Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers.
Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone's potential as a gynecologic cancer therapeutic.


Preparation of new β-D-xyloside- and β-D-xylobioside-based ionic liquids through chemical and/or enzymatic reactions.
Several tetraalkylphosphonium and tetraalkylammonium salts containing xyloside- and xylobioside-based anionic moieties have been prepared. Two stereoselective routes have been developed: i) a chemical pathway in four steps from D-xylose, and ii) a chemoenzymatic pathway directly from biomass-derived xylans. These salts displayed interesting properties as ionic liquids. Their structures have been correlated to their thermal properties (melting, glass transition and decomposition temperatures).


[Percutaneous cholecystectomy and litholysis with methyl tert-butyl ether under ultrasonic control].
The first percutaneous cholecystostomies under ultrasound control with therapeutic purpose, performed in Bulgaria, are reported. They furnish the opportunity for local treatment of acute cholecystitis and chemical litholysis in biliary calculosis. Control of the latter was realized by microscopic determination of the amount of cholesterine crystals in periodically aspirated bile. Indications for this procedure are defined after thorough discussion by internist and surgeon. Transhepatic approach and long-term treatment with methyltertiary-butyl ether are considered obligatory.


The magnitude and predictors of abandonment of therapy in paediatric acute leukaemia in middle-income countries: a systematic review and meta-analysis.
Abandonment of therapy is a significant cause of paediatric cancer treatment failure in low- to middle-income countries (LMIC), but its impact has been underestimated. We performed a meta-analysis to determine the magnitude of abandonment in paediatric leukaemia in LMIC and sought to identify patient-, centre- and country-specific predictors of abandonment. We searched seven databases to identify paediatric oncology cohorts followed up from diagnosis and treated in LMIC. All languages were included. Two reviewers independently selected articles and extracted data. Authors were contacted for additional information. Subgroup analyses were planned a priori. Of 22,384 publications, 318 in eight languages met criteria for full text review. 157 studies met analysis inclusion criteria. Abandonment rates (ARs), obtained for 83 of the 157 studies (52.9%), ranged from 0% to 74.5%. ARs were frequently unreported and available only directly from authors. Forty studies (10,494 children in 20 countries) were quantitatively analysed. ARs for acute lymphoblastic laeukemia in lower-middle-income countries (lower-MICs) were higher than in upper-middle-income countries (29%, 95% confidence interval (CI) 23-36% versus 2%, 95% CI 1-3%; p<0.0001) but were heterogeneous (I(2)=98%; p<0.0001). This heterogeneity was not explained by centre-specific (free versus paid treatment) or country-specific (government health expenditure, per-capital income) subgroups. In LMICs, ARs are highest in lower-MICs. However, their broad range suggests that low ARs are possible in resource-constrained settings. Analysis of outliers may suggest interventions for use at other centres. Methodologically appropriate reporting of ARs should be adopted. Future research should evaluate interventions targeting abandonment.


[Effectiveness of infiltration anesthesia of postoperative abdominal wound using bupivacaine solution for alleviation of postoperative pain].
In a group of 40 patients after abdominal operations a high effectiveness was noted of infiltrations anaesthesia of the postoperative wound with 0.5% bupivacaine solution for alleviation of pain and reduction of requirements for narcotics in early postoperative period (randomized study).


Immunization of cattle against rabies using inactivated cell culture vaccines.
Twenty-one heads of cattle were vaccinated with Madibovin, 31 with Rabdomun and 127 with Rabisin on 4 different farms. Rabies neutralizing antibody titre (> or = 0.5 IU/ml) was detected in 80% of 163 animals tested about 1 month and in 42% of 133 animals tested about 1 year after primary vaccination. On 3 of the farms 86 animals received booster vaccination about 1 year after primary vaccination. All these animals had antibody titre (> or = 0.5 IU/ml) about 1 month after booster and antibody levels were higher than after the primary vaccination. Rabies antibody titres (> or = 0.5 IU/ml) were detected in 96% of 50 animals tested 1 year after the booster. No significant differences (p > 0.05) in antibody levels were detected between animals vaccinated with Madibovin or Rabisin (farm C) respectively with Rabisin or Rabdomun (farm D) at any collection time. Responses to rabies vaccines varied considerably between the farms. After primary vaccination of the animals on 2 farms with the same batch of Rabisin, the antibody levels clearly differed (p < 0.0001) between the farms. Our results indicate that booster is always necessary after primary vaccination to ensure that all animals are protected.


Hinokiflavone induces apoptosis, cell cycle arrest and autophagy in chronic myeloid leukemia cells through MAPK/NF-κB signaling pathway.
Chronic myeloid leukemia (CML) is a myeloproliferative tumor originating from hematopoietic stem cells, and resistance to tyrosine kinase inhibitors (TKI) has become a major cause of treatment failure. Alternative drug therapy is one of the important ways to overcome TKI resistance. Hinokiflavone (HF) is a C-O-C type biflavonoid with low toxicity and antitumor activity. This study investigated the antitumor effect and possible mechanisms of HF in CML cells. Cell viability was measured by CCK-8 assay. Cell apoptosis and cell cycle distribution were analyzed by flow cytometry. Western blotting was used to assess protein expression levels. Our results showed that HF significantly inhibited the viability of K562 cells in a concentration- and time-dependent manner and induced G2/M phase arrest by up-regulating p21 and down-regulating Cdc2 protein. Furthermore, HF induced caspase-dependent apoptosis by activating JNK/p38 MAPK signaling pathway and inhibiting NF-κB activity. In addition, HF induced autophagy by increasing LC3-II expression and p62 degradation. Pretreatment with CQ, a late autophagy inhibitor, significantly increased the levels of LC3-II and p62 proteins and promoted cell survival. HF shows a good anti-leukemia effect and is expected to become a potential therapeutic drug for CML.


Targeted and Controlled Drug Delivery to a Rat Model of Heart Failure Through a Magnetic Nanocomposite.
As a novel cardiac myosin activator, Omecamtive Mecarbil (OM) has shown promising results in the management of systolic heart failure in clinical examinations. However, the need for repeated administration along with dose-dependent side effects made its use elusive as a standard treatment for heart failure (HF). We hypothesized that improved cardiac function in systolic HF models would be achieved in lower doses by targeted delivery of OM to the heart. To test this hypothesis, a nanocomposite system was developed by composing chitosan and a magnetic core (Fe3O4), loaded with OM, and directed toward the rats' heart via a 0.3 T magnet. HF-induced rats were injected with saline, OM, and OM-loaded nanocomposite (n = 8 in each group) and compared with a group of healthy animals (saline injected, n = 8). Knowing the ejection fraction (EF) of healthy (93.68 ± 1.37%) and HF (71.7 ± 1.41%) rats, injection of nanocomposites was associated with improved EF (EF = 89.6 ± 1.40%). Due to increased heart targeting of nanocomposite (2.5 folds), improved cardiac function was seen with only 4% of the OM dose required for infusion, while injecting the same dose of OM without targeting was unable to stop HF progression (EF = 55.33 ± 3.16%) during 7 days. In conclusion, heart nanocomposites targeting improves the EF by up to 18% by only using 4% of the doses traditionally used in treating the HF.


Parathyroid adenoma autoinfarction: a report of a case.
Parathyroid adenoma autoinfarction, although uncommon, is an entity that has been previously reported in the literature; however, the influence of intraoperative parathyroid hormone (PTH) monitoring on therapeutic management has not been reported. We present a case of parathyroid autoinfarction that is unique in that it applies a new technology to parathyroid surgery: intraoperative PTH monitoring. Intraoperative PTH monitoring aided in the successful surgical management of this patient. Intraoperative PTH monitoring can serve as a therapeutic adjunct in the surgical management of parathyroid adenoma autoinfarction.


Coexistent osteoporosis and multiple myeloma: when to investigate further in osteoporosis.
Osteoporosis commonly causes vertebral collapse fractures. We present a patient with multiple vertebral fractures in the context of severe osteoporosis, who, in the course of investigation for intractable spine and hip pain, was found to have an IgA myeloma. At 2 months post diagnosis, she was discharged home to continue outpatient chemotherapy.


Validation of soy protein estimates from a food-frequency questionnaire with repeated 24-h recalls and isoflavonoid excretion in overnight urine in a Western population with a wide range of soy intakes.
Evidence of the benefits of soy on cancer risk in Western populations is inconsistent, in part because of the low intake of soy in these groups. We assessed the validity of soy protein estimates from food-frequency questionnaires (FFQs) in a sample of Adventist Health Study-2 participants with a wide range of soy intakes. We obtained dietary intake data from 100 men and women (43 blacks and 57 nonblacks). Soy protein estimates from FFQs were compared against repeated 24-h recalls and urinary excretion of daidzein, genistein, total isoflavonoids (TIFLs), and equol (measured by HPLC/photodiode array/mass spectrometry) as reference criteria. We calculated Pearson and Spearman correlation coefficients (with 95% CIs) for FFQ-24-h recall, 24 h-recall-urinary excretion, and FFQ-urinary excretion pairs. Among soy users, mean (+/- SD) soy protein values were 12.12 +/- 10.80 g/d from 24-h recalls and 9.43 +/- 7.83 g/d from FFQs. The unattenuated correlation (95% CI) between soy protein estimates from 24-h recalls and FFQs was 0.57 (0.32, 0.75). Correlation coefficients between soy protein intake from 24-h recalls and urinary isoflavonoids were 0.72 (0.43, 0.96) for daidzein, 0.67 (0.43, 0.91) for genistein, and 0.72 (0.47, 0.98) for TIFLs. Between FFQs and urinary excretion, these were 0.50 (0.32, 0.65), 0.48 (0.29, 0.61), and 0.50 (0.32, 0.64) for daidzein, genistein, and TIFLs, respectively. Soy protein estimates from questionnaire were significantly correlated with soy protein from 24-h recalls and urinary excretion of daidzein, genistein, and TIFLs. The Adventist Health Study-2 FFQ is a valid instrument for assessing soy protein in a population with a wide range of soy intakes.


[Localized dermatitis herpetiformis Duhring of the Cottini type].
Dermatitis herpetiformis Duhring restricted to knees and ellbows is relatively unknown and is called Cottini type. We observed a 23 year old female patient, in whom the resolution of the lesions occured after topical steroids. The dermatitis flared possibly following treatment with an iodine-containing coughing sirup.


