Inhibition of binding of benzo(a)pyrene to DNA by 7,8-benzoflavone in organ cultures of human bronchus.
Levels of binding of exogeneously added benzo(a)pyrene to DNA in organ culture were examined in nine specimens of normal human bronchus obtained by bronchoscopy of tumor patients. The specimens were divided into two portions and incubated with [3H]benzo(a)pyrene in the absence or presence of 2 microM 7,8-benzoflavone for 24 h. 7,8-benzoflavone inhibited [3H]benzo(a)pyrene-DNA binding from 24 to 60%. Generally, the levels of binding of [3H]benzo(a)pyrene to DNA in the presence of 7,8-benzoflavone were relatively low and closely bracketed the mean value for the nine specimens. This appears to indicate that there are at least two components to [3H]benzo(a)pyrene-DNA binding catalyzed by the human bronchus. One component is quite variable in activity and is sensitive to inhibition by 7,8-benzoflavone, and may be an environmentally induced activity. The second component is lower in activity, and may be a constitutive portion of the mixed-function oxidase.


II. Methods and measures used for follow-up at 15 years of the English and Romanian Adoptee (ERA) study.
This chapter covers the methods and measures used in the ERA study, with a special focus on age 15 outcomes. First, we outline the sample participation rate for the 15-year follow-up-the percentages in all cases referring to the numbers at the time of initial sample contact. We then describe the measures used in this monograph, starting with those obtained at first contact with respect to functioning at the time of leaving institutional care. Because the group definitions relevant to the follow-up at age 15 are based on assessments at 6 and 11 years of age, we deal with the measures in those assessments first. At 11 years of age, we used a range of specific cognitive tests that might be of predictive value and those are detailed next. Then we discuss measures employed at the 15-year follow-up and those relevant to possible autism as used by Rutter in the separate assessment at 18-20 years. The monograph is structured around the possibility of deprivation-specific psychological patterns (DSPs), and hence on the strategies needed to test for them (see Rutter et al. in chapter I). Accordingly, the next section of this chapter deals with that strategy and details the measures taken to test the assumption's underlying the strategy. In our published papers concerning the 11-year follow-up, we tested whether outcomes were affected by the fact that some parents adopted mainly for altruistic reasons and others because of infertility-affected outcomes. Here we repeat this analysis in relation to DSPs. Similarly, we report findings on gender differences. The longitudinal study involved obtaining DNA for genotyping to examine the possibility that genetic features moderated the young people's response to institutional deprivation. Accordingly, in the next section of the chapter, we outline our genotyping approach. The final section of this chapter describes the statistical techniques we employed in our analyses.


Prevalence of birth defects among infants of Gulf War veterans in Arkansas, Arizona, California, Georgia, Hawaii, and Iowa, 1989-1993.
Epidemiologic studies of birth defects among infants of Gulf War veterans (GWV) have been limited to military hospitals, anomalies diagnosed among newborns, or self-reported data. This study was conducted to measure the prevalence of birth defects among infants of GWVs and nondeployed veterans (NDV) in states that conducted active case ascertainment of birth defects between 1989-93. Military records of 684,645 GWVs and 1,587,102 NDVs were electronically linked with 2,314,908 birth certficates from Arizona, Hawaii, Iowa, and selected counties of Arkansas, California, and Georgia; 11,961 GWV infants and 33,052 NDV infants were identified. Of these, 450 infants had mothers who served in the Gulf War, and 3966 had NDV mothers. Infants conceived postwar to male GWVs had significantly higher prevalence of tricuspid valve insufficicieny (relative risk [RR], 2.7; 95% confidence interval [CI], 1.1-6.6; p = 0.039) and aortic valve stenosis (RR, 6.0; 95% CI, 1.2-31.0; p = 0.026) compared to infants conceived postwar to NDV males. Among infants of male GWVs, aortic valve stenosis (RR, 163; 95% CI, 0.09-294; p = 0.011) and renal agenesis or hypoplasia (RR, 16.3; 95% CI, 0.09-294; p = 0.011) were significantly higher among infants conceived postwar than prewar. Hypospadias was significantly higher among infant sons conceived postwar to GWV women compared to NDV women (RR, 6.3; 95% CI, 1.5-26.3; p = 0.015). We observed a higher prevalence of tricuspid valve insufficiency, aortic valve stenosis, and renal agenesis or hypoplasia among infants conceived postwar to GWV men, and a higher prevalence of hypospadias among infants conceived postwar to female GWVs. We did not have the ability to determine if the excess was caused by inherited or environmental factors, or was due to chance because of myriad reasons, including multiple comparisons. Although the statistical power was sufficient to compare the combined birth defects prevalence, larger sample sizes were needed for less frequent individual component defects.


Synthesis and activity of analogues of SB-219383: novel potent inhibitors of bacterial tyrosyl tRNA synthetase.
SB-219383 is a naturally occurring antibiotic, which acts by inhibition of tyrosyl tRNA synthetase. Semi-synthetic derivatives of SB-219383 were prepared with the objective of elucidating the key features required for inhibition of tyrosyl tRNA synthetase in order to improve the antibacterial activity. Some ester and amide derivatives as well as monocyclic analogues exhibited sub-nanomolar inhibitory activity against tyrosyl tRNA synthetase.


Asymmetric dimethyl-arginine metabolism in a murine model of cigarette smoke-mediated lung inflammation.
There is increasing evidence that the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethyl-arginine (ADMA) is involved in the pathogenesis of chronic lung diseases. One important regulator of this molecule is the ADMA-metabolizing enzyme dimethyl-arginine dimethyl-aminohydrolase (DDAH). The objective of this study was to determine whether perturbation of the ADMA-DDAH pathway contributes to lung inflammation following exposure to cigarette smoke (CS). For these studies, wild-type and DDAH transgenic mice were sham or CS-exposed. Serum ADMA levels were determined by mass spectrometry. ADMA content and DDAH expression were also visualized in mouse lung tissue by immunohistochemistry. DDAH expression was determined by real-time quantitative PCR (qPCR). Inflammation was assessed by H&E staining and analyses of total cell counts and fluid tumor necrosis factor (TNF)-α levels (using ELISA) in lung lavage fluid. NF-κB binding activity in mouse lung epithelial (LA-4) cells was assessed by a transcription factor-binding assay. The results indicated that the concentration of serum ADMA was increased following exposure to CS, and this corresponded with increased ADMA content in bronchial epithelial cells in lung tissue. Total lung DDAH expression was significantly decreased in lung tissue and cultured LA-4 cells following CS exposure. Addition of exogenous ADMA increased CSE-mediated NF-κB binding activity and TNFα production in LA-4 cells more than 2-fold compared to that in CSE-exposed controls. CS-mediated lung inflammation was significantly attenuated in DDAH transgenic mice compared to in wild-type controls. These findings demonstrated that lung ADMA metabolism was altered in mice following CS exposure and suggested that ADMA played a role in CS-mediated inflammation through increasing the presence of inflammatory mediators in lung epithelial cells.


Role of steroid hormones in Trichinella spiralis infection among voles.
Males are generally more susceptible to parasite infection than females. This sex difference may reflect the suppressive effects of testosterone and enhancing effects of estradiol on immune function. This study characterized the role of circulating steroid hormones in sex differences after infection with the nematode Trichinella spiralis. Because testosterone suppresses immune function and because polygynous males have higher circulating testosterone concentrations than monogamous males, sex differences in parasite burden were hypothesized to be exaggerated among polygynous meadow voles compared with monogamous prairie voles. As predicted, sex differences in response to T. spiralis infection were increased among meadow voles; males had higher worm numbers than females. Male and female prairie voles had equivalent parasite burden. Overall, prairie voles had higher worm numbers than meadow voles. Contrary to our initial prediction, differences in circulating estradiol concentrations in females, testosterone concentrations in males, and corticosterone concentrations in both sexes were not related to the observed variation in T. spiralis infection. Taken together, these data suggest that not all sex differences in parasite infection are mediated by circulating steroid hormones and that adaptive-functional explanations may provide new insight into the causes of variation in parasite infection.


Impact of focal cortical dysplasia Type IIIa on seizure outcome following anterior mesial temporal lobe resection for the treatment of epilepsy.
OBJECTIVE Temporal lobe epilepsy (TLE) is the most common type of pharmacoresistant focal epilepsy, for which anterior mesial temporal lobe resection (AMTLR) is a treatment option. Focal cortical dysplasia Type IIIa (FCD IIIa), a developmental lesion resulting from defects in neuronal formation and migration into the temporal pole (FCD I) combined with hippocampal sclerosis (HS), can be a neuropathological finding. In this study, the authors investigate the impact of FCD IIIa on seizure outcome in patients with TLE who underwent AMTLR. METHODS The authors performed a retrospective analysis of all patients with TLE who underwent AMTLR at their institution between June 2011 and April 2014. Histopathological analysis was used to determine whether patients had HS together with FCD I (FCD IIIa) or HS alone. The groups were compared with regard to age, sex, years of epilepsy, and seizure outcome using the Engel classification. RESULTS A total of 51 patients with TLE underwent AMTLR at the authors' institution. FCD IIIa was diagnosed in 13 cases. The patients experienced seizures for a mean duration of 31.1 years. The mean length of follow-up after the procedure was 18 months. All patients with FCD IIIa had a favorable seizure outcome (Engel Class I or II) compared with 71% of the patients with no pathological findings in the temporal pole (p < 0.01). CONCLUSIONS Patients with histopathologically proven FCD IIIa had a significantly better seizure outcome after AMTLR than patients with HS alone. Further effort should be made during presurgical evaluation to detect FCD IIIa so that the most suitable resection technique can be chosen and postoperative seizure outcome can be predicted for patient counseling.


Methods for association analysis and meta-analysis of rare variants in families.
Advances in exome sequencing and the development of exome genotyping arrays are enabling explorations of association between rare coding variants and complex traits. To ensure power for these rare variant analyses, a variety of association tests that group variants by gene or functional unit have been proposed. Here, we extend these tests to family-based studies. We develop family-based burden tests, variable frequency threshold tests and sequence kernel association tests. Through simulations, we compare the performance of different tests. We describe situations where family-based studies provide greater power than studies of unrelated individuals to detect rare variants associated with moderate to large changes in trait values. Broadly speaking, we find that when sample sizes are limited and only a modest fraction of all trait-associated variants can be identified, family samples are more powerful. Finally, we illustrate our approach by analyzing the relationship between coding variants and levels of high-density lipoprotein (HDL) cholesterol in 11,556 individuals from the HUNT and SardiNIA studies, demonstrating association for coding variants in the APOC3, CETP, LIPC, LIPG, and LPL genes and illustrating the value of family samples, meta-analysis, and gene-level tests. Our methods are implemented in freely available C++ code.


