Sample preparation method for the combined extraction of ethyl glucuronide and drugs of abuse in hair.
Often in hair analysis, a small hair sample is available while the analysis of a multitude of structurally diverse substances with different concentration ranges is demanded. The analysis of the different substances often requires different sample preparation methods, increasing the amount of required hair sample. When segmental hair analysis is necessary, the amount of hair sample needed is further increased. Therefore, the required sample amount for a full analysis can quickly exceed what is available. To combat this problem, a method for the combined hair sample preparation using a single extraction procedure for analysis of ethyl glucuronide with liquid chromatography-multistage fragmentation mass spectrometry/multiple reaction monitoring (LC-MS3 /MRM) and common drugs of abuse with LC-MRM was developed. The combined sample preparation is achieved by separating ethyl glucuronide from the drugs of abuse into separate extracts by fractionation in the solid-phase extraction step during sample clean-up. A full validation for all substances for the parameters selectivity, linearity, limit of detection, limit of quantification, accuracy, precision, matrix effects, and recovery was successfully completed. The following drugs of abuse were included in the method: Amphetamine; methamphetamine; 3,4-methylenedioxy-N-methylamphetamine (MDMA); 3,4-methylenedioxyamphetamine (MDA); 3,4-methylenedioxy-N-ethylamphetamine (MDE); morphine; 6-monoacetylmorphine; codeine; acetylcodeine; cocaine; benzoylecgonine; norcocaine; cocaethylene; methadone; 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and methylphenidate. In conclusion, as only 1 sample preparation is needed with 1 aliquot of hair, the presented sample preparation allows an optimal analysis of both ethyl glucuronide and of the drugs of abuse, even when the sample amount is a limiting factor.


Soft tissue balancing: the hip.
During total hip arthroplasty, femoral offset is restored in only 40% of patients. Increased attention to techniques that ensure leg-length and offset restoration improve total hip arthroplasty function and minimize the risk of complications such as dislocation and limp. Preoperative templating, intraoperative leg-length offset measurements, and the availability of high-offset femoral necks can improve the restoration of offset in 90% of patients.


Effect of Collaborative Governance on Medical and Nursing Service Combination: An Evaluation Based on Delphi and Entropy Method.
[Background]: Improvement of synergies in medical and nursing services can help governments to optimize the allocation of medical resources; however, an appropriate evaluation method is critical for a suitable decision process in this regard. [Method]: To assess the medical and nursing service combination (MNSC) at a regional level, this study applied a five-dimension evaluation index composed of 28 basic response areas related to the MNSC development status in China, determining its respective weight through the Delphi and entropy methods. [Result]: This empirical exercise analyzed the MNSC supply system by interviewing nine heads of medical and nursing institutions and eleven healthcare-related government personnel during August of 2020 in Xinxiang City, Henan province, P.R China. Results showed: (1) public satisfaction with the fees charged by Medical and Nursing service Institutions (MNSI); (2) Medicare and supply services' policy publicity; (3) the external financing situation of MNSI; (4) the medical staff's professional quality; (5) the medical facilities and supply of MNSI; and (6) that the recognition level of the development plan of MNSI scored the highest effect on the synergy of MNSC supply among the assessed factors. [Conclusion]: These results showed that an evaluation based on the Delphi and entropy methods can effectively integrate the opinions of experts and related institutions to evaluate synergies on the medical and nursing service supply.


The natural history of ductal carcinoma in situ of the breast: a review.
Ductal carcinoma in situ represents about 20% of all tumours diagnosed within mammographic screening programs. The natural history of DCIS is poorly understood, as it cannot be observed directly. Estimates of the proportion of DCIS that progress to invasive cancer, as well as factors that may influence progression, are important for clinical management. Here we review various sources of evidence regarding the natural history of DCIS. We identified relevant publications of studies on: follow-up studies of DCIS initially misdiagnosed as benign, studies of recurrence of DCIS as invasive cancer, autopsy studies, studies of risk factors for DCIS, animal studies and studies that used mathematical models to study growth of DCIS and invasive cancer. Data sources included the MEDLINE data base, searches of articles cited in key reviews and editorials. The most direct evidence regarding the progression of DCIS to invasive cancer comes from studies where DCIS was initially misdiagnosed as benign and treated by biopsy alone. These studies suggest that between 14-53% of DCIS may progress to invasive cancer over a period of 10 or more years. The reported prevalence of undiagnosed DCIS in autopsy studies, of approximately 9%, has been used to suggest a larger reservoir of DCIS may exist in the population. All types of study designs reviewed had limitations that may bias the estimate of progression in either direction. The available evidence suggests not all DCIS will progress to invasive cancer in the medium term but precise estimates of progression are not possible given the limitations of the data. Mathematical modelling of various scenarios of progression and studies of genetic factors involved in progression may shed further light on the natural history of DCIS.


Emotion and the Interactive Brain: Insights From Comparative Neuroanatomy and Complex Systems.
Although emotion is closely associated with motivation, and interacts with perception, cognition, and action, many conceptualizations still treat emotion as separate from these domains. Here, a comparative/evolutionary anatomy framework is presented to motivate the idea that long-range, distributed circuits involving the midbrain, thalamus, and forebrain are central to emotional processing. It is proposed that emotion can be understood in terms of large-scale network interactions spanning the neuroaxis that form "functionally integrated systems." At the broadest level, the argument is made that we need to move beyond a Newtonian view of causation to one involving complex systems where bidirectional influences and nonlinearities abound. Therefore, understanding interactions between subsystems and signal integration becomes central to unraveling the organization of the emotional brain.


Effect of a 16-week Pilates exercise program on the ego resiliency and depression in elderly women.
This study aims to examine the effect of a 16-week Pilates exercise program on the ego resiliency and depression in elderly women. Before participating in Pilates exercise programs, researcher explained the purpose and the intention of the research to elderly women who were willing to participate in this research. A total of 148 elderly women agreed to participate in the program and they filled in ego resiliency and depression questionnaires. Then, the elderly participated in the 16-week Pilates exercise program and completed the same questionnaires afterwards. Collected data was analyzed by the SPSS ver. 20.0 program and results of paired t-test were as follows; there were statistically significant differences in all subvariables of the ego resiliency such as self-confidence (t=7.770, P<0.001), communication efficiency (t=2.690, P<0.01), optimistic trait (t=1.996, P<0.05), and anger management (t=4.525, P<0.001) after elderly women participated in the 16-week Pilates exercise program, there was a statistically significant difference in depression of elderly women who participated in the 16-week Pilates exercise program (t=-6.506, P<0.001) which was statistically lower than before their participation in the program. Consequently, participating in the Pilates exercise program can help improve the ego-resiliency and alleviate depression of the elderly women.


Oxidation, reduction, and methylation of carnosic acid by Nocardia.
Preparative-scale incubations with Nocardia sp. NRRL 5646 were conducted to produce new derivatives of the abietane diterpene chemoprotectant and antioxidant carnosic acid (1). Reductive biotransformation of the C-20 carboxylic acid functional group followed by biological methylation at the C-11 phenol afforded 4. Oxidative cyclization of 1 to carnosol 5 followed by dihydroxylation at the isopropyl moiety afforded 6. Metabolites 4 and 6 are new carnosic acid derivatives whose structures were confirmed by mass spectrometry and NMR spectroscopic analysis. The radical quenching properties of 4-6 using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging assay showed activities similar to that of mixed tocopherols and carnosic acid.


Exploring complex miRNA-mRNA interactions with Bayesian networks by splitting-averaging strategy.
microRNAs (miRNAs) regulate target gene expression by controlling their mRNAs post-transcriptionally. Increasing evidence demonstrates that miRNAs play important roles in various biological processes. However, the functions and precise regulatory mechanisms of most miRNAs remain elusive. Current research suggests that miRNA regulatory modules are complicated, including up-, down-, and mix-regulation for different physiological conditions. Previous computational approaches for discovering miRNA-mRNA interactions focus only on down-regulatory modules. In this work, we present a method to capture complex miRNA-mRNA interactions including all regulatory types between miRNAs and mRNAs. We present a method to capture complex miRNA-mRNA interactions using Bayesian network structure learning with splitting-averaging strategy. It is designed to explore all possible miRNA-mRNA interactions by integrating miRNA-targeting information, expression profiles of miRNAs and mRNAs, and sample categories. We also present an analysis of data sets for epithelial and mesenchymal transition (EMT). Our results show that the proposed method identified all possible types of miRNA-mRNA interactions from the data. Many interactions are of tremendous biological significance. Some discoveries have been validated by previous research, for example, the miR-200 family negatively regulates ZEB1 and ZEB2 for EMT. Some are consistent with the literature, such as LOX has wide interactions with the miR-200 family members for EMT. Furthermore, many novel interactions are statistically significant and worthy of validation in the near future. This paper presents a new method to explore the complex miRNA-mRNA interactions for different physiological conditions using Bayesian network structure learning with splitting-averaging strategy. The method makes use of heterogeneous data including miRNA-targeting information, expression profiles of miRNAs and mRNAs, and sample categories. Results on EMT data sets show that the proposed method uncovers many known miRNA targets as well as new potentially promising miRNA-mRNA interactions. These interactions could not be achieved by the normal Bayesian network structure learning.


[Development of genetically engineered chimeric and single chain antibodies against human brain glioma: a preliminary report].
In order to improve the clinical usefulness of mAb of mouse origin in targeting diagnosis and therapy for human brain glioma, it is necessary to humanize it and reduce its molecular size. By means of RT-PCR technique, a 348 bp heavy chain variable domain (VH), and a 318 bp light chain variable domains (VL) cDNA fragments were cloned from mouse hybridoma cell line SZ39 secreting mAb against human brain glioma. By recombinant DNA technique, the two cDNA fragments were linked to human IgG1 heavy chain CH1 and light chain kappa constant regions, respectively, to form a chimeric gene which was then inserted into an expression vector pHEN1-SZ39 Fab/Hu. In addition, the two cDNA fragments were connected directly with a universal linker and inserted to an expression vector pHEN1-SZ39 ScFv. The two expression vectors were separately introduced into E. coli HB2151 to secrete chimeric antibodies and single-clain antibodies, respectively. On ELISA and Western blot, the two genetically engineered antibodies bond to the same 180,000 cell surface membrane antigen on human brain glioma cell line SHG44 as did the parental mAb SZ39.


