Endoscopic ultrasound does not accurately assess pathologic stage of esophageal cancer after neoadjuvant chemoradiotherapy.
The accuracy of endoscopic ultrasound (EUS) for initial staging of esophageal cancer is widely accepted. There is, however, considerable variability in the reported accuracy of EUS for restaging of esophageal neoplasms after neoadjuvant therapy. From June 1995 through December 1999, we prospectively studied a series of 26 patients who underwent neoadjuvant treatment for esophageal cancer and were subsequently restaged by EUS before resection. Twenty-four patients had adenocarcinoma (92%), and two patients had squamous cell carcinoma (8%). EUS correctly predicted tumor stage in seven of 26 patients for an overall accuracy of 27 per cent. EUS overestimated the depth of tumor penetration in 18 patients (69%) and underestimated depth of penetration in one patient (4%). Lymph nodes were correctly staged in 15 of 26 patients for an overall accuracy of 58 per cent. Levels of sensitivity for detecting N0 and N1 disease were 44 per cent and 80 per cent respectively. Patients with a complete pathologic response were staged as T4N1 (one patient), T3N1 (three patients), T3N0 (one patient), and T2N1 (two patients). EUS cannot distinguish tumor involvement of the esophageal wall and lymph nodes from the postinflammatory changes that characterize effective neoadjuvant treatment. EUS is of limited utility in guiding clinical decision making after neoadjuvant therapy.


Decreased surfactant dose-response after delayed administration to preterm rabbits.
Preterm rabbits from 14 litters were delivered at 27 d gestation, anesthetized, and treated with surfactant at birth, 15 min, or 30 min after the onset of mechanical ventilation. Doses of surfactant ranging from 0 to 100 mg/kg body weight were given intratracheally and the rabbits were ventilated for 45 min after birth. Pressure-volume curves and dynamic compliances demonstrated that the dose response to surfactant progressively decreased with delayed treatment. Following surfactant treatments of 50 mg/kg at birth, 15 min, and 30 min, peak lung volumes at 35 cm H2O were increased by 49, 30, and 8.4%, respectively over those of untreated controls. Lung lavages from rabbits receiving surfactant at 30 min had significantly higher protein contents and minimum surface tensions on the Wilhelmy balance than those from rabbits treated at birth (23.1 +/- 1.1 versus 16.0 +/- 2.7 dynes/cm), and lung sections from rabbits treated at 30 min had a significantly less uniform distribution of surfactant than those from rabbits treated at birth. While increasing phospholipid concentrations may reverse the inhibition of surfactant by serum proteins in vitro, there was a progressive inability of exogenous surfactant to overcome this inhibition in vivo following delayed administration to very immature rabbits. This inability to overcome inhibition with increasing surfactant dose was associated with a less uniform distribution of surfactant following its delayed administration.


Bone matrix degradation by the plasminogen activation system. Possible mechanism of bone destruction in arthritis.
The observed increase in urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR) in synovial tissue of patients with rheumatoid arthritis (RA) suggests pathophysiological involvement of the plasminogen activation (PA) system in inflammatory joint disease. In the present study, we investigated the capacity of the PA system to degrade non-mineralized and mineralized bone-like matrix in vitro as a model for bone destruction. Transfected mouse LB6 cell lines, that expressed either human u-PA or u-PAR, were cultured separately and simultaneously on radiolabelled bone matrix in the presence of plasminogen. Osteoblast-like murine calvarial MC3T3-E1 cells were used to produce a well-characterized, highly organized bone-like matrix, that could be mineralized in the presence of beta-glycerol phosphate. Bone matrix degradation was followed by the release of radioactivity in the culture medium. u-PA-producing cells, in contrast to u-PAR-producing cells, degraded both non-mineralized and mineralized bone matrix. This effect could be inhibited by anti-u-PA antibodies, as well as by tranexamic acid and by aprotinin, indicating that the degrading activity is u-PA mediated and plasmin dependent. Co-cultivation of a small portion of u-PA-producing cells with u-PAR-expressing cells resulted in a marked increase in degradation activity. Reduction of this potentiating effect by suramin or the amino-terminal fragment of u-PA, both competitive inhibitors of u-PA receptor binding, shows that this synergistic effect is due to binding of u-PA to u-PAR. u-PAR must be cell associated, as binding of u-PA to a soluble u-PAR prevented this enhancement. The capability of the PA system to degrade bone matrix in vitro, and the previously demonstrated increased expression of u-PA and u-PAR in synovial tissue of patients with RA, further support a role for the PA system in the development of bone erosions.


Estimating mean cost using auxiliary covariates.
We study the estimation of mean medical cost when censoring is dependent and a large amount of auxiliary information is present. Under missing at random assumption, we propose semiparametric working models to obtain low-dimensional summarized scores. An estimator for the mean total cost can be derived nonparametrically conditional on the summarized scores. We show that when either the two working models for cost-survival process or the model for censoring distribution is correct, the estimator is consistent and asymptotically normal. Small-sample performance of the proposed method is evaluated via simulation studies. Finally, our approach is applied to analyze a real data set in health economics.


[Modern western medical education in Fujian].
The modem western medical education in Fujian mainly stemmed from three aspects: medical schools established by Missionary, western schools managed by government and western medical education in the Soviet District of Western Fujian. These three educational modalities promoted the development of modern western medical education in Fujian.


Comparative lipid profiling of two endophytic fungal isolates--Colletotrichum sp. and Alternaria sp. having potential utilities as biodiesel feedstock.
Lipid accumulation abilities of two endophytic fungal isolates - Colletotrichum sp. and Alternaria sp. grown under optimum and nutrient-stress conditions were investigated and compared. Significant variations in lipid contents, ranging from 30% to 58% of their dry biomass were found in liquid culture using various carbon sources. Since, >50% of the total lipid was estimated to be neutral lipid for both the fungal species, predicted biodiesel properties were theoretically calculated based upon the determined fatty acid profiles; and the values were found to be comparable to those of commonly used plant oils for biodiesel production. The two endophytes grew successfully on the combined rice straw and wheat bran as substrate that was degraded by their secretory enzymes including cellulase [1.21-2.51 FPU/g dry substrate (gds)] in solid state fermentation and produced substantial amount of lipid (60.32-84.30 mg/gds). Our study highlights the potential utilities of these two novel endophytic fungi as biodiesel feedstock.


Functional differentiation of mouse T lymphocytes. GVHR-precursors: tissue origin and specificity of activity inducer.
For theoretical and practical reasons, it is important to find out whether the differentiation of T cell precursors to the functional lymphocytes can be induced under in vitro conditions. Using the local GVHR assay (based on the enlargement of the popliteal lymph node), the inducibility of the precursors of reactive cells was studied with bone marrow, thymus, spleen, and lymph node cell suspensions submitted to short-term incubation with cell-free extracts from calf thymus, spleen or brain. GVHR-precursors from bone marrow were inducible not only specifically (i.e., with thymus extract) but also--and even to a higher degree--with spleen or brain extract. Thymus and spleen cell suspensions (the latter also depleted of the reactive subpopulation by treatment with anti-Thy 1.2 serum and complement) were, on the other hand, inducible mainly specifically, whereas lymph node cells were refractory to induction. The inductive action of tissue extracts obviously depends on the tissue origin of T cell precursors; their effects on pre- and postthymic differentiation of T lymphocytes are discussed.


Quality of life decisions at the beginning of life: ethical considerations.
The burdens of life with treatment may outweigh the benefits. Under which set of circumstances and to what extent a neonate should receive medical intervention is a difficult ethical issue involving principles and cultural aspects which may be in conflict. The nature of the disease, the risks involved in treatment or non-treatment, the degree to which therapy will extend life, the discomfort associated with therapy, the anticipated quality of life, the wishes of surrogates, and national cultural mores are the important considerations in determination of the neonate's best interest in order to arrive at ethically defensible decisions. These decisions are not necessarily cross-culturally uniform.


Humoral response in hamsters following vaccination with cDNA encoding acey-1 cysteine proteinase of Ancylostoma ceylanicum.
The humoral response in hamsters following vaccination against Ancylostoma ceylanicum infections with DNA construct was investigated. Groups of hamsters were injected intramuscularly with plasmid pcDNA 3.1. containing cDNA of ACEY-1 cysteine proteinase. Vaccination resulted in IgG antibody response to somatic extracts of adult A. ceylanicum. The highest level of antibodies was observed seven weeks after vaccination.


Oleate desaturase enzymes of soybean: evidence of regulation through differential stability and phosphorylation.
The endoplasmic reticulum-associated oleate desaturase FAD2 (1-acyl-2-oleoyl-sn-glycero-3-phosphocholine Delta12-desaturase) is the key enzyme responsible for the production of linoleic acid in non-photosynthetic tissues of plants. Little is known, however, concerning the post-transcriptional mechanisms that regulate the activity of this important enzyme. The soybean genome possesses two seed-specific isoforms of FAD2, designated FAD2-1A and FAD2-1B, which differ at only 24 amino acid residues. Expression studies in yeast revealed that the FAD2-1A isoform is more unstable than FAD2-1B, particularly when cultures were maintained at elevated growth temperatures. Analysis of chimeric FAD2-1 constructs led to the identification of two domains that appear to be important in mediating the temperature-dependent instability of the FAD2-1A isoform. The enhanced degradation of FAD2-1A at high growth temperatures was partially abrogated by treating the cultures with the 26S proteasome-specific inhibitor MG132, and by expressing the FAD2-1A cDNA in yeast strains devoid of certain ubiquitin-conjugating activities, suggesting a role for ubiquitination and the 26S proteasome in protein turnover. In addition, phosphorylation state-specific antipeptide antibodies demonstrated that the Serine-185 of FAD2-1 sequences is phosphorylated during soybean seed development. Expression studies of phosphopeptide mimic mutations in yeast suggest that phosphorylation may downregulate enzyme activity. Collectively, the results show that post-translational regulatory mechanisms are likely to play an important role in modulating FAD2-1 enzyme activities.