The functional role of B cell antigen receptor stimulation and IL-4 in the generation of human memory B cells from germinal center B cells.
The germinal center (GC) is an anatomical site where memory B cells are generated. Ag-Ab complexes presented by follicular dendritic cells in GC select precursors of memory B cells. Using a unique in vitro experimental system in which the survival of GC B cells is supported by a defined follicular dendritic cell-like cell line, we investigated the effects of B cell Ag receptor (BCR) stimulation and IL-4 on the memory B cell generation from centroblasts. IL-4 is reported to be critical for GC formation. Centroblasts differentiated to centrocytes during the culture period of 3 days as demonstrated by the down-regulation of CD77 expression and induction of CD44 as well as Bcl-2 expression. The transition of centroblast to centrocyte was enhanced by BCR stimulation and IL-4. Upon further culture, the centrocytes differentiated to memory B cells, a process that was enhanced by BCR stimulation and IL-4. The presence of IL-4 in the culture did not increase the number of plasma cells. These experimental data provide formal in vitro evidence that Ags in GC may participate not only in the selection but also in the expansion of memory B cells and that IL-4 is a growth factor promoting this expansion.


Changes in Biomarkers of Tobacco Exposure among Cigarette Smokers Transitioning to ENDS Use: The Population Assessment of Tobacco and Health Study, 2013-2015.
Limited data are available for how biomarkers of tobacco exposure (BOE) change when cigarette smokers transition to using electronic nicotine delivery systems (ENDS). Using biomarker data from Waves 1 (2013-2014) and 2 (2014-2015) of the PATH Study, we examined how mean BOE concentrations, including metabolites of nicotine, tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOC) and metals, changed when 2475 adult smokers transitioned to using ENDS or quit tobacco products. Exclusive smokers who transitioned to dual use had a significant decrease in NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol), but not nicotine metabolites, most PAHs, metals, or VOCs. Exclusive smokers who became dual users had significant reductions in total nicotine equivalents, NNAL, and 2CyEMA (acrylonitrile metabolite), but only in those who reduced cigarettes per day (CPD) by >=50%. Smokers who transitioned to exclusive ENDS use had significant reductions in most TSNAs, PAHs, and VOCs; however, nicotine metabolites did not decrease in dual users who became exclusive ENDS users. Smokers who quit tobacco use had significant decreases in nicotine metabolites, all TSNAs, most PAHs, and most VOCs. Cigarette smokers who became dual users did not experience significant reductions in most BOEs. Reductions were impacted by changes in CPD. However, transitioning from smoking to no tobacco or exclusive ENDS use was associated with reduced exposure to most BOEs measured. Future analyses could incorporate additional waves of PATH data and examine changes in biomarker exposure by ENDS device type and CPD.


Effects of acute and chronic treatment with an atypical antidepressant drug, nomifensine, on the sleep-wake activity in rats.
After the chronic administration of saline, rats were treated with nomifensine (0.1 or 1.0 mg/kg, twice a day, at light and dark onset) for 11 days. The sleep-wake activity was recorded for 24 h on the baseline day (saline), on nomifensine days 1, 5 and 11, and also on day 12, when saline was injected again (withdrawal day). Another group of rats was treated with saline throughout the experiment, without significant effect on the sleep-wake activity. The smaller dose of nomifensine increased non-REM sleep (NREMS) at the expense of wakefulness (W) in the light period. The effect persisted throughout the chronic treatment. A late increase in REM sleep (REMS) was noted on nomifensine days 5 and 11. Nomifensine failed to affect the sleep-wake activity in the dark period. On withdrawal, the baseline percentages of the vigilance states were recovered. As evaluated through spectral analysis of the EEG, the increase in NREMS was accompanied by an increase in slow wave activity. The higher dose of nomifensine elicited an increase in W and a reduction in both sleep states, followed by changes in W and NREMS in the opposite directions. These effects were evident in both the light and the dark periods of the day. Chronic treatment resulted in circadian variations in the effects. Withdrawal of the drug abolished the arousal reaction, but the late increase in NREMS persisted. The dose-dependent biphasic effects of nomifensine on sleep-wake activity can be explained by considering the proposed indirect dopamine and possibly noradrenaline agonist activity of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)


Hypothalamic and amygdalar cell lines differ markedly in mitochondrial rather than nuclear encoded gene expression.
Corticotropin-releasing hormone (CRH) plays an important role in regulating the mammalian stress response. Two of the most extensively studied neuronal populations that express CRH are in the hypothalamus and amygdala. Both regions are involved in the stress response, but the amygdala is also involved in mediating response to fear and anxiety. Given that both hypothalamus and amygdala have overlapping functions, but their CRH-expressing neurons may respond differently to a given perturbation, we sought to identify differentially expressed genes between two neuronal cell types, amygdalar AR-5 and hypothalamic IVB cells. Thus, we performed a microarray analysis. Our hypothesis was that we would identify differentially expressed transcription factors, coregulators and chromatin-modifying enzymes. A total of 31,042 genes were analyzed, 10,572 of which were consistently expressed in both cell lines at a 95% confidence level. Of the 10,572 genes, 2,320 genes in AR-5 were expressed at ≥ 2-fold relative to IVBs, 1,104 genes were expressed at ≥2-fold in IVB relative to AR-5 and 7,148 genes were expressed at similar levels between the two cell lines. The greatest difference was in six mitochondrial DNA-encoded genes, which were highly abundant in AR-5 relative to IVB cells. The relative abundance of these genes ranged from 413 to 885-fold according to the microarray results. Differential expression of these genes was verified by RTqPCR. The differentially expressed mitochondrial genes were cytochrome b (MT-CYB), cytochrome c oxidase subunit 1 and 2 (MT-CO1 and MT-CO2) and NADH-ubiquinone oxidoreductase chain 1, 2, and 3 (MT-ND1, MT-ND2, MT-ND3). As expected, the array revealed differential expression of transcription factors and coregulators; however the greatest difference between the two cell lines was in genes encoded by the mitochondrial genome. These genes were abundant in AR-5 relative to IVBs. At present, the reason for the marked difference is unclear. The cells may differ in mtDNA copy number, number of mitochondria, or regulation of the mitochondrial genome. The specific functions served by having such different levels of mitochondrial expression have not been determined. It is possible that the greater expression of the mitochondrial genes in the amygdalar cells reflects higher energy requirements than in the hypothalamic cell line.


Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6.
Recent studies have identified an abundant source of multipotent progenitor cells in subcutaneous human adipose tissue, termed human adipose-derived adult stem cells (ADAS cells). In response to specific media formulations, including transforming growth factor beta1 (TGFbeta1), these cells exhibit significant ability to differentiate into a chondrocyte-like phenotype, expressing cartilage-specific genes and proteins such as aggrecan and type II collagen. However, the influence of other growth factors on the chondrogenic differentiation of ADAS cells is not fully understood. This study was undertaken to investigate the effects of TGFbeta1, TGFbeta3, insulin-like growth factor 1, bone morphogenetic protein 6 (BMP-6), and dexamethasone, in various combinations, on the chondrogenic potential of ADAS cells in alginate beads. The chondrogenic response of alginate-encapsulated ADAS cells was measured by quantitative polymerase chain reaction, 3H-proline and 35S-sulfate incorporation, and immunolabeling for specific extracellular matrix components. Significant differences in chondrogenesis were observed under the different culture conditions for all outcomes measured. Most notably, BMP-6 up-regulated AGC1 and COL2A1 expression by an average of 205-fold and 38-fold, respectively, over day-0 controls, while down-regulating COL10A1 expression by approximately 2-fold. These findings suggest that BMP-6 is a potent inducer of chondrogenesis in ADAS cells, in contrast to mesenchymal stem cells, which exhibit increased expression of type X collagen and a hypertrophic phenotype in response to BMP-6. Combinations of growth factors containing BMP-6 may provide a novel means of regulating the differentiation of ADAS cells for applications in the tissue-engineered repair or regeneration of articular cartilage.


Effect of the non-ionic surfactant Poloxamer 188 on passive permeability of poorly soluble drugs across Caco-2 cell monolayers.
Drug permeability of the model drugs ketoprofen and nadolol across Caco-2 cell monolayers was determined in the absence and presence of the non-ionic surfactant Poloxamer 188 (Pluronic® F68, P-188). Stringent controls confirmed that P-188 in concentrations up to 50 mg/ml did not adversely affect cell viability or monolayer integrity. Equilibrium experiments confirmed that the drugs were merely passively transported. Caco-2 permeability of both drugs was found to be decreased by the surfactant in a concentration-dependent manner. Ultrafiltration revealed that both drugs were associated with surfactant micelles. The systematic investigation of micellization on passive absorption showed that association of drugs with P-188 micelles appears to depress their passive permeability under conditions where other transport mechanisms can be neglected.


Ketotifen inhibits PAF-induced actin polymerization in a human eosinophilic leukaemia cell line, EoL-1.
The inhibitory effect of ketotifen on platelet activating factor (PAF)-induced actin polymerization in a human eosinophilic leukaemia cell line, EoL-1, was examined by flow cytometry with the use of reagents specific for the filamentous form of actin (F-actin). Actin polymerization has been considered to be essential for locomotion of cells, chemotaxis and chemokinesis, and thus it reflects the chemotactic reaction of EoL-1 cells stimulated by PAF. Unstimulated EoL-1 cells showed little PAF-induced actin polymerization, whereas EoL-1 cells cultured for 9 days with the supernatant of a human ATL cell line, HIL-3 (HIL-3 sup), showed marked actin polymerization when stimulated with PAF. The actin polymerization in EoL-1 cells induced by PAF was seen in a dose-dependent manner at concentrations of 10(-10) M to 10(-6) M of PAF, and the maximum effect was seen at 10(-7) M of PAF. CV-3988, a specific antagonist of PAF, inhibited 80% of the actin polymerization in EoL-1 cells induced by PAF at a concentration of 10(-5) M. Ketotifen inhibited up to 40% of the PAF-induced actin polymerization of EoL-1 cells in a dose-dependent manner at concentrations of 10(-9) M to 10(-5) M. These results suggest that ketotifen may play an important role in the prevention of eosinophil-induced inflammation in allergic disorders by inhibiting PAF-induced chemotaxis of eosinophils.


