorption before initiating lysis. The purified vacuoles were also sensitive to polybases though less so than the spheroplasts; however, after lysis of spheroplasts the liberated vacuoles were well protected against the action of polybases. A treatment with polybases which disrupted more than 99% of the spheroplasts left at least 70% of the vacuoles intact. Potassium chloride in high concentrations and calcium chloride in low concentrations inhibited polybase induced lysis of spheroplasts by preventing or even reversing the polybase adsorption. A polyacidic macromolecule, dextran sulfate, could prevent but not reverse the adsorption of polybase and subsequent lysis. Metabolic inhibitors reduced the susceptibility of spheroplasts to polybase induced lysis. Vacuoles isolated from polybase lysed spheroplasts still contained large pools of soluble amino acids, and their ability to transport arginine specifically is a further indication of their functional integrity.


Assessment of magnetic field (4.7 T) induced forces on prosthetic heart valves and annuloplasty rings.
To assess the magnetic field interactions on 11 heart valve prostheses and 12 annuloplasty rings subjected to a 4.7 T MR system. Ex vivo testing was performed to evaluate translational and rotational forces using previously described techniques. Seventeen out of 23 prostheses showed zero interaction with the magnetic field. Translational forces with deflection angles of 2-20 degrees were demonstrated in six prostheses. Only two heart valves and two annuloplasty rings demonstrated rotational forces. The Carpentier Edwards (CE) Physio Ring, which contains Elgiloy, demonstrated deflection angles three times greater than those previously measured at 1.5 T. Furthermore, there was a direct relationship between increasing prosthesis size and increasing translational force. All heart valve prostheses attracted to the magnetic field were slightly paramagnetic/weakly ferromagnetic. Twenty-three heart valve prostheses evaluated for MRI are considered safe in static fields up to 4.7 T based on current safety criteria. However, the CE Physio Ring appeared to develop an increasing magnetism upon re-entry into the MR system. We conclude that prostheses made from Elgiloy may not be acceptable for patients in an MR environment of > or =4.7 T. Further investigations are required to confirm the safety of Elgiloy.


Sleep and older patients.
Sleep disturbances are common among older adults. The elderly population reports more symptoms associated with poor sleep initiation and maintenance and increased daytime napping. Sleep problems may be caused by various factors, including medication use, medical and psychiatric illnesses, and primary sleep disorders. The consequences of poor sleep quality may include cognitive impairment, daytime sleepiness, and reduced quality of life. The evaluation and management of these disorders is discussed in this review.


Design and fabrication of a super-wideband transparent antenna implanted on a solar cell substrate.
In this study, an antenna with transparent super wideband CPW technology has been designed and built with the combination of solar panels for use in wireless communication equipment and systems that require mobile power. The transparency value of the antenna is 63.3%, which is an acceptable value for the optimal use of sunlight. The proposed antenna was designed and measured on a plexi-glass substrate with a dielectric constant of [Formula: see text] and various thicknesses, the proposed antenna was designed and measured. The copper sheet has a high electrical conductivity and therefore it was selected for the antenna's radiating component as compared to earlier techniques that employed metal oxide. All simulations were done with CST microwave studio software and frequency domain solver. The results indicated that the antenna's operating frequency ranges from 2 to 32 GHz. The results of the computations indicated that the antenna's peak gain and peak efficiency are 8.1 dB and 90%, respectively. Various multiple-input and multiple-output (MIMO) performance parameters, including the envelope correlation coefficient (ECC), diversity gain (DG), average effective gain (MEG), total active reflection coefficient (TARC), and channel capacity loss (CCL), were analyzed to demonstrate the antenna's performance.


Relating color discrimination to photopigment genes in deutan observers.
Deutan observers are a heterogeneous group, varying nearly continuously from deuteranomalous trichromats with fine chromatic discrimination in the red/green range to deuteranopes who have none. We sought to relate chromatic discriminative ability among deutans measured psychophysically (phenotypes) to observers' separation between long-wave visual pigments inferred from visual pigment genes (genotypes). If middle-wave pigment genes are assumed not to be expressed in these deutan observers there is a clear relation between phenotype and genotype.


