Gap junctional channels are parts of multiprotein complexes.
Gap junctional channels are a class of membrane channels composed of transmembrane channel-forming integral membrane proteins termed connexins, innexins or pannexins that mediate direct cell-to-cell or cell-to extracellular medium communication in almost all animal tissues. The activity of these channels is tightly regulated, particularly by intramolecular modifications as phosphorylations of proteins and via the formation of multiprotein complexes where pore-forming subunits bind to auxiliary channel subunits and associate with scaffolding proteins that play essential roles in channel localization and activity. Scaffolding proteins link signaling enzymes, substrates, and potential effectors (such as channels) into multiprotein signaling complexes that may be anchored to the cytoskeleton. Protein-protein interactions play essential roles in channel localization and activity and, besides their cell-to-cell channel-forming functions, gap junctional proteins now appear involved in different cellular functions (e.g. transcriptional and cytoskeletal regulations). The present review summarizes the recent progress regarding the proteins capable of interacting with junctional proteins and highlights the function of these protein-protein interactions in cell physiology and aberrant function in diseases. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions.


Expression of endoglin in choroidal neovascularization.
Endoglin (CD105) is a membrane protein involved in the TGF-beta receptor signalling pathway with predominant expression by proliferating endothelial cells. The aim of this study is to analyze the expression of Endoglin in choroidal neovascularization membranes (CNVM) and to compare it to the overall proliferative status of CNVM. Thirty surgically excised CNVM, secondary to age-related macular degeneration, were investigated using light microscopic immunohistochemistry and confocal immunofluorescence microscopy using verified antibodies directed against the endothelial cell markers Endoglin, von Willebrand factor (vWF) and CD34 and the proliferation marker Ki-67. Donor eyes were used as controls. A selective expression of CD34 and vWF as well as Endoglin was found in endothelial cells. Endoglin expression was elevated in vascular endothelial cells contained within CNVM, but a moderate Endoglin expression could also be visualized in quiescent CD34 and vWF positive ocular vasculature. Ki-67 positive cells were detected in CNVM, but these were rarely endothelial cells. Endoglin expression in endothelial cells of CNVM is increased, but rarely associated with a concomitant expression of the proliferation marker Ki-67. The elevated expression of Endoglin in surgically excised CNVM suggests a persisting post-mitotic activation in an advanced stage of this neovascular tissue.


Psychometric considerations in the measurement of event-related brain potentials: Guidelines for measurement and reporting.
Failing to consider psychometric issues related to reliability and validity, differential deficits, and statistical power potentially undermines the conclusions of a study. In research using event-related brain potentials (ERPs), numerous contextual factors (population sampled, task, data recording, analysis pipeline, etc.) can impact the reliability of ERP scores. The present review considers the contextual factors that influence ERP score reliability and the downstream effects that reliability has on statistical analyses. Given the context-dependent nature of ERPs, it is recommended that ERP score reliability be formally assessed on a study-by-study basis. Recommended guidelines for ERP studies include 1) reporting the threshold of acceptable reliability and reliability estimates for observed scores, 2) specifying the approach used to estimate reliability, and 3) justifying how trial-count minima were chosen. A reliability threshold for internal consistency of at least 0.70 is recommended, and a threshold of 0.80 is preferred. The review also advocates the use of generalizability theory for estimating score dependability (the generalizability theory analog to reliability) as an improvement on classical test theory reliability estimates, suggesting that the latter is less well suited to ERP research. To facilitate the calculation and reporting of dependability estimates, an open-source Matlab program, the ERP Reliability Analysis Toolbox, is presented.


Reasons for hospitalisation at the end of life: differences between cancer and non-cancer patients.
Many patients are hospitalised during the final phase of life, even though most prefer to receive care at home until the end. This study aimed to explore the reasons and characteristics of hospitalisation in the final 3 months of life for patients who died non-suddenly, with a comparison between cancer patients and non-cancer patients. This study used a nationwide retrospective cross-sectional survey among Dutch general practitioners. Of the 317 hospitalised patients, 65 % had cancer. Most common reasons for hospitalisation in the final 3 months of life were respiratory symptoms (31 %), digestive symptoms (17 %), and cardiovascular symptoms (17 %). Seventy-three percent of patients experienced an acute episode before hospitalisation, and for 46 % of patients, their own GP initiated the hospitalisation. Compared to non-cancer patients, cancer patients were significantly more likely to be aged less than 80 (81 versus 46 %), were more likely to be hospitalised because of digestive symptoms (22 versus 7 %), were less likely to have a curative treatment goal before the last hospitalisation (6 versus 22 %) and were less likely to die in hospital (22 versus 49 %). Respiratory problems were the most common reasons for hospitalisation in the group of patients as a whole. Digestive problems were a frequent reason for hospitalisation in cancer patients and cardiovascular symptoms in non-cancer patients. Hospitalisation can therefore be anticipated by monitoring these relatively common symptoms. Also, timely communication with the patient is recommended about their preferences for hospital or home treatment in the case of an acute episode.


[Cancer of the breast and the receptor status].
Correlation between survival and hormonal receptor status in patients with breast cancer is still controversial. The results of a study carried out, from 1973 to 1988, on 55 patients (average age 56.7) affected with breast cancer and submitted to radical (Halsted) mastectomy, are reported. Estradiol receptors (ER) and progesterone receptors (PR) were determined using the dextran-coated charcoal (DCC) method and the enzymatic immuno assay (EIA). The threshold value for defining the ER positivity was 10 f/mole/mg of cytosol protein and 50 f/mole/mg for PR positivity. Forty-one patients resulted as ER+, 31 were also PR+. Moreover, 41 patients were treated with tamoxifen (10 mg x 2 die per os). In a 15-year follow-up, no significant difference in survival rate between patients with receptor-positive tumors or treated with tamoxifen and patients with receptor-negative tumors was recorded.


Oncogenic induction of cellular high CpG methylation by Epstein-Barr virus in malignant epithelial cells.
Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancer (GC) worldwide. Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC. However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC. High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified. Further characterization of the epigenomes (genome-wide CpG methylation profile--methylome) of NPC and EBVaGC shows that these EBV-associated tumors display a unique high CpG methylation epigenotype with more extensive gene methylation accumulation, indicating that EBV acts as a direct epigenetic driver for these cancers. Mechanistically, oncogenic modulation of cellular CpG methylation machinery, such as DNA methyltransferases (DNMTs), by EBV-encoded viral proteins accounts for the EBV-induced high CpG methylation epigenotype in NPC and EBVaGC. Thus, uncovering the EBV-associated unique epigenotype of NPC and EBVaGC would provide new insight into the molecular pathogenesis of these unique EBV-associated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.


Effects of all-trans retinoic acid and Ca++ on human skin in organ culture.
In this study, we have established an organ culture model of human skin and examined the effects of both all-trans retinoic acid (RA) and extracellular Ca++ on the epidermal and dermal components of the organ-cultured skin. Our data show that while organ cultures maintained in serum-free, growth factor-free culture medium containing 0.15 mM Ca++ degenerated rapidly, those treated with concentrations of RA that have been shown previously to stimulate fibroblast and keratinocyte proliferation in monolayer culture (J Invest Dermatol 1989, 93:449; 1990, 94:717; Am J Pathol 1990, 136:1275) demonstrated a healthy appearance for up to 12 days. Degeneration of the control cultures was characterized by separation of the epidermis from the underlying dermis, progressive cell necrosis leading to a complete absence of viable cells from both the dermal and epidermal compartments, disintegration and fibrillation of the dermal connective tissue, and a cessation of protein synthesis. RA-treated organ cultures contained large numbers of healthy-appearing cells in both the epidermal and dermal compartments. One or several layers of viable basal cells in the epidermis could be seen at least through day 12. However, the upper layers of the epidermis frequently separated from the cells in the basal layer. The dermal connective tissue was histologically well-preserved. Furthermore, the level of protein synthesis was higher in the RA-treated cultures than in the control cultures. In addition to treating organ cultures with RA, other cultures were exposed to serum-free, growth factor-free culture medium containing 1.4 mM Ca++. The presence of the elevated Ca++ concentration also preserved cellular and connective tissue structures in the dermal and epidermal compartments. In comparison to RA there was better preservation of the overall epidermal structure. The upper layers of epidermal cells did not separate from the basal cells, and the various stages of epithelial differentiation could be seen. Histologically, the dermis was well-preserved in the presence of elevated extracellular Ca++. Specimens treated with a combination of Ca++ and RA demonstrated features consistent with the features induced by each treatment separately. This included an expanded basal layer of epithelial cells and a prominent keratotic layer with a fairly orderly pattern of differentiation. The tendency of the upper epidermis to separate from the basal cells was partially mitigated. Taken together, these data indicate that both RA and extracellular Ca++ act to prevent the degeneration of human skin in organ culture but probably do so through different mechanisms.


The appropriate use of gloves to reduce allergies and infection.
Twenty years ago, the wearing of gloves for non-sterile procedures was viewed as insulting to the patient as it made him/her feel 'unclean'. Today, gloves are worn for all procedures and are often wastefully used. There must be a fine balance between inappropriate and appropriate use of gloves and between the use of latex gloves for comfort and fine movements vs the potential for latex allergies. This article will review the use of synthetic and latex gloves and examine some of the related issues.


Patients with psoriasis feel stigmatized.
Stigmatization is defined as having a discrediting mark that leads to social discrimination and alienation. The aim of this study was to estimate the level of stigmatization experienced by patients with psoriasis. A total of 102 individuals with psoriasis were recruited and was assessed using the 6-item Stigmatization Scale and the 33-item Feelings of Stigmatization Questionnaire. In addition, quality of life, stress and depression were evaluated. The majority of patients felt that they were stigmatized by psoriasis. The most bothersome aspect was that other people stared at their skin changes. According to the 33-item questionnaire, anticipation of rejection and feelings of guilt and shame were the major aspects of stigmatization, the level of which correlated significantly with pruritus intensity, stress prior to exacerbation, depressive symptoms and quality of life. In order to decrease the stigmatization level in patients with psoriasis, greater effort is needed to raise awareness in contemporary societies that psoriasis is not contagious, but is a disease like many other chronic conditions.


