Bm-muted, orthologous to mouse muted and encoding a subunit of the BLOC-1 complex, is responsible for the otm translucent mutation of the silkworm Bombyx mori.
"Tanaka's mottled translucent" (otm) is a mutation of the silkworm Bombyx mori that exhibits translucent skin during larval stages. We performed positional cloning of the gene responsible for otm and mapped it to a 364-kb region on chromosome 5 that contains 22 hypothetical protein-coding genes. We performed RNA-seq analysis of the epidermis and fat body of otm larvae and determined that the gene BGIBMGA002619 may be responsible for the otm mutation. BGIBMGA002619 encodes the biosynthesis of lysosome-related organelles complex 1 (BLOC-1) subunit 5, whose ortholog is responsible for the Muted mutant in mouse. Accordingly, we named this gene Bm-muted. We discovered that the expression of Bm-muted in the epidermis and fat body of otm mutants was dramatically suppressed compared with the wild type. We determined the nucleotide sequences of the full-length cDNA and genomic region corresponding to Bm-muted and found that a 538-bp long DNA sequence similar to B. mori transposon Organdy was inserted into the 3' end of the first intron of Bm-muted in two otm strains. The Bm-muted cDNA of otm mutants lacked exon 2, and accordingly generated a premature stop codon in exon 3. In addition, short interfering RNA (siRNA)-mediated knockdown of this gene caused localized partial translucency of larval skin. These data indicate that the mutation in Bm-muted caused the otm-mutant phenotype. We propose that the insertion of Organdy caused a splicing disorder in Bm-muted in the otm mutant, resulting in a null mutation of Bm-muted. This mutation is likely to cause deficiencies in urate granule formation in epidermal cells that result in translucent larval skin.


[The problem of amblyopia in subluxated lenses (author's transl)].
A re-evaluation of the incidence and development of amblyopia was carried out in 27 patients with a history of lens subluxation at pre-school age. Due to insufficiently accurate histories and the heterogeneous composition of the material it is impossible to make any valid statement regarding the critical phase of development of deprivation amblyopia. However, it appears that "form-deprivation" amblyopia may regress spontaneously up to early school age following hygienization of the optic media and if optimal spectacles or contact lenses are worn. In individual cases it has been shown that unilateral amblyopias can and should be treated (pleoptics) following hygienization of the optic media. Therefore, early surgical treatment should be considered in such cases, above all in view of the fact that complications are rare.


Four-color DNA sequencing with 3'-O-modified nucleotide reversible terminators and chemically cleavable fluorescent dideoxynucleotides.
DNA sequencing by synthesis (SBS) on a solid surface during polymerase reaction can decipher many sequences in parallel. We report here a DNA sequencing method that is a hybrid between the Sanger dideoxynucleotide terminating reaction and SBS. In this approach, four nucleotides, modified as reversible terminators by capping the 3'-OH with a small reversible moiety so that they are still recognized by DNA polymerase as substrates, are combined with four cleavable fluorescent dideoxynucleotides to perform SBS. The ratio of the two sets of nucleotides is adjusted as the extension cycles proceed. Sequences are determined by the unique fluorescence emission of each fluorophore on the DNA products terminated by ddNTPs. On removing the 3'-OH capping group from the DNA products generated by incorporating the 3'-O-modified dNTPs and the fluorophore from the DNA products terminated with the ddNTPs, the polymerase reaction reinitiates to continue the sequence determination. By using an azidomethyl group as a chemically reversible capping moiety in the 3'-O-modified dNTPs, and an azido-based cleavable linker to attach the fluorophores to the ddNTPs, we synthesized four 3'-O-azidomethyl-dNTPs and four ddNTP-azidolinker-fluorophores for the hybrid SBS. After sequence determination by fluorescence imaging, the 3'-O-azidomethyl group and the fluorophore attached to the DNA extension product via the azidolinker are efficiently removed by using Tris(2-carboxyethyl)phosphine in aqueous solution that is compatible with DNA. Various DNA templates, including those with homopolymer regions, were accurately sequenced with a read length of >30 bases by using this hybrid SBS method on a chip and a four-color fluorescence scanner.


Recent testosterone drop-off and risk of cardiovascular events.
Low baseline testosterone level has been associated with the development of risk factors for cardiovascular disease such as insulin resistance and obesity. In addition to the absolute testosterone level, remarkable changes in testosterone level may have an acute effect on cardiovascular disease development and progression, which has been rarely investigated. In this study, we used a clinical dataset of 376 hypogonadal men whose testosterone levels were measured every six months for up to 11 years from a registry study in Germany, and conducted survival analyses to investigate the effect of testosterone changes since the last visit (time-varying) on the risk of cardiovascular events. Given the potential discrepancies in comorbidity conditions among patients with prior cardiovascular events and those without, all the analyses were stratified by patients' prior cardiovascular event status. We found the effects were not different among patients with prior cardiovascular events and those without. Regardless of patients' prior cardiovascular event status, patients with larger testosterone declines (≥3.12 nmol/L, 90th percentile) since the last visit were more likely to experience myocardial infarction. In conclusion, recent pronounced testosterone drop-offs may affect the risk of cardiovascular events among hypogonadal men. Future longitudinal studies are needed to confirm our exploratory study findings.


[A new antigen induced by oncornavirus D in mouse fibroblast culture].
It was established by the CFT and immunofluorescence that oncornavirus D inoculated into continuous mouse fibroblast cultures induced in them a new antigen differing from those of the virus and of the original non-infected cells. The antigen was shown to accumulate during cultivation of the infected cells. No antigen was induced by oncornavirus inactivated by heating or neutralized by antiviral antiserum. The physico-chemical and immunological properties of the new antigen experimentally induced in the mouse fibroblast culture are identical to those of the new antigen present in cultures of human J-96, HeLa and HEp-2 cells.


Differential expression of genes involved in the calcium homeostasis in masticatory muscles of MDX mice.
Duchenne Muscular Dystrophy (DMD) and its murine model, mdx, are characterized by Ca(2+) induced muscle damage and muscle weakness followed by distorted dentofacial morphology. In both, DMD patients and in mdx mice, could be proven so far that only the extraocular muscles (EOM) are not affected by muscular dystrophy. The EOMs are protected against calcium overload by enhanced expression of genes involved in the Ca(2+) homeostasis. We could recently demonstrate that masticatory muscles of mdx mice are differentially affected by muscle dystrophy. The dystrophic masseter and temporalis shows muscle histology comparable to all other skeletal muscles in this animal model, whereas dystrophic tongue muscles seem to develop a milder phenotype. Due to this fact it is to hypothesize that an altered Ca(2+) homeostasis seems to underlie the mdx masticatory muscle pathology. Aim of this study was to examine the mRNA and protein levels of the sarcoplasmic reticulum Ca(2+) ATPases SERCA1 and SERCA2, the plasma membrane Ca(2+) ATPases Atp2b1 and Atp2b4, the sodium/calcium exchanger NCX1, the ryanodine receptor 1, parvalbumin, sarcolipin, phospholamban and the L-type Ca(2+) channel alpha-1 subunit (Cacna1s) in Musculus masseter, temporalis, and tongue of 100 day old control and mdx mice. In mdx masseter muscle significant increased mRNA levels of NCX1 and Cacna1s were found compared to control mice. In contrast, the mRNA amount of RYR1 was significant reduced in mdx temporalis muscle, whereas ATP2b4 was significant increased. In mdx tongue a down-regulation of the ATP2b1, sarcolipin and parvalbumin mRNA expression was found, whereas the phospholamban mRNA level was significantly increased compared to controls. These data were verified by western blot analyses. Our findings revealed that mdx masticatory muscles showed an unequally altered expression of genes involved in the Ca(2+) homeostasis that can support the differences in masticatory muscles response to dystrophin deficiency.


Role of Human Papilloma Virus in Malignant Transformation of Oral Lichen Planus: A Systematic Review.
Lichen planus (LP) is a chronic inflammatory mucocutaneous disease. The disease has a cell-mediated immune reaction which is precipitated by a specific trigger which turns the self-peptides antigenic. The role of human papillomavirus (HPV) in the malignant transformation of oral LP (OLP) has always been debated. Establishing a definitive part played by HPV in the malignant transformation of OLP, would possibly provide screening for the viruses, HPV vaccination, and antiviral therapy along with conventional treatment in LP which could improve prognosis. This systematic review is to assess the role of HPV in the malignant transformation of OLP. We performed a systematic search of PubMed, MEDLINE, and Google. The information was extracted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All full-text papers that assessed the association of HPV in malignant transformation of OLP were considered eligible. The outcome parameter included the malignant transformation of OLP. We found a total of 19 studies from which five were found suitable for the review. Results from this systematic review showed HPV is associated with OLP. There is an increased prevalence of HPV in the erosive-atrophic (EA) variant of OLP compared to non-EA variant. There seems to be no strong evidence to prove the association between HPV and malignant transformation of OLP. Taking up the oncogenic potential of high-risk types and OLP as a potentially malignant disorder, more number of studies need to be performed on the dysplastic subtype of OLP and in those OLP lesions that progress to oral squamous cell carcinomas.


Total internal reflection deflector.
The deflection angle and beam profile are calculated for a total internal reflection deflector. Device performance is shown to be similar to that of a waveguide deflector of the same electrode size. Because this deflector is a bulk device, waveguides are not needed and the ensuing susceptibility to optical damage is eased.


The importance of incorporating functional habitats into conservation planning for highly mobile species in dynamic systems.
The distribution of mobile species in dynamic systems can vary greatly over time and space. Estimating their population size and geographic range can be problematic and affect the accuracy of conservation assessments. Scarce data on mobile species and the resources they need can also limit the type of analytical approaches available to derive such estimates. We quantified change in availability and use of key ecological resources required for breeding for a critically endangered nomadic habitat specialist, the Swift Parrot (Lathamus discolor). We compared estimates of occupied habitat derived from dynamic presence-background (i.e., presence-only data) climatic models with estimates derived from dynamic occupancy models that included a direct measure of food availability. We then compared estimates that incorporate fine-resolution spatial data on the availability of key ecological resources (i.e., functional habitats) with more common approaches that focus on broader climatic suitability or vegetation cover (due to the absence of fine-resolution data). The occupancy models produced significantly (P < 0.001) smaller (up to an order of magnitude) and more spatially discrete estimates of the total occupied area than climate-based models. The spatial location and extent of the total area occupied with the occupancy models was highly variable between years (131 and 1498 km2 ). Estimates accounting for the area of functional habitats were significantly smaller (2-58% [SD 16]) than estimates based only on the total area occupied. An increase or decrease in the area of one functional habitat (foraging or nesting) did not necessarily correspond to an increase or decrease in the other. Thus, an increase in the extent of occupied area may not equate to improved habitat quality or function. We argue these patterns are typical for mobile resource specialists but often go unnoticed because of limited data over relevant spatial and temporal scales and lack of spatial data on the availability of key resources. Understanding changes in the relative availability of functional habitats is crucial to informing conservation planning and accurately assessing extinction risk for mobile resource specialists.


