Prepupal building behavior in Drosophila melanogaster and its evolution under resource and time constraints.
Structures built by animals are a widespread and ecologically important 'extended phenotype'. While its taxonomic diversity has been well described, factors affecting short-term evolution of building behavior within a species have received little experimental attention. Here we describe how, given the opportunity, wandering Drosophila melanogaster larvae often build long tunnels in agar substrates and embed their pupae within them. These embedded larvae are characterized by a longer egg-to-pupariation developmental time than larvae that pupate on the surface. Assuming that such building behaviors are likely to be energetically costly and/or time consuming, we hypothesized that they should evolve to be less pronounced under resource or time limitation. In accord with this prediction, larvae from populations evolved for 160 generations under a regime that combines larval malnutrition with limited developmental time dug shorter tunnels than larvae from control unselected populations. However, the proportion of larvae that embedded before pupation did not differ between the malnutrition-adapted and control populations, suggesting that tunnel length and likelihood of embedding before pupation are controlled by different genetic loci. The behaviors exhibited by wandering larvae of Drosophila melanogaster prior to pupation offer a model system to study evolution of animal building behaviors because the tunneling and embedding phenotypes are simple, facultative and highly variable.


Fibroblast growth factor receptor 3 mutation analysis on voided urine for surveillance of patients with low-grade non-muscle-invasive bladder cancer.
Mutations in the fibroblast growth factor receptor 3 (FGFR3) have been found in 70% of the low-grade non-muscle-invasive bladder cancer (NMI-BC) tumors. We aim to determine the potential of FGFR3 mutation analysis on voided urine to detect recurrences during surveillance of patients with low-grade NMI-BC. FGFR3 mutation status of the study inclusion tumor was determined from 200 low-grade NMI-BC patients. Patients with an FGFR3-mutant inclusion tumor were selected for analysis and monitored by cystoscopy, and voided urine samples were collected. FGFR3 mutation analysis was done on 463 prospectively collected urines. Sensitivity and predictive value of the assay were determined for detection of concomitant recurrences. Longitudinal and Cox time-to-event analyses were done to determine the predictive value for detection of future recurrences. Median follow-up was 3.5 years. The sensitivity of the assay for detection of concomitant recurrences was 26 of 45 (58%). Of the 105 positive urine samples, 85 (81%) were associated with a concomitant or a future recurrence. An FGFR3-positive urine was associated with a 3.8-fold (P < 0.0001) higher risk of having a recurrence in the Cox analysis. In contrast, only 41 of 358 (11%) FGFR3-negative urine samples were associated with a recurrence. Positive predictive value increased from 25% to 90% in patients having consecutive FGFR3-positive urine tests. FGFR3 mutation analysis on voided urine is a simple and noninvasive diagnostic method for detection of recurrences during surveillance of patients presenting with a low-grade FGFR3-mutant NMI-BC tumor.


[Experimental study of dicholine succinate pharmacokinetics].
We have conducted for the first time an experimental study of pharmacokinetics of dicholine succinate (DCS) for different ways of its administration in rats The quantitative evaluation of DCS and its metabolites was performed by the radioactive isotope technique. Various parameters of DCS pharmacokinetics were estimated, including the dose dependence of drug content in the blood plasma, total bioavailability, distribution kinetics, and the main ways of DCS excretion.


Multiple mechanisms contribute to the development of clinically significant azole resistance in Aspergillus fumigatus.
Infections caused by the filamentous fungus Aspergillus fumigatus are a significant clinical issue and represent the second most-common form of fungal infection. Azole drugs are effective against this pathogen but resistant isolates are being found more frequently. Infections associated with azole resistant A. fumigatus have a significantly increased mortality making understanding drug resistance in this organism a priority. The target of azole drugs is the lanosterol α-14 demethylase enzyme encoded by the cyp51A gene in A. fumigatus. Mutations in cyp51A have been described that give rise to azole resistance and been argued to be the primary, if not sole, contributor to azole resistance. Here, I discuss recent developments that indicate multiple mechanisms, including increased expression of ATP-binding cassette (ABC) transporter proteins, contribute to azole resistance. ABC transporters are well-established determinants of drug resistance in other fungal pathogens and seem likely to play a similar role in A. fumigatus.


Transducer for high speed and large thrust ultrasonic linear motor using two sandwich-type vibrators.
A transducer for an ultrasonic motor using two sandwich-type vibrators has been proposed and designed. The vibrators cross at right angles with each other at the tip. The transducer has two vibration modes; one is a symmetrical mode and the other is anti-symmetric. The normal direction motion of the transducer tip is excited by the symmetrical mode. The lateral motion of the tip is excited by the anti-symmetrical mode. The transducer is designed so that these vibration modes are degenerated. To obtain high output force and high power, materials were carefully selected. Heat-treated high strength chromium manganese steel bolts were used for binding the PZT elements. A zirconia ceramics plate was bonded on the transducer tip as frictional material. The no-load maximum speed was 3.5 m/sec. The output force was 39 N at the driving voltage of 500 V(rms) and the preload of 150 N. At this condition the maximum efficiency was 28%, and the velocity was 0.55 m/sec. The maximum output force was 51 N, which was 17 times of the transducer weight. The maximum output power per unit weight was 76 W/kg.


Promoter of a cotton fibre MYB gene functional in trichomes of Arabidopsis and glandular trichomes of tobacco.
Cotton fibres are unicellular seed trichomes. Our previous study suggested that the cotton R2R3 MYB transcript factor GaMYB2 is a functional homologue of the Arabidopsis trichome regulator GLABRA1 (GL1). Here, the GaMYB2 promoter activity is reported in cotton (Gossypium hirsutum), tobacco (Nicotiana tabacum), and Arabidopsis plants. A 2062 bp promoter of GaMYB2 was isolated from G. arboreum, and fused to a beta-glucuronidase (GUS) reporter gene. In cotton, the GaMYB2 promoter exhibited activities in developing fibre cells and trichomes of other aerial organs, including leaves, stems and bracts. In Arabidopsis the promoter was specific to trichomes. Different from Arabidopsis and cotton that have unicellular non-glandular simple trichomes, tobacco plants contain more than one type of trichome, including multicellular simple and glandular secreting trichomes (GSTs). Interestingly, in tobacco plants the GaMYB2 promoter directed GUS expression exclusively in glandular cells of GSTs. A series of 5'-deletions revealed that a 360 bp fragment upstream to the translation initiation codon was sufficient to drive gene expression. A putative cis-element of the T/G-box was located at -233 to -214; a yeast one-hybrid assay showed that Arabidopsis bHLH protein GLABRA3 (GL3), also a trichome regulator, and GhDEL65, a GL3-like cotton protein, had high binding activities to the T/G-box motif. Overexpression of GL3 or GhDEL65 enhanced the GaMYB2 promoter activity in transgenic Arabidopsis plants. A comparison of GaMYB2 promoter specificities in trichomes of different plant species with different types of trichomes provides a tool for further dissection of plant trichome structure and development.


Stromal protein phosphorylation in spinach (Spinacia oleracea) chloroplasts.
When intact spinach chloroplasts were supplied with [32P]Pi, stromal protein phosphorylation was found to occur in the dark. On illumination the thylakoid protein kinase was activated and the amount of label found in thylakoid proteins quickly exceeded that incorporated into stromal protein, such that the latter was found to account for only 10-15% of the total radioactivity bound to chloroplast proteins after 5 min illumination. The rate of phosphorylation of stromal polypeptides was unchanged by light. After SDS/polyacrylamide-gel electrophoresis, more than 15 labelled polypeptides of stromal origin were observed. A polypeptide with an Mr of approx. 70 000 had the highest specific activity of labelling. Both the large and small subunits of the ribulose-1,5-bisphosphate carboxylase were phosphorylated. The level of phosphorylation of stromal protein was increased by CO2 fixation in intact chloroplasts. This increase was not observed in the absence of NaHCO3 or in the presence of the phosphoribulokinase inhibitor DL-glyceraldehyde. These effects appeared to be largely due to changes in the phosphorylation state of the large and small subunits of ribulose-1,5-bisphosphate carboxylase. Studies with the reconstituted chloroplast system showed that the thylakoid protein kinase(s) played no part in the phosphorylation of stromal protein. The rate and level of phosphorylation of stromal protein was unaffected by the activation state of the thylakoid protein kinase and was unchanged when thylakoids were omitted from the reaction medium. The phosphorylation of stromal proteins is therefore catalysed by a discrete soluble protein kinase.


Structures, electronic states, photoluminescence, and carrier transport properties of 1,1-disubstituted 2,3,4,5-tetraphenylsiloles.
The excellent electroluminescent (EL) properties of 1,1-disubstituted 2,3,4,5-tetraphenylsiloles, 1-methyl-1,2,3,4,5-pentaphenylsilole (MPPS), and 1,1,2,3,4,5-hexaphenylsilole (HPS) have been found. Despite some studies devoted to these materials, very little is known about the real origin of their unique EL properties. Therefore, we investigated the structures, photoluminescence (PL), and charge carrier transport properties of 1,1-disubstituted 2,3,4,5-tetraphenylsiloles as well as the effect of substituents on these characteristics. The single crystals of the three siloles involving 1,1-dimethyl-2,3,4,5-tetraphenylsilole (DMTPS), MPPS, and HPS were grown and their crystal structures were determined by X-ray diffraction. Three siloles have nonplanar molecular structures. The substituents at 1,1-positions enhance the steric hindrance and have predominant influence on the twisted degree of phenyl groups at ring carbons. This nonplanar structure reduces the intermolecular interaction and the likelihood of excimer formation, and increases PL efficiency in the solid state. The silole films show high fluorescence quantum yields (75-85%), whereas their dilute solutions exhibit a faint emission. The electronic structures of the three siloles were investigated using quantum chemical calculations. The highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular orbitals (LUMOs) are mainly localized on the silole ring and two phenyl groups at 2,5-positions in all cases, while the LUMOs have a significant orbital density at two exocyclic Si-C bonds. The extremely theoretical studies of luminescent properties were carried out. We calculated the nonradiative decay rate of the first excited state as well as the radiative one. It is found that the faint emission of DMTPS in solutions mainly results from the huge nonradiative decay rate. In solid states, molecular packing can remarkably restrict the intramolecular rotation of the peripheral side phenyl ring, which has a large contribution to the nonradiative transition process. This explains why the 1,1-disubstituted 2,3,4,5-tetraphenylsiloles in the thin films exhibit high fluorescence quantum yields. The charge carrier mobilities of the MPPS and HPS films were measured using a transient EL technique. We obtained a mobility of 2.1 x 10(-)(6) cm(2)/V.s in the MPPS film at an electric field of 1.2 x 10(6) V/cm. This mobility is comparable to that of Alq(3), which is one of the most extensively used electron transport materials in organic light-emitting diodes (LEDs), at the same electric field. The electron mobility of the HPS film is about approximately 1.5 times higher than that of the MPPS film. To the best of our knowledge, this kind of material is one of the most excellent emissive materials that possess both high charge carrier mobility and high PL efficiency in the solid states simultaneously. The excellent EL performances of MPPS and HPS are presumably ascribed to these characteristics.


Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.
Biochemical and molecular genetic evidence is presented that in six independent pedigrees the development of Leber hereditary optic neuropathy (LHON) is due to the same primary mutation in the mitochondrial ND1 gene. A LHON family from the Newcastle area of Great Britain was analyzed in depth to determine the mitochondrial genetic etiology of their disease. Biochemical assays of mitochondrial electron transport in organelles isolated from the platelet/white-blood-cell fraction have established that the members of this family have a substantial and specific lowering of flux through complex I (NADH-ubiquinone oxidoreductase). To determine the site of the primary mitochondrial gene mutation in this pedigree, all seven mitochondrial complex I genes were sequenced, in their entirety, from two family members. The primary mutation was identified as a homoplasmic transition at nucleotide 3460, which results in the substitution of threonine for alanine at position 52 of the ND1 protein. This residue occurs within a very highly conserved hydrophilic loop, is invariantly alanine or glycine in all ND1 proteins, and is adjacent to an invariant aspartic acid residue. This is only the second instance in which both a biochemical abnormality and a mitochondrial gene mutation have been identified in an LHON pedigree. The sequence analysis of the ND81 gene was extended to a further 11, unrelated LHON pedigrees that had been screened previously and found not to carry the mitochondrial ND4/R340H mutation. The ND1/A52T mutation at nucleotide 3460 was found in five of these 11 pedigrees. In contrast, this sequence change was not found in any of the 47 non-LHON controls. The possible role of secondary complex I mutations in the etiology of LHON is also addressed in these studies.


Thromboembolic events and need for anticoagulation therapy following left atrial appendage occlusion in patients with electrical isolation of the appendage.
Electrical isolation of the left atrial appendage (LAA) is an important adjunctive ablation strategy in patients with nonparoxysmal atrial fibrillation (AF). Patients who have impaired LAA contractility following isolation may require long-term oral anticoagulant (OAC) therapy irrespective of their CHADS2 -VASc score. Percutaneous LAA occlusion (LAAO) is a potential alternative to life-long OAC therapy. We aimed to assess the rate of OAC discontinuation and thromboembolic (TE) events following percutaneous LAAO in patients who underwent LAA electrical isolation (LAAI). This is a retrospective two-center study of patients who underwent percutaneous LAAO following LAAI. Patients with at least 3-month follow-up were included in the study. The antithrombotic therapy and TE events at the time of the last follow-up were noted. The LAA was successfully occluded in 162 (with Watchman device in 140 [86.4%] and Lariat in 22 [13.6%]). A total of 32 patients had leaks detected on the 45-day transesophageal echocardiogram (TEE); 21 (15%) Watchman and 11 (50%) Lariat cases (P = 0.0001). Two (one Watchman and one Lariat) of the 32 leaks were more than 5 mm. After the 45-day TEE, 150 (92.6%) patients were off-OAC. No TE events were reported in the 150 patients who stopped the anticoagulants. Four (2.47%) patients experienced stroke following the LAAO (three Watchman and one Lariat) procedure while on-OAC, two of which were fatal. At the median follow-up of 18.5 months, 159 (98.15%) patients were off-anticoagulant. Up to 98% of patients with LAAI could safely discontinue OAC after undergoing the appendage closure procedure.


Mitogen-activated protein kinase translocates to the nucleus during ischaemia and is activated during reperfusion.
Growth factors and various cellular stresses are known to activate mitogen-activated protein (MAP) kinase, which plays a role in conveying signals from the cytosol to the nucleus. The phosphorylation of MAP kinase is thought to be a prerequisite for translocation. Here, we investigate the translocation and activation of MAP kinase during ischaemia and reperfusion in perfused rat heart. Ischaemia (0-40 min) induces the translocation of MAP kinase from the cytosol fraction to the nuclear fraction. Immunohistochemical observation shows that MAP kinase staining in the nucleus is enhanced after ischaemia for 40 min. Unexpectedly, tyrosine phosphorylation of MAP kinase is unchanged in the nuclear fraction during ischaemia, indicating that unphosphorylated MAP kinase translocates from the cytosol to the nucleus. During reperfusion (0-30 min), after ischaemia for 20 min, tyrosine phosphorylation of MAP kinase in the nuclear fraction is increased with a peak at 10 min of reperfusion. The activation is confirmed by MAP kinase activity with similar kinetics to the tyrosine phosphorylation. However, the amount of MAP kinase in the fraction is almost constant during reperfusion for 10 min. Although an upstream kinase for MAP kinase, MAP kinase/extracellular signal-regulated kinase kinase (MEK)-1, remains in the cytosol throughout ischaemia and reperfusion, MEK-2, another upstream kinase for MAP kinase, is constantly present in the nucleus as well as in the cytoplasm, based on analyses by fractionation and immunohistochemistry. Furthermore, MEK-2 activity in the nuclear fraction is rapidly increased during post-ischaemic reperfusion. These findings demonstrate that nuclear MAP kinase is activated by tyrosine phosphorylation during reperfusion, probably by MEK-2.


Multiple P450 genes overexpressed in deltamethrin-resistant strains of Helicoverpa armigera.
Resistance to the pyrethroid insecticide deltamethrin has been a growing problem in the management of Helicoverpa armigera (Hübner) pest populations in West Africa. Detoxification by P450 enzymes appears to be a major mechanism of resistance, but the genes responsible for resistance are unknown. First, it was shown that deltamethrin resistance in strains from Burkina Faso (Kaya) and from Spain (Seville) were suppressible by piperonyl butoxide and by trichlorophenyl propynyl ether, thus indicating a major role of P450 enzyme(s) in resistance. The larval expression of 21 CYP genes encoding P450 enzymes from six CYP families were then compared by quantitative RT-PCR. Five genes, CYP4L5, CYP4L11, CYP6AE11, CYP332A1 and CYP9A14, were significantly overexpressed in the Kaya and Seville strains when compared with Heliar, a susceptible strain. Significant overexpression of multiple CYP genes (CYP4M6, CYP4M7, CYP6AE11, CYP9A12, CYP332A1 and CYP337B1) was also found in six field strains with different levels of resistance from Benin, Burkina Faso and Mali. Although functional or genetic evidence for the role of these P450s in resistance remains to be formally established, results suggest that multiple P450 enzymes contribute to deltamethrin resistance. This study is a first step towards the development of molecular tools for the detection of P450-based resistance in H. armigera.


Hospital volumes and later year of operation correlates with better outcomes in acute Type A aortic dissection.
Acute Type A aortic dissection remains a life-threatening disease, but there are indications that its surgical mortality is decreasing. The aim of this report was to study how surgical mortality has changed and what influences those changes. Nordic Consortium for Acute Type A Aortic Dissection is a retrospective database comprising 1159 patients (mean age 61.6 ± 12.2 years, 68% male) treated for acute Type A aortic dissection at 8 centres in Denmark, Finland, Iceland and Sweden from 2005 to 2014. Data gathered included demographics, symptoms, type of procedure, complications and 30-day mortality. The annual number of operations increased significantly from 85 in 2005 to 150 in 2014 (P < 0.001). Chest pain was present in 85% of patients, 24% were hypotensive on presentation and 28% had malperfusion syndrome. Open distal anastomosis technique under hypothermic circulatory arrest was used in 85% of cases and its use increased significantly throughout the study. The 30-day mortality decreased from 24% in 2005 to 13% in 2014 (P = 0.003). Independent predictors for 30-day mortality were preoperative cardiac arrest, malperfusion syndrome, Penn Class C, Penn Class B and C and cardiopulmonary bypass time, whereas later calendar year and higher hospital operative volumes predicted improved survival. Surgical mortality for acute Type A aortic dissection remains high but has decreased significantly over the last decade. This correlated with later year of operation and increased the number of operations performed per year, indicating that cumulative surgical experience contributes significantly to improved surgical outcomes.


Combined applications of UV and chlorine on antibiotic resistance control: A critical review.
Environmental health problems caused by antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs) have become a global concern. ARB and ARGs have been continuously detected in various water environments, which pose a new challenge for water quality safety assurance. Disinfection is a key water treatment process to eliminate pathogenic microorganisms in water, and combined chlorine and UV processes (the UV/Cl2 process, the UV-Cl2 process, and the Cl2-UV process) are considered potential disinfection methods to control antibiotic resistance. This review documented the efficacy and mechanism of combined UV and chlorine processes for the control of antibiotic resistance, as well as the effects of chlorine dose, solution pH, UV wavelength, and water matrix on the effectiveness of the processes. There are knowledge gaps in research on the combined chlorine and UV processes for antibiotic resistance control, in particular the UV-Cl2 process and the Cl2-UV process. In addition, changes in the structure of microbial communities and the distribution of ARGs, which are closely related to the spread of antibiotic resistance in the water, induced by combined processes were also addressed. Whether these changes could lead to the re-transmission of antibiotic resistance and harm human health may need to be further evaluated.


