Catechin is a phytototoxin and a pro-oxidant secreted from the roots of Centaurea stoebe.
When applied to the roots of Arabidopsis thaliana, the phytotoxin (±)-catechin triggers a wave of reactive oxygen species (ROS), leading to a cascade of genome-wide changes in gene expression and, ultimately, death of the root system. Biochemical links describing the root secreted phytotoxin, (±)-catechin, represent one of most well studied systems to describe biochemically based negative plant-plant interactions, but of late have also sparked controversies on phytotoxicity and pro-oxidant behavior of (±)-catechin. The studies originating from two labs ( 1- 3) maintained that (±)-catechin is not at all phytotoxic but has strong antioxidant activity. The step-wise experiments performed and the highly correlative results reported in the present study clearly indicate that (±)-catechin indeed is phytotoxic against A. thaliana and Festuca idahoensis. Our results show that catechin dissolved in both organic and aqueous phase inflict phytotoxic activity against both A. thaliana and F. idahoensis. We show that the deviation in results highlighted by the two labs ( 1- 3) could be due to different media conditions and a group effect in catechin treated seedlings. We also determined the presence of catechin in the growth medium of C. stoebe to support the previous studies. One of the largest functional categories observed for catechin-responsive genes corresponded to gene families known to participate in cell death and oxidative stress. Our results showed that (±)-catechin treatment to A. thaliana plants resulted in activation of signature cell death genes such as accelerated cell death (acd2) and constitutively activated cell death 1 (cad1). Further, we confirmed our earlier observation of (±)-catechin induced ROS mediated phytotoxicity in A. thaliana. We also provide evidence that (±)-catechin induced ROS could be aggravated in the presence of divalent transition metals. These observations have significant impact on our understanding regarding catechin phytotoxicity and pro-oxidant activity. Our data also illustrates that precise conditions are needed to evaluate the effect of catechin phytotoxicity.


Liver transplantation for primary sclerosing cholangitis: a long-term clinicopathologic study.
The course and outcome of patients after liver transplantation (LT) for primary sclerosing cholangitis (PSC) are still debated. Our purpose is to define retrospectively, the post-LT clinicopathologic findings seen in 51 PSC patients with a follow-up of 2 to 14 years. Of the total 51 patients, 16 with native liver hilar xanthogranulomatous cholangiopathy (XGC) had median graft and patient survival of 573 and 835 days, respectively compared with 2489 and 2794 days, respectively, in 35 patients without XGC. Perioperative complications resulted in 9 early deaths (day 0 to 52). Of the remaining 42 patients, 6 had recurrent PSC (R-PSC) with typical histologic and cholangiographic findings, 12 had autoimmune liver disease-not otherwise specified with histology of autoimmune hepatitis/overlap syndrome, 3 had chronic rejection, 4 had ischemic cholangiopathy, and 17 had no recurrence. The presence of inflammatory bowel disease, total ischemia time of > or =11 hours, recipient-donor ABO and HLA Class I and II matches, and the type of immunosuppression did not affect the post-LT outcome. Recipient-donor gender mismatch was more common in R-PSC than in the nonrecurrent group (P=0.045). Post-LT malignancies were significantly more common in the nonrecurrent cases compared with all others combined (P=0.031) and caused deaths in 4. The majority of deaths (11/13) in other groups were due to sepsis complicating graft dysfunction. In conclusion, allograft autoimmune liver disease was seen in 18 (43%) of 42 long-term post-LT PSC patients, with progression in 5 of 18 patients. Features of PSC were seen in 6 (33%) of 18. Native liver XGC negatively impacted post-LT graft and patient survival. Increased incidence of malignancies in the nonrecurrent group may reflect overimmunosuppression in those patients.


Clinical Drug Development in Epilepsy Revisited: A Proposal for a New Paradigm Streamlined Using Extrapolation.
Data from clinical trials in adults, extrapolated to predict benefits in paediatric patients, could result in fewer or smaller trials being required to obtain a new drug licence for paediatrics. This article outlines the place of such extrapolation in the development of drugs for use in paediatric epilepsies. Based on consensus expert opinion, a proposal is presented for a new paradigm for the clinical development of drugs for focal epilepsies. Phase I data should continue to be collected in adults, and phase II and III trials should simultaneously recruit adults and paediatric patients aged above 2 years. Drugs would be provisionally licensed for children subject to phase IV collection of neurodevelopmental safety data in this age group. A single programme of trials would suffice to license the drug for use as either adjunctive therapy or monotherapy. Patients, clinicians and sponsors would all benefit from this new structure through cost reduction and earlier access to novel treatments. Further work is needed to elicit the views of patients, their parents and guardians as appropriate, regulatory authorities and bodies such as the National Institute for Health and Care Excellence (UK).


Quantification and classification of the main environmental impacts on a Halodule wrightii seagrass meadow on a tropical island in northeastern Brazil.
Multiple stress mechanisms have caused a worldwide decrease in seagrasses, which are vulnerable to environmental and/or anthropogenic pressure. The loss of seagrass meadows of Halodule wrightii is reported for the littoral of Itamaracá Island (Northeastern Brazil). The present study identified the main anthropogenic factors that negatively influenced over the abundance and distribution of seagrass meadows between July and September 2007 at the Jaguaribe and Pilar Beaches, Eastern littoral of Itamaracá. Anthropogenic impact included the discharge of untreated sewage through fluvial channels, urban and commercial development along the coast, the anchoring of motorized and non-motorized boats, diverse fishing techniques and the dumping of solid waste. The data indicates that the Pilar is an environment with a higher impact index (71.43%) when compared with the Jaguaribe (57.14%), standing out the number of boats with a central motor, the total number of boats, the presence of shellfish gatherers and coastal urban development. The present study reinforces the need for defining management and conservation measures for this ecosystem, which has high ecological and economic value.


Siblings of Military Servicemembers: A Qualitative Exploration of Individual and Family Systems Reactions.
How does having a sibling in the military affect young adults? Despite increasing attention to the challenges faced by spouses and children of servicemembers, the siblings of servicemembers have been largely ignored. This qualitative investigation uses unstructured narratives to explore siblings' perceptions of changes in their lives and changes in the family of origin associated with having a family member enlist in the United States military. Thematic analyses revealed an acute period of conflict followed by reorganization, awareness of the parents' distress, changes in the emotional climate of the family, shifts in family roles, admiration for the military sibling, and increased meaning and purpose for the family following the servicemember's enlistment. Computer-assisted text analyses revealed both positive and negative emotional content associated with the siblings' military service. For professional psychologists who come into contact with siblings of servicemembers, it is important to recognize that military enlistment can have ripple effects and complicate other common individual and family stresses. More generally, it is important to provide siblings and the family of origin with information about what to expect during and after the servicemember's enlistment, especially since these families may lack support and contact from others going through similar transitions.


Psycho-social achievement in the latency-aged child with spina bifida within the family structure.
This project aims: 1) to appraise the psycho-social development of a sample of latency-aged spina bifida children upon entry to school; 2) to learn about the social influences that promote or impede the child's development, and 3) to identify ways that psycho-social intervention can be useful to families in which there is a congenitally disabled child. A longitudinal, observational case study was conducted over a six month period. This approach provided information on the impact of social influences, disability, and trauma on the child's development. The results indicate that a delay in reaching the important physical milestones of independent locomotion and continence hinders the achievement of standard psycho-social developmental goals; it does not exclude their achievement. By the sixth month in first grade, all of the children had adapted satisfactorily to school. Thus, the difference between the able-bodied and the spina bifida child was not one of kind, but one of degree. Spina bifida was found to put no ceiling on the child's psycho-social development.


Assessing infant and maternal readiness for newborn discharge.
The review highlights the shift from prescribed length of stay (LOS) to mother-infant dyad readiness as the basis for making discharge decisions for healthy term newborns. We describe the components of readiness that should be considered in making the decision, focusing on infant clinical readiness, and maternal and familial readiness. Although the Newborns' and Mothers' Health Protection Act of 1996 aimed to protect infants and mothers by establishing a minimum LOS, the American Academy of Pediatrics 2015 policy on newborn discharge acknowledges the shift from LOS-based to readiness-based discharge decision-making. Healthcare providers must consider a variety of infant and maternal characteristics in determining the appropriate time to discharge a dyad, and mothers should be actively involved in the decision-making process. Criteria for infant clinical readiness include the following: establishment of effective feeding, evaluation of jaundice risk, review and discussion of infant and household vaccination status, obtainment of specimen for metabolic screening, tests of hearing ability, assessment of sepsis risk factors, screening for congenital heart disease, and evaluation of parental knowledge about infant safety measures. Important consideration should also be given to the mother's sociodemographic vulnerabilities, maternal confidence and perception of discharge readiness, and availability of postdischarge care continuity. The timing of newborn discharge should be a joint decision made by the mother and healthcare providers based on readiness. The decision should consider the infant's health status, the mother's health status, the mother's perception of readiness, and the availability of social and familial support for the mother and infant. Accessible and comprehensive support postdischarge is also important for helping infants achieve optimal health outcomes.


Oral vaccination against tetanus: comparison of the immunogenicities of Salmonella strains expressing fragment C from the nirB and htrA promoters.
We have found the in vivo-regulated nirB promoter (PnirB) to be effective for directing expression of a number of antigens in salmonella in vivo. We wished to determine if other in vivo-regulated promoters have utility for antigen expression in salmonella and to compare the effectiveness of these promoters with that of PnirB. To this end, we have devised a scheme that allows the promoter element of the PnirB-fragment C plasmid pTETnir15 to be swapped with other promoters of interest. We demonstrate the usefulness of this system by replacing PnirB with PhtrA to create plasmid pTEThtrA1. htrA is a stress response gene that is required for virulence of salmonella in mice and survival within macrophages. Expression of fragment C in Salmonella typhimurium BRD509 (aroA aroD) harboring pTEThtrA1 (strain BRD937) correlated with growth temperature in vitro. A comparison was made of the immune responses to fragment C elicited in mice immunized orally with BRD937 or BRD847 (BRD509/pTETnir15) or subcutaneously with purified fragment C plus alhydrogel. High levels of anti-fragment C antibodies that persisted for at least 12 weeks were present in all groups of mice. Vaccination with BRD937 was the most effective means of immunization: the serum immunoglobulin G (IgG), IgA, and IgM anti-fragment C titers were higher in the BRD937-immunized mice throughout the duration of the study than in mice in the other groups. The kinetics of the serum anti-fragment C responses were different in different groups. The response was most rapid in the BRD937 group, with the titers almost at peak levels at 2 weeks postimmunization. Only the mice immunized with BRD937 or BRD847 developed an intestinal IgA response to fragment C. Again, the response was superior in the BRD937 group. The peak of the intestinal response was delayed with respect to the serum response. Analysis of the IgG subtype response to fragment C revealed a dominant IgG2a response in the salmonella-immunized mice, indicating a type 1 helper T-cell response to fragment C, whereas the major subtype in the group parenterally immunized with fragment C plus alhydrogel was IgG1. The IgG1/IgG2a ratio was much higher in sera of BRD937-immunized mice than in sera of BRD847-immunized mice. At 15 to 20 weeks after immunization, the mice immunized with BRD937 or BRD847 were solidly immune to tetanus toxin and salmonella. The immune responses to fragment C seen in mice immunized with BRD937 are the strongest we have observed and indicate that the htrA promoter may be very useful for expressing foreign antigens in salmonella vaccine strains.


