Phenolics in Mediterranean and Middle East Important Fruits.
Phenolic compounds (polyphenols) are common plant secondary metabolites playing different roles in plants, and some of these vegetables and correlated fruits-figs, grapes, pomegranates, olives, date palms, etc.-contain remarkable and diversified amounts of these substances. In addition, polyphenols are reported to show positive effects for human health, because of their antioxidant behavior. Figs are an excellent source of polyphenols with highest concentrations of proanthocyanidins. Actually, figs contain higher amounts of polyphenols than red wine and tea. Antioxidant activity of several flavonoids (a group of polyphenols) in figs is higher than that of, vitamin C, glutathione, or vitamin E. Pomegranates contain very high levels of polyphenols as compared to other fruits and vegetables. It is used in folklore medicine for the treatment of various diseases, such as hepatic damage, snakebite, ulcer, etc. The health-positive potential of pomegranate fruit has been mainly attributed to ellagitannins, the predominant class of phenolics in pomegoxidation. The chief phenolic compound found in fresh olive is the bitter secoiridoid oleuropein.. Processing of table olive decreases levels of oleuropein with correlated increases in the hydrolysis of hydroxytyrosol and tyrosol. Many of the health benefits reported for olives are thought to be associated with the levels of hydroxytyrosol. Date palm represents a staple food in most of the Arabian countries and is commonly consumed in several parts of the world. Numerous researches revealed the antibacterial, anti-hyperlipidemic, hepatoprotective, antimutagenic, and nephroprotective activity of date fruits, with reported anticancer and anti-fungal features.


Effect of naloxone on the induction of immediately early genes following oxygen- and glucose-deprivation in PC12 cells.
Cerebral ischemia/reperfusion involves inflammatory process and naloxone is able to reduce infarct volume and has been used as a therapeutic agent for brain injury. Hypoxia induces the immediate early genes (IEGs) rapidly and transiently that may initiate a cascade of cellular responses that are necessary for survival and normal function. However, the protective effect of naloxone on ischemic/hypoxic neuronal cells was only partly studied. Thus, the effects of naloxone on oxygen- and glucose-deprivation (OGD) and OGD followed by reoxygenation (OGD/R) on the expression of IEGs were examined in PC12 cells. The result showed that lactate dehydrogenase (LDH) released in the media was reduced by naloxone. The temporal response of IEG mRNA encoding c-fos, c-jun, nur77, and zif268 was induced with different degree of intensity following hypoxia, whereas the level of GAPDH mRNA was relatively constant. However, these signals of c-fos, c-jun, and nur77 by hypoxia were reduced significantly by naloxone. Treatment with OGD also activated mitogen-activated protein kinase (MAPK) pathway. The induction of c-fos, c-jun, nur77, and zif268 by hypoxia was inhibited by naloxone (0.1 microM) and MAPK inhibitors (10 microM of U0126, D98059, SB203580). However, naloxone increased the expression of ERK1/2 by OGD concomitantly diminished the LDH release. Thus, the present studies demonstrated that OGD induced IEGs including c-fos, c-jun, nur77, and zif268 and MAPK signaling pathways were regulated differently by naloxone.


Effects of laparoscopic radical prostatectomy on intraoperative autonomic nervous system control of hemodynamics.
Laparoscopic radical prostatectomy induces hemodynamic changes that have been supposed due to autonomic nervous system activity. The aim of this study is to measure the sympathetic and vagal modulation on hemodynamic response to steep Trendelenburg and pneumoperitoneum for laparoscopic surgery. Autonomic nervous system modulation was assessed noninvasively through heart rate variability and arterial pressure variability analysis in patients undergoing elective laparoscopic radical prostatectomy and in awake volunteers during head-down tilt. Forty patients and 14 awake volunteers were studied. The induction of general anesthesia significantly decreased the heart rate, arterial pressure, vagal modulation, and sympathetic modulation. Steep Trendelenburg increased vagal and sympathetic modulation both in anesthetized and awake subjects. Pneumoperitoneum increased arterial pressure without effect on autonomic nervous system control in anesthetized patients. Hemodynamic changes occurring during laparoscopic radical prostatectomy reveal autonomic response to the challenges (i.e. general anesthesia and head down position), and non-neurally mediated increase of arterial pressure caused by pneumoperitoneum. This study supports the notion that during laparoscopic radical prostatectomy the association between the vagal stimulation due to Trendelenburg positioning and sympathetic withdrawal caused by general anesthesia could lead to severe bradycardia and cardiac arrest in risky patients.


Safety and efficacy of vaginal hysterectomy in the large uterus with the LigaSure bipolar diathermy system.
This study was undertaken to assess safety and efficacy of vaginal hysterectomy in case of large uterine size (> or = 250 g) using the LigaSure bipolar diathermy (Valleylab, Boulder, CO). In a retrospective study, medical records of 102 patients who underwent vaginal hysterectomy and who had uterine weight (evaluated after surgery) 250 g or greater were reviewed. All hysterectomies were performed by using the LigaSure vessel sealing system to secure vascular pedicles (uterosacral-cardinal, uterine and ovarian and round ligaments). Of the 102 vaginal hysterectomies, 99 were successfully performed (97.1%; 95% confidence interval, 91.6-99.4%), whereas a conversion from the vaginal to the abdominal route was required in 3 cases. The median uterine weight was 455 g (range, 241-1913 g). The weight of the largest uterus successfully removed vaginally was 1600 g, without intraoperative and postoperative complications. The median operative time was 50 minutes (range, 25-50 minutes). The current study confirms that very large uterine volume does not represent a real obstacle to perform vaginal hysterectomy and that results in a safe and effective technique in cases of uterine weight 250 g or greater.


Effect of mandibular titanium reconstructive plates on radiation dose.
The effects of the mandibular titanium alloy plates on the radiation-tissue interactions are not clearly defined. Photon beam radiation may be modified after striking a metal plate used to reconstruct the mandible after oncologic surgery. The purpose of this study was to determine, in a human mandible model, the effects of a titanium alloy plate on the radiation dose received at the bone/titanium (plate and screws) interface and bone/soft tissue interface. We used an adult male human head and neck ex vivo model. A medical grade titanium alloy 6-hole plate, 2.4 mm, was fixed in the midline of the mandible. The mandible was then irradiated using 6 MV photon beams. Thermoluminescent dosimeters were used to measure the radiation doses anterior and posterior to the mandible. The experiment was then repeated without the plate and screws. The difference between the average doses received by the mandible reconstructed with plate/screws and a mandible without plate/screws was +2.1% at the buccal aspect of the mandible and +3.0% at the lingual aspect; respective P values were.741 and .323. Thus, these differences were not statistically significant. In this study, we did not observe any significant influence of titanium alloy plate/screws on the radiation doses received by tissues anterior or posterior to the mandible.


Does previous exposure to extreme precipitation regimes result in acclimated grassland communities?
Climate change will likely increase weather persistence in the mid-latitudes, resulting in precipitation regimes (PR) with longer dry and wet periods compared to historic averages. This could affect terrestrial ecosystems substantially through the increased occurrence of repeated, prolonged drought and water logging conditions. Climate history is an important determinant of ecosystem responses to consecutive environmental extremes, through direct damage, community restructuring as well as morphological and physiological acclimation in species or individuals. However, it is unclear how community restructuring and individual metabolic acclimation effects interact to determine ecosystem responses to subsequent climate extremes. Here, we investigated, if and how, differences in exposure to extreme or historically normal PR induced long-lasting (i.e. legacy) effects at the level of community (e.g., species composition), plant (e.g., biomass), and molecular composition (e.g., sugars, lipids, stress markers). Experimental grassland communities were exposed to long (extreme) or short (historically normal) dry/wet cycles in year 1 (Y1), followed by exposure to an identical PR or the opposite PR in year 2 (Y2). Results indicate that exposure to extreme PR in Y1, reduced diversity but induced apparent acclimation effects in all climate scenarios, stimulating biomass (higher productivity and structural sugar content) in Y2. In contrast, plants pre-exposed to normal PR, showed more activated stress responses (higher proline and antioxidants) under extreme PR in Y2. Overall, Y1 acclimation effects were strongest in the dominant grasses, indicating comparatively high phenotypical plasticity. However, Y2 drought intensity also correlated with grass productivity and structural sugar findings, suggesting that responses to short-term soil water deficits contributed to the observed patterns. Interactions between different legacy effects are discussed. We conclude that more extreme PR will likely alter diversity in the short-to midterm and select for acclimated grassland communities with increased productivity and attenuated molecular stress responses under future climate regimes.


Neural processes underlying statistical learning for speech segmentation in dogs.
To learn words, humans extract statistical regularities from speech. Multiple species use statistical learning also to process speech, but the neural underpinnings of speech segmentation in non-humans remain largely unknown. Here, we investigated computational and neural markers of speech segmentation in dogs, a phylogenetically distant mammal that efficiently navigates humans' social and linguistic environment. Using electroencephalography (EEG), we compared event-related responses (ERPs) for artificial words previously presented in a continuous speech stream with different distributional statistics. Results revealed an early effect (220-470 ms) of transitional probability and a late component (590-790 ms) modulated by both word frequency and transitional probability. Using fMRI, we searched for brain regions sensitive to statistical regularities in speech. Structured speech elicited lower activity in the basal ganglia, a region involved in sequence learning, and repetition enhancement in the auditory cortex. Speech segmentation in dogs, similar to that of humans, involves complex computations, engaging both domain-general and modality-specific brain areas. VIDEO ABSTRACT.


Recurrent cornual pregnancy after heterotopic cornual pregnancy successfully treated with systemic methotrexate.
This report concerns a recurrent spontaneous cornual pregnancy 2 years after selective feticide of a heterotopic cornual pregnancy which occurred after IVF for tubal pathology. The recurrent cornual pregnancy was treated successfully with systemic methotrexate. Assisted reproductive techniques, especially in patients with tubal pathology, and non-invasive management of cornual pregnancies may lead to a higher incidence of recurrence.


