Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma.
Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow-up of young patients treated with SMOi for recurrent medulloblastoma. Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible. All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including 2 prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for 3 patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in 2 patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for 1 patient although her final height was below estimated target height. Targeting SMO in mutated PTCH1 is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.


Gender reassignment in children: ethical conflicts in surrogate decision making.
Parents, as surrogate decision makers for their infants, are generally expected by health care providers to act in the child's "best interest." However, when the wishes of the parents are contrary to those of the medical profession, an ethical dilemma occurs. Whose decisions are best for the infant? Whose recommendations are in the child's best interest? This article explores an issue that may not involve a life and death decision, but one in which the parents clearly refuse expert medical recommendations for what the providers believe are in the best interest of the infant. Specifically, the case study explores the parents' refusal to proceed with gender reassignment to female for their genetic XY baby born with micropenis and nonpalpable testes. The issue calls into question the possible limits of surrogate decision making. The ethical principles of beneficence, respect for persons, nonmaleficence, and justice are addressed in relation to this particular case.


Radioimmunoassay of oestrone in plasma. A comparison of different methods with respect to the relation between assay specificity, sample purification and antibody specificity.
A radioimmunoassay (RIA) for oestrone (Oe1) in plasma was developed using an ether extraction, a partition between NaOH and light petroleum, and a TLC as sample purification and an antiserum cross-reacting with Oe2 for the final assay (Method A1). The reliability criteria are given in detail. In order to simplify this method a highly specific antiserum was developed by using Oe1-3-hemisuccinate-BSA as an antigen. Using this antiserum for the final assay but omitting the TLC (Method B) the Oe1 concentration in male plasma was 76% overestimated (Method B compared with Method A1). In pregnancy plasma Oe1 could specifically be determined after a simple ether extraction (Method C). It was concluded that the use of a highly specific antiserum (as determined by cross-reaction studies) for the final assay does not necessarily imply that a chromatographic sample purification can be omitted without loss in assay specificity. This appears to be true mainly in cases where the steroid concentration of the sample is low. Normal values of Oe1 from 80 healthy adult males were ascertained by Method A1. Age group I (22-61 years, n = 48) ranged from 1.22-5.60 ng/100 ml, median 2.81; age group II (67-90 years, n = 32) from 1.55-6.40, 100 median 3.41. The small increase of Oe1 with age was highly significant.


HIV status among patients with tuberculosis and HIV testing practices by Connecticut health care providers.
Knowing the human immunodeficiency virus (HIV) status of persons infected with Mycobacterium tuberculosis is important for individual treatment and preventing transmission. This evaluation analyzed surveillance data and surveyed health care providers who care for patients with HIV and tuberculosis (TB) to understand the factors contributing to suboptimal levels of Connecticut patients with TB having a known HIV status. During 2008 to 2010, 208 (76.2%) of 273 patients had a known HIV status; 12 (5.8%) were HIV-positive. Patients who were more likely to have a known HIV status were younger (40.5 vs 54.6 years, P < .001) or received care in a TB clinic (risk ratio, 1.26; 95% confidence interval, 1.12-1.42). Among 77 providers, 48 (62.3%) completed the survey, 42 (87.5%) reported routinely offering HIV testing to patients with TB, and 26 (54.2%) reported routinely offering HIV testing to patients with latent TB infection (LTBI). We conclude that interventions for improving HIV testing should focus on non-TB clinic providers and patients with LTBI.


Occupational exposure to airborne asbestos from phenolic molding material (Bakelite) during sanding, drilling, and related activities.
In this study, a historical phenolic (Bakelite) molding material, BMMA-5353, was tested to determine the airborne concentrations of asbestos fibers released during four different activities (sawing, sanding, drilling, and cleanup of dust generated from these activities). Each activity was performed for 30 min, often in triplicate. The primary objective for testing BMMA-5353 was to quantitatively determine the airborne concentration of asbestos fibers, if any, in the breathing zone of workers. Uses of this product typically did not include sawing or sanding, but it may have been drilled occasionally. For this reason, only small quantities were sawed, sanded, and drilled in this simulation study. Personal (n = 40), area (n = 80), and background/clearance (n = 88) air samples were collected during each activity and analyzed for total fiber concentrations using phase contrast microscopy (PCM) and, for asbestos fiber counts, transmission electron microscopy (TEM). The raw PCM-total fiber concentrations were adjusted based on TEM analyses that reported the fraction of asbestos fibers, to derive a PCM-asbestos concentration that would enable calculation of an 8-hour time-weighted average (TWA). The estimated 8-hour TWAs ranged from 0.006 to 0.08 fibers per cubic centimeter using a variety of worker exposure scenarios. Therefore, assuming an exposure scenario in which a worker uses power tools to cut and sand products molded from BMMA-5353 and similar products in the manner evaluated in this study, airborne asbestos concentrations should not exceed current or historical occupational exposure limits.


The family medicine curriculum resource project structural framework.
In the original contract for the Family Medicine Curricular Resource Project (FMCRP), the Health Resources and Services Administration (HRSA), Division of Medicine and Dentistry, charged the FMCRP executive committee with reviewing recent medical education reform proposals and relevant recent curricula to develop an analytical framework for the project. The FMCRP executive and advisory committees engaged in a review and analysis of a variety of curricular reform proposals generated during the last decade of the 20th century. At the same time, in a separate and parallel process, representative individuals from all the family medicine organizations, all levels of learners, internal medicine and pediatric faculty, and the national associations of medical and osteopathic colleges (Association of American Medical Colleges and the American Association of Colleges of Osteopathic Medicine) were involved in group discussions to identify educational needs for physicians practicing in the 21st century. After deliberation, a theoretical framework was chosen for this undergraduate medical education resource that mirrors the Accreditation Council for Graduate Medical Education (ACGME) competencies, a conceptual design originated for graduate medical education. In addition to reflecting the current environment calling for change and greater accountability in medical education, use of the ACGME competencies as the theoretical framework for the FMCR provides a continuum of focus between the two major segments of physician education: medical school and residency.


Outgrowing endothelial and smooth muscle cells for tissue engineering approaches.
In recent years, circulating progenitors of endothelial cells and smooth muscle cells were identified in the peripheral blood. In our study, we evaluated the utilization of both cell types isolated and differentiated from peripheral porcine blood in terms for their use for tissue engineering purposes. By means of density gradient centrifugation, the monocyte fraction from porcine blood was separated, split, and cultivated with specific culture media with either endothelial cell growth medium-2 or smooth muscle cell growth medium-2 for the differentiation of endothelial cells or smooth muscle cells. Obtained cells were characterized at an early stage of cultivation before the first passage and a late stage (fourth passage) on the basis of the expression of the antigens CD31, CD34, CD45, nitric oxide synthase, and the contractile filaments smooth-muscle alpha-actin (sm-alpha-actin) and smoothelin. Functional characterization was done based on the secretion of nitric oxide, the formation of a coherent monolayer on polytetrafluoroethylene, and capillary sprouting. During cultivation in both endothelial cell growth medium-2 and smooth muscle cell growth medium-2, substantially two types of cells grew out: early outgrown CD45-positive cells, which disappeared during further cultivation, and in 85% (n = 17/20) of cultures cultivated with endothelial cell growth medium-2 colony-forming late outgrowth endothelial cells. During cultivation with smooth muscle cell growth medium-2 in 80% (n = 16/20) of isolations colony-forming late outgrowth smooth muscle cells entered the stage. Cultivation with either endothelial cell growth medium-2 or smooth muscle cell growth medium-2 had selective effect on the late outgrown cells to that effect that the number of CD31-positive cells increased from 34.8% ± 13% to 83.9% ± 8% in cultures cultivated with endothelial cell growth medium-2 and the number of sm-α-actin+ cells increased from 52.6% ± 18% to 88% ± 5% in cultures cultivated with smooth muscle cell growth medium-2, respectively. Functional analyses revealed significantly higher levels of nitric oxide secretion, endothelialization capacity, and capillary formation in not expanded cultures cultivated with endothelial cell growth medium-2 in comparison to later stages of cultivation and mature aortic cells. Blood seems to be a reliable and feasible source for the isolation of both endothelial and smooth muscle cells for application in tissue engineering approaches. Whereas, early co-cultures of early and late outgrowth cells provide functional advantages, the differentiation of cells can be directed selectively by the used culture medium for the expansion of highly proliferative late outgrowth endothelial cells and late outgrowth smooth muscle cells, respectively.


An improved method for the establishment of cell lines from primary skin melanomas.
Fourteen explants of primary skin melanomas and six explants of lymph node metastases were used to establish melanocyte cell lines, and in all twenty experiments the melanocytes became overgrown by fibroblasts. By contrast, eight melanocyte cell lines without fibroblast contamination were established by mechanical cell separation followed by either direct plating in microwells (five out of thirteen primary tumours and three out of four lymph node metastases) or plating of cells from colonies grown in soft agar (three out of five cases). It was also observed that cell crowding and partial (as opposed to total) replacement of the culture medium during the early steps of culture favoured the growth of tumour cells. This observation suggests that melanoma cells are subjected to an autocrine type of growth regulation.


Characterization of a hypothetical protein YVRE from Bacillus subtilis indicates its key role as glucono-lactonase in pentose phosphate pathway and glucose metabolism.
Hypothetical proteins are functionally uncharacterized proteins with assigned function using sequence annotation tools. Almost half of the coding regions of several genomes are hypothetical proteins. Therefore, it is of our interest to characterize a hypothetical protein YVRE from the model system Bacillus subtilis using known data. YVRE is assigned the function as a glucono-lactonase using prediction and phylogenetic analysis. A molecular dynamics simulated homology model of YVRE (with calcium) using human senescence marker protein 30 /SMP30 (PDB ID: 3G4E) as template is reported for functional inference. It is observed that the protein possesses bivalent metal binding domain. Molecular docking studies with the substrate glucono-δ-lactone show YVRE binding with the substrate. This data was further validated using cloning and sub-cloning in pUC57 and pET22b+ respectively, followed by expression and purification using nickel affinity chromatography. The activity of YVRE using the substrate glucono-δ-lactone was calculated. The results show the function of YVRE as a gluconolactonase, with higher preference to zinc than calcium or magnesium. Thus, YVRE is shown to play key role in three metabolic pathways namely, pentose phosphate pathway, ascorbate and aldarate metabolism, and caprolactam degradation.