Postoperative irradiation in endometrial cancer: still a matter of controversy.
Although endometrial cancer is the most common female malignancy, evidence-based uniform guidelines for postoperative therapy have not been established. The most logical management is adjuvant irradiation tailored to the extent of surgery, the tumour grade, depth of myometrial invasion, degree of lymph node involvement and age of the patient. Currently, the only widely accepted treatment recommendations are no further therapy in low-risk patients who underwent extensive surgical staging, and external beam radiotherapy (EBRT) in high-risk patients. Most authors recommend postoperative application of only one radiotherapy modality: either brachytherapy (BRT) or EBRT, as their routine combination does not clearly improve the outcome but does increase the risk of late complications. A combination of BRT and EBRT should however be considered in patients with stage II disease, for infiltration of the lower uterine segment, vaginal involvement, positive or close surgical margins, capillary space involvement or unfavourable histology. Two recent randomized studies including mostly intermediate-risk patients managed with either extensive surgical staging or total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH&BSO) with or without postoperative EBRT, showed better local control but no survival benefit from adjuvant irradiation. Two ongoing Gynecologic Oncology Group (GOG) studies compare adjuvant chemotherapy with pelvic or abdominal irradiation in patients with high risk of local relapse. The role of adjuvant radiotherapy (EBRT with or without BRT) in high-risk patients as well as the value of lymphadenectomy in patients fit for such surgery is being addressed in a trial co-ordinated by the Medical Research Council. Future studies are warranted to define whether any irradiation should be employed in intermediate-risk patients and which radiotherapy modality should be used in high-risk node-negative patients with stage I tumours (stage Ib grade 3 and all stage Ic). Other issues which should be addressed in future studies include the extent of surgery, the role of systemic therapies, the relevance of novel biologic prognostic factors, salvage therapies after recurrence, cost-benefit analysis and quality of life.


Long-term Efficacy of Methotrexate Plus Vinblastine/Vinorelbine in a Large Series of Patients Affected by Desmoid-Type Fibromatosis.
Today, surgery and radiation therapy have a limited role in desmoid-type fibromatosis. Different systemic treatments were shown to be effective. Herein, we report on our institutional experience with low-dose methotrexate (MTX) + vinca alkaloids in this disease over the last 25 years. We retrospectively reviewed data from all adult patients with sporadic desmoid-type fibromatosis treated with MTX and vinca alkaloids at our institution between 1989 and 2014. We identified 75 patients treated with MTX + vinblastine (40%), MTX + vinorelbine (57%), and vinorelbine alone (3%). All patients had progressive disease before chemotherapy; 72%, 10%, and 48% of patients had received previous surgery, radiation therapy, and/or systemic treatments, respectively. Chemotherapy was administered for a median duration of 14 months and a median number of 37.5 cycles. Eight patients interrupted chemotherapy because of toxicity. According to RECIST (Response Evaluation Criteria in Solid Tumors) complete response, partial response, stable disease, and progressive disease were observed in 1%, 47%, 51%, and 1% of patients, respectively. Symptomatic relief was obtained in 80% of symptomatic cases. The median progression-free survival (PFS) was 75 months; it was 136 months in responding patients. Upon progression, after chemotherapy withdrawal, MTX plus vinblastine/vinorelbine was offered to 11 patients with partial response, stable disease, and progressive disease in 4, 6, and 1 cases, resulting in a median PFS of 53 months. In this series, chemotherapy with MTX and vinca alkaloids is confirmed to be active and effective, with a remarkable PFS, higher in responding patients, and limited toxicity. Even progression can be successfully rechallenged.


Antibiotic therapy with metronidazole reduces endometriosis disease progression in mice: a potential role for gut microbiota.
Does altering gut microbiota with antibiotic treatment have any impact on endometriosis progression? Antibiotic therapy reduces endometriosis progression in mice, possibly by reducing specific gut bacteria. Endometriosis, a chronic condition causing abdominal pain and infertility, afflicts up to 10% of women between the ages of 25 and 40, ~5 million women in the USA. Current treatment strategies, including hormone therapy and surgery, have significant side effects and do not prevent recurrences. We have little understanding of why some women develop endometriosis and others do not. Mice were treated with broad-spectrum antibiotics or metronidazole, subjected to surgically-induced endometriosis and assayed after 21 days. The volumes and weights of endometriotic lesions and histological signatures were analysed. Proliferation and inflammation in lesions were assessed by counting cells that were positive for the proliferation marker Ki-67 and the macrophage marker Iba1, respectively. Differences in faecal bacterial composition were assessed in mice with and without endometriosis, and faecal microbiota transfer studies were performed. In mice treated with broad-spectrum antibiotics (vancomycin, neomycin, metronidazole and ampicillin), endometriotic lesions were significantly smaller (~ 5-fold; P < 0.01) with fewer proliferating cells (P < 0.001) than those in mice treated with vehicle. Additionally, inflammatory responses, as measured by the macrophage marker Iba1 in lesions and IL-1β, TNF-α, IL-6 and TGF-β1 in peritoneal fluid, were significantly reduced in mice treated with broad-spectrum antibiotics (P < 0.05). In mice treated with metronidazole only, but not in those treated with neomycin, ectopic lesions were significantly (P < 0.001) smaller in volume than those from vehicle-treated mice. Finally, oral gavage of faeces from mice with endometriosis restored the endometriotic lesion growth and inflammation (P < 0.05 and P < 0.01, respectively) in metronidazole-treated mice. N/A. These findings are from a mouse model of surgically-induced endometriosis. Further studies are needed to determine the mechanism by which gut bacteria promote inflammation, identify bacterial genera or species that promote disease progression and assess the translatability of these findings to humans. Our findings suggest that gut bacteria promote endometriosis progression in mice. This finding if translated to humans, could aid in the development of improved diagnostic tools and personalised treatment strategies. This work was funded, in part, by: a National Institutes of Health (NIH)/ National Institute of Child Health and Human Development (NICHD) grant (R00HD080742) to RK; Washington University School of Medicine start-up funds to RK; an Endometriosis Foundation of America Research Award to R.K.; and an NIH/NICHD grant (R01HD091218) to IUM. The authors report no conflict of interest.


[Frantz-Gruber tumor: a case report].
The objective of this report is to describe the existence of a rare tumor that must be taken into consideration when studying the diagnosis of pancreatic tumors. A 20-year-old female with abdominal pain as an only manifestation was seen. The diagnosis of a pancreatic head and body tumor was made. During surgery, we found a tumor in the head and body of the pancreas that measured approximately 10 x 7 cm; histopathologic study revealed a solid and cystic papillary epithelial neoplasm of the pancreas. Frantz-Gruber tumor is a rare pancreatic tumor suspected during the evaluation of a young female with abdominal pain and confirmed during surgery. It is important to consider the existence of this tumor in the evaluation of patients with these characteristics; even if the tumor's biological behavior is benign Frantz-Gruber tumor is considered a low-grade malignant tumor


Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections.
Palivizumab and Respiratory Syncytial Virus Immune Globulin Intravenous (RSV-IGIV) are licensed by the Food and Drug Administration for use in preventing severe respiratory syncytial virus (RSV) infections in high-risk infants, children younger than 24 months with chronic lung disease (formerly called bronchopulmonary dysplasia), and certain preterm infants. This report summarizes the clinical trial information on which the guidance in the accompanying policy statement for administering RSV prophylaxis to certain children with a history of preterm birth, chronic lung disease, or congenital heart disease is based. On the basis of results of a recently completed clinical trial, palivizumab is appropriate for infants and young children with hemodynamically significant congenital heart disease. RSV-IGIV should not be used in children with hemodynamically significant heart disease. Palivizumab is preferred for most high-risk infants and children because of ease of intramuscular administration. Monthly administration of palivizumab during the RSV season results in a 45% to 55% decrease in the rate of hospitalization attributable to RSV. Because of the large number of infants born after 32 to 35 weeks' gestation and because of the high cost, immunoprophylaxis should be considered for this category of preterm infants only if 2 or more risk factors are present.


Personality and experimentally simulated hearing loss.
Previous studies have suggested that personality factors may affect responses of the normally hearing and those with organic or non-organic hearing losses in audiological assessments. Audiometrically naive (n = 15) and sophisticated (n = 15) subjects who took part in a study of experimentally simulated hearing loss completed the Eysenck Personality Inventory in order that the relationship between personality dimensions and responses on audiometric tests could be investigated for all subjects and for males and females separately. The finding that more anxious males were less able to match pure tone losses with losses for speech suggests that differences in responses of male and female subjects to audiometric tests should be investigated, particularly in view of the preponderance of male subjects in studies of nonorganic hearing loss. A relationship between extraversion and correct speech responses on retest for the sophisticated subjects was thought to reflect abandonment of their strategies in the difficult task of matching hearing loss for speech with that for pure tones. No discernible trends were evident from the remaining analyses.


