[Neuronal intranuclear hyaline inclusion disease (NIHID): an update].
Neuronal intranuclear hyaline inclusion disease (NIHID) is a neurodegenerative disorder characterized by eosinophilic intranuclear inclusions in neuronal cells. Such inclusions are also found in non-neuronal cells. The clinical features and pathological findings in patients with NIHID are highly varied, and NIHID is therefore considered a heterogeneous disease entity. It can be categorized into three clinical subgroups based on disease onset and duration: the infantile, juvenile, and adult forms. The infantile and juvenile forms are generally associated with slowly progressive multiple-system degeneration. Recently, reports of patients with adult form NIHID have increased. Major symptoms in typical adult-onset cases are memory loss, cognitive dysfunction, and disorientation. Autonomic dysfunctions and peripheral neuropathy are also frequently observed. This type of adult-onset NIHID can be predicted by characteristic MRI findings-leukoencephalopathy with high intensity of the corticomedullary junction in diffusion-weighted imaging. Ante-mortem diagnosis of NIHID can be made by identification of intranuclear inclusions in skin or rectal biopsies. Intranuclear accumulation of abnormal proteins and/or dysfunction of protein degradation might underlie the pathogenesis of NIHID; however, the disease mechanisms remain largely unknown.


Behavior of buff-breasted sandpipers (Tryngites subruficollis) during migratory stopover in agricultural fields.
Understanding the behavior of birds in agricultural habitats can be the first step in evaluating the conservation implications of birds' use of landscapes shaped by modern agriculture. The existence and magnitude of risk from agricultural practices and the quality of resources agricultural lands provide will be determined largely by how birds use these habitats. Buff-breasted Sandpipers (Tryngites subruficollis) are a species of conservation concern. During spring migration large numbers of Buff-breasted Sandpipers stopover in row crop fields in the Rainwater Basin region of Nebraska. We used behavioral observations as a first step in evaluating how Buff-breasted Sandpipers use crop fields during migratory stopover. We measured behavior during migratory stopover using scan and focal individual sampling to determine how birds were using crop fields. Foraging was the most frequent behavior observed, but the intensity of foraging changed over the course of the day with a distinct mid-day low point. Relative to other migrating shorebirds, Buff-breasted Sandpipers spent a significant proportion of their time in social interactions including courtship displays. Our results show that the primary use of upland agricultural fields by migrating Buff-breasted Sandpipers is foraging while wetlands are used for maintenance and resting. The importance of foraging in row crop fields suggests that both the quality of food resources available in fields and the possible risks from dietary exposure to agricultural chemicals will be important to consider when developing conservation plans for Buff-breasted Sandpipers migrating through the Great Plains.


Early structural evolution of native cytochrome c after solvent removal.
Electrospray ionization transfers thermally labile biomolecules, such as proteins, from solution into the gas phase, where they can be studied by mass spectrometry. Covalent bonds are generally preserved during and after the phase transition, but it is less clear to what extent noncovalent interactions are affected by the new gaseous environment. Here, we present atomic-level computational data on the structural rearrangement of native cytochrome c immediately after solvent removal. The first structural changes after desolvation occur surprisingly early, on a timescale of picoseconds. For the time segment of up to 4.2 ns investigated here, we observed no significant breaking of native noncovalent bonds; instead, we found formation of new noncovalent bonds. This generally involves charged residues on the protein surface, resulting in transiently stabilized intermediate structures with a global fold that is essentially the same as that in solution. Comparison with data from native electron capture dissociation experiments corroborates both its mechanistic postulations and our computational predictions, and suggests that global structural changes take place on a millisecond timescale not covered by our simulations.


Varicella-zoster virus T cell tropism and the pathogenesis of skin infection.
Varicella-zoster virus (VZV) is a medically important human alphaherpesvirus that causes varicella and zoster. VZV initiates primary infection by inoculation of the respiratory mucosa. In the course of primary infection, VZV establishes a life-long persistence in sensory ganglia; VZV reactivation from latency may result in zoster in healthy and immunocompromised patients. The VZV genome has at least 70 known or predicted open reading frames (ORFs), but understanding how these gene products function in virulence is difficult because VZV is a highly human-specific pathogen. We have addressed this obstacle by investigating VZV infection of human tissue xenografts in the severe combined immunodeficiency mouse model. In studies relevant to the pathogenesis of primary VZV infection, we have examined VZV infection of human T cell (thymus/liver) and skin xenografts. This work supports a new paradigm for VZV pathogenesis in which VZV T cell tropism provides a mechanism for delivering the virus to skin. We have also shown that VZV-infected T cells transfer VZV to neurons in sensory ganglia. The construction of infectious VZV recombinants that have deletions or targeted mutations of viral genes or their promoters and the evaluation of VZV mutants in T cell and skin xenografts has revealed determinants of VZV virulence that are important for T cell and skin tropism in vivo.


Future Directions of Training Physician-Scientists: Reimagining and Remeasuring the Workforce.
In academic medicine, the attrition of the physician-scientist workforce has been significantly discussed for the past three decades, with substantial attention and funding targeted to stop this attrition and attempt to reinvigorate the workforce. Despite these concerns and efforts, the attrition has not been stopped or even significantly slowed, and thus a further understanding of the physician-scientist workforce is needed with a closer look at how this workforce is measured and quantified. Through reviewing three methods by which physician-scientists are identified and understood, limitations in these definitions arise, leading to the basic question: Who qualifies to be a physician-scientist? Answering this question may lead to developing more comprehensive and less restrictive approaches when qualifying and measuring the physician-scientist workforce and appreciating the varying contributions physicians make to research. Through suggesting an expanded appreciation of these research contributions, recognition of collaboration, and funding models that support both of these aspects, the authors hope to add to the conversation by challenging traditional approaches and encouraging movement toward forward-looking definitions that encourage and promote all physicians to engage with research. This reimagining of physician-scientists will result not just in a remeasuring of the workforce but, subsequently, in strengthening the clinical and translational research continuum as well.


Putrescine-modified catalase with preserved enzymatic activity exhibits increased permeability at the blood-nerve and blood-brain barriers.
Much evidence exists in support of the hypothesis that free radicals contribute to the pathogenesis of several neurodegenerative disorders and that mechanisms of free radical generation occur both intracellularly and extracellularly. Previous studies in this laboratory have shown that covalent modification of growth factors and antioxidant enzymes with the naturally occurring polyamine, putrescine, increases their permeability at the blood-nerve and blood-brain barriers (BNB and BBB), but does not significantly inhibit bioactivity. Furthermore, putrescine-modified superoxide dismutase (SOD) was shown to reduce neurodegeneration in a rat model of global cerebral ischemia. The purpose of the present study was to modify the antioxidant enzyme, catalase (CAT), with putrescine (PUT) at carboxylic acid groups whose ionization, and hence reactivity, was controlled with pH and investigate the effects on permeability and enzymatic activity. Modification of CAT with PUT increased its permeability 2-3-fold and preserved 67% of its enzymatic activity compared to native CAT and 137% compared to lyophilized CAT. The results of this study indicate that modification of CAT with putrescine increases its permeability while preserving enzymatic activity. PUT-SOD administered in combination with PUT-CAT may eliminate both the superoxide radical and the H2O2 produced from the dismutation of superoxide, respectively, and thus prevent the formation of hydroxyl radicals. This combination may exhibit increased neuroprotective effects, compared to native enzymes, following systemic administration for the treatment of free radical associated neurodegenerative disorders.


A multicentre analysis of catheter-related infection based on a hierarchical model.
To decrease intensive care unit (ICU)-acquired catheter-related infections (CRI), it is essential that healthcare workers receive training and that quality improvement programmes are in place. The aim of our study was to evaluate risk factors for catheter colonisation and infection, focussing specifically on local care bundles. Data were collected prospectively in 51 ICUs [7,188 patients, 8,626 central venous catheters (CVCs)] during two 6-month periods in 2007 and 2008, using a standardized questionnaire on catheter insertion, care and removal. Colonisation and CRI incidence were 6.1 and 2.2/1,000 CVC-days, respectively. A hierarchical mixed logistic model was used to identify risk factors for CRI and colonisation. Written CVC protocols were available in 46 (90 %) ICUs and were strictly followed in 38 ICUs. Factors significantly associated with CRI fell into three overall categories: (1) patient-related factors-immunosuppression [odds ratio (OR) 1.42, p = 0.02], medical diagnosis at admission (OR 1.64, p = 0.03) and trauma patient (OR 2.54, p < 0.001); (2) catheter-related factors-catheter rank (OR 1.7, p < 0.0001, non-subclavian catheter (OR 2.1, p < 0.001) and longer time with the catheter (p < 10(-4)); (3) centre-related factors-quantitative tip culture method (OR 2.55, p = 0.005) and alcohol-based povidone-iodine [OR 0.68, 95 % confidence interval (CI) 0.49-0.96] or alcohol-based chlorhexidine preparations (OR 0.69, 95 % CI 0.34-1.39) as compared to an aqueous povidone-iodine preparation (p < 0.001). We identified several risk factors for CRI that are amenable to improvement (preference for the subclavian route and use of an antiseptic solution containing alcohol). However, several patient-related factors were also found, and the use of quantitative catheter culture methods increased culture sensitivity, thereby increasing the CRI rate. Case-mix issues and the culture method should be taken into account when assessing the risk of CRI across centres.