Selective isotopic enrichment of synthetic RNA: application to the HIV-1 TAR element.
The introduction of isotopically enriched nucleotides into NMR quantities of a synthetic 29-mer RNA derived from the HIV-1 TAR element is described. RNA enriched in 13C and/or 15N is produced by a procedure which involves isolation of whole cellular RNA from Escherichia coli, nucleolysis, separation of mononucleotides, chemical or enzymatic pyrophosphorylation, and in vitro transcription by T7 RNA polymerase. Spectral characteristics of each residue type are examined in isolation. 13C chemical shifts provide an alternative method to determine ribose puckers for larger RNAs. Nonprotonated sites such as purine N7 groups can now be monitored through the use of multiple-bond 1H-15N coupling. When applied conservatively, coordinate analysis of chemical shift values should prove valuable for NMR studies of RNA structure and recognition. 1H, 13C, and 15N chemical shift data suggest that TAR residue A35 has an unusual local environment, consistent with extrusion of its base from the terminal loop.


Chlorine isotope fractionation in the stratosphere.
Chlorinated organic compounds are important contributors to the anthropogenic enhancement of stratospheric ozone depletion. We report measurements of stratospheric isotope fractionation in such a compound. Stratospheric and tropospheric difluorodichloromethane (CF2Cl2) were found to have the largest relative 37Cl/35Cl isotope ratio difference ever measured for a natural compound. The increase of the relative isotope ratio difference with altitude was tightly correlated to the corresponding decrease in the CF2Cl2 mixing ratio. The observed relationship has a high potential to provide new insights into atmospheric chemistry and transport processes.


Intraductal Papilloma With Carcinoma of the Breast Described by Dedicated Breast 18F-FDG PET.
Intraductal papilloma (IDP) is a benign tumor of the breast. However, IDP has been reported to show high uptake of 18F-FDG using whole-body PET. We experienced IDP with low-grade ductal carcinoma in situ using dedicated breast PET, which is more sensitive than whole-body PET. The 18F-FDG uptake of the whole tumor was high, and differentiation between the carcinoma and the residual benign lesion was difficult. This is the first report of IDP detected with dedicated breast PET. Diagnosis of IDP is sometimes controversial; papilloma may show glucose uptake similar to that of low-grade carcinoma.


An assessment of non-communicable diseases, diabetes, and related risk factors in the Federated States of Micronesia, State of Pohnpei: a systems perspective.
Non-communicable diseases (NCD) have been identified as a health emergency in the US-affiliated Pacific Islands (USAPI).1 This assessment, funded by the National Institutes of Health, was conducted in the Federated States of Micronesia, State of Pohnpei and describes the burden due to selected NCD (diabetes, heart disease, hypertension, stroke, chronic kidney disease); and assesses the system of service capacity and current activities for service delivery, data collection and reporting as well as identifies the issues that need to be addressed. Findings reveal that the risk factors of poor diet, lack of physical activity, and lifestyle behaviors lead to overweight and obesity and subsequent NCD that are significant factors in the morbidity and mortality of the population. Leading causes of death were due to heart disease, diabetes, cancer, and hypertension. Population survey data show that 32.1% of the adult population had diabetes with a higher rate among women (37.1%) when compared to men (26.4%). The data also showed that 73.1% of the adult population was overweight or obese. Other findings show significant gaps in the system of administrative, clinical, data, and support services to address these NCD. There is no overall planning document for the prevention and control of NCDs or diabetes. There is evidence of little communication among the medical and health care providers which leads to fragmentation of care and loss of continuity of care. Based on some of the findings, priority issues and problems that need to be addressed for the administrative and clinical systems are identified.


Second-Generation RT-QuIC Assay for the Diagnosis of Creutzfeldt-Jakob Disease Patients in Brazil.
The recent development of IQ-CSF, the second generation of real-time quaking-induced conversion (RT-QuIC) using cerebrospinal fluid (CSF), for the diagnosis of Creutzfeldt-Jakob Disease (CJD) represents a major diagnostic advance in the field. Highly accurate results have been reported with encouraging reproducibility among different centers. However, availability is still insufficient, and only a few research centers have access to the method in developing countries. In Brazil, we have had 603 suspected cases of CJD since 2005, when surveillance started. Of these, 404 were undiagnosed. This lack of diagnosis is due, among other factors, to the lack of a reference center for the diagnosis of these diseases in Brazil, resulting in some of these samples being sent abroad for analysis. The aim of this research study is to report the pilot use of IQ-CSF in a small cohort of Brazilian patients with possible or probable CJD, implementing a reference center in the country. We stored CSF samples from patients with possible, probable or genetic CJD (one case) during the time frame of December 2016 through June 2018. All CSF samples were processed according to standardized protocols without access to the clinical data. Eight patients presented to our team with rapidly progressive dementia and typical neurological signs of CJD. We used CSF samples from seven patients with other neurological conditions as negative controls. Five out of seven suspected cases had positive tests; two cases showed inconclusive results. Among controls, there was one false-positive (a CSF sample from a 5-year-old child with leukemia under treatment). The occurrence of a false positive in one of the negative control samples raises the possibility of the presence of interfering components in the CSF sample from patients with non-neurodegenerative pathologies. Our pilot results illustrate the feasibility of having CJD CSF samples tested in Brazilian centers and highlight the importance of interinstitutional collaboration to pursue a higher diagnostic accuracy in CJD in Brazil and Latin America.


A new time dependent density functional algorithm for large systems and plasmons in metal clusters.
A new algorithm to solve the Time Dependent Density Functional Theory (TDDFT) equations in the space of the density fitting auxiliary basis set has been developed and implemented. The method extracts the spectrum from the imaginary part of the polarizability at any given photon energy, avoiding the bottleneck of Davidson diagonalization. The original idea which made the present scheme very efficient consists in the simplification of the double sum over occupied-virtual pairs in the definition of the dielectric susceptibility, allowing an easy calculation of such matrix as a linear combination of constant matrices with photon energy dependent coefficients. The method has been applied to very different systems in nature and size (from H2 to [Au147](-)). In all cases, the maximum deviations found for the excitation energies with respect to the Amsterdam density functional code are below 0.2 eV. The new algorithm has the merit not only to calculate the spectrum at whichever photon energy but also to allow a deep analysis of the results, in terms of transition contribution maps, Jacob plasmon scaling factor, and induced density analysis, which have been all implemented.


Forensic kinesiology: foundations of an interdiscipline for accident/crime investigation.
Kinesiology is the study of human movement, and comprises several disciplines, each devoted to a specific aspect of human activity, each with its own set of principles and methods to assess and analyze movement. Forensic kinesiology is the application of kinesiological techniques to accident/crime investigation; specialists in this field can use various tools and procedures to measure, analyze, model, and determine the movement sequences involved in events under investigation. This article will highlight major subdisciplines of kinesiology most relevant to forensics, present the key assessment and analytical tools used by kinesiologists, and demonstrate how both the principles and the practices of kinesiology can be applied to accident/crime investigation.


Inhibition of the acetylcholine-induced relaxation of canine isolated basilar artery by potassium-conductance blockers.
Canine basilar artery rings precontracted with 5-hydroxytryptamine (0.1-0.5 microM) relaxed in the presence of acetylcholine (25-100 microM), sodium nitroprusside (0.1 microM), or stimulation of the electrogenic sodium pump by restoration of extracellular K+ (4.5 mM) after K(+)-deprivation. Acetylcholine-induced relaxation is believed to be caused by the release of endothelium-derived relaxing factor (EDRF) and is prevented by mechanical removal of the endothelium, while relaxations induced by sodium nitroprusside or restarting of the sodium pump are endothelium-independent. Acetylcholine-induced relaxation was selectively blocked by pretreatment of the tissue with the nonselective K+ conductance inhibitors, 4-aminopyridine (4-AP, 3 mM), Ba2+ (1 mM), and tetraethylammonium (20 mM), 4-AP also blocked ACh-mediated relaxation in muscles contracted with elevated external K+. Relaxation of 5-hydroxytryptamine-induced contraction by sodium nitroprusside, or by addition of K+ to K(+)-deprived muscle, was not affected by 4-AP. Relaxation of basilar artery with acidified sodium nitrite solution (containing nitric oxide) was reduced by 4-AP. These results suggest that 4-AP and possibly Ba2+ inhibit acetylcholine-induced endothelium-dependent relaxation by inhibition of the action of EDRF on the smooth muscle rather than through inhibition of release of EDRF. The increase in K+ conductance involved in acetylcholine-induced relaxation is not due to ATP-inhibited K+ channels, as it is not blocked by glyburide (10(-6) M). Endothelium-derived relaxant factor(s) may relax smooth muscle by mode(s) of action different from that of sodium nitroprusside or by hyperpolarization due to the electrogenic sodium pumping.(ABSTRACT TRUNCATED AT 250 WORDS)


Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: role of microRNAs-16, -21, and -126.
Aerobic exercise training (ET) lowers hypertension and improves patient outcomes in cardiovascular disease. The mechanisms of these effects are largely unknown. We hypothesized that ET modulates microRNAs (miRNAs) involved in vascularization. miRNA-16 regulates the expression of vascular endothelial growth factor and antiapoptotic protein Bcl-2. miRNA-21 targets Bcl-2. miRNA-126 functions by repressing regulators of the vascular endothelial growth factor pathway. We investigated whether miRNA-16, -21 and -126 are modulated in hypertension and by ET. Twelve-week-old male spontaneously hypertensive rats (SHRs; n=14) and Wistar Kyoto (WKY; n=14) rats were assigned to 4 groups: SHRs, trained SHRs (SHR-T), Wistar Kyoto rats, and trained Wistar Kyoto rats. ET consisted of 10 weeks of swimming. ET reduced blood pressure and heart rate in SHR-Ts. ET repaired the slow-to-fast fiber type transition in soleus muscle and the capillary rarefaction in SHR-Ts. Soleus miRNA-16 and -21 levels increased in SHRs paralleled with a decrease of 48% and 25% in vascular endothelial growth factor and Bcl-2 protein levels, respectively. Hypertension increased Bad and decreased Bcl-x and endothelial NO synthase levels and lowered p-Bad(ser112):Bad ratio. ET in SHR-Ts reduced miRNA-16 and -21 levels and elevated vascular endothelial growth factor and Bcl-2 levels. ET restored soleus endothelial NO synthase levels plus proapoptotic and antiapoptotic mediators in SHR-Ts, indicating that the balance between angiogenic and apoptotic factors may prevent microvascular abnormalities in hypertension. miRNA-126 levels were reduced in SHRs with an increase of 51% in phosphoinositol-3 kinase regulatory subunit 2 expression but normalized in SHR-Ts. Our data show that ET promoted peripheral revascularization in hypertension, which could be associated with regulation of select miRNAs, suggesting a mechanism for its potential therapeutic application in vascular diseases.