Patients' perspectives of barriers and facilitators to accessing support through primary care for common mental health problems in England: A systematic review.
Common mental disorders (CMDs) are prevalent throughout the population. Psychological therapy is often sought via primary care; however, equitable access is not commonplace. This review aims to investigate the barriers and facilitators adults experiencing CMDs perceive when accessing evidence-based psychological treatment in England. A qualitative systematic review with meta-synthesis was conducted (PROSPERO CRD42020227039). Seven electronic databases were searched for papers from 2008 to October 2022. Searches identified 30 studies from which three themes were developed with seven subthemes. Stigma and patients' perceptions and understandings of CMDs impacted their help-seeking decision-making and engagement with services. This meant that services were not used as a first resort for help-seeking. Upon reaching services, patients appeared to perceive primary care as not prioritising mental health problems, nor as being the place where they would be supported, particularly as healthcare professionals did not appear to know about CMDs and therapy was seen as difficult to access. The interaction between healthcare professional and patients was seen as pivotal to whether patients accessed support or not. The review is limited to research conducted within England. Additionally, it only explores access barriers prior to treatment experiences. Knowledge, attitudinal, systemic and relational barriers and facilitators were identified. Future research should focus on developing stigma reduction initiatives. Clinical implications include provision of standardised training across primary care HCP (healthcare professionals).


Heterogeneity in maternal and child mental health responses to the COVID-19 pandemic.
We used latent profile analysis on a longitudinal dataset to examine changes in maternal and child mental health during COVID-19 and factors that may protect against declines in mental health. Participants were 183 low-income mothers (M = 36 years) with young children (M = 5.31 years) in the City of Toronto with data collected prior to and during the pandemic in 2020. Mothers reported on their own stress, anxiety and depression and their children's emotional, conduct, hyperactivity, peer, and prosocial problems at both timepoints. We found heterogeneity in mental health changes, with 5 distinct patterns of change for mothers, and 4 distinct patterns of change for children during COVID-19. The majority (83%) of mothers experienced significant declines in at least one aspect of mental health. In contrast, the majority of children (65%) experienced either no change or improvements in mental health. Interestingly, patterns of change across these groups were not differentiated by demographic characteristics such as income, education, and family composition. However, for mothers, a higher degree of satisfaction with social support was associated with membership in a profile with better mental health both prior to, and during the pandemic. For children, having a stable history of early childhood education, and care was associated with membership in a profile that showed improvements in mental health during the pandemic. We discuss how our results support the need for proactive and global interventions for at-risk families with raised mental health concerns, and the benefits that stable early childhood education and care may provide for young children.


Formation and metabolism of hepoxilin A3 by the rat brain.
Incubation of homogenates of the rat cerebral cortex with arachidonic acid led to the appearance of hepoxilin A3, analysed as its stable trihydroxy derivative, trioxilin A3, by high resolution gas chromatography/electron impact mass spectrometry. Using the stable deuterium isotope dilution technique, it is estimated that the cerebral cortex generates 5.0 +/- 0.2 ng/mg protein of hepoxilin A3. The formation of this product was stimulated by the addition of exogenous arachidonic acid (12.9 +/- 1.5 ng/mg protein) and blocked by boiling of the tissue. Addition of the dual cyclooxygenase/lipoxygenase inhibitor BW 755C at a concentration of 75 microM did not result in a blockade of hepoxilin formation. Three other regions were also tested for their ability to form hepoxilin A3 upon stimulation with exogenous arachidonic acid, i.e. median eminence, 11.7 +/- 1.6 ng/mg protein, pituitary, 12.3 +/- 0.7 ng/mg protein; pons, 26.6 +/- 0.2 ng/mg protein. In a separate study, 14C-labelled hepoxilin A3 was transformed into 14C-labelled trioxilin A3 by homogenates of the rat whole brain, demonstrating the presence of epoxide hydrolases in the CNS which utilise the hepoxilins as substrates. This is the first demonstration of the occurrence of the hepoxilin pathway in the central nervous system.


Solubilization of the serotonin1A receptor monitored utilizing membrane dipole potential.
Solubilization of membrane proteins by amphiphilic detergents represents a crucial step in studies of membrane proteins in which proteins and lipids in natural membranes are dissociated giving rise to mixed clusters of proteins, lipids and detergents in the aqueous dispersion. Although solubilization is a popular method, physicochemical principles underlying solubilization are not well understood. In this work, we monitored solubilization of the bovine hippocampal serotonin1A receptor, a representative member of the GPCR family, using membrane dipole potential measured by a dual fluorescence ratiometric approach with a potential-sensitive fluorophore. Our results show that membrane dipole potential is a good indicator of solubilization and reflects the change in dipolar environment upon solubilization due to dipolar reorganization associated with solubilization. To the best of our knowledge, these results constitute the first report linking membrane dipole potential with solubilization. We envision that these results are potentially useful in providing a molecular mechanism for membrane protein solubilization.


A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome.
BACKGROUNDSevere forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects.METHODSWe performed a phase I open-label trial assessing safety and feasibility of autologous bone marrow-derived MSCs (BM-MSCs) in children and young adults with severe forms of steroid-dependent nephrotic syndrome. Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy, and immunomodulatory effects in vivo were monitored for 12 months.RESULTSSixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (P = 0.02) and number of relapses was reduced (P = 0.002) after BM-MSC infusion, compared with the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared with baseline (P < 0.05). No treatment benefit was observed in adults.In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction in total CD19+, mature, and memory B cells and an increase in regulatory T cells in vivo up to 3-6 months following BM-MSC infusionCONCLUSIONTreatment with autologous BM-MSCs is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit.TRIAL REGISTRATIONEudraCT 2016-004804-77.FUNDINGAIFA Ricerca Indipendente 2016-02364623.


Health benefits in 2005: premium increases slow down, coverage continues to erode.
This paper reports findings on the state of job-based health insurance in spring 2005 and how it has changed during recent years. Premiums rose 9.2 percent, the first year of single-digit increases since 2000. The percentage of firms offering health benefits has fallen from 69 percent in 2000 to 60 percent in 2005. Cost sharing did not grow appreciably in the past year. Enrollment in preferred provider organizations (PPOs) grew from 55 percent in 2004 to 61 percent in 2005, while enrollment in health maintenance organizations (HMOs) fell from 25 percent to 21 percent of the total.


Serous psammocarcinoma of the ovary: an unusual finding.
Serous psammocarcinoma of the ovary is a rare and infrequently described variant of ovarian cancer, characterized histologically by the pervasive presence of psammoma bodies. The risk of recurrent disease following surgical resection is low. A 70-year-old patient was admitted to the emergency room after falling at home. CT evaluation revealed a pelvic mass and free fluid in the abdomen and pelvis. Her serum CA-125 level was greatly elevated. The patient underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy. Histologic examination revealed serous psammocarcinoma of the ovary. Psammocarcinoma is a rare form of ovarian cancer associated with a favorable prognosis. However, the rare incidence of this disease and inconsistent biological behavior can confound the diagnosis for the treating physician.


Potentially Preventable Hospitalizations Among Adults With Pediatric-Onset Disabilities.
To examine the risk of any and specific potentially preventable hospitalizations (PPHs) for adults with cerebral palsy (CP) or spina bifida (SB). We hypothesize that PPH risk is greater among adults with CP/SB compared with the general population. Using January 1, 2007, to December 31, 2017, national private administrative claims data (OptumInsight) in the United States, we identified adults with CP/SB (n=10,617). Adults without CP/SB were included as controls (n=1,443,716). To ensure a similar proportion in basic demographics, we propensity-matched our controls with cases in age and sex (n=10,617). Generalized estimating equation models were applied to examine the risk of CP/SB on PPHs. All models were adjusted for age, sex, race/ethnicity, health indicators, US Census Division data, and socioeconomic variables. Adjusted odds ratios were compared within a 4-year follow-up. Adults with CP/SB had higher risk for any PPH (odds ratio [OR], 4.10; 95% CI, 2.31 to 7.31), and PPHs due to chronic obstructive pulmonary disease/asthma (OR, 1.85; CI, 1.23 to 2.76), pneumonia (OR, 3.01; 95% CI, 2.06 to 4.39), and urinary tract infection (OR, 6.48; 95% CI, 3.91 to 10.75). Cases and controls who had an annual wellness visit had lower PPH risk (OR, 0.52; 95% CI, 0.41 to 0.67); similarly, adults with CP/SB who had an annual wellness visit compared with adults with CP/SB who did not had lower odds of PPH (OR, 0.75; 95% CI, 0.60 to 0.94). Adults with pediatric-onset disabilities are at a greater risk for PPHs. Providing better access to preventive care and health-promoting services, especially for respiratory and urinary outcomes, may reduce PPH risk among this patient population.


LRP6 lets Merlin go in times of nutrient scarcity.
Cells take advantage of cross-talk in signaling pathways to integrate diverse signals and produce coordinated responses. In this issue of EMBO Reports, Jeong et al discover that the Wnt co-receptor, low-density lipoprotein (LDL) receptor-related protein LRP6, negatively regulates Hippo signaling by serving as a binding sink to sequester and inhibit Merlin, an activator of Hippo signaling (Jeong et al, 2020). This regulation is nutrient-responsive, likely using LRP6 O-GlcNAcylation as a molecular switch.


