Identification of FADS1 Through Common Gene Expression Profiles for Predicting Survival in Patients with Bladder Cancer.
Aim of this study was to identify biomarkers between different grades of bladder cancer (BLCA) and its prognostic value. mRNA expression data from GSE32549 and GSE71576 were extracted for further analysis. Differentially expressed genes (DEGs) were identified using GEO2R web tool. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and protein-protein interaction (PPI) network were conducted to explore the function and relationship of DEGs. The Cancer Genome Atlas (TCGA) database was used for external validation and Gene set enrichment analysis (GSEA) analysis was used to further identify FADS1 pathways. Bladder cancer cells and patient specimens were used to further demonstrate the function of FADS1. Datasets from GEO identified a panel of DEGs. Functional enrichment analysis highlighted that DEGs were associated with nuclear division, spindle, cell cycle and p53 signaling pathway. External validation from TCGA demonstrated that FADS1 was an independent prognostic marker in BLCA patients. In cell lines and tumor specimen analysis, FADS1 was overexpressed in the tumor specimen, compared with adjacent tissues, and positively correlated with tumor grade of BLCA. Moreover, FADS1 could enhance the proliferation ability and influence cell cycle of bladder cancer cells. FADS1 was an independent prognostic biomarker for BLCA and could confer the bladder cancer cells increased proliferation ability.


Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults.
To assess cross-sectional associations of neurofibrillary tangles, measured by tau-PET, with cognitive performance in cognitively unimpaired (CU) adults. Tau- and amyloid-PET were performed in 579 CU participants aged 50-98 from the population-based Mayo Clinic Study of Aging. Associations between tau-PET signal in 43 brain regions and cognitive test scores were assessed using penalized linear regression. In additional models, participants were classified by normal/abnormal global amyloid-PET (A+/A-) and normal/abnormal regional tau-PET (T+/T-). Regional tau-PET cutpoints were defined as standardized uptake value ratio (SUVR) greater than the 95th percentile of tau-PET SUVR in that region among 117 CU participants aged 30-49. Higher tau-PET signal was associated with poorer memory performance in all medial temporal lobe (MTL) regions and also in the middle temporal pole and frontal olfactory regions. The largest association with tau-PET and memory z scores was seen in the entorhinal cortex; this association was independent of tau-PET signal in other brain regions. Tau-PET in the entorhinal cortex was also associated with poorer global and language performance. In the entorhinal cortex, T+ was associated with lower memory performance among both A- and A+. Tau deposition in MTL regions, as reflected by tau-PET signal, was associated with poorer performance on memory tests in CU participants. The association with entorhinal cortex tau-PET was independent of tau-PET signal in other brain regions. Longitudinal studies are needed to understand the fate of CU participants with elevated medial temporal tau-PET signal.


Large and diverse numbers of human diseases with HIKE mutations.
HIKE is a highly conserved sequence motif identified as a candidate pleckstrin-homology (PH) domain binding site in Gbeta proteins, protein kinases, ankyrin and kinesin. HIKE motifs occur also in gelsolin, neurogranin, neuromodulin and in the PH domain of Bruton tyrosin kinase (BTK). Phosphatidylinositol-binding sequences more distantly related to HIKE are present in gelsolin, in the G protein-coupled receptor kinase 4 and in Trop-2. HIKE regions have been demonstrated to bind both proteins and lipids, and to regulate the interaction of Gbeta, neuromodulin and the BTK PH domain with downstream effectors and the cell membrane. Remarkably, mutations of the HIKE regions are common in diverse human genetic diseases. Several HIKE mutations in protein kinases lead to constitutive activation and cellular transformation, e.g. in MEN-2B, acute myeloid and mast cell leukemias, hereditary papillary renal carcinomas and multiple myeloma. Kinase-inactivating HIKE mutations cause Hirschsprung's disease, piebaldism, insulin resistance and developmental dysplasias. HIKE mutations in the PH domain of BTK lead to X-linked agammaglobulinemia, and different forms of amyloidosis are caused by mutations of HIKE-bearing molecules, for example gelsolin, Ret and Trop-2. Thus, quite diverse genetic diseases might share common molecular mechanisms. These include altered interactions of the mutated molecules with downstream effectors or the cell membrane, and defects in intracellular transport.


Giant Aplysia neuron R2 reliably forms strong chemical connections in vitro.
The giant cholinergic neuron R2 of Aplysia was cultured in combination with identified neurons L11 and R15 and members of a group of left upper quadrant (LUQ) cells L2 to L6 from the abdominal ganglion. All of these neurons receive cholinergic input from other cells in vivo, but not from R2. In vitro, R2 reliably formed unidirectional chemical connections with these cells. Single action potentials in R2 produced a dual fast and slow inhibitory response in LUQ cells (L2 to L6), a dual fast inhibitory-slow excitatory response in L11, and a slow inhibitory response in R15. The connections formed on LUQ cells were characteristic of their cholinergic input, but the R2-L11 and the R2-R15 connections also had noncholinergic properties. Thus, unlike L10 which forms connections only with its normal targets in vitro, R2 forms strong chemical connections with other neurons which are not found in vivo. The properties of the R2 connections also suggest that it may release another neurotransmitter besides acetylcholine.


Estrogen does not inhibit 2,3,7, 8-tetrachlorodibenzo-p-dioxin-mediated effects in MCF-7 and Hepa 1c1c7 cells.
The estrogen receptor and aryl hydrocarbon receptor (AhR) are coexpressed in several Ah and estrogen-responsive human breast cancer cell lines. However, a recent study reported that 17beta-estradiol (E2) inhibited Ah responsiveness in mouse Hepa 1c1c7 hepatoma cells (Kharat, I., and Saatcioglu, F. (1996) J. Biol. Chem. 271, 10533-10537), and therefore, estrogen receptor-AhR cross-talk was reinvestigated in MCF-7 and mouse Hepa 1c1c7 cells. Treatment of MCF-7 or Hepa 1c1c7 cells with 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in induction of CYP1A1-dependent activity and mRNA levels. Treatment of both cell lines with E2 had no effect on basal or TCDD-inducible CYP1A1-dependent activity or mRNA levels. In MCF-7 and Hepa 1c1c7 cells transiently transfected with an Ah-responsive plasmid containing the 5'-regulatory region of the human CYP1A1 gene fused to the chloramphenicol acetyltransferase reporter gene 10 nM TCDD significantly induced chloramphenicol acetyltransferase activity; in cells cotreated with TCDD plus E2 the induced response was not affected by the hormone. Nuclear extracts from cells treated with dimethyl sulfoxide, E2, TCDD, and TCDD plus E2 were incubated with the [32P]dioxin-responsive element and analyzed by gel electrophoretic mobility shift assays. A retarded band associated with formation of a [32P]dioxin-responsive element-AhR complex was observed in nuclear extracts from cells treated with TCDD or TCDD plus E2 (cotreated). Collectively these studies suggest that E2 does not modulate AhR-mediated CYP1A1 gene expression in MCF-7 or Hepa 1c1c7 cells.


Micro/nano acoustofluidics: materials, phenomena, design, devices, and applications.
Acoustic actuation of fluids at small scales may finally enable a comprehensive lab-on-a-chip revolution in microfluidics, overcoming long-standing difficulties in fluid and particle manipulation on-chip. In this comprehensive review, we examine the fundamentals of piezoelectricity, piezoelectric materials, and transducers; revisit the basics of acoustofluidics; and give the reader a detailed look at recent technological advances and current scientific discussions in the discipline. Recent achievements are placed in the context of classic reports for the actuation of fluid and particles via acoustic waves, both within sessile drops and closed channels. Other aspects of micro/nano acoustofluidics are examined: atomization, translation, mixing, jetting, and particle manipulation in the context of sessile drops and fluid mixing and pumping, particle manipulation, and formation of droplets in the context of closed channels, plus the most recent results at the nanoscale. These achievements will enable applications across the disciplines of chemistry, biology, medicine, energy, manufacturing, and we suspect a number of others yet unimagined. Basic design concepts and illustrative applications are highlighted in each section, with an emphasis on lab-on-a-chip applications.


Influence of double diffusive effects on miscible viscous fingering.
Miscible viscous fingering classically occurs when a less viscous fluid displaces a miscible more viscous one in a porous medium. We analyze here how double diffusive effects between a slow diffusing S and a fast diffusing F component, both influencing the viscosity of the fluids at hand, affect such fingering, and, most importantly, can destabilize the classically stable situation of a more viscous fluid displacing a less viscous one. Various instability scenarios are classified in a parameter space spanned by the log-mobility ratios R(s) and R(f) of the slow and fast component, respectively, and parametrized by the ratio of diffusion coefficients δ. Numerical simulations of the full nonlinear problem confirm the existence of the predicted instability scenarios and highlight the influence of differential diffusion effects on the nonlinear fingering dynamics.


Oceanographic variation influences spatial genomic structure in the sea scallop, Placopecten magellanicus.
Environmental factors can influence diversity and population structure in marine species and accurate understanding of this influence can both improve fisheries management and help predict responses to environmental change. We used 7163 SNPs derived from restriction site-associated DNA sequencing genotyped in 245 individuals of the economically important sea scallop, Placopecten magellanicus, to evaluate the correlations between oceanographic variation and a previously identified latitudinal genomic cline. Sea scallops span a broad latitudinal area (>10 degrees), and we hypothesized that climatic variation significantly drives clinal trends in allele frequency. Using a large environmental dataset, including temperature, salinity, chlorophyll a, and nutrient concentrations, we identified a suite of SNPs (285-621, depending on analysis and environmental dataset) potentially under selection through correlations with environmental variation. Principal components analysis of different outlier SNPs and environmental datasets revealed similar northern and southern clusters, with significant associations between the first axes of each (R2adj = .66-.79). Multivariate redundancy analysis of outlier SNPs and the environmental principal components indicated that environmental factors explained more than 32% of the variance. Similarly, multiple linear regressions and random-forest analysis identified winter average and minimum ocean temperatures as significant parameters in the link between genetic and environmental variation. This work indicates that oceanographic variation is associated with the observed genomic cline in this species and that seasonal periods of extreme cold may restrict gene flow along a latitudinal gradient in this marine benthic bivalve. Incorporating this finding into management may improve accuracy of management strategies and future predictions.