Artificial Neural Network Approach in Laboratory Test Reporting: Learning Algorithms.
In the field of laboratory medicine, minimizing errors and establishing standardization is only possible by predefined processes. The aim of this study was to build an experimental decision algorithm model open to improvement that would efficiently and rapidly evaluate the results of biochemical tests with critical values by evaluating multiple factors concurrently. The experimental model was built by Weka software (Weka, Waikato, New Zealand) based on the artificial neural network method. Data were received from Dokuz Eylül University Central Laboratory. "Training sets" were developed for our experimental model to teach the evaluation criteria. After training the system, "test sets" developed for different conditions were used to statistically assess the validity of the model. After developing the decision algorithm with three iterations of training, no result was verified that was refused by the laboratory specialist. The sensitivity of the model was 91% and specificity was 100%. The estimated κ score was 0.950. This is the first study based on an artificial neural network to build an experimental assessment and decision algorithm model. By integrating our trained algorithm model into a laboratory information system, it may be possible to reduce employees' workload without compromising patient safety.


Exchange transfusion and multidose activated charcoal following vancomycin overdose.
The inadvertent administration of a concentrated vancomycin solution to a 47 day-old premature male twin resulted in extremely high vancomycin levels and altered renal function. A 1.5 volume exchange transfusion did not change the measured vancomycin level. Multiple doses of oral activated charcoal, 1 g/kg, were administered beginning 5 h after the exchange transfusion. A calculated half-life of vancomycin before the exchange transfusion was 35 h. The half-life after the exchange transfusion and during charcoal administration was calculated to be 12 h. The only apparent adverse effect of this vancomycin overdose was reversible nephrotoxicity. The infant's hearing, tested by brainstem auditory responses, was normal. The higher volume of distribution of vancomycin in infants may preclude removing significant amounts of this drug by exchange transfusion. Gastrointestinal dialysis with activated charcoal warrants consideration in cases of vancomycin overdose in neonates.


Formation of metal-nicotianamine complexes as affected by pH, ligand exchange with citrate and metal exchange. A study by electrospray ionization time-of-flight mass spectrometry.
Nicotianamine (NA) is considered as a key element in plant metal homeostasis. This non-proteinogenic amino acid has an optimal structure for chelation of metal ions, with six functional groups that allow octahedral coordination. The ability to chelate metals by NA is largely dependent on the pK of the resulting complex and the pH of the solution, with most metals being chelated at neutral or basic pH values. In silico calculations using pKa and pK values have predicted the occurrence of metal-NA complexes in plant fluids, but the use of soft ionization techniques (e.g. electrospray), together with high-resolution mass spectrometers (e.g. time-of-flight mass detector), can offer direct and metal-specific information on the speciation of NA in solution. We have used direct infusion electrospray ionization mass spectrometry (time-of-flight) ESI-MS(TOF) to study the complexation of Mn, Fe(II), Fe(III), Ni, Cu by NA. The pH dependence of the metal-NA complexes in ESI-MS was compared to that predicted in silico. Possible exchange reactions that may occur between Fe-NA and other metal micronutrients as Zn and Cu, as well as between Fe-NA and citrate, another possible Fe ligand candidate in plants, were studied at pH 5.5 and 7.5, values typical of the plant xylem and phloem saps. Metal-NA complexes were generally observed in the ESI-MS experiments at a pH value approximately 1-2 units lower than that predicted in silico, and this difference could be only partially explained by the estimated error, approximately 0.3 pH units, associated with measuring pH in organic solvent-containing solutions. Iron-NA complexes are less likely to participate in ligand- and metal-exchange reactions at pH 7.5 than at pH 5.5. Results support that NA may be the ligand chelating Fe at pH values usually found in phloem sap, whereas in the xylem sap NA is not likely to be involved in Fe transport, conversely to what occurs with other metals such as Cu and Ni. Some considerations that need to be addressed when studying metal complexes in plant compartments by ESI-MS are also discussed.


Non-anti-infective effects of antimicrobials and their clinical applications: a review.
Antimicrobial agents are undoubtedly one of the key advances in the history of modern medicine and infectious diseases, improving the clinical outcomes of infection owing to their inhibitory effects on microbial growth. However, many antimicrobial agents also have biological activities stemming from their interactions with host receptors and effects on host inflammatory responses and other human or bacterial cellular biological pathways. These result in clinical uses of antimicrobial drugs that are distinct from their direct bacteriostatic or bactericidal properties. We reviewed the published literature regarding non-anti-infective therapeutic properties and proposed clinical applications of selected antimicrobials, specifically, macrolides, tetracyclines, sulfonamides, and ketoconazole. The clinical applications reviewed were varied, and we focused on uses that were clinically relevant (in terms of importance and burden of disease) and where published evidence exists. Such uses include chronic inflammatory pulmonary and skin disorders, chronic periodontitis, gastrointestinal dysmotility, rheumatoid arthritis, and cancer. Most of these potential therapeutic uses are not Food and Drug Administration approved. Clinicians need to weigh the use of antimicrobial agents for their non-anti-infective benefits, considering potential adverse effects and long-term effect on microbial resistance.


Midterm Results of 2-Stage Hybrid Arch Repair for Extensive Aortic Arch Aneurysms.
This report evaluated the perioperative and midterm results of the 2-stage hybrid arch procedure. This procedure involves total arch replacement with an elephant trunk as the first stage and thoracic endovascular aortic repair as the second stage for patients with extended aortic arch pathology. Between April 2010 and April 2017, 55 consecutive patients (age, 74.2 ± 6.4 years) with extended aortic arch atherosclerotic pathology involving the aortic arch and descending aorta underwent first-stage total arch replacement with the elephant trunk procedure. The second stage was completed for 53 (96.4%) of the 55 patients. The mean duration between the 2 procedures was 2.4 ± 2.2 months. Postoperative follow-up was completed after a mean of 36.6 ± 24.9 months. The in-hospital mortality rate for the first stage was 0%. Two patients died during the interval between surgeries. The in-hospital mortality rate for the second stage was 0%. Two (3.6%) of the 55 first-stage patients and none of the 53 second-stage patients experienced a postoperative stroke. No spinal cord dysfunction occurred during the first-stage and second-stage procedures. The 3- and 5-year survival rates were 88.2% and 67.0%, respectively. The 5-year thoracic aortic intervention-free rate was 95.5%. Extended aortic arch aneurysms were repaired using a 2-stage hybrid arch repair. Perioperative mortality and midterm results were acceptable. Use of an elephant trunk provided a secure landing zone for thoracic endovascular aneurysm repair. This 2-stage hybrid procedure is an alternative approach to extended aortic arch pathology.


Serum and urine nitrate and nitrite are not reliable indicators of intrathecal nitric oxide production in acute brain injury.
This study examined the correlation between nitric oxide (NO) metabolites in the three major body fluid compartments and assessed performance of newly described vanadium-based assay for simultaneous detection of nitrite and nitrate (NO(x)) in human samples. Vanadium reduces nitrate to nitrite, which can be measured after a colorimetric reaction with Griess reagents. Cisternal cerebro spinal fluid (CSF), serum and urine samples from 10 patients with acute brain injury (ABI) were compared to control subjects. Significantly higher CSF NO(x) levels were found in brain injury patients compared to control patients (19.7+/-13.7 vs. 6.5+/-2.3 microM; p=0.01), which persisted for 10-day period of observation. The serum and urine levels of NO(x) on admission were not statistically different (42.8+/-28.2 microM; 584.1+/-337.8 micromol/g Cr, respectively) from controls (36.8+/-14.8 microM; 819.7+/-356.0 micromol/g Cr), but tended to decrease during the disease course reaching the lowest level on day 6 (serum: 19.3+/-8.4 microM, urine: 300.4+/-111.9 micromol/g Cr). CSF levels of NO(x) correlated moderately with those in serum (p=0.001, R=0.5). Serum NO(x) concentrations correlated weakly with urine levels (p=0.04, R=0.3). There was no significant correlation between CSF NO(x) and urine NO(x) levels. In conclusion, patients suffering brain injury had increased NO(x) concentrations in CSF, which remained independent from other body fluid compartments. Serum and urinary NO(x) levels cannot be used as a reliable index to assess intrathecal NO production.


Assessment of Subclinical Atherosclerosis Using Computed Tomography Calcium Scores in Patients with Familial and Nonfamilial Hypercholesterolemia.
The aim of this study was to compare coronary calcium scores and aortic calcium scores between patients with severe hypercholesterolemia having a DNA-based diagnosis of FH (FH group) versus patients with severe hypercholesterolemia without the FH gene mutation (NFH group). A total of 89 FH and 50 NFH patients underwent CT with coronary and thoracic aorta calcium scoring. Their CCS and TCS in ascending aorta (TCSasc) and descending aorta (TCSdesc) were determined and compared between the two patient groups. TCSasc was significantly higher in the FH group when compared to the NFH group (30.6± 59 vs 4.7±13.4, p＜0.001. After adjusting for age, sex, smoking, blood pressure, history of diabetes mellitus and LDL cholesterol levels, FH gene mutation was an independent risk factor of having non-zero TCSasc 3.6 (95% CI, 1.4-9.5, p＜0.01), high TCSasc 9.6 (95% CI, 2.4-38.2, p＜0.01) and high CCS of 4.1 (95% CI, 1.2-13.2. p＜0.05). We found that when computed tomography calcium scores were used as an assessment, patients with familial hypercholesterolemia displayed an increased burden of ascending aorta atherosclerosis when compared to patients with nonfamilial severe hypercholesterolemia. This phenomenon appears to be more dependent on the presence of FH genotype than hypercholesterolemia itself.


Effects of a peracetic acid disinfection protocol on the biocompatibility and biomechanical properties of human patellar tendon allografts.
Patellar tendon allografts, retrieved from cadaveric human donors, are widely used for replacement of damaged cruciate ligaments. In common with other tissue allografts originating from cadaveric donors, there are concerns regarding the potential for disease transmission from the donor to the recipient. Additionally, retrieval and subsequent processing protocols expose the graft to the risk of environmental contamination. For these reasons, disinfection or sterilisation protocols are necessary for these grafts before they are used clinically. A high-level disinfection protocol, utilising peracetic acid (PAA), has been developed and investigated for its effects on the biocompatibility and biomechanics of the patellar tendon allografts. PAA disinfection did not render the grafts either cytotoxic or liable to provoke an inflammatory response as assessed in vitro . However, the protocol was shown to increase the size of gaps between the tendon fibres in the matrix and render the grafts more susceptible to digestion with collagenase. Biomechanical studies of the tendons showed that PAA treatment had no effect on the ultimate tensile stress or Young's modulus of the tendons, and that ultimate strain was significantly higher in PAA treated tendons.