Lessons learned from a black and minority health fair's 15-month follow-up counseling.
Little is known about the impact of community health fairs on participants' health knowledge, literacy, attitudes, or behaviors. Few health fairs have provided followup services for participants. To evaluate the short-term (baseline) and long-term (10-month follow-up) health effects of exposure to the Indiana Black and Minority Health Fair (BMHF) and to assess the impact of personalized 15-month follow-up health counseling sessions for the BMHF participants who agreed to the sessions. A prospective panel study design was utilized with a pre-post test in addition to a cross-sectional survey design. Although few behavioral changes were observed between the baseline and the precounseling 10-month follow-up, more people perceived themselves as overweight (68.1% vs 65.3%, p < .01) and fewer people watched TV/videos 4 hours or more on a usual weekday (25.6% vs 47.0%, p <.001) than 10 months before. After the 15-month follow-up health counseling sessions, the intervention group reported substantial and meaningful improvements in self-reported general health status, health status compared to 6 months earlier, percentage of overweight or obese people, choosing leaner meats over those higher in fat, snacking while watching TV or videos, and placing a high priority on exercise when planning a schedule. A follow-up component to the health fair is not only necessary but also in demand for improving health literacy and healthy outcomes for participants. Efforts should be made to transform health fair encounters from episodic experiences to long-term educational experiences that spur individuals to make the necessary changes to enhance their health.


[Announcing treatment resistance in pediatric oncology: A qualitative study of nurses' experiences].
The announcement of treatment resistance is a key moment in the management of children treated for cancer. Although nurses are present at various stages of this announcement, few studies have examined their role and experience. This study proposes to enhance understanding of the experience of nurses at this time of the pediatric cancer trajectory in France. A qualitative study was conducted in two pediatric oncology departments. Semi-structured research interviews were conducted with seven pediatric nurses (five women) with an average age of 36.9 years. Nurses report not being systematically present during announcements of treatment resistance but being present with the families before and after these announcements. Nurses described their role at this point in the management process as multifaceted. The emotional burden associated with these announcements is significant: nurses must manage their own emotions when faced with the discovery of resistance to treatment, those of the families, and must often answer difficult questions about the prognosis or end of life. In this context, teamwork is an important support. Better awareness and recognition of the role of nurses and the associated emotional burden would enable them to fully carry out their missions.


Study on physicochemical properties and in vitro bioactivity of tricalcium silicate-calcium carbonate composite bone cement.
In this article, a novel bone cement composed of tricalcium silicate (Ca(3)SiO(5); C(3)S) and calcium carbonate (CaCO(3)) was prepared with the weight percent of CaCO(3) in the range of 0, 10, 20, 30, and 40%. The initial setting time was dramatically reduced from 90 to 45 min as the content of CaCO(3) increased from 0 to 40%, and the workable paste with a liquid/powder (L/P) ratio of 0.8 ml/g could be injected between 2 and 20 min (nozzle diameter 2.0 mm). The composite cement showed higher mechanical strength (24-27 MPa) than that of the pure Ca(3)SiO(5) paste (14-16 MPa). Furthermore, the composite cement could induce apatite formation and degrade in the phosphate buffered saline. The results indicated that the Ca(3)SiO(5)-CaCO(3) paste had better hydraulic properties than pure Ca(3)SiO(5) paste, and also the composite cement was bioactive and degradable. The novel bone cement could be a potential candidate as a bone substitute.


Structure elucidation and properties of a non-ionic galactomannan derived from the Cassia pleurocarpa seeds.
A non-ionic water soluble galactomannan made up of d-galactose and d-mannose was isolated from the seed endosperm of Cassia pleurocarpa. Acid catalyzed fragmentation, periodate oxidation, methylation and selective enzymatic hydrolysis revealed that the repeating unit of the heteropolysaccharide had a backbone of beta(1-->4) linked d-mannopyranosyl units to which D-galactopyranosyl units are linked as side chains through alpha(1-->6) linkages. The properties such as viscosity, water/saline retention, gelling behavior, and shelf life of the galactomannan indicated that the material may be exploited in biomedical applications for example drug delivery and tissue engineering fields.


Determination of Illegally Used Chemical Dyes in the Chinese Herbal Medicine "Red Flower Oil".
Red flower oil is a group of herbal medicinal liniments widely used in China and Southeast Asia. The color of red flower oil is adjusted to red or brownish-red by adding natural dyes. The objective of this study is to identify and quantify the synthetic dyes illegally used in red flower oil. Thirty-two batches of red flower oil (from nine manufacturers) were collected from different cities in China. High-performance liquid chromatography-diode array detection-mass spectrometry (HPLC-DAD-MS) analysis was performed to identify the chemical dyes in the samples, and high-performance liquid chromatography-diode array detection (HPLC-DAD) was used to quantify the chemical dyes. Sudan I, Sudan IV, and Solvent Red 207 were detected in nine batches of preparations (from three manufacturers) with concentration ranges of 101.7-214.9 μg/mL for Sudan I, 24.0-41.0 μg/mL for Sudan IV, and 147.5-221.7 μg/mL for Solvent Red 207. In present study, sudan I, sudan IV, and solvent red 207 were detected in red flower oil. The control of chemical dyes in food and drug should be further studied and not limited to sudan dyes. It is the first report about the detection of solvent red 207 in food and drug. The illegal use of those chemical dyes should be regarded as serious violation of good manufacturing practice (GMP) and might be dangerous for the patients.