Application of the International IgA Nephropathy Prediction Tool one or two years post-biopsy.
The International IgA Nephropathy (IgAN) Prediction Tool is the preferred method in the 2021 KDIGO guidelines to predict, at the time of kidney biopsy, the risk of a 50% drop in estimated glomerular filtration rate or kidney failure. However, it is not known if the Prediction Tool can be accurately applied after a period of observation post-biopsy. Using an international multi-ethnic derivation cohort of 2,507 adults with IgAN, we updated the Prediction Tool for use one year after biopsy, and externally validated this in a cohort of 722 adults. The original Prediction Tool applied at one-year without modification had a coefficient of variation (R2) of 55% and 54% and four-year concordance (C statistic) of 0.82 but poor calibration with under-prediction of risk (integrated calibration index (ICI) 1.54 and 2.11, with and without race, respectively). Our updated Prediction Tool had a better model fit with higher R2 (61% and 60%), significant increase in four-year C-statistic (0.87 and 0.86) and better four-year calibration with lower ICI (0.75 and 0.35). On external validation, the updated Prediction Tool had similar R2 (60% and 58%) and four-year C-statistics (both 0.85) compared to the derivation analysis, with excellent four-year calibration (ICI 0.62 and 0.56). This updated Prediction Tool had similar prediction performance when used two years after biopsy. Thus, the original Prediction Tool should be used only at the time of biopsy whereas our updated Prediction Tool can be used for risk stratification one or two years post-biopsy.


Differential Regulation of Two Arms of mTORC1 Pathway Fine-Tunes Global Protein Synthesis in Resting B Lymphocytes.
Protein synthesis is tightly regulated by both gene-specific and global mechanisms to match the metabolic and proliferative demands of the cell. While the regulation of global protein synthesis in response to mitogen or stress signals is relatively well understood in multiple experimental systems, how different cell types fine-tune their basal protein synthesis rate is not known. In a previous study, we showed that resting B and T lymphocytes exhibit dramatic differences in their metabolic profile, with implications for their post-activation function. Here, we show that resting B cells, despite being quiescent, exhibit increased protein synthesis in vivo as well as ex vivo. The increased protein synthesis in B cells is driven by mTORC1, which exhibits an intermediate level of activation in these cells when compared with resting T cells and activated B cells. A comparative analysis of the transcriptome and translatome of these cells indicates that the genes encoding the MHC Class II molecules and their chaperone CD74 are highly translated in B cells. These data suggest that the translatome of B cells shows enrichment for genes associated with antigen processing and presentation. Even though the B cells exhibit higher mTORC1 levels, they prevent the translational activation of TOP mRNAs, which are mostly constituted by ribosomal proteins and other translation factors, by upregulating 4EBP1 levels. This mechanism may keep the protein synthesis machinery under check while enabling higher levels of translation in B cells.


Imaging of the skeleton and soft tissue in children.
Normal metaphyses in infants contain a step-off not to be confused with child abuse. Extension of physeal lucency into the metaphyses can be a sign of healing child-abuse fracture of experimental physeal fracture, as well as deferoxamine overdose. Sonography can reveal costochondral dislocation, the pattern of healing fracture callus, the patellar tendon in jumper's knee, synovium of rheumatoid arthritis, sequestrum in advanced osteomyelitis, the unossified dislocated patella, and, even after 2 years of age, the dislocated femoral head. Further developments concern bone scanning, MR imaging, CT, and plain films of specific trauma, tumor, and infectious, metabolic, and orthopaedic conditions. Ultrasound has been proven useful for radiologist removal of soft tissue foreign bodies, whereas CT can be helpful for osteoid osteoma nidus removal under imaging control.


[The effects of topical steroids in epidemic kerato-conjunctivitis (author's transl)].
Fifty-three patients with proven adenovirus type 8 infection were treated at random, in a prospective study, with either artificial tears or topical steroids over six weeks. Severe cases of nummular keratitis, as well as deep keratitis and slight iritis, were significantly less frequent under steroids. No difference existed with respect to the course of the conjunctivitis and the frequency of a superficial punctate keratitis. Furthermore, the overall frequency of nummular keratitis was equal in both groups, its manifestation merely being somewhat delayed in the steroid group. This may even be disadvantageous, as the natural course of the disease could be prolonged. A significant disadvantage of topical steroids, however, was the high incidence of permanent "dry eye" in the post-infection period. Therefore, as long as no effective antiviral treatment for adenovirus infection is available, steroids should only be administered to relieve symptoms in severe cases for a limited time.


Substrate specificities of tobacco chitinases.
Ten tobacco chitinases (1,4-N-acetyl-beta-D-glucosaminide glycanhydrolase, EC 22.214.171.124) were purified from tobacco leaves hypersensitively reacting to tobacco mosaic virus. The 10 enzymes, which belong to five distinct structural classes of plant chitinases, were incubated with several potential substrates such as chitin, a beta-1,4 N-acetyl-D-glucosamine (GlcNAc) polymer, chitosan (partially deacetylated chitin), chitin oligomers of variable length and bacterial cell wall. Tobacco chitinases are all endotype enzymes that liberate oligomers from chitin and are capable of processing the chito-oligomers further at differential rates. Chitin reaction products were separated and quantified by HPLC and differential kinetics of oligomer accumulation and degradation were observed with the distinct classes of chitinases. Depending on the substrate to be hydrolysed, each isoform displayed a different spectrum of activity. For example, class I isoforms were the most active on chitin and (GlcNAc)4-6 whereas class III basic isoforms were the most efficient in inducing bacterial lysis. Class V and class VI chitinases were shown to more readily hydrolyse chitin oligomers than the chitin polymer itself. Together, these data indicate that the 10 tobacco chitinases represent complementary enzymes which may have synergistic effects on their substrates. This paper discusses their implication in plant defense by attacking pathogen's structural components and in plant development by maturing signal molecules.


Modification of the response to separation in the infant rhesus macaque through manipulation of the environment.
Rhesus mother-infant pairs were housed in a playpen apparatus beginning just before the birth of four male infants. The infants were separated from their mothers four times beginning at a mean age of 218 days. In Type A separations (I and IV) the infants were removed and housed away from their familiar environment in a protected setting; in Type B separations (II and III) the infants remained in the familiar setting and mothers were removed. One pair was separated every 2 weeks for 6 days; for a particular infant, a mean of 8 weeks intervened between each of the separations. On the basis of infant behavior during separation. Type B separations appeared to have a more deleterious effect on the infant: infants did not show the typical behavioral signs of depression under Type A housing conditions, whereas, under Type B conditions, infants expressed the typical depressive reaction to separation. However, comparisons of pre- and postseparation behaviors in the mother-infant pairs indicated that Type A separations were more perturbing. Increases in ventral-ventral contact between mothers and infants were greater following Type A separations and increases in time at nipple occurred only after Type A separations; infant grooming by mother increased only after the first, a Type A, separation. Type B separations may have affected mothers more severely in that reciprocity between maternal cradling and infant clinging was greater following Type B separations than following Type A separations when infants clung significantly more often than mother cradled.


Diagnostic Application of Volatile Organic Compounds as Potential Biomarkers for Detecting Digestive Neoplasia: A Systematic Review.
Volatile organic compounds (VOCs) are part of the exhaled breath that were proposed as non-invasive breath biomarkers via different human discharge products like saliva, breath, urine, blood, or tissues. Particularly, due to the non-invasive approach, VOCs were considered as potential biomarkers for non-invasive early cancer detection. We herein aimed to review the data over VOCs utility in digestive neoplasia as early diagnosis or monitoring biomarkers. A systematic literature search was done using MEDLINE via PubMed, Cochrane Library, and Thomson Reuters' Web of Science Core Collection. We identified sixteen articles that were included in the final analysis. Based on the current knowledge, we cannot identify a single VOC as a specific non-invasive biomarker for digestive neoplasia. Several combinations of up to twelve VOCs seem promising for accurately detecting some neoplasia types. A combination of different VOCs breath expression are promising tools for digestive neoplasia screening.


A new comprehensive gene expression panel to study tumor micrometastasis in patients with high-risk breast cancer.
The incidence and prognostic relevance of bone marrow (BM) and leukapheresis (PBPC) tumor cell contamination (TCC) in breast cancer patients is still to be circumstantiated. We developed a new comprehensive gene expression panel to study cytokeratins (CK), maspin (MAS) and mammaglobin (MAM) as possible predictors of prognosis. Forty-eight patients undergoing high dose chemotherapy (HDCT) and PBPC support were enrolled and analyzed for TCC on 116 PBPC apheresis and 96 BM obtained at basal conditions. All of the patients were evaluated by reverse transcriptase nested PCR (RT-PCR) for MAM and MAS gene expression and by immunocytochemistry (ICC) and nested RT-PCR to evaluate CK expression. PBPC and BM frequency of CK-positive (+) cells was 12-13% by ICC and 71-73% by RT-PCR respectively. Sixty-seven percent of CK ICC+ samples were MAM RT-PCR+ and 89% of them were MAS RT-PCR+. PBPC and BM frequency of MAM+ cells was 21% and 31% respectively, while for MAS+ cells it was 48% and 52% respectively by RT-PCR. After 71 mo median FU, 16 patients (33%) relapsed and 14 (88%) had BM/PBPC TCC. No marker had an impact on overall survival (OS) but MAS expression on BM and MAM expression on PBPC correlated with a statistically significant improved (p=0.05) and worsened RFS (p=0.06) respectively. These data confirm the activity of MAM as a negative prognostic factor and show for the first time that MAS could work as a tumor suppressor gene even in a clinical setting, since it protects from recurrence.


Self-objectification in the context of breastfeeding: A concept analysis.
To increase the overall rate of breastfeeding initiation and duration, factors involved in a mother's decision to breastfeed must be identified. Self-objectification in the context of breastfeeding was a concept selected for exploring factors associated with negative views of breastfeeding. A concept analysis following the eight-step Walker & Avant method provides clarity and context to the concept of self-objectification in the context of breastfeeding. The antecedents of self-objectification in the context of breastfeeding include living in a culture of sexualization and objectification of women and the internalization of the values of objectification. Attributes of self-objectification in the context of breastfeeding are a prioritization of physical appearance attributes of the breast over the health benefits of breastfeeding and a preoccupation with physical appearance. Consequences include negative views toward breastfeeding initiation, duration, and public breastfeeding. A concept analysis on self-objectification in the context of breastfeeding will provide definition and clarity to this phenomenon, lend to theory and measurement, and add literature to the sociocultural factors impacting breastfeeding decisions.