Is moral hazard good for the environment? Revenue insurance and chemical input use.
Using farm level data we evaluate the input use and environmental effects of revenue insurance. A priori, the moral hazard effect on input use is indeterminate. This paper empirically assesses the input use impact of the increasingly popular, and federally subsidized, risk management instrument of revenue insurance and the extent to which its effects on input use may differ from those of the older yield based instruments. We conclude that among winter wheat farmers, those who purchase revenue insurance tend to spend less on fertilizers but do not appreciably alter pesticide expenditures. Thus, any improved environmental outcomes due to crop insurance are likely due to reduced fertilizer not pesticide use. When the environmental indicators included indicated a potential environmental fragility (i.e. high erosion, pesticide leaching or pesticide runoff potential), the input use equation suggested that fertilizer expenditures decreased. Revenue insurance undoubtedly further reduces fertilizer applications on these fields as well, but the marginal environmental benefit of revenue insurance is lessened because the reduction, where it matters most, accrues on land on which fertilizer use has already been curtailed to some degree.


Oxygen-induced changes in the redox state of the cytochrome b559 in photosystem II depend on the integrity of the Mn cluster.
The effect of oxygen and anaerobiosis on the redox properties of Cyt b(559) was investigated in PSII preparations from spinach with different degree of disintegration of the donor side. Comparative studies were performed on intact PSII membranes and PSII membranes that were deprived of the 18-kDa peripheral subunit (0.25 NaCl washed), the 18- and 24-kDa peripheral subunits (1 M NaCl washed), the 18-, 24- and 33-kDa peripheral subunits (1.2 M CaCl(2) washed), Cl depleted and after complete depletion of the Mn cluster (Tris washed). In active PSII centers, about 75% of Cyt b(559) was found in the high-potential form and the rest in the intermediate potential form. With decomposition of the donor side, the intermediate potential form started to dominate, reaching more than 90% after Tris treatment. The oxygen-dependent conversion of the intermediate potential form of Cyt b(559) into the low-potential and high-potential forms was only observed after treatments that directly affect the Mn cluster. In PSII membranes, deprived of all three extrinsic subunits (CaCl(2) treatment), 21% of the intermediate potential form was converted into the low-potential form and 14% into the high-potential form by the removal of oxygen. In Tris-washed PSII membranes, completely lacking the Mn cluster, this conversion amounted to 60 and 33%, respectively. In intact PSII membranes, the oxygen-dependent conversion did not occur. The possible physiological role of this oxygen-dependent behavior of the Cyt b(559) redox forms during the assembly/photoactivation cycle of PSII is discussed.


Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts.
Bone morphogenetic proteins (BMPs) induce the differentiation of cells of the osteoblastic lineage and enhance the function of the osteoblast. Growth factors are regulated by binding proteins, but there is no information about binding proteins for BMPs in skeletal cells. Noggin specifically binds BMPs, but its expression by cells of the osteoblastic lineage has not been reported. We tested for the expression of noggin and its induction by BMP-2 in cultures of osteoblast-enriched cells from 22-d-old fetal rat calvariae (Ob cells). BMP-2 caused a time- and dose-dependent increase in noggin mRNA and polypeptide levels, as determined by Northern and Western blot analyses. The effects of BMP-2 on noggin transcripts were dependent on protein, but independent of DNA synthesis. BMP-2 increased the rates of noggin transcription as determined by nuclear run-on assays. BMP-4, BMP-6, and TGF-beta1 increased noggin mRNA in Ob cells, but basic fibroblast growth factor, platelet- derived growth factor BB, and IGF-I did not. Noggin decreased the stimulatory effects of BMPs on DNA and collagen synthesis and alkaline phosphatase activity in Ob cells. In conclusion, BMPs induce noggin transcription in Ob cells, a probable mechanism to limit BMP action in osteoblasts.


Resveratrol antagonizes thyroid hormone-induced expression of checkpoint and proliferative genes in oral cancer cells.
Dysregulation of cell cycle checkpoint control may lead to the independence of growth regulating signals. Checkpoint protein such as the PD-1/PD-L1 immune checkpoint involving tumor cells and host immune defense lymphocytes is a well-studied therapeutic target in oncology. Acting at a cell surface receptor on plasma membrane integrin αvβ3, thyroxine stimulates intracellular accumulation of PD-L1 in cancer cells. Although resveratrol also binds to integrin αvβ3, it reduces PD-L1 expression. In current studies, we investigated the roles of resveratrol and thyroxine in regulating expression of proliferation-related genes and checkpoint genes, PD-L1, BTLA in two oral cancer cell lines. Thyroxine suppressed the expression of pro-apoptotic BAD but induced proliferative CCND1 expression in SSC-25 cells and OEC-M1 cells. It activated expression of PD-L1 and BTLA in both cell lines. On the other hand, resveratrol suppressed the expression of all. Alternatively, it activated BAD expression. Thus thyroxine induces checkpoint gene expression which may promote proliferation in cancer cells. Alternatively, resveratrol reverses the stimulatory effects of thyroid hormone to induce anti-proliferation. These findings provide new insights into the antagonizing effect of resveratrol on the thyroxine-induced expression of checkpoint genes and proliferative genes in oral cancers.


A Web-Based Game for Young Adolescents to Improve Parental Communication and Prevent Unintended Pregnancy and Sexually Transmitted Infections (The Secret of Seven Stones): Development and Feasibility Study.
Early adolescent unintended pregnancy and sexually transmitted infection prevention are significant public health challenges in the United States. Parental influence can help adolescents make responsible and informed sexual health decisions toward delayed sexual debut; yet parents often feel ill equipped to communicate about sex-related topics. Intergenerational games offer a potential strategy to provide life skills training to young adolescents (aged 11-14 years) while engaging them and their parents in communication about sexual health. This study aims to describe the development of a web-based online sexual health intergenerational adventure game, the Secret of Seven Stones (SSS), using an intervention mapping (IM) approach for developing theory- and evidence-based interventions. We followed the IM development steps to describe a theoretical and empirical model for young adolescent sexual health behavior, define target behaviors and change objectives, identify theory-based methods and practical applications to inform design and function, develop and test a prototype of 2 game levels to assess feasibility before developing the complete 18-level game, draft an implementation plan that includes a commercial dissemination strategy, and draft an evaluation plan including a study design for a randomized controlled trial efficacy trial of SSS. SSS comprised an adventure game for young adolescent skills training delivered via a desktop computer, a text-based notification system to provide progress updates for parents and cues to initiate dialogue with their 11- to 14-year-old child, and a website for parent skills training and progress monitoring. Formative prototype testing demonstrated feasibility for in-home use and positive usability ratings. The SSS intergenerational game provides a unique addition to the limited cadre of home-based programs that facilitate parent involvement in influencing young adolescent behaviors and reducing adolescent sexual risk taking. The IM framework provided a logical and thorough approach to development and testing, attentive to the need for theoretical and empirical foundations in serious games for health.


Zinc, iron, and copper absorption in the streptozotocin-diabetic rat.
Altered tissue levels of trace metals have been reported in streptozotocin-diabetic (STZ) rats. To determine whether increased hepatic and renal levels of Cu and Zn were associated with enhanced intestinal absorption, trace metal absorption was studied in control (C) and STZ rats using dietary balance and in situ ligated-loop techniques. The apparent daily absorption of dietary Zn and Cu per 100 g body wt was threefold higher in STZ than C rats. In comparison, dietary Fe absorption per day was not altered. Increased Zn absorption was closely correlated with diabetes-associated polyphagia. The initial rate of injected 65Zn excretion was more rapid in STZ rats, although the rate of excretion beyond day 7 was similar from C and STZ animals. The quantity of Zn, Fe, and Cu absorbed per 20 cm duodenal loop was similar for C and STZ rats. Zn, Fe, and Cu absorption per gram dry mucosa were reduced 45-53% in STZ rats due to the 50% increase in mucosal mass. Moreover, the quantity of radioisotopes accumulated per gram dry mucosa and the concentration of metallothionein per gram mucosal cytosol protein were similar in C and STZ animals. Together, these data demonstrate that increased absorption of dietary Zn and Cu is in part responsible for accumulation of these elements in STZ tissues and suggest altered metal transport at the luminal (brush border) surface of the intestinal epithelium.


The polysaccharides from fermented Ganoderma lucidum mycelia induced miRNAs regulation in suppressed HepG2 cells.
Medicinal mushroom polysaccharides such as Ganoderma lucidum polysaccharides (GLPs) have been commonly hypothesized to suppress tumor cells proliferation through immune effects. To verify this hypothesis through investigating comprehensive miRNA expression in polysaccharide treated cancer cells, an anticancer mycelia GLP was employed to disclose miRNA differential expression of human hepatocarcinoma cells (HepG2), by using a miRNA microarray assay based on Sanger miR-Base Release 16. The experiment and the analysis result indicates that among the 61 differential expressed miRNAs (p ≤ 0.01), 17 of them were regulated significantly. GLP can inhibit HepG2 cells directly through regulation of hepatocarcinoma genes. A newly found miR-3131 exhibited the strongest upregulation (92-folds, Log2 = 6.53, p = 0.000016). The miRNAs responded synergistically in both hepatocarcinoma and immune-related aspects.


Comfort with motherhood in late pregnancy facilitates maternal role attainment in early postpartum.
Quality of life, comfort, and wellbeing during pregnancy are essential for every country in the world. Pregnancy is considered a preparation period for becoming a mother. Maternal role development, including confidence and satisfaction as a mother, is important in the transition to motherhood. Negative psychosocial affect, such as increased anxiety and distress, during pregnancy adversely influences the childbirth experience and childcare, which contributes to postpartum depression. However, the impact of positive feelings on the maternal role development remains unclear. Therefore, the study purpose was to clarify the relationship between comfort in late pregnancy and maternal role attainment and childcare during early postpartum. We designed a descriptive, longitudinal, correlational study by using the Prenatal Comfort Scale, the Postpartum Maternal Role Confidence Scale, and the Postpartum Maternal Satisfaction Scale. Among 339 participants who had received care at a university hospital located in Sendai city in Japan, 215 subjects completed the longitudinal study by answering a questionnaire for the respective Scale late in their pregnancy or during early postpartum. The subjects consisted of 114 primipara (32.0 ± 5.4 years) and 101 multipara (33.4 ± 4.9 years). In primipara, comfort with motherhood was significantly correlated with maternal confidence regarding knowledge and childcare skills and maternal satisfaction. In multipara, comfort in late pregnancy was related to maternal confidence and satisfaction. Positive affect was related to maternal confidence and maternal satisfaction in early postpartum. Therefore, a prenatal nursing intervention helps women become more comfortable with impending motherhood, thereby promoting maternal role attainment after delivery.


