Some properties and the complete primary structures of two reduced and S-carboxymethylated polypeptides (S5C1 and S5C10) from Dendroaspis jamesoni kaimosae (Jameson's mamba) venom.
Two polypeptides (protein S5C1 and toxin S5C10) were purified from Dendroaspis jamesoni kaimosae venom. Whereas protein S5C1 comprises 61 amino acid residues, toxin S5C10 contains 58 and they each comprise four disulphide bridges. The complete primary structures of the two polypeptides have been elucidated. The sequences of protein S5C1 and toxin S5C10 are structurally homologous to the short neurotoxins Type I, but they are much less toxic. In toxin S5C10 one of the functionally invariant amino acid residues, lysine 26, of the Type I neurotoxin has been replaced by a serine. In contrast protein S5C1 has the feature that it contains ten or eleven structurally invariant amino acids and apparently only one of the five functionally invariant residues.


One abnormal value or vomiting after oral glucose tolerance test in pregnancy: incidence and impact on maternal-fetal outcomes.
To analyze pregnancy outcomes of women with one abnormal value (OAV) during oral glucose tolerance test (OGTT) or OGTT-intolerance, compared with gestational diabetes mellitus (GDM) and normal glucose tolerance (NGT) pregnant women, according to whether they received any health intervention or not. An observational retrospective study was designed including pregnant women who gave birth at Hospital del Mar, Barcelona (Spain) during December/2014-July/2018. Baseline characteristics, pregnancy outcomes and health interventions were obtained from a database collected previously for other study. Inclusion criteria were singleton pregnancies with OAV or OGTT-intolerants who gave birth at the Hospital. GDM screening followed a two-step approach: 50 g O'Sullivan test and 100 g 3-hour OGTT if the former was abnormal. From a total of 2,662 pregnancies, 326 (12.2%) had GDM, 87 OAV (3.3%), 65 OGTT intolerance (2.4%) and 2,184 were NGT women. First trimester HbA1c in both OAV and OGTT-intolerant women was significantly higher than in NGT group, and significantly lower than in GDM pregnants. No differences in obstetric outcomes were found between OGTT-intolerants and NGT/GDM groups. Treated OGTT-intolerants had greater gestational age at delivery than non-treated ones (weeks, 39.6 ± 1.2 vs 38.0 ± 4.0, respectively). In OAV women, significant differences were observed in newborns' birthweight (g, 3227.3 ± 500.8 vs 3351.1 ± 436.7, vs GDM) and gestational age at birth (weeks, 38.7 ± 1.8 vs 39.3 ± 1.9, vs NGT), but not in macrosomia/pre-eclampsia. No differences were found according to treatment in OAV. OAV and OGTT-intolerants account for a third of pregnant women referred to Diabetes Unit. Their rates of preterm birth, pre-eclampsia and macrosomia were not different from NGT or GDM women.


Neuroimaging-Based Phenotyping of the Autism Spectrum.
Recent advances in neuroimaging have offered a rich array of structural and functional markers to probe the organization of regional and large-scale brain networks. The current chapter provides a brief introduction into these techniques and overviews their contribution to the understanding of autism spectrum disorder (ASD), a neurodevelopmental condition associated with atypical social cognition, language function, and repetitive behaviors/interests. While it is generally recognized that ASD relates to structural and functional network anomalies, the extent and overall pattern of reported findings have been rather heterogeneous. Indeed, while several attempts have been made to label the main neuroimaging phenotype of ASD (e.g., 'early brain overgrowth hypothesis', 'amygdala theory', 'disconnectivity hypothesis'), none of these frameworks has been without controversy. Methodological sources of inconsistent results may include differences in subject inclusion criteria, variability in image processing, and analysis methodology. However, inconsistencies may also relate to high heterogeneity across the autism spectrum itself. It, therefore, remains to be investigated whether a consistent imaging phenotype that adequately describes the entire autism spectrum can, in fact, be established. On the other hand, as previous findings clearly emphasize the value of neuroimaging in identifying atypical brain morphology, function, and connectivity, they ultimately support its high potential to identify biologically and clinically relevant endophenotypes.


Chick wing innervation. III. Formation of axon collaterals in developing peripheral nerves.
Axon navigation during vertebrate limb innervation has been shown to be associated with position-dependent changes in size and complexity of the axon growth cones, and sometimes with bifurcation of terminal growth cones and axon branching (Hollyday and Morgan-Carr, companion paper). We have further examined axon branching and asked whether it extends to the projection of collaterals to different nerves. Injections of horseradish peroxidase or Dil were made into individual peripheral nerves in the wings of chick embryos at stages 28-35, and the trajectories of solidly labeled axons were traced proximally from the injection site in tissue sections. During stages when the peripheral nerves were first forming in the shoulder region, collaterals of retrogradely labeled axons were frequently observed to project into uninjected nerves proximal to the injection site. These two-nerve collaterals were formed by a small percentage of axons in a high percentage of the embryos studied and could occur in both motor and sensory axons. Two-nerve collateral projections were observed between nerves separated along both the proximodistal and anteroposterior axes of the limb, but they were limited in spatial extent to nerves supplying adjacent limb regions and were never seen between nerves projecting to widely disparate regions of the limb. Collaterals were not seen at the plexus projecting to both dorsal and ventral pathways. The apparent frequency of two-nerve collaterals was found to decline progressively from stage 28-29 to stage 32; no two-nerve collaterals were seen in the proximal wing at stage 33 and older. The mechanism of their elimination is presently unknown.(ABSTRACT TRUNCATED AT 250 WORDS)


Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating carcinoma.
We report 25 cases of a peculiar sclerosing epithelioid variant of fibrosarcoma (SEF) simulating an infiltrating carcinoma. The tumors occurred primarily in the deep musculature and were frequently associated with the adjacent fascia or periosteum. The patients' ages were 14 to 87 years (median, 45). Fourteen were male and 11 female. The tumors were located in the lower extremities and limb girdles (12 cases), trunk (9), upper limb girdles (2), and neck (2). They measured 2 to 14.5 cm in greatest dimension (median size, 7 cm) and were gray to white and firm. Histologically, the lesions were characterized by a proliferation of rather uniform, small, slightly angulated, round to ovoid epithelioid cells with sparse, often clear cytoplasm arranged in distinct nests and cords. In all cases there was prominent hyaline sclerosis, sometimes reminiscent of osteoid or cartilage and foci of conventional fibrosarcoma. Occasional myxoid zones with cyst formation and foci of hyaline cartilage, calcification, and metaplastic bone were also seen. Mitotic figures were generally scarce. Vimentin was detected in 13 of 14 cases, epithelial membrane antigen in seven, S100 protein in four, and neuron-specific enolase in two. Cytokeratins were detected with AE1/AE3 and CAM 5.2 in two cases. Leukocyte common antigen, CD68 antigen, HMB45, desmin, and alpha-smooth muscle actin were negative in all cases. In 13 of 14 cases, 75% or more of the cells stained for proliferating cell nuclear antigen (PCNA). Ki67 immunostaining with MIB 1 showed low proliferative activity in all cases, averaging 5% of tumor cells or less. In all cases, p53 was detected by immunohistochemical methods; bcl-2, an antiapoptosis marker, was detected in more than 90% of the cells in 11 of 12 cases. Ultrastructurally, both the epithelioid and spindled tumor cells had features of fibroblasts. Follow-up in 16 cases ranging from 13 months to 17 years 3 months (median, 11 years 4 months) revealed persistent disease or local recurrences in 53% of patients and metastases in 43%. The metastases were to the lungs (4 cases), skeleton (3), chest wall/pleura (3), pericardium (1), and brain (1). Four patients died of disease, four were alive with disease, two were known to be alive but disease status unknown, and six had no evidence of further disease at last follow-up. The data suggest that SEF is a relatively low-grade fibrosarcoma; yet it is fully malignant despite the presence of histologically benign-appearing foci. The proliferation markers PCNA and Ki67 did not correlate with prognosis.(ABSTRACT TRUNCATED AT 400 WORDS)


Transplantation of Descemet's membrane carrying viable endothelium through a small scleral incision.
To design a technique for transplantation of the Descemet's membrane (DM) as a carrier for its endothelium, while maintaining the low-astigmatic recipient anterior corneal curvature. In a human eye bank eye model, recipient eyes (n = 15) had a 5.0-mm scleral tunnel incision made, extending 1.0 mm into the peripheral cornea. A 9.0-mm-diameter Descemeto rhexis was created, i.e., a circular portion of DM was stripped from the posterior stroma. With use of a custom-made inserter, a 9.0-mm-diameter donor DM carrying autologous donor endothelium was brought into the anterior chamber and positioned against the recipient posterior stroma. The procedure was evaluated by keratometry, endothelial vital and supravital staining, and light microscopy. Mean postoperative astigmatism was 1.0 D (+/-0.6 D). Implanted donor DM showed an intact endothelial cell layer, with 3.4% (+/-1.1%) dispersed focal cell death. Microscopy showed normal endothelial cell morphology and complete apposition of the donor DM against the recipient posterior stroma. DM can be transplanted in vitro with acceptable damage to the donor endothelium and with little induced astigmatism.


Opinion: emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis.
Malignant tumours can spread to lymph nodes through lymphatic vessels. Recent studies show that tumours produce a range of growth factors that directly or indirectly stimulate lymphatic vessel growth (lymphangiogenesis) and lymphatic metastasis. These findings indicate that tumour lymphangiogenesis, similar to haemangiogenesis, is a complex process that is regulated by multiple growth factors. Understanding the underlying mechanisms by which tumours induce lymphangiogenesis might provide important information for the therapeutic intervention of metastatic spread.


Immunohistochemical detection of cervical lymph node micrometastases from T2N0 tongue cancer.
These results indicate that extensive, multiple cervical micrometastases occurred from an early stage in patients with T2N0 tongue cancer. The presence of micrometastases suggests the necessity of preventive neck dissection for Level I-IV nodes as a radical treatment. Cervical lymph node metastases occur with a relatively high frequency in patients with T2N0 squamous cell carcinoma of the tongue, and control of the metastases greatly influences the prognosis of patients. In this study, micrometastases in the cervical lymph nodes were investigated to clarify the necessity and required extent of preventive neck dissection. We investigated micrometastases in 24 subjects who had previously been diagnosed with T2N0 tongue cancer. We performed immunostaining with anti-cytokeratin antibody cocktail AE1/AE3 of sections of 401 paraffin-embedded lymph nodes obtained from these patients. Micrometastases were observed in 14 patients (58%) and were most abundant in Level II nodes (n=11; 46%). Micrometastases were observed in the Level IV nodes of 3 patients (13%), and upstaging to pN2b occurred in 7 patients (29%).