Changes in microbial nutrient status during secondary succession and its modification by earthworms.
Microbial biomass, nutrient (N and P) status, and carbon and nutrient limitation of the microflora were investigated in soils from five different sites (field, 5-, 12-, and about 50-year-old fallow, beechwood), which represent different stages of a secondary succession from a wheat field to the climax ecosystem of a beechwood on limestone. In addition, the effect of faeces production by the substrate feeding earthworm species Octolasion lacteum (Örley) on the nutrient status of the soil microflora of these sites was studied. Humus had accumulated in the soil of the third fallow site, with an enhanced biomass of microflora. However, in the beechwood soil, which had the highest humus content, microbial biomass was lower than in the soil of the third fallow site and similar to that of the field and the two younger fallow sites. In general, soil microbial biomass was little affected by the passage of soil through the gut of O. lacteum. The soil microflora of the field, the 5-, 12-, and about 50-year-old fallow was limited by carbon, whereas in the beechwood soil phosphorus limited microbial growth. NItrogen availability to the soil microflora was low in the two younger fallow sites and high in the field and the third fallow. In the beechwood soil nitrogen supply did not affect microbial carbon utilization. Application of phosphorus stimulated glucose mineralization in the soil of the field, the third fallow, and the beechwood, but not in the two younger fallow sites. Therefor, the nutrient status of the soil microflora seems to have changed during secondary succession: presumably, during the first phase the availability of nitrogen decreased, whereas during the second phase microbial phosphorus supply became more important, which resulted in phosphorus limitation of the soil microflora in the climax ecosystem. The passage of soil through the gut of O. lacteum caused an alteration in the microbial nutrient status. Generally, microbial growth in earthworm casts was limited by carbon. The relative effect of the gut passage of the soils on microbial carbon utilization seems to increase during succession. Therefore, the effect of decomposer invertebrates on microbial nutrient supply seems to increase during secondary succession. In general, nitrogen did not limit microbial carbon utilization in earthworm casts. Phosphorus requirements of the soil microflora were lowered by the gut passage of the soil of the third fallow site and the beechwood, which indicates an increased phosphorus supply in earthworm casts. Howerver, this additional supply was not sufficient to enable optimal carbon utilization by the soil microflora. The results indicate that the effect of decomposer invertebrates on the soil microflora depends on the nutrient status of the ecosystem.


Persisting Racial Disparities in Total Shoulder Arthroplasty Utilization and Outcomes.
The purpose was to study whether racial disparities in total shoulder arthroplasty (TSA) utilization and outcomes have declined over time. We used the US Nationwide Inpatient Sample from 1998 to 2011. We used chi-squared test to compare characteristics, Cochran-Armitage test to compare utilization rates, and Cochran-Armitage test and logistic regression to compare time-trends in outcomes by race. From 1998 to 2011, 176,141 Whites and 7694 Blacks underwent TSA. Compared to Whites, Blacks who underwent TSA were younger (69.1 vs. 64.2 years; p < 0.0001), more likely to be female (54.9 vs. 71.0 %; p < 0.0001), and have rheumatoid arthritis or avascular necrosis as the underlying diagnosis (1.7 vs. 3.0 % and 1.7 vs. 6.1 %; p < 0.0001 for both) and a Deyo-Charlson index of 2 or higher (8.5 vs. 16.7 %; p < 0.0001). Compared to Whites, Blacks had much lower TSA utilization rate/100,000 in 1998 (2.97 vs. 0.83; p < 0.0001) and in 2011 (12.27 vs. 3.33; p < 0.0001); racial disparities increased from 1998 to 2011 (p < 0.0001). A higher proportion of Blacks than Whites had a hospital stay greater than median in 1998-2000, 62 vs. 51.4 % (p = 0.02), and in 2009-2011, 34.4 vs. 27.3 % (p < 0.0001); disparities did not change over time (p = 0.31). These disparities in utilization were borderline significant in adjusted analyses. There were no racial differences in proportion discharged to inpatient medical facility in 1998-2000, 15.2 vs. 15.0 % (p = 0.95), and in 2009-2011, 12.3 vs. 11.1 % (p = 0.37), respectively. We found increasing racial disparities in TSA utilization. Some disparities in outcomes exist as well. Patients, surgeons, and policy-makes should be aware of these findings and take action to reduce racial disparities.


Immunochemical studies on Shigella dysenteriae type 9 bacterial polysaccharide.
On graded hydrolysis and Smith degradation, the O-somatic polysaccharide isolated from Shigella dysenteriae type 9 bacteria, strain NCTC 7919, yielded five oligosaccharides which were characterized. The positions of the O-acetyl and pyruvic acetal groups in the repeating unit were identified. Immunochemical studies indicated that D-galactose is the immunodominant sugar in the polysaccharide, and one of the oligomers, having the structure Gal-(1 leads to 3)-GlcNAc-(1 leads to 3)-Gal-(1 leads to 4)-Man, showed maximum inhibition of the homologous precipitation.


Platelet-derived growth factor B-chain expression in the rat retina and optic nerve: distribution and changes after transection of the optic nerve.
To test the possible involvement of platelet-derived growth factor B-chain (PDGF-B) in anterograde and retrograde degenerations of the CNS neurons, we studied the changes of PDGF-B localization and its mRNA expression in the rat retina and optic nerve (ON) after unilateral ON transection, using immunohistochemistry and in situ hybridization. In the control retinas immunoreactivity for PDGF-B and its mRNA expression were localized in the retinal ganglion cells (RGCs) and the nerve fiber layer. After ON transection PDGF-B immunoreactivity in the nerve fiber layer started to decrease on post-injury day 3 or 4. Atrophic changes in the RGCs started on day 5 just after the decrease of PDGF expression, and thereafter the RGC number decreased. In the longitudinal section of the ON rostral to the transected site, swollen axons showed intense PDGF-B immunoreactivity and macrophages, and some glial cells revealed a significant increase in both immunoreactivity and hybridization signals. Based on these findings, we hypothesized that the decrease in PDGF-B in RGCs after axotomy causes the loss of RGCs, and that increased PDGF-B expression in the ON plays a role in the cascade of tissue reactions following ON transection.


Efficient identification of somatic mutations in acute myeloid leukaemia using whole exome sequencing of fingernail derived DNA as germline control.
Recent advances in next-generation sequencing have made it possible to perform genome wide identification of somatic mutation in cancers. Most studies focus on identifying somatic mutations in the protein coding portion of the genome using whole exome sequencing (WES). Every human genome has around 4 million single nucleotide polymorphisms (SNPs). A sizeable fraction of these germline SNPs is very rare and will not be found in the databases. Thus, in order to unambiguously identify somatic mutation, it is absolutely necessary to know the germline SNPs of the patient. While a blood sample can serve as source of germline DNA from patients with solid tumours, obtaining germline DNA from patients with haematological malignancies is very difficult. Tumor cells often infiltrate the skin, and their DNA can be found in saliva and buccal swab samples. The DNA in the tips of nails stems from keratinocytes that have undergone keratinization several months ago. DNA was successfully extracted from nail clippings of 5 probands for WES. We were able to identify somatic mutations in one tumor exome by using the nail exome as germline reference. Our results demonstrate that nail DNA is a reliable source of germline DNA in the setting of hematological malignancies.


Association of p73 G4C14-A4T14 polymorphisms with genetic susceptibilities to breast cancer: a case-control study.
The aim of this study was to evaluate the association of p73 G4C14-A4T14 polymorphisms with susceptibility to breast cancer in Chongqing women of Han Nationality in China. In a case-control study, single-nucleotide polymorphisms of p73 G4C14-A4T14 at exon 2 were genotyped by Sequenom MassArray(®) iPLEX GOLD System in 170 patients with breast cancer and 178 healthy controls. Data were analyzed via t test, Chi-square test, and logistic regression analysis. The distribution of p73 genotypes and allelotypes had no significant difference between patients with breast cancer and healthy controls (χ(2) = 2.750, P = 0.253; χ(2) = 2.195, P = 0.138). More risk of developing triple negative breast cancer (TNBC) was found in the individuals who carried with GC/GC genotype than individuals carried with GC/AT and AT/AT genotypes (OR = 2.99; 95 % CI, 1.30-6.89; P = 0.010). p73 G4C14-A4T14 polymorphisms are closely associated with the increased risk for TNBC in Chongqing women of Han Nationality in China; GC/GC genotype is susceptible genotype for TNBC in Chongqing women of Han Nationality in China. The patients with breast cancer who carried with GC/GC genotype may have bad prognosis. Additional larger studies are required to confirm these findings.


Production and property of beta-lactamases in Streptomyces: comparison of the strains isolated newly and thirty years ago.
Productivity and property of beta-lactamases of Streptomyces strains isolated from soil some 30 years ago were studied in comparison with those of the newly isolated strains. At least three-quarters of the Streptomyces strains produced beta-lactamase constitutively and extracellularly, mainly as penicillinases, as in the cases of those from the newly isolated strains. Strains such as S. albus, S. diastatochromogenes, S. fradiae, and S. lavendulae were the highest producing strains, and the amounts of beta-lactamase activity they produced were comparable to those produced by Bacillus cereus 569/H and B. licheniformis 749/C. In isoelectric focusing, most strains contained one main beta-lactamase band with a number of satellite bands, but some strains contained one band only. Although beta-lactamases from most strains showed isoelectric points of pH 5 to 6, some strains produced beta-lactamases with strongly basic isoelectric points of pH 8 to 9. Molecular weights were between 20,000 and 30,000. From these results, it is suggested that the proportion of the producing strains of Streptomyces and the properties of the beta-lactamases have not been affected significantly by the introduction of penicillin into the natural environment, in contrast to the cases of other microorganisms.


Scientific Productivity in Rheumatology Among Countries of the Organisation for Economic Co-operation and Development and Its Correlation to National Economic Indicators.
The purpose of this study was to examine the correlation between research productivity in the field of rheumatology and various updated economic indicators of Countries of the Organisation for Economic Co-operation and Development (OECD). The number of documents published, number of citable documents, number of citations, citations per document, and the H-index for the 36 OECD countries in the field of rheumatology between 1996 and 2017 were obtained from the The Scimago Journal and Country rank source. The recent data regarding gross domestic product (GDP) per capita, total health spending as percent of GDP, and the gross domestic expenditure on research and development as percent of GDP were collected from the World Bank, OECD, and United Nations Educational, Scientific, and Cultural Organization Web sites, accordingly. The relationship between economic indicators and scientific productivity for each of the OECD countries was analyzed. A total of 132,314 documents were analyzed. A moderate to strong significance correlation was found between health expenditure and the number of documents published (r = 0.67, p < 0.001), number of citable documents (r = 0.68, p < 0.001), number of citation (r = 0.76, p < 0.001), and H-index (r = 0.77, p < 0.001). This study provides a current highlight on the relationship between academic productivity in rheumatology and economic indicators of OECD countries. We showed a positive moderate to strong significant correlation between total health expenditure as percent of GDP and different bibliometric indicators, implying another possible advantage of national investment in this filed.


