Recombination between Photogenerated and Electrode-Induced Charges Dominates the Fill Factor Losses in Optimized Organic Solar Cells.
Charge extraction in organic solar cells (OSCs) is commonly believed to be limited by bimolecular recombination of photogenerated charges. However, the fill factor of OSCs is usually almost entirely governed by recombination processes that scale with the first order of the light intensity. This linear loss was often interpreted to be a consequence of geminate or trap-assisted recombination. Numerical simulations show that this linear dependence is a direct consequence of the large amount of excess dark charge near the contact. The first-order losses increase with decreasing mobility of minority carriers, and we discuss the impact of several material and device parameters on this loss mechanism. This work highlights that OSCs are especially vulnerable to injected charges as a result of their poor charge transport properties. This implies that dark charges need to be better accounted for when interpreting electro-optical measurements and charge collection based on simple figures of merit.


Clinical Significance of microRNA-196b-5p in Hepatocellular Carcinoma and its Potential Molecular Mechanism.
Objective: To enquire into the clinical significance and potential molecular mechanism of microRNA (miRNA)-196b-5p in hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription and polymerase chain reaction (qRT-PCR) were utilized to examine miR-196b-5p expression level in 67 HCC paraffin embedded tissues and corresponding adjacent tissues. Correlations of miR-196b-5p expression level with clinicopathological characteristics were analyzed in our study. The expression level and clinical significance of miR-196b-5p in HCC were also evaluated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We made predictions of the target genes of miR-196b-5p by twelve online software and then selected genes predicted by at least 5 software. Subsequently, in order to obtain the potential target genes of miR-196b-5p, we overlapped the predicted target genes and down-regulated mRNAs in HCC based on TCGA database. Then, we performed the Gene Ontology (GO) and the Disease Ontology (DO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network construction of those miR-196b-5p potential target genes. Results: Higher expression level of miR-196b-5p was seen in HCC tissues than in the corresponding adjacent tissues based on qRT-PCR (P = 0.0007). The expression level of miR-196b-5p was linked with tumor size (P = 0.03), tumor node (P = 0.024), vascular invasion (P = 0.029) and capsular invasion (P = 0.026) in HCC patients. Comprehensive meta-analysis of miR-196b-5p expression based on TCGA, GEO and qRT-PCR verified that higher expression level of miR-196b-5p was observed in HCC tissues than in normal control liver tissues (SMD = 0.56, 95%CI: 0.39-0.72, P heterogeneity = 0.275, I2 = 18.3%). GO annotation revealed that the top terms in biological process, cellular component and molecular function were single-organism catabolic process, neuronal cell body and transmembrane receptor protein kinase activity, respectively. The most relevant disease in DO annotation was arteriosclerosis. The tryptophan metabolism pathway ranked first in KEGG pathway enrichment analysis. The PPI network showed that IGF1, FOXO1, AR and FOS were mostly likely to become the core genes of miR-196b-5p potential target genes, which however required further experiments for validation. Conclusion: The miR-196b-5p was observed to show higher expression in HCC tissues than in normal control liver tissues. Moreover, the miR-196b-5p expression level had correlations with the clinicopathological parameters such as vascular invasion of HCC, but the molecular mechanisms of miR-196b-5p in HCC still need further elucidation and verification.


Type-common and type-specific monoclonal antibody to herpes simplex virus type 1.
Hybridoma cells produced by fusing mouse myeloma cells with spleen cells from mice primed with herpes simplex virus (HSV) type 1 yielded five clones producing neutralizing antibody against homologous virus. Two clones, HCl and HC2, produced antibody capable of precipitating glycoprotein C and its precursor, whereas three clones, HD1, HD2, and HD3, produced antibody capable of precipitating glycoprotein D and its precursor. Antibody produced by the HC1 and HC2 clones neutralized HSV type 1 but not HSV type 2 or HSV type 1 strain MP, which is known to lack glycoprotein C. Antibody produced by the HD1 and HD2 clones neutralized both HSV type 1 and HSV type 2, whereas antibody produced by the HD3 clone neutralized HSV type 1 but not HSV type 2. The two clones which produced antibody to glycoprotein C and the two clones which produced type-common antibody to glycoprotein D were independently derived and not clonally related inasmuch as the antibody in each pair belonged to a different subclass of immunoglobulin.


Probiotics: multifarious oral vaccine against infectious traumas.
Microorganisms have been used for a long time in food and alcoholic fermentation. In the last few years they have undergone scientific scrutiny of their preventative and therapeutic aspects. This has led to the discovery of a new term, probiotics. Lactic acid bacteria (LAB) are microbial communities normally present in the intestine of most animals. They play an important role in humans and other animals, and act as immunomodulators. They are helpful in the treatment and prevention of disease as well as improving the digestion and absorption of nutrients. Probiotic microorganisms include the LAB Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus plantarum and Lactobacillus rhamnosus. Use of these live bacteria to elicit an immune response or to carry a vaccine component is a new invention in vaccine development. The advantage of live bacterial vaccines is that they mimic natural infection, have intrinsic adjuvant properties and can be given orally. Components of pathogenic and nonpathogenic food-related microorganisms are currently being evaluated as candidates for oral vaccines.


Selective photodeposition of zinc nanoparticles on the core of a single-mode optical fiber.
An experimental and theoretical study about selective photodeposition of metallic zinc nanoparticles onto an optical fiber end is presented. It is well known that metallic nanoparticles possess a high absorption coefficient and therefore trapping and manipulation is more challenging than dielectric particles. Here, we demonstrate a novel trapping mechanism that involves laser-induced convection flow (due to heat transfer from the zinc particles) that partially compensates both absorption and scattering forces in the vicinity of the fiber end. The gradient force is too small and plays no role on the deposition process. The interplay of these forces produces selective deposition of particles whose size is directly controlled by the laser power. In addition, a novel trapping mechanism termed convective-optical trapping is demonstrated.


The dynamic evolutionary history of the bananaquit (Coereba flaveola) in the Caribbean revealed by a multigene analysis.
The bananaquit (Coereba flaveola) is a small nectivorous and frugivorous emberizine bird (order Passeriformes) that is an abundant resident throughout the Caribbean region. We used multi-gene analyses to investigate the evolutionary history of this species throughout its distribution in the West Indies and in South and Middle America. We sequenced six mitochondrial genes (3744 base pairs) and three nuclear genes (2049 base pairs) for forty-four bananaquits and three outgroup species. We infer the ancestral area of the present-day bananaquit populations, report on the species' phylogenetic, biogeographic and evolutionary history, and propose scenarios for its diversification and range expansion. Phylogenetic concordance between mitochondrial and nuclear genes at the base of the bananaquit phylogeny supported a West Indian origin for continental populations. Multi-gene analysis showing genetic remnants of successive colonization events in the Lesser Antilles reinforced earlier research demonstrating that bananaquits alternate periods of invasiveness and colonization with biogeographic quiescence. Although nuclear genes provided insufficient information at the tips of the tree to further evaluate relationships of closely allied but strongly supported mitochondrial DNA clades, the discrepancy between mitochondrial and nuclear data in the population of Dominican Republic suggested that the mitochondrial genome was recently acquired by introgression from Jamaica. This study represents one of the most complete phylogeographic analyses of its kind and reveals three patterns that are not commonly appreciated in birds: (1) island to mainland colonization, (2) multiple expansion phases, and (3) mitochondrial genome replacement. The detail revealed by this analysis will guide evolutionary analyses of populations in archipelagos such as the West Indies, which include islands varying in size, age, and geological history. Our results suggest that multi-gene phylogenies will permit improved comparative analysis of the evolutionary histories of different lineages in the same geographical setting, which provide replicated "natural experiments" for testing evolutionary hypotheses.


Depression and treatment nonadherence in type 2 diabetes: assessment issues and an integrative treatment approach.
Research has found that depression is more common among individuals with diabetes and is associated with worse diabetes outcomes including treatment nonadherence, worse glycemic control, higher risk of diabetes complications, greater functional impairment, and increased risk of mortality. These patterns of association have led to an increase in research investigating the relationship between diabetes and depression. There remain important questions about the relationship between depression and diabetes and an unmet need for treatment approaches that are successful in ameliorating depression and improving diabetes outcomes. The current commentary discusses several conceptual issues related to the measurement of depression in diabetes, argues for the importance of health behavior and treatment adherence in approaching the problem of depression in diabetes, and provides an example of a treatment approach that incorporates the treatment of depression with strategies aimed at improving treatment adherence in order to maximize effects on diabetes outcomes.


To flip or not to flip: lipid-protein charge interactions are a determinant of final membrane protein topology.
The molecular details of how lipids influence final topological organization of membrane proteins are not well understood. Here, we present evidence that final topology is influenced by lipid-protein interactions most likely outside of the translocon. The N-terminal half of Escherichia coli lactose permease (LacY) is inverted with respect to the C-terminal half and the membrane bilayer when assembled in mutants lacking phosphatidylethanolamine and containing only negatively charged phospholipids. We demonstrate that inversion is dependent on interactions between the net charge of the cytoplasmic surface of the N-terminal bundle and the negative charge density of the membrane bilayer surface. A transmembrane domain, acting as a molecular hinge between the two halves of the protein, must also exit from the membrane for inversion to occur. Phosphatidylethanolamine dampens the translocation potential of negative residues in favor of the cytoplasmic retention potential of positive residues, thus explaining the dominance of positive over negative amino acids as co- or post-translational topological determinants.