Chronic Diseases and COVID-19: A Review.
The existence of a causal relationship between the rise of the death rate in COVID-19 infected patients and their sufferance from non-communicable pathophysiological conditions, particularly chronic diseases, was recently evidenced. In fact, in addition to the immunodeficiency generated by chronic disease conditions, COVID-19 also led to affect the immune system. Furthermore, the novel coronavirus attacks the lungs and other vital organs such as heart, kidneys, and brain. All these outcomes are accused of being involved in the increasing vulnerability and comorbidity in COVID-19- infected people with chronic diseases. Pharmacological, dietetic and natural approaches were suggested after deep bibliographic research for presenting preventive recommendations for this category of patients in order to avoid the fatal complications of this infection, and consequently limiting the risk of comorbidity. In this regard, some medications could enter into interaction with COVID-19 infection in patients with diabetes or hypertension and thereafter lead to fatal complications. Furthermore, regarding their nutritional values, some foods are more useful than others during this pandemic period because they are rich in vitamins, minerals, antioxidants and perhaps some bioactive phytochemicals, which are known to be effective in improving immune response, managing chronic diseases and/or having antiviral activities. In addition, vitamins, minerals, antioxidants, prebiotics and probiotics could be helpful in these conditions. Interestingly, in order to understand the mechanism of this causality and suggesting efficacious solutions, this review deserves considerable epidemiologic, clinical and experimental investigations.


Molecular Characterisation of Equine Herpesvirus 1 Isolates from Cases of Abortion, Respiratory and Neurological Disease in Ireland between 1990 and 2017.
Multiple locus typing based on sequencing heterologous regions in 26 open reading frames (ORFs) of equine herpesvirus 1 (EHV-1) strains Ab4 and V592 was used to characterise 272 EHV-1 isolates from 238 outbreaks of abortion, respiratory or neurological disease over a 28-year period. The analysis grouped the 272 viruses into at least 10 of the 13 unique long region (UL) clades previously recognised. Viruses from the same outbreak had identical multi-locus profiles. Sequencing of the ORF68 region of EHV-1 isolates from 222 outbreaks established a divergence into seven groups and network analysis demonstrated that Irish genotypes were not geographically restricted but clustered with viruses from all over the world. Multi-locus analysis proved a more comprehensive method of strain typing than ORF68 sequencing. It was demonstrated that when interpreted in combination with epidemiological data, this type of analysis has a potential role in tracking virus between premises and therefore in the implementation of targeted control measures. Viruses from 31 of 238 outbreaks analysed had the proposed ORF30 G2254/D752 neuropathogenic marker. There was a statistically significant association between viruses of the G2254/D752 genotype and both neurological disease and hypervirulence as defined by outbreaks involving multiple abortion or neurological cases. The association of neurological disease in those with the G2254/D752 genotype was estimated as 27 times greater than in those with the A2254/N752 genotype.


Threat/control-override symptoms and emotional reactions to positive symptoms as correlates of aggressive behavior in psychotic patients.
This cross-sectional multicenter study was carried out to examine whether the experience of threat/control-override symptoms and emotional reactions to positive symptoms (e.g., anger, anxiety) are related to aggressive behavior. Patients diagnosed with schizophrenia, delusional disorder, psychotic disorder not otherwise specified, or a schizoaffective disorder (N = 124) were interviewed and filled out self-report questionnaires. Results indicated that, in particular, threat/control-override symptoms were significantly related to aggressive behavior in psychotic patients. Further analysis revealed that the threat symptoms especially, but not the control-override symptoms, carried this effect. Anger disposition also accounted for a significant and unique proportion of the variance in the aggressive behavior of psychotic patients, whereas state anger and anxiety in reaction to positive symptoms did not. These results seem to suggest that feeling threatened by positive psychotic symptoms and anger disposition play a role in the origins of aggressive behavior of psychotic patients.


Impact of Screening for Salivary Gland by Ultrasonography.
Ultrasonography is superior to other imaging modalities for detecting salivary gland diseases. However, there have been no reports of the results of salivary gland screening with ultrasonography. In this study, the salivary glands were also observed during thyroid ultrasonography to determine the degree of salivary gland abnormalities detected by ultrasonography. This study was conducted retrospectively using medical records. It assessed the association between the following abnormal findings detected during thyroid ultrasonography and their final diagnoses: atrophy/swelling, unclear demarcation from surrounding tissues, decreased salivary gland parenchyma echo level, heterogeneity of parenchyma, hypervascularity of salivary gland parenchyma, dilatation of the ducts, and a mass within the gland. Of the 908 patients who underwent thyroid ultrasonography, salivary gland abnormalities were detected in 36 (4.0%) patients. Of the 36 patients with abnormal ultrasonographic findings, 22 underwent further examination. Of the 22 patients, 16 received definitive diagnoses of salivary gland diseases. Salivary gland disorders were considered to be absent in patients with only heterogeneity of the salivary glands observed on ultrasonography. Salivary gland disorders in all patients with further abnormal ultrasonographic findings such as atrophy/swelling, unclear boundary, or hypervascularity in addition to internal heterogeneity were confirmed by further blood examinations and imaging studies. We were able to detect autoimmune sialadenitis such as Sjögren's syndrome and IgG4-related sialadenitis by ultrasonography in patients without obvious symptoms. Salivary gland screening during thyroid ultrasonography revealed abnormal findings including Sjögren's syndrome and IgG4-related sialadenitis in about 4% of the patients. Thus, ultrasonography may also be useful for early detection of autoimmune diseases of salivary glands.


Replication control genes of plasmid pE194.
pE194, a 3.7-kilobase plasmid, confers resistance to macrolide, lincosamide, and streptogramin B antibiotics. The previously identified cop and repF genes of pE194 have been further localized by molecular cloning and mutational analysis together with DNA sequencing. The CfoIB fragment of pE194 is capable of autonomous replication and contains both genes. Most of this region has been resequenced, and two errors reported in a previous study have been corrected. The corrected sequence indicates that the replication region contains a single large open reading frame, which we propose encodes the repF product. Northern blot (RNA blot) analysis of this region detected six transcripts, all transcribed in the same direction as one another and opposite to repF. A 350-base transcript is synthesized from the region containing cop. No in vivo transcript for the repF gene was detected, but a protein was observed in an in vitro transcription-translation system which appears to be its product. An ochre mutation was inserted in the putative repF open reading frame, and a nonsense fragment was detected in the in vitro system. When carried passively on a pUB110 replicon, this mutant product appears capable of inhibiting pE194 replicons in trans. The pE194 origin of replication has been localized to within 200 bases.


Chemometric Based Identification and Validation of Specific Chemical Markers for Geographical, Seasonal and Gender Variations in Tinospora cordifolia Stem using HPLC-ESI-QTOF-MS Analysis.
Tinospora cordifolia is a widely distributed medicinal plant used in various traditional and commercial Ayurvedic formulations. Due to the wide use of this plant it is important to know the extent of variability in the metabolite profile resulting from geographical location, season and gender. To develop a statistical approach based on phytochemical markers for confident prediction of variations in metabolic profile and cytotoxicity due to geographical, seasonal and gender difference in T. cordifolia stem. A HPLC-ESI-QTOF-MS method was used for the metabolite profiling of T. cordifolia stem. The data were analysed using chemometric methods including Student's t-test, ANOVA, FA/PCA and ROC curve analysis and validated for the identification of chemical variations. The bioactivity of selected samples was also tested using a cell cytotoxicity assay to assess the functional aspect of the phytochemical variability. The chemometric approach applied here identified marker ions for geographical locations (m/z 294.1139 and 445.2136), seasons (m/z 344.1482, 359.1501, and 373.1305) and gender (m/z 257.1380) with 100% statistical sensitivity and specificity. An in vitro cytotoxicity evaluation revealed that male T. cordifolia stem was the most effective in inhibiting the growth of cancerous cell lines. The developed and validated chemometric approach identified the analytical markers for phytochemical variations in unknown T. cordifolia stem samples from male or female plants and samples collected from different geographical locations and seasons. The results are supported by comparative cytotoxic activity data. Copyright © 2017 John Wiley & Sons, Ltd.


Retention of virulence in viable but non-culturable halophilic Vibrio spp.
The viable but non-culturable (VBNC) forms of two environmental strains of Vibrio alginolyticus 1 and Vibrio parahaemolyticus 66 and one strain of V. parahaemolyticus ATCC 43996 showing virulence characteristics (hemolysin production, adhesive and/or cytotoxic ability, in vivo enteropathogenicity) were obtained by culturing bacteria in a microcosm consisting of artificial sea water (ASW) and incubating at 5 degrees C with shaking. Every 2 days, culturability of the cells in the microcosm was monitored by spread plates on BHI agar and total count and the percentage of viable cells were determined by double staining with DAPI and CTC. When cell growth was not detectable (<0.1 CFU/ml), the population was considered non-culturable and, then, the VBNC forms were resuscitated in a murine model. For each strain, eight male Balb/C mice were intragastrically inoculated with 0.1 ml of concentrated ASW bacterial culture. Two mice from each group were sacrificed at 2, 4, 8, and 12 days after challenge for autopsy and re-isolation of the microorganisms from the intestinal tissue cultures. Isolation was obtained in 25% of the animals challenged with the VBNC V. alginolyticus strain, in 37.5% of those challenged with the VBNC V. parahaemolyticus strain of environmental origin and in 50% of the animals infected with VBNC V. parahaemolyticus ATCC 43996. The strains thus isolated were again subjected to biological assays to determine the retention of pathogenicity. The virulence characteristics that seemed to disappear after resuscitation in the mouse were subsequently reactivated by means of two consecutive passages of the strains in the rat ileal loop model. The results obtained indicate that VBNC forms of the strains examined can be resuscitated and retain their virulence properties.