Hemorheologic effects of Meclomen including effect in malignant melanoma.
Sodium Meclofenamate, (Meclomen) (M) is a non-steroidal anti-inflammatory drug, which inhibits both cyclooxygenases and lipooxygenases of the arachidonic acid cascade (AA). (M) inhibited adenosine diphosphosphate (ADP) induced platelet aggregation, arachidonic acid (AA) induced platelet aggregation and collagen induced platelet aggregation. (M) inhibited platelet factor 3 availability when measured by Stypven clotting time. Red cells from patients with advanced malignancies and normal red cells stored in blood banks exhibited loss of deformability. (M) enhanced red cell deformability in these blood samples.


Tracheal branch repopulation precedes induction of the Drosophila dorsal air sac primordium.
The dorsal air sacs supply oxygen to the flight muscles of the Drosophila adult. This tracheal organ grows from an epithelial tube (the air sac primordium (ASP)) that arises during the third larval instar (L3) from a wing-disc-associated tracheal branch. Since the ASP is generated by a program of both morphogenesis and cell proliferation and since the larval tracheal branches are populated by cells that are terminally differentiated, the provenance of its progenitors has been uncertain. Here, we show that, although other larval tracheae are remodeled after L3, most tracheal branches in the tracheal metamere associated with the wing disc (Tr2) are precociously repopulated with imaginal tracheoblasts during L3. Concurrently, the larval cells in Tr2 undergo head involution defective (hid)-dependent programmed cell death. In BX-C mutant larvae, the tracheal branches of the Tr3 metamere are also repopulated during L3. Our results show that repopulation of the larval trachea is a prerequisite for FGF-dependent induction of cell proliferation and tubulogenesis in the ASP and that homeotic selector gene function is necessary for the temporal and spatial control of tracheal repopulation.


Development and application of a high-throughput microneutralization assay: lack of xenotropic murine leukemia virus-related virus and/or murine leukemia virus detection in blood donors.
Xenotropic murine leukemia virus (MLV)-related virus (XMRV) and other related MLVs have been described with chronic fatigue syndrome and certain types of prostate cancer. In addition, prevalence rates as high as 7% have been reported in blood donors, raising the risk of transfusion-related transmission. Several laboratories have utilized microneutralization assays as a surrogate marker for detection of anti-MLV serologic responses--with up to 25% of prostate cancer patients reported to harbor neutralizing antibody responses. We developed a high-throughput microneutralization assay for research studies on blood donors using retroviral vectors pseudotyped with XMRV-specific envelopes. Infection with these pseudotypes was neutralized by sera from both macaques and mice challenged with XMRV, but not preimmune serum. A total of 354 plasma samples from blood donors in the Reno/Tahoe area were screened for neutralization. A total of 6.5% of donor samples gave moderate neutralization of XMRV, but not control pseudotypes. However, further testing by Western blot revealed no evidence of antibodies against MLVs in any of these samples. Furthermore, no evidence of infectious virus or viral nucleic acid was observed. A microneutralization assay was developed for detection of XMRV and can be applied in a high-throughput format for large-scale studies. Although a proportion of blood donors demonstrated the ability to block XMRV envelope-mediated infection, we found no evidence that this inhibition was mediated by specific antibodies elicited by exposure to XMRV or MLV. It is likely that this moderate neutralization is mediated through another, nonspecific mechanism.


Synergistic effect of interleukin 1 and soluble CD23 on the growth of human CD4+ bone marrow-derived T cells.
Low-affinity Fc epsilon receptor (Fc epsilon RII/CD23) is expressed by various human cells and known to be cleaved into soluble fragments (sCD23). Several biological activities were ascribed to these molecules. In this study, we have assessed the effect of recombinant 25-kDa sCD23 (rsCD23) on human bone marrow-derived T cells. Our results show that rsCD23 in synergy with recombinant interleukin 1 enhances mitogenic responsiveness of CD4+ T cells but does not affect CD8+ cell growth. Furthermore, rsCD23 synergizes autologous marrow cells in enhancement of CD4+ cell growth while CD23 monoclonal antibodies decrease accessory cell effect. Together, these data confirm cytokine-like activity of sCD23 on human T cell lineage.