Superoxide dismutase: tissue, cellular, and subcellular distribution in adult canine heart.
Cell-free extracts of canine myocardial tissue were found to contain two biochemically and electrophoretically distinct superoxide dismutases (SOD), an enzyme that provides defense against the deleterious effect of superoxide radicals (O2.-). Polyacrylamide gel (7.5%) electrophoresis revealed two distinct bands of SOD activity: a slower moving band [retardation factor (Rf) = 0.4] resembling the manganese SOD found in bacteria and mitochondria (which is not inhibited by 2.5 mM cyanide) and a faster moving band (Rf = 0.75) that is sensitive to cyanide. In contrast, extracts from isolated adult canine cardiac myocytes were found to contain only the cyanide-insensitive SOD. Extracts of whole myocardium and isolated cardiac myocytes contain 22.3 +/- 1.2 and 27.0 +/- 1.5 U cyanide-insensitive SOD/mg protein, respectively. However, the activity of cyanide-sensitive SOD in these fractions is 7.9 +/- 2.0 (tissue) and 1.5 +/- 1.4 (cells) U/mg protein. Cardiac myocyte SOD activity was particulate in nature, and the major part of the SOD activity was associated with heavy mitochondrial fractions. The biologic significance of this higher activity of SOD in the heavier mitochondrial fraction remains to be elucidated.


Tandem double acylation/[3,3]-rearrangement of aliphatic nitro compounds: a route to α-oxygenated oxime derivatives.
A new tandem double acylation/rearrangement reaction of nitro compounds is described. It has a broad substrate scope allowing the mild and efficient synthesis of α-acyloxy oxime esters in high yields and regioselectivity. According to the obtained data, the mechanism for transformation was proposed. The utility of the obtained α-hydroxy oxime esters was demonstrated.


MR detectability and appearance of small experimental intracranial hematomas at 1.5 T and 0.5 T. A 6-7-month follow-up study.
To investigate the detectability and appearance of small experimental intracranial hemorrhages on MR at 0.5 T and 1.5 T in a long-term follow-up. Autologous blood (1 ml) was injected into the brain of 7 rabbits to create intraparenchymal hematomas. The injected blood leaked partially into the cerebrospinal fluid (CSF) spaces. MR imaging at 0.5 T and 1.5 T were performed immediately before and after hematoma creation, at 2 weeks and monthly up to 6 or 7 months using T1-, proton density- and T2-weighted (w) spin-echo (SE), FLAIR and T2*-w gradient echo (GE) pulse sequences. Blood was detected both in the brain and in the CSF spaces of all animals during the first hours after hematoma creation at 1.5 T. In the last examination after 6-7 months, the T2*-w GE sequences still showed residues of the intraparenchymal hematomas in all the rabbits at 1.5 T, but the signal pattern was not specific for the age of the hematomas. SE and FLAIR sequences were insensitive. The histopathology revealed iron deposits in all brains. Residues of small intraparenchymal hematomas can be seen for months with T2*-w GE sequences on brain MR imaging at 1.5 T. The age of the microhematomas cannot be estimated with MR imaging.


High rising flames: a sign of complex extraperitoneal bladder rupture.
Extraperitoneal bladder rupture is the most common type of bladder injury following pelvic trauma and is seen in 80-90% of cases. Generally, the contrast extravasation seen on computed tomography (CT) cystography is confined to the perivesical space, giving a characteristic flame-shaped appearance. Occasionally contrast extravasation can extend to the scrotum, thigh or anterior abdominal wall, depending on the extent of injury. Here we report an unusual CT cystogram finding of complex extraperitoneal bladder rupture with associated pelvic fracture urethral distraction defect, showing large-volume contrast extravasation extending beyond the perivesical space to the left perinephric region resembling high rising flames.


Diatom cell size, coloniality and motility: trade-offs between temperature, salinity and nutrient supply with climate change.
Reduction in body size has been proposed as a universal response of organisms, both to warming and to decreased salinity. However, it is still controversial if size reduction is caused by temperature or salinity on their own, or if other factors interfere as well. We used natural benthic diatom communities to explore how "body size" (cells and colonies) and motility change along temperature (2-26°C) and salinity (0.5-7.8) gradients in the brackish Baltic Sea. Fourth-corner analysis confirmed that small cell and colony sizes were associated with high temperature in summer. Average community cell volume decreased linearly with 2.2% per °C. However, cells were larger with artificial warming when nutrient concentrations were high in the cold season. Average community cell volume increased by 5.2% per °C of artificial warming from 0 to 8.5°C and simultaneously there was a selection for motility, which probably helped to optimize growth rates by trade-offs between nutrient supply and irradiation. Along the Baltic Sea salinity gradient cell size decreased with decreasing salinity, apparently mediated by nutrient stoichiometry. Altogether, our results suggest that climate change in this century may polarize seasonality by creating two new niches, with elevated temperature at high nutrient concentrations in the cold season (increasing cell size) and elevated temperature at low nutrient concentrations in the warm season (decreasing cell size). Higher temperature in summer and lower salinity by increased land-runoff are expected to decrease the average cell size of primary producers, which is likely to affect the transfer of energy to higher trophic levels.


Gonadotropin stimulation contributes to an increased incidence of epimutations in ICSI-derived mice.
We previously demonstrated that intracytoplasmic sperm injection (ICSI), a type of assisted reproductive technology (ART), can induce epimutations and/or epimutant phenotypes in somatic tissues of adult mice produced by this method. In the present study, we compared the occurrence of epimutations in mice produced by natural conception, ICSI and somatic cell nuclear transfer. Surprisingly, we observed the highest frequency of epimutations in somatic tissues from ICSI-derived mice. We also observed a delay in reprogramming of the maternal allele of the imprinted H19 gene in spermatogonia from juvenile ICSI-derived male mice. These observations led us to hypothesize that the exposure of the maternal gametic genome to exogenous gonadotropins during the endocrine stimulation of folliculogenesis (superovulation) may contribute to the disruption of the normal epigenetic programming of imprinted loci in somatic tissues and/or epigenetic reprogramming in the germ line of ensuing offspring. To test this hypothesis, we uncoupled superovulation from ICSI by subjecting female mice to gonadotropin stimulation and then allowing them to produce offspring by natural mating. We found that mice produced in this way also exhibited epimutations and/or epimutant phenotypes in somatic tissues and delayed epigenetic reprogramming in spermatogenic cells, providing evidence that gonadotropin stimulation contributes to the induction of epimutations during ART procedures. Our results suggest that gonadotropin stimulation protocols used in conjunction with ART procedures should be optimized to minimize the occurrence of epimutations in offspring produced by these methods.


Endogenous digitalis-like ligands and Na/K-ATPase inhibition in experimental diabetes mellitus.
Dysregulation of the Na/K-ATPase (NKA) in the kidney, cardiovascular system, and peripheral nervous system is believed to contribute to pathogenesis of diabetes mellitus (DM) and its complications. Recently we demonstrated that, in addition to endogenous ouabain (EO), mammalian tissues contain another NKA inhibitor, a bufadienolide marinobufagenin (MBG). In vitro MBG, a natriuretic and a vasoconstrictor, acts as a selective inhibitor of alpha-1 NKA, the main isoform of the sodium pump in renal tubules and vascular smooth muscle. To determine whether digitalis-like NKA inhibitors are linked to NKA dysregulation in DM, we studied changes in renal excretion and plasma levels of MBG and EO and the activity of erythrocyte NKA in male Wistar rats with type 1 DM and type 2 DM. Rats with type 1 DM were studied four weeks following a single intraperitoneal injection of 65 mg/kg streptozotocin (STZ)(n = 12), and rats with type 2 DM were studied 10 weeks after intraperitoneal injection of STZ during the neonatal period (n = 12). Renal excretion and plasma levels of EO did not change in rats with both types of DM as compared to that in the control groups. Renal excretion (57.5 +/- 9.4 pmol/kg/ 3 hours vs. 12.6 +/- 2.1 pmol/kg/ 3 hours; P less than 0.01) and plasma levels (2.23 +/- 0.82 nmol/L vs. 0.29 +/- 0.07 nmol/L; P less than 0.01) of MBG increased, and NKA activity in erythrocytes was inhibited by 50% in rats with type 1 DM as compared to controls. In rats with type 2 DM, plasma levels (1.48 +/- 0.09 nmol/L vs. 0.46 +/- 0.02 nmol/L; P less than 0.01) and renal excretion (21.3 +/- 3.2 pmol/kg/ 3 hours vs. 13.1 +/- 2.1 pmol/kg/ 3 hours) of MBG also became elevated, but less than in the animals with type 1 DM. Accordingly, activity of NKA in erythrocytes from rats with type 2 DM was inhibited by 35%. In vitro treatment of erythrocytes from rats with type 1 and type 2 DM with anti-MBG antibody reversed the DM induced inhibition of the NKA. These results suggest that digitalis-like factors are involved in the pathogenesis of DM and that MBG, rather than EO, is responsible for DM-induced NKA inhibition.


Ecologic observations of Venezuelan encephalitis virus in vertebrates and isolations of Nepuyo and Patois viruses from sentinel hamsters at Pacific and Atlantic habitats in Guatemala, 1968-1980.
La Avellana and Puerto Barrios, two enzootic foci of Venezuelan encephalitis (VE) virus on the Pacific and Caribbean lowlands (respectively) of Guatemala have been studied over a 13-year period. Data from sentinel hamsters and guinea pigs and wild and domestic vertebrates are reported. VE virus strains were isolated from hamsters each period they were exposed during the rainy seasons 1968-1980 and at the end of the dry season 1974. Rates of isolation of VE virus ranged from 0.2%-5.7% hamster/days/exposure. All strains tested were free of epizootic virions. Although virus was isolated from sentinel guinea pigs, their deaths were not attributable to infection with VE virus. Antibody titers in 26 of 28 terrestrial mammals bled at La Avellana in 1971 were higher to enzootic than to epizootic VE strains. Thirty-seven percent of 109 residents of Puerto Barrios had antibody to VE virus. In 13 of 20 tested, antibodies were engendered by the enzootic strain. Nepuyo and Patois viruses were isolated from sentinel hamsters at both La Avellana and Puerto Barrios.