Signal transduction pathways involved in soluble fractalkine-induced monocytic cell adhesion.
Fractalkine displays features that distinguishes it from the other chemokines. In particular, besides its chemoattractant action it promotes, under physiologic flow, the rapid capture and the firm adhesion of a subset of leukocytes or intervenes in the neuron/microglia interaction. This study verified that indeed the human monocytic MonoMac6 cell line adheres to fibronectin-coated filters in response to soluble fractalkine (s-FKN). s-FKN stimulates, with distinct time courses, extracellular signal-related kinases (ERK1 and ERK2) and stress-activated protein kinases (SAPK1/JNK1 and SAPK2/p38). Both p60 Src and p72 Syk were activated under s-FKN stimulation with a rapid kinetic profile compatible with a downstream regulation on the mitogen-activated protein kinase (MAPK) congeners. The use of specific tyrosine kinase inhibitors revealed that the ERK pathway is strictly controlled by Syk, whereas c-Src up-regulated the downstream SAPK2/p38. In contrast, the SAPK1/JNK1 pathway was not regulated by any of these nonreceptor tyrosine kinases. The s-FKN-mediated increased adherence of MonoMac6 cells was partially inhibited by SB202190, a broad SAPKs inhibitor, PD98059, an MEK inhibitor, LY294002, a phosphatidyl inositol 3-kinase inhibitor, and a pertussis toxin-sensitive G protein. These data highlight that the integration of a complex array of signal transduction pathways is necessary to complete the full s-FNK-dependent adherence of human monocytic cells to fibronectin. (Blood. 2001;97:2031-2037)


[The pathogenesis of chronic Chagas' myocarditis: the role of autoimmune and microvascular factors].
The pathogenesis of chronic chagasic myocarditis remains incompletely understood. Several hypotheses have been proposed: (1) direct tissue destruction by Trypanosoma cruzi; (2) neurogenic theory; (3) anti-heart immune reactions; and (4) microvascular disease. We present herein a dynamic alternative hypothesis. We believe that the development of myocarditis is related to progressive and additive focal cellular necrosis, and associated reactive and reparative myocardial fibrosis and surrounding myocytes hypertrophy. These processes may be initiated and perpetuated by autoimmune factors and alterations in the myocardial microcirculation. This could imply future therapeutic strategies in the management of chronic chagasic patients to optimize the medical treatment and hopefully improve the prognosis.


Incomplete data in randomized dermatology trials: consequences and statistical methodology.
Randomized clinical trials can provide the highest level of evidence regarding the effectiveness of therapeutic interventions. When individuals in trials do not complete the planned treatment period it is often not possible to observe the desired outcomes, which results in incomplete data. Here we review various mechanisms which can lead to incomplete data, discuss the impact of these mechanisms, and present strategies for dealing with incomplete data. We discuss these issues in the context of clinical trials in dermatology and provide practical recommendations for planning and drawing conclusions from studies which could involve incomplete data.


The low-spin heme site of cytochrome o from Escherichia coli is promiscuous with respect to heme type.
Cytochrome o of Escherichia coli is able to incorporate two different structures of heme, either heme B (protoheme) or heme O, in its low-spin heme site. In contrast, the heme of the binuclear O2 reduction site is invariably heme O. Heme O is a newly discovered heme that is related to heme A, but with the formyl group of the latter replaced by methyl. Enzyme isolated from wild type E. coli has predominantly heme B in the low-spin site, whereas enzyme isolated from various overexpressing strains contains both types of enzyme in different proportions. In some strains, 70% of the enzyme has heme O in the low-spin site. Despite this variation in the structure of one of the prosthetic groups, the enzymatic activity and polypeptide composition of the enzyme remain virtually constant. EPR and activity data both indicate that heme B and heme O occupy the same low-spin heme site in the enzyme. With heme O in this site, the alpha-absorption band is narrower and further to the blue, and the Em,7 is lower, than when there is heme B in the site. In contrast to previous proposals, we show here that the enzyme does not exhibit significant spectral interactions between the hemes. The structural heterogeneity of the low-spin heme accounts for the variation in the optical spectra and redox properties of the enzyme as isolated from different strains of E. coli.


[DIAGNOSTIC APPROACH TO PATIENTS WITH CHRONIC KIDNEY DISEASE].
According to consensus definition, chronic kidney disease (CKD) includes urinary excretion of albumin >30 mg/day and/ or reduction in kidney function defined as a decrease in estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 for a period longer than three months, in the presence of kidney tissue damage verified by imaging or histologic methods. In developed world, the first cause of CKD is diabetes, followed by arterial hypertension, and the less frequent causes are inflammatory disease (glomerulonephritis, interstitial nephritis) and congenital condition (polycystic kidney disease). Currently, there is valid classification under the acronym CGA, where C stands for the cause, G for glomerular filtration rate (GFR category) and A for the level of albuminuria category. In early stages, patients usually have no symptoms but there are changes in creatinine values, estimated GFR (eGFR) reduction and presence of albuminuria, especially in patients at risk. Determining the grade of renal impairment is important because of different approaches to treatment, monitoring, expected complications, and patient education. Due to improved diagnostic methods and population aging, CKD is diagnosed ever more increasingly. Family physicians should be familiar with the basic principles of screening and diagnosis of CKD to provide them with appropriate care in collaboration with secondary and tertiary health care.


Diversity and Composition of Pelagic Prokaryotic and Protist Communities in a Thin Arctic Sea-Ice Regime.
One of the most prominent manifestations of climate change is the changing Arctic sea-ice regime with a reduction in the summer sea-ice extent and a shift from thicker, perennial multiyear ice towards thinner, first-year ice. These changes in the physical environment are likely to impact microbial communities, a key component of Arctic marine food webs and biogeochemical cycles. During the Norwegian young sea ICE expedition (N-ICE2015) north of Svalbard, seawater samples were collected at the surface (5 m), subsurface (20 or 50 m), and mesopelagic (250 m) depths on 9 March, 27 April, and 16 June 2015. In addition, several physical and biogeochemical data were recorded to contextualize the collected microbial communities. Through the massively parallel sequencing of the small subunit ribosomal RNA amplicon and metagenomic data, this work allows studying the Arctic's microbial community structure during the late winter to early summer transition. Results showed that, at compositional level, Alpha- (30.7%) and Gammaproteobacteria (28.6%) are the most frequent taxa across the prokaryotic N-ICE2015 collection, and also the most phylogenetically diverse. Winter to early summer trends were quite evident since there was a high relative abundance of thaumarchaeotes in the under-ice water column in late winter while this group was nearly absent during early summer. Moreover, the emergence of Flavobacteria and the SAR92 clade in early summer might be associated with the degradation of a spring bloom of Phaeocystis. High relative abundance of hydrocarbonoclastic bacteria, particularly Alcanivorax (54.3%) and Marinobacter (6.3%), was also found. Richness showed different patterns along the depth gradient for prokaryotic (highest at mesopelagic depth) and protistan communities (higher at subsurface depths). The microbial N-ICE2015 collection analyzed in the present study provides comprehensive new knowledge about the pelagic microbiota below drifting Arctic sea-ice. The higher microbial diversity found in late winter/early spring communities reinforces the need to continue with further studies to properly characterize the winter microbial communities under the pack-ice.


[Linear IgA bullous dermatosis: a review].
Linear IgA bullous dermatosis (LABD) is a rare auto-immune bullous disease occurring in adults or childhood. Review of literature about physiopathology, triggering factors, clinical data and treatment of LABD. Research on Medline and Embase database without any time limit until April 2010. Because of the lack of randomized therapeutic trials in LABD, retrospective series and case reports have been analyzed. LABD is due to IgA auto-antibodies typically directed against a proteolytic fragment of BP180 antigen, a 97 or 120kD protein, and/or other components of dermal-epidermal junction. The disease may be either idiopathic or triggered by several medication, most often vancomycin, but also other antibiotics, non-steroid anti-inflammatory, anti-hypertensive and anti-epileptic drugs… Clinically, eruption is typical in childhood with cluster and herpetiform arrangement of blisters and involvement of evocative anatomical sites. In adults, eruption is polymorphic, very atypical presentations are described. Diagnosis is confirmed by direct immunofluorescence which shows linear IgA deposition on the basement membrane zone. Immunoblot and immunoelectron microscopy are evocative in case of diagnosis hesitation. LABD may be associated with some inflammatory bowel disorders. There is no increased risk of cancer or lymphoma. For drug-induced LABD, withdrawal of the medication is followed by a quick healing of the lesions. Dapsone is quickly efficient in idiopathic LABD. Colchicine, sulfapyridine and systemic corticosteroids are used in case of intolerance or inefficiency of dapsone. Some authors emphasize the efficiency of first-intent antibiotics in LABD of childhood. A triggering drug should be always suspected and stopped. Dapsone is the reference treatment in idiopathic cases of LABD.


Pancreatic tissue in teratoma.
Seventeen teratomas with well-differentiated pancreatic tissue were found in 469 cases obtained from the files in our respective departments for the last ten years. These cases included 11 cases with a teratoma located in the anterior mediastinum, five cases with a teratoma located in the sacrococcygeal region, and one case with a teratoma located in the retroperitoneal space. The islets of Langerhans, as well as exocrine elements, were usually found in the pancreatic tissue. The blood glucose level was mildly depressed in one case of five teratomas, and a very high amylase level was observed in one other case. These levels were estimated in the fistulous discharge from the teratoma. Therefore, we felt that the pancreatic tissue observed in the teratomas was similar in nature to normal pancreatic tissue both histologically and functionally.


Haematopoietic stem cell transplantation for the treatment of systemic sclerosis and other autoimmune disorders.
Systemic sclerosis (SSc) with involvement of vital organs has up to 50% 5-year mortality and no treatment is known which changes the natural history. Although components of vascular, immunological and fibrotic processes are involved, drugs such as cyclophosphamide (CY), an alkylating agent and a potent immunosuppressive, have been partially effective in uncontrolled studies. The dose of such agents is limited by the inevitable toxicity on the bone marrow, but this threshold may be superseded by first removing the patient's own haematopoietic stem cells, followed by reconstitution of the marrow after high-dose myeloablative CY or other therapy. This autologous haematopoietic stem cell transplantation (HSCT) technique has been applied to approximately 650 patients with severe autoimmune diseases worldwide, > 100 of whom had SSc. Of these, 75 are included in the Basle registry. Around 70% of patients responded with a significant (> 25%) improvement of the thickened skin and stabilisation of vital organ involvement. Approximately a third achieved a durable remission. The treatment-related mortality was 8.5%. Based on these encouraging Phase I/II study results, several multi-centre, international, prospective randomised Phase III trials are running or being planned. The preliminary data suggest that through such a jolt of heavy immunosuppression, the dysregulated autoaggressive immune system may be re-regulated. It is hypothesised that this results in fewer autoinflammatory and unwanted stimulatory signals to other systems such as vascular endothelium and fibroblasts, and these mechanisms are currently under study.