A chemically sulfated polysaccharide from Grifola frondos induces HepG2 cell apoptosis by notch1-NF-κB pathway.
Sulfated polysaccharides have been known to inhibit proliferation in tumor cells. However, the molecular mechanisms involved in sulfated polysaccharides-induced apoptosis are still uncharacterized. In this study, the effect of a chemically sulfated polysaccharide obtained from Grifola frondosa (S-GFB) on HepG2 cell proliferation and apoptosis-related mechanism were investigated. It was found that S-GFB inhibited proliferation of HepG2 cells in a dose-dependent manner with IC50 at 48 h of 61 μg ml(-1). The results of scanning electron micrographs indicated that S-GFB induced typical apoptotic morphological feature in HepG2 cells. Flow cytometric analysis demonstrated that S-GFB caused apoptosis of HepG2 cells through cells arrested at S phase. Western-blotting results showed that S-GFB inhibited notch1 expression, IκB-α degradation and NF-κB/p65 translocation from cytoplasm into nucleus. Simultaneously, the apoptotic mechanism of HepG2 cells induced by S-GFB was associated with down regulation of FLIP, and activation of caspase-3 and caspase-8. Taken together, these findings suggest that the S-GFB induces apoptosis through a notch1/NF-κB/p65-mediated caspase pathway.


Biological and neurodevelopmental implications of neonatal pain.
Nociceptive pathways are functional following birth. In addition to physiological and behavioral responses, neurophysiological measures and neuroimaging evaluate nociceptive pathway function and quantify responses to noxious stimuli in preterm and term neonates. Intensive care and surgery can expose neonates to painful stimuli when the developing nervous system is sensitive to changing input, resulting in persistent impacts into later childhood. Early pain experience has been correlated with increased sensitivity to subsequent painful stimuli, impaired neurodevelopmental outcomes, and structural changes in brain development. Parallel preclinical studies have elucidated underlying mechanisms and evaluate preventive strategies to inform future clinical trials.


The influence of ambulation time on the incidence of transient neurologic symptoms after lidocaine spinal anesthesia.
The cause of transient neurologic symptoms (TNSs) after lidocaine spinal anesthesia remains unclear. It has been proposed that early ambulation after spinal anesthesia contributes to the development of TNSs. We evaluated the influence of ambulation time on the occurrence of TNSs after spinal anesthesia with 50 mg of 2% plain lidocaine for knee arthroscopy. One-hundred-twenty patients undergoing knee arthroscopy (ASA physical status 1-2) were randomized into 3 groups, i.e., early (Group E), 6-h (Group 6-h), or late ambulation (Group L) groups. In Group E, ambulation was allowed as early as possible after regression of spinal block (on average 229 +/- 21 min; range, 135-247 min). In Group 6-h, the patients remained in bed for approximately 6 h after the block and in Group L until the next morning. The patient groups were comparable with respect to demographic, anesthetic, and surgical variables. The overall incidence of TNSs was 16%. TNSs occurred in 3 patients of Group E (7.5%), in 11 patients of Group 6-h (28%), and in 5 patients of Group L (13%). No significant differences were detected between the patients with and without TNSs. Early ambulation was not found to be a risk factor for TNSs after spinal anesthesia with 50 mg of 2% lidocaine. This study shows that early ambulation time does not increase the incidence of transient neurologic symptoms after spinal anesthesia with 50 mg of 2% lidocaine for elective knee arthroscopy.


Improved finite element method for flow, heat and solute transport of Prandtl liquid via heated plate.
In the current study, a vertical, 3D-heated plate is used to replicate the generation of heat energy and concentration into Prandtl liquid. We discuss how Dufour and Soret theories relate to the equations for concentration and energy. In order to see how effectively particles, interact with heat and a solvent, hybrid nanoparticles are used. It does away with the phenomena of viscous dissipation and changing magnetic fields. The motivation behind the developed study is to optimize solvent and heat storage uses in the biological and industrial domains. This article's major goal is to explore the aspects of thermal energy and mass transfer that influence how nanoparticles, hybrid nanoparticles, and 3D melting surface sheets behave. Variable thermal efficiency and variable mass transfer are combined. The system of generated PDEs (difference equations) includes the concentration, velocity, and heat energy equations. The numerical calculations are done for Silver (Ag), Molybdenum Disulfide (MoS2) nanoparticles with Ethylene glycol (C2H6O2) as the base fluid using a boundary layer approach to the mathematical formulation. The system of ODEs is formulated through transformations in order to find a solution. A Galerkin finite element algorithm (G-FEA) is adopted to analyze various aspects versus different parameters. It has been found that motion into hybrid nanoparticles is reduced by motion into nanoparticles. Additionally, differences in heat energy and solvent particle sizes are associated with modifications in magnetic, Dufour, Eckert, and Soret numbers. In contrast to hybrid nanostructures, the output of thermal energy is usually observed to be substantially higher. The magnetic field parameter decreases the particle velocity. In contradiction to the Eckert number, bouncy parameter, and magnetic parameter set values, the maximum quantity of heat energy is obtained. variable thermal conductivity's function. The 3D heated vertical surface convective heat transfer of nanofluids and hybrid nanofluids under the impact of a heat source, thermal radiation, and viscous dissipation has not yet been studied, as far as the authors are aware.


Profit considerations in vaccine safety-related events in China.
Objectives: China has made remarkable achievements in the field of immunization. However, several widespread vaccine safety-related events have recently received worldwide attention and reflect flaws in vaccine management. This study aimed to summarize vaccine safety-related events between 1985 and 2018 in China and analyze the profit motives of these events.Methods. Literature and media reviews were conducted to discover vaccine safety-related events. We developed a conceptual model with profit-related variables, and using information available from each event, we identified which profit-related variable was implicated, and how it related to the pursuit of higher profits.Results: A total of 39 vaccine safety-related events were found in vaccine production, procurement, transportation, and daily management, along with adverse events following immunization (AEFIs). Overall, 90% (35/39) of the events could be classified as profit-driven. The motives of most events could be tied to one or more reasons, including decreasing costs among vaccine producers (67%, 26/39), reducing actual procurement price (67%, 26/39), and reducing costs of transportation and/or cold chain (24/39, 62%).Conclusions: In order to deal with vaccine-related challenges, a more restrictive supervision system on vaccine production and more emergency preparedness, including health and risk communication strategies, for vaccine safety should be implemented.


Monoclonal antibodies to three epitopic regions of feline leukemia virus p27 and their use in enzyme-linked immunosorbent assay of p27.
Three different monoclonal antibodies were developed against the major core protein (p27) of feline leukemia virus (FeLV). Each antibody was directed against a different epitope of the species-specific portion of FeLV-p27. The 3 antibodies reacted with 5 different isolates of FeLV but not with 7 other retroviruses (MuLV (Rauscher), MuLV (AKR), MPMV, MMTV, SMRV, BAEV, RD 114). These monoclonal antibodies could readily be adapted to an enzyme-linked immunosorbent assay (ELISA) for the specific measurement of FeLV-p27. When compared in an ELISA with conventional reagents, the battery of monoclonal antibodies proved to be as sensitive as conventional polyclonal antibodies.


Sea cucumbers-derived sterol sulfate alleviates insulin resistance and inflammation in high-fat-high-fructose diet-induced obese mice.
Sea cucumbers are widely consumed in traditional medicine and food. Sea cucumbers-derived sulfated sterol exhibits a sulfate group at C-3 position, which is different from phytosterol with a hydroxyl group. However, the effect of sterol sulfate on metabolic syndrome remains unknown. The purpose of the present study is to investigate the alleviation of sterol sulfate on high-fat-high-fructose diet (HFFD)-induced insulin resistance and inflammation. After 2 weeks feeding with HFFD, male C57BL/6J mice were continuously fed with HFFD plus 0.4 % (w/w) sterol sulfate or phytosterol for 6 weeks. The OGTT was carried out at 7 weeks. At the end of the experimental period, the changes of glycogen, circulating glucose, insulin, pro-inflammatory cytokine and adiponectin were measured. H&E staining was used to observe the morphological changes in adipose tissue. Furthermore, the underlying molecular mechanisms were investigated. Dietary sterol sulfate was superior to phytosterol in reducing body weight gain, adipocyte hypertrophy, and levels of circulating glucose and insulin, as well as increasing the glycogen content of tissues. Furthermore, sterol sulfate ameliorated insulin resistance mainly due to the inhibition of gluconeogenesis, the promotion of glycogen synthesis and GLUT4 translocation by activating PI3K/Akt signaling pathway. Additionally, sterol sulfate effectively attenuated inflammation by increasing serum adiponectin and reducing pro-inflammatory cytokine release. Sterol sulfate exhibited a more significant effect than phytosterol in alleviating HFFD -induced insulin resistance and inflammation, which might be closely related to the sulfate group. The results might provide insights into the prevention and alleviation of metabolic syndrome.


Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis.
Breathing and blood pressure are under constant homeostatic regulation to maintain optimal oxygen delivery to the tissues. Chemosensory reflexes initiated by the carotid body and catecholamine secretion from the adrenal medulla are the principal mechanisms for maintaining respiratory and cardiovascular homeostasis; however, the underlying molecular mechanisms are not known. Here, we report that balanced activity of hypoxia-inducible factor-1 (HIF-1) and HIF-2 is critical for oxygen sensing by the carotid body and adrenal medulla, and for their control of cardio-respiratory function. In Hif2α(+/-) mice, partial HIF-2α deficiency increased levels of HIF-1α and NADPH oxidase 2, leading to an oxidized intracellular redox state, exaggerated hypoxic sensitivity, and cardio-respiratory abnormalities, which were reversed by treatment with a HIF-1α inhibitor or a superoxide anion scavenger. Conversely, in Hif1α(+/-) mice, partial HIF-1α deficiency increased levels of HIF-2α and superoxide dismutase 2, leading to a reduced intracellular redox state, blunted oxygen sensing, and impaired carotid body and ventilatory responses to chronic hypoxia, which were corrected by treatment with a HIF-2α inhibitor. None of the abnormalities observed in Hif1α(+/-) mice or Hif2α(+/-) mice were observed in Hif1α(+/-);Hif2α(+/-) mice. These observations demonstrate that redox balance, which is determined by mutual antagonism between HIF-α isoforms, establishes the set point for hypoxic sensing by the carotid body and adrenal medulla, and is required for maintenance of cardio-respiratory homeostasis.