P6 protein of Cauliflower mosaic virus, a translation reinitiator, interacts with ribosomal protein L13 from Arabidopsis thaliana.
The P6 protein of Cauliflower mosaic virus (CaMV) transactivates translation of the CaMV 35S polycistronic pregenomic RNA and its spliced versions, and thus allows synthesis of a complete set of viral proteins. Previous studies have shown that P6 interacts with plant L18 and L24 ribosomal proteins and initiation factor eIF3, and it has been proposed that these interactions are involved in the reinitiation of translation of polycistronic viral RNAs. This study characterizes a novel cellular partner of P6, the ribosomal protein L13 from Arabidopsis thaliana. Far-Western assays performed with several P6 deletion mutants have shown that L13 interacts with the miniTAV of P6, which represents the minimal domain for transactivation, suggesting that the P6-L13 interaction might also be involved in this process. L13 and L18 were found to bind to the same region within the miniTAV. Competition assays between L18 and L13 for binding to miniTAV suggest that interactions between P6 and these ribosomal proteins involve separate P6 molecules, and/or occur at different stages of translation or in the context of another function also mediated by P6.


Dysregulation of allergic airway inflammation in the absence of microbial colonization.
The incidence of allergic disorders is increasing in developed countries and has been associated with reduced exposure to microbes and alterations in the commensal bacterial flora. To ascertain the relevance of commensal bacteria on the development of an allergic response, we used a model of allergic airway inflammation in germ-free (GF) mice that lack any exposure to pathogenic or nonpathogenic microorganisms. Allergic airway inflammation was induced in GF, specific pathogen-free (SPF), or recolonized mice by sensitization and challenge with ovalbumin. The resulting cellular infiltrate and cytokine production were measured. Our results show that the total number of infiltrating lymphocytes and eosinophils were elevated in the airways of allergic GF mice compared with control SPF mice, and that this increase could be reversed by recolonization of GF mice with the complex commensal flora of SPF mice. Exaggerated airway eosinophilia correlated with increased local production of Th2-associated cytokines, elevated IgE production, and an altered number and phenotype of conventional dendritic cells. Regulatory T-cell populations and regulatory cytokine levels were unaltered, but GF mice exhibited an increased number of basophils and decreased numbers of alveolar macrophages and plasmacytoid dendritic cells. These data demonstrate that the presence of commensal bacteria is critical for ensuring normal cellular maturation, recruitment, and control of allergic airway inflammation.


Detection of Methane Eructation Peaks in Dairy Cows at a Robotic Milking Station Using Signal Processing.
The aim of this study was to investigate the use of signal processing to detect eructation peaks in CH4 released by cows during robotic milking, and to compare recordings from three gas analysers (Guardian SP and NG, and IRMAX) differing in volume of air sampled and response time. To allow comparison of gas analysers using the signal processing approach, CH4 in air (parts per million) was measured by each analyser at the same time and continuously every second from the feed bin of a robotic milking station. Peak analysis software was used to extract maximum CH4 amplitude (ppm) from the concentration signal during each milking. A total of 5512 CH4 spot measurements were recorded from 65 cows during three consecutive sampling periods. Data were analysed with a linear mixed model including analyser × period, parity, and days in milk as fixed effects, and cow ID as a random effect. In period one, air sampling volume and recorded CH4 concentration were the same for all analysers. In periods two and three, air sampling volume was increased for IRMAX, resulting in higher CH4 concentrations recorded by IRMAX and lower concentrations recorded by Guardian SP (p < 0.001), particularly in period three, but no change in average concentrations measured by Guardian NG across periods. Measurements by Guardian SP and IRMAX had the highest correlation; Guardian SP and NG produced similar repeatability and detected more variation among cows compared with IRMAX. The findings show that signal processing can provide a reliable and accurate means to detect CH4 eructations from animals when using different gas analysers.


[Morphofunctional characteristics of male gonads in cancer of different localization].
Morphological and histochemical changes in the genital organs in 62 men, who had died of cancer of various localizations, and those in the testes in 65 practically healthy men aged 30-90 years, who had died of various causes, (controls), were studied. The studies conducted showed that changes in the male gonads in cancer of various localizations were similar to involutional ones, the former, however, were more pronounced and occurred in younger men. It was established that the functional activity of granulocytes in cancer dropped,whereas the activity of sustentocytes remained at a high level. This was one of the causes of impairment of the hormonal balance in the organism of a patient, cancer carrier, and of inhibition of the spermatogenesis activity. The degree and depth of changes depended on the stage and duration of the disease, localization of tumours was of no significance.


Hospitalization rates and outcome of invasive bacterial vaccine-preventable diseases in Tuscany: a historical cohort study of the 2000-2016 period.
Invasive bacterial diseases (IBD) are a serious cause of hospitalization, sequelae and mortality. Albeit a low incidence, an increase in cases due to H. influenzae was registered in the past 4 years and, in the Tuscany region, an excess of cases due to N. meningitidis since 2015 is alarming. The purpose of this study is to deepen the knowledge of IBD epidemiology in Tuscany with particular attention to temporal trends. Tuscan residents hospitalized for IBD from January 1st 2000 to March 18th 2016 were selected from the regional hospital discharge database based on ICD-9-CM codes. Age-specific and standardized hospitalization rates were calculated together with case-fatality rates (CFRs). A time-trend analysis was performed; whereas, prognostic factors of death were investigated through univariable and multivariable analyses. The average standardized hospitalization rates for invasive meningococcal diseases (IMD), invasive pneumococcal diseases and invasive diseases due to H. influenzae from 2000 to 2016 were 0.6, 1.8, and 0.2 per 100,000, respectively. The average CFRs were 10.5%, 14.5% and 11.5% respectively with higher values in the elderly. Older age was significantly associated with higher risk of death from all IBD. A significant reduction in hospitalization rates for IMD was observed after meningococcal C conjugate vaccine introduction. The Annual Percentage Change (APC) was -13.5 (95% confidence interval (CI) -22.3; -3.5) in 2005-2013 but has risen since that period. Furthermore, a significant increasing trend of invasive diseases due to H. influenzae was observed from 2005 onwards in children 1-4 years old (APC 13.3; 95% CI 0; 28.3). This study confirms changes in the epidemiology of invasive diseases due to H. influenzae and IMD. Furthermore, attention is called to the prevention of IBD in the elderly because of the age group's significantly higher rate of hospitalizations and deaths for all types of IBD.


SecB-like chaperone controls a toxin-antitoxin stress-responsive system in Mycobacterium tuberculosis.
A major step in the biogenesis of newly synthesized precursor proteins in bacteria is their targeting to the Sec translocon at the inner membrane. In gram-negative bacteria, the chaperone SecB binds nonnative forms of precursors and specifically transfers them to the SecA motor component of the translocase, thus facilitating their export. The major human pathogen Mycobacterium tuberculosis is an unusual gram-positive bacterium with a well-defined outer membrane and outer membrane proteins. Assistance to precursor proteins by chaperones in this bacterium remains largely unexplored. Here we show that the product of the previously uncharacterized Rv1957 gene of M. tuberculosis can substitute for SecB functions in Escherichia coli and prevent preprotein aggregation in vitro. Interestingly, in M. tuberculosis, Rv1957 is clustered with a functional stress-responsive higB-higA toxin-antitoxin (TA) locus of unknown function. Further in vivo experiments in E. coli and in Mycobacterium marinum strains that do not possess the TA-chaperone locus show that the severe toxicity of the toxin was entirely inhibited when the antitoxin and the chaperone were jointly expressed. We found that Rv1957 acts directly on the antitoxin by preventing its aggregation and protecting it from degradation. Taken together, our results show that the SecB-like chaperone Rv1957 specifically controls a stress-responsive TA system relevant for M. tuberculosis adaptive response.


TiS2 Monolayer as an Emerging Ultrathin Bifunctional Catalyst: Influence of Defects and Functionalization.
We have envisaged the hydrogen evolution and oxygen evolution reactions (HER and OER) on a two-dimensional (2D) noble-metal-free titanium disulfide (TiS2 ) monolayer, which belongs to the exciting family of transition metal dichalcogenides (TMDCs). Our theoretical investigation to probe the HER and OER on both the H and T phases of 2D TiS2 is based on electronic-structure calculations witihin the framework of density functional theory (DFT). Since TiS2 is the lightest compound among the group-IV TMDCs, it is worth exploring the catalytic activity of a TiS2 monolayer through the functionalization at the anion (S) site, substituting with P, N, and C dopants as well as by incorporating single sulfur vacancy defects. We have investigated the effect of functionalization and vacancy defects on the structural, electronic, and optical response of a TiS2 monolayer by determining the density of states, work-function, and optical absorption spectra. We have determined the HER and OER activities for the functionalized and defective TiS2 monolayers based on the reaction coordinate, which can be constructed from the adsorption free energies of the intermediates (H*, O*, OH* and OOH*, where * denotes the adosrbed state) in the HER and OER mechanisms. Finally, we have shown that TiS2 monolayers are emerging as a promising material for the HER and OER mechanisms under the influence of functionalization and defects.


Surface-segregating zwitterionic copolymers to control poly(dimethylsiloxane) surface chemistry.
The use of microfluidic devices in biomedicine is growing rapidly in applications such as organs-on-chip and separations. Polydimethylsiloxane (PDMS) is the most popular material for microfluidics due to its ability to replicate features down to the nanoscale, flexibility, gas permeability, and low cost. However, the inherent hydrophobicity of PDMS leads to the adsorption of macromolecules and small molecules on device surfaces. This curtails its use in "organs-on-chip" and other applications. Current technologies to improve PDMS surface hydrophilicity and fouling resistance involve added processing steps or do not create surfaces that remain hydrophilic for long periods. This work describes a novel, simple, fast, and scalable method for improving surface hydrophilicity and preventing the nonspecific adsorption of proteins and small molecules on PDMS through the use of a surface-segregating zwitterionic copolymer as an additive that is blended in during manufacture. These highly branched copolymers spontaneously segregate to surfaces and rearrange in contact with aqueous solutions to resist nonspecific adsorption. We report that mixing a minute amount (0.025 wt%) of the zwitterionic copolymer in PDMS considerably reduces hydrophobicity and nonspecific adsorption of proteins (albumin and lysozyme) and small molecules (vitamin B12 and reactive red). PDMS blended with these zwitterionic copolymers retains its mechanical and physical properties for at least six months. Moreover, this approach is fully compatible with existing PDMS device manufacture protocols without additional processing steps and thus provides a low-cost and user-friendly approach to fabricating reliable biomicrofluidics.