Chronic ethanol-initiated apoptosis in hepatocytes is induced by changes in membrane biogenesis and intracellular transport.
The outcome of chronic ethanol consumption recorded in liver by in situ staining of the genomic DNA in fragmented nuclei indicates the course of cellular events that has been coined as apoptosis or programmed cell death. Hence, we designed the study to determine which ethanol-induced modification of the cellular make-up is responsible for the hastening the cell damage. The in vitro assays were performed with cellular organelles and cytosol prepared from hepatocytes derived from rats subjected to 9 weeks of chronic alcohol consumption. The results were compared with the pair-fed controls receiving isocaloric liquid diet. In the initial phase of the studies, we established that the process of apoptosis was not triggered by the aberrant activity of neutral or acidic sphingomyelinase. The hepatocytes derived from alcohol and control diets manifested equal enzymatic activity. The de novo synthesis of sphingoid bases and ceramides in the alcohol-derived sample of endoplasmic reticulum was reduced, but the in situ apoptosis was up to 36-fold higher than in the control. Also, the isolated hepatocytes contained a 2- to 4-fold higher amount of nucleosomal fragments in the cytosolic extracts. The endosomes from liver hepatocytes of ethanol-consuming rats, in the presence of the cytosol and mitochondria from pair-fed controls, disclosed 2 to 3 times higher apoptotic potential than sample consisting of ethanol-derived fractions only, and 3 to 5 times higher than the control-derived fractions. The substantial increase in apoptosis, as recorded in the amount of DNA fragments released to the cytosol from the fresh nuclei, was also recorded when the microsomal membranes of endoplasmic reticulum and Golgi were incubated in the conditions with preserved intracellular transport. The maximal 20-fold increase of apoptotic activity was recorded in the incubation mixtures of ethanol-derived endoplasmic reticulum-Golgi membranes with control-derived cytosol in the presence of the ATP generating system. Results infer that the intracellular transport vesicles, generated from ethanol-modified membranes in the presence of the substrates that are available in the cytosol of the control hepatocytes, activate the apoptotic activity in the in vitro system. This interpretation is supported by the results of analysis of the clathrin-coated transport vesicles that, in contrast to nonclathrin transport vesicles, contain a sizable accumulation of ceramides that are known to induce apoptosis.


Two quorum sensing systems control biofilm formation and virulence in members of the Burkholderia cepacia complex.
The Burkholderia cepacia complex (Bcc) consists of 17 closely related species that are problematic opportunistic bacterial pathogens for cystic fibrosis patients and immunocompromised individuals. These bacteria are capable of utilizing two different chemical languages: N-acyl homoserine lactones (AHLs) and cis-2-unsaturated fatty acids. Here we summarize the current knowledge of the underlying molecular architectures of these communication systems, showing how they are interlinked and discussing how they regulate overlapping as well as specific sets of genes. A particular focus is laid on the role of these signaling systems in the formation of biofilms, which are believed to be highly important for chronic infections. We review genes that have been implicated in the sessile lifestyle of this group of bacteria. The new emerging role of the intracellular second messenger cyclic dimeric guanosine monophosphate (c-di-GMP) as a downstream regulator of the fatty acid signaling cascade and as a key factor in biofilm formation is also discussed.


Immunogenicity of coiled-coil based drug-free macromolecular therapeutics.
A two-component CD20 (non-internalizing) receptor crosslinking system based on the biorecognition of complementary coiled-coil forming peptides was evaluated. Exposure of B cells to Fab'-peptide1 conjugate decorates the cell surface with peptide1; further exposure of the decorated cells to P-(peptide2)x (P is the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone) results in the formation of coiled-coil heterodimers at the cell surface with concomitant induction of apoptosis. The aim of this study was to determine the potential immunogenicity of this therapeutic system that does not contain low molecular weight drugs. Enantiomeric peptides (L- and D-CCE and L- and D-CCK), HPMA copolymer-peptide conjugates, and Fab' fragment-peptide conjugates were synthesized and the immunological properties of peptide conjugates evaluated in vitro on RAW264.7 macrophages and in vivo on immunocompetent BALB/c mice. HPMA copolymer did not induce immune response in vitro and in vivo. Administration of P-peptide conjugates with strong adjuvant resulted in antibody response directed to the peptide. Fab' was responsible for macrophage activation of Fab'-peptide conjugates and a major factor in the antibody induction following i.v. administration of Fab'-conjugates. There was no substantial difference in the ability of conjugates of D-peptides and conjugates of L-peptides to induce Ab response.


Gametogenesis, fertilization and ookinete differentiation of Leucocytozoon smithi.
Development of Leucocytozoon smithi during gametogenesis, fertilization, and ookinete differentiation was studied by light and electron microscopy. Gametogenesis occurred rapidly, within 1-2 min after gametocytes were ingested by black flies. Usually one axoneme, but not infrequently two, was observed in microgametes. The macrogamete nucleus was characteristically elongated and fragmented, with a convoluted nuclear envelope. Fertilization occurred within five min after ingestion of gametocytes by the vector. The entire axoneme and nucleus of the microgamete entered the cytoplasm of the macrogamete. Zygote differentiation resembled sporozoite formation in that a thickened inner membrane and subpellicular microtubules developed beneath the plasmalemma, followed by cytoplasmic protrusion or evagination to form the anterior end. Extension of the inner thickened membrane continued as the zygote elongated. Development of sausage-shaped ookinetes was completed within 6-8 h after ingestion of a blood meal by a black fly. Mature ookinetes possessed a single nucleus, double-layered pellicle, canopy, apical pore, polar ring complex, subpellicular microtubules, micronemes, crystalloids, abundant mitochondria, endoplasmic reticulum, and ribosomes. Comparison of development of L. smithi with species of Plasmodium and Haemoproteus revealed general similarities in both sexual and asexual development within the insect vector. A diagram summarizing life cycle events for L. smithi is included.


The relative influence of habitat amount and configuration on genetic structure across multiple spatial scales.
Despite strong interest in understanding how habitat spatial structure shapes the genetics of populations, the relative importance of habitat amount and configuration for patterns of genetic differentiation remains largely unexplored in empirical systems. In this study, we evaluate the relative influence of, and interactions among, the amount of habitat and aspects of its spatial configuration on genetic differentiation in the pitcher plant midge, Metriocnemus knabi. Larvae of this species are found exclusively within the water-filled leaves of pitcher plants (Sarracenia purpurea) in a system that is naturally patchy at multiple spatial scales (i.e., leaf, plant, cluster, peatland). Using generalized linear mixed models and multimodel inference, we estimated effects of the amount of habitat, patch size, interpatch distance, and patch isolation, measured at different spatial scales, on genetic differentiation (F ST) among larval samples from leaves within plants, plants within clusters, and clusters within peatlands. Among leaves and plants, genetic differentiation appears to be driven by female oviposition behaviors and is influenced by habitat isolation at a broad (peatland) scale. Among clusters, gene flow is spatially restricted and aspects of both the amount of habitat and configuration at the focal scale are important, as is their interaction. Our results suggest that both habitat amount and configuration can be important determinants of genetic structure and that their relative influence is scale dependent.


Caffeine in floral nectar enhances a pollinator's memory of reward.
Plant defense compounds occur in floral nectar, but their ecological role is not well understood. We provide evidence that plant compounds pharmacologically alter pollinator behavior by enhancing their memory of reward. Honeybees rewarded with caffeine, which occurs naturally in nectar of Coffea and Citrus species, were three times as likely to remember a learned floral scent as were honeybees rewarded with sucrose alone. Caffeine potentiated responses of mushroom body neurons involved in olfactory learning and memory by acting as an adenosine receptor antagonist. Caffeine concentrations in nectar did not exceed the bees' bitter taste threshold, implying that pollinators impose selection for nectar that is pharmacologically active but not repellent. By using a drug to enhance memories of reward, plants secure pollinator fidelity and improve reproductive success.


Insc:LGN tetramers promote asymmetric divisions of mammary stem cells.
Asymmetric cell divisions balance stem cell proliferation and differentiation to sustain tissue morphogenesis and homeostasis. During asymmetric divisions, fate determinants and niche contacts segregate unequally between daughters, but little is known on how this is achieved mechanistically. In Drosophila neuroblasts and murine mammary stem cells, the association of the spindle orientation protein LGN with the stem cell adaptor Inscuteable has been connected to asymmetry. Here we report the crystal structure of Drosophila LGN in complex with the asymmetric domain of Inscuteable, which reveals a tetrameric arrangement of intertwined molecules. We show that Insc:LGN tetramers constitute stable cores of Par3-Insc-LGN-GαiGDP complexes, which cannot be dissociated by NuMA. In mammary stem cells, the asymmetric domain of Insc bound to LGN:GαiGDP suffices to drive asymmetric fate, and reverts aberrant symmetric divisions induced by p53 loss. We suggest a novel role for the Insc-bound pool of LGN acting independently of microtubule motors to promote asymmetric fate specification.


Outcomes of Maintenance Peritoneal Dialysis in Children: A State Hospital Experience from Southeastern Turkey.
This study aimed to evaluate the clinical features, laboratory features, and outcomes of pediatric patients on peritoneal dialysis (PD) and compare the factors affecting mortality. The demographic, clinical, and laboratory data of 50 patients on maintenance PD followed up for more than 3 months were retrospectively analyzed for non-survivors and survivors to evaluate all factors affecting mortality. The patients (26 boys and 24 girls) had a mean age of 85.4 ± 58.7 months (range: 1-194 months) at the initiation of PD. The mean duration of dialysis at follow-up was 27.8 ± 21.7 months (range: 3-115 months). The rate of peritonitis was one episode per 27.27 patient months. PD was discontinued because of transplantation in eight patients, death in eight patients, and shifting to hemodialysis in three patients. In the Kaplan-Meier analysis, the 1-year patient survival rate at 1 year, 2 years, and 5 years was 81.8%, 51.7%, and 12.3%, respectively. Non-survivors were significantly younger at the start of kidney replacement therapy, had a final younger age at dialysis, and had lower albumin levels than survivors. We excluded four patients with a follow-up period of <6 months. Cox regression analysis revealed a low albumin status (P = 0.014, hazard ratio: 0.230) and a high level of ferritin (P = 0.002, hazard ratio: 1.002) to be risk factors for mortality. This study showed a high mortality rate. Hypoalbuminemia, a younger age at the start of kidney replacement therapy, and a younger final age at dialysis had a significant association with mortality.