ONTOFUSION: ontology-based integration of genomic and clinical databases.
ONTOFUSION is an ontology-based system designed for biomedical database integration. It is based on two processes: mapping and unification. Mapping is a semi-automated process that uses ontologies to link a database schema with a conceptual framework-named virtual schema. There are three methodologies for creating virtual schemas, according to the origin of the domain ontology used: (1) top-down--e.g. using an existing ontology, such as the UMLS or Gene Ontology--, (2) bottom-up--building a new domain ontology-- and (3) a hybrid combination. Unification is an automated process for integrating ontologies and hence the database to which they are linked. Using these methods, we employed ONTOFUSION to integrate a large number of public genomic and clinical databases, as well as biomedical ontologies.


[Study of communities of Monogenea Dactylogyridae parasites of the Cyprinidae in Lake Mikri Prespa (northern Greece). Description of 3 new species from an endemic Barbus: Barbus cyclolepis prespensis Karaman, 1924].
In this paper are described 17 species of Monogenea Dactylogyridae, parasites of Cyprinidae from lake Mikri Prespa, in Greece: 14 species have been already reported in mediterranean region; 3 new species have been harvested on an endemic Barbus, B. cyclolepis prespensis, Dactylogyrus balkanicus n. sp., Dactylogyrus crivellius n. sp., Dactylogyrus prespensis n. sp. For these communities of Dactylogyrus, we discuss some problems of parasite specificity, speciation and biogeography. From the morphological types, we suggest for D. crivellius and D. prespensis an allopatric speciation and for D. balkanicus, a synxenic sympatric speciation.


Increased interleukin 1 and tumor necrosis factor alpha levels after thyroid surgery.
The aim of this study was to consider levels of the proinflammatory cytokines IL-1 and TNFα after thyroid surgery. A total of 200 patients who underwent total thyroidectomy enrolled in this study. Drain fluid samples were taken. IL-1 and TNFα results and their relationship with other factors were analyzed. There was a positive correlation between IL-1 and hyperthyroidism (rs=0.614, p<0.001), operative time (rs=0.770, p<0.001), and excised thyroid volume (rs=0.829, p<0.001). Moreover, there was a positive correlation between TNFα and hyperthyroidism (rs=0.430, p<0.001), operative time (rs=0.392, p<0.001), and excised thyroid volume (rs=0.398, p<0.001). The results of this study showed us that the parameters related to increased proinflammatory cytokine levels after thyroid surgery were hyperthyroidism, operative time, and excised thyroid volume, but this increase did not show us any clinical outcomes related to these parameters.


Erratum: Explore the Value of Adding Induction Chemotherapy to Concurrent Chemoradiotherapy in T3-4N0M0 Nasopharyngeal Carcinoma Patients: A Retrospective Study [Corrigendum].
[This corrects the article DOI: 10.2147/CMAR.S321471.].


Radioimmunoassay of free urinary 18-hydroxydeoxycorticosterone (18-OH-DOC) in patients with essential hypertension.
Specific antiserum was raised in white New Zealand rabbits using 18-hydroxydeoxycorticosterone-3-oxime-BSA complex as antigen. The urinary free 18-OH-DOC was estimated after dichloromethane extraction and separation in one paper chromatographic system (propylene glycol/toluene). The mean 18-OH-DOC excretion value (+/- S.D.) in normal subjects was 0.861 +/- 0.527 microgram/24 h (n=23). ACTH produced a 25-fold increase in the excretion of free 18-OH-DOC. Dexamethasone suppressed the values to the lower range of sensitivity. 32% of patients of essential hypertension showed a moderate increase in the free urinary 18-OH-DOC values. The mean value (+/- S.D.) in the low renin hypertension group was 2.50 +/- 1.49 microgram/24 h (n=19), in the normal renin patient group 1.84 +/- 1.22 microgram/24 h (n=38). The difference between controls and the hypertensive groups was statistically significant. Among the different hypertensive groups significant differences could not be calculated.


Generation of alternative Ultrabithorax isoforms and stepwise removal of a large intron by resplicing at exon-exon junctions.
Little is known about mechanisms that regulate and ensure accurate processing of complex transcription units with long introns. We investigate this in the Ultrabithorax gene of Drosophila. A consensus 5' splice site is regenerated at the junction between the first exon and a small internal exon (mI); this splice site is used in a developmentally regulated manner to remove mI during subsequent processing of the downstream intron. Conserved elements within mI and an interaction with exon mII modulate use of the regenerated splice site. Structural similarities predict the same process for mII. This resplicing mechanism avoids competition between distant splice sites for control of exon inclusion and allows removal of a 74 kb intron as a series of smaller fragments.


Two hour exposure to sodium butyrate sensitizes bladder cancer to anticancer drugs.
To investigate the inhibitory effect of sodium butyrate (NaB) on the proliferation of human bladder cancer cell lines and its synergetic effect with anticancer drugs in treating bladder cancer in vitro and in vivo. The inhibitory effects of NaB on human bladder cancer cell lines in vitro and the synergetic effect of NaB with mitomycin c, cisplatin (CDDP) and adriamycin were detected by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Hoechst staining and electron microscopy were used to observe morphology for apoptotic cells after NaB treatment. Fas, bcl-2 and caspase-3 were determined with flow cytometry. In vivo synergetic effects were detected in N-methyl-N-nitrosourea induced bladder cancer model rats. NaB significantly inhibited the growth of bladder cancer cell lines in a concentration and time dependent manner. Better results of tumor inhibition have been achieved when NaB was combined with CDDP, mitomycin c and adriamycin, rather than used alone. Furthermore, 2 h exposure to NaB can sensitize bladder cancer to chemotherapy agents. The Bcl-2 expression in bladder cancer cells is decreased and caspase-3 expression increased after NaB treatment. Intravesical application of NaB combined with CDDP can significantly inhibit tumor growth and progression. NaB has a direct anticancer effect and can markedly enhance the action of several chemotherapy agents. 2 h expose to NaB can also sensitize bladder cancer to anticancer drugs. NaB may be an excellent candidate agent for intravesical application in treating bladder cancer.


Development of a multi-dimensional measure of resilience in adolescents: the Adolescent Resilience Questionnaire.
The concept of resilience has captured the imagination of researchers and policy makers over the past two decades. However, despite the ever growing body of resilience research, there is a paucity of relevant, comprehensive measurement tools. In this article, the development of a theoretically based, comprehensive multi-dimensional measure of resilience in adolescents is described. Extensive literature review and focus groups with young people living with chronic illness informed the conceptual development of scales and items. Two sequential rounds of factor and scale analyses were undertaken to revise the conceptually developed scales using data collected from young people living with a chronic illness and a general population sample. The revised Adolescent Resilience Questionnaire comprises 93 items and 12 scales measuring resilience factors in the domains of self, family, peer, school and community. All scales have acceptable alpha coefficients. Revised scales closely reflect conceptually developed scales. It is proposed that, with further psychometric testing, this new measure of resilience will provide researchers and clinicians with a comprehensive and developmentally appropriate instrument to measure a young person's capacity to achieve positive outcomes despite life stressors.


Pneumocephalus after posterior fossa surgery in prone position: Is that any clinical effect?
The term pneumocephalus refers to the existence of air in any intracranial compartment. Its presence in the follows of a supratentorial craniotomy is very common, and it usually represents a benign complication as it is very rarely responsible for clinical manifestations. We report the case of a 24 years-old man, who underwent posterior fossa surgery in prone position for resection of a vermian tumor. Postoperative, the patient presented a tonic-clonic generalized seizure associated to high levels of arterial pressure and decerebration. Control CT scan showed an important pneumocephalus. On the posterior fossa, the air was responsible for a compression of the brainstem, without any other postoperative complications. Following 12 h of conservative management, a brain MRI showed a total regression of the pneumocephalus. 3 days later, the patient presented a favorable outcome as he was extubated without any major impairments. Transformation of pneumocephalus into tension pneumocephalus responsible for clinical inadvertance is rare. This complication is mainly related to surgeries performed in sitting position. The occurrence of compressive pneumocephalus after a posterior fossa craniotomy performed in a prone position is seldom. Through this case, we discuss pathophysiology and therapeutic approaches for tension pneumocephalus following posterior fossa performed in prone position.


Targeting the VEGF signaling pathway in cancer therapy.
Angiogenesis was first proposed as a possible target for the treatment of human cancer several decades ago. During recent years, the discovery of VEGF as the main mediator of tumor angiogenesis enabled the specific and successful inhibition of angiogenesis in several experimental and clinical studies. This review discusses recent data regarding the molecular mechanisms of VEGF signaling in cancer development, the response of various types of human cancer to anti-VEGF treatment, reasons for a failure of therapy and possible biomarkers for the prediction of therapeutic response. The literature discussed is based on a systematic analysis using PubMed and MEDLINE databases for articles presented in 2000 - 2011. Although anti-VEGF therapy has improved the treatment of several types of cancer during recent years, several questions still remain unanswered. For instance, in some patients, cancer develops resistance to anti-VEGF therapeutics following initially successful therapy, whereas others never show a response. Therefore, a more detailed knowledge of the molecular mechanisms involved in VEGF signaling and predictive biomarkers for a response to anti-VEGF therapy are among the most important challenges for VEGF research today.


Cadaveric and engineering analysis of the septal L-strut.
To identify patterns of failure of the L-strut, to identify elements of the nasal framework that support the L-strut, and to investigate the effect of altering L-strut design on its stability. Laboratory study with human cadaveric heads and computational modeling. Directional forces were applied to cadaveric L-struts and patterns of failure with incremental force were noted. Computational modeling using the finite element method (FEM) was employed to determine quantitatively the effect of various modifications on the stability of the L-strut. The L-strut was found to respond to frontal force initially by buckling. This buckling was reversible until the force exceeded a certain threshold when the L-strut broke at the bony-cartilaginous junction. The threshold force varied depending on the length of the overlap with the bony vault. Intact mucoperichondrium provided significant stability. Modeling with FEM showed that the preservation of a triangular piece of cartilage at the dorsal anchor of a narrowed L-strut can offset some of the loss in mechanical stability. Intrinsic elasticity of the septal cartilage, the mucoperichondrial flap, and overlap with the bony vault all contribute to the stability of the L-strut, which is enhanced by preserving a small segment of cartilage at the bony-cartilaginous junction of the dorsal L-strut.