Evolutionary conservation of otd/Otx2 transcription factor action: a genome-wide microarray analysis in Drosophila.
Homeobox genes of the orthodenticle (otd)/Otx family have conserved roles in the embryogenesis of head and brain. Gene replacement experiments show that the Drosophila otd gene and orthologous mammalian Otx genes are functionally equivalent, in that overexpression of either gene in null mutants of Drosophila or mouse can restore defects in cephalic and brain development. This suggests that otd and Otx genes control a comparable subset of downstream target genes in either organism. Here we use quantitative transcript imaging to analyze this equivalence of otd and Otx gene action at a genomic level. Oligonucleotide arrays representing 13,400 annotated Drosophila genes were used to study differential gene expression in flies in which either the Drosophila otd gene or the human Otx2 gene was overexpressed. Two hundred and eighty-seven identified transcripts showed highly significant changes in expression levels in response to otd overexpression, and 682 identified transcripts showed highly significant changes in expression levels in response to Otx2 overexpression. Among these, 93 showed differential expression changes following overexpression of either otd or Otx2, and for 90 of these, comparable changes were observed under both experimental conditions. We postulate that these transcripts are common downstream targets of the fly otd gene and the human Otx2 gene in Drosophila. Our experiments indicate that approximately one third of the otd-regulated transcripts also respond to overexpression of the human Otx2 gene in Drosophila. These common otd/Otx2 downstream genes are likely to represent the molecular basis of the functional equivalence of otd and Otx2 gene action in Drosophila.


[Transvaginal ultrasonic assessment of the endometrium in menopause].
Early detection of endometrial cancer is hardly possible. In nearly 90% of all cases irregular vaginal bleeding is the first clinical sign of this disease. New ultrasound technique, small scanner probes and especially higher ultrasound frequencies rendered a better resolving power and higher quality medical imaging. Hence, now the examination of the organs in the female pelvis is very exact using vaginal sonography (VS). A clinical study was performed to examine the relevance of VS assessing changes and details of the endometrium. In particular, the sonographical criteria of early endometrial cancer should be defined. In 137 postmenopausal women VS was performed after irregular vaginal bleeding and prior to D&C. All findings were described concerning alteration in echogenicity and thickness of the endometrium. Only one case of 37 histological confirmed endometrial cancers among the study group was not detected by VS prior to curettage. Therefore 0.7% of the sonographical findings showed a false negative result and 6.6% were false positive in comparison to the histological outcome. VS seems to be a relatively reliable technique in assessing the endometrium. In conclusion VS could be a useful additional method to detect hyperplasia or malignant disorders of the endometrium.


An automated system for genome analysis to support microbial whole-genome shotgun sequencing.
We developed a semi-automated genome analysis system called GAMBLER in order to support the current whole-genome sequencing project focusing on alkaliphilic Bacillus halodurans C-125. GAMBLER was designed to reduce the human intervention required and to reduce the complications in annotating thousands of ORFs in the microbial genome. GAMBLER automates three major routines: analyzing assembly results provided by genome assembler software, assigning ORFs, and homology searching. GAMBLER is equipped with an interface for convenience of annotation. All processes and options are manipulatable through a WWW browser that enables scientists to share their genome analysis results without choosing computer platforms.


Tuning Cell and Tissue Development by Combining Multiple Mechanical Signals.
Mechanical signals offer a promising way to control cell and tissue development. It has been established that cells constantly probe their mechanical microenvironment and employ force feedback mechanisms to modify themselves and when possible, their environment, to reach a homeostatic state. Thus, a correct mechanical microenvironment (external forces and mechanical properties and shapes of cellular surroundings) is necessary for the proper functioning of cells. In vitro or in the case of nonbiological implants in vivo, where cells are in an artificial environment, addition of the adequate mechanical signals can, therefore, enable the cells to function normally as in vivo. Hence, a wide variety of approaches have been developed to apply mechanical stimuli (such as substrate stretch, flow-induced shear stress, substrate stiffness, topography, and modulation of attachment area) to cells in vitro. These approaches have not just revealed the effects of the mechanical signals on cells but also provided ways for probing cellular molecules and structures that can provide a mechanistic understanding of the effects. However, they remain lower in complexity compared with the in vivo conditions, where the cellular mechanical microenvironment is the result of a combination of multiple mechanical signals. Therefore, combinations of mechanical stimuli have also been applied to cells in vitro. These studies have had varying focus-developing novel platforms to apply complex combinations of mechanical stimuli, observing the co-operation/competition between stimuli, combining benefits of multiple stimuli toward an application, or uncovering the underlying mechanisms of their action. In general, they provided new insights that could not have been predicted from previous knowledge. We present here a review of several such studies and the insights gained from them, thereby making a case for such studies to be continued and further developed.


Optimization of bacterial plasmid transformation using nanomaterials based on the Yoshida effect.
With the help of sepiolite, a unique method for transforming DNA into bacteria, based on the Yoshida effect, has been developed recently. However, we confronted many problems when this newest method was tried. Only a few transformants could be obtained even when 100 ng of plasmid pET15b was used, and a successful result seemed difficult to repeat. To address this problem, we optimized the operating method and could achieve about 15,000 transformants using the same amount of plasmid, which could match the efficiency gained using the calcium chloride transformation method. Meanwhile, the results could also be reproduced well. In the same way, carbon nanotubes were used to attain more than 15,000 transformants in the same situation. Therefore, the transformation method could be extended to other nanomaterials. Meanwhile, compared with the mechanism previously reported, we verified quite a different principle for the mechanism responsible for such a transformation. In sum, this unique transformation can be developed to become the third widely-used transformation method in laboratories in addition to the chemical method and electroporation.


Bibliometric analysis of scientific papers on adverse reactions to COVID-19 vaccines published between 2019 and 2023.
The Coronavirus Disease 2019 (COVID-19) pandemic has now persisted globally for four years, resulting in a staggering death toll of over 4 million individuals. The COVID-19 vaccine has emerged as a highly effective tool in controlling the spread of this virus. However, as the number of individuals receiving COVID-19. In this context, the investigation of adverse reactions related to COVID-19 vaccines holds paramount importance in relevant research. The purpose is to evaluate the current research status regarding adverse reactions associated with COVID-19 vaccines, offering insights for future research. A total of 3,746 articles were included in this analysis, and there has been a notable upward trajectory in the volume of published articles. The CiteSpace v6.1.R6, VOSviewer, SCImago Graphica, and Excel 2019 were employed to analyze and visualize the results. The institutions, countries, journals, authors, co-cited references, and keywords of these articles were analyzed. Furthermore, this study delves into the characteristics of articles on adverse reactions associated with COVID-19 vaccines. It was observed that the number of studies on COVID-19 vaccines has increased year by year since 2019 and witnessed a surge in output in 2021. The vast majority of studies have affirmed the overall safety of COVID-19 vaccines, with adverse reactions tending to be more concentrated in specific diseases. These findings provide valuable ideas for future research in this field and suggest the importance of strengthening international cooperation on adverse reactions to COVID-19 vaccines.


Chondro-Osseous Respiratory Epithelial Adenomatoid Hamartoma (COREAH): Case Report and Literature Review.
Chondro-osseous respiratory epithelial adenomatoid hamartoma (COREAH) is an extremely rare lesion of the nasal cavity with only 11 reported cases in the literature. COREAH is of interest as it may be easily mistaken for other diseases of the nasal cavity with higher morbidity, which require significantly different management strategies. We report, to the best of our knowledge, the oldest documented case of COREAH in the literature: an 83-year-old female who presented with headaches and was found to have a posterior nasal septal lesion. Uniquely, the patient had sequential scans performed 1 year apart demonstrating only minor interval growth. We describe our experience in managing a patient with COREAH and review the world literature, to better define aspects of the history, presentation, and investigations that may allow differentiation from more sinister disease.


Intracranial spread of squamous carcinoma along the trigeminal nerve.
Two patients with intracranial dissemination of squamous carcinoma along the trigeminal nerve had facial dysesthesias mistakenly diagnosed as tic douloureux. In one case, tumor originated in the skin of the lateral canthus and spread along an orbital nerve to involve the cavernous sinus and Gasserian ganglion. In the other, the primary site was the retromolar trigone, with preponderantly deep intraosseous growth. Perineural spread occurred along the inferior alveolar nerve to eventually involve the facial and the ocular motor nerves. Such neurotropic spread of tumors is unfamiliar to many clinicians, yet early diagnosis may be life-saving. If intracranial foramina have not been transgressed, surgery and radiotherapy have been curative; otherwise, treatment is largely palliative. Adequate initial treatment of the primary lesion would seem to be the best preventive measure. Treatment of recurrent lesions should include consideration of neural invasion.


Pharmacotherapy for methicillin-resistant Staphylococcus aureus nosocomial pneumonia.
To review the evidence for pharmacologic agents available in the treatment of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. A search of PubMed (1975-July 2012) was conducted using a combination of the terms methicillin-resistant Staphylococcus aureus, pneumonia, nosocomial, vancomycin, linezolid, telavancin, ceftaroline, tigecycline, and quinupristin/dalfopristin. Randomized comparative clinical trials, meta-analyses, and review articles published in English were included. A manual review of the bibliographies of available literature was conducted and all relevant information was included. Observational and in vitro studies were incorporated as indicated. Pharmacotherapy for the treatment of nosocomial MRSA pneumonia is limited. Vancomycin has been the treatment of choice for several years. Linezolid has demonstrated similar efficacy to vancomycin in randomized clinical trials and recent data have suggested that it may be superior in some cases, although there are limitations to this conclusion. Telavancin has also demonstrated similar clinical efficacy to vancomycin; however, the drug is not commercially available in the US. Other agents with MRSA activity include ceftaroline, clindamycin, quinupristin/dalfopristin, and tigecycline, although the evidence for their use in nosocomial pneumonia is limited. Based on the currently available evidence and cost-effectiveness, vancomycin should continue to be the drug of choice for most patients with nosocomial MRSA pneumonia. Linezolid is a reasonable alternative for patients with treatment failure while receiving vancomycin, isolates with vancomycin minimum inhibitory concentrations over 2 μg/mL, allergic reactions, or vancomycin-induced nephrotoxicity.