Belief in Unconscious Repressed Memory Persists.
On the basis of converging research, we concluded that the controversial topic of unconscious blockage of psychological trauma (i.e., repressed memory) remains very much alive in clinical, legal, and academic contexts. In his commentary, Brewin (this issue, p. 443) conducted a cocitation analysis and concluded that scholars do not adhere to the concept of unconscious repression. Furthermore, he argued that previous survey research did not specifically assess unconscious repression. Here, we present critical evidence that runs counter to his claims. First, we inspected his cocitation analysis and found that some scholars support notions that are closely related to unconscious repression. Furthermore, we conducted another analysis on the basis of articles' similarity. Again, we found examples of scholars specifically endorsing unconscious repressed memories. Second, as opposed to what Brewin reports, recent survey research now exists that bears directly on people's beliefs regarding unconscious repression. This work reveals that large percentages of people (e.g., students and eye-movement desensitization and reprocessing [EMDR] clinicians) endorse the concept of unconscious repressed memories. The belief in unconscious repressed memory can continue to contribute to harmful consequences in clinical, legal, and academic domains (e.g., false accusations of abuse).


[Evaluation of transitory evoked otoacoustic emissions in children with impaired tubal ventilation].
Transient evoked otoacoustic emission (TEOAE) has proven to be a useful clinical screening test for auditory dysfunction. Problems concerning the evaluation are mainly due to irregularities of the physiological middle ear functions. In this study different degrees of middle ear alterations of otherwise normal-hearing children were quantified by means of tympanometry, otoscopy and pure-tone audiometry and then related to the results of TEOAE registration which were classified by the coefficient of the crosscorrelation and the frequency response spectrum. Data were obtained from 266 ears of 148 children between the age of 3 months and 11 years. The results indicate that even slight middle ear irregularities, e.g. negative pressure between -50 and -100 mm H2O, can reduce the rate of successfully recorded TEOAE from 95% (70/74) in the normal group to 78% (34/47). When children displayed a tympanogramm with no observable peak, a successful registration of TEOAE was possible in only 12% (n = 34) of the cases. Such results are related to serous or mucoid effusions which probably prevent a transmission of the emission from the cochlea to the meatus. In analysing the relation between conductive losses in pure-tone audiometry and TEOAE it was demonstrated that no TEOAE could be recorded in ears with a conductive loss above 20 dB HL. Where the conductive loss is smaller than 20 dB HL it is not possible to predict whether a reliable emission can be recorded or not. This study emphasizes the need to reexamine children who do not show positive emissions connected with middle ear imbalances.(ABSTRACT TRUNCATED AT 250 WORDS)


[Comparative immunological characteristics of Daphnia allergens].
Materials on the study of Daphnia allergens are presented. Daphnia allergens have been shown to possess considerable sensitizing properties. The optimum method for the preparation of the allergen has been selected. The method of measuring the electrophoretic mobility of cells with a view to the evaluation of the specific activity of Daphnia allergen is proposed.


The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19.
Probiotic bacteria are able to modulate general antiviral responsiveness, including barrier functionality and innate and adaptive immune responses. The COVID-19 pandemic, resulting from SARS-CoV-2 infection, has created a need to control and treat this viral infection and its ensuing immunopathology with a variety of approaches; one such approach may involve the administration of probiotic bacteria. As with most viral infections, its pathological responses are not fully driven by the virus, but are significantly contributed to by the host's immune response to viral infection. The potential adoption of probiotics in the treatment of COVID-19 will have to appreciate the fine line between inducing antiviral immunity without over-provoking immune inflammatory responses resulting in host-derived immunopathological tissue damage. Additionally, the effect exerted on the immune system by SARS-CoV-2 evasion strategies will also have to be considered when developing a robust response to this virus. This review will introduce the immunopathology of COVID-19 and the immunomodulatory effects of probiotic strains, and through their effects on a range of respiratory pathogens (IAV, SARS-CoV, RSV), as well as SARS-CoV-2, will culminate in a focus on how these bacteria can potentially manipulate both infectivity and immune responsiveness via barrier functionality and both innate and adaptive immunity. In conclusion, the harnessing of induction and augmentation of antiviral immunity via probiotics may not only act as an ingestible adjuvant, boosting immune responsiveness to SARS-CoV-2 infection at the level of barrier integrity and innate and adaptive immunity, but also act prophylactically to prevent infection and enhance protection afforded by current vaccine regimens.


Gene expression profiles of normal human fibroblasts after exposure to ionizing radiation: a comparative study of low and high doses.
Several types of cellular responses to ionizing radiation, such as the adaptive response or the bystander effect, suggest that low-dose radiation may possess characteristics that distinguish it from its high-dose counterpart. Accumulated evidence also implies that the biological effects of low-dose and high-dose ionizing radiation are not linearly distributed. We have investigated, for the first time, global gene expression changes induced by ionizing radiation at doses as low as 2 cGy and have compared this to expression changes at 4 Gy. We applied cDNA microarray analyses to G1-arrested normal human skin fibroblasts subjected to X irradiation. Our data suggest that both qualitative and quantitative differences exist between gene expression profiles induced by 2 cGy and 4 Gy. The predominant functional groups responding to low-dose radiation are those involved in cell-cell signaling, signal transduction, development and DNA damage responses. At high dose, the responding genes are involved in apoptosis and cell proliferation. Interestingly, several genes, such as cytoskeleton components ANLN and KRT15 and cell-cell signaling genes GRAP2 and GPR51, were found to respond to low-dose radiation but not to high-dose radiation. Pathways that are specifically activated by low-dose radiation were also evident. These quantitative and qualitative differences in gene expression changes may help explain the non-linear correlation of biological effects of ionizing radiation from low dose to high dose.


The efficacy of interviewing young drug users through online chat.
Despite the fact that most young people who use 'party drugs' also use the Internet, accounts of drugs research involving qualitative interviewing using real-time instant messaging or online chat are yet to be published. This paper assesses the efficacy of conducting qualitative research interviews with young party drug users through instant messaging. In 2007-2008, 837 Australian residents who reported recent use of psychostimulants and/or hallucinogens and participated in online drug discussion completed a web survey and a subsample of 27 completed online interviews (median age 21, range 17-37, 59% male). Experienced drug users were more likely to volunteer to be interviewed than novices. The time and space flexibility provided by the online interviews was convenient; however, interviews were more prone to interruption. Establishing legitimacy, personal disclosure, appropriate linguistic style and humour facilitated the development of rapport and enabled the production of more detailed and in-depth data. These strategies were not successful in all cases and when unsuccessful, interviewees were more easily able to exit the interview by choosing not to respond. Young drug users already using the Internet to chat about drugs find online interviewing an acceptable and convenient way to contribute to research. With adequate preparation to develop technical and cultural competencies, online interviewing offers an effective way of engaging with young people that is worthy of consideration by researchers in the alcohol and other drug field.


[Genetic transformation of animals by the insertion of foreign genes into the zygotes].
A review of literature on genetic transformation of animal (mouse and Drosophila) germ cells by microinjection of the cloned genes into the pronuclei or into the early embryos. The fate of foreign genes and mechanisms of their integration into the recipient genome are considered in detail, as well as genetic consequences of the exogenic DNA insertion. Expression of the donor genes in transgenic animals is analyzed, its irregular and unusual pattern is noted in transgenic mice. An attempt has been undertaken not only to stress obvious advances in genetic transformation of animals, but also to outline unsolved problems related to inheritance of exogenous genes, insertion mutagenesis and irregular expression of the donor genes.


Satisfaction With Life and Risk of Dementia: Findings From the Korean Longitudinal Study of Aging.
Life satisfaction is increasingly viewed as an asset associated with better general health, but its association with cognitive health and risk of dementia is less examined. We tested the hypothesis that higher life satisfaction would be associated with lower risk of dementia. Participants were a nationally representative sample of adults (n = 8,021; age range: 45-93 years) from the Korean Longitudinal Study of Aging assessed every 2 years for up to 12 years. Multilevel modeling analysis examined whether life satisfaction is associated with cognitive functioning and decline. The primary analysis used Cox regression to examine the association between baseline life satisfaction and risk of incident dementia. Between-person differences and within-person changes in life satisfaction were associated with cognitive functioning, but life satisfaction was unrelated to the rate of cognitive decline. Higher life satisfaction was also associated with lower risk of dementia, even after accounting for demographic factors, depressive symptoms, cardiovascular and functional risk factors, health behaviors, and social contact. Satisfaction with life may function as a positive psychological resource for maintaining cognitive functioning and protecting against the risk of dementia.


SKF 104353, a high affinity antagonist for human and guinea pig lung leukotriene D4 receptor, blocked phosphatidylinositol metabolism and thromboxane synthesis induced by leukotriene D4.
SKF 104353 (2(S)-hydroxyl-3(R)-carboxyethylthio)-3-[2-(8-phenyloctyl) phenyl] propanoic acid) is a synthetic structural analog of leukotrienes D4 and E4 (LTD4, LTE4). This compound binds to guinea pig and human lung LTD4 receptors with affinities (Ki) of 5 +/- 2 and 10 +/- 3 nM, respectively. The Ki values of a reference compound, FPL 55712, were 2200 and 4500 nM, respectively, approximately 400- and 500-fold less effective than SKF 104353. LTD4- and LTE4-induced biosynthesis of thromboxane B2 has been shown to be mediated by LTD4 receptors in guinea pig lung in vitro. SKF 104353 did not induce synthesis of TxB2 in this system at concentrations of 1-20 microM. When SKF 104353 and increasing concentrations of LTD4 were incubated with guinea pig lung, the dose response curve of LTD4-induced TxB2 biosynthesis was shifted to the right with a -log[KB] = 8.4 +/- 0.2. LTD4-induced phosphatidylinositol (PI) hydrolysis in guinea pig lung has been shown to be the major signal transduction mechanism. In this system, SKF 104353 (1-20 microM) did not promote PI hydrolysis. Pretreatment of the [3H]myo-inositol-labeled guinea pig lung with SKF 104353 shifted the LTD4-induced PI hydrolysis dose response curve to the right, indicating that SKF 104353 inhibited LTD4 receptor-mediated intracellular second messenger formation. These results demonstrate that SKF 104353 is a high affinity, specific LTD4 receptor antagonist. It inhibited LTD4-induced PI hydrolysis and TxB2 biosynthesis in guinea pig lung. SKF 104353 may prove to be an important research tool for research on the activities of leukotrienes and of value therapeutically in the treatment of leukotriene-mediated diseases.