Hydrated calcareous oil-shale ash as potential filter media for phosphorus removal in constructed wetlands.
The P-retention in hydrated calcareous ash sediment from oil-shale burning thermal power plants in Estonia was studied. Batch experiments indicate good (up to 65 mg P g(-1)) P-binding capacity of the hydrated oil-shale ash sediment, with a removal effectiveness of 67-85%. The high phosphorus sorption potential of hydrated oil-shale ash is considered to be due to the high content of reactive Ca-minerals, of which ettringite Ca6Al2(SO4)3(OH)12.26H2O and portlandite Ca(OH)2 are the most important. The equilibrium dissolution of ettringite provides free calcium ions that act as stable nuclei for phosphate precipitation. The precipitation mechanism of phosphorus removal in hydrated ash plateau sediment is suggested by Ca-phosphate formation in batch experiments at different P-loadings. Treatment with a P-containing solution causes partial-to-complete dissolution of ettringite and portlandite, and precipitation of Ca-carbonate and Ca-phosphate phases, which was confirmed by X-ray diffraction (XRD) and scanning electron microscope (SEM)-EDS studies. Thus, the hydrated oil-shale ash sediment can be considered as a potential filtration material for P removal in constructed wetlands for wastewater treatment.


EEG findings in minor head trauma as a clue for indication to CT scan.
In order to investigate the role of EEG in minor head traumata in the pediatric age, EEG and CT scan findings were compared in a series of 103 consecutive cases of children hospitalized within 24 h after head trauma. The EEGs were classified as normal in 50 patients, borderline in 10 patients, and abnormal in 43 patients. CT scan showed contusion in 6 patients and extracerebral hematoma in 4. All cases of abnormal CT scans were reported for patients with frankly abnormal EEG findings. In contrast, no pathological findings were found in CT scans for patients with normal EEG. The data suggest that EEG findings can play a major role in the diagnostic workup of patients with minor head traumata. Specifically, in the case of asymptomatic patients with normal EEG findings, it is likely that the CT scan will also be normal.


Development of one dimensional geomechanical model for a tight gas reservoir.
Estimating rock-mechanical, petrophysical properties and pre-production stress state is essential for effective reservoir planning, development, and optimal exploitation. This paper attempts to construct a comprehensive one-dimensional mechanical earth model (1D MEM) of the Mandapeta gas reservoir of Krishna Godavari (KG) basin, India. The methodology comprises a detailed stepwise process from processing and analysis of raw log data, calibration of log-derived dynamic properties with static ones using regression models developed from tested core samples, and final rock mechanical property estimation. Pore pressure profiles have been estimated and calibrated with the Repeat formation tester (RFT) data for every thirty-five wells. Overburden and horizontal stresses have also been evaluated and calibrated using data from the Leak-off Tests (LOT) or Extended Leak-off Tests (XLOT). A menu-driven program is developed using PYTHON code for visualization and on-time revision of 1D MEM. The resulting comprehensive 1D MEM predicts and establishes the rock-mechanical properties, pore pressure, and in-situ stress values of the basin. Besides its use in planning future wells, development of the field, and yielding insight into the various well challenges, it can also be used to develop a 3D MEM of the reservoir.


Validation of American Society of Echocardiography Guideline-Recommended Parameters of Right Ventricular Dysfunction Using Artificial Intelligence Compared With Cardiac Magnetic Resonance Imaging.
Right ventricular (RV) function is important in the evaluation of cardiac function, but its assessment using standard transthoracic echocardiography (TTE) remains challenging. Cardiac magnetic resonance imaging (CMR) is considered the gold standard. The American Society of Echocardiography recommends surrogate measures of RV function and RV ejection fraction (RVEF) by TTE, including fractional area change (FAC), free wall strain (FWS), and tricuspid annular planar systolic excursion (TAPSE), but they require technical expertise in acquisition and quantification. The aim of this study was to evaluate the sensitivity, specificity, and positive and negative predictive values of FAC, FWS, and TAPSE derived using a rapid, novel artificial intelligence (AI) software (LVivoRV) from a single-plane transthoracic echocardiographic apical four-chamber, RV-focused view without ultrasound-enhancing agents for detecting abnormal RV function compared with CMR-derived RVEF. RV dysfunction was defined as RVEF < 50% and RVEF < 40% on CMR. TTE and CMR were performed within a median of 10 days (interquartile range, 2-32 days) of each other in 225 consecutive patients without interval procedural or pharmacologic intervention. The sensitivity and negative predictive value to detect CMR-defined RV dysfunction when all three AI-derived parameters (FAC, FWS, and TAPSE) were abnormal were 91% and 96%, while those of expert physician reads were 91% and 97%. Specificity and positive predictive value were lower (50% and 32%) compared with expert physician-read echocardiograms (82% and 56%). AI-derived measurements of FAC, FWS, and TAPSE had excellent sensitivity and negative predictive value for ruling out significant RV dysfunction (CMR RVEF < 40%), comparable with that of expert physician readers, but lower specificity. Thus AI, using American Society of Echocardiography guidelines, may serve as a useful screening tool for rapid bedside assessment to exclude significant RV dysfunction.


Use the Environment to Prevent and Control COVID-19 in Senior-Living Facilities: An Analysis of the Guidelines Used in China.
To identify the environmental factors essential for infection control in senior-living facilities. In the COVID-19 pandemic, older adults are more likely to be infected and develop serious outcomes than young people. Worldwide, senior-living facilities face a battle to protect their residents. Compared with age-related declines, the built environment is more modifiable and can be used for infection control. This research conducted content analysis of the guidelines on COVID-19 control issued by the State Council of China in February 2020 for senior-living facilities. Six senior-living facility managers in China were interviewed and shared their experiences using these guidelines. Quantitative and qualitative analyses were conducted to identify the essential environmental factors for infection control. Environmental factors suggested in the guidelines were analyzed for three groups of infection-control strategies: keep COVID-19 from entering the facility, prevent COVID-19 spread in the facility, and manage infection and illness. Key topics of experience using the guidelines were identified, including residents' needs for social interaction and the difficulties of providing dedicated air-conditioning and circulation systems. Based on these analyses, from the perspective of environmental design, environmental factors essential for COVID-19 control in senior-living facilities were summarized at the site, building, and room levels. Proper planning and design of the built environment promote strategies for infection control in senior-living facilities. Findings can be used to guide the new design, renovation, and modification of senior-living facilities for COVID-19 control and future public health emergencies.


Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: effects of pioglitazone and metformin treatment.
Chronic low-grade inflammation is a common feature of insulin resistant states, including obesity and type 2 diabetes. Less is known about inflammation in Polycystic Ovary Syndrome (PCOS). Thus we evaluated the impact of PCOS on circulating cytokine levels and the effects of anti-diabetic therapies on insulin action, cytokine and chemokine levels and inflammatory signaling in skeletal muscle. Twenty subjects with PCOS and 12 healthy normal cycling (NC) subjects of similar body mass index were studied. PCOS subjects received oral placebo or pioglitazone, 45 mg/d, for 6 months. All PCOS subjects then had metformin, 2 g/day, added to their treatment. Circulating levels of cytokines, chemokines, and adiponectin, skeletal muscle markers of inflammation and phosphorylation of signaling proteins, insulin action evaluated by the hyperinsulinemic/euglycemic clamp procedure and Homeostasis Model Assessment of Insulin Resistance were measured. Circulating levels of a number of cytokines and chemokines were generally similar between PCOS and NC subjects. Levels in PCOS subjects were not altered by pioglitazone or metformin treatment, even though whole body insulin action and adiponectin levels increased with pioglitazone. In spite of the lack of change in levels of cytokines and chemokines, several markers of inflammation in skeletal muscle were improved with Pio treatment. PCOS may represent a state of elevated sensitivity of inflammatory cells in skeletal muscle to cytokines and chemokines, a property that could be reversed by pioglitazone treatment together with improved insulin action.


Off-line comprehensive two-dimensional reversed-phase countercurrent chromatography with high-performance liquid chromatography: Orthogonality in separation of Polygonum cuspidatum Sieb. et Zucc.
Off-line comprehensive two-dimensional reversed-phase countercurrent chromatography with high-performance liquid chromatography was investigated in separation of crude ethanol extract from traditional Chinese medicinal herb Polygonum cuspidatum Sieb. et Zucc. Two-dimensional contour plots for countercurrent chromatography with high-performance liquid chromatography was obtained after comprehensive separation was completed. Total peak capacity was evaluated and approximately 810 peaks were obtained through a comprehensive two-dimensional separation. A highly orthogonality of 52.23% and a large separation space occupancy of 88.86% were achieved. Meanwhile, it was found that several components could be well separated by countercurrent chromatography while they could not be separated by high-performance liquid chromatography, and vice versa, which further indicated the orthogonality of the two separation methods. The off-line comprehensive two-dimensional countercurrent chromatography with high-performance liquid chromatography provided a promising and powerful method for separation of complex natural products.


Myocardial regeneration by endogenous adult progenitor cells.
New strategies are urgently needed for the treatment of terminal heart-failure. Recently, new therapeutic strategies were developed to induce cardiac regeneration and thereby enhancing myocardial performance by using the patients own cell pool. In the quest for adequate donor cells skeletal myoblasts, bone marrow (BM) derived cells, endothelial progenitor cells (EPCs) and resident cardiac stem cells but also cytokine application were examined. This review critically discusses the recent findings in the field of endogenous adult progenitor cells and proposes new areas for future research.