Psychotropic drug abuse in pregnancy and its impact on child neurodevelopment: A review.
Substance abuse by women of child-bearing age and fetal in utero drug exposure has increased in the number of infants born with health issues. Prenatal exposure to psychoactive substances can lead to neurological and neurodevelopmental deficits later in life. Useful data concerning the effects of psychoactive drugs on fetal neurodevelopmental status are sparse. Understanding the neurodevelopmental consequences of prenatally drug-exposed children has become a pressing global concern. The aim of this review is to gather current evidence and information on neurodevelopmental outcomes of in utero drug exposure. A literature search was performed on the PubMed, Scopus, and Google Scholar databases using the terms "psychotropic drugs", "neurodevelopmental consequences", "prenatal drug exposure", and "pregnancy". Available studies on in utero drug exposure were reviewed and found to support the idea that some degree of health issues are present in fetuses and children. Different psychoactive substances have profound neurodevelopmental consequences, such as structural brain changes, poor attention span, Down syndrome, attention deficit hyperactivity disorder, autism spectrum disorder, imbalances in neurotransmitter levels, and many structural deficits. The pervasive use of psychoactive drugs in women of child-bearing age is an important health concern. Further scientific efforts are needed to investigate the effect of prenatal exposure to psychoactive drugs on children.


Ovine MHC class II DRB1 alleles associated with resistance or susceptibility to development of bovine leukemia virus-induced ovine lymphoma.
For the further characterization of bovine leukemia virus (BLV)-induced leukemogenesis, we investigated the association between polymorphism of ovine leukocyte antigen (OLA)-DRB1 gene and tumor development after infection of sheep with BLV. We infected 28 sheep with BLV and cloned exon 2 of the OLA-DRB1 gene from asymptomatic animals and from animals with lymphoma Sequence analysis revealed that, among 12 healthy sheep without any evidence of tumor, ten (83.3%) carried DRB1 alleles encoding Arg-Lys (RK) at positions beta70/71 as compared with only 6 (37.5%) of the 16 sheep with lymphoma, which suggested that alleles encoding the RK motif might protect against development of tumors after infection by BLV. By contrast, alleles encoding Ser-Arg (SR) at positions beta70/71 were present at a significantly elevated frequency in sheep with lymphoma as compared with the healthy carriers, which indicated that OLA-DRB1 alleles encoding the SR motif might be positively related to susceptibility to tumor development. The two amino acids in these motifs line a pocket that accommodates the side chain of a bound peptide according to a model of the crystal structure of human leukocyte antigen (HLA)-DR1. To analyze immunoreactions of sheep with alleles that encoded RK or SR at beta70/71, we selected sheep with either the RK/SR genotypes or the SR/SR genotypes and immunized them with a mixture of multiple synthetic antigenic peptides that corresponded to T-helper, T-cytotoxic, and B-cell epitopes of the BLV envelope glycoprotein gp51. Two weeks after the last immunization, all of the sheep were challenged with BLV. Sheep with the RK/SR genotype produced neutralizing antibodies against BLV; they eliminated BLV completely within 28 weeks of the BLV challenge, and they gave strong lymphocyte-proliferative responses to the peptides used for immunization. Moreover, such animals did not develop lymphoma. By contrast, sheep with the SR/SR genotype continued to produce BLV throughout the experimental period and developed terminal disease. Our results indicate that the differences in immunoresponse were due to differences in major histocompatibility complex class II alleles and reflected the risk of BLV-induced leukemogenesis. In addition, it appears that susceptibility to tumor development may be determined to some extent by polymorphic residues binding to antigenic peptides directly within the binding cleft of the OLA-DR molecule.


A sex difference in the human brain and its relation to transsexuality.
Transsexuals have the strong feeling, often from childhood onwards, of having been born the wrong sex. The possible psychogenic or biological aetiology of transsexuality has been the subject of debate for many years. Here we show that the volume of the central subdivision of the bed nucleus of the stria terminals (BSTc), a brain area that is essential for sexual behaviour, is larger in men than in women. A female-sized BSTc was found in male-to-female transsexuals. The size of the BSTc was not influenced by sex hormones in adulthood and was independent of sexual orientation. Our study is the first to show a female brain structure in genetically male transsexuals and supports the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones.


Lung Adenocarcinoma Presenting as Multiple Thromboembolic Events: A Case Report and Review of the Literature.
Patients with malignancy may present with significant thromboembolic complications including deep vein thrombosis (DVT), pulmonary embolism, arterial thrombosis, nonbacterial thrombotic endocarditis, and stroke due to abnormal coagulation cascades. Although these events are typically recognized later in the disease process, complications of a hypercoagulable state can rarely present as the first manifestation of an occult malignancy. We report a case of a young male who was ultimately found to have an aggressive form of lung adenocarcinoma after the initial presentation of multiple thromboembolic events. DVT and stroke as an initial presentation of an active lung adenocarcinoma in a young patient is extremely rare as patients presenting in a hypercoagulable state usually are older. Though testing for a hypercoagulable state is not recommended for the first unprovoked DVT, clinicians should be prompted to screen for malignancy in the setting of cryptogenic strokes, especially in younger patients with no prior risk factors.


Structural and functional analysis of the 5'-flanking region of the rat ceruloplasmin gene.
To characterize the mechanisms determining tissue-specific ceruloplasmin gene expression during development, the rat ceruloplasmin gene was isolated in a series of overlapping phage clones. The 5'-flanking region was characterized and the transcription initiation site was identified by primer extension and RNase protection. Nucleotide sequence analysis of this region revealed a typical eukaryotic promotor structure, but no obvious homology with cis-acting elements previously characterized as determining tissue-specific gene expression. Transient expression of chimeric ceruloplasmin-reporter gene constructs containing up to 5200 base pairs (bp) of the 5'-flanking region revealed that sequences 732 bp upstream of the start nucleotide were sufficient to confer hepatocyte-specific expression. The region from -393 to -348 was determined by deletion analysis to contain a positive-acting element, and includes sequence partially homologous to the rat albumin D site. Mobility shift analysis revealed that this region specifically binds a heat-labile nuclear protein from rat liver and from newborn but not adult rat lung. Binding to this region was competed by oligonucleotides corresponding to the albumin D site, but not by oligonucleotides corresponding to binding sites for the hepatocyte transcription factors HNF-1, HNF-3, HNF-4, and C/EBP. These data indicate that ceruloplasmin gene expression is determined in part by a cis-acting region 393 bp upstream of the transcription start site, which binds a previously uncharacterized nuclear protein. The tissue distribution of this nuclear protein suggests that it plays a role in directing ceruloplasmin gene expression in lung and liver during development.


Factors Affecting the Short-Term Prognosis of Alcohol Dependent Patients Undergoing Inpatient Detoxification.
Stable measures of psychological functioning require a considerable period of abstinence. However, the duration of inpatient detoxification programs has decreased dramatically in most health care systems, posing a novel challenge for clinical evaluation of patients. The present study was carried out to examine whether factors predicting short-term prognosis can be identified in alcohol dependent subjects during early stages of inpatient detoxification. Self-reports of mood states were obtained, and executive cognitive functioning was examined. Outcome was studied at 2-3 months. No correlation was found between self-reported symptoms of depression, hopelessness, and anxiety, and percentage of nondrinking days. A significant positive correlation was found between Wisconsin Card Sorting Test (WCST) performance and short-term prognosis measured by this parameter. Thus, in addition to transient withdrawal-related effects, impairments of WCST performance in early stages of alcohol detoxification may reflect more long standing deficits in problem-solving strategies, of possible relevance for matching patients to treatment services.


[Situational therapy of acute thrombophlebitis].
The insufficiently treated acute phlebothrombosis leads frequently to severe, in social-medical respect remarkable healings of defects (PTS and RDS), in the extreme case to a fatal pulmonary embolism. In order to avoid these complications a differentiated therapy concept is proposed which takes into consideration first therapy measures in the prehospital phase and represents multidisciplinary hospital measures (surgical thrombectomy, medicamentous fibrinolysis, anticoagulant therapy, physicotherapy), including their variants of dosage for risk patients.


Development of Synergy-Based Combination for Learning and Memory Using in vitro, in vivo and TLC-MS-Bioautographic Studies.
The present study is aimed at developing a synergistic combination to enhance learning and memory in Alzheimer's patients with the help of eight common medicinal plants used in the AYUSH system. Aqueous and hydroalcoholic extracts of eight medicinal plants from the AYUSH system of medicine were prepared. These were subjected to in vitro anticholinesterase activity, to find out the combination index of synergistic combination. The synergistic combination and their individual extracts were subjected to total phenol, flavonoid and antioxidant activity estimation. Further, in vivo neurobehavioral studies in rats were carried out followed by TLC-MS-bioautographic identification of bioactive metabolites. Out of the sixteen extracts, aqueous extracts of Withania somnifera (L.) Dunal (WSA) and Myristica fragrans (L.) Dunal (MFA) were selected for the development of synergistic combination based on their IC50 value in vitro anticholinesterase assay. The synergistic combination inhibited the anticholinesterase activity significantly as compared to the individual extracts of WSA and MFA. The synergistic combination also showed more phenolic and flavonoid contents with potential antioxidant activity. The TLC-bioautography showed four white spots in WSA, signifying sitoindosides VII, VIII, quercetin, isopelletierine and Withanolide S as AChE inhibitory compounds while showing five white spots of anti-cholinesterase active metabolites identified as eugenol, methyl eugenol, myristic acid, galbacin and β-sitosterol in MFA. The observation of neurocognitive behavior in amnesia induced subjects manifested that both the synergistic combinations showed comparable results to that of standard piracetam, though the synergistic combination containing a higher concentration of WSA showed more appreciable results in ameliorating dementia in rats. The study suggests that the synergy based combination successfully enhanced memory and learning by abating free radical and acetylcholine levels, and increased learning and memory in rats, providing a strong rationale for its use in the treatment of dementia and Alzheimer's disease.