Exploring Swedish single women's decision to choose motherhood through medically assisted reproduction - a qualitative study.
New legislation was introduced in Sweden in 2016, giving single women access to medically assisted reproduction (MAR). While Swedish single women's characteristics and motivations for choosing motherhood through MAR were assessed in our previous pilot survey, their experience of considering and making the decision to undergo MAR has not been assessed through a qualitative approach. Thus, the aim of this study was to explore Swedish single women´s experience of making the decision to choose motherhood through MAR. The study design was a qualitative method with a semi-structured interview guide used for individual face-to-face interviews. Sixteen single women accepted for MAR were interviewed individually during their waiting time to start treatment. Qualitative content analysis was used to analyse the data. The data analyses resulted in three main categories: (i) longing and belonging; (ii) social exclusion and support; and (iii) evaluation and encounter. The overarching theme reflects the decision to become a single mother by choice: motherhood through MAR - an emotional and ambivalent decision to make on your own. In conclusion, to reach motherhood, by giving birth to one's child and not deviating from the norm as childless, was considered important among these women when making the decision to become a single mother by choice.


Splicing factor gene mutations in acute myeloid leukemia offer additive value if incorporated in current risk classification.
Splicing factor (SF) mutations are important contributors to the pathogenesis of hematological malignancies; however, their relevance in risk classification of acute myeloid leukemia (AML) warrants further investigation. To gain more insight into the characteristics of patients with AML carrying SF mutations, we studied their association with clinical features, cytogenetic and molecular abnormalities, and clinical outcome in a large cohort of 1447 patients with AML and high-risk myelodysplastic syndrome. SF mutations were identified in 22% of patients and were associated with multiple unfavorable clinical features, such as older age, antecedent myeloid disorders, and adverse risk factors (mutations in RUNX1 and ASXL1). Furthermore, they had significantly shorter event-free and overall survival. Notably, in European LeukemiaNet (ELN) 2017 favorable- and intermediate-risk groups, SF3B1 mutations were indicative of relatively poor prognosis. In addition, patients carrying concomitant SF mutations and RUNX1 mutations had a particularly adverse prognosis. In patients without any of the 4 most common SF mutations, RUNX1 mutations were associated with relatively good outcome, which was comparable to that of intermediate-risk patients. In this study, we propose that SF mutations be considered for incorporation into prognostic classification systems. First, SF3B1 mutations could be considered an intermediate prognostic factor when co-occurring with favorable risk features and as an adverse prognostic factor for patients currently categorized as having intermediate risk, according to the ELN 2017 classification. Second, the prognostic value of the current adverse factor RUNX1 mutations seems to be limited to its co-occurrence with SF mutations.


Sperm of patients with severe asthenozoospermia show biochemical, molecular and genomic alterations.
The multifactorial pathological condition, that is, severe low sperm motility is a frequent cause of infertility. However, mechanisms underlying the development of this condition are not completely understood. Single abnormalities have been reported in sperm of patients with asthenozoospermia. In this study, we characterized, in 22 normozoospermic men and in 37 patients with asthenozoospermia, biochemical, molecular and genomic abnormalities that frequently occur in sperm of patients with asthenozoospermia. We evaluated a panel of sperm biomarkers that may affect the motility and fertilizing ability of sperm of patients with severe asthenozoospermia. Since reactive oxygen species (ROS) production is involved in the pathogenesis of such sperm abnormalities, we determined the association between ROS production and sperm abnormalities. High percentage of patients with severe asthenozoospermia showed increased basal and stimulated ROS production. Moreover, these patients showed increased mitochondrial DNA (mtDNA) copy number but decreased mtDNA integrity and they were associated with elevated ROS levels. Furthermore, mitochondrial membrane potential was also significantly decreased and again associated with high ROS production in these patients. However, the rate of nuclear DNA fragmentation was increased only in less than one-fifth of these patients. An important cohort of these patients showed multiple identical biochemical, molecular and genomic abnormalities, which are typical manifestations of oxidative stress. The most frequent association was found in patients with high ROS levels, increased mtDNA copy number and decreased integrity, and low MMP. A smaller cohort of the aforementioned patients also showed nDNA fragmentation. Therefore, patients with asthezoospermia likely present reduced fertilizing potential because of such composed abnormalities.


Homotopic region connectivity during concussion recovery: A longitudinal fMRI study.
To (i) investigate alterations in homotopic functional connectivity (hfc) in concussed patients relative to healthy controls (HC) and to (ii) interrogate whether hfc in concussed patients normalized during the recovery process. The relationship between symptom recovery and change in hfc was assessed using post-hoc analyses. This study included 15 concussed patients (mean age = 39.1, SD = 10.1; sex: 13 females, 2 males) and 15 HC (mean age = 39.1, SD = 11.7; sex: 13 females, 2 males). Hfc patterns were interrogated using resting-state magnetic resonance imaging (rs-MRI) for 29 a priori selected pain-processing regions. Concussed patients underwent imaging at two time-points; at 1-month post-concussion (mean time following concussion: 28 days, SD = 9.5) and again at 5-months post-concussion (mean time following concussion: 121 days, SD = 13). At both time-points, symptoms associated with concussion were assessed using the Sports Concussion Assessment Tool (SCAT-3). Concussed patients had significantly weaker hfc in the following six regions 1-month post-concussion compared to HC: middle cingulate, posterior insula, middle occipital, spinal trigeminal nucleus, precentral and the pulvinar. There were no regions of significantly stronger hfc in concussed patients relative to HC. Longitudinally, patients showed significant symptom recovery 5-months post-concussion and had significant strengthening of hfc patterns in seven homotopic ROIs: middle cingulate, posterior insula, middle occipital, secondary somatosensory area, spinal trigeminal nucleus, precentral, and the pulvinar. Post-hoc analyses indicated a significant negative correlation between somatosensory functional connectivity strengthening and symptom severity. At 1-month post-concussion, patients had significantly weaker hfc in a number of pain-processing regions relative to HC. However, over a period of 5-months, region-pair connectivity showed significant recovery and normalization. Those patients with more successful symptom recovery at 5-months post-concussion had more functional somatosensory strengthening, suggesting an association between functional strengthening and post-concussion symptom recovery.


Self-Interaction of Human Serum Albumin: A Formulation Perspective.
In the present study, small-angle X-ray scattering (SAXS) and static light scattering (SLS) have been used to study the solution properties and self-interaction of recombinant human serum albumin (rHSA) molecules in three pharmaceutically relevant buffer systems. Measurements are carried out up to high protein concentrations and as a function of ionic strength by adding sodium chloride to probe the role of electrostatic interactions. The effective structure factors (S eff) as a function of the scattering vector magnitude q have been extracted from the scattering profiles and fit to the solution of the Ornstein-Zernike equation using a screened Yukawa potential to describe the double-layer force. Although only a limited q range is used, accurate fits required including an electrostatic repulsion element in the model at low ionic strength, while only a hard sphere model with a tunable diameter is necessary for fitting to high-ionic-strength data. The fit values of net charge agree with available data from potentiometric titrations. Osmotic compressibility data obtained by extrapolating the SAXS profiles or directly from SLS measurements has been fit to a 10-term virial expansion for hard spheres and an equation of state for hard biaxial ellipsoids. We show that modeling rHSA as an ellipsoid, rather than a sphere, provides a much more accurate fit for the thermodynamic data over the entire concentration range. Osmotic virial coefficient data, derived at low protein concentration, can be used to parameterize the model for predicting the behavior up to concentrations as high as 450 g/L. The findings are especially important for the biopharmaceutical sector, which require approaches for predicting concentrated protein solution behavior using minimal sample consumption.


Primary porcine brain microvessel endothelial cell isolation and culture.
Cell culture models of the blood-brain barrier (BBB) are useful tools to study the functionality of the BBB in health and disease. Several good in vitro BBB models are available from different species. However, most brain endothelial cells lose some of their in vivo BBB phenotype in culture. Porcine brain endothelial cells (PBECs) tend to retain most of their in vivo BBB characteristics and usually give higher transendothelial electrical resistance (TEER, representing functional well-developed tight junctions) compared to brain endothelial cells from other species. The protocol described in this unit gives detailed instructions for isolation and culture of PBECs from fresh porcine brains. This porcine BBB model generates high TEER without the need for co-culture with astrocytes. However, astrocyte-derived factors can be introduced to the system through the use of astrocyte-conditioned medium or co-culture with astrocytes, which may be necessary for further enhancing the BBB phenotype for certain complex studies.


COVID-19 Pneumonia Precipitating Acute Anterior Wall Myocardial Infarction With Large Left Ventricular Apical Thrombus.
Initial reports suggest an increased thrombotic risk in coronavirus disease 2019 (COVID-19). We present a case of COVID-19 pneumonia that precipitated chest pain, an acute anterior wall ST-elevation myocardial infarction on the fifth day of hospitalization resulting in large left ventricular apical thrombus.


The effects of a thromboxane synthase inhibitor, a prostacyclin analog and PGE1 on the nephritis of the NZB/W F1 mouse.
One hundred NZB/W F1 female mice were studied to compare the effects of a thromboxane synthase inhibitor (TSI), a stable prostacyclin analog (iloprost) and prostaglandin E1 (PGE1) in the evolution of the nephritis. At 10 weeks of age mice were randomly assigned to cohorts of 20 to receive either no treatment, vehicle control, PGE1, iloprost or TSI. Proteinuria, mortality, systemic blood pressure, renal immune complex deposition, urinary TX B2 and 6 keto PGF1 alpha levels were measured. Mice receiving PGE1 and iloprost had a significant delay in the onset of proteinuria and reduction in mortality at 40 weeks. The TSI treatment had no apparent effect on proteinuria or mortality. The amelioration of the nephritis was not associated with an alteration in immune complex deposition in survivors at 40 weeks. Although PGE1 and iloprost lessened the age related increase in urinary TX B2, increased the urinary 6 keto PGF1 alpha levels and the ratio of 6 keto PGF1 alpha to TX B2; so did the TSI. The PGE1 treated mice did experience a marked and persistent reduction in blood pressure but this was not observed in the iloprost- or the TSI-treated mice. All drugs tested reduced the age-related increase in thromboxane B2 but only the PGE1 and iloprost had a significant effect on the evolution of the nephritis.