Synteny mapping of four genes from the short arm of human chromosome 19 to bovine chromosome 7.
Four genes on the short arm of human chromosome 19 (HSA 19p) were assigned to bovine chromosome 7 (BTA 7) using a bovine x rodent somatic hybrid cell panel. These four genes were cartilage oligomeric matrix protein (COMP), lymphoblastic leukemia derived sequence 1 (LYL1), lysosomal alpha-mannosidase (MANB), and RAS oncogene family member RAB3A. Bovine sequence tagged sites were developed for the four genes and used for screening a bovine x rodent somatic cell panel. All four genes were mapped to bovine synteny group U22 (BTA 7) with a correlation coefficient of 0.901-1.000. This study confirms that the centromeric region of BTA 7 is conserved with HSA 19p.


[Alternative approaches to the control of schistosomiasis: trying to include subjective elements in epidemiology]
This study discusses the possibility of integrating the "subjective" in epidemiological research. Alternative approaches are presented for programs to provide health and educational services, as well as others which are the right of citizens to receive and the responsibility of the government to provide. The characteristics of participatory research, community-based epidemiology, and popular education programs are described, with the purpose of constructing a model for the control of schistosomiasis using alternative methodologies, including in the model the perceptions and life styles of populations exposed to Schistosoma mansoni. The Federal Government is indicated as the institution to provide the material conditions necessary to form a citizenry with the collective will to control schistosomiasis.


Involvement of thioredoxin domain-containing 5 in resistance to nitrosative stress.
Living organisms are exposed to nitrosative stress mediated by nitric oxide (NO) and its derivatives. Multiple cellular mechanisms may be needed to cope with nitrosative stress. This work takes advantage of a hypersensitive Escherichia coli genetic system to identify genes involved in resistance to nitrosative stress in mouse lungs. Mouse thioredoxin domain-containing 5 (mTrx 5) was identified as one of the candidate genes. Its ability to complement the hypersensitive phenotype in an E. coli mutant strain was confirmed by genetic analysis. Purified recombinant mouse thioredoxin domain-containing 5 protein reduced DNA damage that is sensitive to cleavage by the deamination repair enzyme endonuclease V, indicating that mTrx 5 may play a role in scavenging the reactive nitrogen species. E. coli thioredoxin 1 and thioredoxin 2 proteins also reduced the DNA damage in a similar manner. Deletion of trxA (encodes thioredoxin 1) or trxC (encodes thioredoxin 2) in E. coli resulted in a slightly higher sensitivity to nitrosative stress. On the other hand, deletion of both trxA and trxC greatly increased its sensitivity to nitrosative stress. Complementation with the mTrx 5 gene rescued the sensitive phenotype of the double deletion mutant. The potential roles that mTrx 5 may play in coping with nitrosative stress are discussed.


Chordee correction by corporal rotation: the split and roll technique.
The optimal approach to correcting ventral chordee associated with severe hypospadias is controversial. Dorsal plication tends to shorten the phallus and ventrally positioned grafts often mandate a staged procedure. An alternative approach is presented using corporal rotation to correct ventral chordee associated with hypospadias. In 6 boys with severe hypospadias the urethral plate was divided and the septum between the corpora cavernosa was partially split with a ventral midline incision. This incision facilitates corporal rotation. Access to the dorsal aspect of the corpora cavernosa was achieved by dissecting Buck's fascia with its encased neurovascular bundles, so that the bundles in the area of chordee were completely elevated and preserved. Using artificial erection as a guide nonabsorbable sutures were placed in the area of maximal curvature from the dorsolateral aspect of 1 corpus cavernosum across the midline to the other side such that, as the knots were tied, the corpora rotated toward the dorsal midline. The knots were buried by apposition of the rotated corporal bodies. Excellent straightening of the phallus was achieved intraoperatively in these patients. The split and roll technique for correcting severe chordee does not require incisions into the corporal substance, involve use of grafts or cause shortening of the phallus. The neurovascular bundles are preserved and are not compressed by the rotational sutures. The surgeon may perform 1-stage reconstruction while achieving maximal penile length.


Conditioned saccharin avoidance and sensitization to drugs of abuse.
Saccharin avoidance conditioned by drugs of abuse (CSA) has been interpreted as an expression of the appetitive, dopamine-dependent, properties of the drug. Repeated exposure to these drugs induces an increase (sensitization) of their motor stimulant properties associated with differential changes in DA transmission in the NAc shell and core. The present study investigated the changes in drug CSA induced by schedules of repeated drug exposure that induce behavioral sensitization. CSA was performed in a two-bottle choice paradigm with two saccharin-drug associations in rats previously sensitized to morphine, cocaine, amphetamine and nicotine. In control rats morphine (1 and 5mg/kg s.c.), cocaine (5 and 10mg/kg i.p.), amphetamine (0.25 and 0.5mg/kg s.c.) and nicotine (0.4 mg/kg s.c.) induced dose-dependent CSA. Sensitization to morphine, cocaine and nicotine, which is known to reduce the responsiveness of NAc shell DA to the same drugs, also reduced CSA. In contrast, sensitization to amphetamine, that does not affect the responsiveness of NAc shell DA to the drug, failed to affect CSA. The results are consistent with the hypothesis that NAc shell DA is a substrate of the appetitive properties of drugs of abuse.


Robust biomarker identification for cancer diagnosis with ensemble feature selection methods.
Biomarker discovery is an important topic in biomedical applications of computational biology, including applications such as gene and SNP selection from high-dimensional data. Surprisingly, the stability with respect to sampling variation or robustness of such selection processes has received attention only recently. However, robustness of biomarkers is an important issue, as it may greatly influence subsequent biological validations. In addition, a more robust set of markers may strengthen the confidence of an expert in the results of a selection method. Our first contribution is a general framework for the analysis of the robustness of a biomarker selection algorithm. Secondly, we conducted a large-scale analysis of the recently introduced concept of ensemble feature selection, where multiple feature selections are combined in order to increase the robustness of the final set of selected features. We focus on selection methods that are embedded in the estimation of support vector machines (SVMs). SVMs are powerful classification models that have shown state-of-the-art performance on several diagnosis and prognosis tasks on biological data. Their feature selection extensions also offered good results for gene selection tasks. We show that the robustness of SVMs for biomarker discovery can be substantially increased by using ensemble feature selection techniques, while at the same time improving upon classification performances. The proposed methodology is evaluated on four microarray datasets showing increases of up to almost 30% in robustness of the selected biomarkers, along with an improvement of approximately 15% in classification performance. The stability improvement with ensemble methods is particularly noticeable for small signature sizes (a few tens of genes), which is most relevant for the design of a diagnosis or prognosis model from a gene signature. Supplementary data are available at Bioinformatics online.


The development of hepatocellular cancer in humans.
The biological characteristics of hepatocellular cancer vary appreciably in different parts of the world, but especially between regions with very high and low incidences of the tumour. Hepatocellular cancer is multifactorial in origin, and the pattern of its aetiological associations differs between populations at high and low risk. In Africans and Chinese, who have the highest incidences of hepatocellular cancer, the hepatitis B virus is the most important causal association. The viral carrier state is acquired during early childhood, and carries a relative risk for the development of the tumour of over 200. Integration of hepatitis B virus DNA probably acts as a genotoxic initiator in the multistep process of hepatocarcinogenesis, although the precise mechanisms involved have not been determined. Aflatoxin ingestion may also have an aetiological role in high incidence regions, probably as a genotoxic or epigenetic promoter to hepatitis B virus-initiated carcinogenesis. In low risk populations cirrhosis is the most important causal association of hepatocellular cancer. The cirrhosis is often the result of alcohol abuse, but the tumour may complicate all aetiological forms of this disease. Whether neoplasia is an inevitable consequence of the hyperplasia of cirrhosis, or the increased hepatocyte turnover rate acts as a promoter is not known. Hepatitis B virus infection plays a lesser part, and aflatoxin no part at all.


Evidence that lysosomes are not involved in the degradation of myofibrillar proteins in rat skeletal muscle.
To examine the role of lysosomes in the degradation of skeletal-muscle myofibrillar proteins, we measured the release of N tau-methylhistidine from perfused muscle of starved and fed rats in the presence or absence of agents that inhibit lysosomal proteinase activity. After 1 day of starvation, the release of N tau-methylhistidine by perfused muscle of 4-, 8- and 24-week-old rats increased by 322, 159 and 134% respectively. On the other hand, total protein breakdown, assessed by tyrosine release, increased by 62, 20 and 20% respectively. Inhibitors of lysosomal proteinases as well as high concentrations of insulin or amino acids failed to diminish the release of N tau-methylhistidine by perfused muscle of starved and fed rats, despite a 25-35% inhibition of total protein breakdown. The data strongly suggest that the complete breakdown of myofibrillar proteins occurs via a non-lysosomal pathway. They also suggest that total proteolysis, which primarily reflects non-myofibrillar protein breakdown, occurs at least in part within lysosomes.


Coupled-ring-resonator-based silicon modulator for enhanced performance.
A compact silicon coupled-ring modulator structure is proposed. Two rings are coupled to each other, and only one of these rings is actively driven and over-coupled to a waveguide, which enables high modulation speed. The resultant notch filter profile is steeper than that of the single ring and has exhibited a smaller resonance shift and lower driving electrical power. Simulation results include: (i) potentially 60-Gb/s non-return-to-zero (NRZ) data modulation and over 20-dB extinction ratio can be achieved by shifting the active ring by a 20 GHz resonance shift, (ii) the frequency chirp of the modulated signals can be adjusted by varying the coupling coefficient between the two rings, and (iii) dispersion tolerance at 0.5-dB power penalty is extended from 18 to 85 ps/nm, for a 40-Gb/s NRZ signal.