Design considerations in coiled-coil fusion constructs for the structural determination of a problematic region of the human cardiac myosin rod.
X-ray structural determination of segments of the myosin rod has proved difficult because of the strong salt-dependent aggregation properties and repeating pattern of charges on the surface of the coiled-coil that lead to the formation of paracrystals. This problem has been resolved in part through the use of globular assembly domains that improve protein folding and prevent aggregation. The primary consideration now in designing coiled-coil fusion constructs for myosin is deciding where to truncate the coiled-coil and which amino acid residues to include from the folding domain. This is especially important for myosin that contains numerous regions of low predicted coiled-coil propensity. Here we describe the strategy adopted to determine the structure of the region that extends from Arg1677 - Leu1797 that included two areas that do not show a strong sequence signature of a conventional left-handed coiled coil or canonical heptad repeat. This demonstrates again that, with careful choice of fusion constructs, overlapping structures exhibit very similar conformations for the myosin rod fragments in the canonical regions. However, conformational variability is seen around Leu1706 which is a hot spot for cardiomyopathy mutations suggesting that this might be important for function.


Charting and unzipping the surface layer of Corynebacterium glutamicum with the atomic force microscope.
Bacterial surface layers (S-layers) are extracellular protein networks that act as molecular sieves and protect a large variety of archaea and bacteria from hostile environments. Atomic force microscopy (AFM) was used to asses the S-layer of Coryne-bacterium glutamicum formed of PS2 proteins that assemble into hexameric complexes within a hexagonal lattice. Native and trypsin-treated S-layers were studied. Using the AFM stylus as a nanodissector, native arrays that adsorbed to mica as double layers were separated. All surfaces of native and protease-digested S-layers were imaged at better than 1 nm lateral resolution. Difference maps of the topographies of native and proteolysed samples revealed the location of the cleaved C-terminal fragment and the sidedness of the S-layer. Because the corrugation depths determined from images of both sides span the total thickness of the S-layer, a three-dimensional reconstruction of the S-layer could be calculated. Lattice defects visualized at 1 nm resolution revealed the molecular boundaries of PS2 proteins. The combination of AFM imaging and single molecule force spectroscopy allowed the mechanical properties of the Corynebacterium glutamicum S-layer to be examined. The results provide a basis for understanding the amazing stability of this protective bacterial surface coat.


Alveolar distraction osteogenesis in the human mandible: a clinical and histomorphometric study.
To identify the quality of newly formed bone in the distraction region and to determine the percentage of mineralized bone formed in the distraction area. Ten patients with vertically deficient mandibular alveolar ridges were treated by means of distraction osteogenesis. Four months after consolidation of distracted segments, a total of 40 dental implants were inserted in native bone and distracted bone. Bone biopsies were taken at the implant sites with trephine burrs for histological and histometric analyses. Four months after implant placement, abutments were connected, and prosthetic loading of the implants was started. The mean bone gain at the end of distraction was 7.2 ± 0.8 mm. The cumulative success rate of implants 3 years after the onset of prosthetic loading was 100%. The newly formed bone consisted of woven bone reinforced by parallel-fibered bone with bone marrow spaces and the percentage of mineralized bone ranged from 50.56% to 76.88%. Alveolar distraction osteogenesis is able to produce adequate mature bone for the correction of mandibular bone deficits before dental implant insertion.


Inhibitory effect of 18beta-glycyrrhetinic acid on 12-O-tetradecanoyl phorbol-13-acetate-induced cutaneous oxidative stress and tumor promotion in mice.
Glycyrrhetinic acid is an aglycone of glycyrrhizic acid, another major active component of licorice roots. Licorice root extract has been used for a long time as a medicine and a natural sweetening additive. In the present study, we found that glycyrrhetinic acid inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA) mediated oxidative stress and tumor promotion in murine skin. Topical application of TPA alone in mouse skin enhances ornithine decarboxylase activity and also increases [3H]-thymidine incorporation in DNA. Topical application of TPA also resulted in the depletion of glutathione, activities of glutathione metabolizing and antioxidant enzymes. Application of glycyrrhetinic acid prior to TPA treatment reduces this enhanced ODC activity, [3H]-thymidine incorporation in DNA and oxidative stress. Glycyrrhetinic acid was also found to inhibit DMBA/TPA-induced skin tumor formation at doses of 1.25 and 2.5 mg by reducing the number of tumors per mouse by 24% (P < 0.05) and 62% (P < 0.05), respectively. These results suggest that glycyrrhetinic acid, an antioxidant, is a potential chemopreventive agent that can inhibit DMBA/TPA-induced cutaneous oxidative stress and tumor promotion.


Applications of DNA integrating elements: Facing the bias bully.
Retroviruses and DNA transposons are an important part of molecular biologists' toolbox. The applications of these elements range from functional genomics to oncogene discovery and gene therapy. However, these elements do not integrate uniformly across the genome, which is an important limitation to their use. A number of genetic and epigenetic factors have been shown to shape the integration preference of these elements. Insight into integration bias can significantly enhance the analysis and interpretation of results obtained using these elements. For three different applications, we outline how bias can affect results, and can potentially be addressed.


Cleavage of human von Willebrand factor by porcine pancreatic elastase.
von Willebrand factor (vWF) was purified from pooled normal plasma, radiolabeled with iodine then cleaved by porcine pancreatic elastase. Cleavage was monitored by sodium dodecylsulphate-polyacrylamide gel electrophoresis (SDS-PAGE), SDS-agarose electrophoresis, crossed immuno-electrophoresis, ristocetin and botrocetin cofactor activities, and ristocetin and botrocetin induced binding to fixed washed platelets. Cleavage of vWF by porcine elastase was dependent on both the concentration of porcine elastase and period of incubation. Incubation of vWF with concentrations of porcine elastase greater than 20 U/mL for 30 minutes resulted in loss of the 240 Kd vWF subunit and a corresponding loss of the high molecular weight multimers and formation of fragments with molecular weights on reduced SDS-PAGE of 150, 125, 115 Kd and minor bands at 44, 28, and 24 Kd and a band at 20 Kd, which increased in intensity as either the concentration of porcine elastase or the period of incubation increased. More than 50% of the ristocetin cofactor activity was lost during a five-minute incubation of vWF with 0.56 U/mL porcine elastase when no detectable structural changes in the vWF molecule had occurred. Botrocetin cofactor activity was more resistant. Similarly botrocetin induced vWF binding to platelets was retained by a fraction produced by digestion of vWF with porcine elastase, which contained predominantly a 20 Kd fragment of vWF. This fragment retained insignificant amounts of ristocetin related functions and therefore represents a useful piece of the vWF molecule for further exploration of the site involved in botrocetin induced binding to platelets.


Gamma knife: an alternative treatment for acoustic neurinomas.
Despite surgical advances and technologic means of better monitoring seventh and eighth nerve function intraoperatively, there remains a group of patients for whom alternative methods of treatment are desirable. These include the elderly, those with bilateral tumors or tumors in only hearing ears, individuals with medical contraindications to major surgery, and those who refuse surgical resection. The University of Pittsburgh became the fifth world center and the first in the United States to install the "gamma knife" for stereotactic radiosurgery. On the basis of the pioneering work done at the Karolinska Institute in Stockholm, acoustic tumor patients who fulfill the above criteria are being treated. A tumoricidal single treatment closed-skull radiation dose is given through 201 sharply focused cobalt 60 sources, minimizing the effects on surrounding brain or other tissues. Our early results are discussed and compared to those from more than 200 cases in Stockholm. Complications and expected long-term results are presented.


Intrapancreatic schwannoma diagnosed by endoscopic ultrasound-guided fine-needle aspiration cytology.
Schwannoma is a tumor of neuro-ectodermal origin, usually occuring in the head and neck and extremities. A retroperitoneal, and particularly intra-pancreatic presentation is very rare, and poses a clinical and diagnostic challenge. We report a case of a male patient who underwent an Endoscopic Ultrasound-guided Fine Needle Aspiration (EUS-FNA) biopsy of a hypoechoic, intra-pancreatic mass. The onsite cytological evaluation was consistent with a spindle cell neoplasm. Further evaluation, aided by immunohistochemical stains, defined the mass as a Schwannoma. The patient then underwent a pancreaticoduodenectomy and the histopathological diagnosis of the surgical specimen confirmed the cytological diagnosis. To our knowledge, this is the first report of intra-pancreatic Schwannoma diagnosed preoperatively by EUS-FNA cytology.


Methotrexate osteopathy in infants with tumors of the central nervous system.
Methotrexate osteopathy, previously reported as a complication of maintenance-therapy for acute lymphoblastic leukemia, is characterized by osteopenia, particularly involving the lower extremities, thick, dense provisional zones of calcification, growth arrest lines, and corner fractures resembling scurvy. In attempts to postpone radiotherapy in infants under three years of age, the multicentric German therapy protocol for childhood central nervous system tumors (HIT-89 protocol) has employed high cumulative methotrexate doses. Here we describe osteopathy in three patients as a toxic side effect after administration of cumulative methotrexate doses of 20 g/m2, 80 g/m2 and 135 g/m2. The high prevalence of this adverse effect in infants with tumors of the central nervous system may be attributed to the long-term therapy with high cumulative methotrexate-doses. Both factors may favor intracellular accumulation of methotrexate and formation of methotrexate-polyglutamates and may be responsible for bone toxicity. Apparently the susceptibility of the rapidly growing skeletal structures of infants under three years of age to this toxic side effect of methotrexate is remarkably high.