Radiotherapeutic management of cervical lymph node metastases from an unknown primary site.
To determine whether ipsilateral radiotherapy affects overall survival, cause-specific survival, or local control in patients with a cancer from an unknown primary of the head and neck compared with comprehensive radiotherapy. Retrospective medical record review. Academic tertiary care hospital. The study population comprised 46 patients with cervical metastases from an unknown primary cancer treated with radiotherapy from 1989 through 2008. Median follow-up was 4.6 years. All patients were treated with radiation therapy. Radiotherapy target volumes were categorized as either ipsilateral neck only (IPSI) or comprehensive (COMP), including both the potential mucosal surfaces and ipsilateral or bilateral neck. Human papillomavirus (HPV) status, as determined by p16 immunohistochemical analysis, was evaluated for 36 patients (74%). Overall survival, cause-specific survival, locoregional control, and rate of distant metastases were analyzed. Overall survival at 2 years and 5 years was 87% and 77%, respectively. Cause-specific survival at 2 years and 5 years was 89% and 81%, respectively. There were no ipsilateral neck failures. There was no difference in overall survival between patients treated with IPSI or COMP radiation therapy. The contralateral neck was controlled in all patients receiving bilateral neck irradiation and in 95% receiving ipsilateral neck irradiation. Of the 34 patients evaluated with p16 immunohistochemical analysis, results for 16 (47%) were positive. There was a nonsignificant trend toward improved overall survival in p16-positive patients (P = .06). IPSI radiation therapy demonstrated excellent locoregional control with no adverse effect on disease-free survival or overall survival.


Nuclear cloning and epigenetic reprogramming of the genome.
Cloning of mammals by nuclear transfer (NT) results in gestational or neonatal failure with at most a few percent of manipulated embryos resulting in live births. Many of those that survive to term succumb to a variety of abnormalities that are likely due to inappropriate epigenetic reprogramming. Cloned embryos derived from donors, such as embryonic stem cells, that may require little or no reprogramming of early developmental genes develop substantially better beyond implantation than NT clones derived from somatic cells. Although recent experiments have demonstrated normal reprogramming of telomere length and X chromosome inactivation, epigenetic information established during gametogenesis, such as gametic imprints, cannot be restored after nuclear transfer. Survival of cloned animals to birth and beyond, despite substantial transcriptional dysregulation, is consistent with mammalian development being rather tolerant to epigenetic abnormalities, with lethality resulting only beyond a threshold of faulty gene reprogramming encompassing multiple loci.


Dynamic NMR study of the rotation around "biphenyl-type" bonds in polycyclic sulfoxides.
In a recent paper, we reported on the base-catalyzed rearrangement of bis-propargylic sulfoxides that eventually leads to polycyclic products featuring an unsaturated, cyclic substituent such as cyclohexenyl or phenyl. Due to steric constraints, the latter is positioned roughly perpendicularly to the tricyclic core, and in most cases, two rotamers can be observed in the ground state. In the present work, we report on the synthesis and the products of both symmetrical and asymmetrical starting materials. We also measure, by NMR techniques, the rotation rate of the side chain for several such polycyclic sulfoxides. The barriers for this process, which is similar to a biphenyl rotation, are very strongly dependent on the nature of the substrate, ranging between <7 and 21.0 kcal.mol(-1) for sulfoxides with two five-membered rings and two seven-membered rings, respectively. These barriers can be successfully simulated by molecular-mechanics calculations, and the geometries of the transition states are discussed.


Management of cervical stab wounds in low volume trauma centres: systematic physical examination and low threshold for adjunctive studies, or surgical exploration.
In Nordic countries penetrating neck injuries (PNIs) are infrequent and management has traditionally been guided by surgeons' preferences. Some form of selective non-operative approach is currently practised in most urban trauma centres. To examine demographic features and treatment outcome of non-ballistic penetrating neck injuries in southern Finland and provide management guidelines for centres with low volume of penetrating neck trauma. Retrospective analysis of 85 platysma penetrating neck injuries in two southern Finland hospitals (Helsinki University Central Hospital, HUCH and Tampere University Hospital, TaUH) was carried out using the ICD-10 based hospital databases to identify PNI-patients. The incidence of admitted patients with penetrating neck injuries was 1.3/100000/year. Fifty-two (61%) injuries were caused by random acts of violence, 28 (38%) were self-inflicted and 5 (6%) were accidents. Of all 85 patients, 52 (61%) underwent operative exploration with a negative exploration rate of 65%. Hard signs for vascular or aerodigestive trauma were present in 23 (27%) patients and all of these were operated with a negative exploration rate of 30%. Two patients had no hard signs on physical examination but were operatively explored and significant injuries were found in both patients. The hospital mortality rate was 0% and the overall complication rate for operated patients was 7.7%. Trauma centres managing PNIs infrequently should have an individually tailored management protocol for penetrating neck injury patients. If mandatory exploration is not practised, a systematic physical examination should be the mainstay of diagnostic work up but the threshold for adjunctive studies should be low. Although not evident by the current data, protocol-based management could be useful in decreasing treatment variation and enhancing residency training.


[A control study of artificial oocyte activation in the same period].
Objective: To compare the fertility rate and embryo outcome between normal fertilization and the use of Calcium ionophore A23187 on the same period of the same cycle of human ovum for artificial activation. Methods: Patients who conducted the intracytoplasmic sperm injection (ICSI) cycle in vitro fertilization assisted reproductive from January 2015 to December in reproductive center of the Third Affiliated Hospital of Zhengzhou University were enrolled.The protocol of this study was approved by the ethics committee of The Third Affiliated Hospital of Zhengzhou University.The subjects must met at least one of the inclusion criteria: (1)the normal fertilization rate was less than 30% ICSI in the previous ICSI cycle; (2)no good quality embryos in a previous period of third days in ICSI; (3)patients with globozoospermia.The ovum were randomly divided into two groups, control group and artificial oocyte activation (AOA) group. In the control group, the eggs were treated with routine ICSI operation, and the AOA group was activated by A23187 after ICSI. Normal fertilization rate, cleavage rate, pregnancy and birth outcome of two groups were compared. Results: The 2PN fertilization rate in the AOA group 65.93% (60/91) was significantly higher than that in the control group 46.67% (41/89) (P<0.05). In addition, in patients who met the inclusion criteria of 1 categories (2PN≤30%), the 2PN fertilization rate was significantly higher (P<0.05) in the AOA group [79.59% (39/49)] compared with the control group [57.14% (28/49)]. In patients who met the inclusion criteria of 3 categories (globozoospermia), the 2PN fertilization rate was significantly higher (P<0.05) in the AOA group [75% (6/8)] compared with the control group [0% (0/5)]. Conclusions: The use of calcium ionophore A23187 assisted activation could be helpful to improve the normal fertilization rate of ICSI. But the effects of early embryonic development and the safety of generation need to be further studied.


Cadmium adsorption by willow root: the role of cell walls and their subfractions.
Plant cell walls may play an important role in the uptake and accumulation of heavy metals. This study was undertaken to obtain a better understanding of the role of the root cell walls (RCW) and their subfractions on adsorption of cadmium (Cd) in a promising woody phytoremediation species, Salix jiangsuensis J172. In order to examine how Cd binding was affected by pectin and hemicellulose, RCW were isolated and sequentially fractioned by removing pectin (RCW1), partial removal of hemicellulose (RCW2), and complete removal of hemicellulose (RCW3). The RCW and fractions were characterized by Fourier transform infrared spectroscopy, which suggested decomposition of hemicellulose and a decline in nitrogen content following cell wall isolation and fractionation. The adsorption affinity of Cd increased gradually following the sequential extraction of root cells, suggesting that hemicellulose negatively impacted Cd adsorption, while pectin and cellulose enhanced Cd adsorption. Cd adsorption dynamics and isotherms could be best described by the pseudo-second-order (R>0.99) and Freundlich (R>0.97) models, respectively. Thermodynamic properties (∆G, ∆H, and ∆S), determined using the van't Hoff equation, indicated that while Cd adsorption was endothermic, and spontaneous for RCW2 and RCW3, adsorption was not spontaneous for the root, RCW, and RCW1. The results provide evidence for the importance of the root cell walls in the adsorption of Cd by willow roots.


Local anesthetics in surgical oral dentistry and in maxillofacial surgery their limits in regard to the cardiovascular system.
The present study was undertaken to investigate the effects of vasopressor substances contained in local anesthetics in dentistry. The results obtained indicate substantial cardiac activity of these anaesthetics, as shown by electrocardiographic (EKG) tracings carried out on patients before and after anesthetization. The vasoconstrictors, adrenaline or noradrenaline, resulted at times in slight cardiac lesions which could not be observed clinically. Careful anamneses could avoid such situations.


Regioselective synthesis of 1,3,5-triaryl-4-alkylpyrazoles: novel ligands for the estrogen receptor.
[reaction: see structure] A regioselective synthesis of 4-alkyl-1,3,5-triarylpyrazoles has been developed for the preparation of unsymmetrically substituted systems of interest as ligands for the estrogen receptor.


Independent association of hip circumference with metabolic profile in different ethnic groups.
In whites, a larger hip circumference has been shown to be associated with a better metabolic profile, after adjustment for BMI and waist circumference. Our aim was to investigate this association in a variety of ethnic groups, some highly susceptible to type 2 diabetes. We measured weight, height, waist and hip circumferences, systolic and diastolic blood pressure, fasting and 2-hour postload glucose, triglycerides, and high-density lipoprotein-cholesterol in 1020 Melanesians, 767 Micronesians, 3697 Indians, and 2710 Creoles from Pacific and Indian Ocean islands. Leptin and body fat percentage were determined in Indian and Creole Mauritians only. In all ethnic groups, larger hip circumference was associated with lower glucose and triglyceride levels in both sexes and higher high-density lipoprotein levels in women only, after adjustment for waist circumference, BMI, and age. Adjustment for height or leptin did not materially change the results. In conclusion, we confirmed the protective association of relatively larger hips in four nonwhite ethnic groups. Leptin does not seem to play a mediating role in this association.