Organochlorine pesticides: Agrochemicals with potent endocrine-disrupting properties in fish.
Organochlorine pesticides (OCPs) are persistent environmental contaminants that act as endocrine disruptors and organ system toxicants. These pesticides (e.g. dichlorodiphenyltrichloroethane (DDT), dieldrin, toxaphene, among others) are ranked as some of the most concerning chemicals for human health. These pesticides (1) act as teratogens, (2) are neuroendocrine disruptors, (3) suppress the immune and reproductive systems, and (4) dysregulate lipids and metabolism. Using a computational approach, we revealed enriched endocrine-related pathways in the Comparative Toxicogenomics Database sensitive to this chemical class, and these included reproduction (gonadotropins, estradiol, androgen, steroid biosynthesis, oxytocin), thyroid hormone, and insulin. Insight from the Tox21 and ToxCast programs confirm that these agrochemicals activate estrogen receptors, androgen receptors, and retinoic acid receptors with relatively high affinity, although differences exist in their potency. We propose an adverse outcome pathway for OCPs toxicity in the fish testis as a novel contribution to further understanding of OCP-induced toxicity. Organochlorine pesticides, due to their persistence and high toxicity to aquatic and terrestrial wildlife as well as humans, remain significant agrochemicals of concern.


Factors affecting bone response around loaded titanium dental implants: A literature review.
This paper was designed as a review of the knowledge concerning bone adaptation around dental implants. Current literature concerning the biomechanics of bone and titanium dental implants as a main focus and pertinent to key aspects of the review was taken into consideration. Implant stiffness, design and surface were considered as factors affecting bone response to loaded dental implants. The emerging data allows the conclusion that implant design influences force transmission to periimplant bone, but seems to have poor power in preventing time-related marginal bone crest resorption. Mechanical stimulation such as prosthetic stress-dependent strains, affects bone tissue adaptation. Therefore, it is crucial to have high biomechanical control on implants to preserve implant ankilosis and to promote periimplant bone deposition.


An Experimental Review of Optical Coherence Tomography Systems for Noninvasive Assessment of Hard Dental Tissues.
Optical coherence tomography (OCT) is a noninvasive, high-resolution, cross-sectional imaging technique. To date, OCT has been demonstrated in several areas of dentistry, primarily using wavelengths around 1,300 nm, low numerical aperture (NA) imaging lenses, and detectors insensitive to the polarization of light. The objective of this study is to compare the performance of three commercially available OCT systems operating with alternative wavelengths, imaging lenses, and detectors for OCT imaging of dental enamel. Spectral-domain (SD) OCT systems with (i) 840 nm (Lumedica, OQ LabScope 1.0), (ii) 1,300 nm (Thorlabs, Tel320) center wavelengths, and (iii) a swept-source (SS) OCT system (Thorlabs OCS1300SS) centered at 1,325 nm with optional polarization-sensitive detection were used. Low NA (0.04) and high NA (0.15) imaging lenses were used with system (iii). Healthy in vivo and in vitrohuman enamel and eroded in vitro bovine enamel specimens were imaged. The Tel320 system achieved greater imaging depth than the OQ LabScope 1.0, on average imaging 2.6 times deeper into the tooth (n = 10). The low NA lens provided a larger field of view and depth of focus, while the high NA lens provided higher lateral resolution and greater contrast. Polarization-sensitive imaging eliminated birefringent banding artifacts that can appear in conventional OCT scans. In summary, this study illustrates the performance of three commercially available OCT systems, objective lenses, and imaging modes and how these can affect imaging depth, resolution, field of view, and contrast in enamel. Users investigating OCT for dental applications should consider these factors when selecting an OCT system for clinical or basic science studies.


Synthesis, Characterization, Theoretical and Experimental Anticancer Evaluation of Novel Cocrystals of 5-Fluorouracil and Schiff Bases against SW480 Colorectal Carcinoma.
The chemotherapeutic agent known as 5-fluorouracil (5-FU) is an artificial fluoropyrimidine antimetabolite that has been widely used for its antineoplastic properties. Cocrystals of 5-fluorouracil (5-FU) with five different Schiff bases (benzylidene-urea (BU), benzylidene-aniline (BA), salicylidene-aniline (SA), salicylidene-phenylhydrazine (SPH), and para-hydroxy benzylideneaniline (HBA)) are reported in this study. The newly synthesized cocrystals were analyzed by FTIR and PXRD. In this study, we investigated the antitumor efficacy of 5-FU derivatives in SW480 colon cancer cells via MTT assay at varying dose concentrations. Molecular docking was performed to predict the binding mechanism of TS with various 5-FU complexes. FTIR revealed the presence of respective functional groups in the prepared cocrystals. The frequencies (v) of N-H (3220.24 cm-1) and carbonyl groups (1662.38 cm-1) in the spectrum of 5-FU shifted considerably in all derivative cocrystal new interactions. There was a noticeable transformation in the PXRD peak of 5-FU at 2θ = 28.37° in all derivatives. The novelty of the present study lies in the fact that 5-FU-BA showed an anticancer potential IC50 (6.4731) far higher than that of 5-FU (12.116), almost comparable to that of the reference drug doxorubicin (3.3159), against SW480 cancel cell lines, followed by 5-Fu-HBA (10.2174). The inhibition rates of 5-FU-BA and 5-FU-HBA were highest among the derivatives (99.85% and 99.37%, respectively) in comparison with doxorubicin (97.103%). The results revealed that the synthesized 5-FU cocrystals have promising antitumor efficacy compared with previously reported 5-FU and 5-FU. The activities of the cocrystals were rationalized by a molecular modeling approach to envisage binding modes with the target cancer protein.


The metazoan protein disaggregase and amyloid depolymerase system: Hsp110, Hsp70, Hsp40, and small heat shock proteins.
A baffling aspect of metazoan proteostasis is the lack of an Hsp104 ortholog that rapidly disaggregates and reactivates misfolded polypeptides trapped in stress induced disordered aggregates, preamyloid oligomers, or amyloid fibrils. By contrast, in bacteria, protozoa, chromista, fungi, and plants, Hsp104 orthologs are highly conserved and confer huge selective advantages in stress tolerance. Moreover, in fungi, the amyloid remodeling activity of Hsp104 has enabled deployment of prions for various beneficial modalities. Thus, a longstanding conundrum has remained unanswered: how do metazoan cells renature aggregated proteins or resolve amyloid fibrils without Hsp104? Here, we highlight recent advances that unveil the metazoan protein-disaggregase machinery, comprising Hsp110, Hsp70, and Hsp40, which synergize to dissolve disordered aggregates, but are unable to rapidly solubilize stable amyloid fibrils. However, Hsp110, Hsp70, and Hsp40 exploit the slow monomer exchange dynamics of amyloid, and can slowly depolymerize amyloid fibrils from their ends in a manner that is stimulated by small heat shock proteins. Upregulation of this system could have key therapeutic applications in various protein-misfolding disorders. Intriguingly, yeast Hsp104 can interface with metazoan Hsp110, Hsp70, and Hsp40 to rapidly eliminate disease associated amyloid. Thus, metazoan proteostasis is receptive to augmentation with exogenous disaggregases, which opens a number of therapeutic opportunities.


[Proliferative processes in the epithelium of colon mucosa in patients with Salmonella infection during first 24 hours after the onset of the disease].
DNA synthesis in the epithelium of a distal portion of human colon was studied by radioautography with 3H-thymidine in patients during the first 24 hours of gastrointestinal salmonellosis. All 13 patients aged 18-50 years were admitted to hospital during 9-20 hours after the disease onset. Nobody had a background of gastrointestinal pathology. The control group consisted of samples from sigmoid colon epithelium of 30 healthy individuals. The labelled nuclei index (LNI) was 5.16 +/- 0.27%, the intensity of labelling (IL) was 13.65x +/- 0.82. Endoscopic and pathomorphological studies of colonic mucosa in salmonellosis by the end of the first 24 hours of the disease showed superficial inflammation. Increased LNI (11.48 +/- 1.07%, p < 0.05) characterized activation of proliferation and increased IL (22.24 +/- 2.1, p < 0.05) showed intensification of DNA synthesis. Additionally, in one third of cases enlargement of proliferation compartment up to 2/3 crypt was noticed. It is unlikely that in this situation immune mechanisms play the key role, it seems that a direct stimulation of proliferative processes by a bacterial agent takes place.


Identification of the regulatory circuit governing corneal epithelial fate determination and disease.
The transparent corneal epithelium in the eye is maintained through the homeostasis regulated by limbal stem cells (LSCs), while the nontransparent epidermis relies on epidermal keratinocytes for renewal. Despite their cellular similarities, the precise cell fates of these two types of epithelial stem cells, which give rise to functionally distinct epithelia, remain unknown. We performed a multi-omics analysis of human LSCs from the cornea and keratinocytes from the epidermis and characterized their molecular signatures, highlighting their similarities and differences. Through gene regulatory network analyses, we identified shared and cell type-specific transcription factors (TFs) that define specific cell fates and established their regulatory hierarchy. Single-cell RNA-seq (scRNA-seq) analyses of the cornea and the epidermis confirmed these shared and cell type-specific TFs. Notably, the shared and LSC-specific TFs can cooperatively target genes associated with corneal opacity. Importantly, we discovered that FOSL2, a direct PAX6 target gene, is a novel candidate associated with corneal opacity, and it regulates genes implicated in corneal diseases. By characterizing molecular signatures, our study unveils the regulatory circuitry governing the LSC fate and its association with corneal opacity.


Paper bezoar in the stomach.
A toilet paper bezoar caused acute abdominal distention and symptoms of an acute condition of the abdomen in a 5-year-old boy. Simple gastrotomy served to clear the paper bezoar and relieve the gastric obstruction after nonoperative methods failed.


Clinical phenotype of ASD-associated DYRK1A haploinsufficiency.
DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background.