Asymmetric distribution of gangliosides in rat renal brush-border and basolateral membranes.
Highly enriched brush-border and basolateral membranes isolated from rat renal cortex were used to study the distribution of endogenous gangliosides in the two distinct plasma membrane domains of epithelial cells. These two membrane domains differed in their glycolipid composition. The basolateral membranes contained more of both neutral and acidic glycolipids, expressed on a protein basis. In both membranes, the neutral glycolipids corresponding to mono-, di-, tri- and tetraglycosylceramides were present. The basolateral membranes contained more diglycosylceramide than the brush-border membranes. The major gangliosides found were GM4, GM3, and GD3 with minor amounts of GM1 and GD1a. The latter were identified and quantified by sensitive iodinated cholera toxin binding assays. When the distribution of individual gangliosides was calculated as a percent of total gangliosides, the brush-border membranes were enriched with GM3, GM1 and GD1a compared to the basolateral membranes, which were enriched with GD3 and GM4. The observation of a distinct distribution of glycolipids between brush-border and basolateral membranes of the same epithelial cell suggests that there may be a specific sorting and insertion process for epithelial plasma membrane glycolipids. In turn, asymmetric glycolipid biogenesis may reflect differences in glycolipid function between the two domains of the epithelial plasma membrane.


Transcriptome analysis of miRNA and mRNA in the livers of pigs with highly diverged backfat thickness.
Fat deposition is very important in pig production, and its mechanism is not clearly understood. MicroRNAs (miRNAs) play critical roles in fat deposition and energy metabolism. In the current study, we investigated the mRNA and miRNA transcriptome in the livers of Landrace pigs with extreme backfat thickness to explore miRNA-mRNA regulatory networks related to lipid deposition and metabolism. A comparative analysis of liver mRNA and miRNA transcriptomes from pigs (four pigs per group) with extreme backfat thickness was performed. We identified differentially expressed genes from RNA-seq data using a Cufflinks pipeline. Seventy-one differentially expressed genes (DEGs), including twenty-eight well annotated on the porcine reference genome genes, were found. The upregulation genes in pigs with higher backfat thickness were mainly involved in fatty acid synthesis, and included fatty acid synthase (FASN), glucokinase (GCK), phosphoglycerate dehydrogenase (PHGDH), and apolipoprotein A4 (APOA4). Cytochrome P450, family 2, subfamily J, polypeptide 34 (CYP2J34) was lower expressed in pigs with high backfat thickness, and is involved in the oxidation of arachidonic acid. Moreover, 13 differentially expressed miRNAs were identified. Seven miRNAs were associated with fatty acid synthesis, lipid metabolism, and adipogenic differentiation. Based on comprehensive analysis of the transcriptome of both mRNAs and miRNAs, an important regulatory network, in which six DEGs could be regulated by differentially expressed miRNAs, was established for fat deposition. The negative correlate in the regulatory network including, miR-545-5p and GRAMD3, miR-338 and FASN, and miR-127, miR-146b, miR-34c, miR-144 and THBS1 indicate that direct suppressive regulation may be involved in lipid deposition and energy metabolism. Based on liver mRNA and miRNA transcriptomes from pigs with extreme backfat thickness, we identified 28 differentially expressed genes and 13 differentially expressed miRNAs, and established an important miRNA-mRNA regulatory network. This study provides new insights into the molecular mechanisms that determine fat deposition in pigs.


Sequencing of laminin B chain cDNAs reveals C-terminal regions of coiled-coil alpha-helix.
cDNAs for laminin B chains have been isolated from a parietal endoderm cDNA library in pUC8 and pUC9. Identification is based on: ability to direct the synthesis in Escherichia coli of polypeptides carrying laminin antigen determinants, in vitro translation of hybrid selected mRNA, and hybridization to high mol. wt. RNA differentially expressed in cells synthesizing large amounts of laminin. The plasmid pPE9 hybrid selects mRNA for the B2 (mol. wt. 185 000) chain and provides 217 residues of C-terminal amino acid sequence. The plasmids pPE386 and 49 both hybrid select mRNAs for the B1a (mol. wt. 205 000) and B1b (mol. wt. 200 000) chains. These two cDNAs are identical over much of their sequence, but pPE386 includes 133 nucleotides of 3' non-coding sequence and a poly(A) tail. Together they provide 495 residues of C-terminal amino acid sequence. Analysis of the predicted sequences reveals a striking heptad repeat, with a high probability that residues a and d are hydrophobic. Such a repeat is typical of the coiled-coil alpha-helices found in proteins such as myosin, tropomyosin and desmin (2-stranded) and fibrinogen (3-stranded).


Conserved sequence blocks 5' to start codons of plant mitochondrial genes.
Three sequence blocks of 10-12 bp are conserved in sequence and order 5' to putative start codons of several higher-plant mitochondrial genes. At least 25 examples were found, primarily associated with coxII, atp6, and orf25, in monocotyledons and dicotyledons. The proximal block can be 9 bp from start codons, and the three blocks generally occur within 100 bp 5' of start codons. In three examples 5' termini of the blocks represent recombination breakpoints, resulting in conservation of the blocks in resultant configurations. The two proximal blocks can form a secondary structure motif. The occurrence of the blocks near start codons, and conserved sequence and order, is consistent with a possible role in translation initiation or regulation.


[Histocompatibility HLA system of man. Considerations in the light of current concepts. VI. HLA-G antigen polymorphism].
The results of hitherto researches over gene products of HLA-G locus, i.e. membrane bound forms (M*HLA-G) and soluble forms (S*HLA-G) were verified. Current opinions connected with synthesis and molecular organisation of five HLA-G isoformic molecules (HLA-G1, -G2, -G3, -G4, -G5) were presented. The polymorphism of HLA-G gene and its expression were qualified. Special attention has been turned on presumably significant function of HLA-G in maintenance of maternal-placenta immunological tolerance, binding of monomeric peptides, and antigens presentation, taking into consideration cytomegaloviruses (CMV). In spite of significant progress in the understanding of mutual relationship between mother and placenta many phenomena with participation of HLA-G gene products, especially in pathological conditions, are still unknown.


Video based non-contact monitoring of respiratory rate and chest indrawing in children with pneumonia.
Objective.Pneumonia is the single largest cause of death in children worldwide due to infectious diseases. According to WHO guidelines, fast breathing and chest indrawing are the key indicators of pneumonia in children requiring antibiotic treatments. The aim of this study was to develop a video based novel method for simultaneous monitoring of respiratory rate and chest indrawing without upsetting babies.Approach.Respiratory signals, corresponding to periodic movements of chest-abdominal walls during breathing, were extracted by analyzing RGB (red, green, blue) components in video frames captured by a smartphone camera. Respiratory rate was then obtained by applying fast Fourier transform on the de-noised respiratory signal. Chest indrawing was detected by analysing relative phases of regional chest-abdominal wall mobility. The performance of the developed algorithm was evaluated on both healthy and pneumonia children.Main results.The proposed method can measure respiratory rate with an overall mean absolute error of 1.8 bpm in the range 18-105 bpm. Phase difference between regional chest wall movements in the chest indrawing (pneumonia) cases was found to be 143 ± 23.9 degrees, which was significantly higher than that in the healthy cases 52.3 ± 32.6 degrees (p< 0.001).Significance.Being non-intrusive and non-subjective, this computer-aided method can be useful in the monitoring for respiratory rate and chest indrawing for the diagnosis of pneumonia and its severity in children.


Dietary intake assessments in epidemiology: can we know what we are measuring?
We discuss fundamental assumptions required for the validation of dietary questionnaire assessments, using latent variable models. We discuss some methodological aspects of latent variable modelling in terms of the triad method, for comparisons between questionnaire assessments, food consumption records and/or biomarkers. In particular, we address the recent proposal (Frazer et al) that biases due to correlated random errors between different measurement types could be overcome by using two biomarkers as instrumental variables, as recently proposed by. The instrumental variable approach proposed by Frazer et al, but also other validation models proposed so far, require the assumption that questionnaire measurements are specific for a defined type of food or nutrient intake (latent variable of interest) - that is, conditionally on the true intake levels of this food or nutrient the questionnaire measurements should have no association with intakes of any other dietary component. More methodological research is needed on the design of multivariate validation studies that might allow the examination of measurement specificity in practice.


Novel D-ring analogues of podophyllotoxin as potent anti-cancer agents.
Several D-ring modified analogues of podophyllotoxin were prepared viz semi-synthesis starting from naturally occurring podophyllotoxin and determined their in vitro anti-cancer activity. Most of the analogues have shown good activity towards human cancer cell lines.


Randomized trial of stent placed above and across the sphincter of Oddi in malignant bile duct obstruction.
Placement of stents above an intact sphincter of Oddi might prevent migration of bacteria and deposition of organic material into the stent. In patients with malignant obstructive jaundice prolongation of function time of the stent would be expected if it is placed above the sphincter of Oddi. Thirty-four patients were randomized to stent placement either above (n = 17) or across (n = 17) the sphincter of Oddi. Straight 10F gauge Teflon stents were used. The patients were evaluated clinically and biochemically at monthly intervals during follow-up. The median stent function time (i.e., the time from insertion of the stent until stent replacement, patient death, or study termination) were 110 days (25th to 75th percentiles, 61 to 320 days) for stents placed above the sphincter of Oddi and 126 days (25th to 75th percentiles, 89 to 175 days) for stents placed across the sphincter of Oddi (nonsignificant [NS]). Stent replacement rates were 58.8% (10 of 17) in patients with stents placed above the sphincter and 29.4% (5 of 17) in patients with stents placed across the sphincter (NS). Significantly more patients in the former group experienced stent migration (9 vs. 2, p = 0.026). The median time from stent insertion until replacement of the stents placed above and across the sphincter of Oddi were 82 days (25th to 75th percentiles, 31 to 185 days) and 89 days (25th to 75th percentiles, 13 to 150 days), respectively (NS). No significant difference in overall stent performance between the two groups was found, although more stents placed above the sphincter of Oddi migrated. The time until dysfunction of the stent might be increased if migration of stents placed inside the common bile duct could be avoided.