The A54T polymorphism at the intestinal fatty acid binding protein 2 is associated with insulin resistance in glucose tolerant Caucasians.
An A54T polymorphism at the fatty acid binding protein 2 (FABP2) locus was found to be associated with insulin resistance in non-diabetic Pima Indians. To see whether this association is present in other populations, we performed a cross sectional study to examine the role of this polymorphism on insulin resistance in 55 healthy and normotensive Caucasian subjects with normal glucose tolerance. Insulin sensitivity (%S) and beta cell function (%B) were assessed using the Homeostasis Model Assessment (HOMA). Their genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism assay. The relationship between the genotypes and the phenotypes was examined. After genotyping, we identified 24 AA, 27 AT and 4 TT subjects. The TT subjects were combined with the AT subjects during the analysis due to its small sample size. No differences were noted in gender distribution, clinical features, and fasting lipid profile between the two genotypic groups (AA vs. AT/TT). The AT/TT group had a higher fasting plasma insulin concentration and a lower %S than the AA group (p = 0.0444 and p = 0.0461, respectively). However, no differences were noted in plasma glucose concentrations and %B. Univariate analysis revealed that this polymorphism explained 7.3% of the variation in %S. Multivariate analysis revealed that the polymorphism was an independent determinant for %S (p = 0.0434) and with body mass index accounted for 28.7% of the variation in %S. In contrast, this polymorphism had no impact on %B. The A54T polymorphism at the FABP2 locus is a risk factor for insulin resistance in a Caucasian population.


Evaluation of student attitudes and knowledge in a new program in international health and medicine.
Ben-Gurion University (BGU) in collaboration with Columbia University inaugurated a medical school in 1998, with the expressed purpose of training physicians in International Health and Medicine (IHM). The Beer-Sheva Survey of Attitudes and Knowledge in International Health and Medicine was given to the first graduating class and three control groups. The graduates of the new program retained their positive attitudes toward IHM and increased their knowledge of the subject. Further studies are necessary to document the effect of the program on the clinical practice of its graduates.


Psychosis in bipolar disorder: phenomenology and impact on morbidity and course of illness.
Although psychosis is common in bipolar disorder, few studies have examined the prognostic significance of psychotic features. In addition, some studies suggest that the presence of mood-incongruent psychosis, in particular, is associated with poorer outcome compared with mood-congruent psychosis. We assesses the phenomenology and prevalence of mood-congruent and mood-incongruent psychotic symptoms in 352 patients with bipolar I disorder participating in the Stanley Foundation Bipolar Treatment Network. We compared the demographic and clinical features, and measures of psychosocial and vocational functioning in patients with and without a history of psychosis. The phenomenology of psychosis in this cohort of patients with bipolar disorder was similar to that reported in earlier studies and supported the lack of diagnostic specificity of any one type of psychotic symptom. There were no significant differences between patients with and without a history of psychosis on any demographic, psychosocial, vocational, or course of illness variables. Only family history of bipolar disorder was significantly more common in patients with nonpsychotic bipolar disorder compared to patients with a history of psychosis. Among bipolar patients with a history of psychosis, only the proportion of women and lifetime prevalence rates of anxiety disorders occurred significantly more in patients with mood-incongruent delusions. In this large cohort of outpatients with bipolar I disorder, neither a history of psychosis nor of mood-incongruent psychosis had prognostic significance at entry into the Network. The lack of observable prognostic impact may have been, in part, due to the relatively high morbidity and poor functional outcome of a substantial portion of the total cohort.


Taxogenomic placement of Rasporella oleae and Rasporella dianae gen. and spp. nov., two insect associated yeast species.
During the course of independent studies in Europe, North America, and Africa, seven yeast strains were isolated from insect frass, decaying wood, tree flux, and olive oil sediment. Phylogenetic analysis of two barcoding DNA regions (internal transcribed spacer and the D1/D2 domain of the LSU rRNA gene) revealed that they belong to two closely related undescribed species distinct from all genera in the family Debaryomycetaceae. For reliable taxonomic placement the genomes of four strains of the two novel species and six type strains of closely related species were sequenced. Orthologous genes from 54 genomes of representatives of the Pichiomycetes and 23 outgroup taxa were concatenated to construct a fully supported phylogenetic tree. Consistent with the assumptions, we found that the two new species belong to a novel genus. In addition, the delimitation of the novel species was supported by genetic distance calculations from average nucleotide identity (ANI) and digital DNA:DNA hybridization (dDDH) values. The physiological characterization of the novel species was generally consistent with their genomic content. All strains had two alleles encoding secretory lipase in either two or three copies depending on the species. However, lipolytic activity was detected only in strains with three copies of the secretory lipase gene. Nevertheless, lipolytic activity might be related to their association with the insect gut. Based on these results, formal descriptions of the new genus Rasporella gen. nov. and of two new species Rasporella dianae sp. nov. (holotype UCDFST 68-643T , MycoBank no.: 850238) and Rasporella oleae sp. nov. (holotype ZIM 2471T , MycoBank no.: 850126) are provided.


Targeted delivery of honokiol by zein/hyaluronic acid core-shell nanoparticles to suppress breast cancer growth and metastasis.
Based on the antisolvent and electrostatic deposition methods, we fabricated zein/hyaluronic acid core-shell nanoparticles loaded with honokiol (HA-Zein-HNK), which could target delivery and enhance the therapeutic effect of the HNK. The prepared nanoparticles were found to have a mean size of 210.4 nm and negative surface charge. The HA-Zein-HNK nanoparticles exhibited improved antiproliferative and pro-apoptotic activities against 4T1 cells. Of note, the wound healing and transwell assessments indicated that the migration and invasion of 4T1 cells were markedly weakened by HA-Zein-HNK. Mechanistic insights revealed that HA-Zein-HNK downregulated the expressions of Vimentin and upregulated the expressions of E-cadherin. More importantly, an in vivo tissue distribution study demonstrated the excellent tumor target ability of HA-Zein. And these results correspond with the superior therapeutic efficacy of HA-Zein-HNK in 4T1 tumor bearing mice. In conclusion, we believe that HA-Zein nanoparticles may be served as a promising HNK delivery carrier for metastatic breast cancer therapy.


Characterization of small-field bistratified amacrine cells in macaque retina labeled by antibodies against synaptotagmin-2.
Macaque retinae were immunostained with monoclonal antibodies directed against the protein synaptotagmin-2 (Syt2). Syt2 was localized in a population of small-field amacrine cells, whose cell bodies formed a regular mosaic within the inner nuclear layer, indicating they represent a single amacrine cell type. The labeled amacrine cells had a bistratified appearance with a dense dendritic plexus in the OFF-layer and only a few lobular processes extending into the ON-layer of the inner plexiform layer, similar to A8 amacrine cells described in cat and human retina. Syt2-labeled cells were immunoreactive for glycine but lacked immunoreactivity for γ-aminobutyric acid (GABA), suggesting they use glycine as their neurotransmitter. The density of these cells increases from ∼200/mm(2) in peripheral retina to ∼1,400/mm(2) in central retina. Their bipolar cell input was studied by immunolabeling experiments using various bipolar cell markers combined with CtBP2, a marker of presynaptic ribbons. Our data show that Syt2-labeled amacrine cells receive input from both OFF and ON cone bipolar cells, as well as from rod bipolar cells. The OFF input is dominated by the diffuse bipolar cell DB1 (44%) and the OFF midget bipolar cell (38%). Here we describe a population of bistratified small-field amacrine cells closely resembling A8 amacrine cells and their cone-dominated bipolar cell input. J. Comp. Neurol. 521:709-724, 2013. © 2012 Wiley Periodicals, Inc.


Parathyroid Hormone Resistance and Autoantibodies to the PTH1 Receptor.
We describe two cases of acquired parathyroid hormone (PTH) resistance consequent to the development of serum PTH type 1 receptor (PTH1R) autoantibodies, which block PTH binding and signaling. Both cases were associated with other autoimmune manifestations, and one case was associated with atypical membranous glomerulonephritis. In vitro binding and signaling assays identified the presence of PTH1R-blocking IgG autoantibodies, which were not present in serum samples from patients with other renal or autoimmune disorders. (Funded by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and others.).


Effect of electroacupuncture at "Neiguan" (PC 6) and "Zusanli" (ST 36) on gastrointestinal hormone in the antral tissue of rats with functional dyspepsia.
To observe the effects of electroacupuncture (EA) at "Neiguan" (PC 6) and "Zusanli"(ST 36) on the gastric emptying rate, the level of serotonin (5-HT) and the protein expression of motilin (MTL), ghrelin, substance P (SP) and vasoactive intestinal peptide (VIP) in the antral tissue of the rats with functional dyspepsia (FD) and explore the effect mechanism of EA in treatment of FD. A total of 21 SPF male SD rat pups were randomly divided into a normal group, a model group and an EA group, with 7 rats in each group. In the model group and the EA group, FD model was prepared by the gavage with 0.1% sucrose iodoacetamide solution combined with the modified small platform method. After the successful modeling, EA was applied to "Neiguan" (PC 6) and "Zusanli"(ST 36) in the rats of the EA group, with disperse-dense wave, 20 Hz/100 Hz in frequency, stimulated for 30 min, once daily, for 7 days consecutively. Before and after intervention, the general condition of the rats was observed in each group. After the completion of intervention, the gastric emptying rate was measured, the morphological changes of gastric antral tissue were observed using HE staining, the level of 5-HT was detected with ELISA method, and the protein expression of MTL, ghrelin, SP, and VIP was determined with Western blot method in the antral tissue of rats. In the normal group, the rats were in a good mental state, with lustrous fur, flexible movement and the increase of food intake and body mass. In the model group, the rats were poor in mental state, lack of lustre in fur, preference for the body curled up, reduced activity and response; and a part of rats had loose stool, obviously enlarged gastric body and gastric food retention. In the EA group, the general condition of rats, e.g. the mental state, food intake and activity, were improved, the gastric body got smaller obviously and the gastric food retention was reduced when compared with the model group. The antral structure was intact, the glands were rich and no injury of the gastric mucosa was found, e.g. inflammatory reaction and edema in the rats of each group. Compared with the normal group, the gastric emptying rate was decreased (P<0.01), 5-HT level was increased (P<0.01), the protein expression of MTL and ghrelin was reduced (P<0.01) and that of VIP was elevated (P<0.01) in the rats of the model group. The gastric emptying rate was increased (P<0.01), 5-HT level was decreased (P<0.01), and the protein expression of MTL and ghrelin was elevated (P<0.05, P<0.01) in the rats of the EA group when compared with those in the model group. Electroacupuncture at "Neiguan" (PC 6) and "Zusanli"(ST 36) may effectively relieve gastric dysfunction, strengthen gastric motility and promote gastric emptying so as to alleviate the symptoms of dyspepsia in FD rats, and its mechanism may be related to the regulation of gastrointestinal hormones in the antral tissue.