Over-production and characterization of the nifA gene product of Klebsiella pneumoniae--the transcriptional activator of nif gene expression.
The nifA gene of Klebsiella pneumoniae, which encodes the transcriptional activator of nif gene expression, was cloned into a number of plasmid vectors to obtain high-level synthesis of nifA product (NifA). When over-produced, NifA was very insoluble and it precipitated with the cell debris after cell lysis. Localization of beta-galactosidase activity from a nifA-lacZ translational fusion confirmed the insoluble nature of NifA. Analysis of two translational fusions in which the last six C-terminal amino acids of NifA were deleted suggests that these residues are required for activity.


Probing pathway-related modules in invasive squamous cervical cancer based on topological centrality of network strategy.
Our work aimed to identify pathway-related modules and hub genes involved in invasive squamous cervical cancer (SCC) based on topological centralities analysis of networks. To determine the functional modules changed in SCC, functional enrichment analyses were performed for differentially expressed genes (DEGs) between invasive SCC samples and normal controls. Then, co-expression network was constructed using EBcoexpress approach based on the DEGs. Moreover, pathway-related modules were probed from the global co-expression network based on pathway genes and their adjacent genes. Finally, topological centralities for co-expression network and pathway-related subnetworks were carried out to explore hub genes and significant pathway-related functional modules. Functional analyses revealed that DEGs mainly involved in three biological processes (metabolic process, cellular process, and cellular component organization) and 8 significant pathways. Furthermore, the co-expression network with 659 nodes and 1087 edges and 8 pathway-related modules were obtained. Topological centralities indicated two significant modules (cell cycle and base excision repair pathway-related modules), in which the common hub gene ARFGAP3 showed the most significant importance. The bioinformatics elucidation of certain pathway-related modules and hub genes might be beneficial to understand the molecular pathogenesis and reveal their potential as novel molecular markers of SCC to a great extent.


Rapid synaptic remodeling in the adult somatosensory cortex following peripheral nerve injury and its association with neuropathic pain.
Structural and functional plastic changes in the primary somatosensory cortex (S1) have been observed following peripheral nerve injury that often leads to neuropathic pain, which is characterized by tactile allodynia. However, remodeling of cortical connections following injury has been believed to take months or years; this is not temporally correlated with the rapid development of allodynia and S1 hyperexcitability. Here we first report, by using long-term two-photon imaging of postsynaptic dendritic spines in living adult mice, that synaptic connections in the S1 are rewired within days following sciatic nerve ligation through phase-specific and size-dependent spine survival/growth. Spine turnover in the S1 area corresponding to the injured paw markedly increased during an early phase of neuropathic pain and was restored in a late phase of neuropathic pain, which was prevented by immediate local blockade of the injured nerve throughout the early phase. New spines that generated before nerve injury showed volume decrease after injury, whereas more new spines that formed in the early phase of neuropathic pain became persistent and substantially increased their volume during the late phase. Further, preexisting stable spines survived less following injury than controls, and such lost persistent spines were smaller in size than the surviving ones, which displayed long-term potentiation-like enlargement over weeks. These results suggest that peripheral nerve injury induces rapid and selective remodeling of cortical synapses, which is associated with neuropathic pain development, probably underlying, at least partially, long-lasting sensory changes in neuropathic subjects.


The a2 mating-type-locus gene lga2 of Ustilago maydis interferes with mitochondrial dynamics and fusion, partially in dependence on a Dnm1-like fission component.
The a2 mating-type-locus gene lga2 of the basidiomycete Ustilago maydis encodes a mitochondrial protein that interferes with mitochondrial morphology and integrity, and that plays a role in uniparental inheritance of mitochondrial DNA. To address the mode of action of Lga2, we investigated its Dnm1 (a dynamin-related protein)-dependent effects. Here, we demonstrate that Dnm1 functions as a mitochondrial fission component in U. maydis and mediates Lga2-induced mitochondrial fragmentation. Mitochondrial fusion occurred very inefficiently in matings of U. maydis wild-type strains, but was strongly stimulated in the absence of dnm1 and highest in either wild-type or Deltadnm1 combinations when the a2 partner was deleted in lga2. This indicates that Dnm1 plays a central role in opposing mitochondrial fusion in response to endogenous lga2 expression and that Lga2 additionally inhibits fusion in a dnm1-independent manner. Our results further show that Lga2 does not stimulate increased turnover of the putative fusion protein Fzo1 and causes mitochondrial branching, loss of mitochondrial DNA and fitness reduction independently of dnm1. We conclude that Lga2 acts upstream of Dnm1, but controls mitochondrial integrity independently of Dnm1-mediated fission. In addition, we demonstrate a role of dnm1 in fungal virulence.


Phylogenomics reveals a complex evolutionary history of lobed-leaf white oaks in western North America.
Species within the genus Quercus (oak) hybridize in complex patterns that have yet to be fully explored with phylogenomic data. Analyses to date have recovered reasonable divergent patterns, suggesting that the impact of introgression may not always be obvious in inferred oak phylogenies. We explore this phenomenon using RADseq data for 136 samples representing 54 oak species by conducting phylogenetic analyses designed to distinguish signals of lineage diversification and hybridization, focusing on the lobed-leaf species Quercus gambelii, Q. lobata, and Q. garryana in the context of a broad sampling of allied white oaks (Quercus section Quercus), and particularly the midwestern Q. macrocarpa. We demonstrate that historical introgressive hybridization between once sympatric species affects phylogeny estimation. Historical range expansion during periods of favorable climate likely explains our observations; analyses support genetic exchange between ancestral populations of Q. gambelii and Q. macrocarpa. We conclude that the genomic consequences of introgression caused the attraction of distant lineages in phylogenetic tree space, and that introgressive and divergent signals can be disentangled to produce a robust estimate of the phylogenetic history of the species.


Microbial production and biomedical applications of lovastatin.
Lovastatin is a potent hypercholesterolemic drug used for lowering blood cholesterol. Lovastatin acts by competitively inhibiting the enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase involved in the biosynthesis of cholesterol. Commercially lovastatin is produced by a variety of filamentous fungi including Penicillium species, Monascus ruber and Aspergillus terreus as a secondary metabolite. Production of lovastatin by fermentation decreases the production cost compared to costs of chemical synthesis. In recent years, lovastatin has also been reported as a potential therapeutic agent for the treatment of various types of tumors and also play a tremendous role in the regulation of the inflammatory and immune response, coagulation process, bone turnover, neovascularization, vascular tone, and arterial pressure. This review deals with the structure, biosynthesis, various modes of fermentation and applications of lovastatin.


Adult seborrheic dermatitis: a status report on practical topical management.
Seborrheic dermatitis is a common chronic-recurrent inflammatory disorder that most commonly affects adults; however, a more transient infantile form also occurs. The definitive cause of seborrheic dermatitis is unknown. However, proliferation of Malassezia species has been described as a contributing factor. The adult form of seborrheic dermatitis affects up to approximately five percent of the general population. The disorder commonly affects the scalp, face, and periauricular region, with the central chest, axillae, and genital region also involved in some cases. Pruritus is not always present and is relatively common, especially with scalp disease. A variety of treatments are available including topical corticosteroids, topical antifungal agents, topical calcineurin inhibitors, and more recently, a nonsteroidal "device "cream. This article reviews the practical topical management of seborrheic dermatitis in the United States, focusing on the adult population.


[Suprarenal surgical pathology. Experience of 10 years and review of the literature].
Our experience with 34 patients who underwent surgery of the adrenal gland over the last 10 years is presented. The most important clinical and pathological aspects are analyzed, particularly from the perspective of surgery, and the literature on the different pathologies observed in our series is reviewed. A retrospective study was conducted to analyze the clinical features, analytical and hormonal data, imaging technique findings, types of anesthesia, surgical approaches, intra and postoperative morbidity and mortality, course of the disease, and pathological diagnosis. 53% were female. Mean age was 48.8 years. Left-sided involvement was more prevalent (70.7%). The most common pathology was adrenal adenoma (21 pts), followed by metastasis (4), cysts-pseudocysts (4), primary carcinoma (2), pheochromocytoma (1), etc. Hyperaldosteronism (16 pts) was the most common hormonal disorder; 2 patients had Cushing's syndrome, 2 virilizing syndrome, 1 pheochromocytoma, and 13 patients had a nonfunctioning tumor (3 were incidentalomas). The mean size and weight were 5.6 cm and 21.1 gm, respectively. Adenomas were the smallest tumors and those that weighed the least (mean 2.5 cm; 11.5 gm). Primary carcinomas were the largest tumors (mean 18 cm; 52 gm). US and CT were diagnostic in 56% and 100% of the cases and indicated the size of the mass correctly in 75% and 77%, respectively. Special anesthetic was required in 31%; nitroprusside, phenoxybenzamine, labetolol, corticosteroids and spironolactone were administered according to the hormone disorder. Lumbotomy via the 11th or 12th rib was the most common approach (58.7%), followed by the subcostal and transpleuro-diaphragmatic approach (14.7%, 11.7%, respectively), etc. The mean operating time was 162.2 min; adenoma of the adrenal gland required the shortest operating time (133.06 min), while carcinoma of the adrenal gland required the longest (405 min). Some type of intraoperative event arising from the hormonal disorder was observed in 44.2% of the patients. At 45.1 months mean follow-up, 70.5% of the patients were asymptomatic, arterial hypertension persisted in 11.7% and there were 5 deaths (all cases had a malignant tumor). The incidence of adrenal gland disease in our series is not unlike that reported in the literature. CT and complementary US are the diagnostic imaging techniques of choice. CT, moreover, has demonstrated a higher specificity. The surgical approach utilized was based on the pathological condition for which surgery had been indicated. The posterolateral and transpleurodiaphragmatic approaches were utilized for small tumors and no remarkable events were observed during the procedure. The anterior and combined approaches were utilized for large or bilateral tumors or obese patients. Our morbidity rate is not unlike that reported in the literature and basically depends on the chronic disease of the patient, type of hormonal disorder and size or malignant nature of the tumor.