Influence of aging on pulmonary hemodynamics in a population free of coronary artery disease.
Previous studies showing an increase in pulmonary artery (PA) pressures and vascular resistance with aging have not systematically excluded subjects with coronary artery disease or left ventricular systolic dysfunction. To better determine the influence of aging on PA hemodynamics in the absence of disease, we identified 47 normal subjects angiographically free of coronary artery disease (18 men, 29 women) with normal left ventricular systolic function (ejection fraction greater than or equal to 50% and left ventricular end-diastolic pressure less than 14 mm Hg) from 5,508 consecutive patients undergoing cardiac catheterization and coronary angiography between September 10, 1982 and March 9, 1987. All subjects met a set of clinical and laboratory criteria identifying them as normal. In group I (age greater than or equal to 60 years) mean PA pressure was 16 +/- 3 mm Hg, pulmonary vascular resistance was 124 +/- 32 dynes s cm-5 and the pulmonary/systemic vascular resistance ratio was 0.099 +/- 0.046. In contrast, in group II (age less than 60 years), these values were lower at 12 +/- 2 mm Hg, 70 +/- 25 dynes s cm-5 and 0.057 +/- 0.019, respectively (all p values less than 0.01 to 0.001). All these parameters increased linearly with age (r = 0.69, p less than 0.001 for pulmonary vascular resistance). The differences were not attributable to body surface area or gender. There was no difference in cardiac output, PA wedge pressure, aortic pressure or systemic vascular resistance between the 2 groups. Thus, PA pressure and vascular resistance increase with aging, a change not attributable to coronary disease or left ventricular systolic dysfunction.


Outcomes of Superficial and Deep Irrigation and Debridement in Total Hip and Knee Arthroplasty.
Following total knee arthroplasty and total hip arthroplasty, wound-related problems and deep periprosthetic joint infection may present in a similar fashion. Irrigation and debridement (I&D) has a great role in management of patients with early infection. The question that often arises is how to tell the difference between superficial and deep infection. This study evaluated the role and outcomes of both superficial and deep I&D in patients with wound-related issues and/or suspected periprosthetic joint infection. A retrospective study was conducted evaluating patients who underwent I&D within 28 days of total joint arthroplasty. A total of 176 cases with a minimum of 1-year follow-up were identified, and clinical records were reviewed in detail. Reoperations included superficial (fascia not opened) or deep (fascia opened) I&D. Failure was defined as the need for further surgical intervention within 1 year of initial I&D. The overall success for superficial I&D was 84.28% vs 68.86% for deep I&D. The success of both deep and superficial I&D was higher if the I&D was performed closer to the index surgery. Superficial I&D in patients with a positive joint aspiration or evidence of intraoperative purulence or those in whom had no subcutaneous fluid had higher failure rates. Superficial I&D is a viable option in patients with wound-related issues as long as joint aspiration is performed to rule out infection involving the prosthesis. If there are findings of no fluid or purulence, fascia may need to be opened and the deeper tissues explored.


Strategies used by adults to reduce their prescription drug costs.
In 2011, Americans spent $45 billion out-of-pocket on retail prescription drugs (1). Some adults reduce prescription drug costs by skipping doses and delaying filling prescriptions (2). Some cost-reduction strategies used by adults have been associated with negative health outcomes. For example, adults who do not take prescription medication as prescribed have been shown to have poorer health status and increased emergency room use, hospitalizations, and cardiovascular events (3,4). This report analyzes different strategies used by U.S. adults to reduce their prescription drug costs, by age, health insurance status, and poverty status, using data from the 2011 National Health Interview Survey (NHIS).


Specific oral tolerance induction for food. A systematic review.
Specific oral tolerance induction (SOTI) is a new therapeutic approach in the treatment of persistent food allergy. The purpose of this article is to systematically review the literature in order to identify, appraise, and synthesize the evidence about SOTI efficacy and safety. A comprehensive search for citations was conducted on May 2, 2009 using MEDLINE via PubMed. Randomized controlled trials (RCTs) including subjects of any age were considered. All these studies were assessed, discussed in details and evaluatedfor quality by authors in a standardized independent way. 15 clinical trials were found. Of these, six trials met the inclusion criteria: three were open label RCT, three were double blind placebo controlled RCT. Two were conducted using sublingual immunotherapy, four using oral desensitization. Overall, the methodological quality of the studies was sufficient. The mean Jadad score of the studies was 3.33 (range = 2-5). Main characteristics and results of the studies were showed and discussed. SOTI seems to be a possible approach to accelerate the development of tolerance in children affected by food allergy. However, other studies are needed to clarify which is the best treatment and protocol to follow in order to reduce the adverse events and to increase the percentage of success, before thinking that SOTI might be part of the clinical practice.


In vivo and in vitro properties of anti-delta 9-tetrahydrocannabinol antibody.
An immune serum to cannabinoids was produced in rabbits. It was tested in vitro by immunoprecipitation, hemagglutination and hemagglutination-inhibition tests. In vivo, when passively transferred into mice, it prevented the effect of delta 9-tetrahydrocannabinol on the barbiturate sleeping time.


Measurement of functional fibrinogen levels using the Thrombelastograph.
To validate a Thromboelastograph (Haemoscope Corporation, Niles, IL) assay for functional fibrinogen. Correlation study of the Thromboelastograph assay with two conventional fibrinogen assays by the standard Clauss method. Research laboratory of a university medical center. Blood samples were obtained from 19 healthy volunteers. Thromboelastograph assays, using heparinized whole blood from 19 healthy donors, indicated that reptilase-XIIIa mixture (Activatorf)-generated clot shear elasticity in dynes per square centimeter (Gf) correlated with fibrinogen (mg/dL). Blood from four donors was used to define the contribution of hematocrit (Hct) to Gf by titration with platelet-rich plasma. The Gf versus Hct gave linear correlations (r2 = 0.746) with Gf = 1258 - 17.8 x % Hct. A commercial collection of 19 normal, 10 borderline, and one deficient for functional fibrinogen-citrated plasmas was assayed for Gf after recalcification using Activatorf. Of the 30 plasma samples, four were from factor X- or factor VII-deficient donors and one was from a coumadin-treated donor. There was a linear correlation of Activatorf Gf with functional fibrinogen (r2 = 0.940) with Gf = -730 + 9.21 x fibrinogen (mg/dL). Thrombelastography with Activatorf may be used to determine fibrinogen levels in whole blood.


A survey of didymozoid trematodes of the barracuda Sphyraena obtusata from Kuwait Bay.
Examination of 120 yellow-finned barracudas, Sphyraena obtusata, from Kuwait Bay revealed 8 species of didymozoid trematodes encapsulated in pairs in the tissues. Four species of the didymozoids, Allodidymozoon operculare, Didymocylindrus sp., Didymocystis sp., and Didymocystoides sp., were found in the head region, 3 species, Didymozoon tetragynae, Lepidodidymozoon sinicum and Platocystoides polyaster, in external surfaces and 1 species, Allodidymozoon sp., in stomach wall. The didymozoid species collected constitute new geographic distribution records and occurrence of D. tetragynae and L. sinicum are new host records.


A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), ameliorates rat pulmonary hypertension with unique relaxant responses of its active form, {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), on rat pulmonary artery.
2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304) is an orally available, long-acting nonprostanoid prostacyclin receptor (IP receptor) agonist prodrug. In a rat model of pulmonary hypertension induced by monocrotaline (MCT), NS-304 ameliorated vascular endothelial dysfunction, pulmonary arterial wall hypertrophy, and right ventricular hypertrophy, and it elevated right ventricular systolic pressure and improved survival. {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), the active form of NS-304, is much more selective for the IP receptor than are the prostacyclin analogs beraprost and iloprost, which also have high affinity for the EP(3) receptor. To investigate the effect of receptor selectivity on vasodilation of the pulmonary artery, we assessed the relaxant response to these IP agonists in rats. MRE-269 induced vasodilation equally in large pulmonary arteries (LPA) and small pulmonary arteries (SPA), whereas beraprost and iloprost induced less vasodilation in SPA than in LPA. An EP(3) agonist, sulprostone, induced SPA and LPA vasoconstriction, and an EP(3) antagonist attenuated the vasoconstriction. Beraprost showed EP(3) agonism and induced LPA and SPA vasoconstriction, whereas the EP(3) antagonist inhibited this vasoconstriction and enhanced beraprost- and iloprost-induced SPA vasodilation. These findings suggest that the EP(3) agonism of beraprost and iloprost interfered with the SPA vasodilation resulting from their IP receptor agonism. Endothelium removal markedly attenuated the vasodilation induced by beraprost, but not that induced by MRE-269 or iloprost. Moreover, the vasodilation induced by beraprost and iloprost, but not that induced by MRE-269, was more strongly attenuated in LPA from MCT-treated rats than from normal rats. NS-304 is a promising alternative medication for pulmonary arterial hypertension with prospects for good patient compliance.


Prevalence of cocaine use among residents of New York City who committed suicide during a one-year period.
In the mid-1980s the form of cocaine called "crack" became widely available in New York City. The authors sought to determine the prevalence of cocaine metabolites detected at autopsy in persons who committed suicide in New York City during this period. Individual reviews of the autopsy and toxicological records of all persons under the age of 61 who had committed suicide in the city during a 1-year period were conducted to determine demographic characteristics, suicide methods, and cocaine and alcohol use at the time of death. In one of every five cases studied, the person who committed suicide had used cocaine within days of his or her death. The prevalence of cocaine use among young Hispanic males who committed suicide was 45%. Persons who were young, black, or Hispanic and who had used alcohol immediately before the fatal injury were most likely to have been recent cocaine users. After controlling for demographic variables and ethanol use, the investigators found that individuals who committed suicide with firearms were twice as likely to have used cocaine as those who used other methods. In contrast to the results of regional and household surveys during this period, which suggested that the current prevalence of cocaine use in New York City was 3%-5%, these results suggest a high prevalence of cocaine use in the days immediately preceding death by young persons who commit suicide. Additional studies are needed to determine how cocaine may act as a risk factor for suicide.


Inhibition of spontaneous leukemia in F-344 rats by tetramethylthiuram disulfide (thiram).
Thiram was added at levels of 0.1 and 0.05% to the diet of F-344 rats for 2 years. The results indicated that thiram significantly reduced the incidence of spontaneous leukemia, and also tended to reduce the incidences of pituitary and thyroid tumors.