Study of the mechanism of bystander effect of KDR-CDglyTK system mediated by adenovirus for the treatment of gastric cancer.
We evaluated the relationship between cellular gap junction and bystander effect in gastric cancer SCG7901 cell killing by adenovirus-mediated KDR-CDglyTK system. SCG7901 and HeLa cells were transfected (MOI-100) with recombinant adenovirus carrying fusion gene. Transfection efficiency/fusion gene mRNA expression were determined; intercellular communications in the presence of apigenin were measured by fluorescence recovery after photobleaching (FRAP). Transfected/non-transfected cells were mixed at 5:95/10:90% ratios, respectively, incubated for 24 h with/without apigenin, and for 72 h with GCV and 5-FU. Cell survival was determined by MTT method. The transfected SCG7901/HeLa cells expressed GFP. Fluorescence intensity in SCG7901 cells decreased after photobleaching but recovered over time. Fluorescence intensity in HeLa cells also decreased after photobleaching with no recovery. Following apigenin treatment, fluorescence intensity differed between SCG7901 and HeLa cells. Survival rates of SCG7901 cells differed among prodrug, apigenin, and prodrug + apigenin groups compared with controls, but no significant difference was observed for HeLa cells. We concluded that the intercellular communication in SCG7901 cells related with the gap junctions, while there was no such communication in HeLa cells. The bystander killing effect related with the intercellular gap junctions and was increased by apigenin with no such effect seen in HeLa cells.


Cost of biologics in the treatment of juvenile idiopathic arthritis: a factor not to be overlooked.
Biologics are a promising treatment option for juvenile idiopathic arthritis (JIA) but drug costs are very high compared to conventional treatment. From a socioeconomic view the additional costs of new interventions should be weighed against their incremental health benefits compared to standard care. Therefore we evaluated data on cost-effectiveness of biologics in JIA. We searched Medline, Embase, and The York Centre for Reviews and Dissemination database for relevant literature. Current data show that biologics are reducing direct and indirect healthcare costs if one excludes the costs of the drug itself. The costs of biologics are more than ten times as high as conventional drug treatment. As a result of limited data, no comparison on cost-effectiveness between biologics could be performed. Although data on long-term cost-effectiveness of biologics are lacking, the expectation is that they will be cost-effective in the long-term. The idea behind this is that biologic treatment should be administered to patients that without these drugs would incur high direct and indirect costs due to continuous severe disease resulting in irreversible disabilities. In our opinion the best cost benefit could be gained if these patients receive biologic treatment introduced early in the disease. This is in order to minimize irreversible damage to the joints and minimize need for long-term biologic therapy by early suppression of the disease. To support these hypotheses future research is needed on long-term cost-effectiveness of all biologics used in JIA.


ATP-dependent activation of atrial muscarinic K+ channels in the absence of agonist and G-nucleotides.
While opening of cardiac muscarinic K+ channels is mediated by a guanine nucleotide-binding protein, GK, and normally requires both ACh and cytosolic GTP, we demonstrate that in the absence of agonist and G-nucleotides guinea-pig atrial muscarinic K+ channels are activated by cytosolic ATP (K50 = 224 microM). This activation involves a phosphorylating reaction and is most probably related to a transphosphorylation by a nucleoside diphosphate kinase (NDPK) from ATP to GK-bound GDP. This ATP-induced response is completely inhibited by nanomolar concentrations of GDP or GTP, suggesting a G-nucleotide specific binding site on NDPK.


Correlation of Dickkopf-1 with Inflammation in Crohn Disease.
To explore the potential roles of Dickkopf-1 (DKK-1) and b-catenin in Crohn disease, and to evaluate the effects of a tumor necrosis factor (TNF)-a inhibitor on Wnt signaling in patients with the disease. We enrolled 21 patients who received infliximab treatment for one year and achieved clinical remission during the treatment period. Disease activity was graded according to the Pediatric Crohn's Disease Activity Index (PCDAI). Peripheral blood and colonic mucosal specimens were collected from all patients with Crohn disease and from 14 healthy controls. DKK-1 levels in serum were detected by enzyme-linked immunosorbent assay (ELISA). Total RNA for DKK-1 and b-catenin from the frozen colonic tissue were obtained via real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), and albumin were also measured in patients with Crohn disease before and after infliximab therapy. The serum levels of DKK-1 were significantly higher in patients with Crohn disease than in healthy controls (P=0.003) and were decreased in those treated with infliximab (P=0.026). Serum DKK-1 level was correlated with levels of ESR (r=0.527, P=0.025), CRP (r=0.502, P=0.034), albumin (r=0.363, P=0.021) and PCDAI (r =0.462, P=0.054) in Crohn disease. DKK-1 mRNA expression in the colonic mucosa was higher in patients than in controls and decreased after infliximab treatment. b-catenin expression in the colonic mucosa was lower in patients than in controls and increased after infliximab treatment. However, the differences were not significant (P<0.05). DKK-1 might be an important mediator of the pathogenesis of Crohn disease, and changes in DKK-1 levels may serve as biomarkers of inflammation in these patients.


Nano-magnetic particles used in biomedicine: core and coating materials.
Magnetic nanoparticles for medical applications have been developed by many researchers. Separation, immunoassay, drug delivery, magnetic resonance imaging and hyperthermia are enhanced by the use of suitable magnetic nanoparticles and coating materials in the form of ferrofluids. Due to their low biocompatibility and low dispersion in water solutions, nanoparticles that are used for biomedical applications require surface treatment. Various kinds of coating materials including organic materials (polymers), inorganic metals (gold, platinum) or metal oxides (aluminum oxide, cobalt oxide) have been attracted during the last few years. Based on the recent advances and the importance of nanomedicine in human life, this paper attempts to give a brief summary on the different ferrite nano-magnetic particles and coatings used in nanomedicine.


Immunologic tests in rheumatology.
Reading this article will familiarize the reader with the application and interpretation of different autoantibody tests used in rheumatology. Recent rheumatologic textbooks, relevant review articles, and seminal articles in English regarding specific tests. An understanding of this review should enable the reader to approach diagnostic testing systematically in a patient with a suspected connective tissue disease. The proper use and interpretation of appropriate immunologic tests are important in the diagnosis and treatment of patients with connective tissue diseases.


TNF-alpha -308G>A polymorphism is associated with suicide attempts in major depressive disorder.
Despite the substantial role of the cytokine network in depression and suicide, few studies have investigated the role of genetic polymorphisms of pro- and anti-inflammatory cytokines in suicide in major depressive disorder (MDD). The aim of this study was to investigate whether tumor necrosis factor-alpha (TNF-alpha) -308G>A, interferon-gamma (IFN-gamma) +874A>T, and interleukin-10 (IL-10) -1082A>G are associated with increased risk for suicide attempts in MDD. Among patients with MDD, 204 patients who had attempted suicide and 97 control patients who had not attempted suicide were recruited. A chi-square test was used to identify a possible risk genotype or allele type for suicide. A subsequent multivariate logistic regression analysis was conducted to investigate the influence of a risk genotype or allele type adjusted for other environmental factors. The lethality of the suicide attempt was also tested between genotype and allele types among suicidal patients with MDD. The GG genotype of the TNF-alpha -308G>A polymorphism was found to significantly increase risk for suicide attempt (adjusted OR=2.630, 95% CI=1.206 to 5.734). IFN-gamma +874A>T and IL-10 -1082A>G were not associated with risk for suicide. Lethality of the suicide attempt was not associated with any of the three cytokine genotypes or allele types. Limitations include a relatively small sample size and a cross-sectional design. TNF-alpha -308G>A polymorphism is an independent risk factor for suicide attempts in MDD. Future studies should clarify the neural mechanisms by which the GG genotype of TNF-alpha -308G>A influences suicide in MDD.


Physicochemical and thermal characterization of babassu oils (Orbignya phalerata Mart.) obtained by different extraction methods.
Babassu oil is a raw material widely used in the pharmaceutical and biofuels industry. However, its physical-chemical and thermal characteristics are not widely described in the literature. This article describes these characteristics and, thus, seeks to increase the application of this raw material in the food industry. In this work, two different types of babassu oils, extra-virgin and virgin, were studied. The physicochemical characteristics, lipid profile, composition of the triacylglycerol and thermal properties of both oils were determined. Moreover, the crystallization and melting behavior was determined and the FTIR-ATR spectra of the oils acquired. The results show that the main fatty acids present are medium-chain and the type of extraction modifies the amounts of fatty acids present in each type of oil. Despite this, its physical-chemical characteristics and thermal properties are the same, except color and thermal stability, where extra-virgin oil is lighter and more stable than virgin babassu oil.


A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections.
Red blood cells can withstand the harsh mechanical conditions in the vasculature only because the bending rigidity of their plasma membrane is complemented by the shear elasticity of the underlying spectrin-actin network. During an infection by the malaria parasite Plasmodium falciparum, the parasite mines host actin from the junctional complexes and establishes a system of adhesive knobs, whose main structural component is the knob-associated histidine rich protein (KAHRP) secreted by the parasite. Here we aim at a mechanistic understanding of this dramatic transformation process. We have developed a particle-based computational model for the cytoskeleton of red blood cells and simulated it with Brownian dynamics to predict the mechanical changes resulting from actin mining and KAHRP-clustering. Our simulations include the three-dimensional conformations of the semi-flexible spectrin chains, the capping of the actin protofilaments and several established binding sites for KAHRP. For the healthy red blood cell, we find that incorporation of actin protofilaments leads to two regimes in the shear response. Actin mining decreases the shear modulus, but knob formation increases it. We show that dynamical changes in KAHRP binding affinities can explain the experimentally observed relocalization of KAHRP from ankyrin to actin complexes and demonstrate good qualitative agreement with experiments by measuring pair cross-correlations both in the computer simulations and in super-resolution imaging experiments.


Can we develop a neurobiological model of human social-emotional development? Integrative thoughts on the effects of separation on parent-child interactions.
After summarizing the main points raised in articles by Kaslow et al. and Plotsk, a number of questions that derive from these authors' work are listed. Additional questions are then posed, the answers to which will likely facilitate one's ability to translate animal models of child psychopathology into human terms. After summarizing the various advantages and disadvantages to models using mice, rats, and monkeys, several examples of recent research that have attempted to meld animal models with human studies are described.