Accuracy of articulatory movements of speech in a group of first-graders.
Associations between different types of misarticulations and morphology as well as function of the speech articulators were assessed in 287 first-grade children. Sounds produced too far anteriorly evidently were due to immaturity of the articulatory speech movements, which showed a tendency to improve spontaneously with age. Sounds produced too far posteriorly correlated positively with problems in coordinating the movements of different muscles of the tongue, indicating a possible dyspractic origin. Children who had problems with lip tonus were prone to have laterally produced misarticulations.


Improvement of kilovoltage intrafraction monitoring accuracy through gantry angles selection.
Kilovoltage intrafraction monitoring (KIM) is a method allowing to precisely infer the tumour trajectory based on cone beam computed tomography (CBCT) 2D-projections. However, its accuracy is deteriorated in the case of highly mobile tumours involving hysteresis. A first adaptation of KIM consisting of a prior amplitude based binning step has been developed in order to minimize the errors of the original model (phase-KIM). In this work, we propose enhanced methods (KIMsub-arc optimand phase-KIMsub-arc optim) to improve the accuracy of KIM and phase-KIM which relies on the selection of the optimal starting CBCT gantry angle. Aiming at demonstrating the interest of our approach, we carried out a simulation study and an experimental study: we compared the accuracy of the conventional versus sub-arc optim methods on simulated realistic tumour motions with amplitudes ranging from 5 to 30 mm in 1 mm increments. The same approach was performed using a lung dynamic phantom generating a 30 mm amplitude sinusoidal motion. The results show that for in-silico simulated motions of 10, 20 and 30 mm amplitude, the three-dimensional root mean square error (3D-RMSE) can be reduced by 0.67 mm, 0.91 mm, 0.94 mm and 0.18 mm, 0.25 mm, 0.28 mm using KIMsub-arc optimand phase-KIMsub-arc optimrespectively. Considering all in-silico simulated trajectories, the percentage of errors larger than 1 mm decreases from 21.9% down to 1.6% for KIM (p < 0.001) and from 6.6% down to 1.2% for phase-KIM (p < 0.001). Experimentally, the 3D-RMSE is lowered by 0.5732 mm for KIM and by 0.1 mm for phase-KIM. The percentage of errors larger than 1 mm falls from 39.7% down to 18.5% for KIM and from 23.2% down to 11.1% for phase-KIM. In conclusion, our method efficiently anticipates CBCT gantry angles associated with a significantly better accuracy by using KIM and phase-KIM.


Distinct patterns of tau-dependent process formation in mammalian cell lines.
Tau is a microtubule-associated protein involved in axonal elongation and central to the pathogenesis of a number of neurodegenerative conditions. To better establish the contribution of the cellular context to tau-dependent microtubule organization, we compared the phenotypes resulting from heterologous tau expression in different mammalian cell lines after disruption of the actin cytoskeleton. After cytochalasin D treatment, tau-expressing CHO cells display one or two long neurite-like extensions whereas cells transfected with MAP2c developed multiple shorter processes. By contrast, under the same conditions, tau-transfected PtK2 cells elaborate microtubule bundles forming numerous processes. These results suggest that cell-specific factors are involved in tau-dependent microtubule organization, a notion that could facilitate functional assessment of tau abnormalities associated with neurodegenerative disease.


Depletion of the mature CD4+8- thymocyte subset by FK506 analogs correlates with their immunosuppressive and calcineurin inhibitory activities.
FK506 blocks T cell activation by preventing the transcription of lymphokine genes through binding to the intracellular protein FKBP12 and formation of complex that inhibits the phosphatase activity of calcineurin. Beside exerting potent suppressive activity on cellular and humoral immune responses, in vivo treatment with FK506 in rodent models induces thymic alterations characterized by a selective reduction of mature CD4+8- cells. The potential relationship between such thymic alterations and the immunosuppressive and calcineurin inhibitory activities of FK506 has not been defined. Here, we took advantage of the availability of FK506 analogs with different immunosuppressive potencies to address this question. Intravenous daily administration of FK506 in Sprague-Dawley rats for 4 days was found to be sufficient to cause a depletion of CD4+8- thymocytes with an ED50=0.06 mg/kg/day. Under the same conditions, L-683,590 which is 2-3-fold less potent than FK506 in inhibiting T cell activation and calcineurin function gave an ED50=0.17 mg/kg/day. In contrast, the nonimmunosuppressive, calcineurin noninhibitory antagonist L-685,818, failed to deplete the CD4+8- thymocyte subset but could reverse the reducing effect of FK506 on this subset. Another analog, L-688,617, which does not completely inhibit T cell activation in vitro, also behaved as a partial agonist of CD4+8- cell depletion. Therefore, the ability of FK506 analogs to deplete the CD4+8- thymocytes subset correlates with their immunosuppressive and calcineurin inhibitory potencies. This suggests that calcineurin is involved in the intra-thymic maturation processes of CD4+8- T cells. Moreover, the short-term treatment protocol described here provides a rapid and quantitative assay to determine the immunosuppressive potency of FK506-like compounds in vivo


Iron Overload Induces Oxidative Stress, Cell Cycle Arrest and Apoptosis in Chondrocytes.
Clinical and experimental evidence point to the presence of considerable links between arthropathy, osteoarthritis (OA) in particular, and iron overload possibly due to oxidative stress and tissue damage. However, the specific cellular targets of iron overload-related oxidative stress in OA remain ambiguous. We examined the effects of iron overload on chondrocyte health using the C-20/A4 chondrocyte cell line. Cells were treated with increasing concentrations of ferric ammonium citrate (FAC) to mimic iron overload in vitro. Treated cells were assessed for cell viability, cycling, apoptosis, collagen II synthesis, and oxidative stress along with cellular iron content and the expression of key iron regulatory genes. FAC treatment resulted in an increase in ferritin expression and a significant decrease in the expression of hepcidin, ferroportin, transferrin receptors 1 (TfR1) and TfR2. Increased labile iron content was also evident, especially in cells treated with high FAC at 24 h. High doses of FAC treatment also induced higher levels of reactive oxygen species, reduced collagen II production, disrupted cell cycle and higher cell death as compared with untreated controls. In conclusion, findings presented here demonstrate that iron overload disrupts cellular iron homeostasis, which compromises the functional integrity of chondrocytes and leads to oxidative stress and apoptosis.


[Color-coded duplex ultrasonography of extracranial vascular lesions].
The diagnostic potential of color-coded duplex sonography in extracranial vascular lesions is evaluated with reference to the literature. Indications for the applications of color-coded duplex sonography comprise congenital vascular anomalies, arteriosclerotic lesions, dissections, aneurysms, arteriovenous fistulas and glomus tumors. New applications consist include monitoring after vascular interventional procedures. Color-coded duplex sonography allows recognition of congenital anatomic variants like agenesis of the internal carotid artery and variations of the origin of the vertebral artery. By superior surface delineation, characterization and quantification of plaques and stenoses are improved because of a new development in ultrasound technique. In cases of vessel dissection color-coded ultrasound is able to depict the dissection membrane, pulse synchronous flow reversal and "reentry" phenomena. Significant carotid bulb ectasia can be demonstrated and differentiated from aneurysm formation by 3D technique and angio-CT. Extracranial arteriovenous fistulas may be localized and detailed with respect to feeding arteries and draining veins. Glomus caroticum and jugular tumors are characterized by a high degree of vascularity and a position in the carotid bifurcation and within the jugular vein, respectively. The position of intravascular devices like detachable balloons and catheters was precisely demonstrated. Color-coded duplex sonography may assume a leading role in the noninvasive evaluation of extracranial vascular lesions. It provides criteria for the necessity and rational application of additional diagnostic procedures (MR, MRA, CT, DSA).


[The outcomes of Tiantan first-aid protocol on critically ill patients with primary central nervous system lymphoma].
Objective: To examine the outcomes of Tiantan first-aid protocol on critically ill patients with primary central nervous system lymphoma (PCNSL). Methods: The clinical data of 18 patients with PCNSL who were treated according to Tiantan first-aid protocol at Department of Neurosurgery,Beijing Tiantan Hospital, Capital Medical University from November 2019 to December 2021 were retrospectively analyzed. There were 9 males and 9 females, aged (56.9±11.1)years (range: 29 to 77 years). The median Karnofsky performance status(KPS) score at admission was 40 (range: 20 to 60). Three patients were mild coma, 3 were lethargy and 12 were conscious. The mean midline shift was 0.7 cm (range: 0 to 1.8 cm). After admission, all patients were treated according to the plan of rapid biopsy, rapid routine pathology and rapid salvage chemotherapy. The treatment procedures, clinical and radiographic outcomes, KPS score and adverse reactions of patients after chemotherapy were collected. Results: All of the 18 patients completed the first-aid treatment. The median duration from admission to the biopsy was 1 day (range: 0 to 5 days), from biopsy to routine pathological diagnosis was 1 day (range: 1 to 4 days) and from routine pathology to salvage chemotherapy was 1 day (range: 0 to 4 days). All the patients were pathologically confirmed with diffuse large B cell lymphoma, 1 patient was double-hit lymphoma. Seventeen patients underwent clinical remission and 1 died of cardiac dysfunction. The successful salvage rate was 17/18. Radiologically, complete remission was observed in 1 case, partial remission in 16 cases, and stable disease in 1 case. The median KPS score at discharge was 60 (range: 30 to 80). The mild gastrointestinal, hematological and hepatic adverse effects were observed after chemotherapy. Conclusion: Tiantan first-aid protocol is effective for critically ill patients with PCNSL, which has the merit to be popularly used and improved.