Investigating Aggregation Using In Situ Electrochemistry and Small-Angle Neutron Scattering.
Using small-angle neutron scattering to investigate the aggregation of self-assembling molecules is well established. Some of these molecules are electrochemically useful, for example, in electrochromic devices. Electrochemistry can also be used in some cases to induce aggregation. Here, we describe an approach whereby electrochemistry can be directly carried out on a sample in the neutron beam, allowing us to monitor changes directly in situ. We exemplify with two examples but highlight that there are many other potential opportunities.


Adjuvant and salvage radiotherapy after prostatectomy for prostate cancer: a literature review.
Given that postprostatectomy recurrence of prostate cancer occurs in 10-40% of patients, the best use of immediate postoperative radiotherapy (RT) in high-risk patients and salvage RT for biochemical recurrence remains a topic of debate. We assessed the levels of evidence (in terms of efficacy, prognostic factors, and toxicity) for the following treatment strategies: immediate postoperative RT alone, salvage RT alone, and the addition of androgen deprivation therapy to the two RT strategies. A systematic literature search for controlled randomized trials, noncontrolled trials, and retrospective studies between 1990 and 2008 was performed on PubMed, CancerLit, and MEDLINE. Only relevant articles that had appeared in peer-reviewed journals were selected. We report on the levels of evidence (according to the National Cancer Institute guidelines) supporting the various treatment strategies. Immediate postoperative RT improves biochemical and clinical progression-free survival (Level of evidence, 1.ii) but has no significant effect on metastasis-free survival or overall survival. A pathologic review is of particular importance for correctly analyzing the treatment strategies. Low-grade morbidity has been significantly greater in the postoperative groups, but no severe toxicity has been observed. The influence of immediate postoperative RT on postprostatectomy continence appears to be slight; therefore, immediate postoperative RT should be considered in patients with major risk factors for local relapse (Level of evidence, 1.ii). On the basis of extensive retrospective data, salvage RT is effective in biochemical relapse after prostatectomy; some patients with few adverse prognostic factors might also benefit from salvage RT (Level of evidence, 3.ii). The addition of androgen deprivation therapy to immediate postoperative or salvage RT has only been supported by weak, retrospective data (Level of evidence, 3.ii). Prospective randomized trials are needed to compare immediate postoperative RT with salvage RT and to assess the value of androgen deprivation therapy in this setting.


Structural classification of CDR-H3 revisited: a lesson in antibody modeling.
Among the six complementarity-determining regions (CDRs) in the variable domains of an antibody, the third CDR of the heavy chain (CDR-H3), which lies in the center of the antigen-binding site, plays a particularly important role in antigen recognition. CDR-H3 shows significant variability in its length, sequence, and structure. Although difficult, model building of this segment is the most critical step in antibody modeling. Since our first proposal of the "H3-rules," which classify CDR-H3 structure based on amino acid sequence, the number of experimentally determined antibody structures has increased. Here, we revise these H3-rules and propose an improved classification scheme for CDR-H3 structure modeling. In addition, we determine the common features of CDR-H3 in antibody drugs as well as discuss the concept of "antibody druggability," which can be applied as an indicator of antibody evaluation during drug discovery.


Molecular portraits of clear cell ovarian and endometrial carcinoma with comparison to clear cell renal cell carcinoma.
Advanced clear cell gynecologic malignancies remain among the most challenging diseases to manage. We evaluated ovarian and endometrial clear cell carcinoma (OCCC and ECCC) specimens using comprehensive sequencing technology to identify mutational targets and compared their molecular profiles to histologically similar clear cell renal cell carcinoma (ccRCC). Using next-generation sequencing (NGS), fragment analysis (FA), and in situ hybridization (ISH), 164 OCCC, 75 ECCC and 234 ccRCC specimens from 2015 to 2018 were evaluated and compared. The highest mutation rates in ECCC and OCCC were noted in: ARID1A (75.0%, 87.5%), TP53 (34.8%, 11.1%), PIK3CA (25.0%, 46.8%), PPP2R1A (8.7%, 16.7%), MSI-high (8.8%, 6.4%) and PTEN (8.3%, 7.1%). Among these mutations, there was no significant difference between OCCC and ECCC mutation prevalence except in TP53, with higher mutation rates in ECCC versus OCCC (34.8 vs. 11.1%, respectively, p < 0.05). ccRCC demonstrated different mutation profiles with higher mutation rates in VHL (80.3%), PBRM1 (43.9%), SETD2 (31.1%), and KDM5C (29.2%). By contrast, VHL, PBRM1, and SETD2 mutations were not found in ECCC and OCCC (0.0%). Compared to ccRCC and ECCC, OCCC was found to have a significantly higher tumor mutation burden (TMB) (19.1%). Gynecologic and renal CCC demonstrate separate and disparate somatic profiles. However, OCCC and ECCC are diseases with similar profiles. TMB and MSI analyses indicate that a subset of OCCC may benefit from immunotherapy. Prospective clinical trials are needed and are underway to examine targeted therapies in these gynecologic disease subtypes.


Diabetes consequences in the fetus liver of the non-obese diabetic mice.
DM type 1 (T1D) incidence is increasing around 3% every year and represents risks for maternal and fetal health. The objective of this study was to explore the effects of diabetes on fetus liver cells in non-obese diabetic (NOD) mice. Hyperglycemic NOD (HNOD), normoglycemic NOD (NNOD) and BALB/c females were used for mating, and the fetus livers were collected at 19.5 gestation day (gd). HNOD group had reduced fetal weight (989.5±68.32 vs 1290±57.39 mg BALB/c, P<0.05) at 19.5 gd and higher glycemia (516.66±28.86 mg dl-1, P<0.001) at both 0.5 gd and 19.5 gd compared to other groups. The protein expression of albumin (ALB) was significantly reduced in HNOD group (0.9±0.2 vs 3.36±0.36 NNOD P<0.01, vs 14.1±0.49 BALB/c P<0.001). Reduced gene expression of ALB (1.34±0.12 vs 5.53±0.89 NNOD and 5.23±0.71 BALB/c, P<0.05), Hepatic Nuclear Factor-4 alpha (HNF-4α) (0.69±0.1 vs 3.66±0.36 NNOD, P<0.05) and miR-122 (0.27±0,10 vs 0.88±0.15 NNOD, P<0.05) was present in HNOD group. No difference for alpha-Fetoprotein (AFP) and gene expression was observed. In conclusion, our findings show the impacts of T1D on the expression of ALB, AFP, HNF-4α and miR-122 in fetus liver cells by using NNOD and HNOD mice.


Ion Mobility-Mass Spectrometry to Evaluate the Effects of Protein Modification or Small Molecule Binding on Protein Dynamics.
Ion mobility-mass spectrometry (IM-MS) of intact protein complexes under native conditions is a powerful tool for the analysis of protein complexes and protein-ligand interactions, permitting insight into ligand-induced changes in protein conformation. Here we describe a procedure for analyzing the effects of phosphorylation and/or inhibitor binding on protein kinase conformational flexibility using Protein Kinase A (PKA) as a model system. By calculating the protein collision cross section (CCS) before and after inhibitor binding, and additionally by performing collision-induced unfolding (CIU), we can establish the effects of protein modification or small molecule binding on protein dynamics.


Thrombopoietin serum concentration in patients with reactive and myeloproliferative thrombocytosis.
We wished to test whether thrombopoietin (TPO) is entirely regulated by receptor binding or if other factors may play a role in the mechanism of TPO regulation. Therefore, we analyzed the TPO serum levels in 43 patients with reactive (secondary) thrombocytosis and in 37 with myeloproliferative thrombocytosis. Thrombocytosis was defined as a platelet level greater than 440 x 10(9)/l. Forty-two patients (98%) with reactive thrombocytosis had high concentrations of IL-6 correlating with elevated C-reactive protein levels. Twenty-three patients (53%) in this group had TPO serum concentrations of more than 300 pg/ml (normal: below 300 pg/ml). Only nine patients (24%) with myeloproliferative thrombocytosis had TPO serum levels above normal range, whereas 28 patients (76%) had normal levels of TPO. No correlation between the TPO serum levels and the concentrations of IL-6 or EPO was established. The other investigated thrombopoietic cytokines (IL-3, IL-11, GM-CSF) were unmeasurable; therefore, a correlation could not be assessed. We conclude that TPO concentrations are not strictly inversely related to platelet count. TPO serum levels are elevated especially in a considerable percentage of patients with reactive thrombocytosis, arguing for the existence of additional mechanisms of TPO regulation.


Pilot study into the IgG1 and IgG2 subclass response to polyvalent Pseudomonas vaccine in burned adults.
The IgG1 and IgG2 subclass response to thermal injury has been measured in a group of eight burned adults who received a single intramuscular injection of 0.5 ml of polyvalent pseudomonas vaccine (PPV), within hours of burn injury. The response in three of these patients is compared with the response in three matched patients who did not receive the vaccine. This single dose regimen of PPV did not appear to stimulate the early production of IgG1 or IgG2 and if subclass deficiency contributes to the risk of sepsis or toxin-mediated disease, as previous workers have established (Schur et al., 1970; Oxelius et al., 1981), then there is no apparent benefit in active immunization to reduce the risk in the early postburn period.


Age-related changes in pial arterial structure and blood flow in mice.
Age-related cerebral blood flow decreases are thought to deteriorate cognition and cause senescence, although the related mechanism is unclear. To investigate the relationships between aging and changes in cerebral blood flow and vasculature, we obtained fluorescence images of young (2-month-old) and old (12-month-old) mice using indocyanine green (ICG). First, we found that the blood flow in old mice's brains is lower than that in young mice and that old mice had more curved pial arteries and fewer pial artery junctions than young mice. Second, using Western blotting, we determined that the ratio of collagen to elastin (related to cerebral vascular wall distensibility) increased with age. Finally, we found that the peak ICG intensity and blood flow index decreased, whereas the mean transit time increased, with age in the middle cerebral artery and superior sagittal sinus. Age-related changes in pial arterial structure and composition, concurrent with the observed changes in the blood flow parameters, suggest that age-related changes in the cerebral vasculature structure and distensibility may induce altered brain blood flow.