Prolonged caloric restriction ameliorates age-related atrophy in slow and fast muscle fibers of rat soleus muscle.
Aging causes loss of skeletal muscle mass and function, which is called sarcopenia. While sarcopenia impairs the quality of life of older adults and is a major factor in long-term hospitalization, its detailed pathogenic mechanism and preventive measures remain to be identified. Caloric restriction (CR) suppresses age-related physiological and pathological changes in many species and prolongs the average and healthy life expectancy. It has recently been reported that CR suppresses the onset of sarcopenia; however, few studies have analyzed the effects of long-term CR on age-related skeletal muscle atrophy. Thus, we investigated the aging and CR effects on soleus (SOL) muscles of 9-, 24-, and 29-month-old ad libitum-fed rats (9AL, 24AL, and 29AL, respectively) and of 29-month-old CR (29CR) rats. The total muscle cross sectional area (mCSA) of the entire SOL muscle significantly decreased in the 29AL rats, but not in the 24AL rats, compared with the 9AL rats. SOL muscle of the 29AL rats exhibited marked muscle fiber atrophy and increases in the number of muscle fibers with a central nucleus, in fibrosis, and in adipocyte infiltration. Additionally, although the decrease in the single muscle fiber cross-sectional area (fCSA) and the muscle fibers' number occurred in both slow-type and fast-type muscle fibers, the degree of atrophy was more remarkable in the fast-type fibers. However, CR suppressed the muscle fiber atrophy observed in the 29AL rats' SOL muscle by preserving the mCSA and the number of muscle fibers that declined with aging, and by decreasing the number of muscle fibers with a central nucleus, fibrosis and denervated muscle fibers. Overall, these results revealed that advanced aging separately reduces the number and fCSA of each muscle fiber type, but long-term CR can ameliorate this age-related sarcopenic muscle atrophy.


Salivary gland thrombostasin isoforms differentially regulate blood uptake of horn flies fed on control- and thrombostasin-vaccinated cattle.
Thrombostasin (TS) is an anticlotting protein found in saliva of Haematobia irritans (horn flies). The polymorphic nature of the ts gene was first associated with success of horn flies blood feeding on a laboratory host, New Zealand White rabbits. In this study, we report results of similar studies testing blood uptake of horn flies feeding on a natural host, cattle. These studies confirmed the association of ts genotype with blood uptake of horn flies and showed that it was host species specific. In contrast to rabbits, blood uptake volumes of homozygous ts10 horn flies were lower than those of other ts genotypes when fed on control (ovalbumin-vaccinated) cattle. Cattle vaccinated with recombinant protein isoforms, rTS9 or rTB8, resisted horn fly feeding by yielding lower blood volumes compared with flies feeding on control cattle. The specific impact of vaccination, however, varied by ts genotype of flies. Cattle vaccinated with isoform rTS9 resisted flies of ts2, ts9, and tb8 genotype. Vaccination with isoform rTB8 produced resistance to ts8, ts9, and tb8 genotype flies. Horn flies of genotype ts10 were not affected by vaccination with either TS isoform and fed as well on rTS9- and rTB8-vaccinated as on control-vaccinated cattle. These experimental results confirm the efficacy of vaccines targeting horn fly salivary proteins and provide new insight into the dynamics of horn fly-cattle interactions in nature.


Role of lipopolysaccharide and complement in susceptibility of Escherichia coli and Salmonella typhimurium to non-immune serum.
The role of lipopolysaccharide (LPS) in the susceptibility of Escherichia coli and Salmonella typhimurium to non-immune human serum was investigated using serum-sensitive strains of both enterobacteria. LPS from serum-resistant strains of E. coli and S. typhimurium could activate and completely remove the serum bactericidal activity, and also showed dose-dependent anti-complement activity. These properties were mainly due to the high-molecular-mass LPS: the low-molecular-mass LPS from serum-resistant strains of E. coli and S. typhimurium had only a slight effect on the serum bactericidal activity, and showed only low anti-complement activity, even at high concentration. The results suggest that LPS composition, especially the O-antigen polysaccharide chains, contributes to the susceptibility of E. coli and S. typhimurium strains to complement-mediated serum bactericidal activity.


Acute copper toxicosis in the Canada goose.
Acute copper toxicosis resulted in Canada geese, Branta canadensis, following ingestion of copper sulfate at about 600mg/kg from a small man-made pond on a game farm. The lesions were those associated with copper toxicosis in other avian species. The primary pathologic change was necrosis and sloughing of the proventriculus and gizzard. A greenish discoloration of the lungs also occurred.


Dansylation of unactivated alcohols for improved mass spectral sensitivity and application to analysis of cytochrome P450 oxidation products in tissue extracts.
Chemical derivatization is useful for improving the ionization characteristics of poorly or nonionizable analytes in liquid chromatography-mass spectrometry (LC-MS). Dansyl chloride has been widely used as a derivatizing reagent for fluorescence detection and for facilitating the MS detection of phenols and amines, but not for general alcohols. A new dansylation method for improving the mass spectral sensitivity of unactivated alcohols was developed. The dansylated derivative was formed after incubation of the test compound cholesterol and excess dansyl chloride in CH(2)Cl(2) in the presence of 4-(dimethylamino)-pyridine (DMAP) plus N,N-diisopropylethylamine at 65 °C for 1 h, with an overall yield of 96%. The versatility of dansylation was investigated by utilizing representative lipid compounds (containing different numbers of hydroxy groups) for dansylation. All dansylated derivatives of the selected compounds were detected by LC-MS/MS in the electrospray ionization (ESI) positive ion mode. Validation of the method was established in terms of the sensitivity, stability, and repeatability of dansylation. The method was then applied to characterizing the P450 7A1 oxidation product (dansylated 7α-hydroxycholesterol) in human liver extracts using an LC-MS metabolomics/isotopic labeling approach (Tang, Z.; Guengerich, F. P. Anal. Chem. 2009, 81, 3071-3078). The dansylated derivative of the product was identified, with the signal increased by 10(3)-fold compared with a previous method (derivatization with succinic anhydride and ESI negative ion MS). Quantitation of testosterone in human liver extracts was also done as an example of the application of the dansylation method. Thus, dansylation is a potential method of modifying many alcohols for detection by fluorescence and LC-MS analysis.


Changes in the use of end points in clinical trials for elderly cancer patients over time.
Physicians need well-addressed clinical trials assessing benefits and harm of treatments to avoid under-treatment or over-treatment of elderly patients. The main objectives of this report were to present an overview of end points used in clinical trials dedicated to elderly patients; and to assess the evolution in chosen end points before and after the creation of the International Society of Geriatric Oncology in the early 2000s. All phases I, II and III trials dedicated to the treatment of cancer among elderly patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. All phase III clinical trials assessing cancer treatments among adults in the same periods were also reviewed to identify subgroup analyses of elderly patients among these trials. Among phase III trials dedicated to elderly patients, overall survival was a common primary end point. Interestingly, tumor centered end points were very common in the first time period and very uncommon in the second time period, whereas composite end points were very uncommon in the first time period but very common in the second time period. Concerningly, disease-specific survival was very infrequently reported in dedicated clinical trials of elderly patients despite their importance in evaluating competing risk of death from non-oncology causes. The use of patient-reported outcomes (PROs) as a primary end point remained very uncommon but the reporting of PROs as a secondary end point tended to increase in the second time period, from 19% to 33% (P = 0.10). Functional status was infrequently reported. During the past decade, the use of clinically meaningful end points such as PROs and functional status in elderly patients remained moderate. Yet, the use of PROs as a secondary end point tended to increase between the two time periods.


[Recent advances in the treatment of presbyopia].
Everyone will experience presbyopia between the age of 45 and 50 years. The classical solution to help these patients is to offer spectacles or multifocal contact lenses. Recent developments in corneal or intraocular surgery may provide new solutions for selected patients to prevent them from always wearing glasses to read.


Genetic parameters of meat quality traits in two pig breeds measured by rapid methods.
To study genetic variation in meat quality traits measured by rapid methods, data were recorded between 2005 and 2008 on samples of M. longissimus dorsi (LD) in Landrace (n = 3838) and Duroc (n = 2250) pigs included in the Norwegian pig breeding scheme. In addition, ultimate pH levels in the glycolytic LD (loin muscle) and M. gluteus medius (GM, ham muscle), and in the oxidative m. gluteus profundus (GP, ham muscle) were recorded as an extended data set (n = 16 732 and n = 7456 for Landrace and Duroc, respectively) from 1998 to 2008. Data were analysed with a multi-trait animal model using AI-REML methodology. Meat from Duroc had considerably more intramuscular fat (IMF), less moisture and protein, appeared darker with higher colour intensity and had lower drip loss than meat from Landrace. The heritability estimates (s.e. 0.01 to 0.07) for pH in LD (0.19 and 0.27 for Landrace and Duroc, respectively), GM (0.12 and 0.22) and GP (0.19 and 0.38), drip loss (0.23 and 0.33), colour values: L* (lightness) (0.41 and 0.28), a* (redness) (0.46 and 0.43), b* (yellowness) (0.31 and 0.33), IMF (0.50 and 0.62), muscle moisture (0.31 and 0.50) and muscle protein content (0.40 and 0.54) in LD all demonstrated moderate-to-high genetic variation for these traits in both breeds. Near infrared spectroscopy and EZ-DripLoss are modern technologies used in this study for the determination of chemical components and drip loss in meat. These methods gave higher heritabilities than more traditional methods used to measure these traits. The estimated genetic correlations between moisture and IMF in Duroc, and pH and drip loss in Duroc were both -0.89. Interesting differences between the two breeds in numerical value of some genetic correlations were observed, probably reflecting the differences in physiology and selection history between Landrace and Duroc. The estimated genetic correlation between drip loss and pH was much stronger in Duroc than in Landrace (-0.89 and -0.63, respectively). This might be due to the high pH in Duroc, whereas Landrace had a lower pH closer to the iso-electric point for muscle proteins. The positive genetic correlation between the L* value in meat and IMF in Duroc (0.50) was an effect of differences in visible marbling, rather than meat colour. For Landrace, this correlation was negative (-0.20). IMF content showed favourable genetic correlations to drip loss (-0.36 and -0.35 for Landrace and Duroc, respectively).


Parenting for mental health: what does the evidence say we need to do? Report of Workpackage 2 of the DataPrev project.
The last decade has witnessed increasing interest in the promotion of mental health and well-being because of its importance for health and social functioning at individual level and for the social and economic well-being of societies. Recent research from a range of disciplines (including neurodevelopment, developmental psychology and genetics) has highlighted the importance of childhood, and particularly the first few years of life, for future mental, social and emotional development. The quality of the parent-child relationship and parenting more generally is one of the factors in determining outcomes. The objective of this review was to identify effective interventions to support parents, parenting and the parent-child relationship from the ante-natal period to adolescence. A systematic search of key electronic databases was undertaken to identify systematic reviews evaluating approaches to parenting support; 52 systematic reviews were identified. Results were synthesized qualitatively and reported under the following headings: (i) perinatal programmes; (ii) parenting support programmes in infancy and early years focused on enhancing caregiver sensitivity and attunement; (iii) formal parenting programmes focused on children's behaviour; (iv) parenting support for highest risk groups. The review provides a robust international evidence base of programmes which have been demonstrated to improve parenting and the mental health and well-being of children. Policies and programmes to support parenting offer much scope for improving mental health. Effective provision requires a skilled workforce and careful application of approaches that have been found to work. More research is needed to develop and identify interventions for some of the highest risk groups.