Histology of salmonid testes during maturation.
The commonly applied classification systems of fish gonad maturity divide the maturation process into certain stages. However, the scales do not entirely reflect the continuity of the maturation process. Based on light microscope observations, the paper describes a comprehensive pattern of testicular transformations during maturation. The study was carried out on precocious underyearling and 1-year-old males of sea trout (Salmo trutta m. trutta L.), 1-year-old males of salmon (Salmo salar L.), and males of brown trout (Salmo trutta m. fario L.) aged from 7 months to 4 years. A total of 821 gonads collected during all seasons of the year were examined. The fish were fixed in Bouin's fluid. Histological slides of the mid-part of the gonad were made using the standard paraffin technique. The 3-6 microm sections were stained with Heidenhain haematoxylin. Histological changes of testes during maturation were similar in the three species studied. Immature and resting gonads contained type A spermatogonia in lobules only. The appearance of cystic structures containing type B spermatogonia in the lobules signalled the beginning of the sexual cycle in male gonads. Type B spermatogonia underwent synchronous mitotic divisions resulting in an increase in the total number of spermatogonia. As the spermatogenesis continued, the gonads showed a gradual increase in the number of cysts containing cells at all the spermatogenetic stages: type B spermatogonia, primary and secondary spermatocytes, spermatids, and spermatozoa. The well-formed spermatozoa were released to the lobule lumen once the Sertoli cells and spermatozoa connections broke up and the cyst disappeared. This was a continuous process observed throughout the spawning season. The spermatozoa were moved to the efferent duct. While some of the germ cells were completing spermatogenesis, the lobules contained less and less cysts with type B spermatogonia, primary and secondary spermatocytes, and spermatids; eventually all the cells completed spermatogenesis. At the end of maturation, vacuoles, up to 18.9 microm in final diameter (brown trout), appeared in the Sertoli cells. The vacuoles were visible in the lobule wall epithelium for a prolonged period of time. In most salmonid individuals examined, the reproductive cycles were observed to overlap. In some fish, the preparation for another cycle began very early, i.e., at the and of preceding spermatogenesis, which had not been observed before. Gonad maturation in some males was incomplete.


Polyelectrolyte-Stabilised Magnetic-Plasmonic Nanocomposites.
In this work, new magnetic-plasmonic nanocomposites have been developed through the use of two complementary polyelectrolytes⁻polystyrene sulfonate (PSS) and poly(allylamine hydrochloride) (PAH). PSS, a negatively charged polyelectrolyte, was utilized as a stabiliser for magnetite nanoparticles, and PAH, a positively charged polyelectrolyte, was used to stabilize gold nanoparticles. The combination of these two entities resulted in a magnetic-plasmonic nanocomposite that is highly reproducible and scalable. This approach was found to work for a variety of PSS concentrations. The produced magnetic-plasmonic nanomaterials have been characterized by vibrational sample magnetometry (VSM), transmission electron microscopy (TEM) and UV-Vis spectroscopy. These nanocomposite materials have the potential to be used in a variety of biological applications including bioseparation and biosensing.


D,L-alpha-difluoromethylornithine inhibits human cytomegalovirus replication.
D,L-alpha-Difluoromethylornithine (DFMO) is an inhibitor of ornithine decarboxylase, the first enzyme in the polyamine biosynthetic pathway. Exposure of human foreskin fibroblast cells to DFMO before their infection with human strains of cytomegalovirus (CMV) resulted in a reduction in the amount of infectious virus produced. A 3-day exposure to the drug was required to elicit maximal antiviral effect. Cells exposed to DFMO at the time of infection produced normal amounts of infectious virus. Preexposure to the drug for 1, 2, or 3 days before infection resulted in at least 10-, 100-, or 1,000-fold decreases, respectively, in the amount of infectious virus produced. This decrease paralleled the loss of intracellular spermidine and was partially spared by the addition of exogenous putrescine, spermidine, or spermine (10 microM). When added 3 days before infection, DFMO depressed production of herpes simplex virus and simian CMV, as well as wild-type and laboratory prototype strains of human CMV. Although some antiviral effect was observed at a drug concentration of 1 mM, 10 mM gave a stronger effect and was the amount routinely used. At 30 mM DFMO, growth of noninfected cells was slowed but not arrested. Studies to investigate the level at which DFMO interferes with CMV replication showed that DFMO-treated, infected cells (i) exhibit a typical CMV-specific cytopathic effect, (ii) synthesize both viral proteins and viral DNA, (iii) contain at least some capsid forms, and (iv) shed greatly reduced amounts of virus particles into the growth medium. Since CMV virions, like those of herpes simplex virus, contain the polyamines spermidine and spermine, and since DFMO essentially eliminates the pool of intracellular spermidine, the possibility is suggested that this drug may exert its antiviral effect by interfering with virus assembly, perhaps at the level of DNA packaging or capsid envelopment or both.


Neuroimaging advances in holoprosencephaly: Refining the spectrum of the midline malformation.
Holoprosencephaly (HPE) is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into two hemispheres, a process normally completed by the fifth week of gestation. Modern high-resolution brain magnetic resonance imaging (MRI) has allowed detailed analysis of the cortical, white matter, and deep gray structural anomalies in HPE in living humans. This has led to better classification of types of HPE, identification of newer subtypes, and understanding of the pathogenesis. Currently, there are four generally accepted subtypes of HPE: alobar, semilobar, lobar, and middle interhemispheric variant. These subtypes are defined primarily by the degree and region of neocortical nonseparation. Rather than there being four discrete subtypes of HPE, we believe that there is a continuum of midline neocortical nonseparation resulting in a spectrum disorder. Many patients with HPE fall within the border zone between the neighboring subtypes. In addition, there are patients with very mild HPE, where the nonseparation is restricted to the preoptic (suprachiasmic) area. In addition to the neocortex, other midline structures such as the thalami, hypothalamic nuclei, and basal ganglia are often nonseparated in HPE. The cortical and subcortical involvements in HPE are thought to occur due to a disruption in the ventral patterning process during development. The severity of the abnormalities in these structures determines the severity of the neurodevelopmental outcome and associated sequelae.


Comparison of false positive rates for screening breast magnetic resonance imaging (MRI) in high risk women performed on stacked versus alternating schedules.
Breast MRI added to mammography increases screening sensitivity for high-risk women but false-positive (FP) rates are higher and the optimal screening schedule for coordination with mammography is unclear. We compare rates of FP MRI when studies were performed on two different schedules. High-risk women at the University of Vermont who had at least 1 MRI and 1 mammogram performed within one year between 2004-2012 were eligible for inclusion in this study. Screening was considered stacked if both studies were performed within 90 days and alternating if studies were 4-8 months apart. False positive was defined in one of three ways. 137 women had screening which met inclusion criteria and 371 MRIs were reviewed. The FP rates were similar for the two schedules when considering BI-RAD 4, 5, 0 or biopsy as a positive test. FP rates were significantly higher for the stacked schedule (18.2 vs. 10.2%, p = 0.026) when considering BI-RADS 3-4-5-0 as positive test, due to the elevated rate of BI-RADS 3 assessments among stacked exams. False positive rates differ based on the type of exam (baseline or subsequent) and definition of positive but do not differ based on imaging schedule (stacked or alternating); suggesting that women and their providers may choose the imaging schedule they prefer. This is significant as a randomized clinical trial comparing the two schedules is not likely to be performed, given the high cost and large number of women needed for such a study.


Cytological and cytochemical investigations on granular cells in oral lichen planus.
Two biopsy specimens showed unusual histology characterized by features consistent with resolving oral lichen planus and voluminous, finely granular cells in the lamina propria, resembling the cells of granular cell tumour. Immunocytochemistry and lipid-pigment histochemistry indicated that the granular cells are macrophages of low proliferative activity laden with early ceroid. It is likely that damaged basal keratinocytes provide debris for the formation of the latter. "Oral ceroid granuloma' would be an appropriate term for collections of such reactive macrophages occurring in the oral tissues.


Four-step iron(ii) spin state cascade driven by antagonistic solid state interactions.
A four-stepped cascade of Fe(ii) high spin (HS) to low spin (LS) states is demonstrated in a family of 2-D Hofmann materials, [Fe3II(saltrz)6(MII(CN)4)3]·8(H2O) (MII = Pd (1Pd ), Pt (1Pt ); saltrz = (E)-2-(((4H-1,2,4-triazol-4-yl)imino)methyl)phenol). Alongside the fully HS and LS Fe(ii) states, fractional spin state stabilization occurs at HS/LS values of 5/6, 2/3, and 1/6. This unconventional spin state periodicity is driven by the presence of multiple spin crossover (SCO) active Fe(ii) sites which are in subtly distinct environments driven by a network of antagonistic host-host and host-guest interactions. Alternating long- and short-range magnetostructural ordering is achieved over the five distinct spin state ratios HS1.0LS0.0, HS0.833LS0.167, HS0.667LS0.333, HS0.167LS0.833, and HS0.0LS1.0 owing to the flexibility of this 2-D interdigitated lattice topology interconnected by intermolecular interactions. A distinct wave-like spin state patterning is structurally evidenced for each intermediate phase.


Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues.
Metastasis is a leading cause of cancer-related deaths, yet understanding how metastatic tumors adapt from their origin to target tissues is challenging. To address this, we assessed whether primary and metastatic tumors resemble their tissue of origin or target tissue in terms of gene expression. We analyzed gene expression profiles from various cancer types, including single-cell and bulk RNA-seq data, in both paired and unpaired primary and metastatic patient cohorts. We quantified the transcriptomic distances between tumor samples and their normal tissues, revealing that primary tumors are more similar to their tissue of origin, while metastases shift towards the target tissue. Pathway-level analysis highlighted critical transcriptomic changes during metastasis. Notably, primary cancers exhibited higher activity in cancer hallmarks, including Activating Invasion and Metastasis , compared to metastatic cancers. This comprehensive landscape analysis provides insight into how cancer tumors adapt to their metastatic environments, providing a transcriptome-wide view of the processes involved.