Benefits and costs of alcoholic relationships and recovery through Al-Anon.
Codependence is an ambiguous and disputed term often used to characterize both those who maintain relationships with alcoholics and those who seek help through resources such as Al-Anon Family Groups. The purpose of this article is to better understand non-pathological reasons for maintaining alcoholic relationships and for help-seeking by detailing the costs and benefits of those choices. The costs and benefits both of remaining in an alcoholic relationship and of seeking help in Al-Anon were identified through a review of available research on alcoholic family systems, Al-Anon, and other mutual-support groups. Alcoholic relationships may benefit concerned others by preserving self-identity, social identity, values, security, stability, and hope. Costs of alcoholic relationships include physical symptoms, injury, mental problems, financial difficulty, legal troubles, and relational distress. Al-Anon is perceived beneficial for six primary reasons: Al-Anon philosophy, format, social support, accessibility, effectiveness, and potential to change the drinker's behavior. Possible costs of Al-Anon include marginalization of the concerned other, blame, codependent pathology, sexist stereotyping, substitute dependency, and perpetuating victimization. Conclusions/Importance: The identified costs and benefits of alcoholic relationships and help-seeking in Al-Anon can help to model decision-making processes using existing behavioral health frameworks without defaulting to the stigmatized and ambiguous codependence terminology.


Herbivore pressure increases toward the equator.
Increases in species diversity and density from higher to lower latitudes are well documented. Nevertheless, the consequences of these changes in diversity for structuring ecological communities and influencing biotic evolution are largely unknown. It is widely believed that this increase in species diversity is associated with increased intensity of ecological interactions closer to the equator. For plant-herbivore interactions in particular, the predictions are that, at lower latitudes, plants will be attacked by more individual herbivores, more herbivore species, and more specialized herbivores and, therefore, will suffer greater damage. We used a large-scale latitudinal transect from Mexico to Bolivia to quantify changes in leaf damage, diversity, and abundance of lepidopteran larvae on two widely distributed host species of the genus Piper (Piperaceae). We show that both density and species richness of herbivores were highest at the equator and decreased with increasing latitude, both northward and southward. Contrary to expectation, however, this increase in herbivore diversity was attributable to the addition of generalist not specialist species. Finally, and again contrary to expectation, the increase in herbivore density with decreasing latitude did not produce a corresponding damage gradient. We propose that the lack of a latitudinal concordance between increases in herbivore density and diversity with decreasing latitude, and the resulting herbivore damage, supports the hypothesis of better plant antiherbivore defenses at lower latitudes. Furthermore, the changes in the relative abundance of generalist vs. specialist species suggest that the nature of the selective pressure is intrinsically different between higher and lower latitudes.


Assessing hospital-associated deaths from discharge data. The role of length of stay and comorbidities.
To assess the meaning of hospital-associated death rates, we studied whether mortality within 30 days of hospital admission (30-day mortality) is more informative than inpatient mortality and whether detailed assessment of additional discharge diagnoses helps in understanding death rates. We examined hospitalizations for elderly Medicare patients with principal diagnoses of stroke, bacterial pneumonia, myocardial infarction, and congestive heart failure; these conditions account for 30.8% of Medicare 30-day mortality. Average hospital stays for these conditions were 99.0% longer, and inpatient mortality was 25.0% higher in New York than in California, but 30-day mortality was 1.6% higher in California. We conclude that inpatient death rates depend on length-of-stay patterns and give a biased picture of mortality. Additional diagnoses such as shock and pneumonia were strongly associated with increased mortality, but Medicare data do not reveal which patients had these conditions at the time of admission. Recorded diagnoses of chronic diseases such as hypertension, diabetes mellitus, obesity, benign prostatic hypertrophy, and osteoarthritis were commonly associated with reduced risk of death; such reduced risk is not clinically plausible. Several lines of evidence suggest that chronic disorders are underreported for patients with life-threatening disorders. We recommend great caution in using discharge diagnoses of comorbid conditions to adjust hospital death rates for clinical differences in the patient populations.


Histatin-5 interacts with cellular copper to promote antifungal activity against Candida albicans.
Histatin-5 (Hist-5) is an antimicrobial peptide found in human saliva that functions to defend the oral cavity from microbial infections, such as those caused by the fungal pathogen Candida albicans (C. albicans). Hist-5 can bind Cu in multiple oxidation states, Cu2+ and Cu+ in vitro, and supplemental Cu2+ has been shown to improve the fungicidal activity of the peptide against C. albicans in culture. However, the exact role of Cu on the antifungal activity of Hist-5 and whether direct peptide-Cu interactions occur intracellularly has yet to be fully determined. Here, we used a combination of fluorescence spectroscopy and confocal microscopy experiments to show reversible Cu-dependent quenching of a fluorescent Hist-5 analogue, Hist-5*, indicating a direct interaction between Hist-5 and intracellular Cu. X-ray fluorescence microscopy images revealed peptide-induced changes to cellular Cu distribution and cell-associated Cu content. These data support a model in which Hist-5 can facilitate the hyperaccumulation of Cu in C. albicans and directly interact with Cu intracellularly to increase the fungicidal activity of Hist-5.


Labelling of prolyl hydroxylase tetrameric subunits in freshly isolated chick-embryo tendon cells and in certain chick-embryo tissues in vivo.
The labelling of the subunits of prolyl 4-hydroxylase tetramers was studied in freshly isolated chick-embryo tendon cells and in chick-embryo tissues. In the former both the alpha- and beta-subunits of the tetramer were labelled during a 4 h labelling and 2 h chase period, although the radioactivity in the beta-subunit was much lower than in the alpha-subunit. The corresponding subunits of the enzyme from 12-day chick-embryo cartilaginous bone and heart were labelled in 7 h, again the beta-subunit much less than the alpha-subunit, the ratio of radioactivity in the beta-subunit to that in the alpha-subunit (beta/alpha-radioactivity) being 0.20 and 0.32 respectively. The beta/alpha-radioactivity then increased almost linearily with time between 7 and 24 h, by 9.5-fold in the cartilaginous bone and 3-fold in the heart, and beta/alpha-radioactivity values above 1.0 were reached. The free beta-subunit-size protein (the beta'-protein), which is also present in cells, had been labelled quite heavily by 7 h. The beta/alpha-radioactivity at 7h, determined in four tissues with different ratios of prolyl hydroxylase tetramers to total immunoreactive protein (tetramer percentage), was low in tissues with a high tetramer percentage. It is thus proposed that only a minor fraction of the beta'-protein must be processed to the tetrameric beta-subunit and utilized in the synthesis of the prolyl 4-hydroxylase tetramers.


Hadza meat sharing.
In most human foraging societies, the meat of large animals is widely shared. Many assume that people follow this practice because it helps to reduce the risk inherent in big game hunting. In principle, a hunter can offset the chance of many hungry days by exchanging some of the meat earned from a successful strike for shares in future kills made by other hunters. If hunting and its associated risks of failure have great antiquity, then meat sharing might have been the evolutionary foundation for many other distinctively human patterns of social exchange. Here we use previously unpublished data from the Tanzanian Hadza to test hypotheses drawn from a simple version of this argument. Results indicate that Hadza meat sharing does not fit the expectations of risk-reduction reciprocity. We comment on some variations of the "sharing as exchange" argument; then elaborate an alternative based partly on the observation that a successful hunter does not control the distribution of his kill. Instead of family provisioning, his goal may be to enhance his status as a desirable neighbor. If correct, this alternative argument has implications for the evolution of men's work.


[Effect of bone marrow mesenchymal stem cells-derived extracellular matrix scaffold on chondrogenic differentiation of marrow clot after microfracture of bone marrow stimulation in vitro].
To evaluate the feasibility and validity of chondrogenic differentiation of marrow clot after microfracture of bone marrow stimulation combined with bone marrow mesenchymal stem cells (BMSCs)-derived extracellular matrix (ECM) scaffold in vitro. BMSCs were obtained and isolated from 20 New Zealand white rabbits (5-6 months old). The 3rd passage cells were cultured and induced to osteoblasts, chondrocytes, and adipocytes in vitro, respectively. ECM scaffold was manufactured using the 3rd passage cells via a freeze-dying method. Microstructure was observed by scanning electron microscope (SEM). A full-thickness cartilage defect (6 mm in diameter) was established and 5 microholes (1 mm in diameter and 3 mm in depth) were created with a syringe needle in the trochlear groove of the femur of rabbits to get the marrow clots. Another 20 rabbits which were not punctured were randomly divided into groups A (n=10) and B (n=10): culture of the marrow clot alone (group A) and culture of the marrow clot with transforming growth factor beta3 (TGF-beta3) (group B). Twenty rabbits which were punctured were randomly divided into groups C (n=10) and D (n=10): culture of the ECM scaffold and marrow clot composite (group C) and culture of the ECM scaffold and marrow clot composite with TGF-beta3 (group D). The cultured tissues were observed and evaluated by gross morphology, histology, immunohistochemistry, and biochemical composition at 1, 2, 4, and 8 weeks after culture. Cells were successfully induced into osteoblasts, chondrocytes, and adipocytes in vitro. Highly porous microstructure of the ECM scaffold was observed by SEM. The cultured tissue gradually reduced in size with time and disappeared at 8 weeks in group A. Soft and loose structure developed in group C during culturing. Chondroid tissue with smooth surface developed in groups B and D with time. The cultured tissue size of groups C and D were significantly larger than that of group B at 4 and 8 weeks (P < 0.05); group D was significantly larger than group C in size (P < 0.05). Few cells were seen, and no glycosaminoglycan (GAG) and collagen type II accumulated in groups A and C; many cartilage lacunas containing cells were observed and more GAG and collagen type II were synthesized in groups B and D. The contents of GAG and collagen increased gradually with time in groups B and D, especially in group D, and significant difference was found between groups B and D at 4 and 8 weeks (P < 0.05). The BMSCs-derived ECM scaffold combined with the marrow clot after microfracture of bone marrow stimulation is effective in TGF-beta3-induced chondrogenic differentiation in vitro.