Risk profiles of pork and poultry meat and risk ratings of various pathogen/product combinations.
Risk profiles of pork and poultry meat were carried out using an Excel-based software program, Risk Ranger. It is a semi-quantitative risk estimator answering various questions relating to the probability of exposure to a hazard, susceptibility of the population of interest, severity of the illness caused by the hazard if present and probability of food containing an infectious dose. Therefore, qualitative and quantitative inputs were used to estimate and rank the risk of various hazards/food combinations. Risk scores provided by the tool were characterized as low, medium and high. Also, health risk was estimated separately, where needed, for low and high risk populations. Low risk scores were obtained for Salmonella spp., Listeria monocytogenes and enterohaemorrhagic Escherichia coli (EHEC) for low risk population. High risk scores were obtained for hepatitis E virus (HEV) in raw pork products (both low and high risk populations). Moderate risk scores for Salmonella spp. and L. monocytogenes in processed pork or poultry-meat products (ready-to-eat or to be reheated) and partially cooked pork products were also obtained (low risk population). Scores for Staphylococcus aureus, Clostridium perfringens and Bacillus cereus and various product types were mostly in the "medium" risk category, except for S. aureus/ready-to-eat pork products able to support growth of the organism, which fell into the high risk category. Campylobacter spp. gave moderate risk scores with one exception (raw poultry products), whereas Y. enterocolitica showed combinations of low risk and few of medium risk. High risk pathogen/product combinations identified were: 1) temperature abused, ready-to-eat pork and/or poultry-meat products with extended shelf life and cross-contaminated by L. monocytogenes (high risk population), EHEC (high risk population) or S. aureus (all population), 2) partially cooked or processed intended to be reheated pork products cross-contaminated by L. monocytogenes, served undercooked and receiving improper cooling or reheating (high risk population), and 3) all people consuming undercooked meals cross-contaminated with Campylobacter spp. (e.g. from raw poultry and raw poultry-meat products) and HEV (e.g. from raw pork and raw pork-meat products). Salmonellae gave high risk scores in all food categories (except preserved meat products) for high risk population. Preserved meats (mainly pork) such as dry fermented sausages gave low risk scores. Only Salmonella spp., L. monocytogenes and E. coli EHEC gave moderate risk ratings in case of ingredients likely to be contaminated at an early stage of processing (e.g. animal at slaughter) and inadequate fermentation process. These results may constitute a source of information for hazard assessment during application of a Food Safety Management System.


A role for protein kinase C activity in interleukin-1 (IL-1) induction of IL-2 gene expression but not in IL-1 signal transduction.
Interleukin-1 (IL-1) is known to synergize with phorbol esters in the induction of interleukin-2 (IL-2) expression in T-lymphoid leukemia cells and proliferation of mouse thymocytes. We used a plasmid construct containing the bacterial gene for chloramphenicol acetyltransferase under the control of the human IL-2 promoter to study the nature of this synergism in the murine thymoma cell line EL4. Although IL-1 induction of the IL-2 promoter in these cells required costimulus with phorbol myristate acetate, the signal induced by IL-1 was qualitatively different. We provide evidence to support the hypothesis that the phorbol ester signal is mediated by protein kinase C, and we show that the IL-1 signal is not. That IL-1 and phorbol myristate acetate represent different stimuli was shown by their response to protein kinase C inhibitors, capacity to synergize with increased intracellular free calcium, and requirement for protein synthesis. In addition we show that pretreatment with IL-1 can prime EL4 cells to subsequent activation by concentrations of phorbol esters not normally sufficient to induce IL-2 expression. Pretreated cells remained primed for at least 40 h after removal of the IL-1. Neither phorbol myristate acetate nor a calcium ionophore was capable of preactivating EL4 cells.


Tumor Cell Lysate-Based Multifunctional Nanoparticles Facilitate Enhanced mRNA Delivery and Immune Stimulation for Melanoma Gene Therapy.
Messenger ribonucleic acid (mRNA)-based gene therapy has great potential for cancer gene therapy. However, the effectiveness of mRNA in cancer therapy needs to be further improved, and the delivery efficiency and instability of mRNA limit the application of mRNA-based products. Both the delivery efficiency can be elevated by cell-penetrating peptide modification, and the immune response can be enhanced by tumor cell lysate stimulation, representing an advantageous strategy to expand the effectiveness of mRNA gene therapy. Therefore, it is vital to exploit a vector that can deliver high-efficiency mRNA with codelivery of tumor cell lysate to induce specific immune responses. We previously reported that DMP cationic nanoparticles, formed by the self-assembly of DOTAP and mPEG-PCL, can deliver different types of nucleic acids. DMP has been successfully applied in gene therapy research for various tumor types. Here, we encapsulated tumor cell lysates with DMP nanoparticles and then modified them with a fused cell-penetrating peptide (TAT-iRGD) to form an MLSV system. The MLSV system was loaded with encoded Bim mRNA, forming the MLSV/Bim complex. The average size of the synthesized MLSV was 191.4 nm, with a potential of 47.8 mV. The MLSV/mRNA complex promotes mRNA absorption through caveolin-mediated endocytosis, with a transfection rate of up to 68.6% in B16 cells. The MLSV system could also induce the maturation and activation of dendritic cells, obviously promoting the expression of CD80, CD86, and MHC-II both in vitro and in vivo. By loading the encoding Bim mRNA, the MLSV/Bim complex can inhibit cell proliferation and tumor growth, with inhibition rates of up to 87.3% in vitro. Similarly, the MLSV/Bim complex can inhibit tumor growth in vivo, with inhibition rates of up to 78.7% in the B16 subcutaneous tumor model and 63.3% in the B16 pulmonary metastatic tumor model. Our results suggest that the MLSV system is an advanced candidate for mRNA-based immunogene therapy.


Do diabetes-specialty clinics differ in management approach and outcome? A cross-sectional assessment of ambulatory type 2 diabetes patients in two teaching hospitals in Nigeria.
To evaluate management approach and outcome in two endocrinologist-managed clinics using data on treatment adherence, diabetes-specific parameters, prescribed medications and self-management practices among ambulatory type 2 diabetes patients. Opinion on cause(s) and perceived fear about diabetes were also explored. A cross-sectional prospective study using semi-structured interview among consented patients for eightweek, and a review of participants' case notes at 3-month post-interactive contact for details of diabetes-specific parameters and antidiabetes medications. The University College Hospital (UCH) and Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC) in southwestern Nigeria. Adult patients with type 2 diabetes, on therapies for >3-month and who had average fasting blood glucose (FBG)>6.0mmol/L were enrolled. All patients with type 1 diabetes, and type 2 diabetes who decline participation were excluded. Out of 185 participants who were approached, 176(95.1%) consented and completed the study including 113(64.2%) from UCH and 63(35.8%) in OAUTHC. Mean FBG for patients were 9.6mmol/L in UCH and 11.0mmol/L in OAUTHC (p=0.03). Medication adherence among patients was 47(46.5%) in UCH and 31(52.5%) in OAUTHC (p=0.46). Prescribed antidiabetes medications between the clinics significantly differ. Practice of self-monitoring of blood glucose among participants was 26(23.0%) in UCH and 13(20.6%) in OAUTHC (p=0.72). Thirty-two participants (29.4%) in UCH and 33(43.4%) from OAUTHC (p=0.02) mentioned complications as perceived fear about type 2 diabetes. There are differences and similarities between the diabetes-specialty clinics with respect to diabetes management and outcome. This underscores the necessity for a protocol-driven treatment approach in ensuring improved diabetes care and outcome. None declared.


Proximity to Legal Cannabis Stores in Canada and Use of Cannabis Sources in the First Three Years of Legalization, 2019-2021.
The accessibility of legal cannabis in Canada may influence how consumers source their cannabis. The aims of this study were to examine (a) the distance between respondents' homes and legal retail stores, (b) the cannabis sources used in the past 12 months, and (c) the association between cannabis sources used and distance to legal retail stores. Data were analyzed from Canadian respondents participating in the International Cannabis Policy Study from 2019 to 2021. Respondents were 15,311 past-12-month cannabis consumers of legal age to purchase cannabis. Weighted logistic regression models examined cannabis sources used and their association with the Euclidean distance to the nearest legal store, province of residence, and year (n = 12,928). Respondents lived closer to a legal retail store in 2021 (1.5 km) versus 2019 (6.8 km) as the number of retail stores increased. Respondents in 2020 and 2021 had higher odds of obtaining cannabis from legal sources (e.g., legal stores: 47.9% and 60.0% vs. 38.6%, respectively, adjusted odds ratio [AOR] range: 1.41-2.42) and lower odds of obtaining cannabis from illegal sources versus 2019 (e.g., dealers: 22.6% and 19.9% vs. 29.1%, respectively, AOR range: 0.65-0.54). Respondents who lived closest to legal stores had higher odds of sourcing from legal stores and lower odds of sourcing from legal websites or growing their own cannabis. Legal cannabis stores are increasingly accessible to people living in Canada 3 years after legalization. Household proximity to a legal cannabis store was associated with sourcing cannabis from legal retail stores, but only among those who live very close (<3 km). Findings suggest that proximity to legal cannabis stores may aid uptake of the legal market, yet there may be diminishing returns after a certain point.


MAP kinase function in amoeboid chemotaxis.
Mutants lacking the MAP kinase DdERK2 show reduced chemotactic responses to folate and cAMP. Analysis of cAMP chemotaxis shows that Dderk2- cells are defective in chemotaxis to high concentrations of cAMP. This defect is due to an inability to repolarize in the continued presence of high concentrations of cAMP. Under these conditions, the speed of movement of mutant cells remains low. Instead of generating a leading pseudopod, mutant cells generate transient crown-like structures over multiple regions of the cell surface. These structures differ from pseudopods in that they contain myosin II as well as F actin and coronin. These studies identify a role for MAP kinases in coordinating the formation of cell projections generated in response to chemoattractants.