Design of low-cost portable ultrasound systems: review.
Ultrasound continues to be one of the major imaging modalities used for the diagnosis and treatment of a number of medical conditions. Therefore emphasis on innovation is continually increasing the quality of the ultrasound systems. However focus is just beginning to shift into the low-cost and portable applications of ultrasound. These systems present interesting constraints which must be considered to transform a standalone system into a portable version. This review takes a look at some of the attempts which have been published, as well as some of the issues which have still yet to be resolved. In conclusion, low-cost portable ultrasound has the capability to be developed and commercialized, but until a suitable replacement to piezoelectric crystals has been developed (possibly CMUTs?) low-cost portable ultrasound system will be held back by the high cost burden associated with the cost of piezoceramics.


Differential expression of a novel gene in response to coronatine, methyl jasmonate, and wounding in the Coi1 mutant of Arabidopsis.
Coronatine is a phytotoxin produced by some plant-pathogenic bacteria. It has been shown that coronatine mimics the action of methyl jasmonate (MeJA) in plants. MeJA is a plant-signaling molecule involved in stress responses such as wounding and pathogen attack. In Arabidopsis thaliana, MeJA is essential for pollen grain development. The coi1 (for coronatine-insensitive) mutant of Arabidopsis, which is insensitive to coronatine and MeJA, produces sterile male flowers and shows an altered response to wounding. When the differential display technique was used, a message that was rapidly induced by coronatine in wild-type plants but not in coi1 was identified and the corresponding cDNA was cloned. The coronatine-induced gene ATHCOR1 (for A. thaliana coronatine-induced) is expressed in seedlings, mature leaves, flowers, and siliques but was not detected in roots. The expression of this gene was dramatically reduced in coi1 plants, indicating that COI1 affects its expression. ATHCOR1 was rapidly induced by MeJA and wounding in wild-type plants. The sequence of ATHCOR1 shows no strong homology to known proteins. However, the predicted polypeptide contains a conserved amino acid sequence present in several bacterial, animal, and plant hydrolases and includes a potential ATP/GTP-binding-site motif (P-loop).


Modulatory effects of PLG and its peptidomimetics on haloperidol-induced catalepsy in rats.
A behavioral model of dopaminergic function in the rat was used to examine the anticataleptic effects of L-prolyl-L-leucyl-glycinamide (PLG) and peptidomimetic analogs of PLG. Administration of 1 mg/kg PLG intraperitoneally significantly attenuated haloperidol (1 mg/kg)-induced catalepsy (as measured by the standard horizontal bar test), whereas doses of 0.1 and 10 mg/kg PLG did not. Eight synthetic PLG peptidomimetics (Calpha, alpha-dialkylated glycyl residues with lactam bridge constraint [1-4] and without [5-8]) were tested in the same manner (at a dose of 1 microg/kg) and categorized according to their activity, i.e. very active (5), moderately active (2, 3, 4, and 6), and inactive (1, 7, and 8). The catalepsy-reversal action of the diethylglycine-substituted peptidomimetic 5 was examined further and found to exhibit a U-shaped dose-response effect with an optimal dose of 1 microg/kg. The similarity between the effects of PLG and the synthetic peptidomimetics suggests a common mechanism of action. Finally, the synthetic peptidomimetics examined here, particularly peptidomimetic 5, were more effective than PLG in attenuating haloperidol-induced catalepsy.


Automatic recording spectroradiometer system.
A versatile, mobile, automatic recording spectroradiometer of high precision and accuracy has been developed. The instrument is a single-beam device with an alternate reference beam intended primarily for measurements of spectral irradiance. However, it is equally useful for measurement of spectral radiance, transmittance, or reflectance. The system is programmed for automatic operation. The output is in the form of an automatic digital recording of both measurements and control data. Instrument operation integrates the following characteristics: wavelength-by-wavelength operation in intervals of 0.1 nm to 50 nm; time-integrated measurements of spectral flux; internal calibration reference source; and monitored signals for wavelength position, test source total output, and photodetector dark current. The system's operating characteristics and specifications have been determined and are set forth here. Performance for three types of sources and correction of measurements to zero-bandpass equivalence is demonstrated.


Protocol for imbibed seed piercing for Agrobacterium-mediated transformation of jute.
Here, we present a streamlined Agrobacterium-mediated transformation protocol for jute (Corchorus sp.). We describe steps to pierce and vacuum infiltrate imbibed jute seeds with Agrobacterium suspension. We then detail procedures for selecting transformed seeds by using a hygromycin-B-supplemented medium. This approach can achieve transformation efficiencies of 20.44% ± 1.17% and 15.55% ± 0.58% for tossa (C. olitorius) and white (C. capsularis) jute, respectively. Demanding minimal resources and time, this protocol can elevate genetic engineering research in jute fiber crops. For complete details on the use and execution of this protocol, please refer to Majumder et al. (2020).1.


Modeling of the human interleukin 12:receptor complex allows to engineer attenuated cytokine variants.
Interleukin 12 (IL-12) plays major roles in immune defense against intracellular pathogens. By activating T cells and increasing antigen presentation, it is also a very potent anti-tumor molecule. Strong immune activation and systemic toxicity, however, so far limit its potential therapeutic use. Building on recent experimental structures of IL-12 related cytokine:receptor complexes, we here provide a high-resolution computational model of the human IL-12:receptor complex. We design attenuated IL-12 variants with lower receptor binding affinities based on molecular dynamics simulations, and subsequently validate them experimentally. These variants show reduced activation of natural killer cells while maintaining T cell activation. This immunological signature is important to develop IL-12 for cancer treatment, where natural killer cells contribute to severe side-effects. Taken together, our study provides detailed insights into structure and dynamics of the human IL-12:receptor complex and leverages them for engineering attenuated variants to elicit fewer side-effects while maintaining relevant biological activity.


Best practices: wellness self-management: an adaptation of the illness management and recovery program in New York State.
Wellness Self-Management (WSM) is a recovery-oriented, curriculum-based practice designed to help adults with serious mental health problems make informed decisions and take action to manage symptoms and improve their quality of life. WSM is an adaptation of the illness management and recovery program, a nationally recognized best practice. WSM uses comprehensive personal workbooks for group facilitators and consumers and employs a structured and easy-to-implement group facilitation framework. Currently, more than 100 adult mental health agencies are implementing WSM in New York State. The authors describe the development and key features of WSM and an initiative to promote widespread adoption and sustainability.


Plasma profiles in active systemic juvenile idiopathic arthritis: Biomarkers and biological implications.
Systemic juvenile idiopathic arthritis (SJIA) is a chronic arthritis of children characterized by a combination of arthritis and systemic inflammation. There is usually non-specific laboratory evidence of inflammation at diagnosis but no diagnostic test. Normalized volumes from 89/889 2-D protein spots representing 26 proteins revealed a plasma pattern that distinguishes SJIA flare from quiescence. Highly discriminating spots derived from 15 proteins constitute a robust SJIA flare signature and show specificity for SJIA flare in comparison to active polyarticular juvenile idiopathic arthritis or acute febrile illness. We used 7 available ELISA assays, including one to the complex of S100A8/S100A9, to measure levels of 8 of the15 proteins. Validating our DIGE results, this ELISA panel correctly classified independent SJIA flare samples, and distinguished them from acute febrile illness. Notably, data using the panel suggest its ability to improve on erythrocyte sedimentation rate or C-reactive protein or S100A8/S100A9, either alone or in combination in SJIA F/Q discriminations. Our results also support the panel's potential clinical utility as a predictor of incipient flare (within 9 wk) in SJIA subjects with clinically inactive disease. Pathway analyses of the 15 proteins in the SJIA flare versus quiescence signature corroborate growing evidence for a key role for IL-1 at disease flare.


Snowball Earth, population bottleneck and Prochlorococcus evolution.
Prochlorococcus are the most abundant photosynthetic organisms in the modern ocean. A massive DNA loss event occurred in their early evolutionary history, leading to highly reduced genomes in nearly all lineages, as well as enhanced efficiency in both nutrient uptake and light absorption. The environmental landscape that shaped this ancient genome reduction, however, remained unknown. Through careful molecular clock analyses, we established that this Prochlorococcus genome reduction occurred during the Neoproterozoic Snowball Earth climate catastrophe. The lethally low temperature and exceedingly dim light during the Snowball Earth event would have inhibited Prochlorococcus growth and proliferation, and caused severe population bottlenecks. These bottlenecks are recorded as an excess of deleterious mutations accumulated across genomic regions and inherited by descendant lineages. Prochlorococcus adaptation to extreme environmental conditions during Snowball Earth intervals can be inferred by tracing the evolutionary paths of genes that encode key metabolic potential. Key metabolic innovation includes modified lipopolysaccharide structure, strengthened peptidoglycan biosynthesis, the replacement of a sophisticated circadian clock with an hourglass-like mechanism that resets daily for dim light adaption and the adoption of ammonia diffusion as an efficient membrane transporter-independent mode of nitrogen acquisition. In this way, the Neoproterozoic Snowball Earth event may have altered the physiological characters of Prochlorococcus, shaping their ecologically vital role as the most abundant primary producers in the modern oceans.


Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye.
As its name suggests, the host receptor herpesvirus entry mediator (HVEM) facilitates herpes simplex virus (HSV) entry through interactions with a viral envelope glycoprotein. HVEM also bridges several signaling networks, binding ligands from both tumor necrosis factor (TNF) and immunoglobulin (Ig) superfamilies with diverse, and often opposing, outcomes. While HVEM was first identified as a viral entry receptor for HSV, it is only recently that HVEM has emerged as an important host factor in immunopathogenesis of ocular HSV type 1 (HSV-1) infection. Surprisingly, HVEM exacerbates disease development in the eye independently of entry. HVEM signaling has been shown to play a variety of roles in modulating immune responses to HSV and other pathogens, and there is increasing evidence that these effects are responsible for HVEM-mediated pathogenesis in the eye. Here, we review the dual branches of HVEM function during HSV infection: entry and immunomodulation. HVEM is broadly expressed; intersects two important immunologic signaling networks; and impacts autoimmunity, infection, and inflammation. We hope that by understanding the complex range of effects mediated by this receptor, we can offer insights applicable to a wide variety of disease states.