Stability properties of nonhyperbolic chaotic attractors with respect to noise.
We study local and global stability of nonhyperbolic chaotic attractors contaminated by noise. The former is given by the maximum distance of a noisy trajectory from the noisefree attractor, while the latter is provided by the minimal escape energy necessary to leave the basin of attraction, calculated with the Hamiltonian theory of large fluctuations. We establish the important and counterintuitive result that both concepts may be opposed to each other. Even when one attractor is globally more stable than another one, it can be locally less stable. Our results are exemplified with the Holmes map, for two different sets of parameter, and with a juxtaposition of the Holmes and the Ikeda maps. Finally, the experimental relevance of these findings is pointed out.


Racial segregation and differential outcomes in hospital care.
This exploratory study of patients in Pennsylvania (PA) and Virginia (VA) hospitals in 1998-1999 measures the segregation of care for Black patients receiving inpatient care for specific medical and surgical conditions. It also examined inpatient mortality risk for Black patients and the impact of treatment in heavily segregated hospitals on mortality for Blacks and non-Blacks. Segregation of hospital care was found across both states but was more pronounced in PA. Blacks did not experience higher mortality rates than non-Blacks either before or after controls for clinical risk factors in either state and for certain admission types had lower mortality. Both Black and non-Black surgical, heart failure, and lung disease patients treated in VA hospitals with more Black patients had poorer outcomes. Future research should examine how access, patient choice, hospital organization, processes of care, and factors related to nursing care might influence hospital outcomes for patients from different racial backgrounds.


New approaches in assessing food intake in epidemiology.
A promising direction for improving dietary intake measurement in epidemiologic studies is the combination of short-term and long-term dietary assessment methods using statistical methods. Thereby, web-based instruments are particularly interesting as their application offers several potential advantages such as self-administration and a shorter completion time. The objective of this review is to provide an overview of new web-based short-term instruments and to describe their features. A number of web-based short-term dietary assessment tools for application in different countries and age-groups have been developed so far. Particular attention should be paid to the underlying database and the search function of the tool. Moreover, web-based instruments can improve the estimation of portion sizes by offering several options to the user. Web-based dietary assessment methods are associated with lower costs and reduced burden for participants and researchers, and show a comparable validity with traditional instruments. When there is a need for a web-based tool researcher should consider the adaptation of existing tools rather than developing new instruments. The combination of short-term and long-term instruments seems more feasible with the use of new technology.


Undiagnosed Diabetes Mellitus in Community-Acquired Pneumonia: A Prospective Cohort Study.
Diabetes mellitus is an important risk factor for community-acquired pneumonia, whereas the prevalence of undiagnosed diabetes mellitus and prediabetes in patients with community-acquired pneumonia is largely unknown. We aimed to determine the prevalence of prediabetes, undiagnosed diabetes mellitus, and risk factors associated with undiagnosed diabetes mellitus in a large European community-acquired pneumonia cohort. This was a multicenter prospective cohort study of hospitals and private practices in Germany and Austria encompassing 1961 adults with community-acquired pneumonia included in the German Community-Acquired Pneumonia Competence Network (CAPNETZ) study between 2007 and 2014. The prevalence of undiagnosed diabetes mellitus and prediabetes was estimated based on hemoglobin A1c measurements. Logistic regression was used to assess risk factors for undiagnosed diabetes mellitus. Fifteen percent of patients had known diabetes mellitus. Among patients without known diabetes mellitus, 5.0% had undiagnosed diabetes mellitus and 37.5% had prediabetes. Male sex (odds ratio [OR], 2.45 [95% confidence interval {CI}, 1.35-4.45]), body mass index ≥25 kg/m2 (OR, 2.64 [95% CI, 1.48-4.72]), and hyperglycemia at admission (6-11 mM: OR, 2.93 [95% CI, 1.54-5.60] and ≥11 mM: OR, 44.76 [95% CI, 17.58-113.98]) were associated with undiagnosed diabetes mellitus. Patients with undiagnosed diabetes mellitus had a higher 180-day mortality rate compared to patients without diabetes mellitus (12.1% vs 3.8%, respectively; P = .001). Undiagnosed diabetes mellitus was prevalent among community-acquired pneumonia. Male sex, overweight, and hyperglycemia at admission were associated with undiagnosed diabetes mellitus. The long-term mortality among patients with undiagnosed diabetes mellitus was high compared to patients without diabetes mellitus.


The influence of arm positions on mechanical dyssynchrony measured by gated myocardial perfusion imaging.
In routine procedures, patient's arms are positioned above their heads to avoid potential attenuation artifacts and reduced image quality during gated myocardial perfusion imaging (G-MPI). However, it is difficult to achieve this action in the acute period following pacemaker implantation. This study aimed to explore the influence of arm positioning on myocardial perfusion imaging (MPI) in different types of heart disease. This study was conducted retrospectively. A total of 123 patients were enrolled and underwent resting G-MPI using a standard protocol with arms positioned above their heads and again with their arms at their sides. All individuals were divided into 3 groups: the normal group, the obstructive coronary artery disease (O-CAD) group, and the dilated cardiomyopathy (DCM) group. The G-MPI data were measured by QGS software and Emory Reconstruction Toolbox, including left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), end-systolic volume (ESV), extent, total perfusion deficit (TPD), summed rest score (SRS), scar burden, phase standard deviation (SD), and phase histogram bandwidth (BW). In total, extent, TPD, EDV, ESV, LVEF, systolic SD, systolic BW, diastolic SD, and diastolic BW were all significantly different between the 2 arm positions (all P<0.01). On the Bland-Altman analysis, both EDV and ESV with the arm-down position were significantly underestimated (P<0.001). Meanwhile, TPD, extent, and LVEF with the arm-down position were significantly overestimated (P<0.05). Systolic SD, systolic BW, diastolic SD, and diastolic BW were systematically overestimated (P<0.001). In the DCM group (n=52), EDV, ESV, systolic SD, systolic BW, diastolic SD, and diastolic BW were identified as significantly different by the paired t-test between the 2 arm positions (P<0.05). In the O-CAD group (n=32), scar burden, ESV, LVEF, and diastolic BW were significantly different between the 2 arm positions (P<0.05). Systolic and diastolic dyssynchrony parameters and most left ventricular (LV) functional parameters were significantly influenced by arm position in both normal individuals and patients with heart failure (HF) with different pathophysiologies. More attention should be given to LV dyssynchrony data during clinical evaluation of cardiac resynchronization therapy (CRT) implantation procedure.


Fibroblast growth factor 21, assisted by elevated glucose, activates paraventricular nucleus NUCB2/Nesfatin-1 neurons to produce satiety under fed states.
Fibroblast growth factor 21 (FGF21), liver-derived hormone, exerts diverse metabolic effects, being considered for clinical application to treat obesity and diabetes. However, its anorexigenic effect is debatable and whether it involves the central mechanism remains unclarified. Moreover, the neuron mediating FGF21's anorexigenic effect and the systemic energy state supporting it are unclear. We explored the target neuron and fed/fasted state dependence of FGF21's anorexigenic action. Intracerebroventricular (ICV) injection of FGF21 markedly suppressed food intake in fed mice with elevated blood glucose. FGF21 induced c-Fos expression preferentially in hypothalamic paraventricular nucleus (PVN), and increased mRNA expression selectively for nucleobindin 2/nesfatin-1 (NUCB2/Nesf-1). FGF21 at elevated glucose increased [Ca2+]i in PVN NUCB2/Nesf-1 neurons. FGF21 failed to suppress food intake in PVN-preferential Sim1-Nucb2-KO mice. These findings reveal that FGF21, assisted by elevated glucose, activates PVN NUCB2/Nesf-1 neurons to suppress feeding under fed states, serving as the glycemia-monitoring messenger of liver-hypothalamic network for integrative regulation of energy and glucose metabolism.


Piperlongumine mediates amelioration of osteoarthritis via inhibition of chondrocyte senescence and inflammation in a goat ex vivo model.
In osteoarthritis (OA), chondrocytes manifest senescence, which results in a vicious signaling loop that aids the progression of the disease. More specifically, inflammation-associated senescence is one of the major regulators of the initiation and progression of OA. Therefore, we targeted senescence through inflammation with a pharmacological approach for OA amelioration. In this study, we first confirmed the suitability of the IL1β-induced goat ex vivo OA model (emphasizing 3R's principle) for the screening of senotherapeutics, namely, ABT-263, ABT-737, and Piperlongumine (PL), wherein PL showed a positive outcome in the preliminary studies. Thereafter, we determined the cytocompatible concentrations of PL using live/dead staining. Further, treatment of ex vivo OA cartilage with PL exhibited a concentration-dependent increase in the retention of key cartilage matrix components. We then examined the effect of PL on chondrocyte senescence and observed a decreased expression of major senescence markers in the PL-treated groups. Interestingly, PL treatment reduced the expression of major downstream effectors of the chondrocyte senescence pathway in a concentration-dependent manner at both gene and protein levels. Moreover, IL1β-induced elevated levels of oxidative stress and DNA damage in cartilage explants were rescued by all the tested concentrations of PL. In addition, PL also reduced the expression of major inflammatory markers of OA in the goat ex vivo OA model. Finally, we proposed a model for the mechanism of action of PL in the treatment of OA. Overall, PL showed a promising outcome as a senotherapeutic for the amelioration of OA in the goat ex vivo OA model.


Cardiac autonomic responses to volume overload in normal subjects and in patients with dilated cardiomyopathy.
This study evaluated the effects of acute isotonic volume expansion on heart rate variability (HRV) in 10 patients with dilated cardiomyopathy (DCM) and in 10 age- and sex-matched normal volunteers. Echocardiographic left ventricular volumes and HRV measurements by continuous Holter recording were assessed at baseline, at 60 and 120 min during intravenous saline load (0.9% NaCl, 0.25 ml. kg(-1). min(-1)), and 60 min after infusion was terminated. Data analysis was performed by repeated-measures ANOVA. After volume expansion, left ventricular ejection fraction increased (F = 9.8; P < 0.001) in normal subjects and decreased (F = 8.7; P < 0.001) in DCM patients. During volume expansion a significant difference was also detectable between the two groups in root-mean-square successive difference (F = 25.2; P < 0.001), percentage of differences between successive normal R-R intervals >50 ms (F = 97.6; P < 0.001), high-frequency power (F = 50.1; P < 0.001), and low-frequency power (F = 41.6; P < 0.001), all of which reflect parasympathetic modulation of heart rate; in fact, these measurements increased in normal subjects and decreased in DCM patients. In normal subjects, the increase in HRV measurements during volume expansion suggests a parasympathetic activation, mediated by stimulation of cardiopulmonary and arterial mechanoreceptors. On the contrary, in DCM patients the parasympathetic withdrawal, already detectable at baseline, increases during volume expansion.