Temporally-patterned deep brain stimulation in a mouse model of multiple traumatic brain injury.
We report that mice with closed-head multiple traumatic brain injury (TBI) show a decrease in the motoric aspects of generalized arousal, as measured by automated, quantitative behavioral assays. Further, we found that temporally-patterned deep brain stimulation (DBS) can increase generalized arousal and spontaneous motor activity in this mouse model of TBI. This arousal increase is input-pattern-dependent, as changing the temporal pattern of DBS can modulate its effect on motor activity. Finally, an extensive examination of mouse behavioral capacities, looking for deficits in this model of TBI, suggest that the strongest effects of TBI in this model are found in the initiation of any kind of movement.


Genetically resistant (Ityr) and susceptible (Itys) congenic mouse strains show similar cytokine responses following infection with Salmonella dublin.
IFN-gamma, TNF-alpha, IL-1, and granulocyte-macrophage CSF (GM-CSF) play an important role in host resistance to infection with nontyphoid Salmonella. In mice, resistance to Salmonella is determined by alleles of the susceptibility gene, Nramp, which maps to the Ity/Lsh/Bcg locus and is expressed in macrophages. In vitro studies suggested that macrophages from Salmonella-susceptible mice (Itys phenotype) are impaired functionally in their ability to produce, or stimulate the production of, cytokines such as TNF-alpha and IFN-gamma. BALB/c and BALB/c.DBA2 Idh-lb-Ityr-Pep-3b mice are congenic strains that differ at the Ity/Lsh/Bcg locus and in their susceptibility to Salmonella infection. These strains were used to question whether differences in the host cytokine response determine the outcome of Salmonella infection in genetically susceptible and resistant mice. As reported in this work, the in vivo response to Salmonella dublin infection in both Itys and Ityr mice was characterized by increased expression of IFN-gamma, TNF-alpha, GM-CSF, IL-1 alpha, IL-2, IL-6, IL-10, and IL-12 p40. In contrast, expression of IL-4, IL-5, and TGF-beta 1 was not altered, or decreased, during the course of infection. Moreover, the kinetics and magnitude of the cytokine response following S. dublin infection were similar in susceptible Itys and resistant Ityr mice, even though the former group died while the latter survived the infection. Thus, in vivo cytokine responses that are associated with survival of Ityr mice following S. dublin infection do not confer protection in mice of the Itys phenotype.


In situ preparation of gold-polyester nanoparticles for biomedical imaging.
The synthesis and application of gold nanoparticles (AuNPs) have attracted much attention due to their interesting optical and chemical properties, as well as their utility in imaging, therapeutics, sensors, electronics, and catalysis. AuNPs are synthesized using multiple approaches, followed by chemical modification or encapsulation, to enhance their colloidal stability, biocompatibility, and targeting. Here, we report the one-step synthesis of gold-polyester nanoparticles for use as an imaging agent. The AuNPs were prepared inside polymeric NPs by means of ultraviolet irradiation of a gold salt in the presence of Irgacure I-2959 photoinitiator. We monitored the kinetic growth and nucleation of AuNPs (in vitro and ex vivo) over time using spectral analysis. Moreover, we investigated the cytotoxicity, localized plasmonic surface resonance (LSPR), and cellular imaging capabilities of the Au-polyester nanoparticles. The resulting Au-polyester NPs were characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), dynamic light scattering (DLS), and transmission electron microscopy (TEM) to probe their chemical structure, size, zeta potential (ζ), and morphology, respectively. Furthermore, in vitro experiments showed that the NP formulation is stable over time and exhibits negligible toxicity against 3T3 fibroblast and U-87 MG glioblastoma cells. The results also demonstrated that the Au-polyester NPs exhibit excellent cellular imaging properties. This one-step strategy goes beyond current syntheses of gold-polyester nanoparticles because it can be used to synthesize the imaging agent in situ (i.e., in living cells) in lieu of conventional ex situ approaches.


Nanofabrication of high Q, transferable diamond resonators.
Advancement of diamond based photonic circuitry requires robust fabrication protocols of key components - including diamond resonators and cavities. Here, we present 1D (nanobeam) photonic crystal cavities generated from single crystal diamond membranes utilising a metallic tungsten layer as a restraining, conductive and removable hard mask. The use of tungsten instead of a more conventional silicon oxide layer enables good repeatability and reliability of the fabrication procedures. The process yields high quality diamond cavities with quality factors (Q-factors) approaching 1 × 104. Finally, we show that the cavities can be picked up and transferred onto a trenched substrate to realise fully suspended diamond cavities. Our fabrication process demonstrates the capability of diamond membranes as modular components for broader diamond based quantum photonic circuitry.


Effects of Thymus vulgaris ethanolic extract on chronic toxoplasmosis in a mouse model.
The current work was undertaken to investigate the potential effectiveness of Thymus vulgaris ethanolic extract (TVE) against Toxoplasma gondii infection in chronic experimental toxoplasmosis. To evaluate prophylactic effects, mice received 500 mg/kg TVE for 5 days before they were infected by an avirulent Me49 T. gondii strain. To investigate the therapeutic effects of the extract postinfection, daily treatment with TVE was initiated at 6 weeks postinfection and continued for 10 days. The following groups of animals were used as controls: uninfected/non-treated, infected/non-treated, and infected/treated with a combination of pyrimethamine and sulfadiazine. Brain cyst count and histopathological changes using H&E and Feulgen stains were used to evaluate the efficacy of TVE. The mean number of brain cysts was significantly decreased by 24 % in mice treated prophylactically with TVE. TVE also significantly reduced the mean number of brain cysts when administered to animals already chronically infected with T. gondii. The effect of TVE was comparable to that of treatment with a mixture of sulfadiazine and pyrimethamine (46 and 51 % reduction, respectively). Moreover, considerable amelioration of the pathological lesions in the brain and retina was observed. The results demonstrate the potential efficacy of T. vulgaris as a new natural therapeutic and prophylactic agent for use in the treatment of chronic toxoplasmosis.


Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA.
Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.


Francisella tularensis Subtype A.II Genomic Plasticity in Comparison with Subtype A.I.
Although Francisella tularensis is considered a monomorphic intracellular pathogen, molecular genotyping and virulence studies have demonstrated important differences within the tularensis subspecies (type A). To evaluate genetic variation within type A strains, sequencing and assembly of a new subtype A.II genome was achieved for comparison to other completed F. tularensis type A genomes. In contrast with the F. tularensis A.I strains (SCHU S4, FSC198, NE061598, and TI0902), substantial genomic variation was observed between the newly sequenced F. tularensis A.II strain (WY-00W4114) and the only other publically available A.II strain (WY96-3418). Genome differences between WY-00W4114 and WY96-3418 included three major chromosomal translocations, 1580 indels, and 286 nucleotide substitutions of which 159 were observed in predicted open reading frames and 127 were located in intergenic regions. The majority of WY-00W4114 nucleotide deletions occurred in intergenic regions, whereas most of the insertions and substitutions occurred in predicted genes. Of the nucleotide substitutions, 48 (30%) were synonymous and 111 (70%) were nonsynonymous. WY-00W4114 and WY96-3418 nucleotide polymorphisms were predominantly G/C to A/T allelic mutations, with WY-00W4114 having more A+T enrichment. In addition, the A.II genomes contained a considerably higher number of intact genes and longer repetitive sequences, including transposon remnants than the A.I genomes. Together these findings support the premise that F. tularensis A.II may have a fitness advantage compared to the A.I subtype due to the higher abundance of functional genes and repeated chromosomal sequences. A better understanding of the selective forces driving F. tularensis genetic diversity and plasticity is needed.


[Postoperative use of nonsteroidal anti-inflammatory agents in orthopedic surgery].
Nonsteroidal antiinflamatory drugs (NSAIDs) lead to satisfactory acute and chronic pain relief. Besides that, they exert potent antiinflamatory effect. Their analgesic potency is dose related and limited. Orthopedic patients are often on these medications preoperatively and experience opioid-sparing effect in the postoperative period. Chronic NSAIDs use is related to higher rate of sistemic adverse effects, but even short time exposure in the postoperative period is not risk-free. Although Coxibs reduce GIT bleeding incidence due to prolonged use of NSAIDs, there has to be judicious decision considering their cardiovascular adverse effects. There is evidence that NSAIDs producing moderate, dose-dependent increased bleeding time within normal values. High risk of bleeding have patients with established coagulopathy, alcohol abuse and on anticoagulant treatment. There is no strong evidence on influence of NSAIDs on bone growth. Nevertheless, there is evidence that NSAIDs do prevent heterotropic ossification. Prostaglandins are vital contributors for maintainig tissue homeostasis and NSAIDs use can lead to many unwanted effects. Those adverse effect are more common with prolonged exposure, are dose-related and risks have to be carefully and individually assesed in the postoperative pain management.


Genetic Variants in Interleukin-28B Are Associated with Diabetes and Diabetes-Related Complications in Patients with Chronic Hepatitis C Virus Infection.
Few studies have shown that host interleukin-28B (IL28B) genetic polymorphisms are associated with insulin resistance in patients with chronic hepatitis C virus (HCV) infection. However, the clinical relevance of this relationship is unclear. We examined the association between IL28B genotype for rs12980275 and risk of type 2 diabetes and diabetes-related complications. We used a cross-sectional study of prospectively recruited male veterans with chronic HCV. We employed logistic regression analysis and adjusted for patients' age, race, body mass index, and hepatic fibrosis. A total of 528 participants were recruited (mean age 59.1 years; 38.5 % African-American; 40.3 % advanced fibrosis). Of these, 36.1 % were homozygous for favorable AA allele for rs12980275, 49.0 % were heterozygous (AG), and 14.0 % were homozygous for the unfavorable allele (GG). Prevalence of diabetes was significantly lower in patients with both favorable alleles (AA) than that with at least one unfavorable IL28B G allele (21.1 vs. 30.2 %, p = 0.02). Similarly, patients who were homozygous for the favorable alleles had lower prevalence of diabetes-related complications than patients with any unfavorable IL28B allele (5.7 vs. 12.2 %, p = 0.01). This association did not change after adjusting for sociodemographic characteristics, body mass index, and stage of hepatic fibrosis (adjusted ORdiabetes 0.56, 95 % CI 0.35-0.89; ORdiabetes-related complications 0.47, 95 % CI 0.23-0.96). Patients who have favorable AA IL28B alleles have a lower prevalence of diabetes and related complications compared with patients with unfavorable IL28B rs12980275 genotype. IL28B genotype information may be used to counsel HCV patients regarding their individualized risk of diabetes and diabetes-related complications.