Structural and Functional Changes of Reconstituted High-Density Lipoprotein (HDL) by Incorporation of α-synuclein: A Potent Antioxidant and Anti-Glycation Activity of α-synuclein and apoA-I in HDL at High Molar Ratio of α-synuclein.
α-synuclein (α-syn) is a major culprit of Parkinson's disease (PD), although lipoprotein metabolism is very important in the pathogenesis of PD. α-syn was expressed and purified using the pET30a expression vector from an E. coli expression system to elucidate the physiological effects of α-syn on lipoprotein metabolism. The human α-syn protein (140 amino acids) with His-tag (8 amino acids) was expressed and purified to at least 95% purity. Isoelectric focusing gel electrophoresis showed that the isoelectric point (pI) of α-syn and apoA-I were pI = 4.5 and pI = 6.4, respectively. The lipid-free α-syn showed almost no phospholipid-binding ability, while apoA-I showed rapid binding ability with a half-time (T1/2) = 8 ± 0.7 min. The α-syn and apoA-I could be incorporated into the reconstituted HDL (rHDL, molar ratio 95:5:1:1, palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol:apoA-I:α-syn with the production of larger particles (92 Å) than apoA-I-rHDL (86 and 78 Å) and α-syn-rHDL (65 Å). An rHDL containing both apoA-I and α-syn showed lower α-helicity around 45% with a red shift of the Trp wavelength maximum fluorescence (WMF) from 339 nm, while apoA-I-HDL showed 76% α-helicity and 337 nm of WMF. The denaturation by urea addition showed that the incorporation of α-syn in rHDL caused a larger increase in the WMF than apoA-I-rHDL, suggesting that the destabilization of the secondary structure of apoA-I by the addition of α-syn. On the other hand, the addition of α-syn induced two-times higher resistance to rHDL glycation at apoA-I:α-syn molar ratios of 1:1 and 1:2. Interestingly, low α-syn in rHDL concentrations, molar ratio of 1:0.5 (apoA-I:α-syn), did not prevent glycation with more multimerization of apoA-I. In the lipid-free and lipid-bound state, α-syn showed more potent antioxidant activity than apoA-I against cupric ion-mediated LDL oxidation. On the other hand, microinjection of α-syn (final 2 μM) resulted in 10% less survival of zebrafish embryos than apoA-I. A subcutaneous injection of α-syn (final 34 μM) resulted in less tail fin regeneration than apoA-I. Interestingly, incorporation of α-syn at a low molar ratio (apoA-I:α-syn, 1:0.5) in rHDL resulted destabilization of the secondary structure and impairment of apoA-I functionality via more oxidation and glycation. However, at a higher molar ratio of α-syn in rHDL (apoA-I:α-syn = 1:1 or 1:2) exhibited potent antioxidant and anti-glycation activity without aggregation. In conclusion, there might be a critical concentration of α-syn and apoA-I in HDL-like complex to prevent the aggregation of apoA-I via structural and functional enhancement.


Site-specific and developmental expression of pannexin1 in the mouse nervous system.
Until recently, members of the connexin gene family were believed to comprise the sole molecular component forming gap junction channels in vertebrates. The recent discovery of the pannexin gene family has challenged this view, as these genes may encode for a putative second class of gap junction proteins in vertebrates. The expression of pannexin genes overlaps with those cellular networks known to exhibit a high degree of gap junctional coupling. We investigated the spatio-temporal mRNA distribution of one member of this gene family, pannexin1 (Panx1), in the brain and retina of mice using quantitative real-time polymerase chain reaction and a combination of in situ hybridization and immunohistochemistry for cellular resolution. Our results demonstrate a widespread expression of Panx1 in the brain, retina and other non-neuronal tissues. In the cortex, cerebellum and eye, Panx1 is expressed at early embryonic time points and peaks around embryonic day 18 followed by a decline towards adulthood. Most notably, Panx1 is detectable in neurons of many brain nuclei, which are known to be coupled by gap junctions as well as in previously unrecognized areas. Abundant expression was found in the adult hippocampal and neocortical pyramidal cells and interneurons, neurons of the reticular thalamus, the inferior olive, magnocellular hypothalamic neurons, midbrain and brain stem motoneurons, Purkinje cells and the retina.


Acidosis and cancer: from mechanism to neutralization.
The extracellular pH of solid tumors is unequivocally acidic due to a combination of high rates of lactic acid production (a consequence of fermentative glycolytic metabolism) and poor perfusion. This has been documented by us and others in a wide variety of solid tumor models, primarily using magnetic resonance spectroscopic imaging (MRSI). This acidity contributes to tumor progression by inducing genome instability, promoting local invasion and metastases, inhibiting anti-tumor immunity, and conferring resistance to chemo- and radio-therapies. Systemic buffer therapies can neutralize tumor acidity and has been shown to inhibit local invasion and metastasis and improve immune surveillance in a variety of cancer model systems. This review will revisit the causes and consequences of acidosis by summarizing strategies used by cancer cells to adapt to acidosis, and how this acidity associated with carcinogenesis, metastasis, and immune function. Finally, this review will discuss how neutralization of acidity can be used to inhibit carcinogenesis and metastasis and improve anti-cancer immunotherapy.


In vitro characterization of skeletal muscle beta-adrenergic receptors coupled to adenylate cyclase.
[3H]Dihydroalprenolol, a potent beta-adrenergic antagonist, was used to identify the adenylate cyclase-coupled beta-adrenoceptors in isolated membranes of rat skeletal muscle. The receptor sites, as revealed by [3H]dihydroalprenolol binding, were predominantly localized in plasmalemmal fraction. That skeletal muscle fraction may also contain the plasmalemma of other intramuscular cells, especially that of blood vessels. Hence, the [3H]dihydroalprenolol binding observed in that fraction may be due partly to its binding to the plasmalemma of blood vessels. Small but consistent binding was also observed in sarcoplasmic reticulum and mitochondria. The level of [3H]dihydroalprenolol binding in different subcellular fractions closely correlated with the level of adenylate cyclase present in those fractions. The binding of [3H]dihydroalprenolol to plasmalemma exhibited saturation kinetics. The binding was rapid, reaching equilibrium within 5 min, and it was readily dissociable. From the kinetics of binding, association (K1) and dissociation (K2) rate constants of 2.21 . 10(7) M-1 . min-1 and 3.21 . 10(-1) min-1, respectively, were obtained. The dissociation constant (Kd) of 15 mM for [3H]dihydroalprenolol obtained from saturation binding data closely agreed with the Kd derived from the ratio of dissociation and association rate constants (K2/K1). Several beta-adrenergic agents known to be active on intact skeletal muscle also competed for [3H]dihydroalprenolol binding sites in isolated plasmalemma with essentially similar selectivity and stereospecificity. Catecholamines competed for [3H]dihydroalprenolol binding sites with a potency of isoproterenol greater than epinephrine greater than norepinephrine. A similar order of potency was noted for catecholamines in the activation of adenylate cyclase. Effects of catecholamines were stereospecific, (-)-isomers being more potent than (+)-isomers. Phenylephrine, an alpha-adrenergic agonist, showed no effect either on [3H]dihydroalprenolol binding or on adenylate cyclase. Known beta-adrenergic antagonists, propranolol and alprenolol, stereospecifically inhibited the [3H]dihydroalprenolol binding and the isoproterenol-stimulated adenylate cyclase. The Ki values for the antagonists determined from inhibition of [3H]dihydroalprenolol binding agreed closely with the Ki values obtained from the inhibition of adenylate cyclase. The data suggest that the binding of [3H]dihydroalprenolol in skeletal muscle membranes possess the characteristics of a substance binding to the beta-adrenergic receptor.


Cough Sensitivity to Several External Triggers is Associated with Multiple Non-respiratory Symptoms.
Enhanced responsiveness to external triggers is thought to reflect hypersensitivity of the cough reflex. It may involve an enhanced sensitivity of the afferent nerves in the airways and/or an abnormal processing of the afferent information by the central nervous system (CNS). The CNS processing of cough has been shown to involve the same regions as those in symptom amplification, a phenomenon that often manifests as multiple symptoms. The main purpose of the present study was to define whether the presence of several cough triggers is associated with multiple symptoms. 2131 subjects with current cough responding to two email surveys filled in a comprehensive questionnaire about social background, lifestyle, general health, doctors' diagnoses and visits, symptoms, and medication. Multiple symptoms was defined as three or more non-respiratory, non-mental symptoms. A carefully controlled multiple regression analysis revealed that the number of cough triggers was the only cough characteristic associating with multiple non-respiratory, non-mental symptoms [aOR 1.15 (1.12-1.19) per one trigger, p < 0.001]. Among the 268 subjects with current cough both in the first survey and in the follow-up survey 12 months later, the repeatability of the trigger sum was good with an intraclass correlation coefficient of 0.80 (0.75-0.84). The association between the number of the cough triggers and multiple symptoms suggests that the CNS component of cough hypersensitivity may be a manifestation of non-specific alteration in the CNS interpretation of various body sensations. The number of cough triggers is a repeatable measure of cough sensitivity.


Retrieval of distally migrated coil using stent retriever and proximal aspiration.
Endovascular coiling has become the preferred treatment of many centers for the management of both ruptured and unruptured aneurysms. Coil migration is a rare complication that can lead to vessel occlusion in 90% of the cases. Endovascular techniques for coil retrieval have shown less complication rates than open surgery. Stent retriever devices have been successfully used for the retrieval of proximally migrated coils, however, distally migrated coils still represent a challenge with greater risk of complications. In the present technical video 1, we demonstrate the successful retrieval of a distally M3 migrated coil using a 3 mm Trevo XP ProVue stent riever (Stryker Neurovascular, Fremont, CA, USA) in combination with proximal aspiration. neurintsurg;13/9/860/V1F1V1Video 1.


Maternal and fetal leptin, adiponectin levels and associations with fetal insulin sensitivity.
It remains uncertain whether leptin and adiponectin levels are correlated in maternal vs. fetal circulations. Little is known about whether leptin and adiponectin affect insulin sensitivity during fetal life. In a prospective singleton pregnancy cohort (n = 248), we investigated leptin and adiponectin concentrations in maternal (at 24-28 and 32-35 weeks of gestation) and fetal circulations, and their associations with fetal insulin sensitivity (glucose/insulin ratio, proinsulin level). Comparing concentrations in cord vs. maternal blood, leptin levels were 50% lower, but adiponectin levels more than doubled. Adjusting for gestational age at blood sampling, consistent and similar positive correlations (correlation coefficients: 0.31-0.34, all P < 0.0001) were observed in leptin or adiponectin levels in maternal (at 24-28 or 32-25 weeks of gestation) vs. fetal circulations. For each SD increase in maternal plasma concentration at 24-28 weeks, cord plasma concentration increased by 12.7 (95% confidence interval 6.8-18.5) ng/ml for leptin, and 2.9 (1.8-4.0) µg/ml for adiponectin, respectively (adjusted P < 0.0001). Fetal insulin sensitivity was negatively associated with cord blood leptin (each SD increase was associated with a 5.4 (2.1-8.7) mg/dl/µU/ml reduction in cord plasma glucose/insulin ratio, and a 5.6 (3.9, 7.4) pmol/l increase in proinsulin level, all adjusted P < 0.01) but not adiponectin (P > 0.4) levels). Similar associations were observed in nondiabetic full-term pregnancies (n = 211). The results consistently suggest a maternal impact on fetal leptin and adiponectin levels, which may be an early life pathway in maternal-fetal transmission of the propensity to obesity and insulin resistance.