Grape exosome-like nanoparticles: A potential therapeutic strategy for vascular calcification.
Vascular calcification (VC) is prevalent in hypertension, diabetes mellitus, chronic kidney disease, and aging and has been identified as an important predictor of adverse cardiovascular events. With the complicated mechanisms involved in VC, there is no effective therapy. Thus, a strategy for attenuating the development of VC is of clinical importance. Recent studies suggest that grape exosome-like nanoparticles (GENs) are involved in cell-cell communication as a means of regulating oxidative stress, inflammation, and apoptosis, which are known to modulate VC development. In this review, we discuss the roles of GENs and their potential mechanisms in the development of VC.


Transport and bioactivity of cyanidin 3-glucoside into the vascular endothelium.
Flavonoids are dietary components involved in decreasing oxidative stress in the vascular endothelium and thus the risk of endothelial dysfunction. However, their very low concentrations in plasma place this role in doubt. Thus, a relationship between the effective intracellular concentration of flavonoids and their bioactivity needs to be assessed. This study examined the uptake of physiological concentrations of cyanidin 3-glucoside, a widespread dietary flavonoid, into human vascular endothelial cells. Furthermore, the involvement of the membrane transporter bilitranslocase (TC No. 2.A.65.1.1) as the key underlying molecular mechanism for membrane transport was investigated by using purified anti-sequence antibodies binding at the extracellular domain of the protein. The experimental observations were carried out in isolated plasma membrane vesicles and intact endothelial cells from human endothelial cells (EA.hy926) and on an ischemia-reperfusion model in isolated rat hearts. Cyanidin 3-glucoside was transported via bilitranslocase into endothelial cells, where it acted as a powerful intracellular antioxidant and a cardioprotective agent in the reperfusion phase after ischemia. These findings suggest that dietary flavonoids, despite their limited oral bioavailability and very low postabsorption plasma concentrations, may provide protection against oxidative stress-based cardiovascular diseases. Bilitranslocase, by mediating the cellular uptake of some flavonoids, is thus a key factor in their protective activity on endothelial function.


Total upright large volume columnar myelography in pediatric scoliosis.
A technique is described whereby large volume columnar myelography is accomplished utilizing diluted aqueous intrathecal contrast media. The problems of maneuvering the radiopaque contrast around scoliotic curves are easily overcome thereby facilitating an otherwise difficult examination.


Formation of granular cytoplasmic aggregates in COS7 cells expressing mutant Cu/Zn superoxide dismutase associated with familial amyotrophic lateral sclerosis.
To investigate the molecular mechanisms of the 'gain of toxic function' of mutant Cu/Zn superoxide dismutase (SOD) associated with familial amyotrophic lateral sclerosis (FALS), mutant (Ala 4 --> Thr, Gly 85 --> Arg, Gly 93 --> Ala, and two base-pair deletion in the 126th codon), as well as wild-type (wt), Cu/Zn SODs were expressed in COS7 cells. The formation of granular cytoplasmic aggregates accompanied by collapse of the cytoplasm was observed in cells expressing mutant (mt) Cu/Zn SODs, but not in cells expressing wt Cu/Zn SOD. The aggregates contained ribosome-like particles and endoplasmic reticulum. These results suggest the possibility that mt Cu/Zn SODs promote the formation of aggregates which are toxic to cells.


Surgical wound infection surveillance in general surgery procedures at a teaching hospital in Pakistan.
A surveillance system was established at the Aga Khan University Hospital in Karachi, Pakistan, to determine surgical wound infection (SWI) rates, trends, and risk factors; and to compare rates with those reported by the National Nosocomial Infection Surveillance (NNIS) system of the Centers for Disease Control and Prevention. Surveillance was performed from January 1997 to December 1999. Risk categorization was on the basis of the NNIS system. P <.05 was set for statistically significant difference between groups. Data were analyzed using the Epi-Info software (version 6.04, CDC, Atlanta, Ga). Overall SWI rates for the NNIS risk categories 0, 1, 2, and 3 were 1.9%, 3.7%, 6.7%, and 5.1%, respectively. SWI rate in 0 risk category decreased from 3% in 1997 to 1.1% in 1999 (P =.06). Multivariate analysis showed that SWI rates were higher after mastectomy (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.8-10), hernia repair (OR 3.28, 95% CI 1.6-6.7), gastrointestinal resection (OR 2.2, 95% CI 0.88-5.9), skin procedures (OR 1.97, 95% CI 0.89-4.3), appendectomy OR 0.57, 95% CI 0.20-1.60, and miscellaneous procedures (OR 3.6, 95% CI 1.6-7.7), as compared with cholecystectomy. Other risk factors were contaminated type of operation (OR 2.6, 95% CI 1.2-5.5), and duration of operation exceeding the NNIS standard of "T" hours (OR 2.6, 95% CI 1.7-4). The SWI rates at the Aga Khan University Hospital are higher than the NNIS standards. There was a downward trend in the SWI rates during the surveillance period. A decrease in the duration of surgical procedures could further reduce the risk.