Comparison of drug delivery from conventional versus "Venturi" nebulizers.
Attempts to improve drug delivery from conventional jet nebulizers have included the use of storage systems to reduce drug wastage during exhalation. Venturi nebulizers enhance drug delivery during inhalation, reducing treatment times and drug wastage. This study investigated the effect of age on inhaled dose from a conventional jet nebulizer (Acorn) used both with and without a storage chamber (Mizer), compared to two Venturi nebulizers (Ventstream and Pari LC). Filters were attached to the four nebulizer systems, containing salbutamol, and 18 children with cystic fibrosis (3-16 yrs) inhaled through these devices. The quantity of drug collected on the filter was assessed using ultraviolet spectrophotometry. The particle size distribution of the aerosol from each nebulizer system was measured using laser diffraction. Inspiratory filter deposition using the Acorn was lower than the Acorn with Mizer, and both Venturi nebulizers. Filter deposition using the Acorn with Mizer was lower than the Pari LC. No trend with age, height or weight was noted using any nebulizer. Aerosol particle size using the Ventstream was lower than the other nebulizer systems. Drug output from both Venturi nebulizers was more efficient than from the jet nebulizer, used with and without the storage chamber, during inhalation by children with cystic fibrosis. The inhaled dose did not change with the patient's age or size using both types of nebulizer.


Localization of tissue plasminogen activator in relation to morphologic changes in human saphenous veins used as coronary artery bypass autografts.
Employing the histochemical fibrin slide technique, we studied the localization of fibrinolytically active sites in relation to morphologic changes in saphenous veins used as coronary artery bypass autografts. Of veins from 100 patients undergoing surgery for coronary heart disease, 63 samples revealed well-demarcated intimal fibrinolytic activity. Distinct foci of lysis were present in the media and adventitia of all vein samples corresponding to the distribution of the vasa vasorum. Graft specimens obtained by autopsy from 13 patients surviving from 30 minutes to 13 days revealed considerable intimal damage with loss of fibrinolytic activity. Medial fibrinolytic activity disappeared early concomitant with disorganization of the medial muscle fibers, followed by necrosis, atrophy and fibrous transformation of the muscular structures. Adventitial activity disappeared later. One reoperation sample obtained after 8 weeks in situ showed moderate proliferative intimal fibrosis without an apparent neo-intima and without fibrinolytic activity, and one section showed evidence of valve cusp fibrosis, while most of the media had been replaced by fibrous tissue. Numerous foci of "medial" -adventitial fibrinolytic activity indicated presence of vascular structures in the venous wall. The fibrin slide technique is a convenient tool for studying the process of revascularization.


Effect of Aromatic Amines on the Properties of Formaldehyde-Based Xerogels.
This study investigates the synthesis of formaldehyde-based xerogels using alternative aromatic precursors, with comparison to traditional resorcinol-formaldehyde analogues, in order to alter the chemical composition of the resulting gels. By replacing resorcinol with aromatic amine molecules, i.e., ammeline, melamine and melem, each expected to undergo similar reactions with formaldehyde as the substituted species, we found that for all substituted gels, at low additive contents, the gel structure was compromised and non-porous materials were formed, as opposed to the most abundant monomers, and therefore, these additives seem to act as impurities at low levels. Working towards higher additive contents, melem monomers exhibited low solubility (~5%), even at elevated temperatures, thereby limiting the range to which melem could act as a substitute, while melamine could be incorporated up to ~40% under acidic conditions, with enhanced microporosity over this range. Pure gels were successfully synthesised from ammeline, but their performance was inferior to resorcinol-formaldehyde gels, while melamine-formaldehyde analogues required acidic reaction conditions but shrank considerably on sub-critical drying, adversely affecting the gel properties and demonstrating their lack of potential as sorbents. This demonstrates the potential for the inclusion of aminated aromatics within resorcinol-based gel systems, however, only as partial substitutes and not complete replacements.


The Roles of Inflammation, Nutrient Availability and the Commensal Microbiota in Enteric Pathogen Infection.
The healthy human intestine is colonized by as many as 1014 bacteria belonging to more than 500 different species forming a microbial ecosystem of unsurpassed diversity, termed the microbiota. The microbiota's various bacterial members engage in a physiological network of cooperation and competition within several layers of complexity. Within the last 10 years, technological progress in the field of next-generation sequencing technologies has tremendously advanced our understanding of the wide variety of physiological and pathological processes that are influenced by the commensal microbiota (1, 2). An increasing number of human disease conditions, such as inflammatory bowel diseases (IBD), type 2 diabetes, obesity, allergies and colorectal cancer are linked with altered microbiota composition (3). Moreover, a clearer picture is emerging of the composition of the human microbiota in healthy individuals, its variability over time and between different persons and how the microbiota is shaped by environmental factors (i.e., diet) and the host's genetic background (4). A general feature of a normal, healthy gut microbiota can generate conditions in the gut that disfavor colonization of enteric pathogens. This is termed colonization-resistance (CR). Upon disturbance of the microbiota, CR can be transiently disrupted, and pathogens can gain the opportunity to grow to high levels. This disruption can be caused by exposure to antibiotics (5, 6), changes in diet (7, 8), application of probiotics and drugs (9), and a variety of diseases (3). Breakdown of CR can boost colonization by intrinsic pathogens or increase susceptibility to infections (10). One consequence of pathogen expansion is the triggering of inflammatory host responses and pathogen-mediated disease. Interestingly, human enteric pathogens are part of a small group of bacterial families that belong to the Proteobacteria: the Enterobacteriaceae (E. coli, Yersinia spp., Salmonella spp., Shigella spp.), the Vibrionaceae (Vibrio cholerae) and the Campylobacteriaceae (Campylobacter spp.). In general, members of these families (be it commensals or pathogens) only constitute a minority of the intestinal microbiota. However, proteobacterial "blooms" are a characteristic trait of an abnormal microbiota such as in the course of antibiotic therapy, dietary changes or inflammation (11). It has become clear that the gut microbiota not only plays a major role in priming and regulating mucosal and systemic immunity, but that the immune system also contributes to host control over microbiota composition. These two ways of mutual communication between the microbiota and the immune system were coined as "outside-in" and "inside-out," respectively (12). The significance of those interactions for human health is particularly evident in Crohn's disease (CD) and Ulcerative Colitis (UC). The symptoms of these recurrent, chronic types of gut inflammation are caused by an excessive immune response against one's own commensal microbiota (13). It is assumed that deregulated immune responses can be caused by a genetic predisposition, leading to, for example, the impairment of intestinal barrier function or disruption of mucosal T-cell homeostasis. In CD or UC patients, an abnormally composed microbiota, referred to as "dysbiosis," is commonly observed (discussed later). This is often characterized by an increased relative abundance of facultative anaerobic bacteria (e.g., Enterobacteriaeceae, Bacilli) and, at the same time, depletion of obligate anaerobic bacteria of the classes Bacteroidia and Clostridia. So far, it is unclear whether dysbiosis is a cause or a consequence of inflammatory bowel disease (IBD). In fact, both scenarios are equally conceivable. Recent work suggests that inflammatory immune responses in the gut (both IBD and pathogen-induced) can alter the gut luminal milieu in a way that favors dysbiosis (14). In this chapter, I present a survey on our current state of understanding of the characteristics and mechanisms underlying gut inflammation-associated dysbiosis. The role of dysbiosis in enteric infections and human IBD is discussed. In addition, I will focus on competition of enteric pathogens and the gut microbiota in the inflamed gut and the role of dysbiotic microbiota alterations (e.g., "Enterobacterial blooms" (11)) for the evolution of pathogenicity.


Where pain meets action in the human brain.
Pain's complex influence on behavior implies that it involves an action component, although little is known about how the human brain adaptively translates painful sensations into actions. The consistent activation of premotor and motor-related regions during pain, including the midcingulate cortex (MCC), raises the question of whether these areas contribute to an action component. In this fMRI experiment, we controlled for voluntary action-related processing during pain by introducing a motor task during painful or nonpainful stimulation. The MCC (particularly the caudal cingulate motor zone [CCZ]), motor cortex, thalamus, and cerebellum responded during action regardless of pain. Crucially, however, these regions did not respond to pain unless an action was performed. Reaction times were fastest during painful stimulation and correlated with CCZ activation. These findings are consistent with the results of an activation likelihood estimate meta-analysis in which activation across experiments involving pain, action execution, or action preparation (with a total of 4929 subjects) converged in a similar network. These findings suggest that specific motor-related areas, including the CCZ, play a vital role in the control and execution of context-sensitive behavioral responses to pain. In contrast, bilateral insular cortex responded to pain stimulation regardless of action.


Amniotic fluid embolism induces uterine anaphylaxis and atony following cervical laceration.
Amniotic fluid embolism (AFE) is a rare, high-risk obstetric complication primarily found in the lungs and potentially related to anaphylaxis. Tryptase release from the mast cell reflects anaphylaxis. Case report and findings: A female, aged over 40 years, presented with uterine atony and lethal hemorrhage after induced vaginal labor. Cervical laceration was accompanied by severe hemorrhage. Stromal edema and myometrial swelling were consistent with uterine atony. Alcian blue staining and zinc coproporphyrin immunostaining disclosed AFE, which was more prominent in the uterus than in the lungs. Tryptase immunostaining was diffuse and prominent around the activated mast cells (halos) in the uterus, including the cervix. Similar distribution of findings on the AFE markers, tryptase halos, complement receptor C5aR, and atony in the uterus suggested the causality of AFE to anaphylaxis, complement activation and atony. It is probable that disseminated intravascular coagulation (DIC), induced by AFE, uterine atony and cervical laceration, caused the lethal hemorrhage. It is likely that AFE, in association with cervical laceration, induces uterine anaphylaxis, complement activation, atony, DIC and lethal hemorrhage.