Multi-Mechanistic In Vitro Evaluation of Antihyperglycemic, Antioxidant and Antiglycation Activities of Three Phenolic-Rich Indian Red Rice Genotypes and In Silico Evaluation of Their Phenolic Metabolites.
The study evaluated the antidiabetic potential of three traditional Indian red rice genotypes/RR (Kattuyanam/KA, Chennangi/CH & Karungkuruvai/KU) using a combination of in vitro, metabolomics (Quadrupole-Time of Flight-Liquid chromatography-Mass spectrometry/Q-TOF-LC-MS/MS), and in silico techniques. In terms of antihyperglycemic potential, KA exhibited the highest inhibitory activity against α-amylase; CH against α-glucosidase; and KU against DPPIV and PTP1B enzymes. KA exhibited the highest antioxidant activity (DPPH, FRAP, and ABTS) and greater inhibition of protein glycation compared to other RR indicating its potential to mitigate diabetic complications. The metabolomic analysis confirmed the presence of 99 phenolics in the sample extracts (KU-71, KA-70, CH-68). Molecular docking studies revealed seven metabolites to be good inhibitors of the four target enzymes and activators of insulin receptor substrate/IRS. The antihyperglycemic and oxidation-glycation reduction composite index revealed KA to have the highest overall antidiabetic potential. Hence, the RR could be utilized in functional foods with a multi-barrelled strategy for diabetes prevention/management.


A longitudinal analysis of urinary biochemical markers and bone mineral density in STR/Ort mice as a model of spontaneous osteoarthritis.
To investigate the longitudinal changes both in the urinary concentrations of biochemical markers and in bone mineral density (BMD) during disease progression in the STR/Ort mouse model of osteoarthritis (OA). Male STR/Ort mice were studied, with CBA mice used as nonarthritic controls. Radiographic evaluation and grading of the knee and measurements of urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II), pyridinoline (Pyr), and deoxypyridinoline were performed between 8 weeks and 40 weeks of age. The BMD of the femoral shaft was measured from 20 weeks to 40 weeks of age and adjusted for body weight. Histologic evaluation and grading were performed at 40 weeks of age. STR/Ort mice were divided into 2 subgroups (STR OA and STR non-OA) based on histologic grading. No significant differences between STR/Ort and CBA mice were observed for any biochemical marker or BMD at any time point. Urinary CTX-II levels and BMD in the STR OA subgroup were higher than those in the STR non-OA subgroup before radiographic changes of OA were apparent. Higher urinary Pyr levels in the STR OA subgroup were observed at the advanced stage of OA. Urinary CTX-II could be a useful marker in the early diagnosis and predicting the progression of OA, and urinary Pyr may be a potential marker to assess the severity of OA at an advanced stage. An increase in BMD prior to the establishment of radiographic OA may be related to the induction of OA.


Unresolved issues in the prevention and treatment of venous thromboembolism.
Venous thromboembolism (VTE) is a major health problem. Anticoagulation can significantly decrease the morbidity and mortality associated with VTE. Heparin and coumarin derivatives have been the standard of care for the last 50 years, and the development of low-molecular-weight heparin preparations has significantly improved the prevention and treatment of venous thromboembolic disease. With these advances, investigators are now able to address some of the unresolved issues in antithrombotic therapy, including the search for the optimal antithrombotic agent in high-risk patients, the optimal timing of thromboprophylaxis initiation in the surgical population, and the duration of prophylaxis for the prevention of initial and recurrent VTE events. Clinical trials have begun to investigate many of these issues, and the resulting data have already contributed to improving the management of patients with a high risk of VTE.


Residual and pre-treatment application of starycide insect growth regulator (triflumuron) to control Aedes aegypti in containers.
Dengue is not endemic in Australia, although the vector mosquito Aedes aegypti is. In order to prevent dengue establishment, Australia maintains tight control of vector mosquitoes. Tight control programs often necessitate regular repeat application of treatments, and this is resource intensive. We sought to investigate the efficacy and longevity of triflurumon Starycide® Insect Growth Regulator under field conditions in tropical Australia against Aedes. We compared two doses (0.48 and 0.96 ppm), applied to water receptacles with delayed flooding by zero, two, and four weeks. We found greater than 90% inhibition of pupae development was achieved for up to 12 weeks. A dose of 0.96 ppm, when delayed for two or four weeks before flooding, provided 50 times inhibition relative to controls, for up to 22 weeks, suggesting triflumuron bound to the plastic substrate and offered a greater residual effect than applications without delayed flooding. We conclude that triflurumon offers excellent efficacy and longevity against Aedes in artificial containers. If deployed under standard conditions, re-application may not be required for up to 22 weeks, furthermore, initial applications could be performed under dry conditions, and this application method may improve the residual effects.


Intrathecal baclofen therapy in children with cerebral palsy: efficacy and complications.
To describe the efficacy of intrathecal baclofen (ITB) therapy in the management of spasticity in young children with cerebral palsy (CP) and to identify risk factors for complications. Consecutive case series of 25 implanted ITB delivery systems during a 48-month period. Pediatric specialty hospital and outpatient department. Twenty-three children (age range, 4.5-17.4y) with CP (spastic diplegia in 22%; spastic quadriplegia in 61%; mixed-type diplegia in 4%; mixed-type quadriplegia in 13%). Intrathecal baclofen therapy in children with cerebral palsy. Ashworth Scale scores before treatment and at 6 and 12 months after ITB therapy; frequency and nature of complications; and relation between patient characteristics and outcomes. Average Ashworth scores +/- standard deviation decreased from 3.26+/-.73 to 2.34+/-.83 (P<or=.01) in the lower extremities and from 2.69+/-.79 to 2.00+/-.55 (P<or=.05) in the upper extremities 6 months after ITB therapy and remained comparably decreased at 12 months. Explantation was required in 44% (11/25), with wound complications as the leading cause in 73% (8/11). Complications were associated with the diagnosis of mixed-type CP, as compared with pure spastic types (P<or=.01). Trends suggest that children of smaller size and younger age, as well as those with gastrostomy tubes and nonambulatory status, were more likely to encounter complications necessitating explantation. ITB therapy effectively reduced spasticity in children with CP. However, complications necessitating explantation can occur. Further research is needed to identify criteria describing the ideal pediatric candidate for ITB.


Site-Specific Integration of TRAIL in iPSC-Derived Mesenchymal Stem Cells for Targeted Cancer Therapy.
Mesenchymal stem cells (MSCs) are a promising cellular vehicle for transferring anti-cancer factors to malignant tumors. Currently, a variety of anti-cancer agents, including the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), have been loaded into MSCs derived from a range of sources through different engineering methods. These engineered MSCs exhibit enormous therapeutic potential for various cancers. To avoid the intrinsic defects of MSCs derived from tissues and the potential risk of viral vectors, TRAIL was site-specifically integrated into the ribosomal DNA (rDNA) locus of human-induced pluripotent stem cells (iPSCs) using a non-viral rDNA-targeting vector and transcription activator-like effector nickases (TALENickases). These genetically modified human iPSCs were differentiated into an unlimited number of homogeneous induced MSCs (TRAIL-iMSCs) that overexpressed TRAIL in both culture supernatants and cell lysates while maintaining MSC-like characteristics over continuous passages. We found that TRAIL-iMSCs significantly induced apoptosis in A375, A549, HepG2, and MCF-7 cells in vitro. After intravenous infusion, TRAIL-iMSCs had a prominent tissue tropism for A549 or MCF-7 xenografts and significantly inhibited tumor growth through the activation of apoptotic signaling pathways without obvious side effects in tumor-bearing mice models. Altogether, our results showed that TRAIL-iMSCs have strong anti-tumor effects in vitro and in vivo on a range of cancers. This study allows for the development of an unlimited number of therapeutic gene-targeted MSCs with stable quality and high homogeneity for cancer therapy, thus highlighting a universal and safe strategy for stem cell-based gene therapy with high potential for clinical applications.


Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann-Pick disease.
Niemann-Pick disease type A (NPA) is a rare lysosomal storage disorder characterized by severe neurological alterations that leads to death in childhood. Loss-of-function mutations in the acid sphingomyelinase (ASM) gene cause NPA, and result in the accumulation of sphingomyelin (SM) in lysosomes and plasma membrane of neurons. Using ASM knockout (ASMko) mice as a NPA disease model, we investigated how high SM levels contribute to neural pathology in NPA. We found high levels of oxidative stress both in neurons from these mice and a NPA patient. Impaired activity of the plasma membrane calcium ATPase (PMCA) increases intracellular calcium. SM induces PMCA decreased activity, which causes oxidative stress. Incubating ASMko-cultured neurons in the histone deacetylase inhibitor, SAHA, restores PMCA activity and calcium homeostasis and, consequently, reduces the increased levels of oxidative stress. No recovery occurs when PMCA activity is pharmacologically impaired or genetically inhibited in vitro. Oral administration of SAHA prevents oxidative stress and neurodegeneration, and improves behavioral performance in ASMko mice. These results demonstrate a critical role for plasma membrane SM in neuronal calcium regulation. Thus, we identify changes in PMCA-triggered calcium homeostasis as an upstream mediator for NPA pathology. These findings can stimulate new approaches for pharmacological remediation in a disease with no current clinical treatments.


Molecular aspects of flower development in grasses.
The grass family (Poaceae) of the monocotyledons includes about 10,000 species and represents one of the most important taxa among angiosperms. Their flower morphology is remarkably different from those of other monocotyledons and higher eudicots. The peculiar floral structure of grasses is the floret, which contains carpels and stamens, like eudicots, but lacks petals and sepals. The reproductive organs are surrounded by two lodicules, which correspond to eudicot petals, and by a palea and lemma, whose correspondence to eudicot organs remains controversial. The molecular and genetic analysis of floral morphogenesis and organ specification, primarily performed in eudicot model species, led to the ABCDE model of flower development. Several genes required for floral development in grasses correspond to class A, B, C, D, and E genes of eudicots, but others appear to have unique and diversified functions. In this paper, we outline the present knowledge on the evolution and diversification of grass genes encoding MIKC-type MADS-box transcription factors, based on information derived from studies in rice, maize, and wheat. Moreover, we review recent advances in studying the genes involved in the control of flower development and the extent of structural and functional conservation of these genes between grasses and eudicots.