Acute Hypoxia Profile is a Stronger Prognostic Factor than Chronic Hypoxia in Advanced Stage Head and Neck Cancer Patients.
Hypoxic head and neck tumors respond poorly to radiotherapy and can be identified using gene expression profiles. However, it is unknown whether treatment outcome is driven by acute or chronic hypoxia. Gene expression data of 398 head and neck cancers was collected. Four clinical hypoxia profiles were compared to in vitro acute and chronic hypoxia profiles. Chronic and acute hypoxia profiles were tested for their association to outcome using Cox proportional hazard analyses. In an initial set of 224 patients, scores of the four clinical hypoxia profiles correlated with each other and with chronic hypoxia. However, the acute hypoxia profile showed a stronger association with local recurrence after chemoradiotherapy (p = 0.02; HR = 3.1) than the four clinical (chronic hypoxia) profiles (p = 0.2; HR = 0.9). An independent set of 174 patients confirmed that acute hypoxia is a stronger prognostic factor than chronic hypoxia for overall survival, progression-free survival, local and locoregional control. Multivariable analyses accounting for known prognostic factors substantiate this finding (p = 0.045; p = 0.042; p = 0.018 and p = 0.003, respectively). In conclusion, the four clinical hypoxia profiles are related to chronic hypoxia and not acute hypoxia. The acute hypoxia profile shows a stronger association with patient outcome and should be incorporated into existing prediction models.


The beat goes on: status of the artificial heart, 1977.
After two decades of continuous research on the artificial heart, survival times of experimental animals indicate that clinical application of such a device is definitely feasible. However, a number of problems remain to be solved. Durability of the device, infection, pannus formation at the interface between the device and natural tissue and thrombosis within the device appear to be the major problems. Development of an implantable power source is also an area of important research. Questions of efficiency, cosmetic and psychological acceptability and cost are just beginning to be considered.


Two Tickets to Paradise: Multiple Dispersal Events in the Founding of Hoary Bat Populations in Hawai'i.
The Hawaiian islands are an extremely isolated oceanic archipelago, and their fauna has long served as models of dispersal in island biogeography. While molecular data have recently been applied to investigate the timing and origin of dispersal events for several animal groups including birds, insects, and snails, these questions have been largely unaddressed in Hawai'i's only native terrestrial mammal, the Hawaiian hoary bat, Lasiurus cinereus semotus. Here, we use molecular data to test the hypotheses that (1) Hawaiian L. c. semotus originated via dispersal from North American populations of L. c. cinereus rather than from South American L. c. villosissimus, and (2) modern Hawaiian populations were founded from a single dispersal event. Contrary to the latter hypothesis, our mitochondrial data support a biogeographic history of multiple, relatively recent dispersals of hoary bats from North America to the Hawaiian islands. Coalescent demographic analyses of multilocus data suggest that modern populations of Hawaiian hoary bats were founded no more than 10 kya. Our finding of multiple evolutionarily significant units in Hawai'i highlights information that should be useful for re-evaluation of the conservation status of hoary bats in Hawai'i.


microRNA 21-mediated suppression of Sprouty1 by Pokemon affects liver cancer cell growth and proliferation.
Transcriptional repressor Pokemon is a critical factor in embryogenesis, development, cell proliferation, differentiation, and oncogenesis, thus behaving as an oncogene. Oncomine database suggests a potential correlation between the expressions of Pokemon and Sprouty1. This study investigated the regulatory role of Pokemon in Sprouty1 expression and the effect on liver cancer cell growth and proliferation, revealing a novel miR-21-mediated regulatory circuit. In normal (HL-7702) and cancer (QGY-7703) liver cell lines, Sprouty1 expression is inversely correlated with Pokemon levels. Targeted expression or siRNA-mediated silencing showed that Pokemon is a repressor of Sprouty1 expression at both mRNA and protein levels, but Pokemon cannot affect the promoter activity of Sprouty1. Sprouty1 is a target of miR-21 and interestingly, we found that miR-21 is up-regulated by Pokemon in liver cancer cells. Luciferase reporter assays showed that Pokemon up-regulated miR-21 transcription in a dose-dependent manner, and ChIP assay exhibited a direct binding of Pokemon to the miR-21 promoter at -747 to -399 bp. Site-directed mutagenesis of the GC boxes at -684 to -679 bp and -652 to -647 bp of miR-21 promoter abolished the regulatory activity by Pokemon. Furthermore, we found that the modulation of Pokemon and miR-21 expression affected the growth and proliferation of liver cancer cells QGY-7703. In summary, our findings demonstrate that Pokemon suppresses Sprouty1 expression through a miR-21-mediated mechanism, affecting the growth and proliferation of liver cancer cells. This study recognized miR-21 and Sprouty1 as novel targets of the Pokemon regulatory network.


The BCG controversy: a reappraisal of the protective effect against tuberculosis and leprosy.
BCG (Bacillus Calmette Guerin) vaccine remains a highly controversial method of preventing tuberculosis and leprosy despite more than eighty years of use. The protective effect against tuberculosis observed in various studies ranged from -56% to 98%. Case-control studies carried out at Nagpur reported moderate effectiveness of BCG vaccination in prevention of tuberculosis. Its effectiveness was higher against extra-pulmonary tuberculosis. The summary protective effects obtained from meta-analysis of trials, cohort studies and case-control studies of BCG vaccination and tuberculosis were 51 (33-64), 76 (63-85), and 65 (57-72) percent respectively. The case-control studies carried out at Nagpur also demonstrated a significant protective association between BCG vaccination and leprosy. The summary protective effects obtained from meta-analysis of trials, cohort studies and case-control studies of BCG vaccination and leprosy were 43 (27-55), 62 (53-69), and 59 (46-68) percent respectively. The results of the current study and systematic review thus supported arguments favoring use of BCG vaccine for prevention of tuberculosis and leprosy.


Chromosome compaction and chromatin stiffness enhance diffusive loop extrusion by slip-link proteins.
We use Brownian dynamics simulations to study the formation of chromatin loops through diffusive sliding of slip-link-like proteins, mimicking the behaviour of cohesin molecules. We recently proposed that diffusive sliding is sufficient to explain the extrusion of chromatin loops of hundreds of kilo-base-pairs (kbp), which may then be stabilised by interactions between cohesin and CTCF proteins. Here we show that the flexibility of the chromatin fibre strongly affects this dynamical process, and find that diffusive loop extrusion is more efficient on stiffer chromatin regions. We also show that the dynamics of loop formation are faster in confined and collapsed chromatin conformations but that this enhancement is counteracted by the increased crowding. We provide a simple theoretical argument explaining why stiffness and collapsed conformations favour diffusive extrusion. In light of the heterogeneous physical and conformational properties of eukaryotic chromatin, we suggest that our results are relevant to understand the looping and organisation of interphase chromosomes in vivo.


Early response of prostate carcinoma xenografts to docetaxel chemotherapy monitored with diffusion MRI.
For many anticancer therapies, it would be desirable to accurately monitor and quantify tumor response early in the treatment regimen. This would allow oncologists to continue effective therapies or discontinue ineffective therapies early in the course of treatment, and hence, reduce morbidity. This is especially true for second-line therapies, which have reduced response rates and increased toxicities. Previous works by others and ourselves have shown that water mobility, measured by diffusion-weighted magnetic resonance imaging (DW-MRI), increases early in tumors destined to respond to therapies. In the current communication, we further characterize the utility of DW-MRI to predict response of prostate cancer xenografts to docetaxel in SCID mice in a preclinical setting. The current data illustrate that tumor volumes and secreted prostate-specific antigen both respond strongly to docetaxel in a dose-responsive manner, and the apparent diffusion coefficient of water (ADC(w)) increases significantly by 2 days even at the lowest doses (10 mg/kg). The ADCw data were parsed by histogram analyses. Our results indicate that DW-MRI can be used for early detection of prostate carcinoma xenograft response to docetaxel chemotherapy.


Addiction to work and factors relating to this: a cross-sectional study on doctors in the state of Paraíba.
Addiction to work is one of the new behavioral phenomena present in organizations and it is characterized by excess work and compulsion to work. This phenomenon may give rise to different sicknesses and may affect different professionals, including doctors. Thus, the aims of this study were to analyze the factorial validity and internal consistency of the Dutch Work Addiction Scale (DUWAS); to evaluate the prevalence of addiction to work among doctors in the state of Paraíba; and to investigate factors relating to addiction to work among these doctors. This was an exploratory, descriptive cross-sectional study with a quantitative approach conducted in municipalities in the state of Paraíba. Data were gathered between June and October 2015, by applying a questionnaire containing sociodemographic questions and the Work Addiction Scale. The results showed that the Work Addiction Scale has internal consistency and factorial validity and that, in the population studied, only one factor was pointed out: addiction to work. Most of the doctors were not addicted to work; among the addicts, the addiction was not excessive; and the addiction had a positive correlation with the number of shifts done and a negative correlation with age. Greater attention to this phenomenon is required and further research on this topic is needed in order to elucidate the harm caused by addiction to work in daily medical practice.


Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat.
Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, which is suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18-fold in SHROB. The rate of insulin-stimulated 3-O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85 alpha regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation fak imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.


Pigmentary changes after alexandrite laser hair removal.
Postinflammatory pigmentary changes are a frequently encountered problem with numerous dermatologic procedures. Limited literature is available that documents this complication with laser hair removal. It is important for all physicians performing laser hair removal to be aware of this potential complication. We present our experience with postinflammatory pigmentary change and discuss some potential etiologic factors. Seven patients who experienced postinflammatory complications after alexandrite laser hair removal are presented. These are all the patients who developed this complication in our office over the past 2.5 years. The patients who we describe in this article all developed a similar pattern of initial hyperpigmented rings, later developing into a thin wafer-like crust followed by hypopigmentation with gradual return to their normal skin color. In general, the alexandrite laser is both safe and effective for hair removal in patients of varying skin types. Complication rates will increase as skin pigment increases and as the power used increases. However, even in light-skinned individuals without recent pretreatment or posttreatment sun exposure, with proper treatment parameters, complications, and side effects can arise. We have found this to be especially true when treating areas other than the face.