Long-term Outcome of 4 Patients With Transcobalamin Deficiency Caused by 2 Novel TCN2 Mutations.
Cobalamin (vitamin B12 [Cbl]) is an essential cofactor for many biochemical pathways. Transcobalamin (TC) is required to internalize Cbl into the cells through membrane receptor-mediated endocytosis. Cbl is then processed in the cytoplasm and mitochondria by complementation factors leading to its active metabolites; methylcobalamin and 5-deoxyadenosyl-cobalamin. Deficiency of TC results in an elevation in methylmalonic acid and homocysteine. Patients usually present with macrocytic anemia, pancytopenia, failure to thrive, gastrointestinal symptoms, and neurological dysfunction. In this study, we report 4 patients from 2 unrelated families, with confirmed diagnosis of TC deficiency. Patients initially had a typical presentation of TC deficiency: severe diarrhea and vomiting, recurrent infections, stomatitis, macrocytic anemia, and neutropenia. Interestingly one of the patients was diagnosed at 3 months of age and developed ataxic gait related to cerebellar atrophy at the age of 14 months. His elder affected sibling was diagnosed at 5 months of age was completely normal. Two sibs, diagnosed at 2 months of age and immediately after birth, had autism spectrum disorder. Molecular investigations showed 2 novel mutations in TCN2 gene. Patients were treated and stayed stable on weekly injection of Cbl. In conclusion, TC deficiency has a wide heterogeneity in clinical phenotype, genotype, laboratory, and radiologic findings. Early detection of the disease and early initiation of aggressive parenteral treatment is probably associated with better prognosis and disease control.


The health system: what should our priorities be?
The way the health system is organised is a critically important social determinant of health. Australia's current health system funding arrangements contain serious barriers to effective health promotion and chronic disease management. The consequences are most evident among disadvantaged people. Major health system reform is needed in Australia to rectify this problem. This paper describes current mechanisms for funding health care in Australia and examines a recent reform experiment, the Co-ordinated Care Trials. It discusses why the trials were unsuccessful and identifies key criteria for future success. Three existing proposals for health system reform are assessed against these criteria - managed competition, a Commonwealth takeover of health and medical saving accounts. Successful reform of Australia's health system will need to ensure that more flexible services are delivered, changes are made on a large scale to affect demand and strong incentives to use cost-effective services are put in place. Of the models considered, managed competition best meets these criteria and is most likely to reduce health disparities and improve health promotion and disease prevention. A Commonwealth takeover of health funding is a less ambitious alternative but because of this, it is also likely to have less impact. It is doubtful whether medical savings accounts meet any of the criteria for success and they would also require a fundamental change in the values that underpin the Austrlian health system. Recent reforms of Australia's health system have been too small and have had little impact. Although radical reform of the health system is politically unpalatable and extremely rare, it may be the only way Australia will be able to meet the health challenges of the 21st Century.


Situational factors involved in college students' safer and risky sexual encounters.
To ascertain the differences between the situational factors of risky and safer sexual encounters in college students. Descriptive. Community-dwelling college students from a large Midwestern university. Participants were 84 college students ages 18 to 20 years. Fifty-five were female (67.5%), the majority (95.2%) were White, and all reported being heterosexual. Use of safer or risky practices in last or most memorable sexual encounter. Important situational characteristics of safer encounters were negative ambiance of the place, type of partner, unattractive qualities of the partner, communication with the partner, and having the encounter because of feeling desire. Important situational characteristics of risky encounters were a cozy ambiance, partner's attractiveness inducing desire, asking directly for the encounter, and encounters occurring after celebration or partying. Many characteristics were similar for both risk groups. However, practitioners can tailor interventions to make clients aware of factors that were more prevalent in risky sexual encounters, such as having the encounter with a boyfriend or girlfriend and having an encounter after drinking alcohol and partying.


Biological modifier therapy for the treatment of rheumatoid arthritis.
The recent elucidation of pathogenic processes involving tumor necrosis factor alpha and interleukin-1beta in the pathogenesis and persistence of rheumatoid arthritis led to the development of biological modifier agents that have had significant impact on disease severity and progression. These agents--etanercept, infliximab, and anakinra--produce a dramatic reduction in RA disease activity with relatively low toxicity compared with currently available disease-modifying antirheumatic drugs. The main prohibition to their broader utilization is cost. The success of these agents underscores the investigative approaches to the pathogenesis of RA and the appropriate design of pharmaceutical agents to target specific proinflammatory molecules.


Prospective partially randomized comparison of clopidogrel loading versus maintenance dosing to prevent periprocedural myocardial infarction after stenting for stable angina pectoris: Results from the "Method of Clopidogrel Pre-treatment Undergoing Conventional Coronary Angiogram in Angina Patients (MECCA)" study.
Pre-treatment of clopidogrel 600 mg is better than 300 mg loading for reducing periprocedural myocardial infarction (PMI). We aimed to evaluate pre-treatment methods for preventing PMI among patients undergoing conventional coronary angiography (CAG) for stable angina pectoris. The study analyzed 402 patients who underwent percutaneous coronary intervention (PCI) during 2010 - 2011 at three Korean hospitals. Clopidogrel-naïve patients received routine maintenance therapy (75 mg/day for ≥ 5 days) and were randomly assigned to a 300-mg reload (RL) or only the maintenance dose (MD). Patients who received a loading dose (LD; 600 mg at 2 - 24 hours before the procedure) were entered into a non-randomized group. After excluding patients who showed an abnormal creatinine kinase myocardial band (CK-MB) level, the study included 233 patients in the LD group, 85 patients in the RL group and 84 patients in the MD group. The LD group had a significantly higher rate of PMI (LD: 21, RL: 3, MD: 0 cases; p = 0.007) and a significant increase in the mean CK-MB levels after 8 hours (p = 0.016) and 24 h (p = 0.01). However, there was no difference in PMI between the RL and MD groups. Furthermore, no significant differences between the three groups were observed in the P2Y12 reaction unit (PRU) values (p = 0.57). Albeit not significantly, the LD group had a higher rate of moderate-to-severe GUSTO bleeding within 7 days. Clopidogrel maintenance is better than 600-mg loading for preventing PMI, and the RL protocol did not further prevent PMI.


Role of IGF-1/IGF-1R in regulation of invasion in DU145 prostate cancer cells.
Prostate cancer progression to androgen independence is the primary cause of mortality by this tumor type. The IGF-1/IGF-1R axis is well known to contribute to prostate cancer initiation, but its contribution to invasiveness and the downstream signalling mechanisms that are involved are unclear at present. We examined the invasive response of androgen independent DU145 prostate carcinoma cells to IGF-1 stimulation using Matrigel assays. We then examined the signaling mechanisms and protease activities that are associated with this response. IGF-1 significantly increased the invasive capacity of DU145 cells in vitro, and this increase was inhibited by blocking IGF-1R. We further demonstrated that specific inhibitors of the MAPK and PI3-K pathways decrease IGF-1-mediated invasion. To determine potential molecular mechanisms for this change in invasive capacity, we examined changes in expression and activity of matrix metalloproteinases. We observed that IGF-1 increases the enzymatic activity of MMP-2 and MMP-9 in DU145 cells. These changes in activity are due to differences in expression in the case of MMP-9 but not in the case of MMP-2. This observation is corroborated by the fact that correlated changes of expression in a regulator of MMP-2, TIMP-2, were also seen. This work identifies a specific effect of IGF-1 on the invasive capacity of DU145 prostate cancer cells, and furthermore delineates mechanisms that contribute to this effect.


Protein names precisely peeled off free text.
Automatically identifying protein names from the scientific literature is a pre-requisite for the increasing demand in data-mining this wealth of information. Existing approaches are based on dictionaries, rules and machine-learning. Here, we introduced a novel system that combines a pre-processing dictionary- and rule-based filtering step with several separately trained support vector machines (SVMs) to identify protein names in the MEDLINE abstracts. Our new tagging-system NLProt is capable of extracting protein names with a precision (accuracy) of 75% at a recall (coverage) of 76% after training on a corpus, which was used before by other groups and contains 200 annotated abstracts. For our estimate of sustained performance, we considered partially identified names as false positives. One important issue frequently ignored in the literature is the redundancy in evaluation sets. We suggested some guidelines for removing overly inadequate overlaps between training and testing sets. Applying these new guidelines, our program appeared to significantly out-perform other methods tagging protein names. NLProt was so successful due to the SVM-building blocks that succeeded in utilizing the local context of protein names in the scientific literature. We challenge that our system may constitute the most general and precise method for tagging protein names. http://cubic.bioc.columbia.edu/services/nlprot/


The relation of inattention and hyperactivity-impulsivity to peer dislike: An examination of potential mediators.
Children who exhibit inattention (IA) and hyperactivity-impulsivity (HI), symptoms often indicative of attention-deficit/hyperactivity disorder (ADHD), have notable social impairments. We investigated whether IA and HI are directly connected to peer difficulties or indirectly connected through their known association with other problem behaviors. Quadratic assignment procedures (QAP) were employed to address the main study questions: Is the relation between a child reporting not wanting to play with a peer who they perceive as HI and/or IA mediated by the child's perception of that same peer as reactively aggressive, instrumentally aggressive, and/or anxiously withdrawn? Participants were 387 fourth and fifth graders nested in 21 classroom-based peer networks. Participants nominated classroom peers as IA, HI, aggressive, anxiously withdrawn, and as liked-least. Analyses were conducted separately for each classroom-based peer network, and meta-analytic procedures were used to compile results and calculate effect sizes across networks. Controlling for gender homophily between nominators and nominees, logistic regression QAPs indicated that reactive and instrumental aggression do not mediate the relation between IA/HI and peer dislike but, rather, add unique information beyond IA/HI. In contrast, nominating a peer as anxious-withdrawn was not tied to nominating that same peer as IA, HI, or disliked. The results suggest that children find IA and HI aversive enough to contribute to their disliking of peers who exhibit these behaviors, even when accounting for co-occurring aggressive behaviors. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Neurocognitive components of the behavioral inhibition and activation systems: implications for theories of self-regulation.
We examined the neurocognitive correlates of the Behavioral Inhibition and Behavioral Activation Systems (BIS/BAS) in an effort to clarify ambiguities concerning interpretations of BIS as reflecting inhibition versus avoidance. We hypothesized that self-reported BIS should relate to neural mechanisms associated with conflict monitoring, whereas self-reported BAS should be associated with neural correlates of approach motivation. Consistent with these predictions, higher self-reported BIS was uniquely related to the N2 event-related potential on No-Go trials of a Go/No-Go task, linking BIS with conflict monitoring and sensitivity to No-Go cues. Higher BAS was uniquely related to greater left-sided baseline frontal cortical asymmetry associated with approach orientation. Implications for theories of self-regulation involving conflict monitoring, cognitive control, and approach/avoidance motivation are discussed.