Complementation in trans of altered thymocyte development in mice expressing mutant forms of the adaptor molecule SLP76.
The adaptor protein SLP76 directs signaling downstream of the T cell receptor (TCR) and is essential for thymocyte development. SLP76 contains three N-terminal tyrosines that are critical for its function. To define the role of these residues in thymocyte development, we generated two lines of "knock-in" mice, one expressing a mutation in tyrosine 145 (Y145F) and a second harboring two point mutations at tyrosines 112 and 128 (Y112-128F). We show here that although thymocyte development requires both Y145- and Y112-128-generated signals, selection was more dependent upon Y145. Although several proximal TCR signaling events were defective in both mutant mice, phosphorylation of the guanine nucleotide exchange factor, Vav1, and activation of Itk-dependent pathways were differentially affected by mutations at Y112-128 and Y145, respectively. Analysis of mice expressing one Y145F and one Y112-128F allele revealed that these mutants could complement one another in trans, demonstrating cooperativity between two or more SLP76 molecules. Thus, the N-terminal tyrosines of SLP76 are required for thymocyte selection but can function on separate molecules to support TCR signaling.


Fibroblast growth factor 21 plays an inhibitory role in vascular calcification in vitro through OPG/RANKL system.
Vascular calcification is prevalent and associated with adverse outcome without available therapy. The benefits of fibroblast growth factor (FGF)-21 on metabolism and atherosclerosis make it a promising therapeutic agent for vascular calcification. We investigated the effects of FGF21 on vascular smooth muscle cell (VSMC) calcification by culturing rat VSMCs in a calcifying medium for 9days. FGF21 markedly attenuated mineral deposition and apoptosis at the indicated time points. In the presence of FGF21, the expression levels of osteoblastic protein including bone morphogenic protein-2, alkaline phosphatase(ALP), runt-related transcription factor(RUNX)-2 and nuclear factor-kappa B ligand (RANKL) were down-regulated, whereas the expression of osteoprotegerin (OPG) increased. Knockdown of OPG significantly impaired inhibition of FGF21 on apoptosis and the expression of pro-apoptotic genes including caspase-3 and Bax and osteoblastic -promoting markers including ALP, RUNX-2 and RANKL. Furthermore, FGF21 facilitated the phosphoryl of AKT but suppressed P38, while OPG knockdown attenuated the effects. LY29400 (inhibitor of PI3K) abrogated the activation of PI3K/AKT and SB203580 (inhibitor of P38) abolished the inhibition of FGF21 on P38, while alteration was observed in the expression of RUNX-2. FGF21 inhibited VSMCs calcification via OPG/RANKL system, and through P38 andPI3K/AKT pathways.


A comparison of patient-reported outcome measures (PROMs) between short and conventional stem hip replacements: a systematic review and meta-analysis.
Short stem hip replacements may allow preservation of proximal bone stock and minimise soft tissue disruption, easing future revision surgery. However patient satisfaction with these implants must be determined before widespread use. We aimed to compare patient reported outcome measures (PROMs) between short and conventional stem hip replacements. A systematic review was conducted according to PRISMA guidelines for studies comparing short and conventional stem hip replacements with validated PROMs. Meta-analyses were performed for studies reporting Harris Hip and WOMAC scores. Study bias was assessed with the Cochrane Risk of Bias tool and Newcastle-Ottawa Scale. 24 studies, incorporating 2593 total hip replacements were included for qualitative analysis. 17 studies were included in the meta-analyses. Of the 7 excluded, 1 study reported the Japanese Orthopaedic Association score and 2 others reported the Oxford Hip score. All three showed no difference between the stems. A meta-analysis of 17 studies reporting Harris hip scores showed no statistically significant difference between short and conventional stems (standard mean difference (SMD) -0.06, 95% CI -0.20-0.07, p = 0.35). 6 studies reported WOMAC scores with higher scores indicating worse outcome. No difference was seen between the two groups (SMD 0.21, 95%CI, -0.01-0.42, p = 0.06). 4 studies reported higher WOMAC scores as better. Once again, a meta-analysis showed no statistically significant difference between the stems (SMD 0.28, 95% CI -0.07-0.63, p = 0.12). Our systematic review showed no difference in PROMs between short and conventional stem total hip replacements. This is in keeping with previous evidence but is a more comprehensive analysis. Short stems may have an important role in younger individuals as they allow preservation of proximal femoral bone, minimal access surgery and are amenable to abnormal anatomy. The current literature is hindered by non-uniform methodologies and outcome assessments across studies. Further, standardised, high quality evidence is required before widespread changes in practice.