Subclassification of autoimmune pancreatitis: a histologic classification with clinical significance.
Autoimmune pancreatitis (AIP) is a chronic inflammatory disease of the pancreas. Examination of pancreatic resection specimens from patients with AIP has shown that there are 2 subclasses of this disease. However, there is no widely accepted pathologic classification scheme and the clinical significance of such a classification remains to be established. In this study, we revisited the subclassification of AIP and examine whether this provides clinically and prognostically meaningful information. We evaluated 29 pancreatic resection specimens from patients with AIP. Demographic, clinical, and imaging data were recorded, as was evidence of extrapancreatic manifestations. In addition to a detailed and semiquantitative histologic evaluation, immunohistochemistry for IgG4 was performed on pancreatic and extrapancreatic tissues. We also evaluated 48 consecutive cases of chronic pancreatitis, not otherwise specified. The resected specimens could readily be subclassified into 2 subtypes: type 1 (n=11) and type 2 (n=18). In comparison with patients with type 2 disease, patients with type 1 disease were significantly more likely to be males (P=0.09), older (P=0.02), and present with jaundice (P=0.01), and less likely to be associated with abdominal pain (P=0.04). On imaging, the pancreatic tail cut-off sign was exclusively seen in patients with type 2 disease (4 of 10 cases). Hypercellular inflamed interlobular stroma was unique to type 1 pattern (91%), whereas significant ductal injury in the form of microabscesses and ductal ulceration was almost exclusively seen in type 2 pattern (78%). Eight of 10 patients with a type 1 pattern had evidence of a systemic disease. Three patients with type 2 disease had recurrent episodes of pancreatitis after their pancreatic resection. In comparison with the cohort of chronic pancreatitis, not otherwise specified, type 2 AIP cases were less likely to be associated with a history of alcohol abuse, and showed significantly more foci of periductal inflammation and neutrophilic microabscesses. Our review of pancreatic resection specimens shows 2 histologically distinct forms of AIP. Our data support the concept that type 1 AIP is a systemic disease and is the pancreatic manifestation of IgG4-related systemic disease. Type 2 disease is confined to the pancreas. The intensity of the periductal inflammatory infiltrate and the presence of ductal neutrophilic abscesses are features that assist in distinguishing type 2 AIP from chronic pancreatitis, not otherwise specified. Although imperfect, clinical and imaging features may help distinguish the 2 subtypes of AIP. On the basis of these significant differences between the 2 types of AIP, we advocate the position that all subsequent studies attempt to substratify their patients into these 2 groups.


Application of carboxymethyl cellulose sodium (CMCNa) in maize-wheat cropping system (MWCS) in coastal saline-alkali soil.
Sodium carboxymethyl cellulose (CMCNa) application has been a promising approach to improve soil quality. The purpose of this study was to explore the effects of CMC-Na on soil infiltration, evaporation, water-salt distribution, crop growth, water use efficiency and net profit (Net) in a coastal saline-alkali soil maize-wheat cropping system (MWCS). Five CMC-Na application amounts (0, 0.1, 0.2, 0.4 and 0.6 g kg-1) were designed for the soil column experiment indoor, and five CMC-Na application amounts were used in 2019-2020 field experiment (CK: 0, C10: 10 kg ha-1, C20: 10 kg ha-1, C30: 10 kg ha-1 and C50: 10 kg ha-1), No treatment will be applied in 2021. The results showed that (1) CMC-Na treatment reduced soil cumulative infiltration, infiltration rate, daily evaporation, and cumulative evaporation. (2) After the application of CMCNa, the average soil water storage (SWS) in the 0-60 cm soil layer increased, and soil salinity (SSC) decreased in most treatments. (3) In the 2019-2020, the maize aboveground biomass (B), yield (Y) and water use efficiency (WUE) were the highest under the C20 and C30 treatments, which were 15.24 and 15.32 t ha-1, 5.67 and 5.49 t ha-1 and 1.74 and 1.52 kg ha-1 mm-1, respectively, and the wheat under C30 treatment is the highest, which were 10.98 t ha-1, 5.27 t ha-1 and 1.78 kg ha-1 mm-1. (4) A dose of 25.5 kg ha-1 and 38.9 kg ha-1 was recommended as the most optimal CMC-Na application for maize and wheat in coastal saline alkali soil, respectively.


Generalization of treatment: a multicontext approach to cognitive perceptual impairment in adults with brain injury.
Cognitive perceptual remedial approaches used by occupational therapists in the treatment of adults with brain injury have been criticized because of claims that the effects are not generalizable. Little information is available, however, that can guide the therapist in directly addressing the generalization process. This paper proposes a multicontext treatment approach that uses five components identified in the cognitive psychology literature as being critical to the process of generalization: (a) use of multiple environments, (b) identification of criteria for transfer, (c) metacognitive training, (d) emphasis on processing strategies, and (e) use of meaningful activities. A case report is used to illustrate this treatment approach.


Analysis of genes under the downstream control of the t(8;21) fusion protein AML1-MTG8: overexpression of the TIS11b (ERF-1, cMG1) gene induces myeloid cell proliferation in response to G-CSF.
The AML1-MTG8 fusion transcription factor generated by t(8;21) translocation is thought to dysregulate genes that are crucial for normal differentiation and proliferation of hematopoietic progenitors to cause acute myelogenous leukemia (AML). Although AML1-MTG8 has been shown to repress the transcription of AML1 targets, none of the known targets of AML1 are probably responsible for AML1-MTG8-mediated leukemogenesis. In this study, 24 genes under the downstream control of AML1-MTG8 were isolated by using a differential display technique. Analysis with deletion mutants of AML1-MTG8 demonstrated that the regulation of the majority of these genes requires the region of 51 residues (488-538) containing the Nervy homology region 2 (NHR2), through which AML1-MTG8 interacts with MTGR1. Among the 24 genes identified, 10 were considered to be genes under the control of AML1, because their expression was altered by AML1b or AML1a or both. However, the other 14 genes were not affected by either AML1b or AML1a, suggesting the possibility that AML1-MTG8 regulates a number of specific target genes that are not normally regulated by AML1. Furthermore, an up-regulated gene, TIS11b (ERF-1, cMG1), was highly expressed in t(8;21) leukemic cells, and the overexpression of TIS11b induced myeloid cell proliferation in response to granulocyte colony-stimulating factor. These results suggest that the high-level expression of TIS11b contributes to AML1-MTG8-mediated leukemogenesis. (Blood. 2000;96:655-663)


Rehabilitation in HIV/AIDS: development of an expanded conceptual framework.
In industrialized countries where HIV infection is becoming a chronic, episodic condition, rehabilitation services have the potential to play an expanded role for people living with HIV/AIDS (PLHAs). However, little is known about rehabilitation in the context of HIV. This paper documents the development of an enhanced, multidisciplinary conceptual framework of rehabilitation in the context of HIV, using the perceptions of PLHAs and rehabilitation professionals. Rehabilitation, broadly defined, is a dynamic process that includes all prevention and/or treatment activities and/or services that address body impairments, activity limitations and participation restrictions for an individual. The framework was developed through broad consultation and interviews with thirteen key informants. Themes that emerged from analysis of interviews related to concepts of rehabilitation in the context of HIV, rehabilitation professionals' roles in the context of HIV, and barriers to access and delivery of rehabilitation services. While there was some variation, key informants generally viewed rehabilitation as a goal-oriented and client-centered process with the potential to impact a range of life domains. Themes were presented to members of a national advisory committee (including PLHAs and health care providers), who produced the foundation of the HIV rehabilitation framework. The framework uses the perspective of the person living with HIV/AIDS, and includes individual life domains that may be affected by HIV, drawing and expanding upon the World Health Organization's (WHO's) International Classification of Functioning, Disability and Health.


[Plasma levels of cytokines in patients with active infiltrative pulmonary tuberculosis].
The levels of interferon-y (IFN-gamma), tumor necrosis factor-gamma (TNF-alpha), and interleukin-8 (IL-8) and their changes during chemotherapy and laser chemotherapy were studied in 97 patients with active infiltrative pulmonary tuberculosis, by taking into account Mycobacterium tuberculosis (MBT) sensitivity to chemical agents. The studies have indicated that the levels of IFN-gamma, TNF-alpha, and IL-8 are increased and may be markers of an active process. Chemotherapy causes a reduction in increased cytokinemia. Complex laser chemotherapy affects the cytokine profile in active tuberculosis caused by not only drug-sensitive, but also drug-resistant MBT.


The structure and interactions of human apolipoprotein C-II in dodecyl phosphocholine.
The structure of human apolipoprotein C-II (apoC-II) in the presence of dodecyl phosphocholine (DPC) micelles has been investigated by NMR spectroscopy. The resulting structural information is compared to that available for apoC-II in the presence of sodium dodecyl sulfate, revealing a high level of overall similarity but several significant differences. These findings further our understandings of the structural basis for apoC-II function. The interactions of the protein with the detergent micelle are probed using intermolecular nuclear Overhauser effects (NOEs) and paramagnetic agents. These interactions are seen across almost the full length of apoC-II and show the periodicity expected for an amphipathic helix interacting with the amphipathic surface of the DPC micelle. Furthermore, we observe specific contacts between lysine residues of apoC-II and protons near the phosphate group of DPC, consistent with the predictions of the so-called "snorkel hypothesis" of the structural basis for the apolipoprotein/lipid interaction (Segrest, J. P., Jackson, R. L., Morrisett, J. D., and Gotto, A. M., Jr. (1974) A molecular theory of lipid-protein interactions in the plasma lipoproteins, FEBS Lett 38, 247-258.). These findings offer the most detailed structural information available for the interaction between an apolipoprotein and the phospholipids of the lipoprotein surface and provide the first direct structural support for the snorkel hypothesis.


Elevation of vacuolar pH inhibits the cytotoxic activity of furin-cleaved exotoxin A.
Exotoxin A (ETA) inhibits protein synthesis in cells by a process that involves receptor-mediated endocytosis and the transport of a 37-kDa proteolytic fragment across a membrane into the cytoplasm. The fragment is apparently generated by the endoprotease furin after the toxin has been endocytosed. Cleavage of ETA by furin requires a low pH in vitro, and presumably also in vivo. Drugs that raise the pH of intracellular compartments are known to protect cells from ETA. The simplest hypothesis to explain this protection has been that the drugs interfere with furin cleavage. To test this idea, we measured the effect of pH-elevating drugs on the action of ETA that had been precleaved with recombinant furin before addition to cells. Surprisingly, we found that pH-elevating drugs protected cells from precleaved ETA as well as intact ETA. These results suggest that the process by which ETA intoxicates cells requires a low vacuolar pH for another event in addition to proteolysis by furin.