Probing the resonance potential in the F atom reaction with hydrogen deuteride with spectroscopic accuracy.
Reaction resonances are transiently trapped quantum states along the reaction coordinate in the transition state region of a chemical reaction that could have profound effects on the dynamics of the reaction. Obtaining an accurate reaction potential that holds these reaction resonance states and eventually modeling quantitatively the reaction resonance dynamics is still a great challenge. Up to now, the only viable way to obtain a resonance potential is through high-level ab initio calculations. Through highly accurate crossed-beam reactive scattering studies on isotope-substituted reactions, the accuracy of the resonance potential could be rigorously tested. Here we report a combined experimental and theoretical study on the resonance-mediated F + HD --> HF + D reaction at the full quantum state resolved level, to probe the resonance potential in this benchmark system. The experimental result shows that isotope substitution has a dramatic effect on the resonance picture of this important system. Theoretical analyses suggest that the full-dimensional FH(2) ground potential surface, which was believed to be accurate in describing the resonance picture of the F + H(2) reaction, is found to be insufficiently accurate in predicting quantitatively the resonance picture for the F + HD --> HF + D reaction. We constructed a global potential energy surface by using the CCSD(T) method that could predict the correct resonance peak positions as well as the dynamics for both F + H(2) --> HF + H and F + HD --> HF + D, providing an accurate resonance potential for this benchmark system with spectroscopic accuracy.


Extracellular vesicles-released parathyroid hormone-related protein from Lewis lung carcinoma induces lipolysis and adipose tissue browning in cancer cachexia.
Cancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.


Proto-oncogene tyrosine-protein kinase SRC (Src) inhibition in microglia relieves neuroinflammation in neuropathic pain mouse models.
Chronic neuroinflammation is an important factor in the development of neuropathic pain (NP). Excess microglia activation releases a mass of pro-inflammatory cytokines during neuroinflammation process, leading to a constant painful irritation of the sensory nerve. Src belongs to a non-receptor tyrosine kinase associated with sarcoma, whereas the role of Src in neuropathic pain is controversial. We designed to testify the inflammation-regulatory role of Src in the lipopolysaccharide (LPS)-induced BV2 microglia line and the mouse model of neuropathic pain by partial sciatic nerve ligation (PNL). In BV2 microglia, Src expression was inhibited using a Src family kinase inhibitor PP2 after LPS induced inflammatory response. In vivo, the neuropathic pain in mice was induced by PNL surgery and then treated with PP2. The neuroinflammation level in vitro was detected by enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), trans-well and Western blotting (WB) assays, in vivo was examined in PNL mice using immunohistochemistry (IHC) and IF. Finally, mechanical allodynia and thermal hyperalgesia assays were used to access the functional evaluation. Inhibition of Src was decreased microglial inflammation and migration after LPS stimuli. Mechanistically, the expression of nuclear factor kappa B (NF-κB) pathway decreased after Src inhibition. The data in vivo showed that the decrease expression of Src reduced neuroinflammation and the amount of microglia in spinal dorsal horn (SDH), the mechanical allodynia of mice thereby attenuated after Src inhibition. These results indicated that the inhibition of Src took a protective effect in neuropathic pain mouse models via reducing microglia-induced neuroinflammation.


Increasing the Responsiveness of Health Services in Mexico's Seguro Popular: Three Policy Proposals for Voice and Power.
Abstract-One of the most relevant market signals that most public health services lack is a drop in revenues. This signal is key because it can help you detect quality problems in your services and enables you to respond accordingly. Our analysis seeks to understand how Mexican public health services can substitute this market signal. To achieve this, we use the accountability framework developed in the World Development Report 2004: Making Services Work for the Poor. Three policy proposals focused on improving voice and power, building on previous efforts developed by Mexico's Ministry of Health and other organizations, are proposed for increasing the responsiveness of Seguro Popular: (1) a countrywide health ranking of states, (2) a national alert system for maternal and infant deaths, and (3) a community-based monitoring system based on the use of report cards.


Nanomaterial coatings applied on stent surfaces.
The advent of percutaneous coronary intervention and intravascular stents has revolutionized the field of interventional cardiology. Nonetheless, in-stent restenosis, inflammation and late-stent thrombosis are the major obstacles with currently available stents. In order to enhance the hemocompatibility of stents, advances in the field of nanotechnology allow novel designs of nanoparticles and biomaterials toward localized drug/gene carriers or stent scaffolds. The current review focuses on promising polymers used in the fabrication of newer generations of stents with a short synopsis on atherosclerosis and current commercialized stents, nanotechnology's impact on stent development and recent advancements in stent biomaterials is discussed in context.


Green and facile fabrication of hollow porous MnO/C microspheres from microalgaes for lithium-ion batteries.
Hollow porous micro/nanostructures with high surface area and shell permeability have attracted tremendous attention. Particularly, the synthesis and structural tailoring of diverse hollow porous materials is regarded as a crucial step toward the realization of high-performance electrode materials, which has several advantages including a large contact area with electrolyte, a superior structural stability, and a short transport path for Li(+) ions. Meanwhile, owing to the inexpensive, abundant, environmentally benign, and renewable biological resources provided by nature, great efforts have been devoted to understand and practice the biotemplating technology, which has been considered as an effective strategy to achieve morphology-controllable materials with structural specialty, complexity, and related unique properties. Herein, we are inspired by the natural microalgae with its special features (easy availability, biological activity, and carbon sources) to develop a green and facile biotemplating method to fabricate monodisperse MnO/C microspheres for lithium-ion batteries. Due to the unique hollow porous structure in which MnO nanoparticles were tightly embedded into a porous carbon matrix and form a penetrative shell, MnO/C microspheres exhibited high reversible specific capacity of 700 mAh g(-1) at 0.1 A g(-1), excellent cycling stability with 94% capacity retention, and enhanced rate performance of 230 mAh g(-1) at 3 A g(-1). This green, sustainable, and economical strategy will extend the scope of biotemplating synthesis for exploring other functional materials in various structure-dependent applications such as catalysis, gas sensing, and energy storage.


[Analysis of accelerant in fire debris by pyrolysis gas chromatography-mass spectrometry].
A strategy for the analysis of the accelerant and combustion residues in fires was developed by pyrolysis gas chromatography-mass spectrometry (PyGC-MS). Two kinds of accelerants (gasoline and diesel) and two kinds of carriers (cotton cloth and polyethylene terephthalate (PET) plastic) were selected for this research. Combustion residues of the accelerant and carrier were prepared. The characteristic temperatures of the samples were determined by thermal analysis technology. Then the analysis conditions were optimized and selected. The samples were subjected to PyGC-MS by a stepwise method consisting of flash analysis and pyrolysis analysis. The experimental results showed that the pyrolysates of the original combustion residues of the PET carrier consisted of 35 components, while the pyrolysates of the combustion residues of the PET carrier with gasoline, and ones of the combustion residues of the PET carrier with diesel oil consisted of only 25 components. The types and contents of the pyrolysates were different. The established method could distinguish the self-combustion residue of the carrier from the combustion residue of the accelerant and the same carrier. It was suitable for the analysis of the accelerant from the fire debris, and could determine the presence of the accelerant in the fire field. The method can provide a scientific basis for the judgement of the fire property and fire investigation work.


Staphylococcal enterotoxins modulate interleukin 2 receptor expression and ligand-induced tyrosine phosphorylation of the Janus protein-tyrosine kinase 3 (Jak3) and signal transducers and activators of transcription (Stat proteins).
Staphylococcal enterotoxins (SE) stimulate T cells expressing the appropriate variable region beta chain of (V beta) T-cell receptors and have been implicated in the pathogenesis of several autoimmune diseases. Depending on costimulatory signals, SE induce either proliferation or anergy in T cells. In addition, SE can induce an interleukin-2 (IL-2) nonresponsive state and apoptosis. Here, we show that SE induce dynamic changes in the expression of and signal transduction through the IL-2 receptor (IL-2R) beta and gamma chains (IL-2R beta and IL-2R gamma) in human antigen-specific CD4+ T-cell lines. Thus, after 4 hr of exposure to SEA and SEB, the expression of IL-2R beta was down-regulated, IL-2R gamma was slightly up-regulated, while IL-2R alpha remained largely unaffected. The changes in the composition of IL-2Rs were accompanied by inhibition of IL-2-induced tyrosine phosphorylation of the Janus protein-tyrosine kinase 3 (Jak3) and signal transducers and activators of transcription called Stat3 and Stat5. In parallel experiments, IL-2-driven proliferation was inhibited significantly. After 16 hr of exposure to SE, the expression of IL-2R beta remained low, while that of IL2R alpha and IL2R gamma was further up-regulated, and ligand-induced tyrosine phosphorylation of Jak3 and Stat proteins was partly normalized. Yet, IL-2-driven proliferation remained profoundly inhibited, suggesting that signaling events other than Jak3/Stat activation had also been changed following SE stimulation. In conclusion, our data suggest that SE can modulate IL-2R expression and signal transduction involving the Jak/Stat pathway in CD4+ T-cell lines.


T-Cell immune activation in children with vertically transmitted hepatitis C virus infection.
Little is known concerning the clinical features, the histological outcome, and the effects on the maturation of immune system of children with vertically-transmitted hepatitis C virus (HCV) infection. Specifically, no data are available on the peripheral distribution of T-cell subsets. The frequency of naive and memory cells, activated T cells, and cytokine-producing T cells was analyzed in nine HCV-infected children born to HCV-positive mothers. In HCV-infected children, the distribution of naive and memory cells was not significantly altered in the CD4 subset whereas within the CD8 subset, an increase of memory and a decrease of naive cells was observed. The frequency of HLA-DR-positive and Fas-positive T cells was increased in HCV-infected children in both CD4 and CD8 subsets. The distribution of Fas-expressing T cells was directly related to that of HLA-DR cells and inversely related to the frequency of naive T cells. In regard with cytokine production we found increased levels of both CD4 and CD8 interferon-gamma (IFN-gamma)-producing cells whereas no difference in the percentage of interleukin-2 (IL-2)-producing T cells was observed. No meaningful correlation was observed between individual T cell subsets and ALT levels or HCV viral load. In conclusion, our results indicate an increased T-cell activation and a shift to a T(H)1 pattern of cytokine production in children with vertically transmitted HCV infection. The cause of this kind of immune response could reside in the persistent antigenic stimulation by chronic HCV infection.