[Modern algorithms of diagnosis of benign tumors of the mammary gland: the role of molecular-genetic methods].
Experience of treatment in 2010-2012 yrs of the patients, suffering mammarial gland tumors, in The Center of Reconstructive and Restoration Medicine (The University Clinic) of The Odessa National Medical University was analyzed. There were examined 143 women with morphologically confirmed mammarial gland cancer (MGT), 56--benign mammary gland tumors and 50 healthy women. Molecular-genetic investigation was performed in the patients-women: there were determined the gene C634G polymorphism of VEGF and of the gene G308A of TNF--a with subsequent estimation of correlation of the mutations quantity and the mammarial gland diseases rate. Algorithm of differential diagnosis of benign tumors must include estimation of polymorphism of the VEGF gene C634G. While revealing of the heterozygous or homozygous bearers of mutation with the gene C634G polymorphism of VEGF the risk of the MGC occurrence is enhancing, what may serve as additional criterion for expedience for conduction of operative treatment in such patients.


SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis.
Two single nucleotide polymorphisms (SNPs) in SERPINA1 (Pi*Z rs28929474 and Pi*S rs17580) are risk factors for developing liver cirrhosis. A recent study identified a common SNP in HSD17B13 (rs72613567) that conferred protection from chronic liver disease. The aim of the present study was to test these associations in a cohort of Lithuanian patients with liver fibrosis or cirrhosis. The study included 302 patients with cirrhosis, 127 patients with liver fibrosis (METAVIR stages I-III) and 548 controls, all from Lithuania. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Adjusted p value of ≤ 0.016 was considered significant. Genotype distributions of SERPINA1 and HSD17B13 SNPs were in Hardy-Weinberg equilibrium. SERPINA1 Pi*Z was not associated with liver fibrosis or cirrhosis. HSD17B13 rs10433937 (in high linkage disequilibrium with rs72613567; r 2 =0.96) also showed no overall association with liver disease, but the GG- genotype was associated with reduced risk of liver fibrosis (aOR 0.37, p=0.03). SERPINA1 Pi*S was associated with higher risk of developing hepatic fibrosis (aOR 3.42, p=0.001) and cirrhosis (aOR 2.59, p=0.02). We found that SERPINA1 Pi*S variant conferred an increased risk of developing liver fibrosis, while SERPINA1 Pi*Z and HSD17B13 rs10433937 were not associated with liver fibrosis or cirrhosis of different aetiology.


Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study.
Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti-programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of any grade were fatigue/asthenia (31.8%), infusion-related reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1-positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.


Antimicrobial peptides within the Yellowtail Kingfish (Seriola lalandi).
A number of Seriola species are currently farmed or being investigated as future aquaculture species in countries around the world. However they face a number of issues and limitations which will need to be overcome to ensure future stability and growth, one of which are disease outbreaks. Despite this, very little has been done to understand the immune system of Seriola species and very few immune genes have been characterised. Antimicrobial peptides (AMP) are naturally occurring low molecular weight polypeptides that play a major role in an organism's immune system and act effectively as a first line of defence. This investigation isolates the full length cDNA sequences of two AMP's, piscidin and hepcidin from the yellowtail kingfish (Seriola lalandi). The full-length cDNA of the piscidin gene encodes a 65 amino acid prepropeptide, containing a 25-residue peptide, predicted to form an amphipathic helix-loop-helix structure. Phylogenetic analysis using fish piscidin sequences, showed that this AMP is only found in bony fish within the Acanthomorpha clade and that a possible three groups within the piscidin family exists, with S. lalandi belonging to a particular group. The full-length cDNA of the hepcidin gene encodes a 90 amino acid preprohepcidin, which contains a typical RX(R/K)R motif for cleavage of the mature peptide which comprises of eight conserved cysteine residues. Phylogenetic analysis of known vertebrate hepcidin antimicrobial peptide (HAMP) sequences, shows sequences from the Neoteleostei clade of bony fish form two very separate groups, HAMP1 and HAMP2, with the S. lalandi hepcidin gene grouped with the HAMP1 sequences. HAMP2 sequences are found to have multiple copies within fish and genome analysis showed very clearly that these two groups of genes are located on separate regions on the genome, with the multiple HAMP2 copies formed from tandem gene duplications. Lastly, using qPCR the expression of the S. lalandi piscidin gene within healthy fish was highest within, spleen and gills and lowest in liver, whereas hepcidin was highest in the liver with little or no expression in the spleen and gills.


Mortality of necrotizing enterocolitis and isolated ileal perforation at a single institution over the past 40 years.
Controversy exists regarding differences in mortality between isolated ileal perforation (IIP) and necrotizing enterocolitis (NEC). We sought to identify risk factors and determine mortality rates for these two entities. A retrospective review was conducted on all patients with NEC or IIP undergoing surgical management at our institution from May 1971 to December 2011. Demographics, birth history, management strategies, and mortality were recorded. Chi-square and unpaired t-test were used where appropriate. During the study period, 236 patients underwent operative management with 17.8% of those being for IIP. Patients with IIP had a lower estimated gestational age (27.8 ± 3.0 vs. 29.5 ± 4.2 weeks, p = 0.014), were more likely to be of multiple gestation (33.3 vs. 16.5%, p = 0.022), and were younger at diagnosis (8.7 ± 8.1 vs. 14.3 ± 11.1 days, p = 0.003) compared with those undergoing operation for NEC. Mortality was threefold lower with IIP (9.5 vs. 36.1%, p < 0.001). IIP carries a unique set of risk factors and has a significantly lower mortality rate when compared with NEC.


[The predictive value of a classification for proliferative diabetic vitreoretinopathy].
Kroll's classification of proliferative diabetic vitreoretinopathy (PDVR) defines stage A (vitreoretinal proliferations without retinal detachment), stage B (partially detached retina not involving the macula), stage C (partially detached macula) and stage D (completely detached macula). The purpose of this study was to analyse the prognostic value of Kroll's classification in respect of the postoperative results of vitreoretinal surgery based on our group of patients. The charts of 563 patients who underwent vitrectomy because of PDVR between 1990 and 1997 were examined retrospectively. Postoperative visual acuity, possible risk factors, frequencies of silicone oil tamponade and revitrectomies were related to the preoperative staging of PDVR. The influence of possible predictive factors on the postoperative visual outcome were evaluated using multivariate logistic regression analysis. After vitreoretinal surgery mean postoperative visual acuity was significantly better in stage A compared to stage C (p < 0.01) or D (p < 0.0001). In 179 out of 563 eyes (31.7 %) revitrectomy (including silicone oil removal) was required and in 51 eyes (9.1 %) more than one revitrectomy was performed. Silicone oil tamponade was used in 22 out of 253 eyes (8.7 %) classified as stage A, in 27 out of 201 eyes (13.4 %) of stage B, in 17 out of 78 eyes (21.8 %) of stage C and in 10 of 31 eyes (32.3 %) of stage D. Postoperative increase of visual acuity of more than 3 lines was significantly less frequent in stage B (p < 0.014), C (p < 0.039) and D (p < 0.001) compared to stage A. Kroll's classification for PDVR has a high prognostic value for the postoperative visual outcome and level of surgical risk management. Thus patients with good prognosis can be identified easily, facilitating the decision for surgery.


Nitrate therapy for congestive heart failure.
A randomized double-blind crossover trial included 16 patients with severe congestive heart failure who received isosorbide dinitrate or placebo for eight weeks, and then the opposite treatment for eight more weeks. All patients received their usual maintenance therapy with digitalis and diuretics. Seven morbid events occurred during 85 patient-weeks of isosorbide dinitrate therapy compared with 17 during 76 patient-weeks of placebo. Severity of congestive heart failure improved in all eight patients who received isosorbide dinitrate compared with two patients who showed improvement and five whose symptoms became worse with placebo. No significant differences in physical findings, cardiac dimensions, or resting hemodynamics were observed. Maximal exercise duration increased significantly by 2.54 minutes with isosorbide dinitrate therapy, and rose insignificantly by 1.24 minutes with placebo. This preliminary trial suggests that long-term vasodilator therapy may be clinically beneficial in congestive heart failure.


Political myths and totalitarianism: an anthropological analysis of their causal interrelationship.
This paper discusses the key political, anthropological and socio-cultural functions of political myths in the appearance and functioning of totalitarian regimes. A special emphasis is put on structural elements of the myth (mythemes) and the mythic content (narratives) in the processes of artificial construction of a new society (community) based on the myth-inspired ideological postulates. The paper argues that the establishment of totalitarianism marked a certain anthropological devolution. This devolution, in turn, proceeds through the deconstruction of civil society as an organic social sphere and the artificial construction of a new political community based on ideological postulates and political myths. In support of this assertion, it is first shown how the mythical narratives--transformed into political concepts and programs--were the basis of (re)interpretation of the world, society and individual, and essentially determined the nature and functioning of the totalitarian regimes. Then, the specific political myths are analyzed and compared, as well as their content and origin, and particularly their dual function. It in turn is analyzed in the framework of the classical society-community dichotomy, where the (civil) society is founded socio-politically on the social contract, and the (political) community socio-anthropologically on political myth. In a situation of identity and legitimacy crisis, anomie and the weakening of social cohesion--the characteristic conditions of the great economic and political crisis of the early twentieth century that enabled the emergence of totalitarianism--society as a contracting community does not work. A strong need for meaning (at the individual and societal level) affects the citizens' susceptibility to (political) concepts of (re)constitution of (political) community with which they can identify. Right there, totalitarian movements use the cohesive power of the political myth that replaces the rationally based constitution of society, and becomes a means of ideological mystification and political manipulation. Affecting the mind of the citizens, it moves their feelings and motivations and directs their behavior toward the goals of the totalitarian political power. Recent iterations of totalitarianism (Great-Serbian aggression), with the same tragic consequences, were a warning on the actuality of political myths and the danger of a resurgence of totalitarian tendencies.