Vascularised bone grafting for fibrous dysplasia of the upper limb.
We describe our experience with vascularised bone grafting for the treatment of fibrous dysplasia of the upper limb in eight patients, five men and three women, aged between 17 and 36 years. The site was in the humerus in six and the radius in two. Persistent pain, progression of the lesion and pathological fracture with delayed union were the indications for surgical intervention. We used a vascularised fibular graft after curettage of the lesion. Function and radiological progress were serially monitored. Early radiological union of the graft occurred at periods ranging from 8 to 14 weeks. The mean period for reconstitution of the diameter of the bone was 14 months (12 to 18) predominantly through inductive formation of bone around the vascularised graft, which was a prominent feature in all patients. There were no recurrences and none of the grafts sustained a fracture or failed to unite. After operation function was excellent in three patients and good in five. Vascularised bone grafts provide a safe and reliable means of ensuring good continuity of bone with little risk of recurrence and failure.


Fatigue at time of CIS is an independent predictor of a subsequent diagnosis of multiple sclerosis.
Fatigue is a common, disabling symptom of multiple sclerosis (MS), but little is known about fatigue in patients with clinically isolated syndrome (CIS), often the presenting symptom of MS. We aimed to investigate the prevalence and severity of fatigue in patients with CIS, and its association with a diagnosis of clinically definite MS (CDMS). 127 patients were consecutively included in our ongoing prospective CIS study. At baseline, clinical, demographic, laboratory and MRI data were collected, and fatigue severity was assessed using Krupp's Fatigue Severity Scale (FSS); fatigue was defined as FSS≥5.0. Fatigue scores were compared with scores of 113 healthy controls and with scores from the literature. The association of fatigue with CDMS was calculated using Cox regression models. The mean FSS of patients with CIS was 4.3, similar to MS patients, and significantly higher than that of healthy individuals (p<0.001). Fatigue prevalence in patients with CIS (46.5%) was significantly higher than in controls (p<0.001). Fifty-two patients (40.9%) reached CDMS during follow-up. Fatigue was associated with a diagnosis of CDMS in univariate analysis (HR 2.6, 95% CI 1.5 to 4.6) and in multivariate analysis correcting for sex, age, neuroanatomical localisation of CIS, 25-OH-vitamin D, anxiety, depression, MRI dissemination in space and gadolinium enhancement (HR 4.5, 95% CI 1.9 to 10.6). Already at the stage of CIS, fatigue is a very common symptom, with a severity similar to fatigue in MS patients. This fatigue seems unrelated to the type or severity of the attack. Importantly, we found that fatigue was an independent predictor of a subsequent diagnosis of MS.


The Safe Dates program: 1-year follow-up results.
An earlier report described desirable 1-month follow-up effects of the Safe Dates program on psychological, physical, and sexual dating violence. Mediators of the program-behavior relationship also were identified. The present report describes the 1-year follow-up effects of the Safe Dates program. Fourteen schools were in the randomized experiment. Data were gathered by questionnaires in schools before program activities and 1 year after the program ended. The short-term behavioral effects had disappeared at 1 year, but effects on mediating variables such as dating violence norms, conflict management skills, and awareness of community services for dating violence were maintained. The findings are considered in the context of why program effects might have decayed and the possible role of boosters for effect maintenance.


Imaging gene expression in the brain in vivo in a transgenic mouse model of Huntington's disease with an antisense radiopharmaceutical and drug-targeting technology.
Disease-specific genes of unknown function can be imaged in vivo with antisense radiopharmaceuticals, providing the transcellular transport of these molecules is enabled with drug-targeting technology. The current studies describe the production of 16-mer peptide nucleic acid (PNA) that is antisense around the methionine initiation codon of the huntingtin gene of Huntington's disease (HD). The PNA is biotinylated, which allows for rapid capture by a conjugate of streptavidin and the rat 8D3 monoclonal antibody (mAb) to the mouse transferrin receptor (TfR), and contains a tyrosine residue, which enables radiolabeling with 125I. The reformulated PNA antisense radiopharmaceutical that is conjugated to the 8D3 mAb is designated 125I-PNA/8D3. This form of the PNA is able to access endogenous transferrin transport pathways at both the blood-brain barrier and the brain cell membrane and undergoes both import from the blood to the brain and export from the brain to the blood through the TfR. The ability of the PNA to hybridize to the target huntingtin RNA, despite conjugation to the mAb, was shown both with cell-free translation assays and with ribonuclease protection assays. The 125I-PNA/8D3 conjugate was administered intravenously to either littermate control mice or to R6/2 transgenic mice, which express the exon 1 of the human HD gene. The mice were sacrificed 6 h later for frozen sectioning of the brain and quantitative autoradiography. The studies showed a 3-fold increase in sequestration of the 125I-PNA/8D3 antisense radiopharmaceutical in the brains of the HD transgenic mice in vivo, consistent with the selective expression of the HD exon-1 messenger RNA in these animals. These results support the hypothesis that gene expression in vivo can be quantitated with antisense radiopharmaceuticals, providing these molecules are reformulated with drug-targeting technology. Drug targeting enables access of the antisense agent to endogenous transport pathways, which permits passage across the cellular barriers that separate blood and intracellular compartments of target tissues.


Antidepressant therapy in post-stroke depression.
About 40% of patients with stroke will develop depression at some stage after the acute event. Post-stroke depression (PSD) is associated with a poor prognosis. Depressed patients have more severe deficits in activities of daily living, a worse functional outcome, more severe cognitive deficits and increased mortality as compared to stroke patients without depression. This review will focus on available controlled trials of treatment for PSD. An unsystematic review of recent studies for the treatment of PSD. Randomized controlled trials have demonstrated the efficacy of sertraline, citalopram and nortriptyline to treat post-stroke depression. Whether antidepressant medication may help to prevent post-stroke depression and decrease post-stroke mortality will require further controlled studies.


Endocrine therapy for breast cancer in the primary care setting.
The treatment of hormone-positive breast cancer (bca) is a rapidly evolving field. Improvement in the understanding of the mechanisms of action and resistance to anti-hormonal therapy has translated, in the past decade, into multiple practice-changing clinical trials, with the end result of increased survivorship for patients with all stages of hormone-positive cancer. The primary care physician will thus play an increasing role in the routine care, surveillance, and treatment of issues associated with anti-hormonal therapy. The aim of the present review was to provide a focused description of the issues relevant to primary care, while briefly highlighting recent advances in the field of anti-hormonal therapy. ■ Hormone-positive bca is the most prevalent form of bca and, compared with the other subtypes, is usually associated with better survival.■ Survivorship has significantly increased for all stages of hormone-positive bca, making the primary care physician a key player in the care of affected patients.■ The two most common classes of anti-hormonal agents used in these patients are selective estrogen receptor modulators and aromatase inhibitors. Each class of medication is associated with signature side effects.■ Within the past decade, multiple novel estrogen receptor blockers (for example, fulvestrant) and agents aimed at circumventing resistance to endocrine therapy [inhibitors of cyclin-dependent kinase 4/6 and of mtor (the mechanistic target of rapamycin)] have gained clinical ground. Understanding their side effects will be increasingly relevant to primary care physicians.■ Multidisciplinary care is always encouraged in the care of cancer patients receiving anti-hormonal therapy.


Acute Tachycardia-Induced Cardiomyopathy: A Case Report.
BACKGROUND Tachycardia from atrial fibrillation or flutter can lead to left ventricular systolic dysfunction. Some patients deteriorate quickly, and there is an acute drop in their left ventricular systolic function; however, they tend to normalize rapidly after treatment of the underlying arrhythmia. The aim of publishing the present case is to maintain awareness that tachycardia is one of the etiologies of acute systolic heart failure, which is potentially reversible by treatment when recognized. CASE REPORT An 88-year-old woman with a history of hypertension and diabetes presented to the emergency department with shortness of breath and new-onset atrial fibrillation. The physical examination revealed jugular vein distention, an irregular heart rate of approximately 140 beats/min, bilateral basal lung crackles, and no murmurs. One week before this presentation, she underwent electrocardiography, which showed she was in sinus rhythm, and transthoracic echocardiography, which indicated an ejection fraction of 65%. After hospital admission, she was started on beta-blockers for heart rate control and diuretics for heart failure management. As her symptoms persisted, she underwent a transesophageal echocardiography-guided cardioversion, where her ejection fraction was 30%. A repeat transthoracic echocardiography 3 days after the cardioversion indicated the ejection fraction had normalized to 60%. She was followed up every month in the Outpatient Cardiology Clinic and has remained asymptomatic for 1 year to date. CONCLUSIONS Although most literature describes tachycardia-induced cardiomyopathy as a chronic process, it can be acute. Patients benefit from rhythm control, and with early diagnosis and appropriate management, the prognosis is good.