Lack of association between alpha2-macroglobulin polymorphisms and Alzheimer's disease.
This study was undertaken to investigate the role of two alpha2-macroglobulin (A2M) polymorphisms, an intronic 5-bp deletion and Ile1000Val, in the development of Alzheimer's disease (AD) and to evaluate the interaction between the apolipoprotein E (APOE) and A2M polymorphisms. The A2M polymorphisms were screened by using polymerase-chain-reaction-based assays in 555 white late-onset AD cases and 446 controls. The gentoype distributions of the 5-bp deletion and Ile1000Val polymorphisms were comparable between cases and controls (P = 0.158 and P = 0.148, respectively). Likewise, there was no significant difference in allele frequencies of each polymorphism among cases and controls (P = 0.361 and P = 0.062, respectively). The stratification of data by APOE*4 status also did not yield any significant association. In conclusion, we observed no association between either the intronic deletion polymorphism or the Ile1000Val polymorphism of A2M and AD in our case-control cohort.


Cognitive representations of AIDS: a phenomenological study.
Cognitive representations of illness determine behavior. How persons living with AIDS image their disease might be key to understanding medication adherence and other health behaviors. The authors' purpose was to describe AIDS patients' cognitive representations of their illness. A purposive sample of 58 men and women with AIDS were interviewed. Using Colaizzi's (1978) phenomenological method, rigor was established through application of verification, validation, and validity. From 175 significant statements, 11 themes emerged. Cognitive representations included imaging AIDS as death, bodily destruction, and just a disease. Coping focused on wiping AIDS out of the mind, hoping for the right drug, and caring for oneself. Inquiring about a patient's image of AIDS might help nurses assess coping processes and enhance nurse-patient relationships.


Advancing cancer systems biology: introducing the Center for the Development of a Virtual Tumor, CViT.
Integrative cancer biology research relies on a variety of data-driven computational modeling and simulation methods and techniques geared towards gaining new insights into the complexity of biological processes that are of critical importance for cancer research. These include the dynamics of gene-protein interaction networks, the percolation of sub-cellular perturbations across scales and the impact they may have on tumorigenesis in both experiments and clinics. Such innovative 'systems' research will greatly benefit from enabling Information Technology that is currently under development, including an online collaborative environment, a Semantic Web based computing platform that hosts data and model repositories as well as high-performance computing access. Here, we present one of the National Cancer Institute's recently established Integrative Cancer Biology Programs, i.e. the Center for the Development of a Virtual Tumor, CViT, which is charged with building a cancer modeling community, developing the aforementioned enabling technologies and fostering multi-scale cancer modeling and simulation.


Conn's syndrome: a simple diagnostic approach.
Primary aldosteronism is usually diagnosed after a battery of biochemical tests and adrenal imaging. If an adrenal tumour (Conn's syndrome) is identified, patients need surgery. However, bilateral adrenal hyperplasia is treated medically. Till 1994, we diagnosed Conn's syndrome using simple biochemical tests and a CT scan of the adrenal glands. Aldosterone and plasma renin activity assay became available in our institution in 1994 and were used subsequently in the work up of patients suspected to have Conn's syndrome. We analysed our data to determine whether simple tests such as serum and urinary potassium values combined with CT imaging of the adrenal glands are adequate to arrive at a diagnosis in these patients. All consecutive patients (n = 17) diagnosed to have Conn's syndrome, managed by the Departments of Endocrinology and Surgical Endocrinology of this institution during a nine-year period from 1990 to 1998, were studied retrospectively. Until 1994, Conn's syndrome was diagnosed after documenting hypertension, hypokalaemia, inappropriate kaliuresis, metabolic alkalosis and CT scanning to localize the tumour. Serum aldosterone and plasma renin activity (PRA) were used in addition since 1994. All patients underwent adrenalectomy after adequate preoperative preparation. There was no operative mortality. Postoperatively, normokalaemia was established in all patients. Persistent postoperative hypertension was present in 43.8% of patients. In our experience, Conn's syndrome could be diagnosed accurately with simple investigations and CT imaging of the adrenal glands. Extensive biochemical testing, including aldosterone and PRA assay, is helpful when the diagnosis is uncertain. While hypokalaemia is curable after surgery, residual hypertension persists in about 45% of patients.


The Levandoski Panoramic Analysis in the diagnosis of facial and dental asymmetries.
Facial and dental asymmetries in 41 children from 8 to 12 year old were evaluated using the Levandoski Panographic Analysis. A high correlation between the standard facial photograph and linear measurement from panoramic radiograph were found. Varying degrees of facial and mandibular asymmetry were common in 100% of the sample. Significant association between the level of the glenoid fossa and the level of the eye from a frontal point of view were found; eleven patients (36.5%) showed left eye higher accompanied by a higher left fossa. Twenty patients (48.78%) presented with mandibular midline deviation toward the left side. The side with the longer condyle was usually accompanied by a longer coronoid in the ipsilateral side. The results of this study support the usefulness of the Levandoski Panographic analysis in diagnosis of facial and dental asymmetries, and its relation to the findings on the facial photographs.


Role of Newman's classification in predicting outcomes in patients with crystal arthritis.
The aim of the study was to evaluate the utility of Newman's classification in predicting outcomes in patients presenting with crystal arthritis. Between January and December 2009, all patients who presented to our institution with acute crystal arthritis and were investigated with microbiological assessment of their synovial fluid were included in the study. Patients were divided into two groups depending on the fulfilment of Newman's criteria for culture-negative septic arthritis. Group 1 included patients that fulfilled Newman's B criteria. Group 2 included patients that fulfilled Newman's C criteria. A database looking at the demographics, mode of presentation, investigations, treatment and outcomes was then established and the results compared between the two groups. A total of 58 patients were identified (group 1: n = 13; group 2: n = 45). The average age was 71 years (range 33-96). The joint most commonly involved was the knee followed by the wrist. Clinical findings at presentation were comparable in both groups; however, WBC and C-reactive protein (CRP) were more likely to be raised in group 1. Although most patients in group 1 were treated with antibiotics (62%) there was still a higher rate of morbidity, greater use of supportive therapy and a longer hospital stay (22.3 days, SD 17.4) in comparison with group 2, where most patients were treated by observation only (76%, mean hospital stay 3.5 days, SD ± 4.4). The difference in length of hospital stay was statistically significant (p < 0.0001). Newman's criteria are a good indicator for prognosis in patients with crystal arthritis. However, the presence of crystals in an acutely inflamed joint does not exclude the need for supportive therapy and long hospital stay even in the absence of positive synovial fluid culture.


Assessment of Medical Students' Ability to Integrate Point-of-Care Cardiac Ultrasound Into a Case-Based Simulation After a Short Intervention.
While a large amount of point-of-care ultrasound (POCUS) undergraduate medical education research exists, very little assesses the effectiveness of teaching on the student's ability to utilize POCUS within a clinical context. We set out to assess the ability of pre-clinical (second year) medical students to perform and interpret a parasternal long axis (PSLA) cardiac ultrasound view, and to diagnose a pericardial effusion on POCUS in a simulated patient with hypotension. This was a prospective study assessing second-year medical students before and after focused cardiac POCUS instruction. Pre-instruction, students completed a pre-assessment and test. They then watched a short video on cardiac ultrasound technique, anatomy, and pathology. Students then participated in 10 minutes of one-on-one hands-on instruction using a simulated patient. Immediately after didactics and hands-on instruction, students in groups of two to four completed a case simulation where they performed a PSLA view, identified pathology, and made a diagnosis. Differences between pre- and post-workshop responses were analyzed using the Chi-square test. We analyzed data on 132 pre-clinical second-year medical students; 126 (95%) had limited to no POCUS experience prior to the workshop. Comparing pre- to post-workshop responses, we found significant improvement in students' ability to identify a pericardial effusion (46% to 69%) (p=0.002) on a PSLA cardiac view. Of the 57 student groups (132 students), 41 (72%) groups were able to adequately obtain a PSLA view on a mannequin using an ultrasound simulator without needing guidance with probe placement or maneuvering. Thirty-five (61%) student groups were able to identify a pericardial effusion and diagnose cardiac tamponade in a simulated patient with hypotension. After short, structured training, pre-clinical medical students, novice to cardiac POCUS, showed improved knowledge with identifying a pericardial effusion on an ultrasound image. The majority of students were able to obtain a PSLA view and diagnose cardiac tamponade in a hypotensive patient during a during a case-based simulation.


β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib.
The overexpression of human epidermal growth factor receptor (HER)-2 in 20% of human breast cancers and its association with aggressive growth has led to widespread use of HER2-targeted therapies, such as trastuzumab (T) and lapatinib (L). Despite the success of these drugs, their efficacy is limited in patients whose tumors demonstrate de novo or acquired resistance to treatment. The β1 integrin resides on the membrane of the breast cancer cell, activating several elements of breast tumor progression including proliferation and survival. We developed a panel of HER2-overexpressing cell lines resistant to L, T, and the potent LT combination through long-term exposure and validated these models in 3D culture. Parental and L/T/LT-resistant cells were subject to HER2 and β1 integrin inhibitors in 3D and monitored for 12 days, followed by quantification of colony number. Parallel experiments were conducted where cells were either stained for Ki-67 and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or harvested for protein and analyzed by immunoblot. Results were subjected to statistical testing using analysis of variance and linear contrasts, followed by adjustment with the Sidak method. Using multiple cell lines including BT474 and HCC1954, we reveal that in L and LT resistance, where phosphorylation of EGFR/HER1, HER2, and HER3 are strongly inhibited, kinases downstream of β1 integrin--including focal adhesion kinase (FAK) and Src--are up-regulated. Blockade of β1 by the antibody AIIB2 abrogates this up-regulation and functionally achieves significant growth inhibition of L and LT resistant cells in 3D, without dramatically affecting the parental cells. SiRNA against β1 as well as pharmacologic inhibition of FAK achieve the same growth inhibitory effect. In contrast, trastuzumab-resistant cells, which retain high levels of phosphorylated EGFR/HER1, HER2, and HER3, are only modestly growth-inhibited by AIIB2. Our data suggest that HER2 activity, which is suppressed in resistance involving L but not T alone, dictates whether β1 mediates an alternative pathway driving resistance. Our findings justify clinical studies investigating the inhibition of β1 or its downstream signaling moieties as strategies to overcome acquired L and LT resistance.