A quantitative proteomic response of hepatocellular carcinoma Hep3B cells to danusertib, a pan-Aurora kinase inhibitor.
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, but the overall prognosis remains disappointing especially in the advanced-stage patients. Aberration expression of Aurora kinases is tumorigenic and thus it has attracted interests as therapeutic targets in cancer treatment. Here, we investigated the proteomic response of HCC Hep3B cells to danusertib (Danu), a pan-Aurora kinase inhibitor, and then validated the proteomic results based on stable-isotope labeling by amino acids in cell culture (SILAC). The proteomic data identified that Danu modulated the expression of 542 protein molecules (279 up-regulated; 260 down-regulated; 3 stable). Ingenuity pathway analysis (IPA) and KEGG pathway analysis identified 107 and 24 signaling pathways were regulated by Danu, respectively. IPA analysis showed cellular growth and proliferation, and cell death and survival were among the top five molecular and cellular functions regulated by Danu. The verification experiments showed that Danu inhibited the proliferation of Hep3B cells with a 24-hr IC50 value of 22.03 µM. Danu treatment also arrested Hep3B cells in G2/M phase via regulating the expression of key cell cycle regulators and induced apoptosis via mitochondria-dependent pathway in a dose-dependent manner. Besides, Danu induced a marked autophagy, and inhibition of autophagy enhanced the anticancer effects of Danu, indicating a cyto-protective role of Danu-induced autophagy. Our proteomic data and Western blotting assays showed the PI3K/Akt/mTOR signaling pathway was involved in the inducing effect of Danu on apoptosis and autophagy. Collectively, our findings have demonstrated that the Aurora kinases inhibition with danusertib results in global proteomic response and exerts anticancer effects in Hep3B cells involving regulation of cell cycle, apoptosis and autophagy and associated signaling pathways.


Upregulated BclG(L) expression enhances apoptosis of peripheral blood CD4+ T lymphocytes in patients with systemic lupus erythematosus.
Increased lymphocyte apoptosis has been suggested to contribute to the development of systemic lupus erythematosus (SLE), but the critical factors involved in the apoptotic pathways are still unknown. By long serial analysis of gene expression (LongSAGE) profiles and microarray analyses, a novel apoptosis-related gene BclG(L) expression was found significantly increased in peripheral blood CD4+ T cells of SLE patients, which was correlated with the enhanced CD4+ T cells apoptosis, anti-nuclear antibody (ANA) titer and proteinuria. In vitro, BclG(L) expression could be specially upregulated by SLE serum stimulation and positively correlated with induced CD4+ T cell apoptosis. Enforcing BclG(L) overexpression by lentivirus could directly enhance CD4+ T cell apoptosis, but these apoptosis-inducing effects could be partially inhibited by knockdown of BclG(L) expression. Collectively, these results indicate that increased BclG(L) expression may contribute to the aberrant CD4+ T cell apoptosis which causes an inappropriate immune response and impaired homeostasis in SLE.


The inhibitory effect of essential oils on herpes simplex virus type-1 replication in vitro.
The antiviral effect of 12 essential oils on herpes simplex virus type-1 (HSV-1) replication was examined in vitro. The replication ability of HSV-1 was suppressed by incubation of HSV-1 with 1% essential oils at 4 C for 24 hr. Especially, lemongrass completely inhibited the viral replication even at a concentration of 0.1%, and its antiviral activity was dependent on the concentrations of the essential oil. When Vero cells were treated with the essential oil before or after viral adsorption, no antiviral activity was found, which suggests that the antiviral activity of essential oils including lemongrass may be due to the direct interaction with virions.


Peripheral arterial thrombosis due to the nephrotic syndrome: the clinical spectrum.
We reviewed the literature concerning arterial thromboses associated with the nephrotic syndrome and the hypercoagulable state. An illustrative case of peripheral arterial thrombosis and pulmonary emboli attributed to the hypercoagulable state of the nephrotic syndrome is included. In our patient, serum levels of antithrombin III, plasminogen, factor VII activity, factor VIII activity, and factor VIII antigen were abnormal. Arterial thromboses in patients with the nephrotic syndrome are often associated with steroid and diuretic use. In pediatric patients, a predisposing factor may be femoral venipuncture.


Customization Methodology for Conformable Grasping Posture of Soft Grippers by Stiffness Patterning.
Soft grippers with soft and flexible materials have been widely researched to improve the functionality of grasping. Although grippers that can grasp various objects with different shapes are important, a large number of industrial applications require a gripper that is targeted for a specified object. In this paper, we propose a design methodology for soft grippers that are customized to grasp single dedicated objects. A customized soft gripper can safely and efficiently grasp a dedicated target object with lowered surface contact forces while maintaining a higher lifting force, compared to its non-customized counterpart. A simplified analytical model and a fabrication method that can rapidly customize and fabricate soft grippers are proposed. Stiffness patterns were implemented onto the constraint layers of pneumatic bending actuators to establish actuated postures with irregular bending curvatures in the longitudinal direction. Soft grippers with customized stiffness patterns yielded higher shape conformability to target objects than non-patterned regular soft grippers. The simplified analytical model represents the pneumatically actuated soft finger as a summation of interactions between its air chambers. Geometric approximations and pseudo-rigid-body modeling theory were employed to build the analytical model. The customized soft grippers were compared with non-patterned soft grippers by measuring their lifting forces and contact forces while they grasped objects. Under the identical actuating pressure, the conformable grasping postures enabled customized soft grippers to have almost three times the lifting force than that of non-patterned soft grippers, while the maximum contact force was reduced to two thirds.


Toxicokinetics of intravenous methanol in the female rat.
The toxicokinetics of intravenously administered methanol were examined in female Sprague-Dawley rats. Animals received a single administration of 100, 500, or 2500 mg methanol/kg; the two lower doses were administered as a bolus, while the high dose was administered over 1.5 min. A small (approximately 3%) but statistically insignificant (p > 0.1) degree of transpulmonary methanol extraction, expressed as the fractional arterial-venous difference in concentration, was observed after administration of 250 mg methanol/kg. The elimination of methanol from the systemic circulation was markedly nonlinear, suggestive of a significant capacity-limited route of elimination. A single set of kinetic parameters (apparent distributional volume of the central compartment [Vc], intercompartmental transfer rate constants [k12 and k21], and Vmax and Km for elimination) described the blood methanol concentration-time data from rats receiving the 100 and 500 mg/kg doses. Blood methanol concentrations declined much more rapidly in animals receiving the 2500 mg/kg dose than would be predicted from the kinetic parameters derived from the other two experimental groups. The data from the 2500 mg/kg group could be described adequately by a kinetic model incorporating parallel first-order and saturable elimination processes. A portion of this apparent linear elimination pathway was due to renal excretion of the unchanged alcohol. The presence of both linear and nonlinear elimination pathways for methanol may have implications regarding high-dose to low-dose toxicologic extrapolations.


Pelvis morphology, trunk posture and standing imbalance and their relations to the Cobb angle in moderate and severe untreated AIS.
Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis and usually affects young girls. Studies mostly describe the differences between scoliotic and non-scoliotic girls and focus primarily on a single set of parameters derived from spinal and pelvis morphology, posture or standing imbalance. No study addressed all these three biomechanical aspects simultaneously in pre-braced AIS girls of different scoliosis severity but with similar curve type and their interaction with scoliosis progression. The first objective of this study was to test if there are differences in these parameters between pre-braced AIS girls with a right thoracic scoliosis of moderate (less than 27°) and severe (more than 27°) deformity. The second objective was to identify which of these parameters are related to the Cobb angle progression either individually or in combination of thereof. Forty-five scoliotic girls, randomly selected by an orthopedic surgeon from the hospital scoliosis clinic, participated in this study. Parameters related to pelvis morphology, pelvis orientation, trunk posture and quiet standing balance were measured. Generally moderate pre-brace idiopathic scoliosis patients displayed lower values than the severe group characterized by a Cobb angle greater than 27°. Only pelvis morphology and trunk posture were statistically different between the groups while pelvis orientation and standing imbalance were similar in both groups. Statistically significant Pearson coefficients of correlation between individual parameters and Cobb angle ranged between 0.32 and 0.53. Collectively trunk posture, pelvis morphology and standing balance parameters are correlated with Cobb angle at 0.82. The results suggest that spinal deformity progression is not only a question of trunk morphology distortion by itself but is also related to pelvis asymmetrical bone growth and standing neuromuscular imbalance.


Dynamin 1 Restrains Vesicular Release to a Subquantal Mode In Mammalian Adrenal Chromaffin Cells.
Dynamin 1 (dyn1) is required for clathrin-mediated endocytosis in most secretory (neuronal and neuroendocrine) cells. There are two modes of Ca2+-dependent catecholamine release from single dense-core vesicles: full-quantal (quantal) and subquantal in adrenal chromaffin cells, but their relative occurrences and impacts on total secretion remain unclear. To address this fundamental question in neurotransmission area using both sexes of animals, here we report the following: (1) dyn1-KO increased quantal size (QS, but not vesicle size/content) by ≥250% in dyn1-KO mice; (2) the KO-increased QS was rescued by dyn1 (but not its deficient mutant or dyn2); (3) the ratio of quantal versus subquantal events was increased by KO; (4) following a release event, more protein contents were retained in WT versus KO vesicles; and (5) the fusion pore size (dp) was increased from ≤9 to ≥9 nm by KO. Therefore, Ca2+-induced exocytosis is generally a subquantal release in sympathetic adrenal chromaffin cells, implying that neurotransmitter release is generally regulated by dynamin in neuronal cells.SIGNIFICANCE STATEMENT Ca2+-dependent neurotransmitter release from a single vesicle is the primary event in all neurotransmission, including synaptic/neuroendocrine forms. To determine whether Ca2+-dependent vesicular neurotransmitter release is "all-or-none" (quantal), we provide compelling evidence that most Ca2+-induced secretory events occur via the subquantal mode in native adrenal chromaffin cells. This subquantal release mode is promoted by dynamin 1, which is universally required for most secretory cells, including neurons and neuroendocrine cells. The present work with dyn1-KO mice further confirms that Ca2+-dependent transmitter release is mainly via subquantal mode, suggesting that subquantal release could be also important in other types of cells.