Urinary fibrinopeptide A levels in ischemic heart disease.
Because acute coronary thrombosis can cause unstable coronary artery disease, fibrinopeptide A, a reliable marker of coagulation activity, may play a role in the evaluation of unstable ischemic syndromes. A new method of fibrinopeptide A sampling, spot urine normalized to urinary creatinine, was evaluated in patients with stable and unstable angina pectoris and acute myocardial infarction. Serial samples were obtained to characterize the changes in urinary fibrinopeptide A levels over time in patients with ischemic heart disease. Admission values (mean +/- SD) were similar in the control group (3.3 +/- 1.4 ng/mg creatinine) and the stable angina group (3.2 +/- 1.1 ng/mg creatinine) (p = NS). Values in the unstable angina group (5.7 +/- 2.6 ng/mg creatinine) were higher than those in the control (p = 0.008) and stable angina (p less than 0.001) groups. Myocardial infarction admission values (8.4 +/- 10.0 ng/mg creatinine) were higher than those in the control (p = 0.005) and stable angina (p less than 0.001) groups, but not higher than those in the unstable angina group. Peak values (the highest of multiple samples) were higher in the unstable angina group (7.6 +/- 5.9 ng/mg creatinine) than in the stable angina group (4.0 +/- 1.0 ng/mg creatinine) (p = 0.04), but not in the control group (4.5 +/- 1.9 ng/mg creatinine) (p = 0.056). The two patients with unstable angina with the highest peak values subsequently exhibited infarction. Peak values in patients with infarction (44.5 +/- 60.0 ng/mg creatinine) were significantly higher than those in patients with unstable (p = 0.03) or stable (p = 0.002) angina and control patients (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Ultra-long-acting (XLA) antivirals for chronic viral hepatitis.
Viral hepatitis is among the top four causes of mortality globally, causing 1.4 million deaths each year, exceeding tuberculosis, malaria and human immunodeficiency virus. Hepatitis B and C are responsible for 90% of hepatitis deaths, and the remaining 10% are caused by other hepatitis viruses. The annual number of deaths from hepatitis C is declining, whereas the numbers of deaths from hepatitis B and D are increasing. Hepatitis B alone represents the seven highest cause of mortality worldwide. Spurred on by development of curative antivirals for hepatitis C and expanding access to hepatitis B virus (HBV) vaccination, the World Health Organization has committed to eliminating viral hepatitis as a public health threat by 2030. Like the majority of current antivirals, those available for HBV are virostatic. They are capable of suppressing viral replication but cannot eliminate the virus from infected patients. Therefore, treatment is lifelong. Long-term adherence to medication continues to represent a major challenge. Importantly, HBV often reactivates, leading to potential life-threatening events in immunosuppressed patients. Therapeutic options are limited for hepatitis D; however, promising new, effective antivirals are on the horizon. Recent advances have emerged in medicinal chemistry and drug delivery approaches to produce ultra-long-acting (XLA) antivirals. These can extend antiviral activity from months to 1 year or even longer. These new formulations can overcome the challenges of daily dosing and maximize drug exposure. The development of XLA antivirals targeting viral hepatitis may also facilitate cure strategies.


Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy.
The effects of inner ear abnormality on audibility have been explored since the early 20th century when sound detection measures were first used to define and quantify 'hearing loss'. The development in the 1970s of objective measures of cochlear hair cell function (cochlear microphonics, otoacoustic emissions, summating potentials) and auditory nerve/brainstem activity (auditory brainstem responses) have made it possible to distinguish both synaptic and auditory nerve disorders from sensory receptor loss. This distinction is critically important when considering aetiology and management. In this review we address the clinical and pathophysiological features of auditory neuropathy that distinguish site(s) of dysfunction. We describe the diagnostic criteria for: (i) presynaptic disorders affecting inner hair cells and ribbon synapses; (ii) postsynaptic disorders affecting unmyelinated auditory nerve dendrites; (iii) postsynaptic disorders affecting auditory ganglion cells and their myelinated axons and dendrites; and (iv) central neural pathway disorders affecting the auditory brainstem. We review data and principles to identify treatment options for affected patients and explore their benefits as a function of site of lesion.