The impact of peer support on testing, linkage to and engagement in HIV care for people who inject drugs in Indonesia: qualitative perspectives from a community-led study.
People who use, including those who inject, drugs in Indonesia are disproportionately affected by HIV, but tend to be diagnosed at a late stage of infection, delay initiation to and have poor rates of retention in antiretroviral treatment, resulting in high rates of morbidity and mortality. In addition to legal, policy and health system barriers, PWID may be hesitant to engage in HIV, treatment and care due to lack of knowledge, distrust of the health care system, and stigma related to their dual drug use and HIV status. Implementation of formal peer support initiatives may reduce provider- and individual-level barriers and increase testing, linkage to, and engagement in HIV care among people who use drugs. We conducted a community-led qualitative study to explore the impacts of peer support for people who inject drugs on HIV care access and engagement in Indonesia. Semi-structured, in-depth interviews were conducted with 20 participants in Jakarta and Bandung. Thematic analysis was used to explore how people who inject drugs living with HIV (PWID LHIV) (n = 8), peer support workers (n = 6), and service providers (n = 6) perceived peer support provision by non-governmental organisations. Participants unanimously described peer support as beneficial. Peer support workers were widely credited with facilitating access to HIV testing, referral to care, uptake of and adherence to antiretroviral treatment, as well as sustaining engagement in care for PWID. Support mechanisms that facilitated positive peer experiences included provision of HIV knowledge and awareness, emotional support, help with navigating complex bureaucracy, developing trust in health care services, enhancing confidence and motivation, and supporting peers to navigate a wide range of health and social welfare services beyond HIV-related care. Findings indicate that peer support can enhance access to testing, linkage to, and engagement in HIV care for people who use drugs living with HIV in Indonesia. In a context of an ongoing HIV epidemic among people who use drugs, reduced funding and policy attention to HIV and harm reduction, there is an urgent need to prioritize peer support interventions to identify people who use drugs facing health risks and link them to appropriate services.


Regulatory role of lysosomal enzymes in rat lymphocyte reactivity in vitro.
The influence of three lysosomal enzymes, beta-glucuronidase, acid phosphatase and hialuronidase, the representatives of lysosomal enzymes which can be released by exocytosis, was tested o reactivity of rat lymph node lymphocytes in vitro. These three enzymes do not change the spontaneous lymphocyte stimulation. However, beta-glucuronidase enhances the lymphocyte response to PHA. On the contrary, acid phosphatase and hialuronidase suppress PHA-induced stimulation of lymphocytes. In the mixed lymphocyte cultures (MLC) beta-glucuronidase enhances or suppresses DNA synthesis depending on the degree of lymphocyte stimulation in control MLC. Acid phosphatase and hialuronidase suppress lymphocyte stimulation in MLC.


Influencing the electronic interaction in diferrocenyl-1-phenyl-1H-pyrroles.
Functionalised diferrocenyl-1-phenyl-1H-pyrroles were synthesised using Negishi C,C cross-coupling reactions. The influence of different substituents at the phenyl moiety on the electronic interaction was studied using electrochemistry (cyclic and square-wave voltammetry) and spectro-electrochemistry (in situ UV/Vis-NIR spectroscopy). The ferrocenyl moieties gave rise to two sequential, reversible redox processes in each of the diferrocenyl-1-phenyl-1H-pyrroles. The observed ΔE(1/2) values (ΔE(1/2) = difference between first and second oxidation) range between 420 and 480 mV. A linear relationship between the Hammett constants σ of the substituents and the separation of the redox potentials exists. The NIR measurements confirm electronic communication between the iron centers as intervalence charge transfer (IVCT) absorptions were observed in the corresponding mixed-valent monocationic species. All compounds were classified as class II systems according to Robin and Day (M. B. Robin and P. Day, Adv. Inorg. Chem., 1967, 10, 247-423). The oscillator strength of the charge transfer transition highly depends on the electron donating or electron withdrawing character of the phenyl substituents. This enables direct tuning of the intermetallic communication by simple modification of the molecule's functional group. Hence, this series of molecules may be regarded as model compounds for single molecule transistors.


Short- and long-term changes in gene expression mediated by the activation of TLR9.
CpG DNA binds to Toll-like receptor 9 to stimulate a strong innate immune response. The magnitude, duration and scope of CpG-induced changes in gene expression are incompletely understood despite extensive studies of TLR9 mediated signal transduction pathways. In particular, the prolonged effects of CpG DNA on gene activation have not been investigated despite evidence that a single dose of CpG DNA alters immune reactivity for several weeks. This study used gene expression analysis to monitor changes in mRNA levels for 14 days, and identified the genes, pathways and functional groups triggered in vivo following CpG DNA administration. Two discrete peaks of gene activation (at 3h and 5 days) were observed after CpG injection. Both the behavior and function of genes activated during the second peak differed from those triggered shortly after CpG administration. Initial gene up-regulation corresponded to a period when TLR9 ligation stimulated genes functionally associated with the generation of innate and adaptive immune responses (e.g. the NF-kappaB and B-cell receptor pathways). The second peak reflected processes associated with cell division (e.g. cell cycle and DNA replication and repair). The complex bimodal pattern of gene expression elicited by CpG DNA administration provides novel insights into the long-term effects of TLR9 engagement on genes associated with immunity and cell proliferation.


On the uptake, metabolism and retention of [h] gibberellin a(1) by barley aleurone layers at low temperatures.
Barley (c.v. Himalaya) aleurone layers were incubated in [(3)H]gibberellin A(1) (GA(1)) at low temperatures. At 3 and 4 C, (3)H-activity was steadily accumulated in aleurone layers, and this accumulation was correlated with significant [(3)H]GA(1) metabolism. At 1 and 1.5 C, metabolism could not be detected, and at these temperatures aleurone layers equilibrated with the [(3)H]GA(1) concentration in the incubation medium. At equilibrium, the total amount of (3)H-activity per unit volume in the aleurone layers was higher than in the incubation medium. Aleurone layers incubated at 0.5 C for 72 hours with [(3)H]GA(1) in the presence of saturating levels of carrier GA(1) consistently retained lower levels of (3)H-activity than when incubated in [(3)H]GA(1) alone. The retention of [(3)H]GA(1) was unaffected by saturating levels of carrier GA(8). GA(1) retained by barley aleurone layers that were incubated at 0.5 C for 72 hours was able to induce alpha-amylase synthesis when aleurone layers were subsequently washed and transferred to a gibberellin-free medium at 25 C.


[Vertical and tortional deviations in early strabismus].
The occlusion of one eye may trigger two types of deviation: 1) Heterophorias: the occluded eye deviates towards a horizontal, vertical or torsional abnormal position of rest. Fusion keeps the eyes straight during binocular fixation. 2) Dissociated deviations, horizontal (DHD), vertical (DVD), torsional (DTD): they are found in infantile strabismus. The deviation without fixation is always smaller than the deviation of the occluded eye. The more typical cases are the ones where the position of rest without fixation is an orthoposition. Normal binocular vision is lacking. Most of the time, an alternant neutralisation is found: the occlusion deviation is not the return of the occluded eye to an abnormal position of rest. The deviation is caused by a disequilibrium of binocular retinal stimulations. Horizontal and vertical deviations are easy to study. It is not the case in dissociated torsional deviation (DTD) where the incyclotorsion does not exist when fixation is absent. An indirect proof of extorsion is given by the study of horizontal and vertical deviations determined in the cardinal position of gaze. Extorsion of the globus leeds always to abnormal actions of the recti. This give a typical synoptometer chart which is found in any extorsion whatever its origins: paralysis, alphabetic patterns or infantile strabismus. Dissociated extorsions are always associated with a bilateral elevation in the primary position. Dissociated deviations are found in infantile strabismus with the other dissociations phenomenon such as nystagmus, optokinetic nystagmus asymmetry, fixation in adduction preference (and incyclotorsion).


The effectiveness of seven denture cleansers on tea stain removal from PMMA acrylic resin.
In this study, seven denture cleansers were evaluated for their mode of action of tea stain removal from Perspex acrylic resin material. Perspex acrylic resin specimens were stained using a combination of chlorhexidine and tea solution. The specimens were also treated with saliva to form an initial pellicle layer and facilitate the uptake of the stain. The capacity for stain removal was determined by measuring the optical density of the treated specimens by using a spectrophotometer. These were then exposed, for 5 minutes, to seven denture cleansers to demonstrate the percentage stain-removal ability of each cleanser. The same procedure was applied for roughened Perspex acrylic resin specimens. Water was used as a control in the two parts of the experiment. The products containing alkaline hypochlorite had the highest ability for removing stain from the acrylic resin material together with a bleaching effect. The results varied when the same denture cleansers were used on the roughened Perspex surface, and this was attributed to the presence of irregularities and porosities on the blocks. Denture cleansing agents containing hypochlorite and Boots Denture Cleaning Powder (constituents not stated by the manufacturer) exhibited the ability to remove stain from the denture base materials most effectively. Irregularities and porosities present on the denture surface played a major role in reducing the activity of denture cleaning agents and hence increased stain and plaque retention.