Nitric oxide levels in the intestines of mice submitted to ischemia and reperfusion: L-arginine effects.
Usually an experimental necrotizing enterocolitis experimental model, we Investigated nitric oxide levels in intestinal tissues of newborn mice with or without l-arginine therapy during sessions of ischemia and reoxygenation. Twenty-six newborn mice from the Wistar EPM-1 lineage, weighing from 4.5 to 6.2 g, were randomly assigned to three groups: G-I/R, hypoxia and reoxygenation; G-Arg, l-arginine treatment I/R; and G-CTL, controls. G-I/R and G-Arg mice underwent twice a day during their first 3 days of life exposure to gas chambers with 100% CO(2) for 5 minutes at 22 degrees C before reoxygenation with 100% O(2) for another 5 minutes. After 12 hours, all animals were sedated, laparotomized, and had samples of ileum and colon taken and- either formalin fixed histopathologic examinations or frozen to -80 degrees C for estimation of tissue nitric oxide levels. Intestinal injuries were classified according to the criteria of Chiu et al. The G-I/R and G-Arg groups showed injuries characteristic of necrotizing enterocolitis (NEC) with an improved structural preservation rate in G-Arg. The concentration of nitric oxide in the Ileum was much higher with G-Arg (16.5 +/- 4.9; P = 0.0019) G-I/R (7.3 +/- 2.0). This effect was not observed in the colon: G-I/R = 10.7 +/- 4.6 versus G-Arg = 15.5 +/- 8.7 (P = .2480). Supply of L-arginine increased tissue levels of nitricoxide and reduced morphologic intestinal injury among mice undergoing I/R.


Cell and molecular cell biology of melanin-concentrating hormone.
Recent advances in the study of melanin-concentrating hormone (MCH) have depended largely on molecular biological techniques. In mammals, which have attracted the most attention, novel findings concern (i) the MCH gene, which can yield several peptides by either posttranslational cleavage or alternative splicing, as well as bidirectional transcription; (ii) the identification of two G protein-coupled MCH receptors in the brain and peripheral tissues; and (iii) the evidence for subpopulations of MCH neurons in the central nervous system, characterized by their chemical phenotypes, connections, and individual physiological responses to different physiological paradigms. The involvement of central MCH in various functions, including feeding, reproduction, stress, and behavior patterns, is reviewed. The stage during evolution at which MCH may have acquired hypophysiotrophic and hormonal functions in lower vertebrates is considered in light of morphological data. Evidence that MCH also has peripheral paracrine/autocrine effects in mammals is provided.


Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants.
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 (MED1) are two rare skeletal disorders caused by cartilage oligomeric matrix protein (COMP) variants. This study aims to analyze the genotype and phenotype of patients with COMP variants. Clinical information for 14 probands was collected; DNA was extracted from blood for COMP variant detection. Clinical manifestations and radiology scoring systems were established to evaluate the severity of each patient's condition. Serum COMP levels in PSACH patients and healthy subjects were measured. Thirty-nine patients were included, along with 12 PSACH probands and two MED1 probands. Disproportionate short stature, waddling gait, early-onset osteoarthritis and skeletal deformities were the most common features. The height Z-score of PSACH patients correlated negatively with age at evaluation (r = - 0.603, p = 0.01) and the clinical manifestation score (r = - 0.556, p = 0.039). Over 50% of the PSACH patients were overweight/obese. The median serum COMP level in PSACH patients was 16.75 ng/ml, which was significantly lower than that in healthy controls (98.53 ng/ml; p < 0.001). The condition of MED1 patients was better than that of PSACH patients. Four novel variants of COMP were detected: c.874T>C, c.1123_1134del, c.1531G>A, and c.1576G>T. Height Z-scores and serum COMP levels were significantly lower in patients carrying mutations located in calmodulin-like domains 6, 7, and 8. As the two phenotypes overlap to different degrees, PSACH and MED1 are suggested to combine to produce "spondyloepiphyseal dysplasia, COMP type". Clinical manifestations and radiology scoring systems, serum COMP levels and genotype are important for evaluating patient condition severity.


Metatarsal head resurfacing arthroplasty in the treatment of hallux rigidus: is it reliable treatment option?
This study looks at the failure and complications arising secondary to resurfacing and hemi-arthroplasty done at the metatarsal head in patients with hallux rigidus. Our report includes a review of the relevant literature to verify the validity of our techniques. We performed metatarsal head resurfacing with hemi-arthroplasty using the HemiCap(®), on 12 patients with hallux rigidus between the dates of March 2010 and October 2013. The mean follow-up period was 22.3 months (range 12-54). All patients were clinically and radiologically evaluated according to the American Orthopedics Foot and Ankle Society (AOFAS) functional scale and the Coughlin and Shurnas classification. The recorded mean AOFAS score showed an increase from the preoperative score of 49.2 ± 13.1 to a postoperative follow-up score of 80.8 ± 13.1 (p < 0.001). Pain scores also showed an improvement from 16.5 ± 7.1 points preoperatively to 32.5 ± 6.9 points during the postoperative follow-up (p < 0.001). The mean function score improved from 17.7 ± 7.6 points preoperatively to 33.2 ± 7.6 points during the final postoperative follow-up (p < 0.001). Furthermore, the mean range of motion improved from 16.3 ± 4.8° preoperatively to 45.4 ± 13.2° postoperatively (p < 0.001). Three patients (25 %) reported pain at rest. Surgical revision was done on these patients who have significant pain that limited their range of motion. Favorable outcomes were achieved by performing minimal bone resection which also helps maintain metatarso-phalangeal joint function through metatarsal head resurfacing arthroplasty. We expect the failure rates to decrease with the advancements of surgical techniques. Selecting the appropriate patient populous in the application of the technique is crucial in attaining successful clinical results.


Genome-wide mapping and prediction of plant architecture in a sorghum nested association mapping population.
Modifying plant architecture is often necessary for yield improvement and climate adaptation, but we lack understanding of the genotype-phenotype map for plant morphology in sorghum. Here, we use a nested association mapping (NAM) population that captures global allelic diversity of sorghum to characterize the genetics of leaf erectness, leaf width (at two stages), and stem diameter. Recombinant inbred lines (n = 2200) were phenotyped in multiple environments (35,200 observations) and joint linkage mapping was performed with ∼93,000 markers. Fifty-four QTL of small to large effect were identified for trait BLUPs (9-16 per trait) each explaining 0.4-4% of variation across the NAM population. While some of these QTL colocalize with sorghum homologs of grass genes (e.g., those involved in transcriptional regulation of hormone synthesis [rice SPINDLY] and transcriptional regulation of development [rice Ideal plant architecture1]), most QTL did not colocalize with an a priori candidate gene (92%). Genomic prediction accuracy was generally high in five-fold cross-validation (0.65-0.83), and varied from low to high in leave-one-family-out cross-validation (0.04-0.61). The findings provide a foundation to identify the molecular basis of architecture variation in sorghum and establish genomic-enabled breeding for improved plant architecture.


Objective measurement of oral function in adults with spinal muscular atrophy.
Impairment of bulbar function in adult individuals with spinal muscular atrophy (SMA) usually is not assessed by established motor scores. Measurements of oral function including quantitative muscle and endurance tests are able to detect subtle changes. The aim of this study was to systematically evaluate the measurement of maximum bite force and endurance, maximum tongue pressure and endurance, as well as maximum mouth opening in adult individuals with SMA types 2 and 3. Data from oral function tests in 43 individuals were analyzed. Differences in oral function between individuals with different SMA types and numbers of SMN2 copies were tested. Spearman´s rho correlations among oral function measures themselves as well as with established clinical outcome scales were analyzed. The absolute maximum measures of oral function (maximum bite force, maximum tongue pressure, maximum mouth opening) were able to discriminate between individuals with different SMA types, individuals with a different number of SMN2 copies and with different walking abilities. The pairwise correlations of the absolute maximum measures of oral function were fair to moderate in size; the same was true for their correlations with the established motor scores. All correlations assessing endurance measures of oral function were weaker and statistically insignificant. Among the oral function tests maximum tongue pressure and maximum mouth opening are particulary promising as clinical and sensitive outcome measures for clinical trials. Oral function tests may supplement existing motor scores, in particular concerning specific questions about bulbar function or in severely affected non-ambulatory individuals where mild (treatment-related) changes would otherwise remain undetected. Trial registration DRKS, DRKS00015842. Registered 30 July 2019, https://drks.de/search/de/trial/DRKS00015842.


Oxygen permeation profile in lipid membranes: comparison with transmembrane polarity profile.
Permeation of oxygen into membranes is relevant not only to physiological function, but also to depth determinations in membranes by site-directed spin labeling. Spin-lattice (T(1)) relaxation enhancements by air or molecular oxygen were determined for phosphatidylcholines spin labeled at positions (n = 4-14, 16) of the sn-2 chain in fluid membranes of dimyristoyl phosphatidylcholine, by using nonlinear continuous-wave electron paramagnetic resonance (EPR). Both progressive saturation and out-of-phase continuous-wave EPR measurements yield similar oxygen permeation profiles. With pure oxygen, the T(2)-relaxation enhancements determined from homogeneous linewidths of the linear EPR spectra are equal to the T(1)-relaxation enhancements determined by nonlinear EPR. This confirms that both relaxation enhancements occur by Heisenberg exchange, which requires direct contact between oxygen and spin label. Oxygen concentrates in the hydrophobic interior of phospholipid bilayer membranes with a sigmoidal permeation profile that is the inverse of the polarity profile established earlier for these spin-labeled lipids. The shape of the oxygen permeation profile in fluid lipid membranes is controlled partly by the penetration of water, via the transmembrane polarity profile. At the protein interface of the KcsA ion channel, the oxygen profile is more diffuse than that in fluid lipid bilayers.


Effect of intessive plasmapheresis on the plasma cholesterol concentration with familial hypercholesterolemia.
Plasmapheresis was studied as a means of reducing the serum cholesterol concentration in 3 hypercholesterolemic patients who each underwent courses of intensive plasmapheresis with removal of 250--500 ml of plasma each day for 5--9 days. In one homozygous Type II patient, the serum cholesterol concentration decreased from 609 +/- 45 mg/100 ml (mean +/- SEM) to 365 +/- 17 mg/100 ml (40% decrease, P less than 0.05) with two different courses of plasmapheresis. In the two other patients with non-homozygous hyperbetalipoproteinemia the serum cholesterol concentration decreased from 289 +/- 27 mg/100 ml to 205 +/- 19 mg/100 ml (29% decrease, p less than 0.05). After cessation of treatment, the cholesterol concentration returned to pre-treatment levels in 10--13 days in the homozygous patient and 7 days in one non-homozygous hyperbetalipoproteinemic patient; clofibrate (2 g/day) in this patient was associated with a smaller reduction of the cholesterol concentration with plasmapheresis and an increased rate of return of pre-treatment levels after plasmapheresis was stopped. Sustained plasmapheresis for 6 days in the other non-homozygous hyperbetalipoproteinemic patient resulted in a new approximate "steady state" with a serum cholesterol concentration of 176--199 mg/100 ml compared with a pre-plasmapheresis value of 227 mg/100 ml. The response of the plasma cholesterol levels to plasmapheresis was subjected to kinetic analysis based on a current model of the regulation of lipoprotein metabolism.