Upregulation of FcγRIIB by resveratrol via NF-κB activation reduces B-cell numbers and ameliorates lupus.
Resveratrol, an anti-inflammatory agent, can inhibit pro-inflammatory mediators by activating Sirt1, which is a class III histone deacetylase. However, whether resveratrol can regulate inhibitory or anti-inflammatory molecules has been less studied. FcγRIIB, a receptor for IgG, is an essential inhibitory receptor of B cells for blocking B-cell receptor-mediated activation and for directly inducing apoptosis of B cells. Because mice deficient in either Sirt1 or FcγRIIB develop lupus-like diseases, we investigated whether resveratrol can alleviate lupus through FcγRIIB. We found that resveratrol enhanced the expression of FcγRIIB in B cells, resulting in a marked depletion of plasma cells in the spleen and notably in the bone marrow, thereby decreasing serum autoantibody titers in MRL/lpr mice. The upregulation of FcγRIIB by resveratrol involved an increase of Sirt1 protein and deacetylation of p65 NF-κB (K310). Moreover, increased binding of phosphor-p65 NF-κB (S536) but decreased association of acetylated p65 NF-κB (K310) and phosphor-p65 NF-κB (S468) to the -480 promoter region of Fcgr2b gene was responsible for the resveratrol-mediated enhancement of FcγRIIB gene transcription. Consequently, B cells, especially plasma cells, were considerably reduced in MRL/lpr mice, leading to improvement of nephritis and prolonged survival. Taken together, we provide evidence that pharmacological upregulation of FcγRIIB expression in B cells via resveratrol can selectively reduce B cells, decrease serum autoantibodies and ameliorate lupus nephritis. Our findings lead us to propose FcγRIIB as a new target for therapeutic exploitation, particularly for lupus patients whose FcγRIIB expression levels in B cells are downregulated.


Multi-holed biplane drill guide-assisted percutaneous anterior odontoid screw fixation.
The use of percutaneous anterior screw fixation for odontoid fractures has been widely reported. Because the anatomical characteristics of the odontoid and the screw occupy three-dimensional space, it is challenging to establish the screw trajectory quickly and correctly during the operation. The purpose of this study was to introduce a multi-holed biplane drill guide that can be used to optimize the guide needle trajectory in percutaneous anterior odontoid screw fixation. Twenty-one patients with type II or rostral type III odontoid fractures were treated with percutaneous anterior single screw fixation. Of these, 12 patients had an unsatisfactory initial guide needle position. A drill guide was used to provide a variety of guide needle tracks. All 12 patients successfully underwent guided screw placement without vascular or neurological complications. Postoperative X-ray and/or CT scans showed that the internal fixation position was satisfactory. At the end of the follow-up period, all patients exhibited bony union without loosening or fractures of the internal fixation. With the imperfect initial position of the guide needle as a reference, the multi-holed biplane drill guide can provide a variety of needle trajectory options in the sagittal and coronal planes for percutaneous anterior odontoid screw fixation. The operator can quickly obtain the ideal guide needle trajectory.


Effect of resistive training on plasma lipid and lipoprotein levels in male adolescents.
We studied fourteen 14 to 17-year old male adolescents before and after a 9-week resistive exercise program and compared the changes in lipid and lipoprotein profiles with those in 14 non-exercising control subjects. Studies included determination of weight, body mass index (weight for height2), percent body fat, blood pressure and resting heart rate, maximum heart rate and maximum oxygen consumption, and plasma lipids and lipoproteins. No significant differences were present between the two groups before training except that percent body fat was lower in the control subjects. After training, low-density lipoprotein cholesterol in the exercising subjects decreased from 120 +/- 15 to 95 +/- 13 mg/dL (P less than 0.001), high-density lipoprotein cholesterol increased from 35 +/- 12 to 45 +/- 8 mg/dL (P less than 0.01), and high-density lipoprotein cholesterol/total cholesterol ratio increased from 0.2 +/- 0.06 to 0.27 +/- 0.05 (P less than 0.001). Control subjects showed a significant increase in weight (P less than 0.01) and body mass index (P less than 0.01) and a decrease in maximum heart rate (P less than 0.01) at the end of the 9 weeks. Adjustment for body mass index resulted in no alteration in the favorable response of the lipoprotein profile. No change occurred in body composition or maximum oxygen consumption with training. These findings indicate that resistive training is associated with a favorable alteration in the lipoprotein profile in adolescent males.