Effect of local A-site strain on dipole stability in A6GaNb9O30 (A = Ba, Sr, Ca) tetragonal tungsten bronze relaxor dielectrics.
A series of isovalently A-site substituted relaxor dielectric tetragonal tungsten bronzes of general formula Ba(6-x-y)Sr(x)Ca(y)GaNb(9)O(30) were investigated. The long-range (average) crystal structure as determined by conventional diffraction techniques varies monotonically according to Vegard's law. The dielectric properties, however, do not display a similar, simple "average size" dependence and instead show a dependence on the statistical size variance, i.e. size mismatch, of the A-cation. The difficulties in Vogel-Fulcher analysis of relative permittivity and the complementary approach of using dielectric loss data fitted to Jonscher's empirical universal dielectric relaxation model is discussed.


Curcuminoids plus piperine improve nonalcoholic fatty liver disease: A clinical trial.
Nonalcoholic fatty liver disease (NAFLD) as a prevalent hepatic disease is associated with an increased risk of morbidity and mortality related to the liver and cardiovascular disease (CVD). Lifestyle modification and good metabolic control is the first line of treatment, but not always efficacious in reversing NAFLD pathogenesis. Curcumin is a dietary phytochemical with hepatoprotective activities, though its low bioavailability is considered as a major challenge for clinical applications. Therefore, in this study, in order to improve the bioavailability of curcumin, it was coadministered with piperine and we investigated the effects of this bioavailability-enhanced curcumin on serum hepatic enzymes, lipid profile, and glycemic indices in patients with NAFLD. In this randomized controlled parallel-group trial, 70 subjects with ultrasound-determined NAFLD were randomized to either 500 mg curcuminoids coadministered with 5 mg piperine daily or placebo for 12 weeks. NAFLD severity (on the basis of sonography) and hepatic function was assessed at baseline and at the study end. Seventy subjects completed the study. Supplementation with curcuminoids plus piperine significantly reduced the hematocrit (P = 0.027), erythrocyte sedimentation rate (P = 0.048) and the serum concentrations of alanine aminotransferase (P = 0.035), aspartate aminotransferase (P = 0.042), alkaline phosphatase (P = 0.004), cholesterol (P < 0.016), low-density lipoprotein cholesterol (P < 0.017), Iron (P = 0.026), and Hemoglobin (P = 0.025) and increased total iron-binding capacity (P = 0.003). However, except albumin, changes in other parameters were not statistically different between groups. In addition, administration of curcuminoids plus piperine significantly improved NAFLD severity (P < 0.001), which was statistically different compared with the placebo group (P = 0.022). Also, the percentage of improved patients was marginally higher in the curcuminoids plus piperine group when compared with the placebo group (P = 0.058). This study suggested beneficial effects of combined curcuminoids and piperine supplementation on disease severity in patients with NAFLD.


Bioactive Peptides: Potential Impact on the Treatment of Gastrointestinal Cancers.
We have reviewed the potential use of bioactive peptides in the treatment of gastrointestinal (GI) malignancies, which are a significant cause of morbidity and mortality globally. Conventional therapies, such as surgery, chemotherapy, and radiotherapy, are associated with numerous side effects that may lead to longterm complications. Bioactive peptides are short-chain amino acids that can be extracted from natural sources or synthesized, and they have various potential health benefits, including anti-inflammatory, anti-hypertensive, antioxidant, antimicrobial, and anti-cancer properties. Bioactive peptides can be acquired from animal or plant sources, and can be classified based on their function, such as ACE-inhibiting, antimicrobial, and electrolyte- regulating peptides. Recent studies have demonstrated the promising role of bioactive peptides in tumor suppression, especially when combined with conventional therapies. In this study, we have reviewed the beneficial properties of bioactive peptides and their role in suppressing tumor activity. The mechanisms of bioactive peptides in tumor suppression are discussed. We have further reviewed the findings of preclinical and clinical studies that have investigated the application of bioactive peptides in the treatment of GI cancers. This review highlights the potential use of bioactive peptides as a promising treatment method for GI malignancies to increase the quality of life of GI cancer patients.


The Fallacy of Average: How Using HbA1c Alone to Assess Glycemic Control Can Be Misleading.
HbA1c is a valuable metric for comparing treatment groups in a randomized trial, for assessing glycemic trends in a population over time, or for cross-sectional comparisons of glycemic control in different populations. However, what is not widely appreciated is that HbA1c may not be a good indicator of an individual patient's glycemic control because of the wide range of mean glucose concentrations and glucose profiles that can be associated with a given HbA1c level. To illustrate this point, we plotted mean glucose measured with continuous glucose monitoring (CGM) versus central laboratory-measured HbA1c in 387 participants in three randomized trials, showing that not infrequently HbA1c may underestimate or overestimate mean glucose, sometimes substantially. Thus, if HbA1c is to be used to assess glycemic control, it is imperative to know the patient's actual mean glucose to understand how well HbA1c is an indicator of the patient's glycemic control. With knowledge of the mean glucose, an estimated HbA1c (eA1C) can be calculated with the formula provided in this article to compare with the measured HbA1c. Estimating glycemic control from HbA1c alone is in essence applying a population average to an individual, which can be misleading. Thus, a patient's CGM glucose profile has considerable value for optimizing his or her diabetes management. In this era of personalized, precision medicine, there are few better examples with respect to the fallacy of applying a population average to a specific patient rather than using specific information about the patient to determine the optimal approach to treatment.


The Financial Impact of the Affordable Care Act on a Level-1 Orthopedic Trauma Service.
To determine the impact of the Affordable Care Act (ACA) on professional fees and proportion of payer type for an orthopedic trauma service at a level-1 trauma center. We analyzed professional fee data and payer mix for the 18 months before and after implementation of the ACA. Data were collected for inpatients (IP) and outpatients (OP). We corrected for changes in patient volume between the 2-time periods by calculating average values per patient. Post ACA, we treated a higher percentage of patients with Medicaid and had a reduction in the percentage of uninsured/county payers. Collections for IPs decreased $75.49/patient and OPs decreased $0.10/patient. Our collection rate decreased 6% for IPs and 5% for OPs. In particular, Medicaid collections decreased by $180/IP, and $4/OP, and Medicare decreased by $61/IP and increased $5/OP post ACA, whereas contract collections increased by $140/IP and $20/OP. The changes in our own institution's insurance were mixed with decreases of $514/IP for partial risk and $735/IP for full-risk insurance and increases of $1/OP for partial risk, and $35/OP for full-risk insurance. Post ACA, we saw less patients, primarily in the OP setting. This shift was accompanied by a significant decrease in our collection rate; specifically, a decrease in the amount we collected per Medicaid patient-the category of payer that increased post ACA. The ACA did allow more uninsured patients access to medical care but was associated with lower IP and OP reimbursements.


Hearts lacking caveolin-1 develop hypertrophy with normal cardiac substrate metabolism.
Long-chain fatty acids (FA) are the primary energy source utilized by the adult heart. However, during pathological cardiac hypertrophy the fetal gene program is reactivated and glucose becomes the major fuel source metabolized by the heart. Herein we describe the metabolic phenotype associated with caveolin-1(Cav1) gene ablation (Cav1ko) in cardiac fibroblasts. Cav1, the primary protein component of caveolae in non-muscle cells co-localizes with a number of proteins involved in substrate metabolism, including, FA translocase (CD36) and the insulin receptor. We demonstrate that Cav1ko hearts develop cardiac hypertrophy and contractile dysfunction at 5-6mos of age. Surprisingly, we observed an increase in the uptake of Intralipid triglyceride and albumin bound FA by 25% and 47%, respectively, in Cav1ko hearts. Isolated perfused heart studies revealed no significant difference in glucose oxidation and glycolysis, however, we observed a trend toward increased FA oxidation in Cav1ko hearts. Real-time PCR analysis revealed no significant changes in the expression of genes involved in FA and glucose metabolism. We also report myocardial triglyceride, fatty acid and cholesterol levels are significantly reduced in Cav1ko hearts. Microarray gene expression analysis revealed changes in genes that regulate calcium ion and lipid transport as well as a number of genes not previously linked to cardiac hypertrophy. We observed a 4-fold increase in tetraspanin-2 gene expression, a transmembrane protein implicated in regulating intracellular trafficking. Oxysterol binding protein related protein-3, which has been implicated in intracellular lipid synthesis and transport, was increased 3.6-fold. In addition, sarcoplasmic reticulum Ca(2+)-ATPase 3, and calcyclin gene transcripts were significantly increased in Cav1ko hearts. In summary, targeted loss of Cav1 produces a unique model of cardiac hypertrophy with normal substrate utilization and expression of genes involved in energy metabolism.


A unified perspective on the hydrogen atom transfer and proton-coupled electron transfer mechanisms in terms of topographic features of the ground and excited potential energy surfaces as exemplified by the reaction between phenol and radicals.
The relation between the hydrogen atom transfer (HAT) and proton-coupled electron transfer (PCET) mechanisms is discussed and is illustrated by multiconfigurational electronic structure calculations on the ArOH + R(*) --> ArO(*) + RH reactions. The key topographic features of the Born-Oppenheimer potential energy surfaces that determine the predominant reaction mechanism are the conical intersection seam of the two lowest states and reaction saddle points located on the shoulders of this seam. The saddle point corresponds to a crossing of two interacting valence bond states corresponding to the reactant and product bonding patterns, and the conical intersection corresponds to the noninteracting intersection of the same two diabatic states. The locations of mechanistically relevant conical intersection structures and relevant saddle point structures are presented for the reactions between phenol and the N- and O-centered radicals, (*)NH2 and (*)OOCH3. Points on the conical intersection of the ground doublet D0 and first excited doublet D1 states are found to be in close geometric and energetic proximity to the reaction saddle points. In such systems, either the HAT mechanism or both the HAT mechanism and the proton-coupled electron transfer (PCET) mechanism can take place, depending on the relative energetic accessibility of the reaction saddle points and the D0/D1 conical intersection seams. The discussion shows how the two mechanisms are related and how they blend into each other along intermediate reaction paths. The recognition that the saddle point governing the HAT mechanism is on the shoulder of the conical intersection governing the PCET mechanism is used to provide a unified view of the competition between the two mechanisms (and the blending of the two mechanisms) in terms of the prominent and connected features of the potential energy surface, namely the saddle point and the conical intersection. The character of the dual mechanism may be understood in terms of the dominant valence bond configurations of the intersecting states, which are zero-order approximations to the diabatic states.