Transport and fate of organochlorine pesticides in the River Wuchuan, southeast China.
Persistent organic pollutants (POPs) such as chlorinated pesticides are of global concern due to their widespread occurrence, persistence, bioaccumulation and toxicity to animals and human. This paper summarises recent research on 18 chlorinated pesticides in an important catchment in China, by determining their concentrations and behaviour in water, sediment, soil and plants. The concentrations of the total pesticides were in the ranges 187-893 ng l(-1) in river water, 8.53-210 ng g(-1) dry weight in soil, 2.66-13.45 ng g(-1) dry weight in river sediment, and 651-2823 ng g(-1) dry weight in plants. The predominance of beta-HCH as the major isomer of HCHs in all water, soil, sediment and plant samples was clearly observed, due to beta-HCH's resistance to biodegradation. On average beta-HCH accounted for 44%, 53%, 50%, and 46% of the total HCH concentration in water, soil, sediment and plant, respectively. Of the DDTs, DDE accounted for 48%, 43%, 53%, 55% of the total DDT, which suggested that DDT had been transformed to its metabolites, DDE and DDD, of which DDE was the more stable. The chlorinated pesticide levels in the River Wuchuan were generally below the guideline values in China, but some sites displayed levels in excess of EC Environmental Quality Standards for HCHs and DDTs. The results therefore provide important information on the current contamination status of a key agricultural watershed in China, and point to the need for urgent actions to evaluate the long-term fate and toxicity of such persistent compounds and an appropriate remediation strategy.


Synthesis, structure and in vitro antiproliferative effects of alkyne-linked 1,2,4-thiadiazole hybrids including erlotinib- and ferrocene-containing derivatives.
Chemotherapy is an indispensable tool to treat cancer, therefore, the development of new drugs that can treat cancer with minimal side effects and lead to more favorable prognoses is of crucial importance. A series of eleven novel 1,2,4-thiadiazoles bearing erlotinib (a known anticancer agent), phenylethynyl, ferrocenyl, and/or ferrocenethynyl moieties were synthesized in this work and characterized by NMR, IR and mass spectroscopies. The solid-phase structures were determined by single-crystal X-ray diffraction. Partial isomerisation of bis(erlotinib)-1,2,4-thiadiazole into its 1,3,4-thiadiazole isomer, leading to the isolation of a 3 : 2 isomer mixture, was observed and a plausible mechanism for isomerisation is suggested. The in vitro cytostatic effect and the long-term cytotoxicity of these thiadiazole-hybrids, as well as that of erlotinib, 3,5-dichloro-1,2,4-thiadiazole and 3,5-diiodo-1,2,4-thiadiazole were investigated against A2058 human melanoma, HepG2 human hepatocellular carcinoma, U87 human glioma, A431 human epidermoid carcinoma, and PC-3 human prostatic adenocarcinoma cell lines. Interestingly, erlotinib did not exhibit a significant cytostatic effect against these cancer cell lines. 1,2,4-Thiadiazole hybrids bearing one erlotinib moiety or both an iodine and a ferrocenethynyl group, as well as 3,5-diiodo-1,2,4-thiadiazole demonstrated good to moderate cytostatic effects. Among the synthesized 1,2,4-thiadiazole hybrids, the isomer mixture of bis-erlotinib substituted 1,2,4- and 1,3,4-thiadiazoles showed the most potent activity. This isomer mixture was proven to be the most effective in long-term cytotoxicity, too. 3,5-Diiodo-1,2,4-thiadiazole and its hybrid with one erlotinib fragment were also highly active against A431 and PC-3 proliferation. These novel compounds may serve as new leads for further study of their antiproliferative properties.


Structure and tensile properties of the forewing costal vein of the honeybee Apis mellifera.
In this study, we investigated the morphological features and tensile properties of the forewing costal vein of the honeybee (Apis mellifera) under fresh, dry and in vitro-time varied conditions. The costal vein is composed of an outer sub-vein and an inner vein starting from the wing base to nearly 50% of the wing span and then they are fused into one vein extending to the wing tip. Confocal laser scanning microscopy revealed that the outer sub-vein with red autofluorescence is stiffer than the inner one with green autofluorescence, and the membrane in the gap between the sub-veins exhibited a long blue-autofluorescence resilin stripe. Considering the irregular cross-sectional shape of the costal vein, cross-sections of the tested specimens after tensile failure were analysed using scanning electron microscopy, to precisely calculate their cross-sectional areas by a customized MATLAB program. The Young's modulus and tensile strength of fresh specimens were ∼4.78 GPa and ∼119.84 MPa, which are lower than those of dry specimens (∼9.08 GPa and ∼154.45 MPa). However, the tensile strain had the opposite relationship (fresh: ∼0.031, dry: ∼0.018). Thus, specimen desiccation results in increasing stiffness and brittleness. The morphological features and material properties of the costal vein taken together represent a tradeoff between both deformability and stiffness. Our study provides guidance for material selection and bionic design of the technical wings of flapping micro aerial vehicles.


Quantitative ultrasound assessment of breast tumor response to chemotherapy using a multi-parameter approach.
This study demonstrated the ability of quantitative ultrasound (QUS) parameters in providing an early prediction of tumor response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC). Using a 6-MHz array transducer, ultrasound radiofrequency (RF) data were collected from 58 LABC patients prior to NAC treatment and at weeks 1, 4, and 8 of their treatment, and prior to surgery. QUS parameters including midband fit (MBF), spectral slope (SS), spectral intercept (SI), spacing among scatterers (SAS), attenuation coefficient estimate (ACE), average scatterer diameter (ASD), and average acoustic concentration (AAC) were determined from the tumor region of interest. Ultrasound data were compared with the ultimate clinical and pathological response of the patient's tumor to treatment and patient recurrence-free survival. Multi-parameter discriminant analysis using the κ-nearest-neighbor classifier demonstrated that the best response classification could be achieved using the combination of MBF, SS, and SAS, with an accuracy of 60 ± 10% at week 1, 77 ± 8% at week 4 and 75 ± 6% at week 8. Furthermore, when the QUS measurements at each time (week) were combined with pre-treatment (week 0) QUS values, the classification accuracies improved (70 ± 9% at week 1, 80 ± 5% at week 4, and 81 ± 6% at week 8). Finally, the multi-parameter QUS model demonstrated a significant difference in survival rates of responding and non-responding patients at weeks 1 and 4 (p=0.035, and 0.027, respectively). This study demonstrated for the first time, using new parameters tested on relatively large patient cohort and leave-one-out classifier evaluation, that a hybrid QUS biomarker including MBF, SS, and SAS could, with relatively high sensitivity and specificity, detect the response of LABC tumors to NAC as early as after 4 weeks of therapy. The findings of this study also suggested that incorporating pre-treatment QUS parameters of a tumor improved the classification results. This work demonstrated the potential of QUS and machine learning methods for the early assessment of breast tumor response to NAC and providing personalized medicine with regards to the treatment planning of refractory patients.


Structural Minimax Probability Machine.
Minimax probability machine (MPM) is an interesting discriminative classifier based on generative prior knowledge. It can directly estimate the probabilistic accuracy bound by minimizing the maximum probability of misclassification. The structural information of data is an effective way to represent prior knowledge, and has been found to be vital for designing classifiers in real-world problems. However, MPM only considers the prior probability distribution of each class with a given mean and covariance matrix, which does not efficiently exploit the structural information of data. In this paper, we use two finite mixture models to capture the structural information of the data from binary classification. For each subdistribution in a finite mixture model, only its mean and covariance matrix are assumed to be known. Based on the finite mixture models, we propose a structural MPM (SMPM). SMPM can be solved effectively by a sequence of the second-order cone programming problems. Moreover, we extend a linear model of SMPM to a nonlinear model by exploiting kernelization techniques. We also show that the SMPM can be interpreted as a large margin classifier and can be transformed to support vector machine and maxi-min margin machine under certain special conditions. Experimental results on both synthetic and real-world data sets demonstrate the effectiveness of SMPM.


Conflicting view support by medical information systems.
One of the advantages of current database systems is the capability to enforce global integrity constraints on a large amount of data. Input of contradicting data will be rejected by database systems in order to maintain correctness. On the other hand, in medical information systems it may be necessary to realize two or more databases in one system, where there are some controlled contradictions among these databases. For example, if a doctor wants to hide the real disease name from the patient in critical condition, the database viewed by the patient should be different from the real database, although each of these databases should be conflict free and large amounts of data are shared by both. This kind of problem was not discussed for commercial business-oriented databases. Data sharing and data security are important functions required for medical information systems. There are, however, cases when we need to show non-real data to some users. Security mechanisms usually prevent a user from retrieving critical data. If a request for retrieval of some data is rejected by the system, a user may find there is something secret being kept from him. In order to cope with these situations, we introduce the POSTGRES database system. POSTGRES is a generalized relational database system developed at the University of California. The form of POSTGRES rule is as follows: On event (To) object WHERE POSTQUEL-qualification Then Do [instead] POSTQUEL-command(s) The POSTGRES rule shows that event is retrieve, replace, delete, append, new (i.e., replace or append) or old (i.e., delete or replace). The concept of objects is introduced in object-oriented databases. In relational database systems, an object corresponds to each data value, an attribute, or a relation. The optional keyword "instead" indicates that the action indicated by POSTQUEL-command(s) is to be performed instead of the action which caused the rule to activate. This keyword plays very important role for our purpose. By preparing a standard story which is consistent with the patient's condition, the doctor can make a smooth explanation to the patient showing the stories instead of the critical data. So, if medical personnel and system designers prepare the standard stories or data for the explanation and store such data in the system, the users of medical information systems (doctors) can take the benefit of the data replacement. For such a purpose, medical personnel and system designers classify the patients' data according to their age, sex, occupational history, personal history, and diseases. Standard story or data should be prepared for each user class in advance. Using POSTGRES rule system in medical information systems, doctors can make a smooth explanation of a patientUs condition in serious cases, when hiding real data is required. The validity of POSTGRES rule system is proved where data exchange is needed for data protection. For example, when a doctor writes a prescription of a placebo through the ordering system, POSTGRES rule system will identify its existence. We believe that POSTGRES rule system can be applied to many fields in medical data processing.