Potential mechanisms for poor glycaemic control in patients with type two diabetes and fear of hypoglycaemia.
The current study aimed to explore the potential effect of diabetes-related distress on the association between fear of hypoglycaemia and poor glycaemic control. We evaluated the specific aspects of fear of hypoglycaemia that affect glycaemic control among Saudi patients with type 2 diabetes (T2D). Descriptive cross-sectional survey of patients with T2D attending a specialist diabetes clinic in Taif, Saudi Arabia. We used the Hypoglycaemia Attitudes and Behaviour Scale (HABS) for assessing fear of hypoglycaemia among our sample. We used Structural Equation Modelling to evaluate the moderators and correlates of fear of hypoglycaemia. We surveyed 365 patients with T2D. Cronbach's alpha for the HABS assessment was 0.84, an indication of excellent internal consistency. The composite reliability for hypoglycaemic anxiety was 86.8%; hypoglycaemic avoidance was 85.2%; and hypoglycaemic confidence was 92.6%. The mean HABS score was 32.7 points (out of 70 points; SD = 9.8 points). Fear of hypoglycaemia was associated with increased levels of glycated haemoglobin (HbA1c), presence of eye disease, heart disease, and stroke. Fear of hypoglycaemia was associated with poor glycaemic control. No significant moderating effect of diabetes-related distress was observed. However, only hypoglycaemic anxiety and avoidance were associated with poor glycaemic control. Confidence in the ability to control low glucose levels was not associated with elevated HbA1c levels. A significant finding of this study highlighted the considerable and direct effect of fear of hypoglycaemia on poor glycaemic control among patients with T2D. However, only fear-related anxiety and avoidance-and not confidence in the ability to control low glucose levels-had an effect on poor glycaemic control.


[Uterus transplantation, current prospect and future indications. State of art with review of literature].
The aim of this review is to summarize the development of UT on worldwide and to develop the new questions posed by this technique in 2020. According to the PRISMA model, via Pubmed, we searched for publications containing the keywords: uterus transplantation; UT and cryopreservation from 2000 to 2020. At least 76 UTx have been carried out around the world and 19 healthy babies were born. The main indication remains the uterine agenesis (MRKH Syndrome>85% cases) then the history of hysterectomy (hemorrhage of the delivery or cervical cancer) and the non-functional uterus (Asherman's syndrome, diffuse adenomyosis). The 2 types of donors (living and deceased) are developed representing respectively 75% and 25% of the TU; the success rate in terms of return of rules is better in the living donor group and is 79% vs 68% in the deceased donor group. The choice of donor type must take into account the constraints of both procedures. Surgical complications (grade III) for the donor are estimated to be 14% mainly represented by ureter wounds. Technical simplifications concerning the venous return of the graft but also the carrying out of robot-assisted surgery would reduce the operating time for the donor and facilitate the collection process. TU is a complementary alternative to GPA and adoption allowing patients to be surrogates, legal and biological of the baby. An extension of the indications to patients with non absolute uterine infertility is in the process of democratization.


High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group.
The activity and toxicity of single-agent standard-dose doxorubicin were compared with that of two schedules of high-dose epirubicin. A total of 334 chemonaive patients with histologically confirmed advanced soft-tissue sarcomas received (A) doxorubicin 75 mg m(-2) on day 1 (112 patients), (B) epirubicin 150 mg m(-2) on day 1 (111 patients) or (C) epirubicin 50 mg m(-2) day(-1) on days 1, 2 and 3 (111 patients); all given as bolus injection at 3-week intervals. A median of four treatment cycles was given. Median age was 52 years (19-70 years) and performance score 1 (0-2). Of 314 evaluable patients, 45 (14%) had an objective tumour response (eight complete response, 35 partial response). There were no differences among the three groups. Median time to progression for groups A, B and C was 16, 14 and 12 weeks, and median survival 45, 47 and 45 weeks respectively. Neither progression-free (P = 0.93) nor overall survival (P = 0.89) differed among the three groups. After the first cycle of therapy, two patients died of infection and one owing to cardiovascular disease, all on epirubicin. Both dose schedules of epirubicin were more myelotoxic than doxorubicin. Cardiotoxicity (> or = grade 3) occurred in 1%, 0% and 2% respectively. Regardless of the schedule, high-dose epirubicin is not a preferred alternative to standard-dose doxorubicin in the treatment of patients with advanced soft-tissue sarcomas.