Highly variable pH effects on the interaction of diclofenac and indomethacin with human UDP-glucuronosyltransferases.
In vitro glucuronidation assays of diclofenac and indomethacin at pH 7.4 are biased by the instability of the glucuronides due to acyl migration. The extent of this acyl migration may be reduced significantly by performing the glucuronidation reaction at pH 6.0. Testing the human UDP-glucuronosyltransferases (UGTs) of subfamilies 1A, 2A and 2B at pH 7.4 revealed that UGT1A10, UGT2B7 and UGT2B17 are the most active enzymes in diclofenac glucuronidation, while the highest indomethacin glucuronidation rates (corrected for relative expression levels) were exhibited by UGT2A1, UGT1A10 and UGT2B7. Interestingly, lowering the reaction pH to 6.0 increased the activity of many UGTs, particularly UGT1A10, toward both drugs, even if the rate of 4-methylumbelliferone glucuronidation by UGT1A10 at pH 6.0 was significantly lower than at pH 7.4. On the other hand, UGT2B15 lost activity upon lowering the reaction pH to 6.0. UGT1A6 does not glucuronidate diclofenac and indomethacin. Nevertheless, both drugs inhibit the 1-naphthol glucuronidation activity of UGT1A6 and their inhibition was stimulated by lowering the reaction pH, yielding significantly lower IC(50) values at pH 6.0 than at pH 7.4. In conclusion, glucuronidation reactions pH affects their outcome in variable ways and could increase the toxicity of drugs that carry a carboxylic acid.


Safety and pharmacokinetics of EMLA in the treatment of postburn pruritus in pediatric patients: a pilot study.
The purpose of this study was to determine the safety and pharmacokinetics of a eutectic mixture of local anesthetics (EMLA) used to ameliorate postburn pruritus after application onto newly formed, intact skin in children. EMLA was applied once to an itchy site where healed skin had formed. Serial blood samples were collected to measure lidocaine, prilocaine, o-toluidine, and methemoglobin. Maximal plasma concentration, minimal plasma concentration, time to achieve the maximal plasma concentration, elimination half-life, and area under the concentration-time curve were calculated. Vital signs, oxygen saturation, clinical signs of hypoxia, and itch intensity were measured. Five children had 15.7 +/- 2.54 g (+/- SD) of EMLA applied to a skin surface area of 93.0 +/- 37.0 cm2. Lidocaine and prilocaine concentrations were below toxic levels; o-toluidine was not detected. Methemoglobin remained between 1 and 3%; patients did not exhibit any clinical signs of hypoxia. Mean oxygen saturation was 98.9 +/- 0.01%. The mean number of pruritic episodes and antihistamine breakthrough doses were greater in the 2 prestudy control days compared with study day 3 (P = 0.01 and P = 0.03, respectively). Skin at the site of EMLA application remained anesthetized for 12 to 13 hours. In this small pilot study, EMLA seems to be a safe, novel treatment for postburn pruritus in burned children when applied to newly healed, intact skin.


Potential role of conjugated bilirubin and copper in the metabolism of lipid peroxides in bile.
Conjugated bilirubin and copper ions at their physiological concentrations in bile may play an important role in hydroperoxide and other detoxification. Conjugated bilirubin may also be an important chain-breaking antioxidant preventing lipid peroxidation. Bilirubin ditaurine (BR-DT), a water-soluble model compound of conjugated bilirubin, completely prevents the peroxyl radical-induced oxidation of phosphatidylcholine in either multilamellar liposomes or micelles. This antioxidant activity is associated with the bilirubin moiety of BR-DT, since taurine alone is inefficient in scavenging peroxyl radicals. The number of peroxyl radicals trapped per molecule of BR-DT is 1.9, compared to 4.7 trapped per molecule of biliverdin, the water-soluble physiological precursor of bilirubin. Peroxyl radical-induced oxidation of BR-DT results in a spectral shift in maximal absorbance toward shorter wavelengths; biliverdin is not formed as a major oxidation product. BR-DT, but neither taurine nor biliverdin, greatly accelerates the cupric ion-catalyzed decomposition of linoleic acid hydroperoxide. In the presence of ferric ion, BR-DT shows no lipid hydroperoxide-degrading activity. Addition of cupric ion to BR-DT results in formation of a complex with spectral features similar to that of a biliverdin-cupric ion complex, indicating that BR-DT and cupric ion undergo redox reactions.


Molecular cloning and bioinformatics analysis of a novel spliced variant of survivin from human breast cancer cells.
Survivin gene and its two alternatively spliced variants, survivin-2 B and survivin- Delta Ex3 gene were cloned from human breast cancer cell lines B-cap37 firstly. A new gene designated as survivin-image (SI) was cloned from above cell lines, which has not been reported yet to clone from any cell lines. It was found that the novel gene 507 bp comprises partial survivin gene (345 bp), partial image gene (155 bp) of eye cancer and other insertion of 7 bp by analyzing with a series of recent bioinformatics software at the level of nucleotide and protein deduced. Predicted 3-D structures of the new molecule showed greatly similar to that of survivin in N-terminal containing BIR by homology modeling. These results suggested SI gene (GenBank accession No.AY830084) might be a novel alternatively spliced isoforms of the survivin gene involved in other functional significances related to tumorigenesis.


Comminuted distal radius fractures.
Comminuted displaced fractures of the distal end of the radius pose a significant treatment challenge. The goal of treatment is to restore functional, painless motion of the wrist and fingers. Although satisfactory results correlate to a large extent with obtaining and maintaining normal anatomy, excessive distraction and a flexed wrist position with external fixation cause more harm than good, even if the anatomy is restored.


Enantiomeric separation and determination of the enantiomeric impurity of armodafinil by capillary electrophoresis with sulfobutyl ether-β-cyclodextrin as chiral selector.
A selective capillary electrophoresis method using sulfobutyl ether-β-cyclodextrin as a chiral selector was developed and validated for the determination of the enantiomeric impurity of (R)-modafinil, i.e., armodafinil. Several parameters were optimized for a satisfactory enantioresolution, including the type and concentration of chiral selector and organic modifier, pH of background electrolyte (BGE), capillary temperature. The finally adopted condition was: 20 mmol/L phosphate buffer at pH 7.5, containing 20 mmol/L sulfobutyl ether-β-cyclodextrin and 20% methanol, at temperature of 25 °C. A good resolution of 3.3 for the two enantiomers of modafinil was achieved by applying the optimal conditions. The limit of detection (LOD) and limit of quantification (LOQ) of (S)-modafinil were 1.25 μg/mL and 2.50 μg/mL, respectively. The established method was also proven to display good selectivity, repeatability, linearity and accuracy. Finally, the method was used to investigate the enantiomeric purity of armodafinil in bulk samples.


Four-barrel aortic dissection involving the ascending aorta. A case report.
A fifty-four-year-old woman was evaluated at the authors' hospital for symptoms of repeated chest and back pain. The symptoms had recurred for five months prior to admission. A dynamic computed tomographic scan was performed on admission and demonstrated an enlarged ascending aorta with four barrels secondary to split intimal flaps. This case is an extremely rare example of a patient with a four-barrel aortic dissection involving the ascending aorta.


IFN-beta pharmacogenomics in multiple sclerosis.
Multiple sclerosis (MS) is a condition of the CNS marked by inflammation and neurodegeneration. Interferon (IFN)-beta was the first, and still is the main, immunomodulatory treatment for MS. Its clinical efficacy is limited, and a proportion of patients, ranging between 20-55%, do not respond to the therapy. Identification and subsequently, implementation in the clinic of biomarkers predictive for individual therapeutic response would facilitate improved patient care in addition to ensuring a more rational provision of this therapy. In this article, we summarize the main findings from studies addressing the pharmacogenomics of clinical response to IFN-beta in MS by either whole-genome association scans, candidate gene or transcriptomics studies. Whole-genome DNA association screens have revealed a high representation of brain-specific genes, and have hinted toward both extracellular ligand-gated ion channels and type I IFNs pathway genes as important categories of genetic IFN-beta response modifiers. One hit, glypican 5 (GPC5), was recently replicated in an independent study of IFN-beta responsiveness. Recent RNA transcriptomics studies have revealed the occurrence of a pre-existing type I IFN gene-expression signature, composed of genes that are predominantly induced by type I IFNs, as a potential contributing feature of poor response to therapy. Thus, while the outlines of a complex polygenic mechanism are gradually being uncovered, the main challenges for the near future will reside in the robust validation of identified response-modifying genes as well as in the decipherment of the mechanistic relationships between these genes and clinical response to IFN-beta.


Extent of sinus surgery, 2000 to 2009: a population-based study.
Sinus surgery is one of the most frequently performed surgical operations. The objective was to determine if rates of surgery have changed over the last 10 years. Secondary data analysis of the State Ambulatory Surgery Database of Florida. We calculated population adjusted rates of ambulatory sinus surgery for all adults, 2000 to 2009. There was a substantial decrease in the proportion of patients who had surgery in a hospital setting and a substantial increase in patients who had surgery with image guidance. Population-adjusted rates of sinus surgery increased over the study period, from a mean of 104 cases per 100,000 population in 2000 to 129 per 100,000 in 2009 (P <0.001). Procedure rates also increased, from a mean of 226 per 100,000 in 2000 to 316 per 100,000 in 2009 (P <0.001). Rates of frontal sinus procedures more than doubled, and rates of cases in which all four sinuses were treated tripled during the same time period. A greater number of sinus procedures was associated with use of image guidance and high annual surgical case volume. The strongest predictor was the individual surgeon. Rates of sinus surgery increased over the study period, with more patients undergoing surgery and more procedures per surgical case. The strong association of procedural patterns with specific surgeons in sinusitis care highlights the importance of future investigations to examine training, technological, and reimbursement factors that may influence surgeons' clinical decision making for this common condition. 2b.


Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials.
Current evidence on dyslipidaemia management has expanded to novel treatments and very low achieved levels of low-density lipoprotein cholesterol (LDL-C). We sought to compare the clinical impact of more-intensive vs. less-intensive LDL-C lowering by means of statins and currently recommended non-statin medications in secondary prevention. We searched Medline, EMBASE, and Cochrane databases for randomized controlled trials of statins, ezetimibe, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, or bile acid sequestrants with >500 patients followed for ≥1 year. We employed random-effects models using risk ratios (RRs) with 95% confidence intervals (CIs) to compare outcomes. We included 19 trials (15 of statins, 3 of PCSK9 inhibitors, and 1 of ezetimibe) with 152 507 patients randomly assigned to more-intensive (n = 76 678) or less-intensive treatment (n = 75 829). More-intensive treatment was associated with 19% relative risk reduction for the primary outcome, major vascular events (MVEs; RR 0.81, 95% CI 0.77-0.86). Risk reduction was greater across higher baseline levels and greater achieved reductions of LDL-C. The clinical benefit was significant across varying types of more-intensive treatment and was consistent for statins (RR 0.81, 95% CI 0.76-0.86) and non-statin agents (PCSK9 inhibitors and ezetimibe; RR 0.85, 95% CI 0.77-0.94) as active (more-intensive) intervention (P-interaction = 0.38). Each 1.0 mmol/L reduction in LDL-C was associated with 19% relative decrease in MVE. Death, cardiovascular death, myocardial infarction, stroke, and coronary revascularization also favoured more-intensive treatment. Reduction of MVE is proportional to the magnitude of LDL-C lowering across a broad spectrum of on-treatment levels in secondary prevention. Statin intensification and add-on treatment with PCSK9 inhibitors or ezetimibe are associated with significant reduction of cardiovascular morbidity in this very high-risk population.


Emotional Campaigning in Politics: Being Moved and Anger in Political Ads Motivate to Support Candidate and Party.
Political advertising to recruit the support of voters is an inherent part of politics. Today, ads are distributed via television and online, including social media. This type of advertisement attempts to recruit support by presenting convincing arguments and evoking various emotions about the candidate, opponents, and policy proposals. We discuss recent arguments and evidence that a specific social emotion, namely the concept kama muta, plays a role in political advertisements. In vernacular language, kama muta is typically labeled as being moved or touched. We compare kama muta and anger theoretically and discuss how they can influence voters' willingness to support a candidate. We then, for the first time, compare kama muta and anger empirically in the same study. Specifically, we showed American participants short political ads during the 2018 United States midterm election campaigns. All participants saw both kama muta- and anger-evoking ads from both Democratic or Republican candidates. In total, everybody watched eight ads. We assessed participants' degree of being moved and angered by the videos and their motivation for three types of political support: ideational, financial, and personal. The emotional impact of an ad depended on its perceived source: Participants felt especially angry after watching the anger-evoking ads and especially moved by moving ads if they identified with the political party that had produced the video. Both emotions mediated were associated with increased intentions to provide support. Importantly, if one of the two emotions was evoked, its effect on political support was enhanced if participants identified with the party that had produced the ad. We discuss limitations of the method and implications of the results for future research and practice.


[The specific features of the blood gas transport system in patients with postinfarction cardiosclerosis].
The specific features of blood gas transport system functioning were analyzed in patients with cardiovascular diseases. In patients with postinfarction cardiosclerosis (PICS), the quantitative mechanism for hypoxia adaptation tended to decrease, which may be considered to be a compensatory-adaptive reaction aimed at eliminating the sludge phenomenon and improving the rheological characteristics of blood. Acute myocardial reinfarction developed in patents with PICS is characterized by the lower functional activity of red blood cells, and developing hypoxia is an important link of activation of apoptotic cell death. The degree of hypoxia may be believed to correlate with the sizes of a myocardial necrosis focus.


SwissPlus Implant System, Part 2: Prosthodontic aspects and intersystem comparisons.
Incompatibility between implant systems and the increasing complexity of esthetic restorative options frequently require dentists to obtain special training in the selection and use of prosthetic components. SwissPlus System implants have been designed to simplify restorative procedures by eliminating many ancillary restorative components. The implants are packaged on a fixture mount that also functions as a transfer and as an abutment for cemented restorations. For multiple-unit, screw-retained restorations, the prosthesis can be splinted directly to the top of the implant without an intermediate abutment. Overdenture attachments, straight, angled, screw-receiving, and custom-cast abutments complete the restorative system. This paper presents an overview of the SwissPlus System's prosthodontic aspects. Test data also illustrate intersystem compatibility and differences between SwissPlus System implants and ITI syn-Octa implants.


Renal artery variations: embryological basis and surgical correlation.
Understanding anatomy of the vascular variations of kidney is essential for the clinician to perform procedures such as renal transplantation, interventional radiological procedures and renal vascular operations more safely and efficiently. In order to facilitate the clinical approaches, we studied renal arterial pattern in 50 formalin-fixed cadavers, on 100 kidneys. We observed prehilar multiple branching patterns in 11 (11.66%) cases, duplication of renal artery in eight (8.33%) cases and superior polar artery in seven (6.66%) cases. In the present study findings discussed with its clinical correlation.


MEADERS: Medication Errors and Adverse Drug Event Reporting system.
The Agency for Healthcare Research and Quality (AHRQ) recently funded the PBRN Resource Center to develop a system for reporting ambulatory medication errors. Our goal was to develop a usable system that practices could use internally to track errors. We initially performed a comprehensive literature review of what is currently available. Then, using a combination of expert panel meetings and iterative development we designed an instrument for ambulatory medication error reporting and createad a reporting system based both in MS Access 2003 and on the web using MS ASP.NET 2.0 technologies.


Autoimmune hepatitis: a noninfectious killer.
This article reviews autoimmune hepatitis (AIH) to promote early recognition, diagnosis, and referral for nurse practitioners (NPs) encountering this rare condition. Selected research and clinical articles from Medline, PubMed, and CINAHL. AIH is a rare condition of unknown etiology affecting women 3.6 times more than men and may result in liver failure, subsequent liver transplantation, and death. Untreated AH is associated with up to 80% mortality. Collaboration and referral to gastroenterologists, hepatologists, and other specialists are needed to improve outcomes for this potentially devastating disease. Corticosteroid treatment has long been the mainstay of treatment of AIH, although newer therapies are promising. NPs can dramatically improve outcomes by early recognition, diagnosis, referral, and monitoring for common side effects of treatment working collaboratively with specialists.


Novel Survivin Peptides Screened With Computer Algorithm Induce Cytotoxic T Lymphocytes With Higher Cytotoxic Efficiency to Cancer Cells.
The identification of novel biomarkers and therapeutic targets in advanced cancer is critical for improving cancer diagnosis and therapeutics. Survivin (SV) is highly expressed predominantly in most cancer cells and tissues but is absent or undetectable in terminally differentiated normal adult tissues. Therefore, it functions as an almost universal tumor antigen. Peptides are short chains of amino acids linked by peptide bonds. To obtain novel SV decamers that are able to induce SV-specific cytotoxic T lymphocytes (CTLs) with a higher cytotoxic efficiency against cancer cells, major histocompatibility complex (MHC) peptide binding algorithms were conducted to predict nine modified SV95 decamers (from SV95-2 to SV95-10) based on the natural SV95-104 peptide sequence of ELTLGEFLKL (here defined as SV95-1). The fluorescent density of each SV95 peptide was determined by a MHC stability assay, followed by the generation of SV95-specific CTLs with each SV95 peptide (from SV95-1 to SV95-10) and human dendritic cells (DCs) loaded with Poly(lactic-co-glycolic) acid (PLGA) nanoparticles encapsulated with SV95 peptide. Finally, IFN-γ ELISpot and CytoTox 96® Non-Radioactive Cytotoxicity Assays were employed to verify their cytotoxic efficiency of the SV95-specific CTLs generated with the corresponding artificial antigen presenting cells (aAPCs) containing SV95 (SV95-1 to SV95-10) peptide. Furthermore, the cytotoxicity of the SV95 specific CTLs generated with nine mutated SV95 peptides was compared to the one generated with natural SV95-1 peptide and TIL2080 cells. The results indicated that the HLA-A2-restricted mutated SV95 epitope decamers (SV95-6 and SV95-7) showed significant higher binding ability compared to natural peptide SV95-1 in MHC stability assay. More importantly, SV95-specific CTLs with higher cytotoxicity were successfully induced with both SV95-6 and SV95-7 peptides, which significantly eliminated target cells (not only SV95-1 peptide pulsed T2 cells, but also both HLA-A2 and SV positive cancer cells) when compared to those generated with natural SV95-1 peptide and TIL2080 cells. These findings suggest that the SV95-6 and SV95-7 peptides are two novel HLA-A2-restricted CTL epitopes and may be useful for the immunotherapy for patients with survivin expressing cancer.


Acute lung injury at Baragwanath ICU. An eight-month audit and call for consensus for other organ failure in the adult respiratory distress syndrome.
To test the expanded definition of acute lung injury (ALI), we prospectively, over a period of 8 months, studied all adult ICU admissions who fitted the definition. Our study consisted of 83 patients with the adult respiratory distress syndrome (ARDS) and 60 with mild to moderate ALI. Sepsis and trauma were the most common diagnoses on admission. The overall mortality rate was 45 percent for ARDS and 38 percent in the other group. Mortality rose significantly with associated other organ failure, the incidence of which was as follows: hepatic, 39 percent; cardiac, 38 percent; hematologic, 22 percent; renal, 21 percent; neurologic, 5 percent. Sepsis syndrome eventually occurred in 73 percent and septic shock in 38 percent of all cases of ALI. We found the expanded definition a useful grading system and consider this definition of ARDS to be currently the best. There are, however, problems with the determination of lung compliance, the effect of inverse ratio ventilation, and the lack of consensus in defining other organ failure.


Medical informatics' promised land: are we there yet?
A decade ago, a "promised land" was envisioned in which the true potential of medical informatics would be realized. A decade later, it is time to assess academic medicine's progress in its journey into this medical informatics promised land. To that end, the author considers how our academic medical centers have been affected by changes in social, financial, and technical forces originating either "inside" or "outside" these institutions. He describes how the Internet and the World Wide Web have brought about an explosion in the availability of biomedical information, eased communication across the globe, made more information available at a lower cost, and changed the pace of everyday work. Although he argues that academic medical centers have not always kept pace with these changes, information systems are improving as the leaders in academic medicine come to appreciate the value of both information technology and the people who understand it. To reach the "promised land" envisioned a decade ago, academic medical centers must treat medical informatics as a central component of their academic mission.