Fatal poisoning by isoniazid and rifampicin.
Isoniazid and rifampicin are used for management of tuberculosis. Acute poisoning due to isoniazid overdose is associated with repetitive generalized tonic-clonic seizures and severe metabolic acidosis. In toxic doses, rifampicin is known to produce hepatic, renal, hematological disorders, and convulsions. Sometimes, it may produce red man syndrome. We report a case of fatal poisoning with isoniazid and rifampicin. The case was characterized by late presentation, lactic acidosis, and renal failure.


Multimodal endoscope can quantify wide-field fluorescence detection of Barrett's neoplasia.
To demonstrate the clinical use of a multimodal endoscope with a targeted fluorescently labeled peptide for quantitative detection of Barrett's neoplasia. We studied 50 patients with Barrett's esophagus using a prototype multimodal endoscope with a fluorescently labeled peptide. Co-registered fluorescence and reflectance images were converted to ratios to correct for differences in distance and geometry over the image field of view. The ratio images were segmented using a unique threshold that maximized the variance between high and low intensities to localize regions of high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Early neoplasia (HGD and EAC) was identified with 94 % specificity and 96 % positive predictive value at a threshold of 1.49. The mean results for HGD and EAC were significantly greater than those for squamous/Barrett's esophagus and low grade dysplasia by one-way analysis of variance (ANOVA). The receiver operator characteristic curve for detection of early neoplasia had an area under the curve of 0.884. No adverse events associated with the endoscope or peptide were found. A multimodal endoscope can quantify fluorescence images from targeted peptides to localize early Barrett's neoplasia. (ClinicalTrials.gov number NCT01630798.).


Controlled slow release of chemotherapeutic drugs for cancer from matrices prepared by radiation polymerization at low temperatures.
The vinyl polymer-chemotherapeutic agent composites of various shapes (rod, tablet, membrane, microsphere, and powder) were prepared by radiation polymerization at low temperatures for the purpose of durable controlled slow release of drugs from implanted matrices. Bleomycin hydrochloric acid, mitomycin C, and 5-fluorouracil were tested as chemotherapeutic drugs entrapped in poly(diethylene glycol dimethacrylate) including a small quantity of a polymer such as poly(styrene), poly(vinyl formal), poly(vinyl acetate), poly(methyl methacrylate) on polyethylene glycol No. 600. The release rates from the matrices depended much on the kind of polymer, drug, and monomer concentration in polymerization and also on the shape of the composite. The release of these drugs from polymer matrices obeyed the diffusion-controlled release mechanism based on Higuchi's equation and was durable for more than thirty days. It was found that the release rate can be controlled easily by design of the shapes and structures of the polymer matrices.


How does experience change cognition? Evaluating the evidence.
Schellenberg (2011) reports the results of an experiment to determine the cause of the association between music training and intelligence quotient (IQ) in children. There was no difference between trained and untrained groups in a set of executive function tasks and no evidence that executive function mediated the effects of music training on IQ, since music training and IQ remained related after controlling for executive function performance. Therefore, he concludes that children with high IQs are more likely to take music lessons, assigning responsibility for the reported correlation to genetic differences in intelligence. The present article challenges that conclusion by discussing the nature of the experience represented by children in the two groups, the validity of the tasks used to measure executive functioning, and the logic of the conclusion from the reported data.


Quantum synchronization and quantum state sharing in an irregular complex network.
We investigate the quantum synchronization phenomenon of the complex network constituted by coupled optomechanical systems and prove that the unknown identical quantum states can be shared or distributed in the quantum network even though the topology is varying. Considering a channel constructed by quantum correlation, we show that quantum synchronization can sustain and maintain high levels in Markovian dissipation for a long time. We also analyze the state-sharing process between two typical complex networks, and the results predict that linked nodes can be directly synchronized, but the whole network will be synchronized only if some specific synchronization conditions are satisfied. Furthermore, we give the synchronization conditions analytically through analyzing network dynamics. This proposal paves the way for studying multi-interaction synchronization and achieving effective quantum information processing in a complex network.


Improvement in perioperative care in pediatric cardiac surgery by shifting the primary focus of treatment from cardiac output to perfusion pressure: Are beta stimulants still needed?
An important aspect of perioperative care in pediatric cardiac surgery is maintenance of optimal hemodynamic status using vasoactive/inotropic agents. Conventionally, this has focused on maintenance of cardiac output rather than perfusion pressure. However, this approach has been abandoned in our center in favor of one focusing primarily on perfusion pressure, which is presented here and compared to the conventional approach. A retrospective study. Regional center for congenital heart disease. University Hospital of Lausanne, Switzerland. All patients with Aristotle risk score ≥8 that underwent surgery from 1996 to 2012 were included. Patients operated between 1996 and 2005 (Group 1: 206 patients) were treated according to the conventional approach. Patients operated between 2006 and 2012 (Group 2: 217 patients) were treated according to our new approach. All patients had undergone surgery for correction or palliation of congenital cardiac defects. Mortality, duration of ventilation and inotropic treatment, use of ECMO, and complications of poor peripheral perfusion (need for hemofiltration, laparotomy for enterocolitis, amputation). The two groups were similar in age and complexity. Mortality was lower in group 2 (7.3% in group 1 vs 1.4% in group 2, P < .005). Ventilation times (hours) and number of days on inotropic/vasoactive treatment (all agents), expressed as median and interquartile range [Q1-Q3] were shorter in group 2: 69 [24-163] hours in group 1 vs 35 [22-120] hours in group 2 (P < .01) for ventilation, and 9 [3-5] days in group 1 vs 7 [2-5] days in group 2 (P < .05) for inotropic/vasoactive agents. There were no differences in ECMO usage or complications of peripheral perfusion. Results in pediatric cardiac surgery may be improved by shifting the primary focus of perioperative care from cardiac output to perfusion pressure.


Oral Nanotherapeutics of Andrographolide/Carbon Monoxide Donor for Synergistically Anti-inflammatory and Pro-resolving Treatment of Ulcerative Colitis.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology affecting the colon and rectum. Current therapeutics are focused on suppressing inflammation but are ineffective. Combining anti-inflammatory therapeutic approaches with pro-resolution might be a superior strategy for UC treatment. Andrographolide (AG), an active compound from the plant Andrographis paniculata, presented anti-inflammatory effects in various inflammatory diseases. Gaseous mediators, such as carbon monoxide (CO), have a role in inflammatory resolution. Herein, we developed a dextran-functionalized PLGA nanocarrier for efficient delivery of AG and a carbon monoxide donor (CORM-2) for synergistically anti-inflammatory/pro-resolving treatment of UC (AG/CORM-2@NP-Dex) based on PLGA with good biocompatibility, slow drug release, efficient targeting, and biodegradability. The resulting nanocarrier had a nano-scaled diameter of ∼200 nm and a spherical shape. After being coated with dextran (Dex), the resulting AG/CORM-2@NP-Dex could be efficiently internalized by Colon-26 and Raw 264.7 cells in vitro and preferentially localized to the inflamed colon with chitosan/alginate hydrogel protection by gavage. AG/CORM-2@NP-Dex performed anti-inflammatory effects by eliminating the over-production of pro-inflammatory mediator, nitric oxide (NO), and down-regulating the expression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), while it showed pro-resolving function by accelerating M1 to M2 macrophage conversion and up-regulating resolution-related genes (IL-10, TGF-β, and HO-1). In the colitis model, oral administration of AG/CORM-2@NP-Dex in a chitosan/alginate hydrogel also showed synergistically anti-inflammatory/pro-resolving effects, therefore relieving UC effectively. Without appreciable systemic toxicity, this bifunctional nanocarrier represents a novel therapeutic approach for UC and is expected to achieve long-term inflammatory remission.


5-Cyclo-hexyl-3-cyclo-hexyl-sulfonyl-2-methyl-1-benzofuran.
In the title compound, C(21)H(28)O(3)S, the benzofuran unit is essentially planar, with a mean deviation of 0.016 (1) Å from the least-squares plane defined by the nine constituent atoms. Both cyclo-hexane rings adopt chair conformations.


Inhibition effect of glycyrrhizin in lipopolysaccharide-induced high-mobility group box 1 releasing and expression from RAW264.7 cells.
High-mobility group box 1 (HMGB1) is a therapeutic target for sepsis. Glycyrrhizin (GL) is the aglycone of glycyrrhizin derived from licorice. We clarified the anti-inflammatory effects of GL. We explored the anti-HMGB1 effect of GL and elucidated its molecular mechanism, which will be of benefit for sepsis treatment. We stimulated murine macrophage-like RAW 264.7 cells with lipopolysaccharide (LPS) and LPS + GL, then measured the expression and release of HMGB1. The expression of related signal transduction factors was detected. High-mobility group box 1 was distributed mainly in the nucleus with lower cytoplasmic levels in RAW 264.7 cells before LPS stimulation. After stimulation, cytoplasmic HMGB1 levels increased gradually, whereas in nuclear fluctuation a trend of HMGB1 expression was observed. Significant upregulation of HMGB1 mRNA occurred 12 h after LPS stimulation. Glycyrrhizin prevented the transfer of HMGB1 from the nucleus to the cytoplasm and inhibited upregulation of HMGB1 mRNA induced by LPS. Phospho-p38 mitogen-activated protein kinase and activated activating protein 1 increased significantly 8 h after LPS stimulation. Tumor necrosis factor α and interleukin 6 increased 4 h after LPS stimulation and peaked at 48 h, and HMGB1 increased at 8 h. The Toll-like receptor 4/MD2/nuclear factor κB signaling pathway was activated 4 h after LPS stimulation. Glycyrrhizin inhibited this pathway. Glycyrrhizin inhibited the expression and release of HMGB1 through blocking the p38 mitogen-activated protein kinase/activating protein 1 signaling pathway then inhibited the massive release of tumor necrosis factor α and interleukin 6.