Dietary fatty acids and risk of coronary heart disease in men: the Kuopio Ischemic Heart Disease Risk Factor Study.
The epidemiological evidence of the role of dietary saturated fatty acids (SFA) in the development of coronary heart disease (CHD) is inconsistent. We investigated the associations of dietary fatty acids with the risk of CHD and carotid atherosclerosis in men with high SFA intake and high rates of CHD. In total, 1981 men from the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42 to 60 years and free of CHD at baseline in 1984 to 1989, were investigated. Food consumption was assessed with 4-day food recording. Multivariate nutrient-density models were used to analyze isocaloric replacement of nutrients. CHD events were ascertained from national registries. Carotid atherosclerosis was assessed by ultrasonography of the common carotid artery intima-media thickness in 1015 men. During the average follow-up of 21.4 years, 183 fatal and 382 nonfatal CHD events occurred. SFA or trans fat intakes were not associated with CHD risk. In contrast, monounsaturated fat intake was associated with increased risk and polyunsaturated fat intake with decreased risk of fatal CHD, whether replacing SFA, trans fat, or carbohydrates. The associations with carotid atherosclerosis were broadly similar, whereas the associations with nonfatal CHD were weaker. Our results suggest that SFA intake is not an independent risk factor for CHD, even in a population with higher ranges of SFA intake. In contrast, polyunsaturated fat intake was associated with lower risk of fatal CHD, whether replacing SFA, trans fat, or carbohydrates. Further investigation on the effect of monounsaturated fat on the CHD risk is warranted.


Effects of acute and chronic nicotine on responses maintained by primary and conditioned reinforcers in rats.
There is growing recognition that nonnicotine factors, such as the sensory stimuli associated with smoking, can play a critical role in the maintenance of cigarette smoking. However, little is known about the effects of nicotine on responding maintained by these stimuli, which are assumed to be conditioned reinforcers. The authors used an animal model to examine the acute and chronic effects of nicotine on responses maintained by food and conditioned reinforcers (i.e., lights) and responses in the absence of programmed consequences (i.e., extinction). During the acute phase, 4 male rats received 5 doses of subcutaneous nicotine. One dose of nicotine was then administered for a minimum of 60 days. Food-maintained and extinction responses did not significantly increase during the acute phase; however, food-maintained responses did increase during the chronic phase. Relative to vehicle, intermediate doses increased responses maintained by conditioned reinforcers during both phases. The results suggest that nicotine enhances responding maintained by conditioned reinforcers and possibly by food.


Contribution of protein kinase C to ET-1-induced proliferation in human myometrial cells.
The role of protein kinase C (PKC) in endothelin-1 (ET-1)-induced proliferation of human myometrial cells was investigated. ET-1 dose dependently stimulated DNA synthesis and the number of cultured myometrial cells. Inhibition of PKC by calphostin C or Ro-31-8220 or downregulation of PKC eliminated the proliferative effects of ET-1. The failure of two protein tyrosine kinase (PTK) inhibitors (tyrphostin 51 and tyrphostin 23) to affect ET-1-induced proliferation supports the hypothesis of noninvolvement of the tyrosine kinase signaling pathway in this process. The expression and distribution of PKC isoforms were examined by Western blot analysis. The five PKC isoforms (PKC-alpha, -beta1, -beta2, -zeta, -epsilon) evidenced in human myometrial tissue were found to be differentially expressed in myometrial cells, with a predominant expression of PKC-alpha and PKC-zeta. Treatment with phorbol 12, 13-dibutyrate (PDBu) resulted in the translocation of all five isoforms to the particulate fraction, whereas ET-1 induced a selective increase in particulate PKC-beta1, PKC-beta2, and PKC-epsilon. Our findings that multiple PKC isoforms are differentially responsive to ET-1 or PDBu suggest that they play distinct roles in the myometrial growth process.


Identifying intervention strategies for preventing the mental health consequences of childhood adversity: A modified Delphi study.
Exposure to childhood adversity is a powerful risk factor for psychopathology. Despite extensive efforts, we have not yet identified effective or scalable interventions that prevent the emergence of mental health problems in children who have experienced adversity. In this modified Delphi study, we identified intervention strategies for effectively targeting both the neurodevelopmental mechanisms linking childhood adversity and psychopathology - including heightened emotional reactivity, difficulties with emotion regulation, blunted reward processing, and social information processing biases, as well as a range of psychopathology symptoms. We iteratively synthesized information from experts in the field and relevant meta-analyses through three surveys, first with experts in intervention development, prevention, and childhood adversity (n = 32), and then within our study team (n = 8). The results produced increasing stability and good consensus on intervention strategy recommendations for specific neurodevelopmental mechanisms and symptom presentations and on strength of evidence ratings of intervention strategies targeting youth and parents. More broadly, our findings highlight how intervention decision making can be informed by meta-analyses, enhanced by aggregate group feedback, saturated before consensus, and persistently subjective or even contradictory. Ultimately, the results converged on several promising intervention strategies for prevention programming with adversity-exposed youth, which will be tested in an upcoming clinical trial.


Transforming growth factor-beta (TGF- 1) down-regulates Notch3 in fibroblasts to promote smooth muscle gene expression.
Select signaling pathways have emerged as key players in regulating smooth muscle gene expression during myofibroblast and smooth muscle differentiation, an event that is important for wound healing and vascular remodeling. These include the transforming growth factor-beta (TGF-beta1) signaling cascade, which has been assigned multiple roles in these cells, and the Notch pathway. Notch family members have been implicated in governing cell fate in a variety of cells; however, the mechanisms are not well understood. We sought to explore how these prominent signaling mediators regulate differentiation, and in particular, how they might converge to control the transcription of smooth muscle genes. Using TGF-beta1 to induce the differentiation of 10T1/2 fibroblasts, we investigated the specific function of Notch3. Overexpression of activated Notch3 caused repression of TGF-beta1-induced smooth muscle-specific genes, whereas knockdown of Notch3 by small interfering RNA did not convincingly alter their expression. Surprisingly, the addition of TGF-beta1 caused a significant decrease in Notch3 RNA and protein and a reciprocal increase in Hes1 gene transcription. The repression of Notch3 was mediated by SMAD activity and p38 mitogen-activated protein (MAP) kinase, whereas analysis of the Hes1 promoter revealed direct activation by Smad2 but not Smad3. Furthermore, the Hes1 repressor protein augmented Smad3 transactivation of the SM22alpha promoter. These results offer a novel mechanism by which TGF-beta1 promotes the expression of smooth muscle differentiation genes through the inhibition of Notch3 and activation of Hes1.


Postoperative pancreatic fistula: an international study group (ISGPF) definition.
Postoperative pancreatic fistula (POPF) is still regarded as a major complication. The incidence of POPF varies greatly in different reports, depending on the definition applied at each surgical center. Our aim was to agree upon an objective and internationally accepted definition to allow comparison of different surgical experiences. An international panel of pancreatic surgeons, working in well-known, high-volume centers, reviewed the literature on the topic and worked together to develop a simple, objective, reliable, and easy-to-apply definition of POPF, graded primarily on clinical impact. A POPF represents a failure of healing/sealing of a pancreatic-enteric anastomosis or a parenchymal leak not directly related to an anastomosis. An all-inclusive definition is a drain output of any measurable volume of fluid on or after postoperative day 3 with an amylase content greater than 3 times the serum amylase activity. Three different grades of POPF (grades A, B, C) are defined according to the clinical impact on the patient's hospital course. The present definition and clinical grading of POPF should allow realistic comparisons of surgical experiences in the future when new techniques, new operations, or new pharmacologic agents that may impact surgical treatment of pancreatic disorders are addressed.


Comparison of microvascular flow imaging and contrast-enhanced ultrasound for blood flow analysis of cervical lymph node lesions.
To compare the diagnostic value of microvascular flow imaging (MVFI) with that of contrast-enhanced ultrasound (CEUS) for the analysis of blood flow in benign and malignant cervical lymph nodes. As a prospective study, 95 cervical enlarged lymph nodes (43 benign and 52 malignant) were observed in 95 patients using conventional ultrasonography (including gray and Color Doppler Flow Imaging), CEUS, and MVFI. Two researchers evaluated vascular parameters of MVFI (vascular distribution, internal vascular features, vascular index) and CEUS (enhancement mode, enhancement type) and compared the diagnostic effects of MVFI and CEUS.All results were compared with pathological findings. There were significant differences in the vascular distribution and internal vascular features of benign and malignant lymph nodes on MVFI (P < 0.05). The vascular distribution of benign lymph nodes was mainly of the central and avascular types, the internal blood vessels were mostly normal, the vascular distribution of malignant lymph nodes was mainly mixed, the internal vessels were mainly tortuous and displaced. The optimal cut-off value of the benign and malignant lymph node vascular index (VI) was 15.55%, and the area under the receiver operating characteristic curve (AUC) of the VI was 0.876. There were also significant differences in the enhancement mode and types of benign and malignant lymph nodes in CEUS (P < 0.05). The benign lymph nodes showed centrifugal perfusion, and the enhancement types were mostly type I and type II. Most malignant lymph nodes showed centripetal or mixed perfusion, and the enhancement types were usually type III and type IV. The accuracy, sensitivity, and specificity of CEUS in the diagnosis of lymph node lesions were 84.2%, 84.6% and 83.7%, respectively, and the AUC was 0.845. The accuracy, sensitivity, and specificity of MVFI in the diagnosis of lymph node lesions were 85.3%, 84.6%, and 86.0%, respectively, and the AUC was 0.886. Both CEUS and MVFI are valuable in differentiating benign and malignant lesions of lymph nodes and have a similar diagnostic performance; however, MVFI is less invasive and simpler than CEUS. Therefore it is preferred for auxiliary examination of enlarged lymph nodes that are difficult to diagnose by conventional ultrasound.


Larynx preservation in surgical treatment of cervical esophageal cancer--combined procedure of laryngeal suspension and cricopharyngeal myotomy.
From July 1994 to July 1998, a larynx-preserving procedure was performed on 10 out of 22 (45%) patients in the surgical treatment of hypopharyngeal and cervical esophageal cancer. At first, all 10 patients were treated with concurrent radiochemotherapy with cisplatin (10 mg/m2/day), 5-fluorouracil (500 mg/m2/day) and radiation (2 Gy/day) five times per week for 4 weeks. After preoperative radiochemotherapy, the larynx-preserving procedure, combining laryngeal suspension and cricopharyngeal myotomy, was performed. The operative and hospital mortality rate was 0%. The incidence of post-operative morbidity with minor complications was 70% in the present study. Laryngeal speech and oral food intake were preserved in all patients after this procedure. The new larynx-preserving procedure combining laryngeal suspension and cricopharyngeal myotomy for cervical esophageal cancer is a favorable operative method for retaining intelligible laryngeal speech and good food intake.