Preemployment urine substance screening. One-year experience of a large hospital system.
Alcohol and drug abuse is estimated to cost our nation more than $160 billion per year in lost productivity, health care costs and crime. Preemployment screening for substances of abuse has become a standard in some industries, including the health care industry. Samaritan Health Services of Phoenix, Arizona, a large health care provider (11,244 employees) began preemployment drug screening and for-cause substance abuse testing March 1, 1991. This paper presents 1-year's statistics for that provider, including problems peculiar to the health care industry, eg, forensic testing stipulation agreements from professional boards. Problems are addressed including the ease of obtaining prescription medications by health care workers ("curbstone consultations") and dealing with a professional population knowledgeable about prescription drug use. It was this corporation's experience that preemployment drug screening can be performed without great hardship to a large health care provider.


Percolation Characteristics and Injection Limit of Surfactant Huff-n-Puff in a Tight Reservoir.
For the development of tight reservoirs, large-scale volume fracturing is frequently utilized as an effective production enhancement strategy. However, there is a significant decrease in productivity after fracturing. Improvement of production through secondary surfactant huff-n-puff has become one of the methods. In this paper, the characteristics of surfactant percolation during huff-n-puff were analyzed from macroscopic and microscopic perspectives. The production variation characteristics of the huff-n-puff were calculated by experiments and numerical methods. From Stokes' equations and phase field equations, solutions were found to analyze the effect of interfacial properties on surfactant percolation from the microscopic perspective. The findings demonstrated that a surfactant with a high displacement efficiency could not considerably increase huff-n-puff production, whereas the percolation rate had a wider influence. The surfactant with ultralow interfacial tension (<1 × 10-2 mN/m) and a higher wetting angle (>12.6°) has a faster percolation rate. Significant huff-n-puff production can be obtained in the percolation rate range of 1.38 to 1.63 m/PV. Simultaneously, the concepts of limit and optimal injection volume were established and utilized to characterize the influence of injection parameters on production under nonextension fracture situations. Based on the data, in order to obtain high production in a short time, the injection strength should be near to the value at fracture extension, and the optimum injection volume is 1000-1200 m3/m. The findings of this study have the potential to guide the selection of the surfactant and injection parameters in the field.


[Use of bevacizumab (Avastin) in KID syndrome: case report].
KID syndrome is a congenital ectodermal dysplasia characterized by the association of keratitis, hyperkeratotic skin lesions and neurosensorial hearing loss. Ocular involvement occurs in 95% of patients. Although KID syndrome cutaneous manifestations have been studied in-depth, the treatment and prognosis of ophthalmic impairment have not been described in detail. At present, the treatment of the ocular damage caused by the syndrome is symptomatic and there are no studies defining a treatment that could change the disease course. In this case, ophthalmologic findings of a patient with KID syndrome and the use of subconjunctival bevacizumab to treat corneal neovascularization are described. In spite of the absence of improvement in this patient and the few reports of this disease, additional studies with bevacizumab to treat corneal deep neovascularization are suggested.


Bioprinting of biomimetic self-organised cartilage with a supporting joint fixation device.
Despite sustained efforts, engineering truly biomimetic articular cartilage (AC) via traditional top-down approaches remains challenging. Emerging biofabrication strategies, from 3D bioprinting to scaffold-free approaches that leverage principles of cellular self-organisation, are generating significant interest in the field of cartilage tissue engineering as a means of developing biomimetic tissue analoguesin vitro.Although such strategies have advanced the quality of engineered cartilage, recapitulation of many key structural features of native AC, in particular a collagen network mimicking the tissue's 'Benninghoff arcade', remains elusive. Additionally, a complete solution to fixating engineered cartilagesin situwithin damaged synovial joints has yet to be identified. This study sought to address both of these key challenges by engineering biomimetic AC within a device designed to anchor the tissue within a synovial joint defect. We first designed and fabricated a fixation device capable of anchoring engineered cartilage into the subchondral bone. Next, we developed a strategy for inkjet printing porcine mesenchymal stem/stromal cells (MSCs) into this supporting fixation device, which was also designed to provide instructive cues to direct the self-organisation of MSC condensations towards a stratified engineered AC. We found that a higher starting cell-density supported the development of a more zonally defined collagen network within the engineered tissue. Dynamic culture was implemented to further enhance the quality of this engineered tissue, resulting in an approximate 3 fold increase in glycosaminoglycan and collagen accumulation. Ultimately this strategy supported the development of AC that exhibited near-native levels of glycosaminoglycan accumulation (>5% WW), as well as a biomimetic collagen network organisation with a perpendicular to a parallel fibre arrangement (relative to the tissue surface) from the deep to superficial zones via arcading fibres within the middle zone of the engineered tissue. Collectively, this work demonstrates the successful convergence of novel biofabrication methods, bioprinting strategies and culture regimes to engineer a hybrid implant suited to resurfacing AC defects.


[Werner syndrome. A prototypical form of segmental progeria.]
Werner syndrome is a segmental progeroid disorder with onset in adolescence or early adulthood. Typical symptoms contributing to patients' prematurely aged appearance include postpubertal development of short stature, cataracts, premature greying/thinning of scalp hair, scleroderma-like skin changes and regional atrophy of subcutaneous fat tissue. In addition, an increased rate and early onset of typical age-related diseases such as type 2 diabetes mellitus, osteoporosis, atherosclerosis, and various malignancies is observed. Werner syndrome is autosomal recessively inherited and caused by mutations in the Werner gene (WRN). To date, more than 70 WRN mutations have been identified. These are spread over the entire gene and typically represent loss of function mutations. WRN encodes a RecQ type helicase involved in DNA repair and the maintenance of DNA integrity, which is reflected by an increased genetic instability in patient cells. Despite the relative rarity of Werner syndrome, its analysis provides important general insights into the roles of DNA stability and integrity for the ageing process and the development of age-associated diseases.


Intramedullary nail fracture compression techniques: when and how to do it?
Fracture compression can be achieved in many ways intraoperatively using either screws in compression plates, compression devices, or using intramedullary nails. The use of locked intramedullary nails combines the advantages of indirect fracture fixation and compression with minimal soft tissue disruption. This article describes the technique, advantages, and limitations of the use of intramedullary nails for compression across fractures, nonunions, and joint arthrodeses.


Hypergastrinemia and mortality in gastric adenocarcinoma: a population-based cohort study, the HUNT study.
Purpose: Hypergastrinemia increases the risk of developing proximal gastric adenocarcinoma. However, it is unclear if hypergastrinemia affects the survival in patients with gastric adenocarcinoma. This study aimed to examine the hypothesis that hypergastrinemia is associated with increased risk of mortality in patients with gastric adenocarcinoma.Materials and methods: This prospective population-based cohort study based on the Trøndelag Health Study (HUNT) included 78,962 adult individuals (≥20 years). During the baseline assessment period (1995-2008) of these participants, serum samples were collected and frozen. All participants with a newly diagnosed gastric adenocarcinoma in the cohort in 1995-2015 were identified and their gastrin levels were measured in the pre-diagnostic serum samples. Gastrin levels were analysed in relation to all-cause mortality until year 2020 using multivariable Cox regression providing hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for sex, age, body mass index (BMI), tobacco smoking, tumour stage, completeness of surgical resection, and peri-operative chemotherapy.Results: Among 172 patients with gastric adenocarcinoma, 81 (47%) had hypergastrinemia (serum gastrin >60 pmol/L) and 91 (53%) had normal gastrin level. The tumour location was proximal in 83 patients (43%) and distal in 78 (41%). Hypergastrinemia was not associated with any increased risk of all-cause mortality in all patients (adjusted HR 0.8, 95% CI 0.5-1.1), or in sub-groups of patients with proximal tumour location (HR 0.9, 95% CI 0.4-2.2) or distal tumour location (HR 0.9, 95% CI 0.5-1.7).Conclusion: This population-based cohort study indicates that hypergastrinemia may not increase the risk of mortality in patients with gastric adenocarcinoma.


Is preoperative pain duration important in spinal cord stimulation? A comparison between tonic and burst stimulation.
Conflicting data have been published as to whether the success rate of spinal cord stimulation (SCS) is inversely proportional to the time interval from the initial onset of symptoms to implantation. Recently, a new stimulation design called burst stimulation has been developed that seems to exert its effect by modulating both the medial and lateral pain pathways and has a better effect than tonic stimulation on global pain, back pain, and limb pain. We analyzed the effect of preoperative pain duration on the degree of pain suppression by both tonic and burst stimulation in a group of patients (n = 49) who underwent both tonic and burst SCS. Using Pearson correlation analysis and controlling for age and duration of SCS, no correlation could be found between the preoperative pain duration and the success of SCS, either for tonic or for burst SCS, as defined by a numeric rating scale for pain. Using a different analysis method, dividing patients into groups according to preoperative pain duration, the same absence of influence was found. Pain was better suppressed by burst stimulation than tonic stimulation, irrespective of the preoperative pain duration. These results suggest that the duration of pain is not an exclusion criterion for SCS and that similar success rates can be obtained for longstanding pain and pain of more recent onset.


BECS-II: an updated bio-inspired electrocommunication system for small underwater robots.
Some weakly electric fish can use electric signals to interact and communicate with each other in dark and complex underwater environments where traditional underwater communication fails. In our previous work, we developed a bio-inspired electrocommunication system (BECS) that serves as an effective alternative to traditional methods in this challenging underwater scenario performing communication at a speed of approximately 1200 bps (bits per second) within approximately 3 m. In this study, a novel underwater wireless communication system (BECS-II) is proposed to upgrade the BECS with much better performance. We first propose theoretical and simulation models for electrocommunication, including the effects of the angular frequency and electrode impedance. A custom-made digital communication system is employed in BECS-II to improve the anti-interference ability and channel capacity of the BECS. In addition, a novel circuit optimization strategy was used to develop a customized circuit to enhance the transmitting and receiving capabilities of the BECS-II. Dual-frequency communication is proposed to meet the communication demands of different tasks by taking inspiration from the task allocation and evolution mechanisms of weakly electric fish. The experimental results showed that BECS-II outperformed BECS in high-frequency mode at both the communication speed (approximately 20 kbps) and distance (approximately 10 m), whereas in low-frequency mode, it extended the communication range by transmitting data up to a distance of approximately 20 m at a speed of approximately 200 bps. A substantial increase in the communication distance can expand the robot motion space in a group and improve group flexibility.