Restraint stress slows cutaneous wound healing in mice.
The impact of stress on cutaneous wound healing was assessed in a murine model. Female, hairless SKH-1 mice, 6-8 weeks of age were subjected to restraint stress (RST) 3 days before and for 5 days following dorsal application of a 3.5-mm sterile punch wound. Control mice were wounded, but not restrained. Using photography and image analysis, the rate of wound healing was compared between the two groups. Wounds on control mice healed on average 3.10 days sooner than RST-treated mice. In addition, cross-sectional, morphometric analysis of the dermal and epidermal layers revealed reduced inflammation surrounding wounds from RST mice at 1, 3, and 5 days after wounding. In the RST group, serum corticosterone levels averaged 162.5 ng/ml compared to 35.7 ng/ml in the controls. Treatment of RST-stressed animals with the glucocorticoid receptor antagonist RU40555 resulted in healing rates comparable to those of control animals. Thus, the reduction in inflammation and delayed healing correlated with serum corticosterone levels and suggest that disruption of neuroendocrine homeostasis modulates wound healing.


Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial.
Rituximab is effective as therapy for induction of remission in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the effect of rituximab is not sustained, and subsequent relapse rates are high, especially in patients with a history of relapse. There is a need to identify whether maintenance therapy with rituximab is superior to the current standard of azathioprine or methotrexate for prevention of relapse following induction with rituximab. RITAZAREM is an international, multicenter, open-label, randomized controlled trial designed to demonstrate the superiority of repeated doses of intravenous rituximab compared to daily orally administered azathioprine as a relapse prevention strategy in patients with AAV with relapsing disease who undergo induction of remission with rituximab. Patients with AAV will be recruited at the time of relapse and will receive rituximab and glucocorticoid induction therapy. If the disease is controlled by 4 months, patients will be randomized in a 1:1 ratio to receive rituximab (1000 mg every 4 months for five doses) or azathioprine (2 mg/kg/day) as maintenance therapy. Patients will be followed for a minimum of 36 months. The primary outcome is the time to disease relapse. It is estimated that 190 patients will need to be recruited to ensure that at least 160 are randomized. The RITAZAREM trial will provide the largest trial dataset for the use of rituximab as remission-induction therapy for patients with AAV comparing two remission-maintenance strategies following induction with rituximab, and explore whether prolonged B-cell depletion leads to sustained treatment-free remissions after discontinuation of immunosuppressive therapy. ClinicalTrials.gov identifier: NCT01697267 . Registered on 31 August 2012.


Giant cell arteritis in a 12-year-old girl presenting with nephrotic syndrome.
Giant cell arteritis (GCA) is rare in children. The kidneys are generally spared. We present a case of GCA in a 12-year-old girl with severe headache and tender scalp especially over the right temporal area. The right superficial temporal artery was cord like and nodular and the pulsations were barely felt. Several small tender nodular swellings were felt in the occipital area. She had been previously diagnosed as a case of nephrotic syndrome due to underlying membranoproliferative glomerulonephritis. This report is aimed at drawing attention to this rare form of vasculitis in children aiming at decreasing its morbidities.


Lack of mutations in the leptin receptor gene in severely obese children.
To analyze the LEPR gene in obese children and to investigate the associations between molecular findings and anthropometric and metabolic features. Thirty-two patients were evaluated regarding anthropometric characteristics, blood pressure, heart rate, serum glucose, insulin, leptin levels, and lipid profile. The molecular study consisted of the amplification and automatic sequencing of the coding region of LEPR in order to investigate new mutations. We identified a high prevalence of metabolic disorders: impaired fasting glucose in 12.5% of the patients, elevated HOMA-IR in 85.7%, low HDL-cholesterol levels in 46.9%, high triglyceride levels in 40.6%, and hypertension in 58.6% of the patients. The molecular study identified 6 already described allelic variants: rs1137100 (exon-2), rs1137101 (exon-4), rs1805134 (exon-7), rs8179183 (exon-12), rs1805096 (exon-18), and the deletion/insertion of the pentanucleotide CTTTA at 3'untranslated region. The frequency of alleles observed in this cohort is similar to that described in the literature, and was not correlated with any clinical feature. The molecular findings in the analysis of the LEPR did not seem to be implicated in the etiology of obesity in these patients.


Characterization of the chemokine CXCL11-heparin interaction suggests two different affinities for glycosaminoglycans.
Chemokines orchestrate the migration of leukocytes in the context of homeostasis and inflammation. In addition to interactions of chemokines with receptors on migrating cells, these processes require interactions of chemokines with glycosaminoglycans (GAGs) for cell surface localization. Most chemokines are basic proteins with Arg/Lys/His residue clusters functioning as recognition epitopes for GAGs. In this study we characterized the GAG-binding epitopes of the chemokine I-TAC/CXCL11. Four separate clusters of basic residues were mutated to alanine and tested for their ability to bind to GAGs in vitro and to activate the receptor, CXCR3. Mutation of a set of basic residues in the C-terminal helix (the 50s cluster, (57)KSKQAR(62)) along with Lys(17), significantly impaired heparin binding in vitro, identifying these residues as components of the dominant epitope. However, this GAG mutant retained nearly wild type receptor binding affinity, and its ability to induce cell migration in vitro was only mildly perturbed. Nevertheless, the mutant was unable to induce cell migration in vivo, establishing a requirement of CXCL11 for GAG binding for in vivo function. These studies also led to some interesting findings. First, CXCL11 exhibits conformational heterogeneity, as evidenced by the doubling of peaks in its HSQC spectra. Second, it exhibits more than one affinity state for both heparin and CXCR3, which may be related to its structural plasticity. Finally, although the binding affinities of chemokines for GAGs are typically weaker than interactions with receptors, the high affinity GAG binding state of CXCL11 is comparable with typical receptor binding affinities, suggesting some unique properties of this chemokine.


The associations among well-being comparisons and affective styles in depression, anxiety, and mental health quality of life.
Frame-of-reference theories suggest that individuals use different comparison types to evaluate their well-being. Research indicates that the frequency of aversive well-being comparisons is related to depression, with engendered comparison affective impact partly accounting for this relationship. We aimed to replicate this finding, examine whether this extends to anxiety and mental health quality of life, and whether these pathways are moderated by affective styles of concealing, adjusting, and tolerating. We expected concealing as a response-focused style to be associated with higher effects of comparison affective impact on depression, anxiety, and mental health quality of life. Adjusting as an antecedent-focused strategy was expected to mitigate the effects of aversive comparison frequency on comparison affective impact, and the effects of comparison affective impact on the outcomes. Finally, tolerating was expected to be associated with lower effects on both pathways. Participants (N = 596) responded to measures of well-being comparisons, affective styles, depression, anxiety, and mental health quality of life. Frequency of aversive well-being comparisons was associated with all outcomes. These relationships were partially mediated by comparison affective impact. Adjustment moderated the pathway between aversive comparison frequency and comparison affective impact. No other moderation effect emerged. The comparison process appears important in well-being evaluations.


Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia.
Apoptotic neuronal cell death has recently been associated with the development of infarction after cerebral ischemia. In a variety of studies, CuZn-superoxide dismutase (CuZn-SOD) has been shown to protect the brain from ischemic injury. A possible role for CuZn-SOD-related modulation of neuronal viability is suggested by the finding that CuZn-SOD inhibits apoptotic neuronal cell death in response to some forms of cellular damage. We evaluated this possibility in the model of transient focal cerebral ischemia in mice bearing a disruption of the CuZn-SOD gene (Sod1). Homozygous mutant (Sod1 -/-) mice had no detectable CuZn-SOD activity, and heterozygous mutants (Sod1 +/-) showed a 50% decrease compared with wild-type mice. Sod1 -/- mice showed a high level of blood-brain barrier disruption soon after 1 hr of middle cerebral artery occlusion and 100% mortality at 24 hr after ischemia. Sod1 +/- mice showed 30% mortality at 24 hr after ischemia, and neurological deficits were exacerbated compared with wild-type controls. The Sod1 +/- animals also had increased infarct volume and brain swelling, accompanied by increased apoptotic neuronal cell death as indicated by the in situ nick-end labeling technique to detect DNA fragmentation and morphological criteria. These results suggest that oxygen-free radicals, especially superoxide anions, are an important factor for the development of infarction by brain edema formation and apoptotic neuronal cell death after focal cerebral ischemia and reperfusion.


Effects of acetazolamide on transient K+ currents and action potentials in nodose ganglion neurons of adult rats.
The aim of the present study was to determine whether acetazolamide (AZ) contributes to the inhibition of the fast inactivating transient K(+) current (I(A) ) in adult rat nodose ganglion (NG) neurons. We have previously shown that pretreatment with either AZ or 4-AP attenuated or blocked the CO(2) -induced inhibition of slowly adapting pulmonary stretch receptors in in vivo experiments. The patch-clamp experiments were performed by using the isolated NG neurons. In addition to this, the RT-PCR of mRNA and the expression of voltage-gated K(+) (Kv) 1.4, Kv 4.1, Kv 4.2, and Kv 4.3 channel proteins from nodose ganglia were examined. We used NG neurons sensitive to the 1 mM AZ application. The application of 1 mM AZ inhibited the I(A) by approximately 27% and the additional application of 4-AP (1 mM) further inhibited I(A) by 48%. The application of 0.1 μM α-dendrotoxin (α-DTX), a slow inactivating transient K(+) current (I(D) ) blocker, inhibited the baseline I(A) by approximately 27%, and the additional application of 1 mM AZ further decreased the I(A) by 51%. In current clamp experiments, AZ application (1 mM) increased the number of action potentials due to the decreased duration of the depolarizing phase of action potentials and/or due to a reduction in the resting membrane potential. Four voltage-gated K(+) channel proteins were present, and most (80-90%) of the four Kv channels immunoreactive neurons showed the co-expression of carbonic anhydrase-II (CA-II) immunoreactivity. These results indicate that the application of AZ causes the reduction in I(A) via the inhibition of four voltage-gated K(+) channel (Kv) proteins without affecting I(D).