Neutrophil adhesion molecule expression in familial Mediterranean fever: discordance between the intravascular regulation of beta2 integrin and L-selectin expression in acute attack.
To determine the surface expression of neutrophil beta2 integrin (CD11b/CD18) and L-selectin (LS) adhesion molecules in patients with familial Mediterranean fever (FMF) and to investigate the in vitro regulation of their expression in response to chemoattractant stimuli. Neutrophil surface expression of CD11b and LS molecules was analyzed by flow cytometry in anticoagulated whole blood drawn from FMF patients and normal controls, and the in vitro regulation of these molecules induced by the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP) was assayed. Patients during acute FMF attacks showed a statistically significant increased neutrophil surface CD11b compared with normal controls (mean fluorescence intensity: 22.8 +/- 13.7 vs 12.8 +/- 10.41, respectively; p = .03). There was no difference in LS expression between the groups. Neutrophils of FMF patients regulate CD11b and LS expression induced by chemoattractant (FMLP) stimulation to a degree similar to that in controls. beta2 Integrin is up-regulated during an acute attack of FMF in dissociation with LS expression, suggesting a unique nonchemoattractant-mediated neutrophil activation.


Lower airway smooth muscle contraction induced by Ptychodiscus brevis (red tide) toxin.
Ptychodiscus brevis toxin (PBTX) is produced by the organism Ptychodiscus brevis. This toxin causes a phenomenon that has come to be known as Florida red tide. It also stimulates neuronal sodium channels, resulting in activation of the cholinergic and adrenergic nerve endings of the autonomic nervous system in upper airway smooth muscle and rat vas deferens, respectively, as previously reported. It is the cholinergic stimulating action that has been implicated as a possible "triggering" event in bronchial asthma. This article concerns the investigation of whether PBTX may also affect lower airways and by what mechanism any contractile response to PBTX in lower airways may be induced. PBTX was found to elicit contractions in isolated canine lower airway smooth muscle. The threshold concentration was 0.15 microgram/ml, the peak response occurred at 6.0 micrograms/ml, and the concentration causing half-maximal response of the group was 0.57 microgram/ml. Pharmacologic analysis demonstrated that atropine (10(-6) mol/L) blocked the response to both PBTX and acetylcholine, tetrodotoxin (10(-7) mol/L) blocked the response to PBTX but not to acetylcholine, and verapamil (10(-5) mol/L) blocked the response to PBTX and reduced the response to acetylcholine. Four consecutive contractile responses to PBTX (3 micrograms/ml) produced rapid tachyphylaxis. The fourth contraction was 60% less than the initial response. A fifth response to PBTX after exposure to indomethacin (2.8 X 10(-6) mol/L) was increased and resulted in a contraction that was only 25% less than the initial response. The exogenous addition of prostaglandins (PG), PGE1 and PGE2, to indomethacin-treated lower airway strips selectively suppressed the contractile response to PBTX. Other PGs tested (PGA2, PGB2, PGD2, PGF2 alpha and PGI2) did not affect the PBTX response. These results indicate that PBTX produces spasm in lower airway smooth muscle and that it does this by stimulation of sodium channels in the cholinergic nerve fibers. The results also demonstrate a rapid reduction in the contractile response to PBTX. The results also demonstrate that the reduction is mediated by PGs of the E series.


ERQC autophagy: Yet another way to die.
A novel autophagy pathway eliminates nonnative polytopic membrane proteins from the endoplasmic reticulum that evade degradation by the ubiquitin proteasome system.


Histopathology combined with transcriptome analyses reveals the mechanism of resistance to Meloidogyne incognita in Cucumis metuliferus.
Root-knot nematodes (Meloidogyne spp.) cause serious threat to cucumber production. Cucumis metuliferus, a relative of cucumber, is reported to be resistant to Meloidogyne incognita, yet the underlying resistance mechanism remains unclear. In this study, the response of resistant C. metuliferus accession PI482443 following nematode infection was studied in comparison with susceptible C. sativus cv. Jinlv No.3. Roots of selected Cucumis seedings were analysed using histological and biochemical techniques. Transcriptome changes of the resistance reaction were investigated by RNA-seq. The results showed that penetration and development of the nematode in resistant plants were reduced when compared to susceptible plants. Infection of a resistant genotype with M. incognita resulted in a hypersensitive reaction. The induction of phenylalanine ammonia lyase and peroxidase activities after infection was greater in resistant than susceptible roots. Several of the most relevant genes for phenylpropanoid biosynthesis, plant hormone signal transduction, and the plant-pathogen interaction pathway that are involved in resistance to the nematode were significantly altered. The resistance in C. metuliferus PI482443 to M. incognita was associated with reduced nematode penetration, retardation of nematode development, and hypersensitive necrosis. The expression of genes resulting in the deposition of lignin, toxic compounds synthesis, cell wall reinforcement, suppression of nematode feeding and resistance protein accumulation, and activation of several transcription factors might all contribute to the resistance response to the pest. These results may lead to a better understanding of the resistance mechanism and aid in the identification of potential targets resistant to pests for cucumber improvement.


Solvent effects on protein motion and protein effects on solvent motion. Dynamics of the active site region of lysozyme.
The stochastic boundary molecular dynamics methodology is applied to the active site of the enzyme lysozyme. A comparison is made of in vacuo dynamics results from the stochastic boundary method and a full conventional molecular dynamics simulation of lysozyme. Excellent agreement between the two approaches is obtained. The influence of solvent on the residues in the active site region is explored and it is shown that both the structure and dynamics are affected. Of particular importance for the structure of the protein is the solvation of polar residues and the stabilization of like-charged ion pairs. The magnitude of the fluctuations is only slightly altered by the solvent; the overall increase in the root-mean-square fluctuations, relative to the vacuum run, is 11%. The solvent effect on dynamical properties is found not to be simply related to the solvent viscosity. Both the solvent exposure and dynamic aspects of protein-solvent interactions, including the relative time scales of the motions, are shown to play a role. The effects of the protein on solvent dynamics and structure are also observed to be significant. The solvent molecules around atoms in charged, polar and apolar side-chains show markedly different diffusion coefficients as well as exhibiting different solvation structures. One key example is the water around apolar groups, which is much less mobile than bulk water, or water solvating polar groups.


Inter-strain comparison by pyrolysis mass spectrometry of Staphylococcus aureus isolates associated with nosocomial infection.
Pyrolysis mass spectrometry was used to characterise Staphylococcus aureus isolates from an outbreak of postoperative wound infections on a mixed surgical ward. The PyMS results were compared with those of phage typing. Both suggested a single strain of S. aureus, of phage type 3C, 55, 71, was responsible for six of the 13 wound infections. PyMS differentiated an isolate from a member of staff of similar phage type to the epidemic strain, which had previously been considered to be the point source for the outbreak. PyMS is a rapid and inexpensive technique for investigating nosocomial outbreaks, including those caused by S. aureus and, in this instance, was more discriminatory than phage typing.


Neuroblastoma double minutes isolated by pulsed-field gel electrophoresis without prior strand-cleaving treatments.
In a human neuroblastoma line, minute chromosomes were separable from the bulk of interphase nuclear DNA by contour-clamped homogeneous electric field (CHEF) gel electrophoresis. The minute chromosomes showed a homogeneous size of approximately 3 Mbp and contained amplified N-myc genes. Fractionation was accomplished without prior strand-cleaving treatment of the DNA, indicating that at least a portion of the minute chromosomes exist as free entities in the interphase nuclei. Human alphoid satellite DNA sequences were also detected in the 3-Mbp band. It is possible that alphoid sequences are contained in the constricted central region that joins these double minutes.


Parameters of cutaneous microvasculature in men of working age with newly diagnosed arterial hypertension.
To investigate structural and functional features of cutaneous microvasculature in men of working age with newly diagnosed arterial hypertension (AH). The study included 161 apparently healthy men from 30 to 60 years, who underwent a comprehensive examination of cardiovascular system "from the heart to the capillaries". Control group (CG) included 60 normotensive men. AH group included 101 men with elevated BP. There is no rarefaction of the capillary bed and latent fluid retention in the interstitial space in the skin in men with AH. No data were obtained for increased endothelial, neurogenic and myogenic tone of resistive cutaneous precapillary arterioles in AH group, but a decrease in the perfusion efficiency of the endothelial and myogenic mechanisms of tissue perfusion modulation was noted. Obtained results allow making the assumption that metabolic disorders at the level of capillaries that are of a systemic nature prevail in men with the onset of AH.


New insight into the structural changes of apoferritin pores in the process of doxorubicin loading at an acidic pH: Molecular dynamics simulations.
Apoferritin (APO-Fr) is one of the most investigated proteins proposed as an advanced structure for drug delivery systems. Herein, molecular dynamics simulation was employed to compare the opening of 3-fold and 4-fold pores in APO-Fr during the partial disassembly process at an acidic pH. We showed that more hydrophilic residues in the surface of 3-fold pores compared to 4-fold pores facilitate increased flexibility and a higher tendency to open. In particular, dissociation is induced by the presence of Doxorubicin (DOX) close to 3-fold pores. Our simulations showed loaded DOXs on the APO-Fr surface were mainly involved in the hydrogen bond interactions with the hydrophilic residues, suggesting the difficulty of hydrophobic drugs loading in APO-Fr with the partial disassembly process. However, π-π interactions as well as hydrogen bonds between protein and DOXs were mediated by the basic and acidic amino acids such as HIP128, GLU17, and LYS143 at the open pores, providing penetration of DOXs into the H-Apo-Fr. We conclude that increased drug encapsulations and loading capacity of hydrophobic drugs into the cavity of APO-Fr are feasible by further disassembly of openings to access the internal hydrophobic portions of the protein.