Preload reserve and mechanisms of afterload mismatch in normal conscious dog.
Preload reserve and mechanisms of afterload mismatch were examined in 10 normal conscious dogs. The left ventricular (LV) pressure, wall thickness, and external major and minor axis diameters (sonomicrometry) were measured during sinus rhythm, and beat-averaged pressure-volume loops were generated. With maximum angiotensin II infusion, LV end-diastolic volume (EDV) increased by 13 +/- 2% (SEM), LV peak pressure (LVSP) increased by 44 +/- 6%, and stroke volume decreased by 12 +/- 3% (P less than 0.01), demonstrating an apparent descending limb of LV performance. With volume load alone, EDV increased by 9 +/- 2% from control (P less than 0.01), and stroke volume increased by 13 +/- 2%; mean wall stress during ejection was not increased, and heart rate and end-systolic pressure-volume relations showed no changes. To test whether the descending limb of function was due to maximum use of preload reserve or to inadequate venous return, angiotensin infusion was repeated during volume load. The descending limb relating LVEDV to stroke volume was always shifted upward and to the right after volume load, and the stroke volume at a comparable wall stress was 12 +/- 3% higher than during control angiotensin infusion (P less than 0.01). During pressure loading plus volume loading, the maximum EDV increase was 16 +/- 2%, and assuming unchanged afterload and end-systolic volume, an average maximum stroke volume reserve of 31 +/- 4% is calculated. 1) We conclude that sizable preload and stroke volume reserves exist in the normal resting dog; and 2) we describe a mechanism for the descending limb of LV performance curves produced by pressure loading in the intact circulation, which is related to inadequate venous return.


Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome.
Mice homozygous for the transgenic insertion in line OVE250 exhibit severe progressive glomerulonephritis. Ultrastructural changes in the glomerular basement membrane (GBM) at 2 weeks of age resemble those in Alport syndrome. The transgenic insertion site was mapped by FISH to mouse chromosome 1 close to Pax3. Genetic and molecular analyses identified a deletion of genomic DNA at the transgene insertion site. Exons 1 through 12 of the collagen IV gene Col4a4, exons 1 and 2 of the adjacent Col4a3 gene, and the intergenic promoter region are deleted. Transcripts of Col4a3 and Col4a4 are undetectable in mutant kidney, and both proteins are missing from the GBM. Persistent cellular proliferation in mutant kidneys suggests that interaction with the extracellular matrix may be important for cell maturation. Evolutionarily conserved sequence elements in the promoter regions of human and mouse Col4a3 and Col4a4 include a 19-bp element that was tandemly duplicated in the human lineage and a CTC box element common to several genes encoding extracellular matrix proteins. This new animal model of Alport syndrome, Col4Delta3-4, lacks both alpha3 and alpha4 chains of collagen IV and exhibits an earlier disease onset than mice lacking alpha3 only.


Factor VIII ectopically expressed in platelets: efficacy in hemophilia A treatment.
Activated platelets release their granule content in a concentrated fashion at sites of injury. We examined whether ectopically expressed factor VIII in developing megakaryocytes would be stored in alpha-granules and whether its release from circulating platelets would effectively ameliorate bleeding in a factor VIIInull mice model. Using the proximal glycoprotein 1b alpha promoter to drive expression of a human factor VIII cDNA construct, transgenic lines were established. One line had detectable human factor VIII that colocalizes with von Willebrand factor in platelets. These animals had platelet factor VIII levels equivalent to 3% to 9% plasma levels, although there was no concurrent plasma human factor VIII detectable. When crossed onto a factor VIIInull background, whole blood clotting time was partially corrected, equivalent to a 3% correction level. In a cuticular bleeding time study, these animals also had only a partial correction, but in an FeCl3 carotid artery, thrombosis assay correction was equivalent to a 50% to 100% level. These studies show that factor VIII can be expressed and stored in platelet alpha-granules. Our studies also suggest that platelet-released factor VIII is at least as potent as an equivalent plasma level and perhaps even more potent in an arterial thrombosis model.


Early impact and performance characteristics of an established anal dysplasia screening program: program evaluation considerations.
Screening for invasive anal cancer and its precursors is being increasingly advocated as a response to increasing incidence among HIV-infected persons. We implemented a comprehensive screening program in 2001 and report our early experience to inform monitoring and evaluation of such programs. Our research aims were: (1) to estimate incidence of and mortality from invasive anal cancer (IAC) before (1995-2000) and after (2001-2005) screening program implementation and (2) to examine potential screening program quality indicators. The study cohort included all patients under care for HIV infection at UCSD Owen Clinic between 1995-2005. Person-time incidence rates (IR) and case survival of IAC were estimated for the pre-screening (1995-2000) and post-screening (2001-2005) periods. High resolution anoscopy (HRA) operator accuracy was estimated by kappa agreement between cyto-histologic comparisons. Program quality indicators included: (1) screening coverage; (2) percent technically unsatisfactory cytology smears; (3) time between 1st abnormal cytology and 1st HRA; and (4) time between last clinic visit and last cytology. 28 cases of IAC and 13,411 person-years were observed between 1995-2005. IRs (95% CI) pre-screening and post-screening were 199 and 216 per 100,000 person-years, respectively. There was no routine treatment of high grade squamous intraepithelial lesions (HSIL) during the study period. The percent of patients with IAC requiring chemoradiation decreased from 90.9% to 70.6% (p=0.36). There was a significant improvement in cyto-histologic agreement at HRA with increasing operator experience (r=0.92, p=0.025). Screening coverage was 73% of the target population. Among 14 providers, the percent unsatisfactory cytology smears averaged 27% but varied from 0 - 62%. The median time from 1st abnormal cytology to 1st HRA was 258 days. The median interval between the last cytology and the last clinic visit was 207 days. (1) The overall IR of IAC did not decline in the screening era and was higher than previous estimates for HIV cohorts; (2) stage shift to IAC of more favorable prognosis is a reasonable screening goal; (3) HRA accuracy varied by provider experience; (4) because of delay in access to HRA, digital rectal exam should be combined with cytology screening to detect palpable disease.


The premonitory phase of migraine--what can we learn from it?
This review aims to understand the prevalence of premonitory symptoms in migraine, postulate their mechanisms, and compare these with functional imaging studies. A thorough literature review was conducted using PubMed for prevalence studies of premonitory symptoms in migraine and functional imaging studies in the premonitory phase. The majority of studies have been retrospective reporting a prevalence of 7-88% for premonitory symptoms in migraine. Only one study has investigated premonitory symptoms prospectively and used preselected patients with recognized premonitory symptoms. The majority of patients were able to predict correctly the onset of migraine headache. Only one functional imaging study has been conducted in the premonitory phase that showed activation of posterolateral hypothalamus, midbrain tegmental area and substantia nigra, periaqueductal gray, dorsal pons, and various cortical areas including occipital, temporal, and prefrontal cortex. Subgroup analysis of patients with photophobia more than without photophobia in the premonitory phase showed activation of the occipital cortex. Comparison of patients with nausea more than without nausea in the premonitory phase showed activation in upper dorsal medulla and periaqueductal gray. Premonitory symptoms are common in migraine, although the true prevalence cannot be stated with certainty in the absence of prospective studies in unselected patients. Hypothalamic involvement can explain many of the premonitory symptoms. Activation of the the brainstem structures and hypothalamus before pain suggests a pivotal role of these structures in the pathogenesis of migraine. Hypersensitivity to light and occurrence of nausea in migraine is associated with activation of central brain structures involved in these pathways, and this can occur in the absence of pain.


Evaluation of outcome and cost-effectiveness using an FDG PET-guided approach to management of patients with coronary disease and severe left ventricular dysfunction (PARR-2): rationale, design, and methods.
Patients with severe ventricular dysfunction and coronary disease have high morbidity and mortality. They may benefit from revascularization but have significant perioperative morbidity and mortality. Positron emission tomography (PET) imaging with F-18-fluorodeoxyglucose (FDG) can detect viable myocardium that may recover from revascularization in such patients. It is unclear whether use of FDG PET in this population improves outcome or is cost-effective. The principal aim of this study is to determine whether FDG PET-guided therapy improves clinical outcome compared to standard care. Secondary objectives are to determine whether FDG PET-guided therapy improves left ventricular (LV) function, improves quality of life, and provides a cost benefit versus standard care. Included in this multicenter randomized controlled trial are patients with coronary artery disease and severe LV dysfunction who are referred for revascularization, heart failure, or cardiac transplantation or in whom FDG PET is potentially useful. Consenting subjects will be randomized to therapy directed by FDG PET or standard care. The primary outcome is the composite cardiovascular endpoint of cardiac death, myocardial infarction, transplantation, or rehospitalization for unstable angina or heart failure. Secondary outcomes include health-related quality of life, costs, mortality, cardiovascular events, and LV function. Assuming two-sided alpha=0.05, power=80%, a sample size of 206 patients per group is required to detect a 15% absolute difference in the primary outcome between PET-directed therapy compared to standard care. Analyses will be conducted on an intention-to-treat basis. To our knowledge, this is the first large trial to evaluate whether FDG PET-directed therapy is effective and provides a cost benefit in patients with severe LV dysfunction. If so, thousands of such patients can be risk-stratified to select who is likely to benefit from revascularization.