Predicted serotype-specific effectiveness of pneumococcal conjugate vaccines V114 and PCV20 against invasive pneumococcal disease in children.
Next-generation, higher-valency pneumococcal conjugate vaccines (PCVs), 15-valent PCV V114 and 20-valent PCV (PCV20), have been assessed by comparing their immune responses across serotypes shared with the 13-valent PCV (PCV13). Without efficacy or real-world vaccine effectiveness (VE) it becomes important to relate IgG titers to VE to aid in the interpretation of the immune response elicited by V114 and PCV20. We estimated the protective antibody concentrations for each serotype in 7-valent PCV (PCV7) and PCV13 which were then used to predict the serotype-specific VE for each PCV7 and PCV13 non PCV7 serotype present in V114 and PCV20. The predicted effectiveness of V114 was comparable to PCV7 and PCV13 for 11 of the 13 shared serotypes (1, 4, 5, 6B, 7F, 9 V, 14, 18C, 19A, 19F, and 23F), with improved effectiveness against serotype 3 and decreased effectiveness against serotype 6A. PCV20 had predicted effectiveness comparable to PCV7 and PCV13 for 7 of the 13 shared serotypes (5, 6A, 7F, 9 V, 18C, 19F, and 23F), with decreased effectiveness against the remaining serotypes (1, 3, 4, 6B, 14, and 19A). Prediction of serotype-specific VE values suggests that V114 retains greater effectiveness than PCV20 toward most serotypes present in PCV7 and PCV13.


Investigating visual expertise in sculpture: A methodological approach using eye tracking.
Research on visual expertise has progressed significantly due to the availability of eye tracking tools. However, attempts to bring together research on expertise and eye tracking methodology provoke several challenges, because visual information processes should be studied in authentic and domain-specific environments. Among the barriers to designing appropriate research are the proper definition of levels of expertise, the tension between internal (experimental control) and external (authentic environments) validity, and the appropriate methodology to study eye movements in a three-dimensional environment. This exploratory study aims to address these challenges and to provide an adequate research setting by investigating visual expertise in sculpting. Eye movements and gaze patterns of 20 participants were investigated while looking at two sculptures in a museum. The participants were assigned to four different groups based on their level of expertise (laypersons, novices, semi-experts, experts). Using mobile eye tracking, the following parameters were measured: number of fixations, duration of fixation, dwell time in relevant areas, and revisits in relevant areas. Moreover, scan paths were analysed using the eyenalysis approach. Conclusions are drawn on both the nature of visual expertise in sculpting and the potential (and limitations) of empirical designs that aim to investigate expertise in authentic environments.


Studies on lymphocyte homing in autoimmune prone NZB mice.
Lymphocyte homing patterns in young (3-5 months old) and old (10-12 months old) autoimmune prone NZB mice were investigated by transferring 51Cr labelled lymphoid cells into syngeneic and H-2 compatible allogeneic recipients. We confirmed that non H-2 alloantigens as well as H-2 alloantigens can be important determinants of apparent abnormalities of cellular distribution with the techniques employed. No gross abnormalities of lymphocyte traffic were present in the young NZB mice as compared to the autoimmune resistant strains of mice when syngeneic cells are used. Spleen of older NZB mice appeared to be less attractive to lymph node cells than was the spleen from young NZB mice. Splenocytes of older NZB mice localized significantly more in the liver and less in the lymph nodes as compared with splenocytes from young NZB mice. The mechanism underlying abnormalities of lymphoid cell distribution which feature the autoimmune-prone NZB mice are not yet clear and further studies will be necessary before they can be characterized definitively. Our findings, using syngeneic cells, are in disagreement with those of Zatz and Lance since evidence of abnormal distribution of lymphocytes in young NZB mice were not seen when syngeneic cells were employed.


Postbiotics in the medical field under the perspective of the ISAPP definition: scientific, regulatory, and marketing considerations.
Diverse terms have been used in the literature to refer to the health benefits obtained from the administration of non-viable microorganisms or their cell fragments and metabolites. In an effort to provide continuity to this emerging field, the International Scientific Association of Probiotics and Prebiotics (ISAPP) convened a panel of experts to consider this category of substances and adopted the term postbiotic, which they defined as a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host." This definition does not stipulate any specific health benefit, finished product, target population or regulatory status. In this perspective article, we focused on postbiotics developed for pharmaceutical uses, including medicinal products and medical devices. We address how this field is regulated for products based on inanimate microorganisms, marketing considerations and existing examples of postbiotics products developed as cosmetics for the skin, for vaginal health, and as orally consumed products. We focus on the European Union for regulatory aspects, but also give examples from other geographical areas.


Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients.
Sulfamethoxazole (SMX) is a commonly used antibiotic for prevention of infectious diseases associated with HIV/AIDS and immune-compromised states. SMX-induced hypersensitivity is an idiosyncratic cutaneous drug reaction with genetic components. Here, we tested association of candidate genes involved in SMX bioactivation and antioxidant defense with SMX-induced hypersensitivity. Seventy seven single nucleotide polymorphisms (SNPs) from 14 candidate genes were genotyped and assessed for association with SMX-induced hypersensitivity, in a cohort of 171 HIV/AIDS patients. SNP rs761142 T > G, in glutamate cysteine ligase catalytic subunit (GCLC), was significantly associated with SMX-induced hypersensitivity, with an adjusted p value of 0.045. This result was replicated in a second cohort of 249 patients (p = 0.025). In the combined cohort, heterozygous and homozygous carriers of the minor G allele were at increased risk of developing hypersensitivity (GT vs TT, odds ratio = 2.2, 95% CL 1.4-3.7, p = 0.0014; GG vs TT, odds ratio = 3.3, 95% CL 1.6 - 6.8, p = 0.0010). Each minor allele copy increased risk of developing hypersensitivity 1.9 fold (95% CL 1.4 - 2.6, p = 0.00012). Moreover, in 91 human livers and 84 B-lymphocytes samples, SNP rs761142 homozygous G allele carriers expressed significantly less GCLC mRNA than homozygous TT carriers (p < 0.05). rs761142 in GCLC was found to be associated with reduced GCLC mRNA expression and with SMX-induced hypersensitivity in HIV/AIDS patients. Catalyzing a critical step in glutathione biosynthesis, GCLC may play a broad role in idiosyncratic drug reactions.


Weather influences survival probability in two coexisting mammals directly and indirectly via competitive asymmetry.
Ecologists have studied the role of interspecific competition in structuring ecological communities for decades. Differential weather effects on animal competitors may be a particularly important factor contributing to the outcome of competitive interactions, though few studies have tested this hypothesis in free-ranging animals. Specifically, weather might influence competitive dynamics by altering competitor densities and/or per capita competitive effects on demographic vital rates. We used a 9-year dataset of marked individuals to test for direct and interactive effects of weather and competitor density on survival probability in two coexisting mammalian congeners: Columbian ground squirrels (Urocitellus columbianus) and northern Idaho ground squirrels (Urocitellus brunneus). Ambient temperature and precipitation influenced survival probability in both species, but the effects of weather differed between the two species. Moreover, density of the larger Columbian ground squirrel negatively impacted survival probability in the smaller northern Idaho ground squirrel (but not vice versa), and the strength of the negative effect was exacerbated by precipitation. Cooler, wetter conditions benefited the larger competitor to the detriment of the smaller species. Consequently, our results suggest weather-driven environmental variation influences the competitive equilibrium between ecologically similar mammals of differential body size. Whether future climate change leads to the competitive exclusion of either species will likely depend on the mechanism(s) explaining the coexistence of these competing species. Divergent body size, and hence, differences in thermal tolerance and giving up densities offers a potential explanation for the weather-dependent competitive asymmetry we documented, especially if the larger species competitively excludes the smaller species via interference. This article is protected by copyright. All rights reserved.


[Expression of contractile and cytoskeletal proteins in myocardium of patients with dilated cardiomyopathy.].
Dilated cardiomyopathy (DCM) is characterized by enlargement and dilation of all heart compartments associated with serious decrease of its contractile function. DCM hallmark is the combination of dystrophic and hypertrophic alterations of cardiomyocytes. Since the power output of cardiac cells is directly related to remodeling of their contractile machinery we investigated expression of selected contractile and cytoskeletal proteins in the left ventricle of DCM patients using immunoblotting. The content of the recognized protein markers of cardiomyocyte hypertrophy such as tubulin, desmin and slow skeletal myosin heavy chain isoform, MHCbeta, was significantly elevated in DCM compared to normal myocardium. In addition, marked increase in the content of several smooth muscle proteins (smooth muscle alpha-actin, Myosin Light Chain Kinase, Kinase Related protein SM22) that are normally expressed in embryonic myocardium, was observed in DCM hearts. Thus, cardiomyocyte hypertrophy in DCM is associated with activation of embryonic protein expression program and smooth muscle proteins could serve as markers of this process. Understanding their involvement in sarcomere assembly and pathways of their expression activation during cardiac hypertrophy may bring new insights in treatment of various forms of cardiomyopathy.


Localization of sarcolemmal proteins to lipid rafts in the myocardium.
The localization of sarcolemmal proteins within the membrane can have a dramatic effect on excitation-contraction coupling. We examine the localization of the Na+-Ca2+ exchanger, the dihydropyridine receptor, and other proteins involved in excitation-contraction coupling in rat heart using biochemical and immunolocalization techniques. Specifically, we assess the distribution of proteins within the lipid raft fraction of the sarcolemma. We find that the distribution of proteins in lipid raft fractions is very dependent on the solubilization technique. A common technique using sodium carbonate/pH 11 to solubilize non-lipid raft proteins was inappropriate for use with sarcolemmal membranes. Use of Triton X-100 was more efficacious as a solubilization agent. A large majority of the Na+-Ca2+ exchanger, Na+/K+-ATPase, and plasma membrane Ca2+ pump are not present in lipid rafts. In contrast, most adenosine A1 receptors and dihydropyridine receptors were in lipid raft fractions. Most of the adenosine A1 receptors could be co-immunoprecipitated with caveolin indicating a localization to caveolae (a subclass of lipid rafts). In contrast, the dihydropyridine receptors could not be co-immunoprecipitated with caveolin. Most biochemical data were confirmed by high resolution immunolocalization studies. Using correlation analysis, only a small fraction of the Na+-Ca2+ exchangers colocalized with caveolin whereas a substantial fraction of dihydropyridine and adenosine A1 receptors did colocalize with caveolin. The most pertinent findings are that the Na+-Ca2+ exchanger and the dihydropyridine receptor are in separate sarcolemmal subcompartments. These spatial relationships may be relevant for understanding excitation-contraction coupling.