The structure of the notation system in adults' number line estimation: An eye-tracking study.
Research on rational numbers suggests that adults experience more difficulties in understanding the numerical magnitude of rational than natural numbers. Within rational numbers, the numerical magnitude of fractions has been found to be more difficult to understand than that of decimals. Using a number line estimation (NLE) task, the current study investigated two sources of difficulty in adults' numerical magnitude understanding: number type (natural vs rational) and structure of the notation system (place-value-based vs non-place-value-based). This within-subjects design led to four conditions: natural numbers (natural/place-value-based), decimals (rational/place-value-based), fractions (rational/non-place-value-based), and separated fractions (natural/non-place-value-based). In addition to percentage absolute error (PAE) and response times, we collected eye-tracking data. Results showed that participants estimated natural and place-value-based notations more accurately than rational and non-place-value-based notations, respectively. Participants were also slower to respond to fractions compared with the three other notations. Consistent with the response time data, eye-tracking data showed that participants spent more time encoding fractions and re-visited them more often than the other notations. Moreover, in general, participants spent more time positioning non-place-value-based than place-value-based notations on the number line. Overall, the present study contends that when both sources of difficulty are present in a notation (i.e., both rational and non-place-value-based), adults understand its numerical magnitude less well than when there is only one source of difficulty present (i.e., either rational or non-place-value-based). When no sources of difficulty are present in a notation (i.e., both natural and place-value-based), adults have the strongest understanding of its numerical magnitude.


Effects of testosterone upon the chest-rubbing behavior of Galago crassicaudatus umbrosus.
The chest-rubbing behavior of 8 male greater galagos was studied. Castration of 4 males resulted in a sharp decrease in chest-marking, while testosterone replacement therapy resulted in an increased frequency. The 4 male controls generally maintained a stable relationship between chest-rubbing frequency and serum testosterone levels. Results of the study indicate that while chest-rubbing frequency may initially vary individually in relation to testosterone levels, drastic fluctuations in serum testosterone are accompanied by a corresponding fluctuation in chest-rubbing behavior.


Enhanced Performance of Protonic Solid Oxide Steam Electrolysis Cell of Zr-Rich Side BaZr0.6Ce0.2Y0.2O3-δ Electrolyte with an Anode Functional Layer.
Proton-conducting solid oxide electrolysis cells (H-SOEC) containing a 15-μm-thick BaZr0.6Ce0.2Y0.2O3-δ (BZCY622) electrolyte thin film, porous cathode cermet support, and La0.6Sr0.4Co0.2Fe0.8O3-δ anodes were fabricated using a reactive cofiring process at approximately 1400 °C. Steam electrolysis was conducted by supplying wet air to the anode at a water partial pressure of 20 kPa. The performance was evaluated using electrochemical measurements and gas chromatography. At 600 °C, the cells generated an electrolysis current of 0.47 A cm-2 at a 1.3 V bias while the Faradaic efficiency reached 56% using 400 mA cm-2. The electrolysis performance was efficiently improved by introducing a 40-nm-thick La0.5Sr0.5CoO3-δ (LSC) nanolayer as an anode functional layer (AFL). The cells with LSC AFL produced an electrolysis current of 0.87 A cm-2 at a 1.3 V bias at 600 °C, and the Faradaic efficiency reached 65% under 400 mA cm-2. Impedance analysis showed that the introduction of the AFL decreased the ohmic resistances and improved interfacial proton transfer across the anode/electrolyte interface and polarization resistances related to the anode reaction. These results demonstrate opportunities for future research on AFL to improve the performance of H-SOECs with Zr-rich BaZr x Ce1-x-y Y y O3-δ electrolytes.


Furlow Palatoplasty for Velopharyngeal Dysfunction Management: Auditing and Predicting Outcomes.
The Furlow palatoplasty is a proven procedure in the management of secondary velopharyngeal dysfunction in patients with cleft palate. But the selection of cases, the degree of clinical success, and the preoperative predictors of the same are less established. This study is an effort to retrospectively look at outcomes, in a large series of velopharyngeal dysfunction cases treated with the Furlow palatoplasty alone. Retrospective analysis of preoperative and postoperative speech and videofluoroscopic data. Tertiary care center. Ninety-two patients who were diagnosed with velopharyngeal dysfunction post primary cleft palate repair. Furlow palatoplasty for velopharyngeal dysfunction post primary cleft palate repair. Variables analyzed were perceptual speech parameters and, closure ratios obtained from lateral video-fluoroscopic images. Overall, 81.5% had postoperative improvements in their lateral video-fluoroscopic parameters, 63% improved their nasality scores, and 65.2% had improved speech intelligibility. A simple linear regression was done to predict the postoperative closure ratio. Preoperative closure ratio, hypernasality (moderate and severe), and audible nasal air emission are predictors for postoperative closure ratio. The Furlow palatoplasty alone led to complete resolution, or significant improvement of velopharyngeal dysfunction in a majority of patients, despite the cohort having a wide range of severity in terms of degree of dysfunction. The predictive formula will be validated in a further study.


Vegetarianism, coronary disease risk factors and coronary heart disease.
Recent studies of vegetarians confirm a lower risk of fatal heart disease amongst such subjects. Lipid levels are lower in vegetarians, even when the diet of comparable meat-eaters is low in fat. This may partly explain the lower mortality, but it is not clear whether the absence of meat or some other aspect of the vegetarian diet is causal in this relationship.


Harriet Tubman's last work: the Harriet Tubman Home for Aged and Indigent Negroes.
This article focuses on the important contributions the venerable Harriet Tubman made to the field of housing for older persons and other populations at risk. It uses an historical approach to document the importance of early housing and self-help initiatives in the African American community. It embraces Harriet Tubman and other early housers for their good works and acknowledges them as contributors to the rich legacy of community social work practice and its sage principles of empowerment and self-help. The article presents a nexus between the current housing status of older Blacks and the double jeopardy status imposed by historical discrimination.


Investigate the Effect of Thawing Process on the Self-Assembly of Silk Protein for Tissue Applications.
Biological self-assembly is a process in which building blocks autonomously organize to form stable supermolecules of higher order and complexity through domination of weak, noncovalent interactions. For silk protein, the effect of high incubating temperature on the induction of secondary structure and self-assembly was well investigated. However, the effect of freezing and thawing on silk solution has not been studied. The present work aimed to investigate a new all-aqueous process to form 3D porous silk fibroin matrices using a freezing-assisted self-assembly method. This study proposes an experimental investigation and optimization of environmental parameters for the self-assembly process such as freezing temperature, thawing process, and concentration of silk solution. The optical images demonstrated the possibility and potential of -80ST48 treatment to initialize the self-assembly of silk fibroin as well as controllably fabricate a porous scaffold. Moreover, the micrograph images illustrate the assembly of silk protein chain in 7 days under the treatment of -80ST48 process. The surface morphology characterization proved that this method could control the pore size of porous scaffolds by control of the concentration of silk solution. The animal test showed the support of silk scaffold for cell adhesion and proliferation, as well as the cell migration process in the 3D implantable scaffold.


Relation of secondhand smoking to mild cognitive impairment in older inpatients.
Up to now, controversy still exists regarding the role of secondhand smoking (SHS) in developing cognitive impairment. This study aimed to evaluate the prevalence of SHS in hospitalized older patients with cognitive deficit, particularly in those with mild cognitive impairment (MCI). Smoking history was classified into four groups: never smokers, former-active smokers/no SHS, active smokers, and secondhand smokers, and cognitive function into three levels: normal cognition (C), MCI, and dementia. A total of 933 older subjects with diagnoses of MCI (n = 98), dementia (n = 124), or C (n = 711) were enrolled in this cross-sectional study. As expected, patients with dementia had significantly higher frequency of former-active smokers than cognitively normal. Moreover, patients with MCI showed a significantly higher frequency of active and secondhand smokers than patients with dementia or C. A smoking history is very frequent in older patients with dementia. Patients with MCI had even higher rate of exposure to active or secondhand smoking.


System for time-resolved laser absorption spectroscopy and its application to high-power impulse magnetron sputtering.
This paper deals with the development and construction of an apparatus for time-resolved tunable diode laser absorption spectroscopy (LAS) for the diagnostics of pulsed plasma. A detailed description of the extension of a progressive method of laser absorption spectroscopy in continuous regime to a direct triggering method of the time-resolved laser absorption spectroscopy (TR-LAS) is presented. The main advantage of the developed method is its capability to measure the time evolution of the whole absorption profile with a preset time resolution, which can be less than 1 μs. Therefore, the presented method of repetitive sampling applied on LAS in plasma processes is capable of simultaneous measurement of the density and kinetic temperature of selected particles. Its appropriate applications are to periodical processes in technological plasma, namely pulsed plasma discharges. The developed method of TR-LAS was applied to measurements of the temporal evolution of density and kinetic temperature of argon metastable species during high-power impulse magnetron sputtering of titanium and titanium dioxide thin films.


Repetitive Supra-Physiological Shear Stress Impairs Red Blood Cell Deformability and Induces Hemolysis.
The supra-physiological shear stress that blood is exposed to while traversing mechanical circulatory assist devices affects the physical properties of red blood cells (RBCs), impairs RBC deformability, and may induce hemolysis. Previous studies exploring RBC damage following exposure to supra-physiological shear stress have employed durations exceeding clinical instrumentation, thus we explored changes in RBC deformability following exposure to shear stress below the reported "hemolytic threshold" using shear exposure durations per minute (i.e., duty-cycles) reflective of that employed by circulatory assist devices. Blood collected from 20 male donors, aged 18-38 years, was suspended in a viscous medium and exposed to an intermittent shear stress protocol of 1 s at 100 Pa, every 60 s for 60 duty-cycles. During the remaining 59 s/min, the cells were left at stasis until the subsequent duty-cycle commenced. At discrete time points (15/30/45/60 duty-cycles), an ektacytometer measured RBC deformability immediately after shear exposure at 100 Pa. Plasma-free hemoglobin, a measurement of hemolysis, was quantified via spectrophotometry. Supra-physiological shear stress impaired RBC properties, as indicated by: (1) decreased maximal elongation of RBCs at infinite shear stress following 15 duty-cycles (P <0.05); (2) increased real-time RBC deformability during application of the supra-physiological shear stress protocol (100 Pa) following exposure to 1 duty-cycle (F (1.891, 32.15) = 12.21, P = 0.0001); and (3) increased plasma-free hemoglobin following 60 duty-cycles (P < 0.01). The present study indicates that exposure of RBCs to short-term, repeated supra-physiological shear stress, impairs RBC deformability, with the extent of impairment exacerbated with each duty-cycle, and ultimately precipitates hemolysis.