Penile implant infections: prevention and treatment.
Penile implants remain a mainstay in treating erectile dysfunction (ED). Despite competing therapies, the number of devices implanted has increased each year. Implant infection continues to be a problem, but recent advances in antibiotic-coated devices and copious use of antiseptic irrigation have reduced the incidence. When confronted with an implant infection, a salvage procedure has gained acceptance that involves immediate replacement of the infected implant after antiseptic washing of the implant cavities. This procedure minimizes shortening of the implant erection and facilitates placement of cylinders in corporal bodies. Among patients and health care providers, satisfaction with penile implant remains the highest for all ED treatments.


Ventilation monitoring during moderate sedation in GI patients.
Sedation in locations outside the operating room (OR) is common. Guidelines for safe patient monitoring have been updated by the American Society of Anesthesiology to include monitoring of ventilation and/or carbon dioxide (CO2). Although technologies exist to monitor these variables, the quality and/or availability of these measurements in non-OR settings is not optimal. This quality improvement project assessed the value of impedance technology for monitoring minute ventilation (MV) compared to standard end-tidal monitoring of CO2 (ETCO2). Patients undergoing GI exams with moderate sedation provided by anesthesia providers were monitored for MV with a respiratory volume monitor (ExSpiron 1Xi, Respiratory Motion, Waltham, MA) and ETCO2 via nasal cannula (NC). Calibration and baseline data were collected prior to sedation. Continuous MV and ETCO2 data were collected and averaged, providing minute values after sedation medications throughout the procedure. Stable periods of reduced MV were averaged and used in comparison to ETCO2. Data from 20 patients were evaluated. After sedation, the expected decrease in MV after sedation was observed in 18 of 20 patients (average -47.82 %), while an increase in ETCO2 was observed in just 10 of 20 patients (average -5.17 mm Hg). The correlation coefficient between changes in MV and ETCO2 in response to sedation administration was positive and not significant, r = 0.223. Ventilation monitoring may provide an element of safety for earlier and more reliable detection of reduced ventilation compared to a surrogate for hypoventilation, ETCO2, in patients undergoing sedation for GI procedures outside of the OR.


Silybin inhibits NLRP3 inflammasome assembly through the NAD+/SIRT2 pathway in mice with nonalcoholic fatty liver disease.
Silybin is one of the effective, traditional Chinese medicines used as a hepatoprotective agent in nonalcoholic fatty liver disease (NAFLD) therapy worldwide, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been recognized as an important factor involved in NAFLD development. However, little is known about the mechanisms of silybin in the regulation of high-fat diet (HFD)-induced liver inflammation. In our study, we found that silybin inhibited endoplasmic reticulum stress and NLRP3 inflammasome activation in the livers of HFD-fed mice and in cultured hepatocytes. Phosphorylation of inositol-requiring enzyme (IRE)1α and eIF2α, expression of thioredoxin-interacting protein and cleaved caspase-1, and release of IL-1β were reduced by silybin. In addition, silybin inhibited the approach of calreticulin and translocase of outer membrane 20 (Tom20), prevented assembly of the NLRP3 inflammasome complex, and suppressed the accumulation of acetylated α-tubulin in the perinuclear region. Both MEC-17 and sirtuin 2 (SIRT2) were influenced by palmitate and silybin, whereas histone deacetylase 6 was not affected. In addition, supplementing NAD+ directly or increasing NAD+ concentration with silybin could maintain the activity of SIRT2. The anti-inflammatory effect of silybin was blocked by SIRT2 silencing or by the SIRT2 inhibitor AGK2, as evidenced by NLRP3/ASC colocalization, AC-α-tubulin expression, and IL-1β release. These findings indicate that the NAD+/SIRT2 pathway is an important mediator through which silybin prevents NLRP3 inflammasome activation during NAFLD.-Zhang, B., Xu, D., She, L., Wang, Z., Yang, N., Sun, R., Zhang, Y., Yan, C., Wei, Q., Aa, J., Liu, B., Wang, G., Xie, Y. Silybin inhibits NLRP3 inflammasome assembly through the NAD+/SIRT2 pathway in mice with nonalcoholic fatty liver disease.


Quantifying Donor Effects on Transplant Outcomes Using Kidney Pairs from Deceased Donors.
In kidney transplantation, the relative contribution of donor versus other factors on clinical outcomes is unknown. We sought to quantify overall donor effects on transplant outcomes for kidney donations from deceased donors. For paired donations from deceased donors resulting in transplants to different recipients, the magnitude of donor effects can be quantified by examining the excess of concordant outcomes within kidney pairs beyond chance concordance. Using data from the Organ Procurement and Transplantation Network between the years 2013 and 2017, we examined concordance measures for delayed graft function, death-censored 1-year graft failure, and death-censored 3-year graft failure. The concordance measures were excess relative risk, excess absolute risk, and the fixation index (where zero is no concordance and one is perfect concordance). We further examined concordance in strata of kidneys with similar values of the Kidney Donor Profile Index, a common metric of organ quality. If the transplant of the kidney mate resulted in delayed graft function, risk for delayed graft function was 19% higher (95% confidence interval [95% CI], 18% to 20%), or 1.76-fold higher (95% CI, 1.73- to 1.80-fold), than baseline. If a kidney graft failed within 1 year, then the kidney mate's risk of failure was 6% higher (95% CI, 4% to 9%), or 2.85-fold higher (95% CI, 2.25- to 3.48-fold), than baseline. For 3-year graft failure, the excess absolute risk was 7% (95% CI, 4% to 10%) but excess relative risk was smaller, 1.91-fold (95% CI, 1.56- to 2.28-fold). Fixation indices were 0.25 for delayed graft function (95% CI, 0.24 to 0.27), 0.07 for 1-year graft failure (95% CI, 0.04 to 0.09), and 0.07 for 3-year graft failure (95% CI, 0.04 to 0.10). Results were similar in strata of kidneys with a similar Kidney Donor Profile Index. Overall results indicated that the donor constitution has small or moderate effect on post-transplant clinical outcomes.


Encapsulation of manganese dioxide nanoparticles into layer-by-layer polymer capsules for the fabrication of antioxidant microreactors.
Oxidative stress is caused by the accumulation of reactive oxygen and nitrogen species (ROS and RNS) in the cellular microenvironment. These ROS and RNS damage important cell structures leading to cell apoptosis and senescence, thus causing a detrimental effect on numerous disease pathologies such as osteoarthritis, neurodegeneration and cardiovascular diseases. For this reason, there is a growing interest in the development of antioxidant biomaterials that can eventually regulate the levels of ROS/RNS and prevent oxidative stress. The encapsulation of antioxidant enzymes (e.g., catalase or superoxide dismutase) on polymer microcapsules fabricated via the layer-by-layer (LbL) approach represents a promising strategy within this context. The diffusion of reagents and by-products through the shell of these microcapsules is timely and spatially controlled, allowing the bio-chemical reaction between ROS/RNS and the encapsulated enzyme. However, natural enzymes usually present low stability, high cost and difficult storage, which could limit their potential application in the biomedical field. Hence, nanomaterials with intrinsic enzyme-like characteristics (i.e., nanozymes) have been considered as inorganic alternatives. In the present work, manganese dioxide nanoparticles were encapsulated into LbL polymer microcapsules to yield synthetic antioxidant microreactors. These microreactors efficiently scavenged hydrogen peroxide (H2O2) from solution and protected cells from oxidative stress in an in vitro model. The versatility of the synthetic procedure presented herein allows the fabrication of capsules with either positive or negative surface charge, which has a direct impact on the cytotoxicity and cell interaction. This study represents accordingly a novel strategy to obtain antioxidant polymer microreactors based on synthetic (nano)materials for the treatment of oxidative stress.


Physician buy-in helps PI team reduce LOS.
Benchmarking database helps win oversceptical physicians. The Initiative is positioned as an education collaborative. An opportunity assessment is conducted to identify clinical area to target.


Prognostic analysis in a Chinese population with T1-2N1 breast cancer: Did patients with 1 or 2, and 3 positive axillary lymph nodes have similar survival outcomes?
There is a paucity of data examining whether 1-3 positive lymph nodes patients have similar survival outcomes. The present studies separately analyse survival outcomes of T1-2N1 breast cancer patients according to the number of positive lymph nodes. A total of 1,030 patients with T1-2N1 breast cancer were available for analysis. Survival estimates were calculated using the Kaplan-Meier method, univariate, and multivariate logistic regression models Kaplan-Meier analysis showed progressively worse survival with the increased number of positive lymph nodes. Log-rank test P values were 0.003 (1 vs. 2 positive LNs), <0.0001 (1 vs. 3), and 0.006 (2 vs. 3) for recurrence-free survival (RFS). Log-rank test P values were 0.045 (1 vs. 2), <0.0001 (1 vs. 3), and 0.018 (2 vs. 3) for metastasis-free survival (MFS). Log-rank test P values were 0.101 (1 vs. 2), <0.0001 (1 vs. 3), and 0.005 (2 vs. 3) for overall survival (OS). Multivariate analysis showed that 3 and 2 positive lymph nodes had worse survival compared with 1 positive axillary lymph nodes. Our study does suggest that T1-2N1 patients showed progressively worse survival outcomes with the increased number of positive lymph nodes.


Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer.
BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells. Ovarian cancer cell lines (UWB1.289, UWB1.289.BRCA, SKOV3, OVCAR5, A2780 and C200) were treated with a combination of metformin and olaparib. Cell viability was assessed by MTT and colony formation assays. Flow cytometry was used to detect cell cycle events. In vivo studies were performed in SKOV3 or A2780 xenografts in nude mice. Animals were treated with single agent, metformin or olaparib or combination. Molecular downstream effects were examined by immunohistochemistry. Compared to single drug treatment, combination of olaparib and metformin resulted in significant reduction of cell proliferation and colony formation (p<0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p<0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p<0.001). Metformin did not affect DNA damage signaling, while olaparib induced adenosine monophosphate activated kinase activation; that was further potentiated with metformin combination in vivo. Combining PARP inhibitors with metformin enhances its anti-proliferative activity in BRCA mutant ovarian cancer cells. Furthermore, the combination showed significant activity in BRCA intact cancer cells in vitro and in vivo. This is a promising treatment regimen for women with epithelial ovarian cancer irrespective of BRCA status.