Nitric oxide mediates sympathetic vasoconstriction at supraspinal, spinal, and synaptic levels.
The purposes of this study were to investigate the level of the sympathetic nervous system in which nitric oxide (NO) mediates regional sympathetic vasoconstriction and to determine whether neural mechanisms are involved in vasoconstriction after NO inhibition. Ganglionic blockade (hexamethonium), alpha1-receptor blockade (prazosin), and spinal section at T1 were used to study sympathetic involvement. NO was blocked with Nomega-nitro-L-arginine methyl ester (L-NAME). Regional blood flow in the mesenteric and renal arteries and terminal aorta was monitored by electromagnetic flowmetry in conscious rats. L-NAME (3-5 mg/kg iv) increased arterial pressure and peripheral resistance. Ganglionic blockade (25 mg/kg iv) significantly reduced the increase in resistance in the mesentery and kidney in intact and spinal-sectioned rats. Ganglionic blockade significantly decreased hindquarter resistance in intact rats but not in spinal-sectioned rats. Prazosin (200 micrograms/kg iv) significantly reduced the increased hindquarter resistance. We concluded that NO suppresses sympathetic vasoconstriction in the mesentery and kidney at the spinal level, whereas hindquarter tone is mediated at supraspinal and synaptic levels.


Intestinal SGLT1 in metabolic health and disease.
The Na(+)-glucose cotransporter 1 (SGLT1/SLC5A1) is predominantly expressed in the small intestine. It transports glucose and galactose across the apical membrane in a process driven by a Na(+) gradient created by Na(+)-K(+)-ATPase. SGLT2 is the major form found in the kidney, and SGLT2-selective inhibitors are a new class of treatment for type 2 diabetes mellitus (T2DM). Recent data from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs such as canagliflozin (SGLT1 IC50 = 663 nM) warrant evaluation of SGLT1 inhibition for T2DM. SGLT1 activity is highly dynamic, with modulation by multiple mechanisms to ensure maximal uptake of carbohydrates (CHOs). Intestinal SGLT1 inhibition lowers and delays the glucose excursion following CHO ingestion and augments glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion. The latter is likely due to increased glucose exposure of the colonic microbiota and formation of metabolites such as L cell secretagogues. GLP-1 and PYY secretion suppresses food intake, enhances the ileal brake, and has an incretin effect. An increase in colonic microbial production of propionate could contribute to intestinal gluconeogenesis and mediate positive metabolic effects. On the other hand, a threshold of SGLT1 inhibition that could lead to gastrointestinal intolerability is unclear. Altered Na(+) homeostasis and increased colonic CHO may result in diarrhea and adverse gastrointestinal effects. This review considers the potential mechanisms contributing to positive metabolic and negative intestinal effects. Compounds that inhibit SGLT1 must balance the modulation of these mechanisms to achieve therapeutic efficacy for metabolic diseases.


Parent-child relationship of directly measured physical activity.
Studies on parent-child correlations of physical activity have been mixed. Few studies have examined concurrent temporal patterns of physical activity and sedentary behaviors in parents and children using direct measures. The purpose of this study was to examine parent-child activity correlations by gender, day of week, and time of day, using accelerometers - a method for direct assessment of physical activity. Accelerometers were used to assess physical activity and sedentary time in 45 fathers, 45 mothers and their children (23 boys, 22 girls, mean age 9.9 years) over the course of 4 days (Thursday - Sunday). Participants were instructed to wear accelerometers for 24 hours per day. Data from accelerometers were aggregated into waking hours on weekdays and weekends (6:00 am to midnight) and weekday after-school hours (3:00 - 7:00 pm). Across the 4 days, the mean minutes per day of moderate-to-vigorous physical activity (MVPA) for fathers was 30.0 (s.d. = 17.3), for mothers was 30.1 (s.d. = 20.1) and for children was 145.47 (s.d. = 51.64). Mothers' and fathers' minutes of MVPA and minutes of sedentary time were positively correlated with child physical activity and sedentary time (all ps < .05, with the exception of mothers' and children's sedentary time on weekdays from 6 am to 12 am). Multivariate linear regression analyses resulted in significant effects between parents and children for MVPA across all time segments. For sedentary activity, significant associations were observed only between father and child on the weekend. Sedentary activity of parents and children were not related for other time segments. Models examining the associations of one or two parents with high levels of MVPA or sedentary time indicated a dose response increase in child activity relative to parent. Greater parental MVPA was associated with increased child MVPA. In addition, having two parents with higher levels of MVPA was associated with greater levels of activity in children. Sedentary time in children was not as strongly correlated with that of their parents. Findings lend support to the notion that to increase childhood activity levels it may be fruitful to improve physical activity among parents.


Gender-specific effect of uric acid on resting-state functional networks in de novo Parkinson's disease.
The pattern of resting-state networks is influenced by several factors besides the underlying pathological changes of Parkinson's disease (PD). Uric acid (UA), as an antioxidant, has a neuroprotective property against PD-related microenvironment; however, this effect would be gender-specific. We aimed to evaluate a gender-sensitive resting-state networks (RSN) according to the UA level in drug naïve de novo patients with PD to elucidate the role of antioxidant in cortical functional networks of PD. This study enrolled 135 de novo patients with PD underwent functional magnetic resonance imaging (MRI). Based on the distribution, the serum UA level was stratified into tertiles in the PD patients by gender. With a seed-based approach, we investigated the pattern of RSN within the dorsal attention network (DAN), executive control network (ECN), and default mode network (DMN). Interaction analysis showed a significant interaction between the lowest (PD-L-UA) and the highest UA level (PD-H-UA) groups according to gender within the DAN, ECN, and DMN. Compared to the control subjects, male patients with PD-H-UA had higher cortical functional connectivity (FC), while female patients had lower cortical FC regardless of UA level within all seeds. In a direct comparison, male patients with PD-H-UA had increased FC than did those with PD-L-UA. However, there was no significant difference in FC between PD-L-UA and PD-H-UA in female PD patients. These data suggest that RSN might be closely and gender-specifically associated with the status of serum UA in de novo PD patients.


Elimination of central sleep apnea by cardiac valve replacement: a continuous follow-up study in patients with rheumatic valvular heart disease.
Recent studies have suggested that cardiac surgery may affect sleep-disordered breathing (SDB) in chronic heart failure patients. However, the dynamic changes in sleep apnea and heart function after cardiac surgery and the mechanisms responsible for these changes remain unknown. Patients with rheumatic valvular heart disease (RVHD) and SDB were enrolled and followed up at three, six and 12 months after cardiac valve replacement (CVR). Baseline and follow-up clinical data consisting of NYHA classification, 6min walk distance (6-MWD), medications, echocardiography, electrocardiography, chest X-ray, arterial blood gas, lung-to-finger circulation time (LFCT), and sleep data were collected and evaluated. Twenty-four central sleep apnea (CSA) patients and 15 obstructive sleep apnea (OSA) patients completed three follow-up assessments. Comparison of the baseline parameters between OSA patients and CSA patients showed that CSA patients had a worse baseline cardiac function assessed by higher NYHA class, shorter 6-MWD, larger left atrial diameter, longer LFCT, and enhanced chemosensitivity (higher pH and lower arterial carbon dioxide tension (PaCO2)). A continuous significant elevation in 6-MWD and left ventricular ejection fraction and decrease in NYHA class, plasma BNP, and left atrial diameter were found in both CSA and OSA patients. When comparing CSA and OSA patients, the CSA indices were remarkably reduced at month 3 post CVR and sustained throughout the trial, whereas there were no significant decreases in OSA index and hypopnea index. pH values and LFCT were markedly decreased and PaCO2 markedly increased in patients with CSA at the end of the third months following CVR. These changes were sustained until the end of the trial. CSA patients with RVHD had a worse baseline cardiac function, enhanced chemosensitivity and disordered hemodynamic as compared with OSA patients with RVHD. CSA were eliminated after CVR; however, there were no changes in OSA. The elimination of CSA, post CVR, is associated with the combined efficacies of improvement of cardiac function, normalized chemosensitivity, and stabilized hemodynamic.


Myocardial transcriptome analysis of human arrhythmogenic right ventricular cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC-affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown. We therefore analyzed the transcriptomes of six ARVC hearts and compared our findings to six nonfailing donor hearts (NF). To characterize the ARVC-specific transcriptome, we compared our findings to samples from seven patients with idiopathic dilated cardiomyopathy (DCM). The myocardial DCM and ARVC samples were prepared from hearts explanted during an orthotopic heart transplantation representing myocardium from end-stage heart failure patients (NYHA IV). From each heart, left (LV) and right ventricular (RV) myocardial samples were analyzed by Affymetrix HG-U133 Plus 2.0 arrays, adding up to six sample groups. Unsupervised cluster analyses of the groups revealed a clear separation of NF and cardiomyopathy samples. However, in contrast to the other samples, the analyses revealed no distinct expression pattern in LV and RV of myocardial ARVC samples. We further identified differentially expressed transcripts using t-tests and found transcripts separating diseased and NF ventricular myocardium. Of note, in failing myocardium only ~15-16% of the genes are commonly regulated compared with NF samples. In addition both cardiomyopathies are clearly distinct on the transcriptome level. Comparison of the expression patterns between the failing RV and LV using a paired t-test revealed a lack of major differences between LV and RV gene expression in ARVC hearts. Our study is the first analysis of specific ARVC-related RV and LV gene expression patterns in terminal failing human hearts.


Kinetics and mechanism of the reaction of cysteine and hydrogen peroxide in aqueous solution.
The oxidation of thiol-containing small molecules, peptides, and proteins in the presence of peroxides is of increasing biological and pharmaceutical interest. Although such reactions have been widely studied there does not appear to be a consensus in the literature as to the reaction products formed under various conditions, the reaction stoichiometry, and the reaction mechanisms that may be involved. This study examines the reaction kinetics of cysteine (CSH) with hydrogen peroxide (H(2)O(2)) in aqueous buffers (in the absence of metal ions) over a wide range of pH (pH 4-13) and at varying ratios of initial reactant concentrations to explore the range of conditions in which a two-step nucleophilic model describes the kinetics. The disappearance of CSH and H(2)O(2) and appearance of cystine (CSSC) versus time were monitored by reverse-phase high-performance liquid chromatography (HPLC). The effects of oxygen, metal ions (Cu(2+)), pH (4-13), ionic strength, buffer concentration, and temperature were evaluated. Data obtained at [H(2)O(2)](0)/[CSH](0) ratios from 0.01-2.3 demonstrate that the reaction of CSH with H(2)O(2) in the absence of metal ions is quantitatively consistent with a two-step nucleophilic reaction mechanism involving rate-determining nucleophilic attack of thiolate anion on the unionized H(2)O(2) to generate cysteine sulfenic acid (CSOH) as an intermediate. Second-order rate constants for both reaction steps were generated through model fitting. At [H(2)O(2)](0)/[CSH](0) > 10, the % CSSC formed as a product of the reaction declines due to the increased importance of alternative competing pathways for consumption of CSOH. A thorough understanding of the mechanism in aqueous solution will provide valuable background information for current studies aimed at elucidating the influence of such factors on thiol oxidation in solid-state formulations.