MicroRNA reins in embryonic and cancer stem cells.
MicroRNAs represents a new layer of gene regulation in stem cells by controlling the molecular mechanisms involved in modulating stem cell fate and behavior. Such a role of microRNA is seen in embryonic stem cell as well, maintaining a delicate balance between survival, proliferation, and self-renewal signals. Further, dysregulation of stem cell self-renewal is a likely requirement for the initiation and formation of cancer stem cells that probably pose resistance to current cancer treatments. In fact, the precise mechanism that regulates embryonic as well as cancer stem cell self-renewal and pluripotency remains largely unknown. Understanding the miRNA related stem cell biology and pathways offers great promise for improving stem cell mediated regenerative therapy as well as cancer therapies. Here we summarize some of the emerging evidences demonstrating the role of these molecular switches in embryonic and cancer stem cells.


Quantifying energy expenditure in Göttingen Minipigs with the 13C-bicarbonate method under basal and drug-treated conditions.
Effective treatments of obesity focusing on energy expenditure (EE) are needed. To evaluate future EE-modulating drug candidates, appropriate animal models and methods to assess EE are needed. This study aimed to evaluate the stable isotope 13C-bicarbonate method (13C-BM) for estimating EE in Göttingen minipigs under basal and drug-treated conditions. Four experiments (Expt.1-4) were conducted to assess: 1) the 13C-BM reproducibility using breath sample collection (n = 8), on two consecutive days, 2) the effect of two dose levels (5 and 10 mg/kg body weight (BW)) of the mitochondrial uncoupler dinitrophenol (DNP) in a crossover design (n = 8), 3) sampling method agreement; blood vs. exhaled air (n = 6) and 4) 13C-BM using constant isotope infusion compared with indirect calorimetry (IC) (n = 3). Results correlated significantly (p < 0.001) between days (Expt.1), with an average coefficient of variance of 5.4 ± 2.3%. Administration of 10 mg DNP/kg BW increased (p < 0.01) EE by 33.2 ± 6.4% (Expt.2). Results based on different sampling methods correlated significantly (p < 0.001) and EE increased after 10 mg DNP/kg BW (p < 0.05) in Expt.3. However, results based on blood sampling were significantly higher (p < 0.01) than those of exhaled air. No effect of DNP and significantly different EE results (p < 0.05) was observed in a limited number of animals, when constant isotope infusion and blood sampling was compared with IC (Expt.4). In conclusion, the 13C-BM is useful for investigating treatment effects on EE in minipigs. However, further validation under standardized conditions is needed to provide accurate estimates of the 13C recovery factor and respiratory quotient, both of decisive importance when using the 13C-BM.


Manual localization of lateralized visual targets.
The effects of visual field, responding limb and extrapersonal space on the ability to localize visual targets using slow positioning movements of the arm were examined. Special contact lenses were used to lateralize visual information and to make comparisons with localization under monocular control conditions. Subjects made slow positioning movements to place a cursor directly beneath target lights. They saw target lights but not the moving limb during the trial. For directional error, results indicated that subjects were more accurate localizing targets lateralized to the right hemisphere than targets lateralized to the left hemisphere, indicating right hemisphere superiority for localization of visual targets in grasping space. Localization performance was significantly better with the right hand than the left hand. the left hand demonstrated a directional bias to the right of the targets. Responding hand and visual field did not interact. Finally, contrary to subjects' awareness and verbal reports, target localization was not less accurate in lens than in monocular control conditions. This was true for both amplitude and directional error. This is consistent with other studies where visual information about limb position is not available.


Evidence of intense ongoing endemic transmission of hepatitis C virus in Egypt.
Egypt has the highest prevalence of antibodies to hepatitis C virus (HCV) in the world, estimated nationally at 14.7%. An estimated 9.8% are chronically infected. Numerous HCV prevalence studies in Egypt have published various estimates from different Egyptian communities, suggesting that Egypt, relative to the other nations of the world, might be experiencing intense ongoing HCV transmission. More importantly, a new national study provided an opportunity to apply established epidemiologic models to estimate incidence. Validated mathematical models for estimating incidence from age-specific prevalence were used. All previous prevalence studies of HCV in Egypt were reviewed and used to estimate incidence provided that there was sufficient age-specific data required by the models. All reports of anti-HCV antibody prevalence were much higher than any single other national estimate. Age was the strongest and most consistently associated factor to HCV prevalence and HCV RNA positivity. It was not possible to establish a prior reference point for HCV prevalence or incidence to compare with the 2009 incidence estimates. The modeled incidence from the national study and collectively from the modeled incidence from the previous community studies was 6.9/1,000 [95% confidence interval (CI), 5.5-7.4] per person per year and 6.6/1,000 (95% CI, 5.1-7.0) per person per year, respectively. Projected to the age structure of the Egyptian population, more than 500,000 new HCV infections per year were estimated. Iatrogenic transmission is the most likely, underlining exposure to the ongoing transmission. The study demonstrates the urgency to reduce HCV transmission in Egypt.


Comparison between European and Iranian cutoff points of triglyceride/high-density lipoprotein cholesterol concentrations in predicting cardiovascular disease outcomes.
High triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) are important cardiovascular risk factors. The exact prognostic value of the TG/HDL-C ratio, a marker for cardiovascular events, is currently unknown among Iranians so this study sought to determine the optimal cutoff point for the TG/HDL-C ratio in predicting cardiovascular disease events in the Iranian population. The Isfahan Cohort Study (ICS) is an ongoing, longitudinal, population-based study that was originally conducted on adults aged ≥ 35 years, living in urban and rural areas of three districts in central Iran. After 10 years of follow-up, 5431 participants were re-evaluated using a standard protocol similar to the one used for baseline. At both measurements, participants underwent medical interviews, physical examinations, and fasting blood measurements. "High-risk" subjects were defined by the discrimination power of indices, which were assessed using receiver operating characteristic (ROC) analysis; the optimal cutoff point value for each index was then derived. The mean age of the participants was 50.7 ± 11.6 years. The TG/HDL-C ratio, at a threshold of 3.68, was used to screen for cardiovascular events among the study population. Subjects were divided into two groups ("low" and "high" risk) according to the TG/HDL-C concentration ratio at baseline. A slightly higher number of high-risk individuals were identified using the European cutoff points of 63.7% in comparison with the ICS cutoff points of 49.5%. The unadjusted hazard ratio (HR) was greatest in high-risk individuals identified by the ICS cutoff points (HR = 1.54, 95% CI [1.33-1.79]) vs European cutoff points (HR = 1.38, 95% [1.17-1.63]). There were no remarkable changes after adjusting for differences in sex and age (HR = 1.58, 95% CI [1.36-1.84] vs HR = 1.44, 95% CI [1.22-1.71]) for the ICS and European cutoff points, respectively. The threshold of TG/HDL ≥ 3.68 is the optimal cutoff point for predicting cardiovascular events in Iranian individuals.


Suppression of puberty in girls with short-acting intranasal versus subcutaneous depot GnRH agonist.
Central precocious puberty (CPP) is more common in females than in males. During the last few decades a new group of patients with CPP has been seen frequently in Northern Europe, namely children adopted from developing countries. GnRH analogue preparations, administered either as intranasal spray or as depot preparations, are the drugs of choice for inhibiting the release of gonadotropins. The aim of this study was to compare the effect of buserelin given by intranasal spray with that of the same compound given as a subcutaneous depot preparation. The study group comprised 46 pubertal girls below the age of 9.5 years, adopted from a developing country. During the first 2 years, the treatment used was buserelin acetate 300 microg 6 times daily as a nasal spray. During the third year the treatment was changed to Suprefact Depot, 6.3 mg, given as a subcutaneous implant every 8 weeks. Half of the girls were randomized to growth hormone treatment in addition to the pubertal inhibition. GnRH provocation tests after 6 weeks, 1 year and 2 years of treatment with intranasal GnRH analogue showed suppression of gonadotropin secretion except in 1 case of noncompliance. During the third year, when the long-acting depot preparation was used, suppression was more pronounced. The peak LH response, especially, was considerably lower than during treatment with the nasal spray preparation. In all cases the clinical inhibition of puberty was adequate both during the first two years and during the third year. Even though the clinical suppression of puberty was adequate with both modes of administration, the effect of the depot preparation, in this study Suprefact Depot, was more pronounced in terms of gonadotropin suppression and less dependent on patient compliance.


Regulation of dynorphin gene expression by kappa-opioid agonist treatment.
The effects of K-opioid agonist treatment on prodynorphin mRNA expression in the rat brain were studied. Rats were treated with the selective kappa-opioid agonist U-69593 or vehicle for 5 days and prodynorphin mRNA was measured on day 8 (3 days after the last injection) or 22 (17 days after the last injection). On day 8 prodynorphin mRNA was increased in the hypothalamus and decreased in the striatum, frontal cortex, and hippocampus of rats treated with U-69593. On day 22, prodynorphin mRNA was increased in the hypothalamus, frontal cortex and striatum of U-69593 treated rats. These findings suggests that kappa-opioid receptor agonist treatment has long-term, continually changing effects on prodynorphin mRNA expression.


Transit tumor retrieval preserves RNA fidelity and obviates snap-freezing.
Genetic expression profiling is enabling investigators to discover new diagnostic and possibly therapeutic pathways in sarcoma biology. To draw substantial conclusions from these molecular analyses, adequate tissue samples must be accrued. Beyond cohort size, the most variable and limiting aspect of doing gene expression analyses on fresh human tissue is the preservation of labile ribonucleic acids extracted from clinical specimens. We have developed a novel retrieval protocol that is readily amenable to the clinical constraints placed on surgeons and pathologists that minimizes variables that can corrupt ribonucleic acid fidelity. We evaluate critically genomic message integrity of mesenchymal tumors derived from transcontinental inter-institutional collaboration. Intact total ribonucleic acid was isolated and assessed for quality and quantity. Ribosomal RNA integrity was quantified using a bioanalyzer. Ribonucleic acid from 42 mesenchymal tumors was isolated and quantified, with selected samples amplified. The mean ribosomal ratios for collaborative institutions ranged from 1.0 to 1.18. Samples remained at 4 degrees C before processing from 1 to 17 days. Tumors stabilized using this protocol retained total ribonucleic acid integrity suitable for amplification and genomic expression analysis regardless of the institutional source or preprocessing duration, enabling a potential consortium of investigators to collaborate in the expression profiling of sarcomas. Diagnostic study, Level III-3 (no consistently applied gold standard). See the Guidelines for Authors for a complete description of levels of evidence.