G-protein involvement in central-nervous-system muscarinic-receptor-coupled polyphosphoinositide hydrolysis.
Potentiation of muscarinic-agonist-stimulated polyphosphoinositide (PPI) hydrolysis was demonstrated in a rat cerebral-cortical membrane preparation prelabelled with myo-[3H]inositol. Accumulation of myo-[3H]inositol 1,4-bisphosphate ([3H]IP2) was used to assess brain [3H]phosphatidylinositol 4,5-bisphosphate hydrolysis as its immediate metabolite, myo-[3H]inositol 1,4,5-trisphosphate, was rapidly hydrolysed to [3H]IP2. Inclusion of ATP (100 microM) and Mg2+ (5 mM) in the assay medium was necessary to demonstrate the effect of GTP analogues on carbachol-stimulated brain [3H]PPI turnover. Carbachol (100 microM) induced only a small increment in [3H]IP2 accumulation (142% of control) in 1 min. However, its effect was markedly enhanced, to 800% and 300% of control, by 100 microM-guanosine 5'-[gamma-thio]triphosphate (GTP[S]) and guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG) respectively. GTP[S] and p[NH]ppG also stimulated [3H]IP2 accumulation by over 500% and 200% of control, respectively. The GTP-analogue-potentiated carbachol effect was antagonized by 10 microM-atropine, whereas the GTP-analogue stimulation was unaffected. This report confirms the involvement of a G (GTP-binding) protein(s) in brain PPI metabolism and provides new evidence for the role of G protein(s) in the coupling of stimulated muscarinic receptors to PPI hydrolysis in the central nervous system.


Location of immunization and interferon-γ are central to induction of salivary gland dysfunction in Ro60 peptide immunized model of Sjögren's syndrome.
Anti-Ro antibodies can be found in the serum of the majority of patients with Sjögren's syndrome (SS). Immunization with a 60-kDa Ro peptide has been shown to induce SS-like symptoms in mice. The aim of this study was to investigate factors involved in salivary gland (SG) dysfunction after immunization and to test whether the induction of SS could be improved. Ro60 peptide immunization was tested in Balb/c mice, multiple antigenic peptide (MAP)-Ro60 and Pertussis toxin (PTX) were tested in SJL/J mice. In addition, two injection sites were compared in these two strains: the abdominal area and the tailbase. Each group of mice was tested for a loss of SG function, SG lymphocytic infiltration, anti-Ro and anti-La antibody formation, and cytokine production in cultured cells or homogenized SG extracts. Ro60 peptide immunization in the abdominal area of female Balb/c mice led to impaired SG function, which corresponded with increased Th1 cytokines (IFN-γ and IL-12) systemically and locally in the SG. Moreover, changing the immunization conditions to MAP-Ro60 in the abdominal area, and to lesser extend in the tailbase, also led to impaired SG function in SJL/J mice. As was seen in the Balb/c mice, increased IFN-γ in the SG draining lymph nodes accompanied the SG dysfunction. However, no correlation was observed with anti-MAP-Ro60 antibody titers, and there was no additional effect on disease onset or severity. Effective induction of salivary gland dysfunction after Ro60 peptide immunization depended on the site of injection. Disease induction was not affected by changing the immunization conditions. However, of interest is that the mechanism of action of Ro60 peptide immunization appears to involve an increase in Th1 cytokines, resulting in the induction of SG dysfunction.


Mid-infrared spectrometer using opto-nanofluidic slot-waveguide for label-free on-chip chemical sensing.
A mid-infrared (mid-IR) spectrometer for label-free on-chip chemical sensing was developed using an engineered nanofluidic channel consisting of a Si-liquid-Si slot-structure. Utilizing the large refractive index contrast (Δn ∼ 2) between the liquid core of the waveguide and the Si cladding, a broadband mid-IR lightwave can be efficiently guided and confined within a nanofluidic capillary (≤100 nm wide). The optical-field enhancement, together with the direct interaction between the probe light and the analyte, increased the sensitivity for chemical detection by 50 times when compared to evanescent-wave sensing. This spectrometer distinguished several common organic liquids (e.g., n-bromohexane, toluene, isopropanol) accurately and could determine the ratio of chemical species (e.g., acetonitrile and ethanol) at low concentration (<5 μL/mL) in a mixture through spectral scanning over their characteristic absorption peaks in the mid-IR regime. The combination of CMOS-compatible planar mid-IR microphotonics, and a high-throughput nanofluidic sensor system, provides a unique platform for chemical detection.


Treatment of inflammatory bowel disease in the elderly: an update.
Inflammatory bowel disease (IBD) is most common in young adults, but it can also present in the elderly. Furthermore, with the aging of the population, the number of elderly patients with IBD is expected to grow. Other conditions, such as diverticulitis and ischaemic colitis, may be more common in the elderly and need to be considered in the differential diagnosis. Management of elderly patients with IBD follows the same principles as in younger patients, with a few exceptions. For patients with mild-to-moderate colitis, a 5-aminosalicylate drug is often used (sulfasalazine, olsalazine, mesalazine, balsalazide). Topical therapy may be sufficient for those with distal colitis, whereas an oral preparation is used for more extensive disease. In those with more severe or refractory symptoms, corticosteroids are used, although the elderly appear to be at increased risk for corticosteroid-associated complications. For patients with corticosteroid-dependent or corticosteroid-refractory disease, immunosuppression with azathioprine or mercaptopurine may help avoid surgery. In patients with Crohn's disease, a similar approach is followed, with the additional consideration that the formulation of drug used must ensure delivery of drug to the site of inflammation. In fistulising Crohn's disease, antibacterials, immunosuppressive drugs, infliximab and surgery are often used in combination. Controlled trials and clinical experience have shown that infliximab is a significant addition to the therapeutic armamentarium for patients with Crohn's disease.


A Space of One's Own: Barbosa du Bocage, the Foundation of the National Museum of Lisbon, and the Construction of a Career in Zoology (1851-1907).
This paper discusses the life and scientific work of José Vicente Barbosa du Bocage (1823-1907), a nineteenth-century Portuguese naturalist who carved a new place for zoological research in Portugal and built up a prestigious scientific career by securing appropriate physical and institutional spaces to the discipline. Although he was appointed professor of zoology at the Lisbon Polytechnic School, an institution mainly devoted to the preparatory training of military officers and engineers, he succeeded in creating the conditions that allowed him to develop consistent research in zoology at this institution. Taking advantage of the reconstruction and further improvement of the building of the Lisbon Polytechnic, following a violent fire in 1843, Bocage transferred a natural history museum formerly located at the Academy of Sciences of Lisbon to his institution, where he conquered a more prestigious place for zoology. Although successive governments were unwilling to meet Bocage's ambitions for the Zoological Section of the newly created National Museum of Lisbon, the collaborators he found in different parts of the Portuguese continental territory and colonial empire supplied him the specimens he needed to make a career as a naturalist. Bocage ultimately became a renowned specialist in Southwestern African fauna thanks to José de Anchieta, his finest collaborator. Travels to foreign museums, and the establishment of links with the international community of zoologists, proved fundamental to build up Bocage's national and international scientific reputation, as it will be exemplified by the discussion of his discovery of Hyalonema, a specimen with a controversial identity collected off the Portuguese coast.


Modality and variability of synesthetic experience.
In synesthesia, stimulation of one sensory or cognitive pathway leads to additional, involuntary experiences in a second sensory or cognitive pathway. We here review previous surveys on this neurologically based phenomenon and report the results of 63 synesthetes who completed our Internet and paper questionnaire on synesthesia. In addition to asking for personal data and information on the participant's synesthesia, the questionnaire focused on the components of the inducer that elicit or modulate synesthesia. Synesthesia was most often developmental (92%) and of the grapheme-color type (86%). Sixty-two percent of the participants perceived time-related words in a spatial configuration. Music-color synesthesia was common (41%), and synesthesia for natural and artificial sounds (33%) was higher than in previous estimates. Eighty-one percent of participants experienced more than one form of synesthesia. Multimodal synesthesia, in which inducer and concurrent belong to 2 different sensory modalities, occurred in 92% of the participants. Overall, auditory stimuli were most often reported as inducers, and visual concurrents were most common. Modulations of the synesthetic experiences such as changes of the concurrent color, expansion within the same or to a different sensory modality, or reduction of the number of inducers over time were reported by 17% of participants. This challenges the presumed consistency of synesthesia and the adequacy of the test-retest consistency score still most commonly used to assess the veracity of reported synesthesia. Implications of the high prevalence of cross-modal synesthesia and the variability of synesthesia are discussed.


Beware the solitary maxillary median central incisor.
The incidence of a solitary maxillary median central incisor (SMMCI) tooth in the general population is low, in either the primary or secondary dentition. The most common cause of a missing maxillary central incisor is trauma, or more rarely hypodontia. However, SMMCI is also a recognized genetic anomaly and affected individuals can be carriers for a potentially more serious condition affecting midline development of the brain and face, holoprosencephaly (HPE). The presence of an SMMCI of unknown aetiology is therefore considered a risk factor for HPE, even in the absence of any other clinical signs. The orthodontist may be responsible for diagnosing cases of SMMCI with no obvious cause, and in these subjects due consideration should be given to referral for the appropriate genetic testing and counselling.


Gut-Brain Axis: Insights from Hippocampal Neurogenesis and Brain Tumor Development in a Mouse Model of Experimental Colitis Induced by Dextran Sodium Sulfate.
Chronic inflammatory bowel disorders (IBD) are idiopathic diseases associated with altered intestinal permeability, which in turn causes an exaggerated immune response to enteric antigens in a genetically susceptible host. A rise in psych cognitive disorders, such as anxiety and depression, has been observed in IBD patients. We here report investigations on a model of chemically induced experimental colitis by oral administration of sodium dextran sulfate (DSS) in C57BL/6 mice. We investigate, in vivo, the crosstalk between the intestine and the brain, evaluating the consequences of intestinal inflammation on neuroinflammation and hippocampal adult neurogenesis. By using different DSS administration strategies, we are able to induce acute or chronic colitis, simulating clinical characteristics observed in IBD patients. Body weight loss, colon shortening, alterations of the intestinal mucosa and fecal metabolic changes in amino acids-, lipid- and thiamine-related pathways are observed in colitis. The activation of inflammatory processes in the colon is confirmed by macrophage infiltration and increased expression of the proinflammatory cytokine and oxidative stress marker (Il-6 and iNOS). Interestingly, in the hippocampus of acutely DSS-treated mice, we report the upregulation of inflammatory-related genes (Il-6, Il-1β, S-100, Tgf-β and Smad-3), together with microgliosis. Chronic DSS treatment also resulted in neuroinflammation in the hippocampus, indicated by astrocyte activation. Evaluation of stage-specific neurogenesis markers reveals deficits in the dentate gyrus after acute and chronic DSS treatments, indicative of defective adult hippocampal neurogenesis. Finally, based on a possible causal relationship between gut-related inflammation and brain cancer, we investigate the impact of DSS-induced colitis on oncogenesis, using the Ptch1+/-/C57BL/6 mice, a well-established medulloblastoma (MB) mouse model, finding no differences in MB development between untreated and DSS-treated mice. In conclusion, in our experimental model, the intestinal inflammation associated with acute and chronic colitis markedly influences brain homeostasis, impairing hippocampal neurogenesis but not MB oncogenesis.