[Late postoperative results of anti-reflux ureterocystoneostomy].
Presented are the postoperative results of 13 of the 15 operations on the urethrovesicular junction. Most (8) were treated by the Politano-Leadbetter method; three (3) by Cohen, and two (2) by the Swinney-Avata modification of the Politano-Leadbetter method which is described and shown schematically. Reasons for applying these treatments were stenosis of various origins localized in the terminal part of the urethra, gynecological damages to the urethra ("iatrogenic" injuries), displacement of the urethra, vesicular-urethral reflux, and megaurethra. At check-ups from 3 months to 6 years after the operation, 84.6% of the operations proved successful. In comparison with 18 operations for the same reasons in which an ordinary reimplantation of the urethra was performed, the former is 12.3% better. The Cohen operations achieved good results. However, should the need arise later, it is impossible to perform retrograde manipulations of the urethra with a probe in the usual way. Thus the authors ascribe the advantages to those operations that can develop naturally with the reimplantation of the submucous membrane of the urethra.


Importance of pharmacokinetics in the determination of withdrawal times.
Models for the statistical determination of withdrawal times have been compared using computer-generated kinetic residue data. Estimates of withdrawal times obtained by direct evaluation of the 'known' frequency distributions of residue contents of very large samples have been compared to results obtained by regression analysis of the data on very small samples of the same populations. In this context, the hypothesis was tested that the natural logarithms of the residue contents were normally distributed and that the decrease of the natural logarithms was linear with time. Withdrawal times were then determined as the times when the upper limit of the (statistical) tolerance interval in a given percentile was below the acceptable daily intake. From the results obtained with computer-generated small data bases, it was concluded that adequate, but not necessarily precise, withdrawal times could be determined on a limited base of suitable kinetic residue data.


High-calorie diet inflates steatogenic effects of valproic acid in mice.
Valproic acid (VPA) is an anti-epileptic drug used in patients with convulsive seizures and psychic disorders. Despite its therapeutic use, VPA administration is associated with several side effects of which hepatosteatosis (lipid deposition in liver >10% of organ weight) is of concern. Recently, the consumption of western-type diet rich in fat and simple sugar has increased, the pathological consequences of which has been linked to the escalating incidence of metabolic disorders. The hypothesis of the study is that the metabolic stress induced by high-calorie diet may potentiate VPA-induced hepatosteatosis. Two groups of Swiss Mus musculus male mice weighing 25-35 g were fed either normal chow or high fat and high fructose diet (HFFD) and maintained for 30 days. On the 16th day of the experiment, VPA (100 mg/kg bw) administration was initiated in one set of animals from each group and the other set was left without VPA treatment. Assays were done in the hemolysate, plasma and liver tissue of mice after the experimental period. Deregulated lipid metabolism, loss of insulin sensitivity, enhanced CYP2E1 activity and oxidative damage, and diminution of cellular antioxidants were observed in animals that received HFFD and VPA. HFFD-fed mice are sensitized to VPA toxicity than the normal chow-fed counterparts. The results of this study show that preformed metabolic derangements due to high-energy diet may infuriate VPA-induced hepatosteatosis and insulin resistance.


[Comparison of three dosimetric techniques for lung tumor irradiation].
Comparison of three dosimetric techniques of lung tumor delineation to integrate tumor motion during breathing. Nineteen patients with T1-3N0M0 malignant lung tumor were treated with definitive chemoradiotherapy (14 cases) or pre-surgery chemoradiation. Doses were, respectively, 66 and 46Gy. CT-scan for delineation was performed during three phases of breathing: free breathing and deep breath-hold inspiration and expiration. GTV (gross tumor volume) was delineated on the three sequences. The classic technique included GTV from the free-breathing sequence plus a CTV (clinical target volume) margin of 5 to 8mm plus a PTV (planning target volume) margin of 7 to 10mm (including ITV [internal target volume] margin and set-up margin). The gating-like technique included GTV from the deep breath-hold inspiration sequence plus a CTV margin of 5 to 8mm plus a PTV margin of 2mm. The three-volume technique, included GTV as a result of the fusion of GTVs from the three sequences plus a CTV margin of 5 to 8mm plus a PTV margin of 2mm. Dosimetry was calculated for the three PTVs, if possible, with the same fields number and position. Dose constraints and rules were imposed to accept dosimetries: firstly spinal cord maximal dose less than 45Gy, followed by V95 % for PTV greater than or equal to 95 %, and V20 GY(Gy) for lung less than or equal to 30 %, V30 GY(Gy) for lung less than or equal to 20 %. GTVs were not statistically different between the three methods of delineation. PTVs were significantly lower with the gating-like technique. V95% of the PTV were not different between the three techniques. With the classic-, the gating-like- and the 3-volume techniques, dosimetry was considered as acceptable, respectively in 15, 18 and 15 cases. Comparisons of constraint values showed that the gating-like method gave the best results. In the case of pre-operative management, the gating-like method allowed the best results even for the V95% values. However, in the absence of gating device or without the possibility to use it, the 3-volume method allowed to take into account more precisely the organ motion than the classical technique. The 3-volume method can be done. It is a good method to take into account the organ motions. However, the gating-like method gives the best results leading to propose its use even for pre-operative patients with upper tumors.


Psychometric properties of the "Modified Transplant Symptom Occurrence and Symptom Distress Scale".
The aim of this study was to assess key aspects of the reliability and validity of the "Modified Transplant Symptom Occurrence and Distress Scale," an instrument measuring symptom experience associated with side effects of triple drug therapy in transplant patients. This cross-sectional, comparative study included 108 renal transplant recipients (61% men; 39% women) with a median age of 47 years and a median posttransplant status of 5.5 years. Renal transplant patients were matched by age and gender with 108 healthy control persons not taking immunosuppressive drugs. Content validity, construct validity and discriminant validity of the instrument were substantiated. Internal consistency reliability was not useful to assess in this instrument, as the conditions for calculating Cronbach's alpha were not satisfied. These findings document the validity of the "Modified Transplant Symptom Occurrence and Symptom Distress Scale" as an instrument to measure symptom experience with immunosuppressive drugs.


Capping hazardous red mud using acidic soil with an embedded layer of zeolite for plant growth.
A nearly three-year microcosm experiment was conducted to test the effectiveness of capping red mud using acidic soil with an embedded layer of zeolite in sustaining the growth of a grass species. This 'sandwich-structured' design allowed self-sustaining growth of the plants under rain-fed conditions no matter whether the underlying red mud was neutralized or not. During the initial stage, the plants grew better when the red mud was not neutralized with MgCl2 probably due to pH rise in the root zone. Neutralization of red mud led to salinization and pH decrease in the root zone. However, the difference in plant growth performance between these scenarios became less remarkable over time due to gradual improvement of soil conditions in the neutralized scenarios. Continuous leaching of soluble salts and alkali by rainwater extended the root zone to the red mud layer. As a result of vegetative production, soil organic matter rapidly accumulated. This, combined with increase in pH and decrease in salinity, markedly facilitated microbial activities and consequently improved the supply of nutrients. This study provides abasis for field-scale experimental design that will have implications for effectively establishing vegetative cover in red mud disposal sites to control dust hazards.


Infants' visual sustained attention is higher during joint play than solo play: is this due to increased endogenous attention control or exogenous stimulus capture?
Previous research has suggested that when a social partner, such as a parent, pays attention to an object, this increases the attention that infants pay to that object during spontaneous, naturalistic play. There are two contrasting reasons why this might be: first, social context may influence increases in infants' endogenous (voluntary) attention control; second, social settings may offer increased opportunities for exogenous attentional capture. To differentiate these possibilities, we compared 12-month-old infants' naturalistic attention patterns in two settings: Solo Play and Joint Play with a social partner (the parent). Consistent with previous research, we found that infants' look durations toward play objects were longer during Joint Play, and that moments of inattentiveness were fewer, and shorter. Follow-up analyses, conducted to differentiate the two above-proposed hypotheses, were more consistent with the latter hypothesis. We found that infants' rate of change of attentiveness was faster during Joint Play than Solo Play, suggesting that internal attention factors, such as attentional inertia, may influence looking behaviour less during Joint Play. We also found that adults' attention forwards-predicted infants' subsequent attention more than vice versa, suggesting that adults' behaviour may drive infants' behaviour. Finally, we found that mutual gaze did not directly facilitate infant attentiveness. Overall, our results suggest that infants spend more time attending to objects during Joint Play than Solo Play, but that these differences are more likely attributable to increased exogenous attentional scaffolding from the parent during social play, rather than to increased endogenous attention control from the infant.


Immune responses following killed whole vibrio-B subunit oral cholera vaccine in human volunteers.
Immunogenicity of killed whole vibrio and B subunit oral cholera vaccines in American and Thai volunteers were analysed in terms of significant rise of antibody titre. Three doses of 2 x 10(11) killed vibrios and 5 mg of cholera toxin B subunit were given at two-week intervals. There were no differences in the percent of volunteers with significant rise of serum immunoglobulin G and secretory immunoglobulin A (sIgA) to cholera toxin. However, the percent with significant rises of serum antibody to whole cell V. cholerae Inaba measured by vibriocidal titre and serum immunoglobulin G, and secretory immunoglobulin A to lipopolysaccharide (LPS) measured by ELISA in American volunteers were significantly different from those in Thai volunteers (89% VS 45%, 68% VS 9% and 53% VS 0%, respectively) (p less than 0.05).


[Sampling and detection methods of bioaerosols for the risk assessment of microorganisms in work environments].
Bioaerosols including bacteria and fungi have been almost unrecognized as pollutants of work environments in Japan. The combination of filter sampling and DNA staining by ethidium bromide (EtBr) was examined for the detection and evaluation of total numbers of bioaerosols, including viable and dead microorganisms, for risk assessment in work environments. With direct counting of microorganisms by EtBr concentrations of total cells were obtained in a shorter time than plate culture, the traditional method for detection of microorganisms. Total cell concentrations (cells/m3) were about 100 times greater than colonized cell concentrations (CFU/m3) in all samples. In some microscopic fields, macro conidia produced from some kinds of fungi were observed, but they were not detected by plate culture. Airborne bacterial 16S rDNA amplified by PCR were determined for their base sequences by DNA sequence analysis and classified by sequence-based homologies. Base sequences from 2 samples each contained 6 common groups of phylum. The combination of filter sampling and direct counting by EtBr staining was shown to be a better method for detecting and evaluating total cell concentrations in the risk assessment of sick building syndrome and allergy.


[Severe Aeromonas hydrophila infections. Apropos of 2 cases].
The authors describe two personal cases of severe Aeromonas hydrophila infection. They review the symptomatology and treatment of such cases and insist on the unusual features in their patients.