Correlation between prostate volume and single nucleotide polymorphisms implicated in the steroid pathway.
A few preliminary studies have suggested a link between some genetics variants and benign prostatic hyperplasia (BPH). Our goal was to study the link between a set of single nucleotide polymorphisms (SNPs) implicated in the steroid pathway and accurate measurement of prostate volume in a cohort of men who underwent radical prostatectomy. Clinical and pathological data including prostate weight were obtained from 611 Caucasian patients with small volume, localized prostate cancer treated by radical prostatectomy. Patients were genotyped for 90 SNPs located inside or nearby genes implicated in the steroid pathway (Sequenom iPLEX). Correlation between prostate weight and genotypes from each SNP was studied by analysis of covariance, adjusted on age and tumor stage. A Bonferroni correction was applied, and the SNPs implicated were then incorporated in a multivariable model. Seven SNPs located in or nearby genes implicated in steroid hormone metabolism were significantly associated with prostate volume: HSD17B2 (rs1119933), ESR2 (rs8006145), SULT2B1 (rs279451), NQO1 (rs2917670), ESR1 (rs1569788), GSTP1 (rs1138272), and CYP19A1 (rs17523880). Significant association was maintained after multivariate analysis for four SNPs, indicating their independent association with prostate volume. The power of the association of each SNP with prostate volume was comparable to the effect of age. The strongest associations were found with variants in ESR1, ESR2, HSD17B2, and CYP19A1 genes, indicating a potential role of the estrogen signaling pathway in genesis of BPH. Our results are in favor of an implication of estrogen biotransformation and signaling pathways in the pathophysiology of BPH.


Solute transport and separation in nanochannel chromatography.
An analytical model is developed to study the solute transport and separation in pressure-driven liquid flow through cylindrical nanochannels. The flow-induced streaming potential is found to significantly affect the solute speed, retention and dispersion in nanochannel chromatography. These effects are sensitive to the solute charge, and found to be mainly dependent on an electrokinetic "figure of merit".


Does compression of the base of the penis improve the efficacy of intracavernosal injection of prostaglandin E1 for impotence? A randomized controlled study.
The objective of this study was to evaluate the effect on erections of impeding venous blood flow following intracavernosal injections of prostaglandin E1. Dispersion of injected X-ray contrast medium indicated that application of the RMRI penile clamp to the base of the penis retarded venous outflow. The clamp was then tested in impotent men to determine whether their erectile response was enhanced. Erectile response was assessed using a Rigiscan monitor, palpation of the penis by a staff nurse and the patient's subjective impression. The results demonstrate that there is no significant improvement in erectile response following venous compression.


Intravesical pressure induces hyperplasia and hypertrophy of human bladder smooth muscle cells mediated by muscarinic receptors.
Bladder outlet obstruction with intravesical pressures exceeding 40 cmH(2)O results in a progressive increase in wall thickness, eventually causing low compliance. We investigated whether intravesical pressure induces hypertrophy and/or hyperplasia of human bladder smooth muscle cells (HBSMC) mediated by a muscarinic (M) receptor, and evaluated the relationship between intravesical pressure and M receptor antagonists. HBSMC were exposed to 40 cmH(2)O pressure and/or acetylcholine (10 nM-100 microM) for 24h. Cells exposed to hydrostatic pressure were treated with either 1 microM AF-DX 16 (M(2) antagonist), 1 microM 4-DAMP (M(3) antagonist) or 1 microM atropine (both M(2) and M(3) antagonists). DNA and protein synthesis of HBSMC were measured by (3)H-thymidine and leucine incorporation assays, respectively. (3)H-thymidine incorporation increased following exposure to increasing concentrations of acetylcholine (at 100 microM, P<0.05). When cells were exposed to 40 cmH(2)O for 24h, (3)H-thymidine incorporation increased by 31.4%, 33.3% and 39.5% in 1 microM, 10 microM and 100 microM of acetylcholine, respectively. With exposure to 100 microM acetylcholine, a hydrostatic pressure of 40 cm, and both of these together, (3)H-thymidine incorporation increased by 16.7%, 25.9% and 39.4%, respectively, and leucine incorporation increased by 66.5%, 66.5% and 81.8%, respectively (P<0.05). Antimuscarinic agents had no apparent effect on the proliferative rate of cells grown at atmospheric pressure, but there was a dramatic decrease in thymidine and leucine incorporation for cells that were simultaneously exposed to increased hydrostatic pressure, most pronounced when the combined M(2)/M(3) receptor antagonist was applied. Intravesical pressure may induce hypertrophy/hyperplasia of HBSMC mediated by M receptors. Early use of an M receptor antagonist in cases of high intravesical pressure may have a positive effect on bladder compliance.


Comparison of analysis methods and design choices for treatment-by-period interaction in unidirectional switch designs: a simulation study.
Due to identifiability problems, statistical inference about treatment-by-period interactions has not been discussed for stepped wedge designs in the literature thus far. Unidirectional switch designs (USDs) generalize the stepped wedge designs and allow for estimation and testing of treatment-by-period interaction in its many flexible design forms. Under different forms of the USDs, we simulated binary data at both aggregated and individual levels and studied the performances of the generalized linear mixed model (GLMM) and the marginal model with generalized estimation equations (GEE) for estimating and testing treatment-by-period interactions. The parallel group design had the highest power for detecting the treatment-by-period interactions. While there was no substantial difference between aggregated-level and individual-level analysis, the GLMM had better point estimates than the marginal model with GEE. Furthermore, the optimal USD for estimating the average treatment effect was not efficient for treatment-by-period interaction and the marginal model with GEE required a substantial number of clusters to yield unbiased estimates of the interaction parameters when the correlation structure is autoregressive of order 1 (AR1). On the other hand, marginal model with GEE had better coverages than GLMM under the AR1 correlation structure. From the designs and methods evaluated, in general, parallel group design with a GLMM is, preferred for estimation and testing of treatment-by-period interaction in a clustered randomized controlled trial for a binary outcome.


Muscle cramping over the diagnosis.
A 44-year-old man with hypogonadism and adrenal insufficiency presented with transient blurred vision and halos around lights. Visual acuity was 20/20 in both eyes, and he had mild bilateral optic disk edema. Brain imaging was unremarkable, and lumbar puncture showed an opening pressure of 28.5 cm H2O with elevated protein. He also complained of muscle cramping, and magnetic resonance imaging of the spine demonstrated a heterogenous bone marrow signal. Bone survey showed a mixed lytic and sclerotic lesion within the left femur that proved to be a plasmacytoma. Serum protein electrophoresis had a small IgA spike, and plasma vascular endothelial growth factor (VEGF) was elevated. He was diagnosed with POEMS syndrome and underwent radiation to the plasmacytoma. Two years later he had a stable neuro-ophthalmologic exam with no signs of multiple myeloma. POEMS syndrome is a rare paraneoplastic syndrome from a plasma cell dyscrasia that may cause optic disk edema.


History and national survey on reflex hammers: which is the chosen one of Brazilian neurologists?
Percussion is an important part of the neurological examination and reflex hammers are necessary to obtain it properly. We aimed to review the historical aspects of the main reflex hammers and to define the favorite one of Brazilian neurologists. We searched original and review articles about historical aspects of the reflex hammers in Scielo and Pubmed and conducted an online survey to investigate the favorite reflex hammer of Brazilian neurologists. In the first part, we describe the major milestones in the creation of the reflex hammers. Following, we exhibit the results of the online survey: Babinski-Rabiner was the most voted. The origins of the reflex hammers goes back long before their creation, from a basic clinical examination method: percussion. Since the description of deep tendon reflexes and the creation of percussion hammers, much has been improved in this technique. Among all the hammers surveyed, the Babinski-Rabiner was the chosen one by a significant portion of Brazilian neurologists.


T-cell differentiation and maturation.
Understanding of the differentiation and maturation of T cells has been greatly enhanced by several technical developments. Certainly, the most important of these has been the rapid expansion in the availability of monoclonal antibodies to identify surface markers on T cells. Utilization of these antibodies has permitted the description of the developmental sequence of T cells both within the thymus and peripherally. Equally impressive have been the rapid advances in the understanding of the cellular events involved in antigen activation of T cells. These events are MHC restricted. The biochemical description of the class I and class II molecules that are involved in antigen presentation and the biochemical description of the T-cell receptor have provided a framework that should allow a more definitive picture of these specificity-determining molecular structures to emerge in the coming years. Several soluble growth and maturation factors (IL-1, IL-2, and BCGF), which are involved in the generation of cellular immune responses, have also been integrated into the above framework. Finally, ongoing studies on products of activated T lymphocytes (lymphokines) are providing clearer insights into the mechanisms by which immune T cells influence other cells. An additional benefit from the study of T cell development has been a more biochemically based classification of T-cell malignancies. The powerful tools of molecular genetics are beginning to have an impact on research in T-cell differentiation and maturation, and will likely have an ever-growing influence on research into the phenomena surrounding the activities of these immune cells.


Ubiquitous Sensor Networking for Development (USN4D): an application to pollution monitoring.
This paper presents a new Ubiquitous Sensor Network (USN) Architecture to be used in developing countries and reveals its usefulness by highlighting some of its key features. In complement to a previous ITU proposal, our architecture referred to as "Ubiquitous Sensor Network for Development (USN4D)" integrates in its layers features such as opportunistic data dissemination, long distance deployment and localisation of information to meet the requirements of the developing world. Besides describing some of the most important requirements for the sensor equipment to be used in a USN4D setting, we present the main features and experiments conducted using the "WaspNet" as one of the wireless sensor deployment platforms that meets these requirements. Furthermore, building upon "WaspNet" platform, we present an application to Air pollution Monitoring in the city of Cape Town, in South Africa as one of the first steps towards building community wireless sensor networks (CSN) in the developing world using off-the-shelf sensor equipment.


Detection and localization of prostate cancer with the targeted biopsy strategy based on ADC map: a prospective large-scale cohort study.
To investigate the usefulness of targeted biopsy strategy based on apparent diffusion coefficient (ADC) maps in the detection and localization of prostate cancer. Institutional review board approval and informed consent from all participants were obtained. This study included 1448 consecutive patients suspected of having prostate cancer based on PSA level, who were divided into two groups: Group A included 890 patients with low-ADC lesions who underwent targeted and systematic biopsies; Group B included 558 patients with no low-ADC lesions who underwent only systematic biopsies. The cancer detection rates (CDR) of each group, positive predictive value (PPV), and negative predictive value (NPV) of ADC maps were calculated. The CDR was 70.1% for Group A, higher than those for overall patients (48.1%) and for Group B (13.1%) with significant difference (P < 0.001). In the serum, PSA range from 4 to 20 ng/mL, the CDR was higher for the Group A than for the Group B and overall patients with significant differences. PPV and NPV of MR findings were 70.1% and 86.9%, respectively. Especially, the PPV of the MR findings for the anterior portion was as high as 90.1%. Among the false negatives of MR findings, Gleason score proved 6 or smaller in 79.5%, and positive core number was merely one or two in 80.8%. The targeted biopsy strategy based on ADC maps can be useful in the detection and localization of prostate cancer with high PPV.


Epistaxis: an overview.
This article provides a review of epistaxis for the emergency clinician. The anatomy, incidence, etiology, diagnosis, and management of posterior and anterior epistaxis are discussed.