Subtypes of brain somatostatin receptors couple to multiple cellular effector systems.
To investigate whether somatostatin (SRIF) receptor subpopulations mediate different physiological actions of SRIF, we tested the effects of SRIF and the SRIF agonists MK 678 and CGP 23996 on different biological responses in rat neocortical neurons in culture. Neocortical cells in culture express SRIF receptors that can be labeled with 125I-MK 678 and 125I-CGP 23996. Pharmacological analysis of the binding sites indicates that the radioligands label SRIF receptor subtypes with distinct pharmacological characteristics. These receptor subpopulations are similar to those expressed in adult rat brain. SRIF, MK 678, and CGP 23996 are able to inhibit forskolin-stimulated adenylate cyclase activity in rat neocortical membranes by 25-30%. Furthermore, they inhibit a high voltage-activated Ca2+ current in rat neocortical neurons in culture by 25-35%. Both SRIF and MK 678 potentiate a delayed rectifier K+ current in rat neocortical neurons in culture by 25-30%. In contrast, high concentrations of CGP 23996 do not alter the K+ current. In cells that do not respond to CGP 23996, MK 678 increases the delayed rectifier K+ current. The findings of these studies indicate that rat neocortical neurons in culture express functionally distinct SRIF receptor subtypes that can be differentially activated by SRIF agonists.


Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis.
Berberine, an isoquinoline alkaloid derived from a plant used traditionally in Chinese and Ayurvedic medicine, has been reported to exhibit chemopreventive and anti-inflammatory activities through unknown mechanism. Because of the critical role of the transcription factor nuclear factor-kappaB (NF-kappaB) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-kappaB activation found in certain tumor cells. Suppression of NF-kappaB activation occurred through the inhibition of phosphorylation and degradation of IkappaBalpha by the inhibition of IkappaB kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-kappaB reporter activity. Inhibition of IKK by berbeine was direct and could be reversed by reducing agents. Site-specific mutagenesis suggested the involvement of cysteine residue 179 in IKK. Berberine also suppressed the expression of NF-kappaB-regulated gene products involved in antiapoptosis (Bcl-xL, Survivin, IAP1, IAP2, and cFLIP), proliferation (cyclin D1), inflammation (cyclooxygenase-2), and invasion (matrix metalloproteinase-9). Suppression of antiapoptotic gene products correlated with enhancement of apoptosis induced by tumor necrosis factor (TNF)-alpha and chemotherapeutic agents and with inhibition of TNF-induced cellular invasion. Overall, our results indicate that chemopreventive, apoptotic, and anti-inflammatory activities displayed by berberine may be mediated in part through the suppression of the NF-kappaB activation pathway. This may provide the molecular basis for the ability of berberine to act as an anticancer and anti-inflammatory agent.


[Therapeutic and corrective work with stammering preschool children in a daytime semi-hospital].
Therapeutic and corrective work with stammering preschool children conducted at a day-time semi-hospital institution presents a complex of measures aimed at improving the speech and the entire psychic activity of the child. A semi-hospital form of the organization makes it possible, along with therapeutic and corrective measures, to constantly train the speech in the most diverse situations of the microsocial environment outside the hospital and thus contributes to the development of social and adaptive behaviour which the child needs for further studying in the general education school.


Embodied knowledge in chronic illness and injury.
When people experience chronic illness or serious injury, changes occur not just within their physical bodies but also in their embodiments, that is, how they view the world through their bodies. For such patients, dualistic (mind-body) notions of the body as object and the mind as subject can devalue experiences that are necessary for healing and for managing everyday problems related to their illness or injury. Nurses need to be able to guide people with illness or injury to new levels of wellness, but may lack appropriate theoretical conceptualizations. Philosophies that underlie embodied knowledge--in particular, philosophies of Merleau-Ponty and Polanyi--were explored yielding two new ways to understand the body. The body as "silent partner" fosters an appreciation of the body's own subjectivity that can be enhanced in nursing care through sensitivity, listening, and creative coaching. Nurses can assist their patients to identify new and positive understandings of what their bodies mean to them after bodily changes. The body as "informant" holds much promise for solving some of the everyday problems that people with chronic illness or injury experience. By using phenomenological and other naturalistic methods, researchers and patients can find clues to solving such problems, clues that are known through daily living but hidden beneath conscious awareness. As a result, some of the practical know-how of the body as "informant" can be transformed into testable nursing interventions.


A molecular analysis of African lion (Panthera leo) mating structure and extra-group paternity in Etosha National Park.
The recent incorporation of molecular methods into analyses of social and mating systems has provided evidence that mating patterns often differ from those predicted by group social organization. Based on field studies and paternity analyses at a limited number of sites, African lions are predicted to exhibit a strict within-pride mating system. Extra-group paternity has not been previously reported in African lions; however, observations of extra-group associations among lions inhabiting Etosha National Park in Namibia suggest deviation from the predicted within-pride mating pattern. We analysed variation in 14 microsatellite loci in a population of 164 African lions in Etosha National Park. Genetic analysis was coupled with demographic and observational data to examine pride structure, relatedness and extra-group paternity (EGP). EGP was found to occur in 57% of prides where paternity was analysed (n = 7), and the overall rate of EGP in this population was 41% (n = 34). Group sex ratio had a significant effect on the occurrence of EGP (P < 0.05), indicating that variation in pride-level social structure may explain intergroup variation in EGP. Prides with a lower male-to-female ratio were significantly more likely to experience EGP in this population. The results of this study challenge the current models of African lion mating systems and provide evidence that social structure may not reflect breeding structure in some social mammals.


High-throughput cryopreservation of plant cell cultures for functional genomics.
Suspension-cultured cell lines from plant species are useful for genetic engineering. However, maintenance of these lines is laborious, involves routine subculturing and hampers wider use of transgenic lines, especially when many lines are required for a high-throughput functional genomics application. Cryopreservation of these lines may reduce the need for subculturing. Here, we established a simple protocol for cryopreservation of cell lines from five commonly used plant species, Arabidopsis thaliana, Daucus carota, Lotus japonicus, Nicotiana tabacum and Oryza sativa. The LSP solution (2 M glycerol, 0.4 M sucrose and 86.9 mM proline) protected cells from damage during freezing and was only mildly toxic to cells kept at room temperature for at least 2 h. More than 100 samples were processed for freezing simultaneously. Initially, we determined the conditions for cryopreservation using a programmable freezer; we then developed a modified simple protocol that did not require a programmable freezer. In the simple protocol, a thick expanded polystyrene (EPS) container containing the vials with the cell-LSP solution mixtures was kept at -30 °C for 6 h to cool the cells slowly (pre-freezing); samples from the EPS containers were then plunged into liquid nitrogen before long-term storage. Transgenic Arabidopsis cells were subjected to cryopreservation, thawed and then re-grown in culture; transcriptome and metabolome analyses indicated that there was no significant difference in gene expression or metabolism between cryopreserved cells and control cells. The simplicity of the protocol will accelerate the pace of research in functional plant genomics.


Right ventricular systolic function for risk stratification in patients with stable left ventricular systolic dysfunction: comparison of radionuclide angiography to echoDoppler parameters.
Previous studies have demonstrated that the radionuclide right ventricular (RV) ejection fraction (RVEF), tricuspid annular plane systolic excursion (TAPSE), and tissue Doppler peak systolic tricuspid annular velocity (STr) were independent predictors of cardiac survival in stable patients with left ventricular systolic dysfunction (LVSD). No study has compared the prognostic value of these three RV parameters. The aim of this study was to compare the prognostic value of RVEF, TAPSE, and STr in a large group of patients with LVSD. We analysed 527 consecutive patients who underwent an extensive prognostic evaluation (clinical data, biological data, radionuclide angiography, echoDopplercardiography, cardiopulmonary exercise test). Tricuspid annular plane systolic excursion and STr were weakly correlated with RVEF (r = 0.20). During a follow-up period of 1268 days (802-1830), there were 121 cardiovascular deaths. Best cut-off values were 37%, 9.7 cm/s, and 18.5 mm for RVEF, STr, and TAPSE, respectively. Right ventricular ejection fraction was a powerful independent predictor of cardiac survival [relative risk (RR): 2.05 (1.29-3.26), P = 0.002]. Peak systolic tricuspid annular velocity added a modest prognostic information [RR: 1.56 (1.02-2.39), P = 0.04]. However, the combination of STr with RVEF was the most powerful predictor of cardiovascular death. Tricuspid annular plane systolic excursion was not an independent predictor of cardiac survival. Right ventricular systolic function remains a powerful independent predictor of the clinical outcome. Even in the context of a complete echocardiographic assessment, radionuclide RVEF continues to be the most powerful RV systolic parameter for cardiac survival prediction. However, the determination of STr, in addition to RVEF, could improve risk stratification.


Prediction of drug-drug interactions between various antidepressants and efavirenz or boosted protease inhibitors using a physiologically based pharmacokinetic modelling approach.
The rate of depression in patients with HIV is higher than in the general population. The use of antidepressants can have a beneficial effect, improving antiretroviral therapy adherence and consequently their efficacy and safety. Efavirenz and protease inhibitor boosted with ritonavir are major components of the antiretroviral therapy and are inducers and/or inhibitors of several cytochrome P450 (CYP) isoforms. Although antidepressants are prescribed to a significant proportion of patients treated with antiretrovirals, there are limited clinical data on drug-drug interactions. The aim of this study was to predict the magnitude of drug-drug interactions among efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants using an in vitro-in vivo extrapolation (IVIVE) model simulating virtual clinical trials. In vitro data describing the chemical characteristics, and absorption, distribution, metabolism and elimination (ADME) properties of efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants were obtained from published literature or generated by standard methods. Pharmacokinetics and drug-drug interaction were simulated using the full physiologically based pharmacokinetic model implemented in the Simcyp™ ADME simulator. The robustness of our modeling approach was assessed by comparing the magnitude of simulated drug-drug interactions using probe drugs to that observed in clinical studies. Simulated pharmacokinetics and drug-drug interactions were in concordance with available clinical data. Although the simulated drug-drug interactions with antidepressants were overall weak to moderate according to the classification of the US FDA, fluoxetine and venlafaxine represent better candidates from a pharmacokinetic standpoint for patients on efavirenz and venlafaxine or citalopram for patients on boosted protease inhibitors. The modest magnitude of interaction could be explained by the fact that antidepressants are substrates of multiple isoforms and thus metabolism can still occur through CYPs that are weakly impacted by efavirenz or boosted protease inhibitors. These findings indicate that IVIVE is a useful tool for predicting drug-drug interactions and designing prospective clinical trials, giving insight into the variability of exposure, sample size and time-dependent induction or inhibition.