Tandem Wittig rearrangement/aldol reactions for the synthesis of glycolate aldols.
A new tandem Wittig Rearrangement/aldol reaction of O-benzyl or O-allyl glycolate esters is described. This reaction generates two carbon-carbon bonds and two contiguous stereocenters in a single step from simple starting materials. The [1,2]-Wittig rearrangement proceeds under very mild reaction conditions that do not require the use of a strong base, and the 1,2-diol products are obtained in good yield with excellent diastereoselectivity (>20:1).


Low glucose availability alters the expression of genes involved in initial adhesion of human glioblastoma cancer cell line SF767.
Studying the metabolic pathways of cancer cells is considered as a key to control cancer malignancies and open windows for effective drug discovery against cancer. Of all the properties of a tumor, metastasis potential is a defining characteristic. Metastasis is controlled by a variety of factors that directly control the expression of cell adhesion proteins. In this study we have investigated the expression of cell to cell and cell to matrix adhesion protein genes during the initial phases of attachment of human glioblastoma cancer cell line SF767 (66Y old human female: UCSF Neurosurgery Tissue Bank) to the attachment surface under (Cell culture treated polystyrene plate bottom) glucose-rich and glucose-starved conditions. The aim was to imitate the natural microenvironment of glucose availability to cancer cells inside a tumor that triggers epithelial to mesenchymal transition (EMT). In this study, we have observed the gene expression of epithelial and mesenchymal isoforms of cadherin (E-CAD and N-CAD) and Ig like cell adhesion molecules (E-CAM and N-CAM) along with Integrin family subunits for the initial attachment of cancer cells. We observed that high glucose environments promoted cell survival and cell adhesion, whereas low glucose accelerated EMT by downregulating the expression level of integrin, E-CAD, and N-CAD, and upregulation of N-CAM during early period of cell adhesion. Low glucose availability also downregulated variety of structural and regulatory genes, such as zinc finger E-box binding home box 1A), cytokeratin, Snail, and β catenin, and upregulation of hypoxia-inducible factor 1, matrix metalloprotease 13/Collagenase 3, vimentim, p120, and fructose 1,6 bisphosphatase. Glucose conditions are more efficient for cancer studies in this case glioblastoma cells.


The inactivation gate of the Shaker K+ channel behaves like an open-channel blocker.
Following voltage-dependent activation, Drosophila Shaker K+ channels enter a nonconducting, inactivated state. This process has been proposed to occur by a "ball-and-chain" mechanism, in which the N-terminus of the protein behaves like a blocker tethered to the cytoplasmic side of the channel and directly occludes the pore to cause inactivation. To complement the ample evidence for the involvement of the N-terminus, we sought evidence that it blocks the pore directly. We found that inactivation exhibits several distinctive properties of pore blockade. First, recovery was speeded by increased external K+ concentrations, just as blockade can be relieved by trans-permeant ions. Second, single-channel experiments show that the channel reopens from the inactivated state upon repolarization. These openings were usually required for recovery, as though the blocking particle must exit the pore before the channel can close.


Assessment of metal content and toxicity of leachates from teapots.
Metallic teapots traditionally used in Morocco were investigated for release of toxic metals from the teapots and their toxicity, as determined by MetPAD, a bacterial toxicity test that is specific for heavy metal toxicity. Our data show that some teapots were non-toxic while a few others were highly toxic, as shown by MetPAD. Tea addition reduced somewhat heavy metal toxicity due possibly to the complexing ability of tea. Chemical analysis of teapot leachates showed that some contained zinc and copper. Teapot No. 5, which showed the highest toxicity, also displayed the highest Zn concentration (7.39 mg/l), confirming the toxicity data. Based on estimates of tea consumption in Morocco, we showed that the extra daily burden of Zn ranged from 1.75 to 4.2 mg/day, assuming the maximum zinc concentration of 7.4 mg/l, as found in our study. This represents 3.5-8% of the LOAEL for zinc of 50 mg/day and would not be important as compared to other sources zinc intake.


Paternal care in the social and diurnal striped mouse (Rhabdomys pumilio): laboratory and field evidence.
Paternal care is rare in mammals, occurring mainly in carnivores and neotropical primates, in which the difficulties of long generation time and large individuals lead to small sample sizes. Here, the authors show that paternal care can be easily studied in the four-striped mouse (Rhabdomys pumilio) because (a) captive males show all the patterns of parental care as do females, with the obvious exception of nursing; (b) in the field, wild males act amicably toward juveniles and retrieve pups experimentally presented to them; (c) the striped mouse facilitates experimental approaches in captivity because it has a short generation period and can be kept in large numbers; and (d) the striped mouse is diurnal, not only making observations in captivity easier but also enabling direct observations in the field.


Transcriptional mechanisms that control expression of the macrophage colony-stimulating factor receptor locus.
The proliferation, differentiation, and survival of cells of the macrophage lineage depends upon signals from the macrophage colony-stimulating factor (CSF) receptor (CSF1R). CSF1R is expressed by embryonic macrophages and induced early in adult hematopoiesis, upon commitment of multipotent progenitors to the myeloid lineage. Transcriptional activation of CSF1R requires interaction between members of the E26 transformation-specific family of transcription factors (Ets) (notably PU.1), C/EBP, RUNX, AP-1/ATF, interferon regulatory factor (IRF), STAT, KLF, REL, FUS/TLS (fused in sarcoma/ranslocated in liposarcoma) families, and conserved regulatory elements within the mouse and human CSF1R locus. One element, the Fms-intronic regulatory element (FIRE), within intron 2, is conserved functionally across all the amniotes. Lineage commitment in multipotent progenitors also requires down-regulation of specific transcription factors such as MYB, FLI1, basic leucine zipper transcriptional factor ATF-like (BATF3), GATA-1, and PAX5 that contribute to differentiation of alternative lineages and repress CSF1R transcription. Many of these transcription factors regulate each other, interact at the protein level, and are themselves downstream targets of CSF1R signaling. Control of CSF1R transcription involves feed-forward and feedback signaling in which CSF1R is both a target and a participant; and dysregulation of CSF1R expression and/or function is associated with numerous pathological conditions. In this review, we describe the regulatory network behind CSF1R expression during differentiation and development of cells of the mononuclear phagocyte system.


Matrix-assisted laser desorption/ionization mass spectrometry of acidic glycoconjugates facilitated by the use of spermine as a co-matrix.
Negative-ion matrix-assisted laser desorption/ionization mass spectra of sialyated glycoconjugates were acquired employing 2,5-dihydroxybenzoic acid (DHB) in conjunction with spermine as a co-matrix. The addition of spermine to DHB permitted an improved crystal formation as well as a higher analyte solubility. Moreover, DHB/spermine appears to minimize alkali adduct formation, thus allowing the sample analysis without desalting. The combined matrix permitted the analysis of complex sialylated and sialylated/fucosylated structures down to the femotomole range. The ability to use such a matrix also facilitates determination of the sialic acid linkages (in combination with a specific enzyme cleavage). The matrix also appears suitable for studies on gangliosides.


Overexpression of Vα14Jα18 TCR promotes development of iNKT cells in the absence of miR-181a/b-1.
Expression of microRNA miR-181a/b-1 is critical for intrathymic development of invariant natural killer T (iNKT) cells. However, the underlying mechanism has remained a matter of debate. On the one hand, growing evidence suggested that miR-181a/b-1 is instrumental in setting T-cell receptor (TCR) signaling threshold and thus permits agonist selection of iNKT cells through high-affinity TCR ligands. On the other hand, alterations in metabolic fitness mediated by miR-181a/b-1-dependent dysregulation of phosphatase and tensin homolog (Pten) have been proposed to cause the iNKT-cell defect in miR-181-a/b-1-deficient mice. To re-assess the hypothesis that modulation of TCR signal strength is the key mechanism by which miR-181a/b-1 controls the development of iNKT cells, we generated miR-181a/b-1-deficient mice expressing elevated levels of a Vα14Jα18 TCRα chain. In these mice, development of iNKT cells was fully restored. Furthermore, both subset distribution of iNKT cells as well as TCR Vβ repertoire were independent of the presence of miR-181a/b-1 once a Vα14Jα18 TCRα chain was overexpressed. Finally, levels of Pten protein were similar in Vα14Jα18 transgenic mice irrespective of their miR-181a/b-1 status. Collectively, our data support a model in which miR-181 promotes development of iNKT cells primarily by generating a permissive state for agonist selection with alterations in metabolic fitness possibly constituting a secondary effect.


Influence of Caregiver's Sociodemographic Background on the Oral Health Status and Care of HIV-infected Children.
The purpose of this study was to evaluate the relationship between socio-demographic characteristics of caregivers and the oral health of their children infected with human immunodeficiency virus (HIV+) compared to a group of HIV-children and their caregivers. One hundred forty HIV+ and 140 healthy two- to five-year-old children and their caregivers who sought care at hospitals in Rio de Janeiro, Brazil, participated. Caregivers were interviewed for sociodemographic characteristics, and knowledge and attitudes regarding oral health. The decayed, missing and filled primary teeth (dmft) index was obtained for the children. Chi-square and Mann-Whitney tests were used (five percent significance level). Content analysis method was used for qualitative evaluation. Most interviewees were mothers (83.6 percent), did no work outside the home (69.3 percent), had low educational status (47.1 percent), and were born in the South/Southeast regions of Brazil (83.6 percent). The mean dmft was 3.48±3.14 for the HIV+ group and 1.02±1.00 for the healthy children. Oral care was reported as important by 54.1 percent of the caregivers. Those who didn't consider oral care important had never received information about oral health (P<0.01). Caregivers born in the North/Northeast regions took their children to the dentist less frequently than mothers born in other areas (P=0.02). Low educational status influenced the attitudes about oral health (P<0.01), irregular dental visits for the children (P<0.01), and the dmft index (P<0.01). Caregivers' low educational status and birthplace influenced the importance given to HIV+ children's oral health as well as the oral health knowledge and practices for both HIV+ and healthy children.