Intraarterial contrast-enhanced ultrasound to predict the short-term tumour response of hepatocellular carcinoma to Transarterial chemoembolization with Lipiodol.
Transarterial chemoembolization (TACE) is an effective locoregional therapy in hepatocellular carcinoma (HCC). However, it is difficult to predict the tumour response (TR) of TACE intraprocedurally. The aim of this study was to predict the TR after TACE (1-3 months) in HCC patients using intraprocedural intraarterial contrast enhanced ultrasound (IA-CEUS). In this case-control study, consecutive patients who received TACE in our hospital from September 2018 to May 2019 were enrolled. IA-CEUS was performed before and after TACE. Postoperative contrast-enhanced liver MRI was performed 1-3 months after TACE as the gold standard. According to the modified Response Evaluation Criteria in Solid Tumours (mRECIST), ultrasonic manifestations were compared between the complete remission (CR) group and non-CR group by univariate and multivariate analyses. A logistic predictive model was established and validated, and its diagnostic efficiency was evaluated. Forty-four patients with sixty-one lesions were enrolled in the study. Multivariate analysis identified, the risk factors as a large lesion diameter (OR: 1.84; 95% confidence interval [CI]: 1.009, 3.080; P = 0.020), a larger dimension of non-enhancing area in superior mesenteric artery (SMA)-CEUS than the size in B-mode ultrasound preoperatively (OR: 3.379; 95% CI: 1.346,8.484; P = 0.010), presence of corona enhancement in hepatic artery (HA)-CEUS postoperatively (OR: 6.642; 95% CI: 1.214, 36.331; P = 0.029), and decreased corona enhancement thickness (per centimetre) postoperatively (OR: 0.025; 95% CI: 0.006,0.718; P = 0.025). The area under the receiver operating characteristic curve (AUROC) of the predictive model was 0.904 (95% CI: 0.804, 0.966; P < 0.001). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 81.08, 91.67, 85.25, 93.75, and 75.86%, respectively. Leave-one-out cross-validation (LOOCV) showed that the accuracy was 77.05%. Intraprocedural IA-CEUS can be used to predict the TR in HCC patients after TACE.


Developmental toxicity of 3,4-dichloroaniline on rare minnow (Gobiocypris rarus) embryos and larvae.
Gobiocypris rarus is a freshwater cyprinid, which possesses lots of attractive features (short life cycle, high fecundity, and especially the transparent trait during early life stage) that make it a suitable model in aquatic toxicity tests. In this study, the effects of 3,4-dichloroaniline (3,4-DCA) on the early life stages of G. rarus were measured. As endpoints, normal developmental parameters (survival rate, malformation rate, total body length and average heart rate) as well as biomarker genes (stress response (hsp70), organizer function and axis formation (wnt8a), vascular system development (vezf1), detoxification (cyp1a) and endocrine disruption (erα)) in the developing embryos and larvae were recorded during a 72 h exposure. The results revealed that reduced survival rate, increased malformation, changes in heart rate and total body length provide a gradual dose-response relationship, values of 72 h LC(50) were 4.146 (3.665-4.713) mg L(-1) for embryos and 1.088 (0.832-1.432) mg L(-1) for larvae. The developmental biochemical biomarkers are very promising tools to determine the severity of toxicants in the growing G. rarus embryos and larvae, even at a concentration of 1% for LC(50). Gene expressions of wnt8a and cyp1a in embryos were highly up-regulated (more than 100-fold) after exposure to 3,4-DCA. Overall, the present study points out that 3,4-DCA is high toxic to the early development of G. rarus, and offers a practicable and highly sensitive bioassay for the general assessment of chemical toxicity.


Prospective evaluation and treatment of familial carcinoid small intestine neuroendocrine tumors (SI-NETs).
The aim of this study was to prospectively screen patients with a positive family history of carcinoid small intestine neuroendocrine tumors (SI-NETs) to elucidate the benefits of early detection and operative intervention. A single-center, prospective trial was conducted from 2008 to 2014 that evaluated patients with 2 or more blood relatives with carcinoid SI-NETs. All eligible patients were screened with urine/serum biochemistries and various imaging modalities. Operative intervention was elected in patients found to have at least 1 positive diagnostic study. Twenty-nine patients from 13 families had occult carcinoid SI-NETs (15 female, 14 male). Twenty-four of the 29 patients (83%) had multifocal disease found in either the distal jejunum or ileum. On average, 75.9 cm (range, 13-195) of bowel was resected in 1 segment. Three patients were found to have stage IV disease at operation. All stage I-IIIB patients who had R0 resections have remained disease-free, with a median follow-up of 35 months. Familial carcinoid SI-NETs often are asymptomatic and can be diagnosed with aggressive screening. With early detection, there may be a window of opportunity for operative resection to change the natural history of this disease and even prove to be curative.


Cross-sectional and longitudinal relations among children's trust beliefs, psychological maladjustment and social relationships: are very high as well as very low trusting children at risk?
Four hundred and thirty-four children enrolled in school years 5 and 6 in the United Kingdom were administered measures of trust beliefs in peers/best friends and psychosocial functioning (internalized maladjustment, self-perceived social acceptance, social preference, and social exclusion) across an 8-month period (mean age = 9 years-9 months at Time 1). The relation between children's trust beliefs in peers or trust beliefs within best friend dyads and measures of psychosocial functioning conformed to a quadratic pattern. Compared to children in the middle range of trust beliefs, children with very low trust beliefs and those with very high trust beliefs in peers and/or within best friend dyads displayed higher internalized maladjustment, lower self-perceived social acceptance, higher social exclusion, and lower social preference. The relation between the trust beliefs and internalized maladjustment was asymmetrical, with children who held very low trust beliefs being comparatively more disadvantaged.


Peritoneal fluid accumulation with dextran 70 instilled at time of laparoscopy.
A patient is presented that had instillation of Hyskon at the time of laparoscopy and then had a laparotomy. Fifty milliliters of Hyskon was instilled into the abdomen, and the next day at laparotomy 255 ml of peritoneal fluid was present, demonstrating that Hyskon was able to promote the transfer of a large volume of fluid into the peritoneal cavity. By separating fibrin-covered surfaces, this hydroflotation effect inhibits adhesion formation.


Prosthetic reconstruction to restore function in transcarpal amputees.
Mutilated hands at the distal level may pose a challenge for reconstruction. Biological treatment options may require multiple surgical interventions and a long rehabilitation course with little hope of good functional outcome. Standard hand prostheses are also not an ideal solution, as they are too long and cumbersome for partial hand injuries. This paper outlines the functional outcomes of prosthetic reconstruction with devices customized for the transcarpal amputation levels. The functional outcome was evaluated with the Action Research Arm Test (ARAT), Southampton Hand Assessment Procedure (SHAP), and the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH). Functional evaluation was performed at least 12 months after final fitting. Psychological assessment was performed with the Short Form-36. The three patients achieved a mean ARAT score of 35.67 ± 0.58. The average SHAP score was 74 ± 7.81. The average DASH score was found to be 16.11 ± 12.03. The reconstructed hand achieved a score of 75.27 ± 8.16% in SHAP and 62.57 ± 1.02% in ARAT in relation to the healthy hand. All patients exhibited average physical and mental component summary scales in the Short Form-36. The majority of transcarpal amputations are seen in manual laborers due to work-related trauma. Returning to work is the main goal in such young and otherwise-healthy patients. As shown with this study, prosthetic fitting results in quick and reliable functional reconstruction. Therefore, this treatment should be considered as an option during the initial decision-making process of reconstructing difficult traumatic injuries of the hand.


Parathyroidectomy improves hypercalciuria in patients with primary hyperparathyroidism.
Hypercalciuria is an important manifestation of primary hyperparathyroidism and may contribute to the risk of nephrolithiasis. This study examined the impact of parathyroidectomy on 24-hour urinary calcium (24-hour UCa) levels and rates of resolution of hypercalciuria after surgery. A retrospective cohort study was performed of patients who underwent curative parathyroidectomy for primary hyperparathyroidism from 2007 to 2017. Baseline and postoperative urine and serum biochemistry levels were analyzed. The relationship between preoperative 24-hour UCa levels and the absolute decrease in postoperative UCa excretion was assessed using Spearman's rank correlation coefficient. Of 110 patients, 84 (76.4%) experienced a ≥20% decrease in 24-hour UCa level postoperatively. These patients had a higher baseline median 24-hour UCa level (293.5 vs 220.5 mg/24-hour; P = .001), higher baseline mean serum parathyroid hormone (106.5 vs 83; P = .05) and were more likely to have single gland disease (85.7% vs 65.4%, P = .04) compared with patients in whom 24-hour UCa excretion did not improve. Of the 28 patients (25%) who were hypercalciuric (24-hour UCa >400 mg/day) at baseline, 22 (79%) became normocalciuric postoperatively. A linear correlation was observed between preoperative 24-hour UCa levels and the decline in 24-hour UCa excretion after surgery (R2 = 0.59, P < .0001) such that the degree of improvement could be predicted using the following equation: absolute decrease in postoperative 24-hour UCa = 0.68 × preoperative 24-hour UCa-68. Parathyroidectomy reduces 24-hour UCa excretion in the majority of patients with PHPT and restores normocalciuria in 79% of patients with hypercalciuria at baseline.