Venous extravasation of doxorubicin HCl with secondary skin ulceration.
With increased use of the potent anticancer drug doxorubicin HCl (Adriamycin), there are increasing numbers of reports of local severe tissue damage at the venous administration sites. I have described a 70-year-old woman in whom extravasation of this drug produced a characteristic indolent ulcer on the hand and wrist. Expectant nonoperative care was followed six weeks later by debridement and a split-thickness skin graft which failed to take. Repeat debridement with porcine grafts stimulated granulation tissue, so that split-thickness skin grafting could give an acceptable functional and cosmetic result.


Racial and ethnic differences in the mental health needs and access to care of older adults in california.
Little is known about the unmet mental health needs of minority older adults. Racial and ethnic differences in the prevalence rates of psychological distress and reported need and use of mental health services were examined in a population-based sample of older adults using the 2005 California Health Interview Survey. The sample comprised 16,974 people aged 55 and older, with 13,974 non-Hispanic whites, 719 African Americans, 1,215 Asians, and 1,066 Latinos. Respondents were compared in terms of prevalence of symptoms of mental distress and serious mental illness, reported need for help, and access to mental health services. African Americans, Asians, and Latinos were more likely to have mental distress than whites (21.2-24.2% vs 14.4%, P<.001) and a higher prevalence of serious mental illness (4.1-7.7% vs 2.5%, P<.001). After adjustment for age, sex, birthplace, marital status, education, limited English proficiency, chronic health conditions, and insurance status, older African-American (adjusted odds ratio (aOR)=1.37, 95% confidence interval (CI)=1.04-1.81) and Asian (aOR=1.50, CI=1.13-2.00) adults still had greater odds of mental distress than whites. Furthermore, all three groups had worse access to mental health services than whites (African American aOR=0.64, 95% CI=0.43-0.96; Asian aOR=0.32, CI=0.16-0.63; Latino aOR=0.35, CI=0.17-0.70). Clinicians caring for older individuals should be aware of their high risk for mental health needs. Given that minorities' access to mental health services is worse than whites', even after adjusting for health insurance status, providing insurance alone will not eliminate this disparity. Innovative clinical and systemic strategies are needed to better identify individuals at risk and to provide needed services.


Metal bridges illuminate transmembrane domain movements during gating of the cystic fibrosis transmembrane conductance regulator chloride channel.
Opening and closing of the cystic fibrosis transmembrane conductance regulator are controlled by ATP binding and hydrolysis by the cytoplasmic nucleotide-binding domains. Different conformational changes in the channel pore have been described during channel opening and closing; however, the relative importance of these changes to the process of gating the pore is not known. We have used patch clamp recording to identify high affinity Cd(2+) bridges formed between pairs of pore-lining cysteine residues introduced into different transmembrane α-helices (TMs). Seven Cd(2+) bridges were identified forming between cysteines in TMs 6 and 12. Interestingly, each of these Cd(2+) bridges apparently formed only in closed channels, and their formation stabilized the closed state. In contrast, a single Cd(2+) bridge identified between cysteines in TMs 1 and 12 stabilized the channel open state. Analysis of the pattern of Cd(2+) bridge formation in different channel states suggests that lateral separation and convergence of different TMs, rather than relative rotation or translation of different TMs, is the key conformational change that causes the channel pore to open and close.


Interview with Alberto Zanchetti, MD.
This month, The Journal of Clinical Hypertension features a hypertension icon from outside of the United States. Professor Alberto Zanchetti of Milan, Italy has been one of the most prominent researchers and teachers in the field of hypertension in Europe for the past 40 years. Those of us who have attended the European or International Society of Hypertension meetings have marveled at his energy, breadth of knowledge, and his ability to translate science into clinical practice. He has been in the forefront of new drug research for many years and has chaired or participated in almost all of the guideline committees in Europe that have set policy and established hypertension treatment recommendations. My own memories of Alberto conjure images of a man who truly had influence, not only in medicine, but in the outside world as well. Professor Zanchetti delayed a TWA flight from Milan to New York when I was late in arriving at the airport. He convinced La Scala to present an unscheduled opera for attendees at the European Society of Hypertension in Milan. That gives a picture of the man who gets things done. For these gracious acts, and for his enormous positive influence on generations of physicians not only in Europe, but also around the world, we salute him as one of the icons in hypertension.


Dynamic Geometric Analysis of the Renal Arteries and Aorta following Complex Endovascular Aneurysm Repair.
Aneurysm regression and target vessel patency during early and mid-term follow-up may be related to the effect of stent-graft configuration on the anatomy. We quantified geometry and remodeling of the renal arteries and aneurysm following fenestrated (F-) or snorkel/chimney (Sn-) endovascular aneurysm repair (EVAR). Twenty-nine patients (mean age, 76.8 ± 7.8 years) treated with F- or Sn-EVAR underwent computed tomography angiography at preop, postop, and follow-up. Three-dimensional geometric models of the aorta and renal arteries were constructed. Renal branch angle was defined relative to the plane orthogonal to the aorta. End-stent angle was defined as the angulation between the stent and native distal artery. Aortic volumes were computed for the whole aorta, lumen, and their difference (excluded lumen). Renal patency, reintervention, early mortality, postoperative renal impairment, and endoleak were reviewed. From preop to postop, F-renal branches angled upward, Sn-renal branches angled downward (P < 0.05), and Sn-renals exhibited increased end-stent angulation (12 ± 15°, P < 0.05). From postop to follow-up, branch angles did not change for either F- or Sn-renals, whereas F-renals exhibited increased end-stent angulation (5 ± 10°, P < 0.05). From preop to postop, whole aortic and excluded lumen volumes increased by 5 ± 14% and 74 ± 81%, whereas lumen volume decreased (39 ± 27%, P < 0.05). From postop to follow-up, whole aortic and excluded lumen volumes decreased similarly (P < 0.05), leaving the lumen volume unchanged. At median follow-up of 764 days (range, 7-1,653), primary renal stent patency was 94.1% and renal impairment occurred in 2 patients (6.7%). Although F- and Sn-EVAR resulted in significant, and opposite, changes to renal branch angle, only Sn-EVAR resulted in significant end-stent angulation increase. Longitudinal geometric analysis suggests that these anatomic alterations are primarily generated early as a consequence of the procedure itself and, although persistent, they show no evidence of continued significant change during the subsequent postoperative follow-up period.


Rigorous 3-D coupled wave diffraction analysis of multiple superposed gratings in anisotropic media.
The diffraction by two planar slanted fringe gratings superposed in the same volume of an anisotropic medium is treated using rigorous 3-D vector coupled wave analysis. Arbitrary angle of incidence and polarization are included. Both phase and/or amplitude slanted gratings in anisotropic media are treated in the analysis. The external boundary regions can be either isotropic (for bulk applications) or uniaxial anisotropic (for integrated applications). Both forward- and backward-diffracted orders are characterized by a number pair (i(l),i(2)), where i(l) and i(2) are integers. The Floquet condition is discussed for the case of two superposed gratings. When the external regions are anisotropic, each diffracted order has an ordinary (O), and an extraordinary (E) component. The analysis is also generalized for an arbitrary number of superposed gratings. The numerical complexity is discussed. In the case of equal grating periodicities along the boundaries, the diffracted orders become degenerate in the external regions. In this case, an alternative analysis that utilizes a cascaded stack of unslanted gratings can be used. Limiting cases are also presented. The various Bragg conditions are identified and quantified. Sample calculations presented include the quantification of the crosstalk between two superposed gratings, the evaluation of the effects of coupled Bragg conditions in beam combining applications, design and analysis of a beam splitter and a beam combiner, demonstration of the use of a cascaded stack of unslanted gratings of constant modulation to represent two superposed gratings that have the same periodicity along the boundaries, and finally evaluation of the effect of the phase difference between two gratings. The same analysis applies in the limiting cases of isotropic materials, single slanted gratings, etc. Applications of this analysis include optical storage, optical digital truth table look-up processing, neural nets, optical interconnects, beam splitting, and beam combining.


Two new species of socially parasitic Nylanderia ants from the southeastern United States.
In ants, social parasitism is an umbrella term describing a variety of life-history strategies, where a parasitic species depends entirely on a free-living species, for part of or its entire life-cycle, for either colony founding, survival, and/or reproduction. The highly specialized inquiline social parasites are fully dependent on their hosts for their entire lifecycles. Most inquiline species are tolerant of the host queen in the parasitized colony, forgo producing a worker caste, and invest solely in the production of sexual offspring. In general, inquilines are rare, and their geographic distribution is limited, making it difficult to study them. Inquiline populations appear to be small, cryptic, and they are perhaps ephemeral. Thus, information about their natural history is often fragmentary or non-existent but is necessary for understanding the socially parasitic life history syndrome in more detail. Here, we describe two new species of inquiline social parasites, Nylanderia deyrupi sp. nov. and Nylanderia parasitica sp. nov., from the southeastern United States, parasitizing Nylanderia wojciki and Nylanderia faisonensis, respectively. The formicine genus Nylanderia is large and globally distributed, but until the recent description of Nylanderia deceptrix, social parasites were unknown from this genus. In addition to describing the new social parasite species, we summarize the fragmentary information known about their biology, present a key to both the queens and the males of the Nylanderia social parasites, and discuss the morphology of the social parasites in the context of the inquiline syndrome.