Carotid body potentiation during chronic intermittent hypoxia: implication for hypertension.
Autonomic dysfunction is involved in the development of hypertension in humans with obstructive sleep apnea, and animals exposed to chronic intermittent hypoxia (CIH). It has been proposed that a crucial step in the development of the hypertension is the potentiation of the carotid body (CB) chemosensory responses to hypoxia, but the temporal progression of the CB chemosensory, autonomic and hypertensive changes induced by CIH are not known. We tested the hypothesis that CB potentiation precedes the autonomic imbalance and the hypertension in rats exposed to CIH. Thus, we studied the changes in CB chemosensory and ventilatory responsiveness to hypoxia, the spontaneous baroreflex sensitivity (BRS), heart rate variability (HRV) and arterial blood pressure in pentobarbital anesthetized rats exposed to CIH for 7, 14, and 21 days. After 7 days of CIH, CB chemosensory and ventilatory responses to hypoxia were enhanced, while BRS was significantly reduced by 2-fold in CIH-rats compared to sham-rats. These alterations persisted until 21 days of CIH. After 14 days, CIH shifted the HRV power spectra suggesting a predominance of sympathetic over parasympathetic tone. In contrast, hypertension was found after 21 days of CIH. Concomitant changes between the gain of spectral HRV, BRS, and ventilatory hypoxic chemoreflex showed that the CIH-induced BRS attenuation preceded the HRV changes. CIH induced a simultaneous decrease of the BRS gain along with an increase of the hypoxic ventilatory gain. Present results show that CIH-induced persistent hypertension was preceded by early changes in CB chemosensory control of cardiorespiratory and autonomic function.


Effects of mianserin on negative symptoms in schizophrenia.
The efficacy of mianserin as a supplement in treating chronic schizophrenia was tested in 20 inpatients with schizophrenia who were receiving fixed doses of neuroleptics. Mianserin was given for six weeks with a starting dose of 60 mg/day. A brief psychiatric rating scale (BPRS) was completed before starting mianserin and thereafter BPRS scoring was carried out once weekly. The total BPRS score and the score for negative symptoms were decreased by mianserin treatment as compared to the pre-treatment values. Plasma 5-HIAA concentrations were increased after medication in both responding patients and nonresponding patients. However, the 5-HIAA values of responders were lower than those of nonresponders. Plasma HVA levels were slightly increased by mianserin in the responders. There were no significant changes in MHPG levels. These results suggest that the negative symptoms of schizophrenia may be improved by mianserin treatment.


Potential role of metabolomics in diagnosis and surveillance of gastric cancer.
Gastric cancer is one of the deadliest cancers worldwide, and is especially prevalent in Asian countries. With such high morbidity and mortality, early diagnosis is essential to achieving curative intent treatment and long term survival. Metabolomics is a new field of study that analyzes metabolites from biofluids and tissue samples. While metabolomics is still in its infancy, there are numerous potential applications in oncology, specifically early diagnosis. Only a few studies in the literature have examined metabolomics' role in gastric cancer. Various fatty acid, carbohydrate, nucleic acid, and amino acid metabolites have been identified that distinguish gastric cancer from normal tissue and benign gastric disease. However, findings from these few studies are at times conflicting. Most studies demonstrate some relationship of cancer cells to the Warburg Effect, in that glycolysis predominates with conversion of pyruvate to lactate. This is one of the most consistent findings across the literature. There is less consistency in metabolomic signature with respect to nucleic acids, lipids and amino acids. In spite of this, metabolomics holds some promise for cancer surveillance but further studies are necessary to achieve consistency and validation before it can be widely employed as a clinical tool.


Chemical renal medullectomy. Effect on urinary prostaglandin E2 and plasma renin in response to variations in sodium intake and in relation to blood pressure.
We have studied the possible vasodepressor role of the renal medulla by chemical medullectomy. Bromoethylamine hydrobromide (200 mg/kg) was injected to induce selective renal medullary necrosis in rats. The acute effects on sodium balance and long-term effects on blood pressure, plasma renin concentration (PRC) and urinary prostaglandin E2 (PGE2) were studied and compared with saline injected controls. There was an immediate and sustained increase in urine volume of low osmolality. Direct blood pressure in conscious free-moving animals was higher at 2 and 10 weeks after injection in medullary-damaged rats, although this was only significant at 10 weeks (136 +/- 3.3 vs 118 +/- 4.5 mm Hg, p less than 0.01). An initial negative sodium balance returned to normal by 7 days and rats with established medullary damage tolerated a wide range of sodium intakes. Although there was no evidence of sodium retention on the normal diet, with very high sodium loads some sodium retention was apparent since PRC was suppressed and body weight increased. Plasma creatinine and creatinine clearance were normal. PRC in rats with medullary damage was unchanged on normal diet and rose to similar levels as in control rats on low sodium intake. Urinary PGE2 was markedly reduced (148 +/- 54 vs 536 +/- 71 ng/day, p less than 0.01) in medullary damaged rats, consistent with the renal medulla being the major source of urinary PGE2. High salt intake increased urinary PGE2 in normal and proportionally in medullary damaged rats, whereas on a low sodium intake, urinary PGE2 was not different from that on the normal diet in either group.(ABSTRACT TRUNCATED AT 250 WORDS)


Personality Traits in Former Spanish Substance Users Recovered with Ayahuasca.
Ayahuasca is a psychoactive brew that contains N,N-dimethyltryptamine and monoamine oxidase-inhibiting alkaloids. It is originally from the Amazon rainforest, but since the 1990s it has expanded worldwide. The compound is used in different religious, spiritual, and therapeutic settings. One of its common applications is for the treatment of addiction. The current study is an assessment of the impact of ayahuasca on personality traits in former substance users from Catalonia and surrounding areas. When compared with a control group, the ayahuasca group had statistically significantly higher scores in the dimensions Novelty Seeking and Self-Transcendence, and in the traits Attachment, Impulsivity, Compassion, and Spiritual Acceptance. Results suggest that recovery could be related less to a reduction of Impulsivity and Novelty Seeking, main features of substance use disorder (SUD), and more to an increase of Character dimensions and traits, especially Self-Transcendence and Cooperativeness. Those changes could be triggered by self-reflective, prosocial, and transcendental ayahuasca ritual experiences, which in the qualitative part of the research were described by the participants as being of great importance for their recovery, helping with the reconstruction of personal goals, gratifications, social bonds, and the general life's projection.


Magnetic force driven nanogenerators as a noncontact energy harvester and sensor.
Nanogenerator has been a very important energy harvesting technology through directly deforming piezoelectric material. Here, we report a new magnetic force driven contactless nanogenerator (CLNG), which avoids the direct contact between nanogenerator and mechanical movement source. The CLNG can harvest the mechanical movement energy in a noncontact mode to generate electricity. Their output voltage and current can be as large as 3.2 V and 50 nA, respectively, which is large enough to power up a liquid crystal display. We also demonstrate a means by which a magnetic sensor can be built.


Molecular self-recognition: rotational spectra of the dimeric 2-fluoroethanol conformers.
Fluoroalcohols show competitive formation of intra- and intermolecular hydrogen bonds, a property that may be crucial for the protein-altering process in a fluoroalcohol/water solution. In this study, we examine the intra- and intermolecular interactions of 2-fluoroethanol (FE) in its dimeric conformers by using rotational spectroscopy and ab initio calculations. Three pairs of homo- and heterochiral dimeric FE conformers are predicted to be local minima at the MP2/6-311++G(d,p) level of theory. They are solely made of the slightly distorted most stable G+g-/G-g+ FE monomer units. Jet-cooled rotational spectra of four out of the six predicted dimeric conformers were observed and unambiguously assigned for the first time. All four observed dimeric conformers have compact geometries in which the fluoromethyl group of the acceptor tilts towards the donor and ensures a large contact area. Experimentally, the insertion of the O-H group of one FE subunit into the intramolecular O-H...F bond of the other was found to lead to a higher stabilisation than the pure association through an intermolecular O-H...O-H link. The hetero- and homochiral combinations were observed to be preferred in the inserted and the associated dimeric conformers, respectively. The experimental rotational constants and the stability ordering are compared with the ab initio calculations at the MP2 level with the 6-311++G(d,p) and aug-cc-pVTZ basis sets. The effects of fluorination and the competing inter- and intramolecular hydrogen bonds on the stability of the dimeric FE conformers are discussed.


Localization of epileptogenic zone in temporal lobe epilepsy by ictal scalp EEG.
Our aim was to evaluate the ability to localize the epileptogenic zone in temporal lobe epilepsy (TLE) by ictal scalp electroencephalogram (EEG). Using simultaneous video recording, we analysed scalp EEG activity during ictal periods in 38 patients (30 patients with medial TLE (MTLE) and eight with lateral TLE (LTLE)). In 14 patients, intracranial ictal EEGs were recorded with depth electrodes, and simultaneous recordings of scalp and intracranial EEG were performed in 11 patients. Scalp EEG showed that, in all 30 patients with MTLE (71 of 72 seizures), an attenuation of background activity was observed before the appearance of ictal activity. Ictal discharges first appeared in the scalp EEG when the ictal discharges reached the lateral part of the temporal lobe on the intracranial EEG. While, in all eight patients with LTLE (25 of 25 seizures), the attenuation of background activity did not occur before the appearance of ictal activity. When the ictal discharges started in the lateral temporal lobe on intracranial EEG, ictal discharges appeared on the scalp. MTLE and LTLE could be diagnosed by the presence or absence of attenuation of background activity with clinical ictal signs before the appearance of ictal discharges.