[Laparoscopic cholecystectomy: the first 50 patients].
Laparoscopic cholecystectomy (LC) has rapidly gained wide acceptance in the United States. The applicability, safety and efficacy of this new procedure for the treatment of cholelithiasis in Taiwan, however, needs evaluation. We performed LC in 50 out of 98 cases of cholelithiasis at Cathay General Hospital from 28 December 1990 to 28 April 1991. We found that the applicability rate was 51%. The reasons for not selecting LC in the 48 open cases were: acute and gangrenous cholecystitis (13), common bile duct stones (11), concomitant intra-abdominal malignancy (5), intrahepatic stones (5), multiple upper abdominal incisions (4), pancreatitis or pancreatic abscesses (3) and other causes (7). In the LC group, there were 44 patients with symptomatic chronic calculus cholecystitis, 3 patients with acute calculus cholecystitis and 3 patients with gall bladder polyps. The age of the patients ranged from 27 to 79. There were 14 males and 36 females. All of the patients had a detailed preoperative workup including complete liver function test and sonographic examination of the hepatobiliary system. Additional pre-operative endoscopic retrograde cholangiopancreatographies were done in 3 and operative cholangiograms were done in another 3 to confirm the absence of common bile duct stones or to delineate anatomy. Although we encountered a few problems during the operations, such as severe adhesion, bleeding, difficult dissection, CO2 leakage, difficult insufflation, or large stones, all of the 50 patients completed the LC successfully without conversion to open cholecystectomy. The average operation time was 60 minutes, ranging from 30 to 135 minutes. Drain tubes were used in 7 cases.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of regional intravenous anaesthesia on blood flow.
Forearm blood flow after regional i.v. anaesthesia in volunteers was compared with the predicted blood flow after arterial occlusion alone, using venous occlusion plethysmography. After arterial occlusion alone for 20 min, marked hyperaemia occured after cuff release. Flows returned to normal within 5 min. Both prilocaine and bupivacaine reduced the hyperaemic response to arterial occlusion. Forearm muscle paralysis using gallamine triethiodide was also associated with a statistically significant but smaller reduction in the hyperaemic response.


Effects of 5 µg/kg intrathecal morphine for postoperative analgesia in pediatric patients undergoing major surgery.
The effects and analgesic adequacy of intrathecal morphine (ITM) administration have been studied less frequently than other regional analgesia techniques in pediatric surgical procedures. To evaluate the efficacy and adverse event rate of 5 µg/kg ITM administration for postoperative analgesia according to age group. We retrospectively evaluated the medical records of patients who underwent major pediatric surgery and were administered ITM for postoperative analgesia. Patients were divided into three age groups: ≤ 5 years (group I), 5.1-13 years (group II) and > 13 years (group III). All patients received ITM 5 µg/kg (max 300 μg) through the L4-5 or L5-S1 interspace. Postoperative pain (modified pediatric objective pain score > 4), need for rescue analgesics, sleep interruption due to pain, sedation (Ramsay sedation scale score > 3), opioid-related postoperative adverse events (at 0, 4, 8, 12, and 24 h after intervention), hemodynamic data and nurse satisfaction with the analgesic method were compared between groups. The analysis included 100 children (47 girls, 9 ± 5.4 years). Groups were similar regarding postoperative rescue analgesia consumption and sleep interruption (p = 0.238, p = 0.958), 96% of the children did not require rescue analgesia, and sleep interruption was not observed in 97%. Postoperative adverse events were pruritus in 14 and nausea/vomiting in 9 patients (p = 0.052). Overall, nurses were satisfied or very satisfied in 99% of the cases. Administration of 5 µg/kg ITM can be used for postoperative analgesia in pediatric surgery in all age groups, with no severe adverse events and high nurse satisfaction with analgesic management.


Substrate-specific regulation of RNA deadenylation in Xenopus embryo and activated egg extracts.
The poly(A) tail of mRNAs plays an important role in translational control. In Xenopus laevis matured oocytes, maternal mRNAs that contain a cytoplasmic polyadenylation element (CPE) are polyadenylated, whereas CPE deficient mRNAs are deadenylated by a default process. Eg mRNAs are maternal transcripts that are poly(A)+ in matured oocytes and rapidly deadenylated after fertilization. This post-fertilization deadenylation of Eg mRNAs requires specific sequence information. Such a deadenylation element has been identified previously in the 3'UTR of Eg2 mRNA. In this study, we show that cell-free extracts made from embryos or activated eggs contain two kinetically distinct deadenylation activities, with different substrate specificities. One, responsible for the slow deadenylation of RNAs that are devoid of a functional CPE, has the characteristics of a default PAN activity. The other effectuates the rapid deadenylation of RNAs containing a deadenylation element. The in vitro system described here will allow the characterization of factors controlling the deadenylation of Eg mRNAs in embryos.


Enhanced SiV photoluminescence by oxidation-induced nano-structures on diamond particle surfaces.
We successfully constructed nanostructures on the surface of diamond particles by oxidation, which drastically enhanced their silicon-vacancy (SiV) photoluminescence (PL) intensity. The {100} plane of the diamond crystal initially had a smooth surface and strong anti-oxidation ability, which converted to a nano-pyramid structure with the sides resembling a {111} crystal plane orientation after oxidation. The {111} plane originally presented vertically layered or scale-like structures, but exhibited irregular nanoporous structures with some ridges perpendicular to the {111} plane in the edge area after oxidation. Since the crystal orientation of these nano-structures matches the <111> aligned split-vacancy structure of the SiV center, the collection efficiency of SiV luminescence increased, such that the SiV emission intensity increased by 27-fold and 4-fold for the nano-pyramid and the irregular nano-porous structure, respectively. Oxidation also significantly improved the crystal quality of diamond, such that the lattice stress around the SiV color center reduced, narrowing the linewidth of the SiV PL peak to nearly 3 nm. This study provides a feasible way to optimize SiV photoluminescent properties by building nanostructures on the surface of diamond particles.


Ruthenium(II)-carbonyl complexes containing two N-monodentate 1,8-naphthyridine ligands: active catalysis in transfer hydrogenation reactions.
The reaction of 2-aminonicotinaldehyde with 2- or 4-methoxyacetophenone in basic media leads to the new ligands 2-(4-methoxyphenyl)-1,8-naphthyridine and 2-(2-methoxyphenyl)-1,8-naphthyridine, respectively, in high yield. The reaction of these naphthyridine derivatives with [RuCl2(CO)2]n leads to the respective complexes cis-dicarbonyldichloridobis[2-(4-methoxyphenyl)-1,8-naphthyridine-κN8]ruthenium(II) and cis-dicarbonyldichloridobis[2-(2-methoxyphenyl)-1,8-naphthyridine-κN8]ruthenium(II), both [RuCl2(C15H12N2O)2(CO)2], in good yield. Both ruthenium(II) complexes display a slightly distorted octahedron with two cis carbonyl, two cis chloride and two cis naphthyridine ligands, the latter coordinated in a monodentate fashion through the N atom in the 8-position. Both complexes exhibit a moderate catalytic activity in the hydrogen-transfer reaction from propan-2-ol to acetophenone in the presence of a base, with 100% selectivity.


NDM-1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism.
The specter of a return to an era in which infectious disease looms as a significant threat to human health is not just hyperbole; there are serious concerns about the widespread overuse and misuse of antibiotics contributing to increased antibiotic resistance in pathogens. The recent discovery of a new enzyme, first identified in Klebsiella pneumoniae from a patient from New Delhi and denoted as NDM-1, represents an example of extreme promiscuity: It hydrolyzes and inactivates nearly all known β-lactam-based antibiotics with startling efficiency. NDM-1 can utilize different metal cofactors and seems to exploit an alternative mechanism based on the reaction conditions. Here we report the results of a combined experimental and theoretical study that examines the substrate, metal binding, and catalytic mechanism of the enzyme. We utilize structures obtained through X-ray crystallography, biochemical assays, and numerical simulation to construct a model of the enzyme catalytic pathway. The NDM-1 enzyme interacts with the substrate solely through zinc, or other metals, bound in the active site, explaining the observed lack of specificity against a broad range of β-lactam antibiotic agents. The zinc ions also serve to activate a water molecule that hydrolyzes the β-lactam ring through a proton shuttle.


Identifying determinants of variability to tailor aspirin therapy.
Once-daily, low-dose aspirin is a cornerstone in the prophylaxis and treatment of cardiovascular diseases. Aspirin 'resistance' still lacks definition, a standardized reference assay, underlying mechanisms, clinical impact or efficacy of alternative antiplatelet drugs. Aspirin response in several studies has been measured by different platelet function tests, not always reflecting aspirin pharmacodynamics, thus generating significantly heterogeneous results. The EMA indicated serum thromboxane B2 as the only valid surrogate assay to study different aspirin formulations. Rather than resistance, recent studies focused on sources of intra- and inter-individual variability in response to aspirin, based on pharmacokinetic and/or pharmacodynamic mechanisms. Drug interactions, diabetes, conditions of increased platelet output, obesity and aging can potentially increase the variability of aspirin response. Preliminary studies testing different aspirin regimens showed that twice-daily low doses were more effective than once-daily higher aspirin doses on surrogate end points of platelet inhibition. Large studies are needed to test new disease-tailored, low-dose aspirin regimens.


[Efficacy and tolerability of long term topiramate in drug resistant epilepsy in adults].
With the objective of evaluating the efficacy and tolerability of topiramate (TPM) in resistant epilepsy, we did a retrospective, open, multicentric analysis of 56 patients aged over 15 years in whom TPM was given as the second, third or fourth drug. All patients had already been on treatment for at least 18 months when topiramate was started. The average follow up was 27.2 months. At the close of the study 16% of the patients were asymptomatic, 23% had a 75% reduction in seizures and 36% a 50% reduction. The drug was withdrawn in 25% of the cases. The adverse effects noted were: nephrolithiasis, asthenia, loss of hair, diarrhoea, weight loss of over 5kg., agitation, aggressiveness, language disorders, ataxia, tremor, somnolence and confusion. The drug had to be suspended when these adverse effects affected the central nervous system moderately or severely, and when there were general effects such as renal calculi in one case and weight loss associated with symptoms which worried the patients in two cases. Thus, TPM is an effective drug in refractory epilepsy and most patients continue on this treatment. The side effects are typical of the drug, and although there is no risk to life, the patient should be warned of them.