Nanoparticles in Agroindustry: Applications, Toxicity, Challenges, and Trends.
Nanotechnology is a tool that in the last decade has demonstrated multiple applications in several sectors, including agroindustry. There has been an advance in the development of nanoparticulated systems to be used as fertilizers, pesticides, herbicides, sensors, and quality stimulants, among other applications. The nanoencapsulation process not only protects the active ingredient but also can affect the diffusion, interaction, and activity. It is important to evaluate the negative aspects of the use of nanoparticles (NPs) in agriculture. Given the high impact of the nanoparticulated systems in the agro-industrial field, this review aims to address the effects of various nanomaterials on the morphology, metabolomics, and genetic modification of several crops.


The nature and outcome of infection in systemic lupus erythematosus.
Infection remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). To describe the nature and outcomes of infection and determine their associated risk factors in patients with SLE, we performed a nested case-control study at the University of Toronto Lupus Clinic, with prospective follow-up according to a standard protocol since 1970. Cases were SLE patients seen between January 1987 and January 1992 who had documented infections and controls were patients without infection from the same cohort matched for age, gender and time of visit. The type, site and outcome of infection were recorded for each case. A conditional logistic regression analysis was performed to compare factors associated with infection in cases and their controls. Ninety-three patients had 148 infection episodes; the majority were bacterial, but viral, fungal and protozoan organisms were also identified (multiple organisms in seven). Forty-eight patients required hospital admission and three patients died. Steroids at time of infection, as well as use ever, duration and dose, immunosuppressives at time of infection and use ever, active renal disease, CNS damage, SLEDAI at the time of infection, adjusted mean SLEDAI and variability measure were significantly associated with infection by univariate analysis. By multivariate analysis one factor remained statistically significant: use of steroids ever (P = 0.029). Infection carries a large burden for SLE patients. Until new medications which will control disease activity without predisposing to infection are developed, careful titration of steroids and cytotoxic drugs to control disease activity will remain crucial.


The Cost of Postoperative Complications and Economic Validation of the Comprehensive Complication Index: Prospective Study.
To validate the Comprehensive Complication Index (CCI) via an assessment of its relation to postoperative costs. The CCI summarizes all the postoperative complications graded by the Clavien-Dindo classification (CDC) on a numerical scale. Its relation to hospital costs has not been validated to date. Prospective observational cohort study, including all patients undergoing surgery at a general surgery service during the 1-year study period. All complications graded with the CDC and CCI and related to the initial admission, or until discharge if the patient was readmitted within 90 days of surgery, were included. The surgeries were classified according to their Operative Severity Score (OSS) and in 4 groups of homogeneous surgeries. All postoperative costs were recorded. In all, 1850 patients were included, of whom 513 presented complications (27.7%). The CDC and the CCI were moderately to strongly correlated with overall postoperative costs (OPCs) in all OSS groups (rs = 0.444-0.810 vs 0.445-0.820; P < 0.001), homogeneous surgeries (rs = 0.364-0.802 vs 0.364-0.813; P < 0.001), prolongation of postoperative stay (rs = 0.802 vs 0.830; P < 0.001), and initial operating room costs (rs = 0.448 vs 0.451; P < 0.001). This correlation was higher in emergency surgery. With higher CDC grades, the OPC tended to increase an upward trend. In the multivariate analysis, CDC, CCI, age, and duration of surgery were all associated with OPC (P < 0.001). In our environment, the CCI presented associations with OPC. This demonstration of its economic validity enhances its clinical validity.


[The role of gamma-interferon in blister formation of bullous pemphigoid].
Recently it has been reported that cell-mediated immune (CMI) reaction is related to the blister formation as well as the reaction of autoantibody against the basement membrane zone (BMZ-Ab) in bullous pemphigoid (BP). Previously we reported that T-cells infiltrated were producing gamma-interferon (IFN-gamma) and that high levels of IFN-gamma were detected in the blister fluids of BP. In the present study, in order to find the effect of IFN-gamma on the skin, we have done the organ culture of normal skin explants with IFN-gamma. The dermal-epidermal separation (DES) was histologically observed in skin explants which were incubated with high level of IFN-gamma after 24 hours. The DES was found to be located between the basal layer and the site of laminin and type IV collagen. It is considered that IFN-gamma alters the antigenicity and mediates to release some other cytokines in CMI reaction. In addition to these, IFN-gamma seems to directly work on the DES in normal skin. Around the DES of the skin explants, plasminogen activator was accelerated immunohistologically. The results suggest that IFN-gamma mediated by CMI response also plays an important role as well as the autoantibody in the blister formation of BP.


PCR primers for the amplification of the 16S rRNA gene of oral bacteria and for the specific identification of Actinobacillus actinomycetemcomitans.
The aim of this study was to develop a PCR reaction specific to Actinobacillus actinomycetemcomitans, which targets a widely conserved gene of this bacterium. Two sets of primers were designed based on published sequences of the 16S rRNA of several microorganisms. The first set amplifies a major part of the 16S small subunit rRNA gene of several strains of bacteria commonly found in the periodontal pocket. This reaction produced a 1306 bp-long product and served as a positive control. The second set was specific to A. actinomycetemcomitans and produced a 449 bp-long product. H. aphrophilus and E. coli yielded positive results with the control primers and negative results with the A. actinomycetemcomitans-specific primers. DNA-DNA hybridization was used to validate the identify of the amplified sequences. B. cereus, which is a common contaminator in the laboratory, and human DNA did not generate PCR products in either reaction. The developed primers seen useful for the identification of A. actinomycetemcomitans strains.


Gastroenterology and the provision of care to Panjabi patients in the UK.
Panjabi is spoken by 1.3 million people in the UK. It is the second most common language used in the country and is the first choice of 75% of Panjabis. It is becoming more common. For many patients it forms part of the barrier which limits access to gastrointestinal services. The provision of appropriate support services is woeful and yet seldom leads to formal complaints. This review considers the impact of gastrointestinal disorders on the Panjabi community and assesses some of the interventions that could be developed to ensure equity of care.


[Effect of prolonged administration of beta-blockers on the hemodynamics of patients who have sustained a myocardial infarct].
The effect of prolonged treatment with the beta-blocker trimepranol on left-ventricular function was assessed in patients who survived myocardial infarction. Pulmonary arterial catheterization with a floating catheter was used for hemodynamic investigation. Hemodynamic parameters were compared in the treated (20 patients) and control (20 patients matched for age and infarction site) groups. The treated patients showed a reduction in heart rate and cardiac output at rest, as well as stress-induced elevation of the pulmonary arterial pressure and peripheral resistance. Patients with pulmonary hypertension often demonstrated changes of the pressure curve in the pulmonary artery as a possible manifestation of stress-induced mitral regurgitation. Prolonged treatment with trimepranol is associated with increased incidence of pulmonary hypertension in myocardial infarction survivers. The clinical significance of this observation is yet to be established by further studies. Stress-induced mitral regurgitation associated with a mitral subvalvular dysfunction may occasionally be the cause of elevated pulmonary blood pressure.


Liquid crystal-carbon nanotubes mixtures.
The self-organizing properties of nematic liquid crystals (LCs) can be used to align carbon nanotubes (CNTs) dispersed in them. In the previous paper [P. van der Schoot, V. Popa-Nita, and S. Kralj, J. Phys. Chem. B 112, 4512 (2008)], we have considered the weak anchoring limit of the nematic LC molecules at the nanotube's surface, where the CNT alignment is caused by the anisotropic interfacial tension of the nanotubes in the nematic host fluid. In this paper, we present the theoretical results obtained for strong enough anchoring at the CNT-LC interface for which the nematic ordering around nanotube is apparently distorted. Consequently, relatively strong long-range and anisotropic interactions can emerge within the system. In order to get insight into the impact of LC ordering on the alignment of nanotubes we treat the two mixture components on the same footing and combine Landau-de Gennes free energy for the thermotropic ordering of the liquid crystal and Doi free energy for lyotropic nematic ordering of carbon nanotubes caused by their mutually excluded volume. The phase ordering of the binary mixture is analyzed as a function of the volume fraction of the carbon nanotubes, the strength of coupling, and the temperature. We find that the degree of ordering of the nanorods can be tuned by raising or lowering the temperature or by increasing or decreasing their concentration.


Young's modulus of elasticity of Schlemm's canal endothelial cells.
Schlemm's canal (SC) endothelial cells are likely important in the physiology and pathophysiology of the aqueous drainage system of the eye, particularly in glaucoma. The mechanical stiffness of these cells determines, in part, the extent to which they can support a pressure gradient and thus can be used to place limits on the flow resistance that this layer can generate in the eye. However, little is known about the biomechanical properties of SC endothelial cells. Our goal in this study was to estimate the effective Young's modulus of elasticity of normal SC cells. To do so, we combined magnetic pulling cytometry of isolated cultured human SC cells with finite element modeling of the mechanical response of the cell to traction forces applied by adherent beads. Preliminary work showed that the immersion angles of beads attached to the SC cells had a major influence on bead response; therefore, we also measured bead immersion angle by confocal microscopy, using an empirical technique to correct for axial distortion of the confocal images. Our results showed that the upper bound for the effective Young's modulus of elasticity of the cultured SC cells examined in this study, in central, non-nuclear regions, ranged between 1,007 and 3,053 Pa, which is similar to, although somewhat larger than values that have been measured for other endothelial cell types. We compared these values to estimates of the modulus of primate SC cells in vivo, based on images of these cells under pressure loading, and found good agreement at low intraocular pressure (8-15 mm Hg). However, increasing intraocular pressure (22-30 mm Hg) appeared to cause a significant increase in the modulus of these cells. These moduli can be used to estimate the extent to which SC cells deform in response to the pressure drop across the inner wall endothelium and thereby estimate the extent to which they can generate outflow resistance.