Analysis of the interactions of viral and cellular factors with human cytomegalovirus lytic origin of replication, oriLyt.
Human cytomegalovirus transient lytic DNA replication relies on the cis-acting element oriLyt, six viral-encoded core proteins, the proposed DNA replication initiator protein UL84, IE2, IRS1 and the gene products from the UL112/113 loci. In an effort to elucidate cellular and viral-encoded factors that may play a role in oriLyt-dependent replication we used DNA-affinity purification and mass spectrometry to isolate and identify several previously unknown cellular and viral factors that interact with HCMV oriLyt DNA. These proteins include the multifunctional hnRNP-K, BUB3, HMGB1, PTB-1, UL83, UL112/113, and IRS1. Chromatin immunoprecipitation (ChIP) assays confirmed an interaction of several of these factors with oriLyt. Co-immunoprecipitation experiments detected an interaction between UL84 and hnRNP-K in infected and transfected cells. Knockdown of hnRNP K expression by siRNA inhibited the amplification of oriLyt in the transient assay. Together, these data suggest a possible regulatory role in DNA replication for several previously unidentified viral and cellular factors.


Biodegradation of kraft lignin by a newly isolated anaerobic bacterial strain, Acetoanaerobium sp. WJDL-Y2.
An anaerobic kraft lignin (KL)-degrading bacterial strain was isolated from sludge of a pulp and paper mill. It was characterized as Acetoanaerobium sp. WJDL-Y2 by 16S rRNA gene sequencing. The maximum KL degradation capability of strain Y2 was determined to be 24·9% on a COD basis under an optimal condition with temperature of 31·5°C, initial pH of 6·8 and KL to nitrogen (as NH4 Cl) ratio of 6·5 by mass. Growth kinetic studies showed that the KL tolerance of strain Y2 was relatively high (Ki = 8120·45 mg l(-1) ). Analysing KL degradation products by GC-MS revealed the formation of low-molecular-weight aromatic compounds (LMWACs), including benzene-propanoic acid, syringic acid and ferulic acid. This indicates that strain Y2 can oxidize lignin structure's p-hydroxyphenyl (H) units, guaiacyl (G) units and syringyl (S). In addition, the inoculated sample also contained low-molecular acid compounds, such as hexanoic acid, adipic acid and 2-hydroxybutyric acid, further validating strain Y2's ability to degrade KL. Kraft lignin containing effluents discharged from pulp and paper industries causes serious environmental pollution in developing countries. Due to the immense environmental adaptability and biochemical versatility, bacterial ligninolytic potential deserve to be studied for application in effluent treatment of pulp and paper industry. In this study, an anaerobic lignin-degrading bacterium, Acetoanaerobium sp. WJDL-Y2 (accession no. KF176997),was isolated from the sludge of a pulp and paper mill. Strain Y2 can play an important role in treating pulp and paper wastewater, as well as breaking down materials for biofuel and chemical production.


A cell atlas of adult muscle precursors uncovers early events in fibre-type divergence in Drosophila.
In Drosophila, the wing disc-associated muscle precursor cells give rise to the fibrillar indirect flight muscles (IFM) and the tubular direct flight muscles (DFM). To understand early transcriptional events underlying this muscle diversification, we performed single-cell RNA-sequencing experiments and built a cell atlas of myoblasts associated with third instar larval wing disc. Our analysis identified distinct transcriptional signatures for IFM and DFM myoblasts that underlie the molecular basis of their divergence. The atlas further revealed various states of differentiation of myoblasts, thus illustrating previously unappreciated spatial and temporal heterogeneity among them. We identified and validated novel markers for both IFM and DFM myoblasts at various states of differentiation by immunofluorescence and genetic cell-tracing experiments. Finally, we performed a systematic genetic screen using a panel of markers from the reference cell atlas as an entry point and found a novel gene, Amalgam which is functionally important in muscle development. Our work provides a framework for leveraging scRNA-seq for gene discovery and details a strategy that can be applied to other scRNA-seq datasets.


[Gamma-delta T-cell lymphoma: outcome of a hyperactive malarial splenomegaly?].
We report a gamma-delta T-cell lymphoma, in a male patient having a hyperactive malarial splenomegaly. The immunological disorder caused by chronic antigenic stimulation could be one of the causes leading to the occurrence of such hematologic disease. The prognosis of this type of lymphoma remains poor, partly due to delayed diagnosis. Therefore, it seems appropriate to investigate any atypical hyperactive malarial splenomegaly. In our observation, the macrophagic activation syndrome led us to discover the lymphoma.


The chronically reserpinized rat as a possible model for cystic fibrosis. VI. Synergistic effects of isoproterenol on Ca++ and protein in the submaxillary gland.
Elevated calcium and protein concentration are a consistent abnormality in submaxillary saliva from patients with cystic fibrosis (CF) and from experimental animal models developed by the chronic administration of either isoproterenol (IPR) or reserpine. The possibility that the effects of the two drugs may be additive was investigated by assessing their combined effects on glandular and salivary C++ and protein in the rat submaxillary gland. Individually, their effects were also assessed in relation to the dose used. Results indicate that: (1) treatment for 7 days with 0.05, 0.50, and 5.0 mg/kg daily dose of reserpine caused, respectively, a 45%, 95%, and 120% increase in glandular Ca++ and a 9.3%, 16.5%, and 37.4% increase in glandular protein; (2) treatment for 7 days with a 5.0 mg/kg daily dose of isoproterenol caused a 138% increase in gland Ca++ and a 12.38% increase in gland protein. Treatment with a 5.0 mg/rat daily dose of this drug caused increases of 166% and 10.3% in gland Ca++ and protein; (3) in experiments involving a combination of the two drugs, isoproterenol was administered in a 5.0 mg/kg daily dose from days 1-7 and reserpine in a 0.5 mg/kg daily dose from days 4-10 of the treatment schedule. This procedure resulted in (a) a 217% increase in gland Ca++ and a 25.7% increase in gland protein; (b) a marked accumulation of a granular, basophilic material in acinar cells and the development of intraductal precipitates; (c) the secretion of turbid saliva with high Ca++ and protein concentrations after a secretory dose of isoproterenol (this type of stimulation also reduced the gland Ca++ (50%) and protein (20%) contents and produced vacuolization in the acinar cells); (d) the secretion of saliva with elevated Ca++ and protein in response to pilocarpine (these elevated concentrations were, however, one-fifth of those obtained after isoproterenol stimulation); (e) the secretion of smaller volume of saliva after both types of stimulation. These findings indicate that both IPR and reserpine have a dose-related and significant effect on submaxillary gland Ca++ and protein and that their individual effects are synergistic. The implications of this synergism for the physiologic state of the submaxillary gland and for the secretory abnormality of cystic fibrosis are discussed.


Unusual collision tumor with infiltrating ductal carcinoma and breast skin squamous cell carcinoma: A case report and literature review.
Breast cancer is the most common diagnosed cancer among women worldwide. Invasive ductal carcinoma (IDC) is the most common type, on the other hand, squamous cell carcinoma of the skin (SCC) overlying the breast is a rare tumor. The co-presence of two tumor types in one organ is even a rarer entity, termed as collision tumor. Only 3 known cases of collision tumor with breast invasive ductal and skin squamous carcinoma were reported in the literature. An otherwise medically free 91-year-old, postmenopausal, female presented with left breast fungating mass for four months. Pre-operative core tissue biopsy and incisional skin biopsy revealed two distinct tumor subtypes of invasive ductal carcinoma, positive for progesterone, estrogen receptors and negative for human epidermal growth factor receptor 2, as well as skin squamous cell carcinoma, and axillary lymph node metastasis. Patient underwent left breast modified radical mastectomy and split skin grafting for wound closure. The final histopathology was consistent with grade 2 IDC. The nipple and areola complex were involved by moderately differentiated squamous cell carcinoma. Currently patient on adjuvant hormonal treatment. Follow up showed no local recurrence or distal metastasis. Collision tumors of the breast with IDC and SCC of the overlying skin is very rare. The surgeon has to be aware of of such entity as the proper peri-operative management should be tailored to target the most aggressive histologic subtype.


Penetration of piperacillin/tazobactam into gynecologic tissues following a single loading dose prior to hysterectomy.
This study was undertaken to determine plasma and pelvic tissue concentrations of piperacillin/tazobactam following a single intravenous administration. Plasma and tissue samples were obtained following administration of 3 g of piperacillin and 0.375 g of tazobactam. Concentrations of these agents were determined by chromatography. Plasma concentrations (mean +/-SD) for piperacillin/tazobactam were 208 +/- 87/27 +/- 8 and 95 +/- 53/14 +/- 2, respectively, at 30 and 60 min after the start of the infusion. The 8:1 ratio between piperacillin and tazobactam in plasma remained constant for up to 96 min. Tissue concentrations yielded a broader range, but each agent achieved significant penetration in each of the tissues studied. Piperacillin/tazobactam demonstrates favorable penetration in female genital tract tissues and Should be considered a potentially effective agent for female pelvic infections.


Mineral substance of bone tissue and of experimental cutaneous calcinosis in rats: chemical analysis and ESR study.
The evolution of the mineral constituents of subcutaneous calcinosis induced in rats by topical calciphylaxis was studied by the method of quantitative chemical analysis, and after treatment with excited gases by electron spin resonance (ESR) analysis. Chemical data show that the genesis of the subcutaneous calcinosis does not significantly alter the concentration of Ca, P, F, CO3, Mg, and Fe in the mineral phase of the femoral bone of calciphylactic rats. In the calcinosis an important increase of the fluoride concentration is noticed in function of the time after challenging. There is also a high concentration of Mg2+ ions in the early stages of the experimental calcification. Iron injected for the challenging is continuously present in the calciphylactic tissue after this treatment. This suggests that subcutaneous calcinosis might be a means of fixing certain heavy metal ions. After treatment with excited gases, the proportions of the trapped CO33- and O3- radicals are of the same order of magnitude in calciphylactic tissue after 12 days and observations in bone mineral. These suggest that after 12 days the mineral of the calciphylactic tissue has a crystalline state close to that of bone.