Does Dietary Deoxynivalenol Modulate the Acute Phase Reaction in Endotoxaemic Pigs?--Lessons from Clinical Signs, White Blood Cell Counts, and TNF-Alpha.
We studied the interaction between deoxynivalenol (DON)-feeding and a subsequent pre- and post-hepatic immune stimulus with the hypothesis that the liver differently mediates the acute phase reaction (APR) in pigs. Barrows (n = 44) were divided into a DON-(4.59 mg DON/kg feed) and a control-diet group, surgically equipped with permanent catheters pre- (V. portae hepatis) and post-hepatic (V. jugularis interna) and infused either with 0.9% NaCl or LPS (7.5 µg/kg BW). Thus, combination of diet (CON vs. DON) and infusion (CON vs. LPS, jugular vs. portal) created six groups: CON_CON(jug.)-CON(por.), CON_CON(jug.)-LPS(por.), CON_LPS(jug.)-CON(por.), DON_CON(jug.)-CON(por.), DON_CON(jug.)-LPS(por.), DON_LPS(jug.)-CON(por.). Blood samples were taken at -30, 15, 30, 45, 60, 75, 90, 120, 150, 180 min relative to infusion and analyzed for leukocytes and TNF-alpha. Concurrently, clinical signs were scored and body temperature measured during the same period. LPS as such induced a dramatic rise in TNF-alpha (p < 0.001), hyperthermia (p < 0.01), and severe leukopenia (p < 0.001). In CON-fed pigs, an earlier return to physiological base levels was observed for the clinical complex, starting at 120 min post infusionem (p < 0.05) and persisting until 180 min. DON_LPS(jug.)-CON(por.) resulted in a lower temperature rise (p = 0.08) compared to CON_LPS(jug.)-CON(por.). In conclusion, APR resulting from a post-hepatic immune stimulus was altered by chronic DON-feeding.


Expanding the Limits of Organic Energetic Materials: High-Performance Alliance of 1,3,4-Thiadiazole and Furazan Scaffolds.
A majority of known and newly synthesized energetic materials comprise polynitrogen or nitrogen-oxygen heterocycles with various explosophores. However, available structural combinations of these organic scaffolds are finite and are about to reach their limits. Herein, we present the design and synthesis of a series of sulfur-containing polyazole structures comprising 1,3,4-thiadiazole and furazan rings linked by C-C bonds and enriched with energetic nitro and azo functionalities. In terms of detonation performance, all synthesized 1,3,4-thiadiazole-furazan assemblies (D = 7.7-7.9 km s-1; P = 26-28 GPa) lie between the powerful explosive TATB (D = 8.0 km s-1; P = 31 GPa) and melt-cast material TNT (D = 6.9 km s-1; P = 23 GPa). In the synthesized series, azo-bridged derivative 5 seems to be most practically interesting, as it combines a relatively high energetic performance (D = 7.9 km s-1; P = 28 GPa), a very high thermal stability (271 °C), and insensitivity to friction. By these functional properties, 5 outperforms the benchmark heat-resistant explosive hexanitrostilbene (HNS). To the best of our knowledge, this is the first example of an energetic alliance of furazan and 1,3,4-thiadiazole scaffolds and a rare case of sulfur-containing high-energy materials, which can certainly be considered as an evolutionary step in energetic materials science.


Optimal tube current for lung cancer screening with low-dose spiral CT.
To determine the optimal tube current for spiral CT for lung cancer screening. Low-dose spiral CT images from 20 subjects were obtained with 50 mA, 25 mA, 10 mA and 5 mA tube currents. The accuracy in detecting 21 nodules measuring 3 to 14 mm in diameter was tested using receiver operating characteristics (ROC) to determine the diagnostic accuracy and statistical significance. Compared with 50 mA, 25 mA showed no statistical difference. A significant difference was seen between 50 mA and 5 mA images and between 25 mA and 10 mA images, in the detection of lung parenchymal nodular lesions. Approximately 25 mA is the optimal tube current for the detection of pulmonary nodules as it allows a reduction of the radiation dose without sacrificing diagnostic accuracy.


Trajectory of social isolation following hip fracture: an analysis of the English Longitudinal Study of Ageing (ELSA) cohort.
social isolation is defined as a lack of meaningful and sustained communication or interactions with social networks. There is limited understanding on the prevalence of social isolation and loneliness in people following hip fracture and no previous understanding of how this changes over time. to determine the prevalence and trajectory of social isolation and loneliness before a hip fracture, during the recovery phase and a minimum of 2 years post-hip fracture in an English population. data were from the English Longitudinal Study of Ageing (ELSA) cohort (2004/5-2014/15). The sample comprised of 215 participants who had sustained a hip fracture. Measures of social isolation and loneliness were analysed through multilevel modelling to determine their trajectories during three-time intervals (pre-fracture; interval at hip fracture and recovery; minimum 2 years post-fracture). The prevalence of social isolation and loneliness were determined pre- and post-fracture. prevalence of social isolation was 19% post-hip fracture and loneliness 13% post-hip fracture. There was no statistically significant change in social isolation pre-fracture compared to a minimum of 2 years post-fracture (P = 0.78). Similarly, there was no statistically significant change in loneliness pre-fracture compared to a minimum of 2 years post-fracture (P = 0.12). this analysis has determined that whilst social isolation and loneliness do not change over time following hip fracture, these remain a significant problem for this population. Interventions are required to address these physical and psychological health needs. This is important as they may have short and longer term health benefits for people post-hip fracture.


Financial implications of refugee malaria: the impact of pre-departure presumptive treatment with anti-malarial drugs.
This study is a cost-benefits analysis of the recommendations of the Centers for Disease Control and Prevention for presumptive anti-malarial treatment among departing West African refugees. We conducted a retrospective chart review of symptomatic, blood smear-positive cases of malaria seen in Minneapolis, Minnesota, from 1996 through 2005. Billing charges of U.S. care were compared with estimates of implementation costs for overseas treatment. Fifty-eight symptomatic malaria infections occurred among West African refugees. After overseas pre-departure presumptive treatment, symptomatic malaria in arriving refugees decreased from 8.2% to 0%. The pre-departure number needed to treat to prevent one case of symptomatic malaria is 13.9 (95% confidence interval = 9.8-24). The average U.S. billing charge for each malaria case is $1,730. Overseas implementation costs for presumptive treatment are estimated to be between $141 and $346 to prevent one U.S. malaria case. Overseas presumptive pre-departure anti-malarial therapy prevents clinical malaria in refugees and results in cost-benefits when the malaria prevalence is > 1%. Overseas presumptive therapy has greater cost-benefits than U.S. based screening and treatment strategies.


Phase contrast visualization of squamous cell microridges.
A successful attempt has been made to identify microridges on squamous cells in routine smears using phase contrast microscopy. Microridges may be identified on mature cells of buccal mucosa and in cervical smears, either alcohol or spray fixed, and even in smears up to five years old. The features identified with phase contrast may also be observed with scanning electron microscopy. Identification of microridges may be of diagnostic interest in the evaluation of cervical smears.


Performance Outcomes After Hook of Hamate Fractures in Major League Baseball Players.
Major League Baseball (MLB) players are at risk of hook of hamate fractures. There is a paucity of data assessing the effect of a hook of hamate fracture on MLB players' future athletic performance. To determine if MLB players who sustain hook of hamate fractures demonstrate decreased performance upon return to competition when compared with their performance before injury and that of their control-matched peers. Retrospective case-control design. Retrospective database study. 18 MLB players who sustained hook of hamate fractures. Data for 18 MLB players with hook of hamate fractures incurred over 26 seasons (1989-2014) were obtained from injury reports, press releases, and player profiles ( www.mlb.com and www.baseballreference.com ). Player age, position, number of years in the league, mechanism of injury, and treatment were recorded. Individual season statistics for the 2 seasons immediately prior to injury and the 2 seasons after injury for the main performance variable-Wins Above Replacement-were obtained. Eighteen controls matched by player position, age, and performance statistics were identified. A performance comparison of the cohorts was performed. Postinjury performance compared with preinjury performance and matched-controls. Mean age at the time of injury was 25.1 years with a mean of 4.4 seasons of MLB experience prior to injury. All injuries were sustained to their nondominant batting hand. All players underwent operative intervention. There was no significant change in Wins Above Replacement or isolated power when preinjury and postinjury performance were compared. When compared with matched-controls, no significant decline in performance in Wins Above Replacement the first season and second season after injury was found. MLB players sustaining hook of hamate fractures can reasonably expect to return to their preinjury performance levels following operative treatment.


Risk factors of familial pancreatic cancer in Japan: current smoking and recent onset of diabetes.
In western countries, 7% to 10% of patients with pancreatic cancer (PC) have a familial predisposition to their disease. The aim of this study was to determine the familial susceptibility to PC in Japan. Five hundred seventy-seven patients with PC and 577 age- and gender-matched controls were analyzed for cancer history in their first-degree relative(s) (FDRs) and demographic factors. The patients with PC were more likely to have an FDR with PC (6.9%) than the controls (2.9%; odds ratio [OR], 2.5; P = 0.02). Three patients (0.5%), but none of the controls, had a family history of PC in multiple FDRs. Smoking, especially current smoking (OR, 1.5; P = 0.005), and diabetes mellitus (OR: 1.7, P = 0.001) were also associated with PC. The odds increased up to 10-fold if the patients were positive for these 3 factors. The patients with familial PC were more likely to be current smokers (40%) and to have diabetes mellitus (32.5%) than the sporadic cases (30.1% and 20.1%; OR, 1.6 and 1.9). A family history of PC is a risk of PC in Japan (6.9%) as is a personal history of diabetes and smoking. It is prudent to inform the kindred of patients with familiar PC of the risk of smoking and to follow carefully if they develop diabetes.