[Clinical course of restenosis after carotid endarterectomy].
Angiologic and neurologic examinations, ultrasonic dopplerography were performed in 89 patients after operation of carotid endarterectomy. Period of observation was 6-182 months after operation (61 months on the average). Positive clinical effect (absence of disorders of cerebral circulation-DCC) was achieved in 91% of cases. The frequency of both repeated transitory ischemic attacks and the strokes was 9%, the best frequency being in patients with initially asymptomatic course. It was found that the degree of restenosis directly correlated with frequency of neurologic symptom development: there were no repeated DCC in normal state of the operated artery. Meanwhile DCC frequency was less than 4% in cases with the degree of restenosis less than 60% and was equal to 15.8% in more than 60% restenosis. DCC were more frequently found in occlusion of internal carotid artery. Rather favourable course of restenosis of carotid artery was also conditioned by low content of the plaques dangerous in terms of embolism. Progression of atherosclerotic damages in other parts of extracranial arteries promoted clinical manifestation of cerebral ischemia. Moreover, negative neurologic dynamics developed in 7% of the patients with restenosis less than 60%, and in 13.8% of cases with restenosis more than 60%. The conclusion was made about efficiency of carotid endarterectomy in patients with atherosclerotic damages of carotid arteries. For prevention of repeated DCC it is recommended both to perform conservative therapy after the operation and to examine dynamically the patients using ultrasonic dopplerography beginning 6 months after the operation.


Death receptors.
Death receptors [Fas/Apo-1/CD95, TNF-R1 [tumour necrosis factor (TNF) receptor 1], DR3 [death receptor 3], TRAIL-R1 [TNF-related apoptosis-inducing ligand receptor 1], TRAIL-R2, DR6, p75-NGFR [p75-nerve growth factor receptor], EDAR [ectodermal dysplasia receptor]] form a subgroup of the TNF-R superfamily that can induce apoptosis (programmed cell death) via a conserved cytoplasmic signalling module termed the death domain. Although death receptors have been recognized mainly as apoptosis inducers, there is growing evidence that these receptors also fulfil a variety of nonapoptotic functions. This review is focused on the molecular mechanisms of apoptotic and non-apoptotic death receptor signalling in light of the phenotype of mice deficient in the various death receptors.


A rapid method for cross-species quantitation of apolipoproteins A1, B48 and B100 in plasma by ultra-performance liquid chromatography/tandem mass spectrometry.
Apolipoprotein B100 (apoB100) and apolipoprotein A1 (apoA1) are the primary protein components of low density lipoprotein (LDL) and high density lipoprotein (HDL) particles, respectively, and plasma levels of these proteins are associated with risks of cardiovascular disease. Existing apoB100 quantitation methods for animal models have been limited to affinity capture techniques such as enzyme-linked immunosorbent assay (ELISA) and Western blot which require specialized reagents for each species and in many cases are not readily available. Here we demonstrate a single translatable ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) assay that is fast and robust and can be used to measure apolipoprotein concentrations in plasma for six species. When possible, peptide sequences that are conserved across species were identified for this assay. The sample preparation is limited and can be carried out in 96-well microtiter plates and thus allows for multiplexed preparation of samples for analysis of large numbers of samples in a short time frame when combined with UPLC/MS/MS. Separation and quantitation of the tryptic peptides is carried out at 700 μL/min using a 1.7 µm core shell C18 column (2.1 × 50 mm). The chromatography is designed for the analysis of over 100 samples per day, and the UPLC run is less than 10 min. This assay is capable of supporting cardiovascular research by providing a single assay to measure critical biomarkers across multiple species without the need for antibodies, and does so in a high-throughput manner.


Distinct clonal lineages and within-host diversification shape invasive Staphylococcus epidermidis populations.
S. epidermidis is a substantial component of the human skin microbiota, but also one of the major causes of nosocomial infection in the context of implanted medical devices. We here aimed to advance the understanding of S. epidermidis genotypes and phenotypes conducive to infection establishment. Furthermore, we investigate the adaptation of individual clonal lines to the infection lifestyle based on the detailed analysis of individual S. epidermidis populations of 23 patients suffering from prosthetic joint infection. Analysis of invasive and colonizing S. epidermidis provided evidence that invasive S. epidermidis are characterized by infection-supporting phenotypes (e.g. increased biofilm formation, growth in nutrient poor media and antibiotic resistance), as well as specific genetic traits. The discriminating gene loci were almost exclusively assigned to the mobilome. Here, in addition to IS256 and SCCmec, chromosomally integrated phages was identified for the first time. These phenotypic and genotypic features were more likely present in isolates belonging to sequence type (ST) 2. By comparing seven patient-matched nasal and invasive S. epidermidis isolates belonging to identical genetic lineages, infection-associated phenotypic and genotypic changes were documented. Besides increased biofilm production, the invasive isolates were characterized by better growth in nutrient-poor media and reduced hemolysis. By examining several colonies grown in parallel from each infection, evidence for genetic within-host population heterogeneity was obtained. Importantly, subpopulations carrying IS insertions in agrC, mutations in the acetate kinase (AckA) and deletions in the SCCmec element emerged in several infections. In summary, these results shed light on the multifactorial processes of infection adaptation and demonstrate how S. epidermidis is able to flexibly repurpose and edit factors important for colonization to facilitate survival in hostile infection environments.


The RNA-binding protein IMP-3 is a translational activator of insulin-like growth factor II leader-3 mRNA during proliferation of human K562 leukemia cells.
IMP-3, a member of the insulin-like growth factor-II (IGF-II) mRNA-binding protein (IMP) family, is expressed mainly during embryonic development and in some tumors. Thus, IMP-3 is considered to be an oncofetal protein. The functional significance of IMP-3 is not clear. To identify the functions of IMP-3 in target gene expression and cell proliferation, RNA interference was employed to knock down IMP-3 expression. Using human K562 leukemia cells as a model, we show that IMP-3 protein associates with IGF-II leader-3 and leader-4 mRNAs and H19 RNA but not c-myc and beta-actin mRNAs in vivo by messenger ribonucleoprotein immunoprecipitation analyses. IMP-3 knock down significantly decreased levels of intracellular and secreted IGF-II without affecting IGF-II leader-3, leader-4, c-myc, or beta-actin mRNA levels and H19 RNA levels compared with the negative control siRNA treatment. Moreover, IMP-3 knock down specifically suppressed translation of chimeric IGF-II leader-3/luciferase mRNA without altering reporter mRNA levels. Together, these results suggest that IMP-3 knock down reduced IGF-II expression by inhibiting translation of IGF-II mRNA. IMP-3 knock down also markedly inhibited cell proliferation. The addition of recombinant human IGF-II peptide to these cells restored cell proliferation rates to normal. IMP-3 and IMP-1, two members of the IMP family with significant structural similarity, appear to have some distinct RNA targets and functions in K562 cells. Thus, we have identified IMP-3 as a translational activator of IGF-II leader-3 mRNA. IMP-3 plays a critical role in regulation of cell proliferation via an IGF-II-dependent pathway in K562 leukemia cells.


The effects of an alpha-glucoside hydrolase inhibitor on glycemia and the absorption of sucrose in man determined using a tracer method.
Acarbose, an alpha-glucosidase inhibitor, lowers the glycemic excursion following the ingestion of carbohydrates, in particular, sucrose. This was confirmed with increasing doses of acarbose (0, 50, and 100 mg) and the causes investigated. The absorption of the glucose moiety of sucrose was determined from plasma tracer concentrations when overnight-fasted normal subjects received a 100-g oral sucrose load labeled with sucrose [(1-14C]glucose and a simultaneous intravenous infusion of [3-3H]glucose. As the dose of acarbose given with the sucrose load was increased from 0 to 100 mg, the percentage of the load appearing in the peripheral circulation decreased from 90% to 62%. Malabsorption was confirmed by the appearance of breath hydrogen. Simultaneously, absorption time increased from 243 to 411 min. Maximal glycemic excursions were therefore lowered from 64 to 31 mg/dl. The plasma concentrations of gastric inhibitory polypeptide and insulin decreased with the acarbose dose so that the fractional disappearance rate of glucose also decreased. However, the concentrations of glucagon-like immunoreactivity (GLI) rose, confirming the ileal appearance of malabsorbed sucrose.


Saudi women in academic medicine. Are they succeeding?
The main purpose of this study is to assess the achievements and barriers to advancement for Saudi women in a medical academic setup. We studied the career progression of female medical graduates, who were appointed an academic position in King Faisal University, Dammam, Kingdom of Saudi Arabia (KSA) between 1982 and 2003 and compared it to the male counterpart. The information was collected from the Dean's ship of admission and registration, employees and faculty affairs administration office, self completed and telephone surveys. The percentage of medical graduates who were appointed on an academic post in the University was 4.4% for females and 4% for males. The females specialized in various fields and progressed equitably with the males in their postgraduate studies. Academic promotion to higher ranks was slower for females in comparison to males. This was related to various reasons related to family responsibilities, social strains, lack of family friendly policies in the institutions, lack of mentoring relationship, and bias against females. Saudi women in academic medicine have succeeded at the junior level. They specialized in various fields and excelled. Their further academic progression needs the support of senior academic staff, the chairs and the institution administration.


Electroencephalographic variants and genetic predisposition to schizophrenia.
Schizophrenic patients (249) were divided into those with and those without a family history of major functional psychosis. The same patients were then divided into those with entirely normal electroencephalograms and those whose traces contained some variant of normal. Traces were interpreted without knowledge of the patients' identities, and the question of the presence or absence of positive heredity had been decided without knowledge of the patients' electroencephalographic status, so that the discovery that normal electroencephalograms correlated highly significantly with positive heredity, and vice versa, commands attention. It is considered in the setting of previous work on psychoses and organic and electroencephalographic findings.