Expression of syndecan-1 in paired samples of normal and malignant breast tissue from postmenopausal women.
The mammary stroma is important for modulating epithelial breast cell response to sex steroid hormones. Proteoglycans, such as syndecan-1, promote the integration of cellular signals. The immunohistochemical expression of syndecan-1 and of the androgen receptor (AR) was analyzed in paired samples of cancer and adjacent normal tissue from postmenopausal women. Normal and cancer tissue showed dramatic differences in the expression of syndecan-1. In malignant breast stroma, mean values were more than 10-fold higher than in normal tissue (p<0.001). There was also a marked redistribution from the epithelium to the stroma. The expression of AR was on average 2-fold higher in cancerous than in normal tissue (p<0.01). Breast cancer patients have very different prognoses. Syndecan-1 and the AR may be new molecular markers relevant to clinical outcome. The redistribution from the epithelium and the dramatic increase of syndecan-1 in cancerous stroma may be related to the natural history of the disease.


Ramp lesion in anterior cruciate ligament injury: a review of the anatomy, biomechanics, epidemiology, and diagnosis.
Ramp lesions, commonly observed in patients with anterior cruciate ligament (ACL) injuries, have been previously defined as longitudinal tears around the meniscocapsular junction. However, the definitions and interpretations of ramp lesions have varied, emphasizing the need to confirm their presence before surgery and the importance of direct visualization using arthroscopy. Recent histological studies have reported new findings on ramp lesions, shedding light on their attachment mechanisms. The anatomical structures around the ramp lesion, such as the posterior horn of medial meniscus (PHMM), semimembranosus (SM), posteromedial (PM) capsule, and meniscotibial ligament (MTL), were assessed regarding how these structures could be attached to each other. The studies of ramp lesions have also contributed to the progression of biomechanical studies explaining the cause and effects of ramp lesions. Ramp lesion has been proven to stabilize the anteroposterior (AP) instability of ACL. In addition, various laboratory studies have demonstrated the relationship between rotational instability of the knee joint and ramp lesions. The analysis of risk factors of ramp lesion helped to understand the injury mechanism of the lesion. Many authors have evaluated the prevalence of ramp lesions in patients with ACL injuries. The development of arthroscopy techniques has influenced the outcomes of ACL reconstruction with the easy detection of ramp lesions. This review article aims to analyze the past findings and recent advancements in anatomical, biomechanical, and epidemiological studies of ramp lesions in patients who underwent ACL reconstruction, and provide various perspectives ramp lesions in patients with ACL reconstruction.


Lithium vanadate nanowires@reduced graphene oxide nanocomposites on titanium foil with super high capacities for lithium-ion batteries.
With a theoretically high capacity and suitable discharge/charge plateaus, lithium vanadates (such as Li0.04V2O5) can be used as cathode material for lithium ion batteries. Herein, Li0.04V2O5 nanowires are densely anchored onto reduced graphene oxide (rGO) nanosheets to form a Li0.04V2O5@rGO nanocomposite by a hydrothermal method with subsequent thermal treatment. Due to this unique structure, the Li0.04V2O5@rGO exhibits remarkable rate performance and excellent cycling stability. Specifically, it delivers a reversible discharge capacity of 738.09mAhg-1 at a current density of 100mAg-1 in the voltage range of 2.0-4.0V. After 500 cycles, it still maintains a high capacity of 731.70mAhg-1, which represents 95.01% retention of the original reversible capacity. These results indicate that the Li0.04V2O5@rGO could be a promising candidate as cathode active material for long-term cycling performance in lithium-ion batteries.


[Hypocholesterolemia ].
In the present study 140 patients with serum cholesterol concentrations below 3.885 mmol/l (150 mg/dl) were examined. The most frequent diagnoses were diseases of the thyroid gland, of the intestines and the liver, malignant tumours, anaemias, pyelonephritis as well as bronchopneumonias. Hypocholesterolaemias sporadically occur also in cardio-vascular and venous diseases. Reductions of the serum cholesterol concentrations are in most cases of secondary nature and can reveal relations to the severity as well as to the prognosis of a disease.


Development and evaluation of a one-month research track in emergency medicine for medical students.
We present our experience with the development and evaluation of a one-month research track in emergency medicine for medical students. The curriculum includes reading and problem-solving in research methods, biostatistics, and design (80 hours); data collection in one or more of the ongoing studies in the department (usually chart review--40 to 60 hours); one major literature search using Index Medicus and Science Citation Index (20 to 40 hours); and participation in all research-related meetings in the Division, as well as the hospital's Institutional Review Board. Evaluation of the student is done by a pretest and final exam covering the topics of the readings. Pre- and post-testing demonstrated increased understanding of basic research concepts and the use of statistics.


Early inflammatory-immunological lesions in juvenile atherosclerosis from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY)-study.
The Pathobiological Determinants of Atherosclerosis in Youth (PDAY)-study gave insight into the correlation between the classical risk factors for atherosclerosis development, such as hypercholesterolemia, hyperglycemia, high blood pressure and smoking in young Americans. We now present immunohistochemical data showing that immunological-inflammatory signs represent the first step towards atherosclerosis development in the arteries of young adults. In previous publications, we coined the term 'vascular-associated lymphoid tissue' (VALT) for the accumulation of mononuclear cells at regions of the arterial wall in healthy children and adolescents that are predisposed to the development of atherosclerotic lesions later in life if risk factors are present. In the present communication, we intended to close the gap between data from atherosclerotic arteries and those of healthy young children studied previously by our group. The PDAY-study comprising 15-34-year-old Americans who had no clinical symptoms of cardiovascular diseases offered a good basis for our intention. We document that inflammatory activity was found in all specimens, represented by activated T-lymphocytes, dendritic cells, macrophages and aberrant MHC class II expression in the intima. We therefore demonstrated that immunological-inflammatory cells are present in the earliest stages of atherogenesis in 15-34-year-old subjects, arguing in favour of an initiating role of the immune system in atherosclerosis development.


Does the spleen regenerate after partial splenectomy in the dog?
Four dogs underwent two thirds partial splenectomy and the remaining spleens were followed up to 6 months by radioisotope studies and finally measured at the time of sacrifice. In this study we showed that the remaining spleens after partial splenectomy did not show any signs of regeneration.


Pentasaccharide resin glycosides from Ipomoea cairica and their cytotoxic activities.
Six partially acylated pentasaccharide resin glycosides, cairicosides A-F, were isolated from the aerial parts of Ipomoea cairica. These compounds were characterized as a group of macrolactones of simonic acid A, partially acylated with different organic acids. The lactonization site of 11S-hydroxyhexadecanoic acid (jalapinolic acid) was bound to the second saccharide moiety at C-3 in cairicosides A-E, while at C-2 in cairicoside F. Structures were established by spectroscopic and chemical methods. Compounds cairicosides A-E exhibited moderate cytotoxicity against a small panel of human tumor cell lines with IC50 values in the range of 4.28-14.31μM.


Carcinoid tumor arising in a horseshoe kidney.
Carcinoid tumors are common neoplasms developing in gastrointestinal and respiratory tract. They are rarely found in the kidney. To date, approximately 40 cases of primary renal carcinoid tumors have been reported, with less of a third of them occurring within a horseshoe kidney. These cases appear to have a better prognosis, even in the presence of distant metastases, compared to those arising in normal kidneys.


Encapsulation of volatile compounds in liquid media: Fragrances, flavors, and essential oils in commercial formulations.
The first marketed example of the application of microcapsules dates back to 1957. Since then, microencapsulation techniques and knowledge have progressed in a plethora of technological fields, and efforts have been directed toward the design of progressively more efficient carriers. The protection of payloads from the exposure to unfavorable environments indeed grants enhanced efficacy, safety, and stability of encapsulated species while allowing for a fine tuning of their release profile and longer lasting beneficial effects. Perfumes or, more generally, active-loaded microcapsules are nowadays present in a very large number of consumer products. Commercial products currently make use of rigid, stable polymer-based microcapsules with excellent release properties. However, this type of microcapsules does not meet certain sustainability requirements such as biocompatibility and biodegradability: the leaking via wastewater contributes to the alarming phenomenon of microplastic pollution with about 4% of total microplastic in the environment. Therefore, there is a need to address new issues which have been emerging in relation to the poor environmental profile of such materials. The progresses in some of the main application fields of microencapsulation, such as household care, toiletries, cosmetics, food, and pesticides are reviewed herein. The main technologies employed in microcapsules production and the mechanisms underlying the release of actives are also discussed. Both the advantages and disadvantages of every technique have been considered to allow a careful choice of the most suitable technique for a specific target application and prepare the ground for novel ideas and approaches for encapsulation strategies that we expect to be proposed within the next years.


Compartmentation of metabolites in regulating epigenome of cancer.
Covalent modification of DNA and histones are important epigenetic events and the genome wide reshaping of epigenetic markers is common in cancer. The epigenetic markers are produced by enzymatic reactions and some of these reactions require the presence of metabolites as cofactors (termed Epigenetic Enzyme Required Metabolites, EERMs). Recent studies found that the abundance of these EERMs correlates with epigenetic enzyme activities. Also, the subcellular compartmentation, especially the nuclear localization of these EERMs may play a role in regulating the activities of epigenetic enzymes. Moreover, gene specific recruitment of enzymes which produce the EERMs in the proximity of the epigenetic modification events accompanying the gene expression regulation, were proposed. Therefore, it is of importance to summarize these findings of the EERMs in regulating the epigenetic modifications at both DNA and histone levels, and to understand how EERMs contribute to cancer development by addressing their global versus local distribution.


Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy.
Mucopolysaccharidosis type I is caused by deficiency of α-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of alloimmune responses in these patients remain unknown. We developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism. High titer immune responses were seen in 87.5% (7/8) patients following exposure to α-L-iduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26-137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels. We found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy.