Epilepsy: Is there hope?
Epilepsy is a highly prevalent chronic neurologic disorder and leads to social, behavioural, health and economic consequences. 'Treatment gap' varies from 10 per cent in developed countries to 75 per cent in low-income countries. Stigma and discrimination related to epilepsy are prevalent worldwide. Electroencephalography (EEG) is considered the most important tool for evaluating the patient with epilepsy. Video-EEG monitoring is an important tool for confirming the seizure type and estimating the epileptogenic zone in the brain. Neuroimaging evaluation is important to determine the aetiology of the epilepsies. Genetic testing has increased the probability of identifying the causes of some types of epilepsies. Epilepsy can be treated in an affordable way with low-cost medications. Refractory epilepsies occur in approximately one-third of recently diagnosed patients with epilepsy. For this group of patients, there are options of surgical treatment, diets and neurostimulation to improve seizure control and quality of life. In poorly organized societies, there is a lack of prioritization of epilepsy in national health policies, limited resources for trained personnel and a shortage of basic antiepileptic medications. There is evidence of improvement in the understanding of epilepsy and a clear progress in the management of epileptic seizures in recent times.


Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice.
Breast cancer cells modulate lipid and fatty acid metabolism to sustain proliferation. The role of adipocytes in cancer treatment efficacy remains, however, to be fully elucidated. We investigated whether diet-induced obesity (DIO) affects the efficacy of doxorubicin treatment in a breast tumor-bearing mouse model. Female C57BL6 mice were fed a high fat or low fat diet for the full duration of the study (12 weeks). After 8 weeks, mice were inoculated with E0771 triple-negative breast cancer cells in the fourth mammary gland to develop breast tumor allographs. Tumor-bearing mice received either vehicle (Hank's balanced salt solution) or doxorubicin (chemotherapy). Plasma inflammatory markers, tumor, and mammary adipose tissue fatty acid composition, as well as protein expression of lipid metabolism markers were determined. The high fat diet (HFD) attenuated the treatment efficacy of doxorubicin. Both leptin and resistin concentrations were significantly increased in the HFD group treated with doxorubicin. Suppressed lipogenesis (decreased stearoyl CoA-desaturase-1) and lipolysis (decreased hormone-sensitive lipase) were observed in mammary adipose tissue of the DIO animals, whereas increased expression was observed in the tumor tissue of doxorubicin treated HFD mice. Obesogenic conditions induced altered tissue fatty acid (FA) compositions, which reduced doxorubicin's treatment efficacy. In mammary adipose tissue breast cancer cells suppressed the storage of FAs, thereby increasing the availability of free FAs and favored inflammation under obesogenic conditions.


Estimating urea volume in amputees on peritoneal dialysis by modified anthropometric formulas.
Body composition determines body water content (the fraction body water/body weight). With developing obesity, body weight and body water increase, but body water content decreases. The anthropometric formulas for urea volume (body water) for Kt/V computations in nonamputated peritoneal dialysis subjects reflect this fundamental rule of body composition. However, the use of uncorrected anthropometric formulas in amputees provides body water content estimates inconsistent with the estimates of body composition obtained from nutritional assessment. Corrected estimates of urea volume can be obtained in three steps: (1) The non-amputated weight at the same body composition is computed by dividing the weight at the urea kinetic study (postamputation) by (1-the fractional weight loss from the amputation); (2) body water and body water content at this nonamputated weight are obtained from the appropriate anthropometric formula; (3) at the time of the urea kinetic study, post-amputation, body water is equal to the estimate of body water content obtained from step 2 times the body weight at the urea kinetic study. The corrected estimates of urea volume provide body water content values agreeing with the estimates from nutritional assessment.


Assessment of antianginal efficacy of long-acting sustained release isosorbide dinitrate in comparison with short-acting isosorbide dinitrate.
A quadruple blind randomized cross-over study evaluated the therapeutic efficacy of twice a day long acting sustained release isosorbide dinitrate (SRISDN) in comparison with 4 times daily of the short acting isosorbide dinitrate in 18 patients with stable angina pectoris (NYHA class II-III) with a positive exercise treadmill test. The antianginal effect of sustained release isosorbide dinitrate (SRISDN) (exercise duration 472.61 +/- 112.49 sec and anginal episodes per week (1.33 +/- 1.18) was not significantly different (p less than 0.05) when compared to conventional isosorbide dinitrate (exercise duration 468.33 +/- 135.28 sec and anginal episodes per week 1.55 +/- 104). Twice a day long acting sustained release isosorbide dinitrate is as effective as four times a day conventional short acting isosorbide dinitrate. Such a regimen is likely to lead to a better patient compliance and ease of antianginal therapy.


Differential fitness of mitochondrial DNA in perturbation cage studies correlates with global abundance and population history in Drosophila simulans.
Mitochondria are often referred to as the powerhouse of the cell. However, research linking intraspecific differences in organismal fitness with genotypic mitochondrial DNA (mtDNA) variation has been hampered by the lack of variation in experimentally tractable species. This study examines whether fly lines harbouring three distinct Drosophila simulans mtDNA types (siI, -II and -III) exhibit differential fitness in laboratory perturbation cages. Comparison of the pre-perturbation and post-perturbation data shows that both the mtDNA and mitonuclear interactions have a significant and repeatable effect on the frequency of flies with specific genotypes in population cages (siII > -III > -I) and that coadapted mitonuclear interactions are greatest in the siI type. The rank order of mtDNA frequency correlates with the observed worldwide distribution of the haplogroups while mitonuclear interactions are most significant in the siI haplogroup that is likely to have been subject to repeated population bottlenecks. One possible explanation for the maintenance of the least fit siI haplogroup on Pacific islands is that it is protected from extinction by Wolbachia infection.


Esophageal dysphagia in neuromuscular disorder patients with validity and reliability study of the brief esophageal dysphagia questionnaire.
Esophageal dysphagia (ED) is often underestimated in neuromuscular disorders (NMD) and it is important to evaluate the esophageal phase of swallowing with an easy and rapid screening test. We aimed both to assess the prevalence of ED in NMD and to perform validity and reliability study of the brief easophageal dysphagia questionnaire (BEDQ) screening test in NMD patients. This prospective cross-sectional clinical study was performed on NMD patients. Demographic features and disease characteristics were recorded. Endoscopic evaluation for oropharyngeal dysphagia (OD) and high-resolution esophageal manometry for ED were performed. In addition, the BEDQ and the 10-item eating assessment tool (EAT-10) were used to all subjects. Cronbach's α and principle components factor analysis (PFCA) with varimax rotation were used for reliability. The Chicago Classification version 3 (CCv3) level (high-resolution esophageal manometry) and EAT-10 was used for validity. A total of 50 patients were included in the study. Thirty-four (68%) patients were diagnosed with myasthenia gravis and 16 (32%) patients were diagnosed with myopathy. Esophageal dysphagia according to the CCv3 was found in 33 (66%) of patients. While the Cronbach's α was excellent as 0.937 for test overall the T-BEDQ scale. The PCFA included all scale items and resulted in a single factor (eigenvalue = 5.72, 71.5%). The all BEDQ scores were demonstrated good correlation with EAT-10 score and very good correlation with CCv3 level. Evaluation of swallowing in patients with NMD should include not only the oropharyngeal phase of swallowing, but also esophageal phase. For this purpose, the BEDQ can be used as a rapid, valid, and reliable test for the evaluation of ED.


Time to Sputum Smear Conversion in Smear-Positive Pulmonary Tuberculosis Patients and Factors for Delayed Conversion.
Pulmonary tuberculosis is a common infection worldwide. In the eastern part of Iran, fluctuations in tuberculosis prevalence are seen due to the migration of people from Afghanistan. The aim of this study was to evaluate the time of bacteriologic sputum conversion after treatment and affecting factors in those whose smear does not become negative. This study was carried out on 85 smear-positive pulmonary tuberculosis patients with the mean age of 65.6±16.7 years. There were 38 male patients (44.7%), 47 urban residents (55.3%), and only 6 patients (7.1%) from Afghanistan. The mean time of sputum conversion after starting treatment was 1.99±1.06 months. The mean time of sputum conversion was significantly higher in males (P=0.046), increased bacilli density in the primary sputum sample (P<0.0001, R=0.507), and pre-existing medical illness (P=0.001). In this study, it was revealed that pre-existing illness, bacilli density in initial smear, and severe involvement of the lung on radiography, could be associated with delay in sputum smear conversion.


Aetiology of cerebrospinal fluid rhinorrhoea in a Dutch retrospective cohort from two tertiary referral centres.
Cerebrospinal fluid (CSF) rhinorrhoea has different aetiologies, with spontaneous leaks related to female gender and obesity. Limited data is available on patient characteristics and surgical outcomes across different aetiologies of CSF leaks in relatively non-obese populations. Retrospective cohort study from two tertiary referral centres including adult patients that underwent surgical closure of a CSF leak, divided into four aetiologies: traumatic, iatrogenic, secondary to structural intracranial pathology (SIP), and spontaneous. Data included patient characteristics, presenting symptoms, preoperative radiologic findings, intracranial pressure (ICP) and surgical outcomes. 72 patients were included: 9 traumatic, 15 iatrogenic, 4 SIP and 44 spontaneous leaks. Primary surgical success was 79%, rising to 93% with reinterventions. Spontaneous leak cases displayed highest female proportion and BMI. A meningo(-encephalo)cele was present in 33 patients and was associated with surgical failure and previous meningitis. No significant differences were observed between different aetiologies regarding patient characteristics, presenting symptoms, or surgical success rates. Even in a relatively non-obese population, the majority of CSF leaks is spontaneous and associated with female gender and obesity. Otherwise, no differences exist across aetiologies regarding patient characteristics, presenting symptoms or surgical success.