Rapid design and development of CRISPR-Cas13a targeting SARS-CoV-2 spike protein.
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide epidemic of the lethal respiratory coronavirus disease (COVID-19), necessitating urgent development of specific and effective therapeutic tools. Among several therapeutic targets of coronaviruses, the spike protein is of great significance due to its key role in host invasion. Here, we report a potential anti-SARS-CoV-2 strategy based on the CRISPR-Cas13a system. Methods: A comprehensive set of bioinformatics methods, including sequence alignment, structural comparison, and molecular docking, was utilized to identify a SARS-CoV-2-spike(S)-specific segment. A tiling crRNA library targeting this specific RNA segment was designed, and optimal crRNA candidates were selected using in-silico methods. The efficiencies of the crRNA candidates were tested in human HepG2 and AT2 cells. Results: The most effective crRNA sequence inducing a robust cleavage effect on S and a potent collateral cleavage effect were identified. Conclusions: This study provides a rapid design pipeline for a CRISPR-Cas13a-based antiviral tool against SARS-CoV-2. Moreover, it offers a novel approach for anti-virus study even if the precise structures of viral proteins are indeterminate.


Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss.
Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).


Magnetic field exposure assessment in a case-control study of childhood leukemia.
Epidemiologic evaluation of the relation between magnetic field exposures and cancer depends critically on study design, particularly the methods used for exposure assessment. We incorporated a complex magnetic field exposure assessment protocol into a large incident case-control study of childhood leukemia. We measured residential magnetic fields using a standard protocol in current and former homes of 638 cases and 620 controls and determined wire codes for 414 case-control pairs. We chose a time-weighted average of magnetic field measurements in each eligible home, weighted by the time the subject lived in each home as the main exposure metric for each subject. We found that 24-hour bedroom magnetic field measurements adequately characterize children's residential exposure and that measuring other rooms contributes only slightly to the estimate of average residential exposure to magnetic fields. Front door measured fields provide useful exposure information when interior measurements are missing. If feasible, measuring multiple homes in which the subject has resided is preferable to measuring a single home. A similar distribution of wire codes for controls agreeing or refusing to participate in our study implies that risk estimates derived from wire code data will not be influenced by response bias.


[Long-term experiences with elbow arthroscopy].
The purpose of this study was to present our long-term experience in elbow arthroscopy with special regard to diagnosis specific results. 103 out of 121 patients after elbow arthroscopy were evaluated with a mean followed-up time of 6.2 years. The age of the patients at time of surgery ranged between 3 and 72 years. For documentation the Figgie-Score was used. The results were documented in relation to the patients pathology. The total score improved significantly from 49.3 to 89.3 (p < 0.05). There was no age dependency of the results, but a correlation to the preoperative duration of symptoms and the individual job situation. Between the different score parameters pain showed the highest improvement. While patients with free bodies as well as bacterial or rheumatic arthritis had a more noticeable gain, the postoperative improvement for the patients with severe degenerative arthritis was only limited. Patients with unclear preoperative problems showed no improvement at all. While patients with free joint bodies or synovitis without degenerative joint disease have a significant benefit from elbow arthroscopy, patient with severe degenerative joint disease or patients with restricted range of motion will hardly show any improvement after surgery.


A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder.
In carcinoma of the bladder, both intravesical chemotherapy and immunotherapy can induce tumor regression and reduce the rate of recurrence, but the relative merits of these two therapies are unclear. We conducted a multi-institutional study to address this question. Patients with rapidly recurrent (stage Ta and T1) or in situ transitional-cell carcinoma of the bladder were randomly assigned to receive either doxorubicin administered intravesically or bacille Calmette-Guérin (BCG) administered both intravesically and percutaneously. The 262 eligible patients were followed for a median of 65 months. Complete responses to treatment of carcinoma in situ were confirmed by biopsy and cytologic analysis of the urine. For patients with Ta and T1 tumors without carcinoma in situ, the estimated probability of being disease free at five years was 17 percent after doxorubicin, as compared with 37 percent after immunotherapy with BCG (P = 0.015). The median times to treatment failure (termination of treatment, due to persistence, recurrence, or progression of disease) were 10.4 and 22.5 months, respectively. For patients with carcinoma in situ the complete-response probability estimates (i.e., the estimated probability of documented disappearance of disease) were 34 percent for doxorubicin (23 of 67 patients) and 70 percent for BCG (45 of 64 patients) (P less than 0.001); the median times to treatment failure were 5.1 and 39 months, respectively. The probability of being disease-free at five years survival among the patients with carcinoma in situ was 18 percent after treatment with doxorubicin and 45 percent after BCG therapy. Patients treated with BCG had a higher incidence of toxic systemic effects and a larger number of local irritative symptoms than patients treated with doxorubicin, but few of these adverse reactions were severe. As compared with intravesical doxorubicin, immunotherapy with BCG provides improved protection against the recurrence of superficial bladder cancer.


Nanosheets of Nickel Iron Hydroxy Carbonate Hydrate with Pronounced OER Activity under Alkaline and Near-Neutral Conditions.
Evaluation of unique catalysts of the iron group metals with activity in the OER region similar to that of scarce metals is of great importance to achieve sustainable production of H2 on a large scale. Herein, we report the unique nanosheets of nickel iron hydroxy carbonate hydrate (NiFeHCH) which were prepared through a wet-chemical route within 1 h of reaction time, acting as an efficient electrocatalyst for the oxygen evolution reaction (OER) in both alkaline and near-neutral media. The NiFeHCH was prepared with different concentrations of Fe in different ratios: 1:0.2, 1:0.4, 1:0.6, 1:0.8, and 1:1. Among them, nanosheets of NiFeHCH (1:0.2) were found to have superior OER activity, which required an overpotential of 250 mV to reach 20 mA cm-2 with a very low Tafel slope value of 39 mV/decade in 1 M KOH. Nanosheets with other ratios also had comparable OER activity with overpotentials ranging from 256 to 290 mV with Tafel slope values from 39 to 49 mV/decade. Nanosheets of NiFeHCH electrocatalysts screened for the OER in 1 M NaHCO3 (pH ∼8.5) required overpotentials for all of the ratios ranging from 389 to 507 mV at 10 mA cm-2 and Tafel slope values from 155 to 205 mV/decade, of which nanosheets of NiFeHCH (1:0.4) showed better activity by requiring an overpotential of 389 mV at 10 mA cm-2 and Tafel slope value of 155 mV/decade. With these fruitful advantages, these prepared nanosheets of NiFeHCH can be a better alternative to scarce metals for industrial water electrolysis.


Clinical Course of Small Subepithelial Tumors of the Small Bowel Detected on CT.
This study aimed to evaluate the natural growth of subepithelial tumors of the small bowel detected on CT. Consecutive patients who were suspected of having subepithelial tumors of the small bowel between January 2005 and December 2020 were reviewed. Eligible patients with suspected small (< 30 mm) subepithelial tumors on at least two CT evaluations were included in the analysis. The patients' data on demographic characteristics, tumoral characteristics, and tumoral size changes during the follow-up were collected. This study included 64 patients with suspected small subepithelial tumors (n = 64) of the small bowel. After a median follow-up of 15.8 months, the diameter and volume growth rates were 0.02 mm/month and 1.5 mm3/month, respectively. A significant correlation was observed between the initial size and the growth rate of the small bowel subepithelial tumors. The group of large-sized tumors (initial diameter ≥ 10 mm) tended to show lobulated contours, heterogeneous enhancement, and necrotic changes more frequently than the group of small-sized tumors (initial diameter < 10 mm). Small bowel subepithelial tumors measuring less than 10 mm grew more slowly than those measuring 10-30 mm.


Sustainable effectiveness of single-treatment autologous fat grafting in adherent scars.
Following severe injury, not just the skin but also the subcutis may be destroyed. Consequently, the developing scar can become adherent to underlying structures. Reconstruction of the subcutis can be achieved by autologous fat grafting. Our aim was to evaluate the long-term scar outcome after single-treatment autologous fat grafting using a comprehensive scar evaluation protocol. Scar assessment was performed preoperatively in 40 patients. A 12-month follow-up assessment was performed in 36 patients, using the Cutometer, the Patient and Observer Scar Assessment Scale, and DSM II ColorMeter. The Cutometer parameters elasticity and maximal extension improved with 28 and 22% (both p < 0.001), respectively. Nearly all scores of the scar assessment scale decreased significantly, which corresponds to improved scar quality. In addition, the mean melanin score was ameliorated over time. Thus, we demonstrated the sustainable effectiveness of single-treatment autologous fat grafting in adherent scars, indicated by improved pliability, and overall scar quality.


Effect of Resident and Fellow Involvement in Adult Spinal Deformity Surgery.
Adult spinal deformity (ASD) operations are complex and often require a multisurgeon team. Simultaneously, it is the responsibility of academic spine surgeons to train future complex spine surgeons. Our objective was to assess the effect of resident and fellow involvement (RFI) on ASD surgery in 4 areas: 1) perioperative outcomes, 2) length of stay (LOS), 3) discharge status, and 4) complications. Adults undergoing thoracolumbar spinal deformity correction from 2008 to 2014 were identified in the National Surgical Quality Improvement Program database. Cases were divided into those with RFI and those with attendings only. Outcomes were operative time, transfusions, LOS, discharge status, and complications. Univariate and multivariable regression modeling was used. Covariates included preoperative comorbidities, specialty, and levels undergoing instrumentation. A total of 1471 patients underwent ASD surgery with RFI in 784 operations (53%). After multivariable regression modeling, RFI was independently associated with longer operations (β = 66.01 minutes; 95% confidence interval [CI], 35.82-96.19; P < 0.001), increased odds of transfusion (odds ratio, 2.80; 95% CI, 1.81-4.32; P < 0.001), longer hospital stay (β = 1.76 days; 95% CI, 0.18-3.34; P = 0.030), and discharge to an inpatient rehabilitation or a skilled nursing facility (odds ratio, 2.02; 95% CI, 1.34-3.05; P < 0.001). However, RFI was not associated with any increase in major or minor complications. RFI in ASD surgery was associated with increased operative time, the need for additional transfusions, longer LOS, and nonhome discharge. However, no increase in major, minor, or severe complications occurred. These data support the continued training of future deformity and complex spine surgeons without fear of worsening complications; however, areas of improvement exist.