Oral candidiasis among African human immunodeficiency virus-infected individuals: 10 years of systematic review and meta-analysis from sub-Saharan Africa.
Oral candidiasis (OC) is the most common opportunistic fungal infection among immunocompromised individuals. This systematic review and meta-analysis reports on the contribution of non-albicans Candida species in causing OC among human immunodeficiency virus (HIV)-infected individuals in sub-Saharan Africa between 2005 and 2015. Thirteen original research articles on oral Candida infection/colonization among HIV-infected African populations were reviewed. The prevalence of OC ranged from 7.6% to 75.3%. Pseudomembranous candidiasis was found to range from 12.1% to 66.7%. The prevalence of non-albicans Candida species causing OC was 33.5% [95% confidence interval (CI) 30.9-36.39%]. Of 458 non-albicans Candida species detected, C. glabrata (23.8%; 109/458) was the most common, followed by C. tropicalis (22%; 101/458) and C. krusei (10.7%; 49/458). The overall fluconazole resistance was 39.3% (95% CI 34.4-44.1%). Candida albicans was significantly more resistant than non-albicans Candida species to fluconazole (44.7% vs 21.9%; p < 0.001). One-quarter of the cases of OC among HIV-infected individuals in sub-Saharan Africa were due to non-albicans Candida species. Candida albicans isolates were more resistant than the non-albicans Candida species to fluconazole and voriconazole. Strengthening the capacity for fungal diagnosis and antifungal susceptibility testing in sub-Saharan Africa is mandatory in order to track the azole resistance trend.


An immunoglobulin superfamily-like domain unique to the Yersinia pseudotuberculosis invasin protein is required for stimulation of bacterial uptake via integrin receptors.
The binding of the Yersinia pseudotuberculosis and Yersinia enterocolitica invasin proteins to beta(1) integrin receptors allows internalization of these organisms by cultured cells. The C-terminal 192-residue superdomain of the Y. pseudotuberculosis invasin is necessary and sufficient for integrin recognition, while a region located outside, and N-terminal to, this superdomain strongly enhances the efficiency of bacterial uptake. Within the enhancer region is a domain called D2 that allows invasin-invasin interaction. To investigate the role of the enhancer region, bacterial cell binding and entry mediated by the Y. pseudotuberculosis invasin protein (invasin(pstb)) was compared to that of Y. enterocolitica invasin (invasin(ent)), which lacks the D2 self-association domain. Invasin(ent) was shown to be unable to promote self-interaction, using the DNA binding domain of lambda repressor as a reporter. Furthermore, two genetically engineered in-frame deletion mutations that removed D2 from invasin(pstb) were significantly less proficient than wild-type invasin(pstb) at promoting uptake, although the amount of surface-exposed invasin as well as the cell binding capacity of the recombinant Escherichia coli strains remained similar. Competitive uptake assays showed that E. coli cells expressing invasin(pstb) had a significant advantage in the internalization process versus either E. coli cells expressing invasin(ent) or the invasin(pstb) derivatives deleted for D2, further demonstrating the importance of invasin self-interaction for the efficiency of invasin-mediated uptake.


Resting heart rate as a prognostic factor for mortality in patients with breast cancer.
Although elevated resting heart rate (RHR) has been shown to be associated with mortality in the general population and patients with certain diseases, no study has examined this association in patients with breast cancer. A total of 4786 patients with stage I-III breast cancer were retrospectively selected from the Severance hospital breast cancer registry in Seoul, Korea. RHR was measured at baseline and the mean follow-up time for all patients was 5.0 ± 2.5 years. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated using Cox regression models. After adjustment for prognostic factors, patients in the highest quintile of RHR (≥85 beat per minute (bpm)) had a significantly higher risk of all-cause mortality (HR: 1.57; 95 %CI 1.05-2.35), breast cancer-specific mortality (HR: 1.69; 95 %CI 1.07-2.68), and cancer recurrence (HR: 1.49; 95 %CI 0.99-2.25), compared to those in the lowest quintile (≤67 bpm). Moreover, every 10 bpm increase in RHR was associated with 15, 22, and 6 % increased risk of all-cause mortality, breast cancer-specific mortality, and cancer recurrence, respectively. However, the association between RHR and cancer recurrence was not statistically significant (p = 0.26). Elevated RHR was associated with an increased risk of mortality in patients with breast cancer. The findings from this study suggest that RHR may be used as a prognostic factor for patients with breast cancer in clinical settings.


[Influence of the growth phase of Neisseria meningitidis on the accumulation of antigens cross-reacting with human antigens in the culture].
The content of N. meningitidis antigens with epitopes cross-reacting with human antigens was studied in the dynamics of the meningococci cultivation. The absence of these antigens in the culture in the middle of the exponential phase of growth and their presence in the culture at the end of the stationary growth phase of growth were shown. Thus the expediency of using the culture in the middle of the exponential phase of growth for obtaining meningococcal (serogroups A, B and C) vaccines was demonstrated. The trend, found to be promising for the development of immunologically safe vaccines which contained no antigens having common epitopes with human antigens, was determined.


Predictors for Using a HIV Self-Test Among Migrant and Seasonal Farmworkers in North Carolina.
Approximately, two million migrant and seasonal farmworkers (MSF) work in the United States annually. Several factors, such as lack of access to healthcare services and health behaviors, contribute to risk of HIV transmission. Relatively few studies have explored MSF knowledge of HIV transmission and testing options. A 12-question, self-administered survey of farmworkers (n = 178) from 19 migrant camps was conducted. The survey assessed knowledge of factors related to HIV transmission, testing, and intention to use a HIV home-test kit. Participants with knowledge of treatment for HIV (p = 0.03) and that condom use protects against HIV (p = 0.04) were more willing to express intent to use a home test kit than those with less knowledge. Concern among farmworkers that HIV was a very or somewhat serious problem in their community was associated with expressing intent to use a home test kit (OR = 2.3, 95% CI = 0.92-5.5). Respondents with less knowledge were less likely to use a home test kit. MSF were concerned about HIV in their community and would be willing to use to a home test kit. This pilot study provides a basis for additional research related to HIV testing within the MSF community.


Cyclosporine trough levels and its side effects in kidney transplant recipients.
Cyclosporine is the backbone of immunosuppression in kidney transplantation. However, it is associated with side effects, some of which are dose-dependent. We evaluated association between cyclosporine trough level and its side effects. In 50 kidney transplant recipients, serum cyclosporine level, fasting blood glucose, and serum creatinine were measured 7 times during first 6 months after transplantation. The participants were also assessed for blood pressure, hand tremor, and headache at each visit. The relationship between cyclosporine trough level and hypertension, hyperglycemia, hand tremor, and headache were evaluated. There were no significant relationship between cyclosporine levels and allograft function. Except at the second week and sixth month, there were no significant differences between drug doses in various serum cyclosporine trough level groups. At the second week, the mean drug dose in patients with cyclosporine trough levels less than the target therapeutic level was 279.16 +/- 56.23 mg/d, while in the patients with cyclosporine levels higher than the therapeutic level, its dose was 302.08 +/- 66.61 mg/d (P < .05). At the sixth month, the mean drug dose was 137.50 +/- 17.67 mg/d in the patients with lower than target cyclosporine levels, and it was 242.18 +/- 58.25 mg/d in those with cyclosporine levels higher than the therapeutic level (P < .05). There was no significant relationship between serum cyclosporine level and its side effects. We demonstrated cyclosporine trough level had no direct relation with drug side effects and it is not a suitable measure for assessment of drug side effects.


Measurement equivalence testing of the American Identity Questionnaire across Black, Latino, and White adolescents.
The current study examined the psychometric properties of the American Identity Questionnaire (Phinney & Devich-Navarro, Journal of Research on Adolescence, 1997, 7, 3). American identity has been associated with societal and personal benefits for ethno-racially diverse populations, but limited research has assessed whether American identity measures function equivalently across members of different groups. Thus, the current study examined the measurement equivalence and construct validity of the American Identity Questionnaire among Black, Latino, and White adolescents. Using a cross-sectional design, adolescents completed self-administered surveys during regular school time. The current study included U.S.-born adolescents (N = 1,326; M age = 16.16 years; SD = 1.12; 53% female) who self-identified as either Black (n = 315), Latino (n = 345), or White (n = 666). Multigroup confirmatory factor analysis was carried out using ethnic-racial group membership as the grouping variable. Findings suggested that the American Identity Questionnaire demonstrated configural (equivalent factor structures) and metric (equivalent factor loadings) invariance across the three groups. Partial scalar invariance was supported after allowing one item intercept to be freely estimated among Latino youth. Regarding construct validity, American identity was positively associated with self-esteem and personal identity, and negatively associated with depressive symptoms across the three groups. Findings suggest that the American Identity Questionnaire can be used to assess associations between American identity and other constructs with samples of Black, Latino, and White adolescents. Mean-level comparisons across the three groups may also be possible. Construct validity results indicated that American identity was positively associated with adolescents' psychosocial adjustment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Duty to warn at-risk relatives for genetic disease: genetic counselors' clinical experience.
When a patient refuses to inform relatives of their risk for genetic disease, the genetic healthcare professional is faced with conflicting ethical obligations. On one side of the issue is the obligation to respect and protect patients' right to privacy. On the other side is the obligation to prevent harm and promote the welfare of the family members, which suggests a responsibility to warn at-risk relatives, even without the patient's consent. In an effort to examine the actual clinical impact of this issue, we conducted a pilot study that explored genetic counselors' experience with this conflict. A survey was developed and made available to members of the National Society of Genetic Counselors. Questions were either multiple-choice responses or open-ended. Almost half of respondents (119/259; 46%) had had a patient refuse to notify an at-risk relative. The most commonly cited reasons for refusal were estranged family relationships, altering family dynamics, insurance discrimination, and employment discrimination, respectively. Of these 119 counselors, 24 (21%) reported that they seriously considered warning the at-risk relatives without patient consent, and one actually did disclose. Three factors consistently made the counselors less likely to disclose: their patient's potential emotional reaction, the relationship between the relative and patient, and the chance that the relative could be aware of the disease by another means. These results suggest that while the conflict is often encountered in clinical practice, it is rare that the situation remains unresolved to the extent that genetic counselors actually consider warning at-risk relatives. However, when the situation was encountered, the counselors in this study reported a lower rate of disclosure without consent than would have been anticipated based on previous studies that used hypothetical situations. It may be that counselors do not recognize a duty to warn at-risk relatives as integral to their role and professional obligations.