Mechanotransduction in bone: genetic effects on mechanosensitivity in mice.
Bone formation is enhanced by mechanical loading, but human exercise intervention studies have shown that the response to mechanical loading is variable, with some individuals exhibiting robust osteogenic responses while others respond modestly. Thus, mechanosensitivity - the ability of bone tissue to detect mechanical loads - could be under genetic control. We applied controlled mechanical loading to the ulnae of 20-week-old (adult) female mice derived from three different inbred strains (C3H/He, C57BL/6, and DBA/2), and measured the bone formation response with fluorochrome labels. Mechanical properties, including mechanical strain, second moments of area, and cortical bone material properties, were measured in a group of calibration animals not subjected to in vivo loading. The C3H/He mice were significantly less responsive to mechanical loading than the other two biological strains. Material properties (flexural elastic modulus, ultimate stress) were greatest in the C3H/He cortical tissue. Geometric and areal properties at the midshaft ulna were also greatest in the C3H/He mice. Based on the presumed role of osteocytes in strain detection, we measured osteocyte lacuna population densities in decalcified midshaft ulna sections. Osteocyte lacuna density was not related to mechanosensitivity. Our data suggest that bone mechanosensitivity has a significant genetic component. Identification of the genes that exert their influence on mechanosensitivity could ultimately lead to therapies that enhance bone mass and reduce fracture susceptibility.


Wettability of some packable resin-based composites. An in vitro study.
The purpose of this research was to measure the contact angles of some packable resin-based composites in order to determine their wettability related to the surface energy. Materials were manipulated according to the manufacturer's instructions and were inserted in a circular metallic matrix and photo cured for 40 seconds on both sides. The specimens were removed and finished with silicon carbide metallurgical finishing paper (800 gifts). Half of each specimen was covered by a layer of Bis-GMA and photo cured for 20 seconds. The specimens were then submitted to measurements in a contact angle goniometer with two different liquids and polarities in three points. The materials without Bis-GMA covering layer showed statistically significant differences related to contact angles and among the materials and liquids (p<0/05).


Commentary and an illustration on the use of outcome data in life care planning for persons with acquired neurological injuries.
This article reviews the current status of life care planning efforts and provides an illustration, in the clinical arena of acquired neurological injury. An argument could easily be made that life care planning as an applied discipline, is quite new and is only now beginning to access national data bases for plan development purposes. In many respects, life care planning is approaching a transitional period of art and science. Given the individualistic nature of the life care planning process, the process itself will unlikely embrace decisions solely based upon population statistics, mathematical models, and the like. Nonetheless, objectivity and reliability must characterize the process. This article attempts to set the stage for the transition of utilizing outcome studies and databases in the life care planning process.


Zn(2+)-mediated structure formation and compaction of the "natively unfolded" human prothymosin alpha.
Human recombinant prothymosin alpha (ProTalpha) is known to have coil-like conformation at neutral pH; i.e., it belongs to the class of "natively unfolded" proteins. By means of circular dichroism, SAXS, and ANS fluorescence, we have investigated the effect of several divalent cations on the structure of this protein. Results of these studies are consistent with the conclusion that ProTalpha conformation is unaffected by large excess of Ca(2+), Mg(2+), Mn(2+), Cu(2+), and Ni(2+). However, Zn(2+) induces compaction and considerable rearrangement of the protein structure. This means that ProTalpha can specifically interact with Zn(2+) (K(D) approximately 10(-3) M), and such interactions induce folding of the natively unfolded protein into a compact partially folded (premolten globule-like) conformation. It is possible that these structural changes may be important for the function of this protein.


Structurally Diverse Cytotoxic Polyphenols from Garcinia gracilis.
Thirty-five diverse polyphenols, belonging to seven structure classes, were isolated from Garcinia gracilis, a medicinal and edible plant sampled from Laos. The structures of nine new compounds, gargarcilones A-I (1-3, 5-7, 10, 12, and 17), were established using spectroscopic, X-ray diffraction, and experimental and calculated ECD methods. Additionally, we revised the stereochemical assignment of cochinchinoxanthone and cochinchinoxanthone C. The compounds were evaluated for antiproliferative activity against five human tumor cell lines (HL-60, A549, SMMC-7721, MDA-MB-231, and SW480). Compounds 1-4, 7, and 8 exhibited cytotoxic activity with IC50 values of 0.5-8.9 μM. Compound 3 significantly induced apoptosis in SMMC-7721 cells.


Treatment of hypertensive patients according to the conventional or ambulatory pressure: a progress report on the APTH trial. APTH Investigators. Ambulatory Blood Pressure and Treatment of Hypertension.
The main objective of the Ambulatory Blood Pressure and Treatment of Hypertension (APTH) trial is to test the hypothesis that antihypertensive treatment based on ambulatory monitoring may be more beneficial than treatment guided by conventional sphygmomanometry. After a 2-month run-in period on single-blind placebo, hypertensive patients were randomized to two groups, one in which the target pressure was a sitting diastolic pressure from 80 through 89 mm Hg on conventional sphygmomanometry (conventional blood pressure [CBP] group), and one in which a daytime (from 10 to 20 h) diastolic pressure from 80 through 89 mm Hg had to be achieved (ambulatory blood pressure [ABP] group). After randomization all patients were started on lisinopril 10 mg/day. One month later lisinopril could be continued at 10 or 20 mg/day or discontinued depending on the attained blood pressure level. This article is an interim report on 207 patients followed for two months into the trial. At one month lisinopril was discontinued more frequently in the ABP than the CBP group (24 vs 9 patients, p = 0.004). Nevertheless at two months, blood pressure control was not significantly different in the two treatment groups. The baseline-adjusted differences in systolic pressure between the two treatment arms of the trial (ABP-CBP group) were +2.7 mm Hg (95% confidence interval [CI]): -2.9, +8.3) for the conventional pressure, +0.4 mm Hg (CI: -4.3, +5.1) for the 24 h pressure, -0.1 mm Hg (CI: -5.1, +4.8) for the daytime pressure and -0.7 mm Hg (CI: -6.7, +5.4) for the night-time pressure. The corresponding differences in diastolic pressure were -1.3 mm Hg (CI: -4, +1.4), +0.1 mm Hg (CI: -3, +3.1), -1.1 mmgH (CI: -4.4, +2.1) and +0.3 mm Hg (CI: -3.7, +4.3), respectively. Thus, the present findings do not refute the APTH research hypothesis. In terms of blood pressure control and the number of patients remaining on antihypertensive drugs, treatment based on ambulatory recordings may be preferable to treatment guided by conventional sphygmomanometry.


Time-dependent wave packet studies on the Cl + HCl hydrogen exchange reaction.
The initiation of the hydrogen exchange reaction Cl((2)P)+HCl --> ClH+Cl((2)P) by excitation of the HCl molecular stretch to v=2 is studied for total angular momentum quantum number J=(1)/(2) and both even and odd parity. The calculations were performed using a time-dependent propagation from an initial quasi-bound state and employed all three relevant potential energy surfaces and the nonadiabatic couplings between them. Coriolis and spin-orbit coupling were also taken into account. The electronic and HCl rotational distributions of the products in both dissociation channels are analyzed, and the results are interpreted using features of the potential energy surfaces.


Primary closure of gunshot wounds caused by high-velocity rifles.
Sixty gunshot injuries in 48 patients were treated in Mobile Surgical Hospital (30-bed capacity) of the Mountain and Commando Brigade in Hakkari, Türkiye, between May 1990 and May 1991. The David Sisk method was used for the classification of the injuries. Eleven type 1 injuries were treated conservatively, 39 type 2 and 10 type 3 injuries were treated by extensive debridement with suction drainage and primary closure. No infection was seen in type 1 injuries. The infection rate was 2.56% in type 2 and 20% in type 3 injuries. The following results were obtained: type 1 injuries must be treated by conservative measures; type 2 injuries must be treated by primary closure following extensive debridement and suction drainage; type 3 injuries can be treated by extensive debridement with suction drainage and primary closure.


Glucose monitoring by microdialysis: performance in a multicentre study.
The aim of this study was to assess the performance of the Continuous Research Tool (CRT) in a multicentre clinical-experimental study. Three patient groups totalling 28 subjects with diabetes [group A 10 Type 1 (Ulm), group B 10 Type 1 (Neuss), group C eight Type 2 (Aarhus)] participated in this trial. Two CRT microdialysis probes were inserted in parallel in the abdominal subcutaneous tissue for 120 h in each subject. In subjects in group A, glucose excursions were induced on one study day and those in group B underwent a glucose clamp (eu-, hypo- or hyperglycaemic) on one study day. CRT data were calibrated once with a retrospective calibration model based on a run-in time of 24 h and three blood glucose measurements per day. All analysable experiments, covering a broad range of blood glucose values, yielded highly accurate data for the complete experimental time with a mean relative absolute difference of 12.8 +/- 6.0% and a predictive residual error sum of squares of 15.6 +/- 6.3 (mean +/- SD). Of all measurement results, 98.2% were in zones A and B of the error grid analysis. The average absolute differences were 1.14 mmol/l for Type 1 and 0.88 mmol/l for Type 2 diabetic patients. Relative absolute differences were 16.0% for Type 1 and 12.6% for Type 2 diabetic patients. These results demonstrate that this microdialysis system allows reliable continuous glucose monitoring in patients with diabetes of either type.


meiRNA, A Polyvalent Player in Fission Yeast Meiosis.
A growing number of recent studies have revealed that non-coding RNAs play a wide variety of roles beyond expectation. A lot of non-coding RNAs have been shown to function by forming intracellular structures either in the nucleus or the cytoplasm. In the fission yeast Schizosaccharomyces pombe, a non-coding RNA termed meiRNA has been shown to play multiple vital roles in the course of meiosis. meiRNA is tethered to its genetic locus after transcription and forms a peculiar intranuclear dot structure. It ensures stable expression of meiotic genes in cooperation with an RNA-binding protein Mei2. Chromosome-associated meiRNA also facilitates recognition of homologous chromosome loci and induces robust pairing. In this review, the quarter-century history of meiRNA, from its identification to functional characterization, will be outlined.