[A statistical definition of aortic pulse wave velocity normality in a Portuguese population: a subanalysis of the EDIVA project].
Aortic pulse wave velocity (PWV) has been associated with cardiovascular risk in different clinical subsets. This subanalysis of the EDIVA project aimed to establish criteria for normality of PWV based on a statistical definition that considers the fundamental physiological role of aging in arterial stiffness. A sample of 668 healthy subjects (412 male) enrolled in the EDIVA Project (a prospective, multicenter, observational study) were studied. Mean age was 40.00 ± 13.42 years, body mass index was 25.90 ± 4.21kg/m(2), and systolic and diastolic blood pressure were respectively 125.47 ± 11.18 and 75.75 ± 9.27mmHg. PWV was determined annually using a Complior device, and mean follow-up was 23.3 ± 3.34 months. Personal and family history, physical examination, electrocardiogram and biochemical analysis were used to determine individual health. In the overall population PWV was 8.8 ± 1.4m/sec, 8.7 ± 1.6m/sec in men and 8.9 ± 1.5m/sec in women (p=NS). Normal PWV was defined as the 95th percentile adjusted for age and gender, above which PWV was considered abnormal. Serial evaluation of PWV also enabled the annual age-dependent increase in PWV to be estimated at 5%, values above this cut-off being defined as abnormal vascular deterioration. This study establishes criteria for normality based on a statistical definition that takes into account the fundamental physiological role of aging in arterial stiffness. Additionally, it provides a cut-off for the clinical interpretation of serial PWV measurements.


Possible involvement of Notch signaling in the pathogenesis of Buerger's disease.
Under pathological conditions, the Notch signal pathway is involved in the inflammatory process in arteriosclerosis, atherosclerosis and angiogenesis under ischemic conditions. The purpose of this study was to observe whether or not Buerger's disease is associated with Notch signal activation. All the patients were diagnosed between 1980 and 2009 at Nagoya University Hospital. Twenty-two specimens from 12 patients with Buerger's disease (TAO) and 13 specimens from nine patients with arteriosclerosis obliterans (ASO) were analyzed by immunohistochemistry for Notch1, Jagged-1 (a Notch ligand) and Hes-1 (a Notch 1 target transcription factor). Notch1 and Jagged-1 were highly expressed in the endothelium in the new vasa vasorum and in the smooth muscle cells in the media of specimens from both groups. These Notch-related proteins were also remarkably expressed in inflammatory cells in the intima of specimens from TAO patients. Fewer inflammatory cells expressed Notch-related proteins in atheromatous plaques (Notch1 (%): 8.4 ± 0.76 versus 1.3 ± 0.43, P < 0.001; Jagged-1(%): 9.3 ± 1.1 versus 5.2 ± 1.1, P = 0.03). Indeed, Hes-1, which is a transcription factor downstream of Notch1, was remarkably expressed in the endothelium of new capillary vessels and inflammatory cells in TAO patients. Notch1-positive mononuclear cells were also seen in the thrombus in samples from the TAO group. Our findings are the first demonstration that Notch signal activation in inflammatory cells may be involved in the pathophysiological mechanism underlying Buerger's disease.


Palliative care needs and utilization of specialist services for people imminently dying with dementia: A national population-based study.
There is a growing emphasis on the importance of availability of specialist palliative care for people living with dementia. However, for people imminently dying with dementia, we still have little knowledge about their palliative care needs and utilization of different specialist services. To (i) assess palliative care needs and other clinical and social characteristics of people imminently dying with dementia on their last admission in the context of community and inpatient palliative care services before death; (ii) compare care needs between patients requiring community-based and inpatient services; (iii) determine how and whether such care needs affect utilization of different palliative care services. Observational study using data from the Australian Palliative Care Outcomes Collaboration. Specialist palliative care services across Australia registered in the Palliative Care Outcomes Collaboration. A total of 3361 people who required specialist palliative care principally for dementia (including Alzheimer's disease and other dementias), and whose death occurred between 1 January 2013 and 31 December 2018. Five validated clinical instruments were used to collect point-of-care outcomes on each individual's function (Resource Utilisation Groups - Activities of Daily Living & Australia-modified Karnofsky Performance Status), symptom distress (Symptoms Assessment Scale & Palliative Care Problem Severity Score) and other clinical characteristics (Palliative Care Phases). We fitted multivariate logistic regression models to examine the association between these clinical outcomes and utilization of different specialist palliative care services. The majority of people imminently dying with dementia had absent or mild levels of symptom distress but experienced high levels of functional decline and needed substantial assistance with basic tasks of daily living in their last days of life. Large disparities in symptoms distress and functional decline between inpatient and community groups were not observed although differences in assessment scores were often statistically significant. Poor functional outcomes (odds ratio = 1.77, 95% confidence interval: 1.24-2.52) and "non-stable" palliative care phases (odds ratio =24.51, 95% confidence interval: 12.03-49.96) were positively associated with use of inpatient versus community palliative care, whereas there was no clear association between the majority of symptoms and use of different care services. The majority of people imminently dying with dementia could potentially benefit from greater access to supportive services in the community. Development of a dementia-specific palliative care pathway is needed to promote needs-based palliative care delivery models. TWEETABLE ABSTRACT: the majority of people imminently dying with dementia could potentially benefit from greater access to supportive services in community.


HIV-positive Mothers' Communication About Safer Sex And STD Prevention With Their Children.
Mothers play an important role in promoting the sexual health of their adolescent children. Fifty-seven HIV-positive mothers with adolescent children participated in an in-depth, qualitative interview regarding whether they have talked to their children about safer sex and STD prevention, including at what age they began such discussions, and what messages they gave to their children. The majority of mothers (95%) had talked with their child about safer sex; some began such discussions when the children were as young as 6 years old, but most began when the children were around 12 years old. Mothers' messages fell into the following areas: (1) protecting oneself from STDs; (2) giving factual information regarding STDs, including HIV; (3) avoiding pregnancy; (4) empowering and respecting oneself; and (5) communicating with sexual partners. The mothers' own HIV status impacted the discussions with their children. Content of mothers' messages, child reactions, and child outcomes are discussed.


Fixation and immunoperoxidase staining of oligopeptides after isoelectric focusing in thin polyacrylamide slab gels.
In this paper a new method for immunological detection of small peptides after isoelectric focusing in thin (200 micron) polyacrylamide slab gels is presented. The peptides are immobilized immediately after focusing by pressing a sheet of glutaraldehyde-impregnated filter paper onto the gel. By this procedure, the gel adheres to the paper and this press-blot can be stained using immunoperoxidase staining procedures. Using the two-step peroxidase conjugate and the three-step peroxidase-antiperoxidase method, several oligopeptides could be visualized after focusing. The detection limit of this method appears to be in the nanogram range.


Effective intranasal therapeutics and prophylactics with monoclonal antibody against lethal infection of H7N7 influenza virus.
Recurrence of highly pathogenic avian influenza (HPAI) virus subtype H7 in humans and poultry continues to be a serious concern to public health. No effective prevention and treatment are currently available against H7 infection. One H7 monoclonal antibody, Mab 62 was selected and characterized. Mab 62 presented efficient neutralization activity against all six representative H7 strains tested, including the H7N9 strain from the recent outbreak in China. The epitope of 62 identified on H7 HA1 exists in all the human H7 strains, including the recent H7N9 strains from China. Mab 62 when administered passively, pre or post challenge with 5 MLD50 (50% mouse lethal dose) HPAI H7N7 influenza viruses could protect 100% of the mice from death. The efficacy of intranasal administration of the Mab was evaluated versus the intraperitoneal route. In the therapeutic study, body weight loss and virus load were reduced in intranasally inoculated mice, as compared to the intraperitoneal group. Intranasal administration results in early clearance of the virus from the lungs and completely prevents lung pathology of H7N7. The study confirmed that intranasal administration of Mab 62 is either an effective prophylactic or therapeutic means against H7 lethal infection. The results of epitope analysis suggest the potential of Mab 62 to be used for the efficacious prevention and treatment against the recent human H7N9 strains.


Update on the epidemiology of rotavirus in the Middle East and North Africa.
Rotavirus (RV) is the leading cause of severe acute gastroenteritis (AGE) worldwide. Consequently, we conducted a systematic literature review on articles studying RV in the 25 countries of the MENA region during the past 15years (2000-2015). The methods and reporting were set according to the 2015 preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) and based on the elements from the international prospective register of systematic reviews (PROSPERO). Our literature search identified 169 studies meeting our predefined inclusion criteria. Studies reporting on RV were conducted in 19 out of the 24 countries of the MENA region. The largest number of studies was reported in Turkey (n=32), Iran (n=31), Saudi Arabia (n=19) and Egypt (n=17). The majority of studies reporting on RV gastroenteritis rates were clinical observational studies. In 115 studies out of 169, RV was reported among in-patients whereas 35 studies reported RV among outpatients. The predominantly reported RV genotype in the region was G1[P8] followed by G2[P4] and G9[P8]. The majority of studies (n=108) were conducted among children less than 5years of age whereas the remaining studies reported on AGE among other age groups and rarely adults. In MENA countries, RV infection was reported all year round with peaks described in cold as well as hot months. This systematic review provides a current update on the epidemiology of RV-associated gastroenteritis in countries of the MENA region and draws attention to the major gaps existing in the continuous monitoring of RV.


Bromocriptine and lisuride stimulate the accumulation of cyclic AMP in intact slices but not in homogenates of rat neostriatum.
The effects of bromocriptine and lisuride on cyclic AMP concentrations in homogenates and in intact slices of rat neostriatum were investigated. Significant increases in cyclic AMP concentration were found after a 10-min exposure to bromocriptine and lisuride in striatal intact slices. On the contrary, as previously found, the two dopaminergic ergot derivatives did not stimulate dopamine-senstiive adenylate cyclase present in striatal homogenates. The stimulatory effects observed only in intact tissues were blocked by the specific dopamine receptor blocking agent fluphenazine. It is tempting to conclude that dopaminergic ergot derivatives have a site of action different from that stimulated by classic dopamine agonists in tissue homogenates.