Birth date determines early calf survival in migratory caribou.
The decline of most caribou (Rangifer tarandus) populations underlines the need to understand the determinants of key demographic parameters. In migratory caribou, we have limited information on rates and drivers of pre-weaning mortality. We fitted 60 pregnant females of the Rivière-aux-Feuilles caribou herd with GPS camera collars to track the survival of calves from birth to weaning in 2016-2018. Over the three years, calf survival rate before weaning, i.e. to 01-Sep, approximately three months of age, was 0.63 (CI 0.50-0.77). Summer mortality risk was mainly influenced by calf birth date, with calves born earlier in the calving season having a lower mortality risk than those born later. Mortality also increased when calves experienced low or high temperature during calving. This study provides the first estimates of pre-weaning survival of migratory caribou calves in this herd, illustrating the value of new technologies to collect data otherwise difficult to obtain in widely distributed migratory populations. This approach can easily be extended to other large herbivores and predators. Our study brings new insights on how climate change may affect summer juvenile survival given the increased temperatures and faster changes in plant phenology expected in the future.


miR-15a-5p enhances the malignant phenotypes of colorectal cancer cells through the STAT3/TWIST1 and PTEN/AKT signaling pathways by targeting SIRT4.
Colorectal cancer (CRC) continues to represent one of the major causes of cancer-related mortality and morbidity. MicroRNAs (miRNAs) are confirmed to be involved in modulating substential biological processes by affecting the expression of targeted genes, including carcinogenesis. In the present study, the expression pattern and functional roles of microRNA-15a-5p (miR-15a-5p) in CRC cells were investigated. The data from TCGA database indicated that miR-15a-5p is highly expressed in CRC tissues. Moreover, ectopic expression of miR-15a-5p facilitated the proliferation, migration, and invasion of CRC cells. Furthermore, bioinformatic analysis combinating with dual-luciferase assay revealed that SIRT4 acts as a crucial target of miR-15a-5p. Accordingly, overexpression of SIRT4 suppresses the miR-15a-5p-mediated enhancement in the proliferation, migration, and invasion of CRC cells, while the opposite phenotypes were observed after inhibition of SIRT4. Moreover, we further revealed that miR-15a-5p restrained the expression of SIRT4 to exacerbate the malignant phenotypes by modulating STAT3/TWIST1 and PETN/AKT signaling in CRC cells. Alternatively, inhibition of the miR-15a-5p/SIRT4 axis enhanced the chemosensitivity of 5-fluorouracil- and oxaliplatin-resistant HCT116 cells. Altogether, our evidence suggests that miR-15a-5p plays an essential role in promoting the proliferation, migration, and chemoresistance of CRC cells via targeting SIRT4 to modulate STAT3/TWIST1 and PETN/AKT signaling, which may serve as a promising therapeutic target for CRC therapy.


Synthesis of defense response characteristics.
In previous chapters, the available theories and experimental findings related to animals' defense responses have been reported and discussed in detail. This chapter reports their comprehensive synthesis, considering the main immobility-related responses in defense. Within the same modality (i.e., immobility) different kinds of immobility may in fact correspond to different functions and motivations, as proved by their neurobiological correlates profile.


Idiopathic pneumatosis intestinalis secondary to lactulose use in patients with cirrhosis.
Few case reports exist that link lactulose use with pneumatosis intestinalis in cirrhotics. This study investigates the relationship between lactulose use and idiopathic pneumatosis intestinalis in a cohort of cirrhotic patients. This case series considers several notable cases of patients with idiopathic pneumatosis intestinalis and concurrent lactulose use. Idiopathic pneumatosis intestinalis was defined as pneumatosis intestinalis with no identifiable etiology. A cohort of 119 patients with cirrhosis and pneumatosis intestinalis were identified in a tertiary care setting, via chart review by a multidisciplinary team. Eleven of these patients were found to have idiopathic pneumatosis intestinalis. Nine of these patients were being treated with lactulose. Six out of 9 patients with idiopathic pneumatosis intestinalis that were being treated with lactulose saw resolution of pneumatosis intestinalis following discontinuation of treatment. The etiology of idiopathic pneumatosis intestinalis is likely multifactorial, but lactulose might play a preventable role in its formation.


Reunification trajectories in Quebec: Acknowledging chronic family challenges to support stability.
While family reunification following out-of-home placement is a goal of child protection policy, complex family needs may not be met at the point that child protection systems reunify families. Permanency legislation creating maximum placement timeframes prompts questions regarding what families need to be supported in stably reunifying following a child's removal from the home. We aim to identify clinical risk factors salient for initial placements and placements following a child reunifying with their family to inform successful reunification and improve children's stability. The study includes a representative sample of children in Quebec with a child protection investigation in 2008 (N = 3051) followed for nine years. Cross-sectional clinical data from the Quebec Incidence Study (QIS) on Evaluated Child Protection Reports (2008) were linked with longitudinal administrative data from 16 provincial child protection agencies. Canadian Census data (2006) were used to create a factorial index measure for poverty. Chi-square automatic interaction detector (CHAID) decision tree analysis was used to compare risk factors salient for initial placements (n = 1120) with post-reunification placements (n = 455). For the placement sample (n = 1120), significant factors were: attachment issues, caregiver drug use, child's suicidal thoughts, child's self-harming behavior, and academic difficulties. Of the children who reunified with their families (n = 847), over half (n = 455; 54%) returned to out-of-home placements. Certain factors remained significant for placement after reunification: academic difficulties, attachment issues, and caregiver drug use. The CHAID model fit estimates suggest 70.9% (SE = 0.008) accuracy predicting out-of-home placement following child protection investigation and 58.2% (SE = 0.017) accuracy predicting re-placement following family reunification. Complex needs among families most likely to experience reunification breakdown indicate potential service gaps. When legislated placement timeframes prompt quick resolution of family challenges, these analyses can contribute to policy discussions regarding clinical family challenges that impact stability.


Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors).
The nuclear hormone receptor (NR) superfamily complement in humans is composed of 48 genes with diverse roles in metabolic homeostasis, development, and detoxification. In general, NRs are strongly conserved between vertebrate species, and few examples of molecular adaptation (positive selection) within this superfamily have been demonstrated. Previous studies utilizing two-species comparisons reveal strong purifying (negative) selection of most NR genes, with two possible exceptions being the ligand-binding domains (LBDs) of the pregnane X receptor (PXR, NR1I2) and the constitutive androstane receptor (CAR, NR1I3), two proteins involved in the regulation of toxic compound metabolism and elimination. The aim of this study was to apply detailed phylogenetic analysis using maximum likelihood methods to the entire complement of genes in the vertebrate NR superfamily. Analyses were carried out both across all vertebrates and limited to mammals and also separately for the two major domains of NRs, the DNA-binding domain (DBD) and LBD, in addition to the full-length sequences. Additional functional data is also reported for activation of PXR and the vitamin D receptor (VDR; NR1I1) to gain further insight into the evolution of the NR1I subfamily. The NR genes appear to be subject to strong purifying selection, particularly in the DBDs. Estimates of the ratio of the non-synonymous to synonymous nucleotide substitution rates (the omega ratio) revealed that only the PXR LBD had a sub-population of codons with an estimated omega ratio greater than 1. CAR was also unusual in showing high relative omega ratios in both the DBD and LBD, a finding that may relate to the recent appearance of the CAR gene (presumably by duplication of a pre-mammalian PXR gene) just prior to the evolution of mammals. Functional analyses of the NR1I subfamily show that human and zebrafish PXRs show similar activation by steroid hormones and early bile salts, properties not shared by sea lamprey, mouse, or human VDRs, or by Xenopus laevis PXRs. NR genes generally show strong sequence conservation and little evidence for positive selection. The main exceptions are PXR and CAR, genes that may have adapted to cross-species differences in toxic compound exposure.


Multiple stable subharmonics for a periodic epidemic model.
The S leads to I leads to R epidemic model of K. Dietz with annual oscillation in the contact rate is shown to have multiple stable subharmonic solutions of different integral year periods.


Identification of metastasis-related genes by genomic and transcriptomic studies in murine melanoma.
We systematically characterized metastatic murine B16-F10 melanoma, a sub-line derived from murine melanoma B16-F1 cells. RNA-sequencing and network analyses (Ingenuity Pathway Analysis) were performed to identify novel potential metastasis mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) using all 21 murine whole chromosome painting probes. Numerous genes were overexpressed in B16-F10 cells, some of which have been already described as being metastasis-linked. Nr5a1/sf1, a known prognostic marker for adrenal tumors, was 177-fold upregulated in B16-F10 cells compared to B16-F1 cells. Hoxb8 was 75-fold upregulated, which was previously associated with gastric cancer progression and metastasis. Ptk7, which is linked with tumorigenesis and metastasis of esophageal squamous carcinoma, was 67-fold upregulated. B16-F10 cells acquired additional chromosomal aberrations compared to B16-F1 cells, including dic(4)(pter->qter:qter->pter), +dic(6;15), +der(10)t(10;?1;16). In addition to well-known metastatic genes, numerous novel genes and genomic aberrations were identified, which may serve as targets for treatment in the future. Transcriptomic and genetic analyses in B16-F10 cells unraveled a range of novel metastasis mechanisms, which may also have important implications for future treatment strategies.


Influence of summer rainfall on root and shoot growth of a cold-winter desert shrub, Atriplex confertifolia.
The influence of irrigation and nitrogen fertilization in early summer on root and shoot growth of Atriplex confertifolia, a C4 shrub species, was examined in a cold-winter desert community in northern Utah. Soil water and xylem pressure potentials were monitored during the summer period.At the time of watering the surface soil (0-30 cm) was dry but there were turgid fine roots in this horizon. Watering of the soil reduced plant water stress from-30 to-15 bars (dawn values) indicating that roots near the surface were capable of absorbing water, and induced root growth in the 0-30 cm zone. The addition of N to the water treatment did not further increase root production. However, watering and watering +N fertilizer failed to stimulate shoot elongation or any dry weight increase of shoots. This shoot dormancy during summer is not typical of C4 plants and is probably associated with adaptation to the cool arid environment.


Image Gently: a campaign to reduce children's and adolescents' risk for cancer during adulthood.
Recently, the Cancer Prevention Across the Lifespan workgroup at the Centers for Disease Control held a workshop entitled "Identifying Opportunities for Cancer Prevention During Pre-Adolescence and Adolescence." With the goal of raising awareness and developing community and policy interventions to decrease risk factors for cancer, one session highlighted the danger of ionizing radiation exposure from diagnostic medical imaging. This session focused on the Image Gently campaign, which is a multidisciplinary partnership focused on increasing awareness, developing education materials, and advocating for children to protect them from unnecessary radiation. Such protection is important because emerging data suggest that preadolescents and adolescents may be at increased risk for future malignancy if they are exposed to radiation from diagnostic imaging. Many health care practitioners may not understand how to decrease children's radiation exposure; the goals of Image Gently are to increase all stakeholders' understanding of these risks and to encourage radiation reduction strategies. Clearly, diagnostic imaging is an important and necessary tool for certain medical care. Image Gently advocates methods to reduce the use of unnecessary ionizing radiation by sharing best practices of imaging protocols for children and using alternative imaging that avoids ionizing radiation. This article summarizes our recent presentation on Image Gently to this workgroup: It focuses on the risks for preadolescents and adolescents and on strategies to minimize these risks.


RPL-6: An Achilles Needle in the Malaria Haystack?
Malaria is a global health scourge for which a highly effective vaccine remains frustratingly elusive. Recent identification of an endogenous malaria antigen that stimulates robust TRM-mediated immunity in mice by Valencia-Hernandez et al. strengthens the case for prime-and-trap malaria vaccines and will greatly aid further investigations of cellular antimalarial immunity.