MicroRNA-122 in patients with hepatitis B and hepatitis B virus-associated hepatocellular carcinoma.
Hepatitis B virus (HBV) infection is known as a serious problem in the domain of public health and approximately 350 million people across the world are affected with this infectious disease. As well, microRNAs are recognized as a type of small non-coding RNAs that can be widely used as a diagnostic biomarker and prognosis method of special diseases. In this respect, microRNA-122 or miR-122 can play a significant role in the pathogenesis of several hepatic diseases. Given the importance of microRNA-122 in the liver as well as its pathology, this study focused on the potential functions of microRNA-122 in pathogenesis, diagnosis, and treatment of HBV infection. In this regard, the findings of previous studies had indicated that expression of microRNA-122 in patients with HBV infection could be significantly deregulated. The results of this study were consistent with the idea that diagnosis and treatment of this infectious disease using microRNA-122 could be an efficient method.


Macrophage Effects on Mesenchymal Stem Cell Osteogenesis in a Three-Dimensional In Vitro Bone Model.
As musculoskeletal (MSK) disorders continue to increase globally, there is an increased need for novel, in vitro models to efficiently study human bone physiology in the context of both healthy and diseased conditions. For these models, the inclusion of innate immune cells is critical. Specifically, signaling factors generated from macrophages play key roles in the pathogenesis of many MSK processes and diseases, including fracture, osteoarthritis, infection etc. In this study, we aim to engineer three-dimensional (3D) and macrophage-encapsulated bone tissues in vitro, to model cell behavior, signaling, and other biological activities in vivo, in comparison to current two-dimensional models. We first investigated and optimized 3D culture conditions for macrophages, and then co-cultured macrophages with mesenchymal stem cells (MSCs), which were induced to undergo osteogenic differentiation to examine the effect of macrophage on new bone formation. Seeded within a 3D hydrogel scaffold fabricated from photocrosslinked methacrylated gelatin, macrophages maintained high viability and were polarized toward an M1 or M2 phenotype. In co-cultures of macrophages and human MSCs, MSCs displayed immunomodulatory activities by suppressing M1 and enhancing M2 macrophage phenotypes. Lastly, addition of macrophages, regardless of polarization state, increased MSC osteogenic differentiation, compared with MSCs alone, with proinflammatory M1 macrophages enhancing new bone formation most effectively. In summary, this study illustrates the important roles that macrophage signaling and inflammation play in bone tissue formation.


Quantitative trait Loci analysis using the false discovery rate.
False discovery rate control has become an essential tool in any study that has a very large multiplicity problem. False discovery rate-controlling procedures have also been found to be very effective in QTL analysis, ensuring reproducible results with few falsely discovered linkages and offering increased power to discover QTL, although their acceptance has been slower than in microarray analysis, for example. The reason is partly because the methodological aspects of applying the false discovery rate to QTL mapping are not well developed. Our aim in this work is to lay a solid foundation for the use of the false discovery rate in QTL mapping. We review the false discovery rate criterion, the appropriate interpretation of the FDR, and alternative formulations of the FDR that appeared in the statistical and genetics literature. We discuss important features of the FDR approach, some stemming from new developments in FDR theory and methodology, which deem it especially useful in linkage analysis. We review false discovery rate-controlling procedures--the BH, the resampling procedure, and the adaptive two-stage procedure-and discuss the validity of these procedures in single- and multiple-trait QTL mapping. Finally we argue that the control of the false discovery rate has an important role in suggesting, indicating the significance of, and confirming QTL and present guidelines for its use.


Regionally autonomous segmentation within zebrafish presomitic mesoderm.
Similar to chick, mouse, and Xenopus, a number of intercellular signaling pathways are required for zebrafish segmentation. However, the spatial scales over which these signaling pathways operate in zebrafish remain largely unknown. During zebrafish segmentation, waves of her1 transcription (a) initiate within the tailbud region, (b) propagate anteriorly through presomitic mesoderm (PSM), and (c) terminate in the anlage of newly-forming somites. These observations raise the question of whether the tailbud region serves as a "pacemaker" or "organizing center" for the initiation of propagating her1 expression waves. Microsurgical manipulations reveal that the anteriorly waves of her1 transcription are not perturbed by removal of the zebrafish tailbud. Furthermore, expression patterns of deltaD, paraxial protocadherin C (papc), and myoD within recently formed somites also appear to be relatively unperturbed by either removal of the tailbud, or by removal of lateral plate mesoderm. Although dynamic gene networks rapidly specify mesenchymal or epithelial cellular identities within forming somites, this specification is plastic. Time-lapse analysis has shown that the cellular progeny of mitotically-active epithelial border cells within newly formed somites can adopt different cellular identities than their precursor cells. Overall, these results indicate that sustained long-range intercellular communication with the tailbud, anterior somites, or lateral plate mesoderm is not necessary for segmentation or somitogenesis to proceed within the PSM. The basic segmentation and somitogenesis processes in zebrafish presomitic mesoderm appear to be largely regionally autonomous and governed by local morphogenetic cell behaviors.


Impurity effect on weak antilocalization in the topological insulator Bi2Te3.
We study the weak antilocalization (WAL) effect in topological insulator Bi(2)Te(3) thin films at low temperatures. The two-dimensional WAL effect associated with surface carriers is revealed in the tilted magnetic field dependence of magnetoconductance. Our data demonstrate that the observed WAL is robust against deposition of nonmagnetic Au impurities on the surface of the thin films, but it is quenched by the deposition of magnetic Fe impurities which destroy the π Berry phase of the topological surface states. The magnetoconductance data of a 5 nm Bi(2)Te(3) film suggests that a crossover from symplectic to unitary classes is observed with the deposition of Fe impurities.


CKD-MBD spectrum at the time of initiation of hemodialysis in Pakistani chronic kidney disease patients.
Chronic kidney disease (CKD) is associated with mineral and bone disorder (MBD), which results in significant morbidity and mortality. To determine the spectrum of CKD- MBD in the Pakistani population, we performed a retrospective review of the medical records of 63 native Pakistani CKD stage-5 patients at our unit at the initiation of hemodialysis from March 2009 to September 2011. The cohort included 28 males and 35 females, with an age range of 18- 87 years (mean age 51 years). We reviewed the serum parathormone (PTH) levels along with other serum biochemical markers according to the KDIGO 2009 guidelines. There were 25 (40%) patients who had PTH <150 pmol/L, 15 (22%) patients who had PTH from 150 to 300 pmol/L and 24 (38%) patients who had PTH >300 pmol/L. Subgroup analysis and follow-up of patients with initial PTH >300 pmol/L (n = 24) showed treatment response in nine patients (38%). We conclude that at initiation of hemodialysis, a significant number of patients had low PTH and a similar percentage of high PTH in our population states. Therefore, we recommend early assessment of renal bone disease spectrum to prevent morbidity and mortality associated with mineral bone disorder in CKD patients.


Thalidomide in type-2 lepra reaction--a clinical experience.
A clinical experience of using thalidomide in type-2 lepra reaction (ENL) in 90 male patients--57 with lepromatous leprosy (LL) and 33 with borderline lepromatous leprosy (BL)--is described. All the patients responded well although some took a longer time to improve. No major side effects were observed except for giddiness in 10 and gastrointestinal upsets in 7 patients. Thalidomide thus appears to be a very effective drug in the treatment of severe type-2 lepra reaction and apart from its historically well-documented embryopathic effects, does not seem to have any other serious side effects in the patients under study.


Prevolutionary dynamics and the origin of evolution.
Life is that which replicates and evolves. The origin of life is also the origin of evolution. A fundamental question is when do chemical kinetics become evolutionary dynamics? Here, we formulate a general mathematical theory for the origin of evolution. All known life on earth is based on biological polymers, which act as information carriers and catalysts. Therefore, any theory for the origin of life must address the emergence of such a system. We describe prelife as an alphabet of active monomers that form random polymers. Prelife is a generative system that can produce information. Prevolutionary dynamics have selection and mutation, but no replication. Life marches in with the ability of replication: Polymers act as templates for their own reproduction. Prelife is a scaffold that builds life. Yet, there is competition between life and prelife. There is a phase transition: If the effective replication rate exceeds a critical value, then life outcompetes prelife. Replication is not a prerequisite for selection, but instead, there can be selection for replication. Mutation leads to an error threshold between life and prelife.


Total body irradiation in non-Hodgkin lymphoma.
17 patients with non-Hodgkin lymphomas were treated by total body irradiation (TBI). 94% went into remission. Response in lymphosarcomas was found to be extremely good with long periods of unmaintained remission. Reticulumcell sarcomas responded poorly.


Microbial rock inhabitants survive hypervelocity impacts on Mars-like host planets: first phase of lithopanspermia experimentally tested.
The scenario of lithopanspermia describes the viable transport of microorganisms via meteorites. To test the first step of lithopanspermia, i.e., the impact ejection from a planet, systematic shock recovery experiments within a pressure range observed in martian meteorites (5-50 GPa) were performed with dry layers of microorganisms (spores of Bacillus subtilis, cells of the endolithic cyanobacterium Chroococcidiopsis, and thalli and ascocarps of the lichen Xanthoria elegans) sandwiched between gabbro discs (martian analogue rock). Actual shock pressures were determined by refractive index measurements and Raman spectroscopy, and shock temperature profiles were calculated. Pressure-effect curves were constructed for survival of B. subtilis spores and Chroococcidiopsis cells from the number of colony-forming units, and for vitality of the photobiont and mycobiont of Xanthoria elegans from confocal laser scanning microscopy after live/dead staining (FUN-I). A vital launch window for the transport of rock-colonizing microorganisms from a Mars-like planet was inferred, which encompasses shock pressures in the range of 5 to about 40 GPa for the bacterial endospores and the lichens, and a more limited shock pressure range for the cyanobacterium (from 5-10 GPa). The results support concepts of viable impact ejections from Mars-like planets and the possibility of reseeding early Earth after asteroid cataclysms.