Partial purification of collagenase and gelatinase from human polymorphonuclear leucocytes. Analysis of their actions on soluble and insoluble collagens.
The separation and further purification of human polymorphonuclear-leucocyte collagenase and gelatinase, using modifications of the method of Cawston & Tyler [(1979) Biochem J. 183, 647-656], are described. The final preparations yielded collagenase of specific activity 260 units/mg and gelatinase of specific activity 13 000 units/mg. Gelatinase was purified to apparent homogeneity in a latent form, and analysis of the activation of 125I-labelled latent enzyme by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and gel-filtration techniques suggested that no peptide material was lost on conversion into the active form. The purified natural inhibitors alpha 2-macroglobulin, tissue inhibitor of metalloproteinases ('TIMP') and amniotic-fluid inhibitor of metalloproteinases all inhibited the two polymorphonuclear-leucocyte metalloproteinases, but the last two inhibitors were slow to act and complete inhibition was difficult to attain. Collagenase degraded soluble types I and III collagen equally efficiently, but soluble type II collagen less well. Gelatinase alone had little activity on these substrates, although it enhanced the action of collagenase. Gelatinase was capable of degrading soluble types IV and V collagen at 25 degrees C, whereas collagenase was only active at higher temperatures when the collagens were susceptible to trypsin activity. By using tissue preparations of insoluble collagens (type I, II or IV) the activity of leucocyte collagenase was low and gelatinase activity was negligible, as measured by the solubilization of hydroxyproline-containing material. The two enzymes together were two or three times more effective in the degradation of these insoluble collagens.


[Eosinophils in nasal polyposis pathogenia. Bibliographic revision].
The aim of this work is to do a review on relations between the eosinophils and nasosinusal polyps. The etiopathogenical action of eosinophils are reviewed, from bone narrow to nasal mucosa infiltration. The mechanism of tissue eosinophilic mediated inflammation, his regulation and the significance of the balance between positive (IL-5) and negative (TGFbeta and IL10) mediators are discussed. We conclude that the degree of eosinophilic infiltration and degranulation's patterns are important aspects conditioning the severity and prognosis of chronic rhinosinusitis and nasosinusal polyps.


[An investigation on anxiety and coping patterns of patients under cancer chemotherapy and the strategies].
100 cases of patients under cancer chemotherapy were investigated by using Self-Rating Anxiety Scale (SAS) and questionnaire on coping patterns. The results showed that scores of SAS were significantly higher than that of the normal population. The state of the anxiety reached 45% among the patients. The patients' coping patterns tended to be passive. Linear analysis revealed a negative correlation between the coping patterns and the scores of SAS. It is recommended that cognitive behavioral therapy can be used to relieve the anxiety of patients under cancer chemotherapy.


Habitat destruction and overexploitation drive widespread declines in all facets of mammalian diversity in the Gran Chaco.
Global biodiversity is under high and rising anthropogenic pressure. Yet, how the taxonomic, phylogenetic, and functional facets of biodiversity are affected by different threats over time is unclear. This is particularly true for the two main drivers of the current biodiversity crisis: habitat destruction and overexploitation. We provide the first long-term assessment of multifaceted biodiversity changes caused by these threats for any tropical region. Focussing on larger mammals in South America's 1.1 million km2 Gran Chaco region, we assessed changes in multiple biodiversity facets between 1985 and 2015, determined which threats drive those changes, and identified remaining key areas for all biodiversity facets. Using habitat and threat maps, we found, first, that between 1985 and 2015 taxonomic (TD), phylogenetic (PD) and functional (FD) diversity all declined drastically across over half of the area assessed. FD declined about 50% faster than TD and PD, and these declines were mainly driven by species loss, rather than species turnover. Second, habitat destruction, hunting, and both threats together contributed ~57%, ~37%, and ~6% to overall facet declines, respectively. However, hunting pressure increased where TD and PD declined most strongly, whereas habitat destruction disproportionally contributed to FD declines. Third, just 23% of the Chaco would have to be protected to safeguard the top 17% of all three facets. Our findings uncover a widespread impoverishment of mammal species richness, evolutionary history, and ecological functions across broad areas of the Chaco due to increasing habitat destruction and hunting. Moreover, our results pinpoint key areas that should be preserved and managed to maintain all facets of mammalian diversity across the Chaco. More generally, our work highlights how long-term changes in biodiversity facets can be assessed and attributed to specific threats, to better understand human impacts on biodiversity and to guide conservation planning to mitigate them.


Silicon nanosheets and their self-assembled regular stacking structure.
Silicon nanomaterials are encouraging candidates for application to photonic, electronic, or biosensing devices, due to their size-quantization effects. Two-dimensional silicon nanosheets could help to realize a widespread quantum field, because of their nanoscale thickness and microscale area. However, there has been no example of a successful synthesis of two-dimensional silicon nanomaterials with large lateral size and oxygen-free surfaces. Here we report that oxygen-free silicon nanosheets covered with organic groups can be obtained by exfoliation of layered polysilane as a result of reaction with n-decylamine and dissolution in an organic solvent. The amine residues are covalently bound to the Si(111) planes. It is estimated that there is ca. 0.7 mol of residue per mole of Si atoms in the reaction product. The amine-modified layered polysilane can dissolve in chloroform and exfoliate into nanosheets that are 1-2 microm wide in the lateral direction and with thicknesses on the order of nanometers. The nanosheets have very flat and smooth surfaces due to dense coverage of n-decylamine, and they are easily self-assembled in a concentrated state to form a regularly stacked structure. The nanosheets could be useful as building blocks to create various composite materials.


Intravitreal injection of Bevacizumab in diabetic macular edema.
To assess the effectiveness of intravitreal injection of Bevacizumab in the treatment of diabetic macular edema. This case series was conducted at Department of Ophthalmology, Jinnah Post Graduate Medical Centre (JPMC), Karachi. The duration of study was six months from May 26, 2011 to November 25, 2011. The study group comprised of 54 patients of the Diabetic Macular Edema (DME). Intravitreal injection of 1.25 mg of bevacizumab (Avastin) was injected 3.5 mm from the limbus under topical anaesthetic drops. Post procedure follow up was scheduled on 1(st) post procedure day and after one month. Post procedure Optical Coherence tomography (OCT) was performed in all patients 1 week before and 1(st) month after 1(st) injection. The results were statistically analyzed through SPSS 17. Out of the 54 Eyes of 54 Patients who were given the Intravitreal injection of Avastin (Bevacizumab), 43 Eyes (79.6%) showed more than ten percent decrease in macular thickness from pre-injection thickness, 10 Eyes (18.5%) showed less than ten percent decrease and 1 Eye (1.9%) showed increase in macular thickness post operatively after one month. Intravitreal injection of Bevacizumab (Avastin) is effective in the treatment of diabetic macular edema.


Fractal and spectral dimension analysis of liver fibrosis in needle biopsy specimens.
To evaluate the usefulness of a reliable and reproducible mathematical scoring system based on fractal geometry for quantifying the irregular pattern in fibrosis commonly seen in liver biopsy specimens from chronic liver diseases. The study used 26 standard liver biopsy specimens obtained from patients with chronic hepatitis C virus-related liver disease. The degree of fibrosis in each specimen was estimated using a quantitative scoring system based on the computer-assisted evaluation of both the fractal and spectral dimensions of deposited collagen. The fractal dimension was then compared with the percent area of collagen measured using an image analysis system. The fractional dimension of its irregular shape defines fibrosis as a natural fractal structure. The complex distribution of its collagenous components (unmeasurable by means of the usual morphometric parameters) can be optimally quantified using a single numerical score that seems to be a better alternative to the semiquantitative methods adopted so far. The proposed method is reproducible, rapid and inexpensive; furthermore, supported by specific software, its mathematical approach excludes subjectivity and eliminates the external factors capable of influencing staging and classification. This study demonstrated that it is possible to quantify the irregularity of the structures of the liver in an objective manner and that the box-counting fractal dimension does not depend on the amount of collagen deposited on the slide. Furthermore, as has been found in other fields of investigation, study of the fractal properties of the liver is likely to reveal more about its structure and the pathogenesis of liver diseases.


Decreased expression of SCUBE2 is associated with progression and prognosis in colorectal cancer.
Signal peptide-CUB-epidermal growth factor-like domain-containing protein 2 (SCUBE2), a member of the SCUBE protein family, is a secreted and membrane-associated multi-domain glycoprotein. SCUBE2 is known as a novel tumor suppressor and a useful prognostic marker in breast cancer. In the present study, we investigated the expression (including mRNA and protein levels) of SCUBE2 in colorectal cancer (CRC) and adjacent normal tissues, using quantitative real-time PCR, western blot analysis and immunohistochemistry on a tissue microarray. Upregulation of SCUBE2 was achieved by transient transfection in RKO cell lines, and the effects of SCUBE2 on tumor proliferation, invasion, migration and apoptosis were evaluated by a series of functional experiments. The results indicated that SCUBE2 expression was decreased at the transcriptional and translational levels in CRC tissues and significantly associated with clinical stage, the depth of tumor invasion, lymph‑node metastasis, distant metastasis and histological grade. Patients with SCUBE2‑positive tumors had a lower recurrence rate and better survival than patients with SCUBE2-negative tumors. Moreover, upregulation of SCUBE2 had a limited effect on cell apoptosis but significantly inhibited tumor cell proliferation, migration and invasion in vitro. In conclusion, SCUBE2 plays an important role in suppressing CRC progression and prognosis. Our findings suggested that SCUBE2 may serve as a novel tumor suppressor and a potential therapeutic target for CRC patients.


New approach to the mechanism of antiasthmatic action of Tranilast.
The mechanism proposed to explain the antiasthmatic antiallergic action of Tranilast is the inhibition of chemical mediator release from mast cells and leukocytes as well as the antagonism of smooth muscle contracting activity of leukotrienes. It has been shown that this drug inhibits platelet aggregation induced "in vitro" by different stimuli. We investigated the effect of Tranilast on the release of thromboxane from guinea pig isolated lungs stimulated by the calcium ionophore A 23187 and the contraction of smooth muscle induced by this eicosanoid. Tranilast did not inhibit the release of arachidonic acid metabolites from the lungs but it prevented the contraction of the rat aorta induced by thromboxane released from lungs. Moreover, the drug antagonized the contraction of rat and rabbit isolated aortas stimulated by the thromboxane/endoperoxide mimetic U 46619. These effects might be mediated by a blockade of calcium uptake, since the drug was able to induce the relaxation of rabbit aortas previously contracted by potassium. Calcium ions are involved in the activation of mast cells, leukocytes, platelets and smooth muscle; therefore, the inhibition of calcium uptake might mediate the pharmacological properties of Tranilast.