Use of the "supercharge" technique in esophageal and pharyngeal reconstruction to augment microvascular blood flow.
Although gastric tubes are commonly used in thoracic esophageal reconstruction, sometimes circumstances are such that an alternative method must be found. On these occasions, pedicled jejunum transfer and colonic interposition are used. After reconstruction, partial necrosis can occur because of poor blood flow in the oral end of the segment used to restore esophageal continuity. To improve this blood flow, we created a technique-the "supercharge" technique-in which we perform additional microvascular blood flow augmentation. The supercharge technique was performed in 82 esophageal reconstructions with microvascular blood flow augmentation. Reconstructive methods included a gastric tube in 5 patients, a gastric tube combined with a free jejunal graft in 2, an elongated gastric tube in 6, a pedicled colonic interposition in 26, and a pedicled jejunum in 43. Recipient vessels were located in the neck or chest regions. After microvascular blood flow augmentation, the color and blood flow of the transferred intestine appeared greatly improved. During the operation, thrombosis was noticed in 3 patients and successfully salvaged by reanastomosis. Partial graft necrosis of the oral end of the segment occurred in only 2 patients; 2 patients had anastomotic leakage. The risk of leakage and partial necrosis of the transferred gut conduit appear to be reduced by using the supercharge technique to augment microvascular blood flow. This reliable technique contributes to the successful reconstruction of esophageal defects.


Standardization of functional reporter and antibiotic resistance cassettes to facilitate the genetic engineering of filamentous fungi.
The unique physiological properties of fungi are useful for a myriad of applications, which could greatly benefit from increased control of native pathways and introduction of recombinant genes. However, fungal genetic engineering is still limited in scope and accessibility, largely due to lack of standardization. To help standardize the genetic engineering of filamentous fungi, we created BioBricks of commonly used antibiotic resistance genes, neomycin phosphotransferase (nptII) and hygromycin phosphotransferase (hph), which confer resistance to G418 (Geneticin) and hygromycin B, respectively. Additionally, we created a BioBrick of the constitutive trpC promoter, from the tryptophan biosynthesis pathway of Aspergillus nidulans, and used it to create a composite part including the GFP gene. The functionality of these parts was demonstrated in the model fungal organism Cochliobolus heterostrophus, and as these tools are in modular BioBrick format, they can be easily used to facilitate genetic engineering of other fungal species.


Medicinal plants--old and new.
The historic role of plants in healing declined early in the twentieth century with the ascendency of synthetic drugs, even though a number of basic medical tools, such as opium, strychnine, and cocaine, are of botanical origin. In recent years, interest in natural products has been restored dramatically by the discovery of penicillin, plant-derived tranquilizers, and plant precursors of cortisone. Contrary to previous beliefs, botanical drugs are proving more economical than synthetics and hold forth encouraging prospects of inhibiting or destroying tumors without undue damage to healthy tissue. Extensive plant screening programs are being conducted by governmental agencies and pharmaceutical houses. Folk remedies, still common in many tropical areas, are being evaluated. As a result of such research by Canadian and American scientists, alkaloids extracted from the Madagascar periwinkle (Vinca rosea) are being effectively employed to achieve regression in childhood leukemia. Potentially more rewarding are investigations of compounds obtained from the Australian tree, Acronychia baueri and a Chinese species, Camptotheca acuminata. Universities are reestablishing medicinal plant gardens and placing more emphasis on pharmacognosy. Experimental work with narcotic plants in psychiatric treatment has given rise to popular fascination with and abuse of certain natural hallucinogens. Among scientists engaged in chemical studies, there is an active demand for information about plants, their properties and therapeutic uses. Even the general public is being made aware that plant drugs are not obsolete but offer new hope for conquering disease.


Temporal reorganization to overcome monocular demyelination.
To identify the source of delayed visual evoked potential (VEP) latencies in the fellow eyes of patients with optic neuritis (ON) and determine whether these latencies stem from clinically silent demyelination or reflect an adaptive process for synchronization with the affected eyes. The study sample comprised 17 patients whom we followed for 12 to 26 months after unilateral first-ever ON diagnosis and 17 age-matched controls. To avoid confounding effects of axonal loss, only intact fellow eyes (except for VEPs) were included. Subjects underwent standard visual evaluation, motion perception, as well as static and time-constrained stereo tasks. Assessments included VEP, optical coherence tomography, high-resolution MRI, and diffusion tensor imaging. We observed delayed VEP peaks (P100) in both affected and fellow eyes. However, while these were derived from prolonged time-to-start in the affected eyes, supporting the existence of demyelination, time-to-start in the fellow eyes was intact. VEP latencies in the fellow eyes could not be explained by demyelinative lesions along postchiasmal pathways (assessed by diffusion tensor imaging). Delayed peaks in fellow eyes resulted from a wider waveform, which evolved over time and occurred with a concomitant decrease in the gap in time between VEP peaks of both eyes. These changes offered a functional advantage; synchronization of inputs highly correlated with improved time-constrained binocular perception. Delayed latencies in the fellow eyes may reflect adaptive mechanisms at the cortical level that improve binocular integration over time to adjust for the damage incurred. These data provide a unique demonstration of temporal reorganization that compensates for delayed transmittal of visual information to the cortex.


Suppression of Wnt/β-catenin Signaling in PDAC via METTL16-mediated N6-methyladenosine Modification of DVL2.
Pancreatic cancer is a formidable cause of cancer-related deaths worldwide and has witnessed a more than twofold increase in incidence over the last 25 years. The most frequently occurring form of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), accounting for the majority of pancreatic cancer cases. N6-methyladenosine (m6A), the most abundant transcript modification, has been implicated in the pathogenesis of numerous human cancers, including pancreatic cancer. Despite this, the functional role of methyltransferase-like 16 (METTL16), a critical m6A methyltransferase, in PDAC remains elusive. In this study, we demonstrate that METTL16 expression is significantly diminished in PDAC, rendering it a promising prognostic indicator. Strikingly, both in vitro and in vivo assays revealed accelerated metastasis and invasion of PDAC cells upon METTL16 knockdown, while overexpression of METTL16 exerted an opposite effect. Mechanistically, METTL16 regulates DVL2 expression by suppressing its translation via m6A modification, thereby regulating Wnt/β-catenin signaling., Our results unveil the downregulation of METTL16 as a concomitant increase in DVL2 levels via m6A modification promoting the progression of PDAC. Thus, we propose METTL16 as a novel therapeutic candidate for targeted PDAC treatment.


Ovarian Development in the Class Holothuroidea: a Reassessment of the "Tubule Recruitment Model".
The "tubule recruitment model" for the development of the holothurian gonad was proposed (a) to connect the stages of oogenesis with ovarian morphology in holothurians throughout the reproductive season and (b) to emphasize the potential for the holothurian ovary as a model system for cytological and biochemical study of echinoderm oogenesis. To reassess the evidence for this model, we have examined published accounts and unpublished observations on gonad development in holothurians from both temperate and tropical habitats, in shallow water and in the deep sea. A very limited number of species were found to conform to the predictions of the tubule recruitment model. The patterns of gonad development vary substantially in holothurians, even at the individual level, and with taxonomic position, geographical location, and habitat. The tubule recruitment model can be applied to only a small subset of holothurians, specifically those in the families Stichopodidae and Holothuriidae that have gonad morphology similar to that of Parastichopus californicus. However, the tubule recruitment model is invalid for many other aspidochirotes, and does not have wider applicability within the class Holothuroidea.


Changes in structural integrity are correlated with motor and functional recovery after post-stroke rehabilitation.
Diffusion tensor imaging (DTI) studies indicate the structural integrity of the ipsilesional corticospinal tract (CST) and the transcallosal motor tract, which are closely linked to stroke recovery. However, the individual contribution of these 2 fibers on different levels of outcomes remains unclear. Here, we used DTI tractography to investigate whether structural changes of the ipsilesional CST and the transcallosal motor tracts associate with motor and functional recovery after stroke rehabilitation. Ten participants with post-acute stroke underwent the Fugl-Meyer Assessment (FMA), the Wolf Motor Function Test (WMFT), the Functional Independence Measure (FIM), and DTI before and after bilateral robotic training. All participants had marked improvements in motor performance, functional use of the affected arm, and independence in daily activities. Increased fractional anisotropy (FA) in the ipsilesional CST and the transcallosal motor tracts was noted from pre-treatment to the end of treatment. Participants with higher pre-to-post differences in FA values of the transcallosal motor tracts had greater gains in the WMFT and the FIM scores. A greater improvement on the FMA was coupled with increased FA changes along the ipsilesional CST. These findings suggest 2 different structural indicators for post-stroke recovery separately at the impairment-based and function-based levels.


L-carnitine supplementation decreases lipid peroxidation and improves cardiopulmonary function in broiler chickens reared at high altitude.
An experiment was carried out to examine the effects of L-carnitine supplementation on growth performance and cardiopulmonary function of broiler chickens reared at high altitude (2100 m above sea level). A total of 96 day-old male chicks (Cobb 500) were randomly assigned into two dietary treatments containing 0 (control group) and 200 mg/kg L-carnitine. The experimental diets were fed for a period of 42 days consisting of the starting (days 1 to 21) and growing periods (days 21 to 42). Nutrient requirements of chickens met the NRC (1994) recommendations. The results showed that dietary L-carnitine had no significant influence on body weight gain, feed intake and feed conversion ratio. L-carnitine reduced plasma concentration of malondialdehyde, packed cell volume (PCV) and abdominal fat deposition compared to the control (P < 0.05). A significant (P < 0.05) decrease was observed in the right to total ventricular weight ratio (RV:TV) in birds receiving L-carnitine when compared to the control. Supplementation of L-carnitine increased plasma nitric oxide and immune responsiveness, which manifested in an increased toe-web thickness index measured at 24 h following the injection of phytohaemagglutinin P. In conclusion, supplementation of L-carnitine had beneficial effects on preventing lipid peroxidation and pulmonary hypertension in broiler chickens raised at high altitude.