Risk factors associated with a breast cancer in a population of Moroccan women whose age is less than 40 years: a case control study.
Breast cancer is the most common cancer in morocco women were it occupies the first place in term of incidence and mortality. The aim of the present paper is to evaluate the risk factors associated with a breast cancer in a population of Moroccan women. A case-control study was conducted with population women whose age is less than 40 years during 2008-2010 at the National Institute of Oncology of Rabat. These women were interviewed for Epidemiological information and risk factor for breast cancer. Included in this study were 124 cases and 148 age matched controls. No statistically significant case-control difference was found for the early age of menarche (OR = 2.474; CI 95%: 1.354- 4.521), and family antecedents of first degree of breast cancer (OR = 11.556; 95% CI: 2.548-52.411). However physical activity (OR = 0.507; 95% CI: 0.339 -0.757) early maternity age (OR = 0.212; 95% CI: 0.087 - 0.514), multiparity (OR = 0.742; 95% CI: 0.359 -1.539) and breastfeeding than 6 months (OR = 0.739; 95% CI: 0.357 -1.523) appear as significant protective factors. This study show the criminalization of only part of the known risk factors of breast cancer in this age group and confirms the probable protective role of physical activity and factors related to life reproductive women in our study (early childbearing, multiparity and lactation).


Solvent-controlled synthesis of hydrophilic and hydrophobic carbon dots.
Hydrophilicity and hydrophobicity are of paramount importance in surface chemistry. In this study, a solvent-controlled synthesis of hydrophilic and hydrophobic carbon dots (CDs) was prepared via a solvothermal process using pentafluorobenzyl alcohol as the carbon source in either deionized water or N,N-dimethylformamide (DMF) medium. By simply varying the reaction solvent to control the doping of nitrogen and fluorine elements, the hydrophilicity or hydrophobicity of the CDs could be regulated. Hydrophobic and hydrophilic CDs showed blue and green light under a UV lamp, respectively. Besides, we regulated the volume ratio of water/DMF (1 : 2, 1 : 1 and 2 : 1) in the reaction solvent to prepare amphiphilic CDs and further studied their hydrophilicity and hydrophobicity. Furthermore, the sensitivity of hydrophobic CDs to water was investigated. In water detection, the photoluminescent intensity of the blue peak and green peak showed high linearity within the water content of 4-80% and 10-80%, respectively (limit of detection = 0.08%, v/v, in DMF).


Synergetic ligand and size effects of boron cage based electrolytes in Li-ion batteries.
We explore the potential application of boron-based clusters as high-performance electrolytes in lithium-ion batteries using first-principles density functional theory. We use small and halogen-free ligands (such as CN, BO, NH2, NO2, and CH3) to replace H in closo-boron cages with different sizes to investigate the ligand and size effects. According to their geometric and electronic stability, Li+ dissociation energy in the lithium salt form, and electrochemical stabilities, we screen nine candidate electrolyte anions potentially overcoming the currently used electrolytes in lithium-ion batteries. We show that, when CH3 is used as a boron cage ligand, both the highest occupied molecular orbital and the lowest unoccupied molecular orbital levels are high, ensuring their electrochemical stability against the oxidation (or reduction) reaction at the anode (or cathode). Solvent effects are also evaluated and high electrostatic screening was found to be favorable for practical usage.


Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists.
Sepsis is more common in the elderly. TNF⍺ is recognized as an important mediator in sepsis and Toll-like receptors (TLRs) play an important role in initiating signaling cascades to produce TNF⍺. Little is known about how innate immunity is altered in healthy human aging that predisposes to sepsis. We tested the hypothesis that aging dysregulates the innate immune response to TLR 2 and 4 ligands. We performed whole blood assays on 554 healthy subjects aged 40-80 years. TNFα production was measured at baseline and after stimulation with the TLR2 agonists: peptidoglycan, lipoteichoic acid, Pam3CysK, Zymosan A and the TLR4 agonist lipopolysaccharide (LPS). In a subset of subjects (n = 250), we measured Toll-like receptor (TLR) 2, 4 and MyD88 expression using real-time PCR. We measured a 2.5% increase per year in basal secretion of TNFα with aging (n = 554 p = 0.02). Likewise, TNFα secretion was increased with aging after stimulation with peptidoglycan (1.3% increase/year; p = 0.0005) and zymosan A (1.1% increase/year p = 0.03). We also examined the difference between baseline and stimulated TNFα for each individual. We found that the increase was driven by the elevated baseline levels. In fact, there was a diminished stimulated response to LPS (1.9% decrease/year; p = 0.05), lipoteichoic acid (2.1% decrease/year p = 0.03), and Pam3CysK (2.6% decrease/year p = 0.0007). There were no differences in TLR or MyD88 mRNA expression with aging, however, there was an inverse relationship between TLR expression and stimulated TNFα production. With aging, circulating leukocytes produce high levels of TNFα at baseline and have inadequate responses to TLR2 and TLR4 agonists. These defects likely contribute to the increased susceptibility to sepsis in older adults.


Association of antisocial personality disorder and substance disorder morbidity in a clinical sample.
The aims were to determine among patients with substance use disorder (SUD) whether those with antisocial personality disorder (ASPD) manifest less, the same, or more of the following: 1) temporal course of substance use, 2) severity of substance-related symptoms and problems, 3) familial SUD, 4) number and type of SUD diagnoses, and 5) extent of SUD treatment, as compared to patients without ASPD. DESIGN AND DEFINITION: Scheduled interviews using Diagnostic and Statistical Manual (DSM) criteria were used to determine ASPD, which required childhood conduct disorder plus adult antisocial behavior. Clinicians blind to the ASPD assessment collected the remainder of the data. Alcohol-drug treatment programs were located in two university medical centers. Six hundred and six voluntary patients aged 18 and older met diagnostic criteria for SUD. SUD patients with ASPD reported more substance-related problems in seven out of eight areas of the interview-based Minnesota-Substance Abuse Problems scale. On a self-rated scale, the Michigan Assessment Screening Test/Alcohol-Drug, the difference was unremarkable. The ASPD group reported slightly, but significantly, more relatives with SUD. Lifetime use of tobacco and most illicit drugs was greater in the ASPD group. Age at first use of alcohol and tobacco was less in the ASPD group, but age at first use of other substances did not show a difference. Indicators of SUD course, such as years of use, days of use in the last year, duration of periods of abstinence, and number of self-help efforts showed no differences between the two groups. Types and numbers of SUD diagnoses showed no difference. However, all treatment indicators (i.e., lifetime number of admissions, modalities of care, days of care, and cost of care) were significantly higher in the ASPD group. A regression analysis revealed that family and legal problems remained strongly associated with ASPD, but other substance-related problems and SUD treatment dropped out. Despite the many similarities in SUD among those with and without ASPD, the morbidity in the ASPD as measured by number and types of substance-related problems and by all treatment variables is considerably greater. Legal and family problems appear to be powerfully associated with ASPD and predictive of other problems as well as SUD treatment.


The place of science in a continent at the crossroads.
I have mentioned it before and I want to repeat it now, that we in Africa share a common history, heritage and basic problems of development. We, therefore, have an inescapable responsibility of pooling our talents and resources in shaping our common destiny. In fulfillment of its mission, AFHES, through its organized con notgresses and this Journal, is an invaluable vessel for enabling us to promote better health for the peoples of this continent. Africa is a continent endowed with great potential that, for one reason or an notother, has been ignored or misused, resulting in the current crisis now enveloping the continent. There is the escalating debt burden, falling agricultural productivity and the ever-increasing population. Efforts to improve the situation are hampered by adverse factors such as malnutrition, HTV/AIDS, malaria and other causes of ill health; wars, poor environmental management and the ever-worrisome problem of refugees. At the sunrise of the 21st Century, we must wake up and reverse the current trend by focusing our resources on priority areas of development. The fight for freedom from the yoke of colonialism and the traumatic experience of apartheid has been won. In some African countries, however, the winning of the fight for freedom has opened up a new fight, a fight that is more fierce and bloody than that which set us free. These include civil strife and internecine wars giving rise to a new black Diaspora, which is far greater than the one experienced during the period of slavery and slave trade. People supposed to build these nations have either been killed or forced into exile. Those intellectually endowed have sought refuge in safer and economically developed countries and, by the same process, also weaken the al notready weak economies of their mother countries. They have, therefore, helped to strengthen the already strong economies of the developed nations. This is indeed, a sad situation that poses a formidable challenge to the future well being of the conti notnent. Civil strife has resulted in the increased numbers of displaced persons and has caused a big setback in the fight against diseases and causes of ill health. In addition, there are new challenges created by emergence of new infections, re-emergence of diseases that had been put under control; and the changing epidemiological patterns and manifestations of existing diseases. Since disease and ill health know no bound notary, we must all be prepared to find solutions to diseases and causes of ill health that continuously haunt this continent. As health experts, we are concerned. We should not be responding to health emergencies occasioned by civil strife. We need peace as it will guarantee not only freedom and personal security, but it will also guarantee our future and the future of those to come after us. We are well aware that as is the case with developed nations, the development of our continent rests on the utilization of research findings, which must be useful, contextual and must stand the test of time. This is our mission and our hope. Africa is at the crossroads. We must not despair or quit, lest we become irrel notevant both to ourselves and to the rest of mankind. Let African governments give science a chance. As I have said several times before and I am still saying it now, quitters never win and winners never quit. We have no alternative but to be winners!


Electrochemical modulation of antigen-antibody binding.
The label-free amperometric detection of a rabbit IgG antigen by an anti-rabbit IgG antibody is achieved by observing the electrochemistry at a glassy carbon electrode modified with antibody entrapped in an electrodeposited polypyrrole membrane. In a flow injection apparatus the electrode is pulsed between -0.2 and +0.4 V versus Ag/AgCl. The pulsing of the electrode switches the polypyrrole membrane between the oxidised and reduced states. When antigen is injected into the flow stream a change in current is observed at the electrode despite the antigen or antibody being redox inactive at the potentials employed. It is proposed that this current is due to a change in the flux of ions into and out of the polypyrrole matrix during a pulse when the poly-anionic antigen is present. The immunoreaction was reversible because the 200 ms pulse at each potential was too short to allow secondary bonding forces (hydrogen bonding and hydrophobic forces) which are responsible for the strength of the antibody-antigen complex to be established. The consequence of the reversibility of the antigen-antibody binding is a low apparent affinity constant but an easily regenerated recognition interface.