Monte Carlo simulations of microchannel plate detectors. I. Steady-state voltage bias results.
X-ray detectors based on straight-channel microchannel plates (MCPs) are a powerful diagnostic tool for two-dimensional, time-resolved imaging and time-resolved x-ray spectroscopy in the fields of laser-driven inertial confinement fusion and fast Z-pinch experiments. Understanding the behavior of microchannel plates as used in such detectors is critical to understanding the data obtained. The subject of this paper is a Monte Carlo computer code we have developed to simulate the electron cascade in a MCP under a static applied voltage. Also included in the simulation is elastic reflection of low-energy electrons from the channel wall, which is important at lower voltages. When model results were compared to measured MCP sensitivities, good agreement was found. Spatial resolution simulations of MCP-based detectors were also presented and found to agree with experimental measurements.


Hyperekplexia: A Frequent Near Miss in Infants and Young Children.
Hyperekplexia, an underdiagnosed motor paroxysm of infancy, mimics epilepsy closely. It is hallmarked by episodic and excessive startle response, brief episodes of intense, generalized hypertonia, or stiffness in response to unexpected auditory and/or tactile stimuli right from birth. Though a seemingly benign entity with an excellent prognosis, hyperekplexia has been occasionally associated with recurrent apneas, feeding difficulties, and sudden infant death syndrome (SIDS). We describe three unrelated children with hyperekplexia (two SLC6A5; one GLRA1). All three children had the onset of motor paroxysms from the neonatal period and were initially labeled as drug-resistant epilepsy leading to a variable diagnostic delay, the longest being 2.5 years. An excellent response to oral clonazepam with a good neurodevelopmental outcome was observed. The lack of habituation on the nose-tapping test is a simple clinical clue to the diagnosis. Early differentiation from epilepsy minimizes treatment cost, allays caregiver anxiety, and empowers them with abortive measures.


Diabetes and risk of cancer incidence: results from a population-based cohort study in northern Italy.
Aim of this study was to compare cancer incidence in populations with and without diabetes by cancer site. Furthermore, we aimed at comparing excess risk of cancer according to diabetes type, diabetes duration and treatment, the latter as regards Type 2 diabetes. By use of the Reggio Emilia diabetes registry we classified the resident population aged 20-84 at December 31st 2009 into two groups: with and without diabetes. By linking with the cancer registry we calculated the 2010-2013 cancer incidence in both groups. The incidence rate ratios (IRR) by cancer site, type of diabetes, diabetes duration, and as concerns Type 2 diabetes, by treatment regimen were computed using Poisson regression model and non-diabetic group as reference. The cohort included 383,799 subjects without diabetes and 23,358 with diabetes. During follow-up, we identified 1464 cancer cases in subjects with diabetes and 9858 in the remaining population. Overall cancer incidence was higher in subjects with diabetes than in those without diabetes (IRR = 1.22, 95%CI 1.15-1.29), with similar results focusing on subjects with at least 2-year diabetes duration. Cancer sites driving overall increased risk were liver, pancreas, Colon rectum, and bladder in both sexes, corpus uteri for females. There was also suggestion of an increased risk for kidney cancer in females and a decreased risk for prostate cancer. Excess risk was found in patients with Type 2 diabetes, more marked among insulin users, especially with combined therapy. We observed an increasing risk for diabetes duration up to 10 years from diagnosis (IRR = 1.44, 95%CI 1.29-1.61) and a subsequent decrease to moderate-higher risk (IRR = 1.15, 95%CI 1.04-1.30). Our study indicates that the strength of association depends on specific cancer site. Insulin, monotherapy or combined therapy, per se or as an indication of poor blood glucose control, in addition to diabetes duration, may play a role in the association of diabetes and cancer.


[Influence of the catheter-top-position upon the distribution pattern of continuous intra-arterially infused chemotherapeutic agent (author's transl)].
The whole body scanning showed the distribution pattern of infused drug in continuous intra-arterially infused chemotherapy by using a gamma camera and infused RI (99mTc-MAA) from catheter. I measured the whole body scanning counts without shield (A) and with lead shield (B) on ROI and natural back ground counts (BG). Then I calculated the distribution ratio on ROI as following. [(A-B)/(A-BG)] x 100 (%). It was easy to find a certain relation between the catheter-top-position and the distribution ratio. As a result of investigating data, there were about 4 catheter-top-positions in aorta. Case by case, we put the catheter-top in better position and prevented technical side effects and measured roughly total dose on ROI.


Enhanced analysis of metastatic prostate cancer using stable isotopes and high mass accuracy instrumentation.
The primary goal of proteomics is to gain a better understanding of biological function at the protein expression level. As the field matures, numerous technologies are being developed to aid in the identification, quantification and characterization of protein expression and post-translational modifications on a near-global scale. Stable isotope labeling by amino acids in cell culture is one such technique that has shown broad biological applications. While we have recently shown the application of this technology to a model of metastatic prostate cancer, we now report a substantial improvement in quantitative analysis using a linear ion-trap Fourier transform ion cyclotron resonance mass spectrometer (LTQ FT) and novel quantification software. This resulted in the quantification of nearly 1400 proteins, a greater than 3-fold increase in comparison to our earlier study. This dramatic increase in proteome coverage can be attributed to (1) use of a double-labeling strategy, (2) greater sensitivity, speed and mass accuracy provided by the LTQ FT mass spectrometer, and (3) more robust quantification software. Finally, by using a concatenated target/decoy protein database for our peptide searches, we now report these data in the context of an estimated false-positive rate of one percent.


TGA-DSC Combined Coal Analysis as a Tool for QC (Quality Control) and Reactivity Patterns of Coals.
Coal is at present a major fuel source for power generation worldwide and will remain as such in the near future. The most important property of coal that determines its price is its calorific value. However, volatiles, ash, and moisture content are also very important properties needed for the quality control (QC) of the coal used to maintain an optimal operation of coal combustion in a boiler. The determination of these properties is carried out via well-established ASTM/DIN methods, which are slow and time-consuming. This study uses combined thermogravimetric analysis (TGA)/differential thermal calorimetry (DSC) instrumentation as a tool to evaluate the reactivity patterns of the aliphatic versus aromatic content of coals, which is correlated to the volatile content of coals. Two coals, bituminous (American Baily Pittsburgh No. 6) used in Israeli utilities and lignite (brown coal Hambach) used in German power plants, have been investigated in this study. The results show that the combined TG/DSC method can provide a much better understanding of the chemical reactivity of coals in the combustion process.


Τelomerase inhibitors and activators in aging and cancer: A systematic review.
The main aim of the present systematic review was to summarize the most frequently used telomerase regulators with an impact on aging and cancer that are referred to in in vitro and in vivo studies. For this purpose, a systematic review of the available literature on telomerase regulators referred to in articles from PubMed and Scopus libraries published from 2002 to 2021 and in accordance with PRISMA 2020 criteria, was conducted. Articles were included if they met the following criteria: They referred to telomerase modulators in aging and in cancer and were in vitro and/or in vivo studies, while studies that did not provide sufficient data or studies not written in English were excluded. In the present systematic review, 54 publications were included, of which 29 were full‑text published studies, 11 were full‑text reviews, 10 structure‑based design studies and 4 abstracts are reported in this review. Telomerase regulators were then categorized as synthetic direct telomerase inhibitors, synthetic indirect telomerase inhibitors, synthetic telomerase activators, natural direct telomerase activators, natural telomerase inhibitors and natural indirect telomerase activators, according to their origin and their activity. On the whole, as demonstrated herein, telomerase regulators appear to be promising treatment agents in various age‑related diseases. However, further in vivo and in vitro studies need to be performed in order to clarify the potentiality of telomerase as a therapeutic target.


Evaluation of a caries prevention programme for preschool children in Switzerland: is the target group being reached?
With the goal of reducing the prevalence of early childhood caries, the city of Zurich, Switzerland, started a specific prevention programme in 2010. All 2-year-olds are invited to a free dental check-up at a local public dental health service before the first legally mandated yearly dental check-up for school children between 4 and 5 years of age (at kindergarten). However, for the success of this prevention programme, it is of particular importance that children at high risk of caries are reached. The objective of our study was to assess the effectiveness of the prevention programme in (1) reaching the children who needed it the most and (2) improving subsequent oral health. This retrospective cohort study included all children born between July 1, 2013 and July 15, 2014 who had lived in Zurich between the ages of 23 and 36 months. Socio-economic data were extracted from official school records, and dental health data from public dental clinic records. Binomial and quasi-binomial generalised linear models were used to identify the socio-economic factors associated with toddler check-up attendance and to assess the associations between attendance and caries experience (dmft [Formula: see text] 1) as well as degree of treatment (proportion m+f out of dmft) at the kindergarten check-up, adjusting for socio-economic factors. From a total of 4376 children, 2360 (54%) attended the toddler check-up (mean age 2.4 years) and 3452 (79%) had a dental examination at kindergarten (mean age 5.3 years). Non-Swiss origin of the primary caretaker, presence of older siblings, low amount of savings and allocation to certain public dental clinics were associated with a lower odds of attendance. Factors associated with a higher odds of caries experience were similar to those associated with a lower odds of attendance at the toddler check-up, but additionally included low income. Attendance at the toddler check-up was non-significantly associated with a lower odds of caries experience at kindergarten (adjusted OR 0.84, 95% CI from 0.70 to 1.01), but was significantly associated with a higher degree of treatment at this stage (adjusted OR 2.41, 95% CI from 1.79 to 3.24). Our study suggests that children with a high caries risk are less likely to attend the toddler check-up. Greater effort should be put into reaching these children.


Oral adverse effects of head and neck radiotherapy: literature review and suggestion of a clinical oral care guideline for irradiated patients.
Radiotherapy, alone or associated with surgery or chemotherapy, produces a significant increase in cure rates for many malignancies of the head and neck region. However, high doses of radiation in large areas, including the oral mucosa, may result in several undesired reactions that manifest during or after the completion of therapy. The multidisciplinary management is the best alternative to minimize or even prevent such reactions, and the dentist has a fundamental role in this context. This paper reviews the literature related to the main oral sequelae from head and neck radiotherapy and establishes clinical oral management protocol for these irradiated patients.