Benthic algal production across lake size gradients: interactions among morphometry, nutrients, and light.
Attached algae play a minor role in conceptual and empirical models of lake ecosystem function but paradoxically form the energetic base of food webs that support a wide variety of fishes. To explore the apparent mismatch between perceived limits on contributions of periphyton to whole-lake primary production and its importance to consumers, we modeled the contribution of periphyton to whole-ecosystem primary production across lake size, shape, and nutrient gradients. The distribution of available benthic habitat for periphyton is influenced by the ratio of mean depth to maximum depth (DR = z/ z(max)). We modeled total phytoplankton production from water-column nutrient availability, z, and light. Periphyton production was a function of light-saturated photosynthesis (BPmax) and light availability at depth. The model demonstrated that depth ratio (DR) and light attenuation strongly determined the maximum possible contribution of benthic algae to lake production, and the benthic proportion of whole-lake primary production (BPf) declined with increasing nutrients. Shallow lakes (z < or =5 m) were insensitive to DR and were dominated by either benthic or pelagic primary productivity depending on trophic status. Moderately deep oligotrophic lakes had substantial contributions by benthic primary productivity at low depth ratios and when maximum benthic photosynthesis was moderate or high. Extremely large, deep lakes always had low fractional contributions of benthic primary production. An analysis of the world's largest lakes showed that the shapes of natural lakes shift increasingly toward lower depth ratios with increasing depth, maximizing the potential importance of littoral primary production in large-lake food webs. The repeatedly demonstrated importance of periphyton to lake food webs may reflect the combination of low depth ratios and high light penetration characteristic of large, oligotrophic lakes that in turn lead to substantial contributions of periphyton to autochthonous production.


Amorphous photonic crystals with only short-range order.
Distinct from conventional photonic crystals with both short- and long-range order, amorphous photonic crystals that possess only short-range order show interesting optical responses owing to their unique structural features. Amorphous photonic crystals exhibit unique light scattering and transport, which lead to a variety of interesting phenomena such as isotropic photonic bandgaps or pseudogaps, noniridescent structural colors, and light localization. Recent experimental and theoretical advances in the study of amorphous photonic crystals are summarized, focusing on their unique optical properties, artificial fabrication, bionspiration, and potential applications.


Mechanical phenotyping of breast cancer using MEMS: a method to demarcate benign and cancerous breast tissues.
The mechanical properties of tissue change significantly during the progression from healthy to malignant. Quantifying the mechanical properties of breast tissue within the tumor microenvironment can help to delineate benign from cancerous stages. In this work, we study high-grade invasive ductal carcinoma in comparison with their matched tumor adjacent areas, which exhibit benign morphology. Such paired tissue cores obtained from eight patients were indented using a MEMS-based piezoresistive microcantilever, which was positioned within pre-designated epithelial and stromal areas of the specimen. Field emission scanning electron microscopy studies on breast tissue cores were performed to understand the microstructural changes from benign to malignant. The normal epithelial tissues appeared compact and organized. The appearance of cancer regions, in comparison, not only revealed increased cellularity but also showed disorganization and increased fenestration. Using this technique, reliable discrimination between epithelial and stromal regions throughout both benign and cancerous breast tissue cores was obtained. The mechanical profiling generated using this method has the potential to be an objective, reproducible, and quantitative indicator for detecting and characterizing breast cancer.


Effects of gonadectomy and hormonal replacement on rat hearts.
To evaluate the effects of sex hormones on heart function and biochemistry, gonadectomy (GX) was performed in postpubertal male (M) and female (F) rats and compared with sham-operated controls (SH). The groups were MSH; MGX; MGX replaced with testosterone 3 mg/day s.c. (MGX + T), FSH, and FGX replaced with estrogen 2 mg/day (FGX + E), progesterone 0.4 mg/day (FGX + P), estrogen and progesterone (FGX + EP), or testosterone 2 mg/day (FGX + T). Body weight was decreased in MGX and was decreased further in MGX + T. Heart weight was decreased in both MGX and MGX + T. Body weights were increased in FGX and FTX + P and were increased further in FGX + T but were normal in FGX + E and FGX + EP. Heart weights were unchanged in F groups except in FGX + T, where it was increased. Cardiac performance in perfused hearts, as measured by stroke work, ejection fraction, fractional shortening and mean velocity of circumferential fiber shortening, was decreased in MGX but was slightly increased in MGX + T. Papillary muscle studies showed increases in time to peak tension and one-half relaxation in MGX, but these were decreased in MGX + T. Isotonic shortening studies showed decreased velocity of shortening in MGX and increased velocity in MGX + T. Heart function was significantly decreased in FGX and FGX + P compared with FSH but was similar to FSH in FGX + E and FGX + EP. FGX + T had greater stroke work and ejection fraction than FSH and FGX.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparative Study of Proximal Tibia and Iliac Crest Bone Graft Donor Sites in Treatment of Orthopaedic Pathologies.
Introduction: Bone graft is harvested from bone and used to stimulate bone healing due to its properties. The aims of the study were to compare the quantity of graft harvested from proximal tibia and iliac crest, and the complications at these donor sites. Materials and Methods: This was a prospective study carried out on all consecutive patients who had orthopaedic procedures that required bone grafting at the study centre, from April, 2015 to March, 2016. Results: During the study period, 86 patients were recruited; 43 of these patients had bone graft harvested from the proximal tibia, while the other 43 patients had graft harvested from the iliac crest. There were 53 males, and 33 females. Mean age of patients was 41.2 ± 11 years and 40.8 ± 16 years, for proximal tibia and iliac crest group respectively. Average compressed volume of graft harvested from proximal tibia and iliac crest were 7cm3 and 5.5cm3 respectively. Non-unions were the commonest indications for bone grafting, femur was the commonest bone requiring bone grafting. Complications such as primary haemorrhage, pain and surgical site infection were commoner with iliac crest than proximal tibia donor sites, however bone graft harvested from both proximal tibia and iliac crest provided adequate bone union of the indicated procedure. Conclusion: Larger quantity of graft can be harvested from proximal tibia than the iliac crest. Though graft harvested from both the proximal tibia and the iliac crest have good healing properties, the proximal tibia donor site gave less complication than the iliac crest.


A cysteine protease inhibitor prevents suspension-induced declines in bone weight and strength in rats.
In this study, we examined the effects of a potent cysteine protease inhibitor, N-(L-3-trans-carboxyoxirane-2-cabonyl)-L-leucine-4-aminobutylamide (E-64a), on bone weight and strength in tail-suspended rats. We first administered a vehicle or 4 or 8 mg/rat of E-64a to rats fed with a low calcium diet for 7 wks to determine effective doses of E-64a on bone resorption in vivo. Femoral cathepsin K-like activity and serum hydroxyproline level in rats fed with a low calcium diet were significantly higher than those in rats fed with a standard diet. The intraperitoneal injection of 8 mg/rat of E-64a to rats decreased their serum calcium and hydroxyproline concentrations after 3 to 6 hrs in parallel with changes in femoral cathepsin K-like activity, while 4 mg/rat of E-64a had weaker effects on these parameters. Based on these results, we injected 8 mg/rat of E-64a to tail-suspended rats twice a day for 2 wks and compared the results with those of treatment with 1 mg/rat of etidronate, a bisphosphonate, twice a week. In tail-suspended rats, femoral weight and strength, assessed by three-point bending test, significantly decreased from Day 5 to 21, while femoral cathepsin K-like activity and serum calcium and hydroxyproline concentrations did not change. E-64a inhibited femoral cathepsin K-like activity in tail-suspended rats, but etidronate did not. E-64a as well as etidronate significantly prevented the suspension-induced declines in bone weight and strength. However, more frequent injection and higher doses were required for E-64a to exhibit significant efficacy of antiresorption, compared with those of etidronate. Our results suggest that a cysteine protease inhibitor could improve suspension-induced osteopenia by inhibiting cathepsin K-like activity in bone; however, it needs several improvements in the effect as a clinical drug.


Multiple sclerosis: some epidemiological clues to etiology.
The diagnosis of multiple sclerosis is frequently made with undue haste and without a firm basis. A false positive diagnosis is made in about 20 to 30% of the cases originally labeled as multiple sclerosis. The proportion of false positive diagnosis is probably still higher in countries where this disease is less frequent. An exhaustive investigation (neurological, clinical, neurorradiological, isotopic, etc.) is necessary before accepting such a diagnosis. This is particularly important because many of the lesions which can masquerade as multiple sclerosis are amenable to medical or surgical treatment. The prevalence of multiple sclerosis varies widely throughout the world, with a very definite preference for the white race. This difference seems to be caused, at least in part, by dietary habits. Lack of breastfeeding and excessive consumption of cow's milk during infancy is postulated as an important factor in the appearance of multiple sclerosis later in life. A lack of essential fatty acids (and may be of certain minerals and vitamins) in such a diet during pregnancy and childhood may result in the synthesis of abnormally unstable myelin. This underlying deficiency in myelin composition may be the substrate on which immunological factors act to produce the disease. The breakdown of this unstable myelin may be initiated by a variety of factors; natural decay of abnormally weak bonds in proteolipids, viral infection, immune reactions or even trauma. Immune reactions can explain, at least in part, the onset and the course of the disease, and probably immunodeficiency is the most important factor. Demyelination, once it starts, may continue until all abnormally formed myelin is destroyed, or until the building up of immunological defenses can stop the process. It follows from this that prevention of multiple sclerosis should be based mainly on dietic measures which ensure a sufficient supply of essential fatty acids, minerals and vitamins, during pregnancy and childhood. Breast feeding is probably the most important preventive factor. Skin pigmentation, either natural or from exposition to sunshine also seems to act as a preventive factor, and its mode of action deserves further investigation. Treatment of multiple sclerosis should be based on the improvement of immunological defenses, the elimination of possible allergens and saturated fats from the diet, and on the administration of sufficient amounts of essential fatty acids and of other various elements.