Targeting the androgen receptor signaling pathway in advanced prostate cancer.
This article summarizes current androgen receptor (AR)-directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC). PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone-releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR gene overexpression, and mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism, possess a higher affinity for AR, and are postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects. Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.


Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects and patients with chemical diabetes.
Plasma insulin responses and insulin resistance were determined in 75 subjects, defined as having a normal, borderline abnormal, or abnormal oral glucose tolerance test (OGTT). Although considerable heterogeneity of insulin response existed, most patients with abnormal OGTT's had insulin responses greater than normal; none had insulin responses less than normal. The degree of insulin resistance also varied, but most patients with abnormal OGTT's were also abnormally insulin resistant A significant correlation (r=0.64, p+/-0.001) existed between insulin response and the degree of insulin resistance. However, when both variables were taken into consideration, the entire population could be divided into two groups. One group was characterized by both normal insulin responsiveness and sensitivity, the other by increased insulin response, associated with greater insulin resistance. Most patients with abnormal OGTT's fell into the latter group, but some had glucose intolerance without either an exaggerated insulin response or insulin resistance. These results suggest that true heterogeneity exists in patients with abnormal OGTT's.


Disulfide bond shuffling in bovine alpha-lactalbumin: MD simulation confirms experiment.
A simple and straightforward classical molecular dynamics simulation technique is proposed to predict possible disulfide bridge shuffling. Application to bovine alpha-lactalbumin shows that shuffling can be observed on short simulation time scales and yields results in agreement with experiment.


Axonal degeneration induced by intraneural injection of Campylobacter jejuni antiserum containing high titer anti-GM1 antibody.
Ganglioside-like structures in CAMPYLOBACTER JEJUNI ( C. JEJUNI) lipooligosaccharide (LOS) can induce antiganglioside antibodies, which might cause nerve damage. In this study, we injected the following three antisera directly into the sciatic nerve of guinea pigs, to investigate the role of anti-glycolipids antibody in inducing neural injury: (i) the wild strain antiserum, a mixture of the sera obtained from the guinea pigs immunized with C. JEJUNI wild-type strain (HS:19) that had a high titer anti-GM1 IgG antibody (range: 800-6,400; median: 2,400) and a high titer anti-LOS IgG antibody; (ii) the GALE mutant antiserum, a mixture of the sera obtained from the guinea pigs immunized with the GALE mutant strain that had only a high titer anti-LOS IgG antibody but no anti-GM1 antibody; and (iii) the control antiserum, a mixture of the sera obtained from the guinea pigs immunized with Freund's complete adjuvant alone which had no anti-GM1 or anti-LOS IgG antibody. Pathological examinations showed that the wild strain C. JEJUNI antiserum produced axonal degeneration in sciatic nerves. Demyelination was rare, and no inflammatory cells were present. The pathological features are consistent with those seen in human patients with axonal GBS. No such changes were observed in nerves injected with the GALE mutant antiserum. The experiment showed that passive transfer of serum containing high titer GM1 antibody caused axonal degeneration of peripheral nerves. The result, which reproduced our previous findings in an active immunization study, therefore further confirmed the critical role of the anti-glycolipid antibody in the induction of neuropathy.


A universal snap-fit endoprosthesis for the treatment of subcapital fractures of the femur: a preliminary report.
A new endoprosthesis for the treatment of subcapital fractures is described. It is hemispherical with a high density polyethylene (HDP) core which is snap-fitted onto a Charnley-type femoral prosthesis. The aim is to prevent acetabular erosion by its virtual lack of movement of the cartilage-metal interface. If this should occur then conversion to a total hip is readily performed without removing the femoral stem. So far 14 have been inserted without any complications. In fact, they are easily mobilized with very little pain.


Severe pulmonary toxicity in a patient treated with gemcitabine.
Gemcitabine is a pyrimidine analog of deoxycytidine with activity against nonhematologic and hematologic malignancies. Its pulmonary toxicity is usually mild and self-limiting. We describe a male patient with lung cancer in whom severe dyspnea and interstitial infiltrates developed after the administration of gemcitabine.


Transient protein-losing gastropathy (Menetrier's disease) in childhood.
Two cases of transient protein-losing gastropathy (PLG) or Menetrier's disease in childhood are described. Both cases presented with an abrupt onset of edema due to hypoalbuminemia and were diagnosed by an upper gastrointestinal series. One of the cases was further diagnosed and followed by ultrasound. We believe that this is the first description of the ultrasonic picture of transient PLG in children. In both cases complete recovery was evident after a few weeks.


Computational and experimental approaches for investigating nanoparticle-based drug delivery systems.
Most therapeutic agents suffer from poor solubility, rapid clearance from the blood stream, a lack of targeting, and often poor translocation ability across cell membranes. Drug/gene delivery systems (DDSs) are capable of overcoming some of these barriers to enhance delivery of drugs to their right place of action, e.g. inside cancer cells. In this review, we focus on nanoparticles as DDSs. Complementary experimental and computational studies have enhanced our understanding of the mechanism of action of nanocarriers and their underlying interactions with drugs, biomembranes and other biological molecules. We review key biophysical aspects of DDSs and discuss how computer modeling can assist in rational design of DDSs with improved and optimized properties. We summarize commonly used experimental techniques for the study of DDSs. Then we review computational studies for several major categories of nanocarriers, including dendrimers and dendrons, polymer-, peptide-, nucleic acid-, lipid-, and carbon-based DDSs, and gold nanoparticles. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.


Metal ion-binding studies highlight important differences between flaviviral RNA polymerases.
West Nile virus (WNV) is a member of the Flaviviridae family which includes a number of important human pathogens. The WNV NS5 protein harbors an RNA-dependent RNA polymerase activity which is required both for replication and transcription of the viral genome. To extend our studies on the role of metal ions in the activity of flaviviral polymerases, we have used fluorescence spectroscopy, circular dichroism, and a combination of chemical and thermal denaturation assays to monitor the consequences of metal ion binding to the enzyme. We demonstrate that the binding of magnesium is not critical for the structural stabilization of the enzyme. Moreover, structural studies indicate that the protein does not undergo conformational change upon the binding of magnesium ions. Additional binding assays also indicate that the interaction of magnesium ions with the enzyme does not significantly stimulate the interaction with the RNA or NTP substrates. The inability of cobalt hexamine, an exchange-inert metal complex structurally analogous to magnesium hexahydrate, to support the catalytic activity also allowed us to demonstrate a direct role of magnesium ions in the catalytic activity of the enzyme. Finally, a three-dimensional structural model of the active center of the enzyme was generated which highlighted the importance of two aspartate residues involved in the coordination of two metal ions. Mutational analyses confirmed the importance of these two amino acids for the binding of magnesium ions. Our data provide further insight into the precise role of magnesium ions for the RNA polymerase activity of the protein, and more importantly, highlight key differences between the RNA polymerases of the Flaviviridae family.


Atrophic effects of proximal tendon transection with and without denervation on mouse soleus muscles.
The response of mouse soleus muscles to transection of the proximal tendon was examined at both gross and microscopic levels. Changes in length and mass of the muscle, and in the dimensions, number, and ATPase staining characteristics of the muscle fibers, were determined at various times to 4 to 6 weeks after tenotomy. Muscles shortened by more than 50% and lost about 60% of their mass. Fiber cross-sectional area increased, and then decreased and stabilized below control after 7 days, and degenerative lesions appeared in some fibers. Fiber numbers decreased by nearly 20% and then remained constant, apparently by regeneration of new fibers replacing atrophied ones. The proportion of muscle fibers of the slow-twitch type was reduced. No structural or functional changes in motor nerve terminals could be detected, except for detachment from severely atrophied fibers. Concurrent denervation decreased both shortening and the loss of mass after tenotomy. Fiber diameter decreased but no significant degenerative lesions or loss of fibers could be detected. Fiber-type composition was unchanged. These experiments provide quantitative information about the degenerative changes in tenotomized muscles without the variable complications arising from tendon reattachment. Comparison of the responses with those that follow transection of the Achilles tendon shows that the degree of atrophy is independent of the extent of active muscle shortening after tenotomy.


Performance of Early Warning Scoring Systems Regarding Adverse Events of Unanticipated Clinical Deterioration in Complementary and Alternative Medicine Hospitals.
This study aims to examine the performance of early warning scoring systems regarding adverse events of unanticipated clinical deterioration in complementary and alternative medicine hospitals. A medical record review of 500 patients from 5-year patient data in two traditional Korean medicine hospitals was conducted. Unanticipated clinical deterioration events included unexpected in-hospital mortality, cardiac arrest, and unplanned transfers to acute-care conventional medicine hospitals. Scores of the Modified Early Warning Score (MEWS), National Early Warning Score (NEWS), and National Early Warning Score 2 (NEWS2) were calculated. Their performance was evaluated by calculating areas under the receiver-operating characteristic curve for the event occurrence. Multiple logistic regression analyses were performed to determine the factors associated with event occurrence. The incidence of unanticipated clinical deterioration events was 1.1% (225/21101). The area under the curve of MEWS, NEWS, and NEWS2 was .68, .72, and .72 at 24 hours before the events, respectively. NEWS and NEWS2, with almost the same performance, were superior to MEWS (p = .009). After adjusting for other variables, patients at low-medium risk (OR = 3.28; 95% CI = 1.02-10.55) and those at medium and high risk (OR = 25.03; 95% CI = 2.78-225.46) on NEWS2 scores were more likely to experience unanticipated clinical deterioration than those at low risk. Other factors associated with the event occurrence included frailty risk scores, clinical worry scores, primary medical diagnosis, prescribed medicine administration, acupuncture treatment, and clinical department. The three early warning scores demonstrated moderate-to-fair performance for clinical deterioration events. NEWS2 can be used for early identification of patients at high risk of deterioration in complementary and alternative medicine hospitals. Additionally, patient, care, and system factors need to be considered to improve patient safety.