In vitro binding affinities of a series of flavonoids for μ-opioid receptors. Antinociceptive effect of the synthetic flavonoid 3,3-dibromoflavanone in mice.
The pharmacotherapy for the treatment of pain is an active area of investigation. There are effective drugs to treat this problem, but there is also a need to find alternative treatments free of undesirable side effects. In the present work the capacity of a series of flavonoids to bind to the μ opioid receptor was evaluated. The most active compound, 3,3-dibromoflavanone (31), a synthetic flavonoid, presented a significant inhibition of the binding of the selective μ opioid ligand [(3)H]DAMGO, with a Ki of 0.846 ± 0.263 μM. Flavanone 31 was further synthesized using a simple and cheap procedure with good yield. Its in vivo effects in mice, after acute treatments, were studied using antinociceptive and behavioral assays. It showed no sedative, anxiolytic, motor incoordination effects or inhibition of the gastrointestinal transit in mice at the doses tested. It evidenced antinociceptive activity on the acetic acid-induced nociception, hot plate and formalin tests (at 10 mg/kg and 30 mg/kg). The results showed that the 5-HT2 receptor and the adrenoceptors seem unlikely to be involved in its antinociceptive effects. Naltrexone, a nonselective opioid receptors antagonist, totally blocked compound 31 antinociceptive effects on the hot plate test, but naltrindole (δ opioid antagonist) and nor-binaltorphimine (κ opioid antagonist) did not. These findings demonstrated that 3,3-dibromoflavanone (31), at doses that did not interfere with the motor performance, exerted clear dose dependent antinociception when assessed in the chemical and thermal models of nociception in mice and it seems that its action is related to the activation of the μ opioid receptor.


Requirement of the MEK5-ERK5 pathway for neural differentiation in Xenopus embryonic development.
Although previous studies have identified several key transcription factors in the generation process of the vertebrate nervous system, the intracellular signalling pathways that function in this process have remained unclear. Here we identify the evolutionarily conserved mitogen-activated protein kinase kinase 5 (MEK5)-extracellular signal-regulated kinase 5 (ERK5) pathway as an essential regulator in neural differentiation. Knockdown of Xenopus ERK5 or Xenopus MEK5 with antisense morpholino oligonucleotides results in the reduced head structure and inhibition of neural differentiation. Moreover, forced activation of the MEK5-ERK5 module on its own induces neural differentiation. In addition, we show that the MEK5-ERK5 pathway is necessary for the neuralizing activity of SoxD, a regulator of neural differentiation, and is sufficient for the expression of Xngnr1, a proneural gene. These results show that the MEK5-ERK5 pathway has an essential role in the regulation of neural differentiation downstream of SoxD and upstream of Xngnr1.


Dynamic Interplay of RNA and Protein in the Human Immunodeficiency Virus-1 Reverse Transcription Initiation Complex.
The initiation of reverse transcription in human immunodeficiency virus-1 is a key early step in the virus replication cycle. During this process, the viral enzyme reverse transcriptase (RT) copies the single-stranded viral RNA (vRNA) genome into double-stranded DNA using human tRNALys3 as a primer for initiation. The tRNA primer and vRNA genome contain several complementary sequences that are important for regulating reverse transcription initiation kinetics. Using single-molecule Förster resonance energy transfer spectroscopy, we demonstrate that the vRNA-tRNA initiation complex is conformationally heterogeneous and dynamic in the absence of RT. As shown previously, nucleic acid-RT interaction is characterized by rapid dissociation constants. We show that extension of the vRNA-tRNA primer binding site helix from 18 base pairs to 22 base pairs stabilizes RT binding to the complex and that the tRNA 5' end has a role in modulating RT binding. RT occupancy on the complex stabilizes helix 1 formation and reduces global structural heterogeneity. The stabilization of helix 1 upon RT binding may serve to destabilize helix 2, the first pause site for RT during initiation, during later steps of reverse transcription initiation.


Ziegler and Nichols meet Kermack and McKendrick: Parsimony in dynamic models for epidemiology.
The COVID-19 crisis popularized the importance of mathematical modeling for managing epidemics. A celebrated pertinent model was developed by Kermack and McKendrick about a century ago. A simplified version of that model has long been used and became widely popular recently, even though it has limitations that its originators had clearly articulated and warned against. A basic limitation is that it unrealistically assumes zero time to recovery for most infected individuals, thus underpredicting the peak of infectious individuals in an epidemic by a factor of as much as about 2. One could avoid this limitation by returning to the original comprehensive model, at the cost of higher complexity. To remedy that, we blend Ziegler-Nichols modeling ideas, developed for automatic controller tuning, with Kermack-McKendrick ideas to develop novel model structures that predict infectious peaks accurately yet retain simplicity. We illustrate these model structures with computer simulations on real epidemiological data.


A Systematic Review and Meta-analysis of Telephone-Based Therapy Targeting Depressive Symptoms Among Low-Income People Living with HIV.
People living with human immunodeficiency virus (PLWH) has been reported to have a high prevalence of depressive symptoms. Low-income populations account for a large proportion of PLWH, hence indicating a high level of depressive symptoms in low-income PLWH. Telephone-based therapy has been shown to be effective for treating PLWH's depressive symptoms, but its effects among low-income PLWH remain unclear. The purpose of this meta-analysis was to evaluate the effects of telephone-based therapy targeting depressive symptoms among low-income PLWH. Six databases (PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, VIP Database and Wanfang Data) were searched until May 2020 using search terms related to telephone-based therapy, depressive symptoms, and PLWH. Eight studies were included in the meta-analysis. Both postintervention effects (primary outcome) and long-term effects (secondary outcome) were evaluated using a random effects model. The meta-analysis revealed a small to moderate effect size (ĝ = - 0.29, 95% CI - 0.51, - 0.06) on reducing depressive symptom scores (Z = 2.51, p = 0.01) in telephone-based intervention group compared with the control group at postintervention. However, there was no statistically significant long-term effects (Z = 0.77, p = 0.44) at follow-up. For postintervention effects, calculation of the I2 index indicated moderate heterogeneity (I2 = 50%); sensitivity analysis and subgroup analysis were performed to explore the source of heterogeneity. Ethnic group was classified into minority and majority which refers to most of the population were ethnic minority and majority respectively. Between-group differences were found across ethnic groups. The results suggested that there was a slightly stronger effect of telephone-based therapy in low-income PLWH than among PLWH in general, but its long-term effect requires future investigation. The effects of the intervention were better among the ethnic majority subgroups of low-income PLWH. Treatment format and intervention duration might also influence the intervention effects. However, the overall quality of evidence was low and directly impacted on the interpretation of our results, suggesting that more high-quality random controlled trial (RCT)/longitudinal studies with less selection and detection bias, less inconsistency and less indirectness are needed when applying telephone-based therapy to low-income PLWH with depressive symptoms in further studies.


CatBoost-based improved detection of P-wave changes in sinus rhythm and tachycardia conditions: a lead selection study.
Examining P-wave morphological changes in Electrocardiogram (ECG) is essential for characterizing atrial arrhythmias. However, standard 12-lead ECGsuffer from diagnostic redundancy due to low signal-to-noise ratio of P-waves. To address this issue, various optimal leads have been proposed for improved atrial activity recording, but the right selection among these leads is crucial for enhancing diagnostic efficacy. This study proposes an automated lead selection technique using the CatBoost machine learning (ML) model to improve the detection of P-wave changes among optimal bipolar leads under different heart rates. ECGs were obtained from healthy participants with a mean age of 25 ± 3.81 years (34% women), including 114 in sinus rhythm (SR) and 38 in sinus tachycardia (ST). The recordings were made using a newly designed atrial lead system (ALS), standard limb lead (SLL), modified limb lead (MLL), modified Lewis lead (LLM) and P-lead. P-wave features and Atrioventricular (AV) ratio were extracted for statistical analysis and ML classification. The optimum ML model was chosen to identify the best-performing optimal lead, which was selected based on the SLL metrics among different ML classifiers. CatBoost was found to outperform the other ML models in SLL-II with the highest accuracy and sensitivity of 0.82 and 0.90, respectively. The CatBoost model, amid other optimal leads, gave the best results for AL-I and AL-II (0.86 and 0.83 in accuracy and 0.91 and 0.93 in sensitivity). The developed CatBoost model selected AL-I and AL-II as the top two best-performing optimal leads for the enhanced acquisition of P-wave changes, which may be useful for diagnosing atrial arrhythmias.


Attributable factors for the rising cesarean delivery rate over 3 decades: an observational cohort study.
Cesarean delivery rates continue to rise globally, the reasons for which are incompletely understood. We aimed to characterize the attributable factors for the increasing cesarean delivery rates over a 30-year period within our health network. This was a planned observational cohort study across 2 hospitals (a large tertiary referral hospital and a metropolitan hospital) in Sydney, Australia using data from a previously published study. The following 2 time periods were compared: 1989-99 and 2009-16, between which the cesarean delivery rate increased from 19% to 30%. The participants were all women who had a cesarean delivery after 24 weeks' gestational age. The data were analyzed using multiple imputation and robust Poisson regression to calculate the differences in the adjusted and unadjusted relative risk of cesarean delivery and estimate the changes in the cesarean delivery rate attributable to maternal and clinical factors. The primary outcome was cesarean delivery. After 576 exclusions, 102,589 births were included in the analysis. Fifty-six percent of the increase in the rate of cesarean delivery was attributed to changes in the distribution of the maternal age, body mass index, and parity and to a history of previous cesarean delivery. An additional 10% of the increase was attributed to changes in the obstetrical management of the following high-risk pregnancies: multiple gestation, malpresentation (mainly breech), and preterm singleton birth. When prelabor cesarean deliveries for maternal choice, suspected fetal compromise, previous pregnancy issues, and suspected large fetus were excluded, 78% of the increase was attributed to either maternal factors or changes in the obstetrical management of these high-risk pregnancies. Most of the steep rise in the cesarean delivery rate from 19% to 30% was attributed to changes in the maternal demographic and clinical factors. This observation is relevant to developing preventative strategies that account for nulliparity, age, body mass index, and management of high-risk pregnancies.


Dissociation of the site of origin from the site of cryo-termination of ventricular tachycardia.
We performed conventional electrogram mapping and cryomapping in dogs with one-week-old experimentally-induced myocardial infarctions and programmed stimulation-induced sustained ventricular tachycardias to assess whether there is a correlation between the "site of origin" and site of cryo-termination of ventricular tachycardia (VT). Electrogram maps showed that 4 of 8 induced sustained VTs were due to macro- and 4 of 8 to microre-entry. Local cooling of the site of origin terminated 4 of 4 microre-entrant VTs, but only 1 of 4 macrore-entrant VTs. In the other 3 macrore-entrant VTs, the sites of cryo-termination were 2, 2.5, and 4 cm distant from the sites of origin. In contrast, cooling of the mid-to-late diastolic portions of the re-entry loops terminated all 8 VTs. These data demonstrate a dissociation of the site of origin from the site of cryo-termination of macrore-entrant VT.