Arterial oxygen saturation before intubation of the trachea. An assessment of oxygenation techniques.
Arterial oxygenation in patients was measured with an ear oximeter to assess factors that were associated with hypoxaemia at the induction of anaesthesia. Twenty patients breathed air during the induction of anaesthesia with thiopentone and following neuromuscular blockade with suxamethonium. Mean SaO2 decreased from 95.7% before induction to 85.5% 1 min after induction. The SaO2 at 1 min was less in those patients whose weight was more than expected (SaO2 80.5%), than in those patients whose weight was as expected or less than expected (SaO2 88.8%). Other factors such as haemoglobin concentration, FEV1, FVC, age, or smoking habits, were not related to the degree of arterial desaturation. To assess the efficacy of different methods of oxygen administration, four groups of 10 patients, were given oxygen in different ways using a Magill anaesthetic system with a supply of 10 litre min-1. Measurements were made for up to 3 min after the induction of anaesthesia and maintenance of apnoea. Group I breathed normally from the system for 1 min before anaesthesia was induced. Group II were treated similarly, but the mask had a standardized "leak", a 9.5-mm diameter hole. Group III took three vital capacity breaths from the system before anaesthesia, and group IV breathed air before anaesthesia, but their lungs were given three maximal manual inflations after the induction of anaesthesia. Mean SaO2 values after 3 min apnoea were: 96.8% (group I), 93.6% (group II), and 98.0% (group III). In group IV, measurements were stopped at 2 min when mean SaO2 was 92.9%.(ABSTRACT TRUNCATED AT 250 WORDS)


Progesterone receptors and Sp/Krüppel-like family members in the uterine endometrium .
Sp/KLF family members, of which at least 20 distinct nuclear proteins are known to date, serve as transcription factors by binding to GC-enriched sites within target gene promoters. These molecules regulate diverse cellular processes such as proliferation, differentiation, and apoptosis, via their interactions with various other nuclear proteins in promoter- and cell-context-dependent pathways to effect transactivation or transrepression. Recent studies indicate that Sp-family members may functionally interact with ligand-activated nuclear receptors, especially those for steroid hormones. This review provides a discussion of the putative mechanisms and important participants involved in the crosstalk between selected members of this family and the receptor for the pregnancy hormone progesterone, and the relevant outcomes to the control of the transcriptional network in the uterine endometrium.


Generation of four iPSC lines from Neurofibromatosis Type 1 patients.
We describe the generation and characterisation of four human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMC) from individuals with neurofibromatosis type (NF1). PBMC reprogramming was performed using a non-integrative Sendai virus containing the reprogramming factors OCT4, SOX2, MYC and KLF4. All iPSC lines exhibited a normal karyotype, and pluripotency was validated by flow cytometry (EPCAM, TRA-1-81, SSEA1 and CD9) and immunofluorescence (OCT4 and Nanog). Differentiation of the cells into the three embryonic germ layers was confirmed using immunofluorescence. These iPSC lines are a valuable pre-clinical resource to study the molecular mechanisms underlying NF1.


Trends in health research ethics in the Philippines during the American Colonial Period (1898-1946).
Research involving human participants has been conducted in the Philippines since the beginning of the Spanish colonial period. Such studies are expected to adhere to internationally accepted ethical guidelines. This paper discusses trends in clinical research ethics in the Philippines during the American colonial period (1898-1946). Specifically, studies were assessed on: 1) their observance of ethical protocols, including review; 2) identification of inclusion and exclusion criteria in the selection of participants; 3) use of vulnerable subjects; and 4) practice of the informed consent process. Only the informed consent process had a significant logistic correlation with progression of years. Recruitment of vulnerable groups was common during this period; children and prisoners were the most common participants. Trends in medical ethics in the Philippines reflected those in the United States prior to the publication of the Nuremberg Code, which served as a milestone in the protection of human welfare in clinical research.


From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story.
Natural products are a rich source of bioactive compounds, and numerous natural compounds have found application in cancer chemotherapy. However, unfavorable physicochemical properties often prevent the use of the original natural product as a drug. A prominent example is camptothecin from the Chinese tree Camptotheca acuminata, which shows extraordinary cytotoxic activity based on a specific molecular mode of action (inhibition of human topoisomerase I). Due to its extremely poor solubility, the original natural product cannot be used as a drug. The marketed drug topotecan was developed from this lead structure by semi-synthesis utilizing a Mannich aminomethylation as the crucial step. In this review, the long-distance run leading to this drug and further perspectives are summarized.


Relationships of race and ethnicity to progression of kidney dysfunction and clinical outcomes in patients with chronic kidney failure.
In the United States, the incidence of end-stage renal disease (ESRD) is much higher for blacks, Native Americans, and Asians than for whites. The incidence of kidney disease is also higher for populations of Hispanic ethnicity. ESRD attributed to diabetes (ESRD-DM), hypertension (ESRD-HT), and glomerulonephritis (ESRD-GN), in this order of frequency, are the major categories of ESRD in the United States for all race/ethnic groups. By using the incidence rates of ESRD, during the period from 1997 through 2000, and with whites as reference, the highest rate ratio (RR) was observed for ESRD-HT in blacks (RR = 5.96), ESRD-DM in Native Americans (RR = 5.11), and ESRD-GN in Asians (RR=2.20). The data suggest that the excess of ESRD observed for racial/ethnic minorities may be reduced by interventions aimed at prevention/control of hypertension and diabetes. The data suggest that before developing ESRD, patients with chronic renal failure from minority groups have to face more barriers to receive high-quality health care. This may explain why they see nephrologists later and are less likely to receive renal transplantation at initiation of renal replacement therapy (RRT). Improvements in quality of care after initiating RRT may explain the lower mortality and higher scores in heath-related quality of life observed for patients from racial/ethnic minorities.


The inhibition of cultured myoblast differentiation by the simian virus 40 large T antigen occurs after myogenin expression and Rb up-regulation and is not exerted by transformation-competent cytoplasmic mutants.
We have investigated the mechanism by which the simian virus 40 large T antigen (SVLT) interferes with the differentiation of C2 myoblasts. SVLT mutants, defective either in the Rb binding site, near the N-terminal end, in a region that affects binding to p53, or in the nuclear transport signal, were also employed to determine whether the interference was especially dependent on these functional domains. It was found that wild-type (wt) SVLT strongly inhibited the terminal differentiation of mouse C2 myoblasts, but this arrest occurred only after the synthesis of myogenin, an initial step in biochemical differentiation. Neither the synthesis nor some basic activities of MyoD appeared to be affected by wt SVLT. In these transformants, mitogen depletion elicited an increase in the Rb level comparable to that in normal C2 cells; wt SVLT, however, promoted the phosphorylation of a large part of the induced Rb. Mutations affecting nuclear transport were far more critical for the ability to interfere with myogenic differentiation than were those affecting the transforming potential; cytoplasmic SVLT expression was fully compatible with the terminal differentiation of C2 cells, despite enabling them to grow in semisolid medium, thus showing that the myogenesis-inhibiting property can be dissociated from transforming competence. The remaining SVLT mutants presented different degrees of ability to inhibit differentiation (as shown by the expression of tissue-specific markers in transformants). The inhibiting mutants, including the Rb binding site mutant, were able to promote a higher state of Rb phosphorylation than that observed in either normal cells or cytoplasmic-SVLT transformants.


Mechanism of stimulation of DNA synthesis induced by epinephrine in primary culture of adult rat hepatocytes.
Addition of epinephrine to primary cultured adult rat hepatocytes stimulated their DNA synthesis dose-dependently, especially in presence of insulin and epidermal growth factor. This effect of epinephrine was strongly inhibited by an alpha 1-antagonist, prazosin, but not by a beta-antagonist, propranolol, and was also slightly inhibited by an alpha 2-antagonist, yohinbin. These results indicate that the stimulation of DNA synthesis of hepatocytes by epinephrine is mediated predominantly by an alpha 1-action. 12-o-Tetradecanoylphorbol-13-acetate (TPA) or Ca2+-ionophore A-23187 stimulated DNA synthesis of Swiss 3T3 cells, but did not induce DNA synthesis of hepatocytes either singly or in combination. The fact that pretreatment of hepatocytes with TPA caused down-regulation of the stimulatory effect of epinephrine on DNA synthesis of hepatocytes within 15 min suggested that the effect of epinephrine on hepatocytes is mediated by its alpha 1 receptor and that TPA activated protein kinase c in the hepatocytes. Addition of dibutyryl cGMP did not induce DNA synthesis of hepatocytes. Therefore, the alpha 1-action of epinephrine that induce stimulation of DNA synthesis of primary cultured adult rat hepatocytes was apparently not mediated by either activation of phospholipid-dependent protein kinase or Ca2+ mobilization. Possible alternative mechanism was discussed.


Clinical and Radiographic Evaluation of Allium sativum Oil (Garlic Oil) in Comparison with Formocresol in Primary Molar Pulpotomy.
Given the side effects of formocresol as a common substance in dental pulpotomy, its substitution with a safe substance seems mandatory. To compare the clinical and radiographic success of Allium sativum oil and formocresol in the pulpotomy of the primary molars. A randomized, split-mouth, double-blind, controlled clinical trial was conducted on children with at least two asymptomatic primary molars requiring pulpotomy. A total of 90 teeth were examined in this study. They were randomly divided into two groups: the A. sativum (ALL) group (n = 45) and the formocresol (FC) group (n = 45). After pulpotomy, A. sativum oil was applied to the radicular pulp in the ALL groups and formocresol in the FC group. The pulp chamber was then filled with reinforced Zinc oxide Eugenol and finally restored by a stainless steel crown. Three and six months after the intervention, the teeth were evaluated by a colleague based on a modified criteria system. The results were analyzed using Wilcoxon's test. The clinical success rate was 100% in both groups after 3 and 6 months. The radiographic success rate in the ALL group and the FC group after 3 and 6 months was 82.2% and 80% and 88.9% and 84.4%, respectively. The difference between the two groups was not statistically significant (P = 0.46). According to the results of this study, A. sativum oil can be used in the pulpotomy of the primary molars.


Iodine-catalyzed highly diastereoselective synthesis of trans-2,6-disubstituted-3,4-dihydropyrans: application to concise construction of C28-C37 bicyclic core of (+)-sorangicin A.
A novel iodine-catalyzed highly diastereoselective synthesis of trans-2,6-disubstituted-3,4-dihydropyrans have been achieved from delta-hydroxy alpha,beta-unsaturated aldehydes by treating with allyltrimethyl silane in THF at room temperature with good to excellent yields. This methodology has been successfully implemented for a concise asymmetric synthesis of C28-C37 dioxabicyclo[3.2.1]octane ring system of (+)-sorangicin A in 8 steps with 21% overall yield.