Space efficient system for small animal, whole body microwave exposure at 1.6 GHz.
A space efficient, whole body microwave exposure system for unrestrained laboratory animals utilizing a flared parallel plate waveguide is described. The system comprises an Iridium wireless signal source, signal generator, power supply and amplifier (400 W), a coax to waveguide transition, an open ended, flared parallel plate waveguide, and animal exposure area with a dipole field sensing antenna. Across the waveguide aperture the system provides uniform exposure (+/-3 dB incident RF power density) for small animals (rats, mice or hamsters) in up to 18 standard cages for housing groups of animals. Overall system dimensions are 3.6 m (d)x2.4 m (w)x1.6 m (h). Operating at 1.62 GHz, the system provided average power density of 3.7 W/m(2) in the cage area, resulting in a calculated whole body dose of 0.07 W/kg and a calculated average brain dose of 0.19 W/kg.


The new antidepressants. Selective serotonin reuptake inhibitors.
This article provides a resource for choosing among available SSRIs to treat pediatric patients. SSRIs are addressed according to five areas of interest: treatment efficacy data, untoward effects profile, pharmacokinetic characteristics, potential drug-drug interactions, and cost. Strategies for SSRI dosing and pretreatment work-up are also discussed. Included in the article is a reference table for SSRI dosing, available preparations, and cost per dose. Also included is an abbreviated reference table of important cytochrome P-450 isoenzymes, isoenzyme inhibition by SSRIs, and selected psychotropic and somatic medication substrates.


Vaginal microbiota of healthy pregnant Mexican women is constituted by four Lactobacillus species and several vaginosis-associated bacteria.
To identify the microbiota communities in the vaginal tracts of healthy Mexican women across the pregnancy. Vaginal swabs were obtained during the prenatal visit of women from all trimesters (n = 64) of healthy pregnant women of Mexico City. DNA was isolated from each sample, and PCR-DGGE and sequencing of 16S rRNA gene fragments were used to identify the bacterial communities. 21 different microorganisms were identified in the vaginal samples. Lactobacillus genus was present in 98% of women studied. Four lactobacilli species were identified in vaginal samples. L. acidophilus was the predominant (78%) followed by L. iners (54%), L. gasseri (20%), and L. delbrueckii (6%). 17 different microorganisms related to bacterial vaginosis conditions were identified. Ureaplasma urealyticum was the predominant (21%) followed by BVAB1 (17%) and Gemella bergeriae (7.8%). Lactobacillus genus predominates in the vaginal samples of Mexican pregnant women associated with different microorganisms related to bacterial vaginosis conditions.


A Core Outcome Set and minimum reporting set for intervention studies in growth restriction in the NEwbOrN: the COSNEON study.
Different interventions and treatments are available for growth-restricted newborns to improve neonatal and long-term outcomes. Lack of outcome standardization across trials of feeding interventions limits pooled analysis of intervention effects. This study aimed to develop a core outcome set (COS) and minimum reporting set (MRS) for this research field. A scoping search identified relevant outcomes and baseline characteristics. These outcomes were presented to two stakeholder groups (lay experience and professional experts) in three rounds of online Delphi surveys. The professional experts were involved in the development of the MRS. All items were rated for their importance on a 5-point Likert scale and re-rated in subsequent rounds after presentation of the results at the group level. During a face-to-face consensus meeting the final COS and MRS were determined. Forty-seven of 53 experts (89%) who completed the first round completed all three survey rounds. After the consensus meeting, consensus was reached on 19 outcomes and 17 baseline characteristics. A COS and MRS for feeding interventions in the newborn after growth restriction were developed. Use of these sets will promote uniform reporting of study characteristics and improve data synthesis and meta-analysis of multiple studies. Both a COS and MRS for growth restriction in the newborn were developed. This study provides the first international combined health-care professional and patient consensus on outcomes and baseline characteristics for intervention and treatment studies in growth-restricted newborns. The use of COS and MRS results in the development of more uniform study protocols, thereby facilitating data synthesis/meta-analysis of multiple studies aiming to optimize treatment and interventions in growth restriction in the newborn.


Surgical treatment and outcome in patients with a hepatocellular carcinoma greater than 10 cm in diameter.
Hepatocellular carcinoma (HCC) over 10 cm in diameter at the time of diagnosis continues to account for a number of patients undergoing hepatic resection. This study evaluated the clinicopathological features and outcome following surgery for large HCC. Forty patients with a large HCC (greater than 10 cm) (group 1) resected between 1991 and 1996 were studied retrospectively. They were compared with 245 patients who had smaller HCCs (10 cm or less) (group 2). No patient in group 1 had hepatitis C infection compared with 22.9 per cent in group 2 (P=0.001). Patients in group 1 were significantly younger, had higher alpha-fetoprotein levels (16750 versus 1864 ng/ml; P < 0.001), better liver function, a higher incidence of multiple tumours (27 of 40 versus 42.0 per cent; P=0.003) and venous invasion (35 of 40 versus 52.2 per cent; P < 0.001), and underwent more major resections (37 of 40 versus 26.5 per cent; P < 0.001) than those in group 2. Morbidity and mortality rates and hospital stay were comparable in the two groups. For group 1, the 1-, 3- and 5-year disease-free survival rates were 42, 30 and 28 per cent respectively. Multiple tumours, venous invasion and impaired liver function were factors associated with recurrence. Large HCC had specific clinicopathological features. In selected patients, resection is safe and offers the chance of long-term disease-free survival.


Ratio of organs to blood of mercury during its uptake by normal and acatalasemic mice.
The brain/blood, liver/blood, and heart/blood ratios of acatalasemic mice after intraperitoneal injection of metallic mercury or after exposure to metallic mercury vapor were significantly higher than those of normal mice. These ratios of normal or acatalasemic mice after injection with metallic mercury or exposure to metallic mercury vapor were significantly higher than those of normal and acatalasemic mice injected with mercuric ion. The amount of metallic mercury exhaled from acatalasemic mice injected with metallic mercury was greater than that from normal mice, indicating that the level of metallic mercury in blood of the former was higher than that of the latter. Actually, metallic mercury in the blood of acatalasemic mice injected with metallic mercury is higher than that in the blood of normal mice, suggesting that metallic mercury is easily transfered from blood to brain, liver, kidney, and heart.


The CFTR-mediated protein secretion defect: pharmacological correction.
The cystic fibrosis transmembrane conductance regulator (CFTR) mediates secretion of mucins and serous proteins. The aim was to correct pharmacologically the CFTR defect in protein secretion in airway gland cells and so to correct the viscous mucous secretions in cystic fibrosis (CF) airways and lungs. The strategies tested included direct activation of CFTR, bypass of CFTR-mediated protein secretion and movement of the mutated form of CFTR (DeltaF(508)-CFTR) to the cell membrane. Compounds related to 3-isobutyl-1-methylxanthine (IBMX), including a selective type-IV phosphodiesterase inhibitor and the adenosine receptor antagonists 8-cyclopentyltheophylline (CPT) and 8-cyclopentyl-1,3-dipropylxanthine (CPX), corrected the defective beta-adrenergic stimulation of mucin secretion in CFTR antibody-inhibited submandibular gland cells. CPT also corrected lactoferrin secretion in DeltaF(508)/DeltaF(508)-CFTR nasal gland cells. The data suggest that correction of CFTR protein secretion activity is not mediated by excessive increase in cyclic AMP, involves direct interaction with CFTR but does not require increase in CFTR Cl(-) channel activity. Regulated glycoprotein secretion was characterised in the airway gland cell line Calu-3 to investigate whether a CFTR bypass is present. Studies of DeltaF(508)-CFTR trafficking using confocal imaging showed that some DeltaF(508)-CFTR colocalised with the apical membrane protein CD59; however a large amount was mislocalised within the cell. The results showing pharmacological correction of the defective CFTR-mediated protein secretion afford promise for the development of a rational drug therapy for CF patients.


[Effect of thymalin on protein synthesis in the brain and conditioned-reflex activity of the progeny of neurosensitized female rats].
Thymalin administration to two-week-old offspring of neurosensitized female rats prevented the development of protein synthesis disturbances in the central nervous system and the retention of conditioned reflex of passive avoidance. Thymalin injection to the offspring of intact female rats improved conditioned reflex retention and did not affect brain protein synthesis. A possible mechanism of thymalin effect in conditions of congenital neuroimmunopathology is discussed.


Sensitivity and specificity of a rapid whole-blood assay for D-dimer in the diagnosis of pulmonary embolism.
Patients with suspected pulmonary embolism often have nondiagnostic lung scans and may present in circumstances where lung scanning is unavailable. Levels of D-dimer, a fibrin-specific product, are increased in patients with acute thrombosis; this may simplify the diagnosis of pulmonary embolism. To determine the sensitivity and specificity of a whole-blood D-dimer assay in patients with suspected pulmonary embolism and in subgroups of patients with low pretest probability of pulmonary embolism or nondiagnostic lung scans. Prospective cohort. Four tertiary care hospitals. 1177 consecutive patients with suspected pulmonary embolism. All patients underwent an assessment of pretest probability by use of a standardized clinical model, a D-dimer assay, ventilation-perfusion lung scanning, and bilateral compression ultrasonography. Patients in whom pulmonary embolism was not initially diagnosed were followed for 3 months. Accordingly, patients were categorized as positive or negative for pulmonary embolism. Of the 1177 patients, 197 (17%) were classified as positive for pulmonary embolism. Overall, the D-dimer assay showed a sensitivity of 84.8% and a specificity of 68.4%. In 703 patients (3.4%) with a low pretest probability of pulmonary embolism, the likelihood ratio associated with a negative D-dimer test result was 0.27, resulting in a posterior probability of 1.0% (95% CI, 0.3% to 2.2%). In 698 patients with nondiagnostic lung scans (previous probability, 7.4%), the likelihood ratio associated with a negative D-dimer test result was 0.36, resulting in a posterior probability of 2.8% (CI, 1.4% to 4.8%). A normal D-dimer test result is useful in excluding pulmonary embolism in patients with a low pretest probability of pulmonary embolism or a nondiagnostic lung scan.


Retention and dispersion of buoyant plastic debris in a well-mixed estuary from drifter observations.
Buoyant plastics enter estuaries largely from urban streams and an unknown fraction is retained before further transport to the open ocean. Plastic drifters were launched in a well-mixed estuary to simulate the movement of surface buoyant plastics. Two experiments were conducted, one during spring tides and one during neap tides, both with similar river flows and winds. Stronger tidal currents during spring tides resulted in larger dispersion and further downstream transport of the drifters. Half of the drifters were grounded within two tidal cycles. During the neap experiment, even more of the drifters (87%) were retained in the estuary. The grounding of such a high proportion of drifters suggests that much of the plastic pollution in estuaries of this type remains close to the riverine source. These findings imply that local clean-up programs removing grounded litter can reduce over half of the plastic pollution input to these estuaries.