Quantitation of factor XIII by SDS polyacrylamide gel electrophoresis.
An electrophoretic method for the determination of f.XIII, based on the capability of f.XIIIa to cross-link fibrin clots (5) was studied, and the great sensitivity of the method confirmed. Thus, with suitable technical conditions, f.XIII activities less than 0.1% of that in normal human plasma could be detected. The results obtained in plasma from various patients and in f.XIII concentrates (cryoprecipitates) corresponded well with those obtained with the dansylcadaverine method (3) and with the urea solubility test, with two exceptions: In a patient with severe congenital f.XIII deficiency, only the present method was sensitive enough to detect any f.XIII-activity (about 0.1%), and in a patient with an inhibitor against f.XIIIa, the dansylcadaverine method failed to detect this. The present method is too laborious for routine screening, but is recommended as an alternative references method. It may prove especially suitable to detect minute amounts of f.XIII.


Auditory-nerve integrity after middle-fossa acoustic-tumor removal.
We sought to investigate the functional integrity of the auditory nerve in patients with postoperative hearing loss after middle cranial fossa acoustic-tumor removal in a case-series descriptive study. The study setting was a tertiary referral center, a private otologic practice. The study population comprised seven patients who underwent a middle-cranial-fossa approach for unilateral acoustic-tumor resection and sustained postoperative anacusis with an anatomically intact auditory nerve. Four were men and three women; they ranged in age from 30 to 60 years; all underwent surgery between 1990 and 1994 and agreed to return to the center to participate in the study during 1995. Diagnostic electrical promontory stimulation was used to determine the functional integrity of the auditory nerve. Our main outcome measures were the presence or absence of discrete tone perception, electrical threshold, maximum acceptable level and dynamic range, gap detection and temporal difference limen during electrical promontory stimulation. Three of the seven patients demonstrated positive responses to electrical promontory testing (e.g., discrete tone perception). All three were able to perform the gap-detection and temporal difference limen tests. None of the preoperative characteristics was related to performance on promontory stimulation testing. We conclude that the middle cranial fossa approach permits anatomic--and, in some cases, functional auditory-nerve preservation. These data suggest that auditory rehabilitation in some patients who sustain anacusis after the middle cranial fossa approach to acoustic tumors, as in neurofibromatosis 2, may be provided with cochlear implantation.


Nickel-(II)-Catalyzed N-Formylation and N-Acylation of Amines.
A highly efficient protocol of Ni(II) metal complex, [Ni(quin)2], catalyzing N-formylation and N-acylation of amines with moderate to excellent yields, using N,N-dimethylformamide and N,N-dimethylacetamide in the presence of imidazole, is described here. The protocol shows broad substrate scope for aliphatic, aromatic, and heterocyclic amines.


[Anti-inflammatory effect of hydroxy-9-ellipticine].
The anti-inflammatory activity of 9-hydroxy-ellipticine is studied through various experimental models. It is particularly interesting in the guinea-pig cutaneous erythema, in the carragenin-induced oedema and in the adjuvant-induced polyarthritis in the rat. It appears in immune or non-immune induced inflammatory responses. Its important thymolytic activity can be related to its immunosuppressive effect.


Perspectives in biomolecular therapeutic intervention in cancer: from the early to the new strategies with type I interferons.
Interferon (IFN) was the first cytokine produced by recombinant DNA technology used in wide-spread clinical treatment of infectious diseases as well as malignancies. The IFN clinical potential was clearly realized from the outset. However, IFN represents one of the most controversial drugs of our time, as remarkable cycles of promise and disappointment have affected its development and use. Considerable evidence regarding anti-tumor activities of IFNs has been reported. In this paper we focus on molecular bases of the IFN system that may relate to its antitumor activities. Many of the numerous genes transcriptionally activated by IFNs have been shown to encode proteins that activate immune recognition of tumor cells, directly or indirectly exert tumor suppressor activity and/or control tumor cell cycle and programmed cell death. In addition, a physiological relevant function for endogenous type I IFN in cancer immunoediting process and a new way to IFN clinical use based on gene therapy or vaccine-like approaches have recently been suggested. The identification of selected tissue-specific and/or tumor-specific target pathways as well as of different type I IFN tumor escape and resistance mechanisms may provide novel approaches in the search for new IFN-based therapeutic strategies to circumvent cancer disease or improve clinical outcome. Promising IFN treatment has been recently defined by using novel pharmaceutical preparations with a more favourable pharmacokinetic response, also in combination with other bioreagents or other modalities of therapy. Translational research, linking both basic and clinical research, will lead to a new rationale for the use of IFN in cancer therapy.


Type 1 diabetes mellitus: primary, secondary, and tertiary prevention.
We have entered the era of clinical trials to prevent type 1 diabetes mellitus (T1DM). Before 1922, when insulin was first given to a patient with diabetes, a diagnosis of T1DM was considered a death sentence. Advances in treatment for subjects with diabetes are not yet sufficient to prevent the deleterious impact of diabetes on both day-to-day activities and the early morbidity and mortality still associated with the disease. We now understand a great deal about blood glucose regulation and potential health complications associated with long-term T1DM, but the mystery of why, or the pathogenesis of this devastating disease, remains elusive. Great strides toward unraveling this mystery have been made over the past several decades. Even without definitive answers, we are moving from the period of discovery and animal research to the era of clinical trials. In this review, we wish to convey the palpable excitement in the field. It is time to determine if we can safely change the course of T1DM.


Pipoxolan inhibits CL1-5 lung cancer cells migration and invasion through inhibition of MMP-9 and MMP-2.
Pipoxolan has been reported to have antitumor activity. However, the effects of pipoxolan on lung cancer cell metastasis remains unclear. This study examined the anti-metastatic effects of pipoxolan on lung adenocarcinoma cancer cells (i.e. CL1-5, CL1-0, and A549) and its underlying molecular mechanisms. Firstly, CL1-5 cell migration was markedly suppressed by pipoxolan when examined by wound scratch assay. Furthermore, transwell and matrigel invasion assays revealed that pipoxolan inhibited lung cancer cells (i.e. CL1-5, CL1-0, and A549) migration/invasion, and showed more sensitive to CL1-5 cell. Therefore, the anti-metastatic effects from pipoxolan have been focused on CL1-5 lung cancer cells. Secondly, these observations have been associated with the reduction in the activities and expressions of matrix metalloproteinase (MMP)-2 and -9 in CL1-5 lung cancer cells. Lastly, pipoxolan administration significantly inhibited phosphorylation c-Jun N-terminal kinase (p-JNK), and p38 MAP Kinase (MAPK) of CL1-5 cells. Based on these results, our results showed that management CL1-5 cells with pipoxolan down-regulated phosphorylation JNK and p38, and then, MMP-2 and -9. These results suggest that pipoxolan might have a new therapeutic potential for anti-metastatic effects in lung cancer cells.


Value assessment of immuno-oncology in the treatment of rare tumors in the era of accelerated conditional approvals.
Aim: To conduct a value assessment of an immuno-oncology (IO) therapy for a rare cancer and evaluate whether existing frameworks consider challenges associated with valuing IOs for rare cancers. Materials & methods: Value frameworks developed by American Society of Clinical Oncologists, Memorial Sloan Kettering Cancer Center and National Comprehensive Cancer Network were used to estimate the value of an IO therapy in a rare cancer based on single-arm trial data and retrospective studies. Results: Paucity of direct evidence comparing rare cancer treatments and lack of acceptance of indirect comparisons hinder appropriate value assessment. Measurement of value based on short-term outcomes may not capture the value of IOs, where survival is often characterized by a plateau. Conclusion: Further work is required to factor in nuances associated with rare cancers and guide end users of the frameworks. To capture true value, multiple or more holistic value assessments are required.


Fibre optic coupler as a detector for microfluidic applications.
A new construction of a fibre optic coupler is presented in the paper. Two polymer optical fibres were used to build a coupler in which coupling efficiency of optical power depends on the refractive index of liquid delivered to a microchannel formed by the fibres. The coupler was tested as a detector in saccharose concentration measurements, and was used in absorbance measurements. A red light emitting diode and a spectrometer were used as a light source and a photodetector, respectively. Experiments confirmed that the coupler can be used for the real time monitoring of the changes in the refractive index of a saccharose solution exhibiting repeatable changes in the signal, with no hysteresis. Absorbance tests were performed with a solution of bromothymol blue at different pH.


Prolonged mivacurium-induced neuromuscular block. Case report.
A 38-year-old white male patient was admitted to the hospital for elective surgery. General anesthesia was performed with propofol, alfentanil, nitrous oxide and mivacurium as neuromuscular blocker. Seven months before he had the same surgery without anesthetic problems (he received: propofol, vecuronium bromide, fentanil, nitrous oxide). Neuromuscular monitoring was carried out because the patient was included in a study assessing the clinical effect of mivacurium in microlaryngoscopy surgery. After mivacurium administration the first signs of recovery from neuromuscular block were observed after 255 min. The tracheal tube was withdrawn after 410 min from mivacurium administration, at this time the T1 was 80% of the control values and 7 min later the T1 reached 98%.


Enhancement of antitumor potency of extracellular vesicles derived from natural killer cells by IL-15 priming.
Natural killer (NK) cells are the key subset of innate-immunity lymphocytes; they possess antitumor activities and are used for cancer immunotherapy. In a previous study, extracellular vehicles (EVs) from NK-92MI cells were isolated and exploited for their ability to kill human cancer cells in vitro and in vivo (multiple injection methods). Here, the potential of NK-cell-derived EVs (NK-EVs) for immunotherapy was improved by priming with interleukin (IL)-15. NK-EVs were isolated from the culture medium without or with IL-15 (NK-EVsIL-15) by ultracentrifugation and were purified via density gradient ultracentrifugation. In addition, NK-EVs and NK-EVsIL-15 were characterized by transmission electron microscopy, nanoparticle-tracking analysis, and western blotting. Flow cytometry, bioluminescence imaging, and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were performed for apoptosis, protein expression, cell proliferation, and cytotoxicity analyses. Furthermore, xenograft tumor-bearing mice were injected with PBS, NK-EVs, or NK-EVsIL-15 intravenously five times. Tumor growth was monitored using calipers and bioluminescence imaging. Toxicity of the nanoparticles was evaluated by measuring the body weight of the mice. NK-EVsIL-15 showed significantly higher cytolytic activity toward human cancer cell lines (glioblastoma, breast cancer, and thyroid cancer) and simultaneously increased the expression of molecules associated with NK-cell cytotoxicity. When compared with NK-EVs, NK-EVsIL-15 significantly inhibited the growth of glioblastoma xenograft cells in mice. In addition, both NK-EVs and NK-EVsIL-15 were not significantly toxic to either normal cells or mice. IL-15 may improve the immunotherapeutic effects of NK-EVs, thus improving the applications of NK-EVs in the future.