Case study on the orientation of phaco hand pieces during steam sterilization processes.
Steam sterilization is an essential part of infection prevention. The literature shows that sterilization of medical instruments containing channels is not trivial. Phaco hand pieces have a simple configuration: a device contains a channel with a constant radius. No literature was found indicating whether the sterilization conditions on the inner surface of a phaco hand piece are influenced by the orientation of the hand piece. To determine whether the orientation of a phaco hand piece influences the results of a sterilization process of this device. A qualitative case study, including experiments, is performed with a protocolled combination of steam sterilizer, process, phaco hand piece, orientation of the phaco hand piece, and wrapping. In this specific case, the orientation of the hand piece influenced the result of the steam sterilization process; in vertically (upright) oriented phaco hand pieces with free water drainage, sterilization conditions are reproducibly established. In the same process, in horizontally oriented or vertically oriented hand pieces without free drainage, these conditions are not established in a reproducible way. In the investigated combination of sterilizer, process, load, loading pattern and wrapping, phaco hand pieces have to be oriented vertically (upright) with free water drainage to obtain steam sterilization conditions on the inner surface. It is likely that instruments with comparable configuration and dimensions will yield comparable results. It is therefore recommended that this issue is considered during the development of medical instruments and during performance qualifications of such instruments.


[Prevalence of dermatoses in residents of institutions for the elderly].
To determine the prevalence of dermatoses in 75 elderly residents in an institution of long permanence in the city of Santos, and to compare findings with those in literature. Seventy five healthy elderly persons were submitted to a dermatological exam. The prevalence, the average number per elderly person and the frequency of dermatoses were calculated from the data collected. An analysis was then made of the distribution in the subgroups of, gender, race, age bracket as well as of dermatosis in the main sub-groups. The total number of diagnoses of dermatosis was 280 with an average number of 3.73/per elderly person and 32 different types of dermatosis: were found. The prevalence of the dermatosis most often found was respectively: melanosis (53.3%), seborrheic keratosis (46.6%), onychomycosis (37.3%), nevus (33.3%), senile purpura (29.3%), xerosis (14.6%), scabies (12.0%) and malignant neoplasm (1.3%). The distribution of dermatosis was 70% (CI95%: 59% to 81%) higher in the female population than in the male. Notwithstanding the small number of cases, these data are compatible with the few reports available in literature. This study of prevalence defined the distribution of dermatosis in a fraction of the elderly population. However the aggregate data of subsequent casuistries may provide the more precise information whose relevance is undeniable in the orientation of individual and collective future health measures.


Outcome after surgical resections of recurrent chest wall sarcomas.
Sarcomas of the chest wall are rare, and wide surgical resection is generally the cornerstone of treatment. The objective of our study was to evaluate outcome of full-thickness resections of recurrent and primary chest wall sarcomas. To evaluate morbidity, mortality, and overall and disease-free survival after surgical resection of primary and recurrent chest wall sarcomas, we performed a retrospective review of all patients with sarcomas of the chest wall surgically treated at two tertiary oncologic referral centers between January 1980 and December 2006. Patient, tumor, and treatment characteristics, as well as the follow-up of these patients, were retrieved from the patients' original records. One hundred twenty-seven patients were included in this study, 83 patients with a primary sarcoma and 44 patients with a recurrence. Age, sex, tumor size, histologic type, grade and localization on the chest wall were similar for both groups. Fewer neoadjuvant and adjuvant therapies were used in the treatment of recurrences. Chest wall resection was more extensive in the recurrent group, which did not result in more complications (23%) or more reinterventions (5%). Microscopically radical resection was achieved in 80% of the primary sarcomas and 64% of the recurrences. With a median follow-up of 73 months, disease-free survival after surgery for recurrences was 18 months versus 36 months for primary sarcomas, with 5-year survival rates of 50% and 63%, respectively. Although chances for local control are lower after surgical treatment of recurrent chest wall sarcoma, chest wall resection is a safe and effective procedure, with an acceptable survival.


Activation of signaling pathways and stress-response genes in an experimental model of retinal detachment.
Despite the high metabolic demands of the neural retina, its detachment from the retinal pigment epithelium does not lead to immediate death for most of the cells. This study was undertaken to test the hypothesis that intrinsic protective mechanisms are activated in the neural retina during early stages of retinal detachment. Retinal detachments were created in Brown Norway rats by injection of 1% hyaluronic acid into the subretinal space. Gene expression profiles of retinas detached for 24 hours were generated with a gene microarray (rat U34 GeneChips; Affymetrix, Santa Clara, CA) and compared to the profiles from control attached retinas in a robust multiarray protocol and false-discovery-rate analysis. Changes in individual, differentially expressed genes were validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Additional qRT-PCR and immunoblot analyses were performed for additional selected genes. Genome-wide expression profiling revealed 27 genes that are differentially expressed in retinas detached for 24 hours. In silico analysis and functional clustering suggested that most genes belonged to three signaling pathways: interleukin-6/STAT, transforming growth factor-beta/Smad, and aryl hydrocarbon receptor oxidative stress response. Additional analyses of selected genes from these pathways demonstrated a time-dependent increase in their expression in detached retinas. Retinal detachment results in the early activation of stress-response genes and specific signaling pathways. This adaptive response may enable the photoreceptor cells to survive the acute phase of a retinal detachment, and it is the breakdown of these protective mechanisms in chronic disease that leads to the ultimate death of the cell.


Lessons from the synthetic chemist nature.
This conceptual review examines the ideal multistep synthesis from the perspective of nature. We suggest that besides step- and redox economies, one other key to efficiency is steady state processing with intermediates that are immediately transformed to the next intermediate when formed. We discuss four of nature's strategies (multicatalysis, domino reactions, iteration and compartmentation) that commonly proceed via short-lived intermediates and show that these strategies are also part of the chemist's portfolio. We particularly focus on compartmentation which in nature is found microscopically within cells (organelles) and between cells and on a molecular level on multiprotein scaffolds (e.g. in polyketide synthases) and demonstrate how compartmentation is manifested in modern multistep flow synthesis.


The Effects of Milkweed Induced Defense on Parasite Resistance in Monarch Butterflies, Danaus plexippus.
Many plants express induced defenses against herbivores through increasing the production of toxic secondary chemicals following damage. Phytochemical induction can directly or indirectly affect other organisms within the community. In tri-trophic systems, increased concentrations of plant toxins could be detrimental to plants if herbivores can sequester these toxins as protective chemicals for themselves. Thus, through trophic interactions, induction can lead to either positive or negative effects on plant fitness. We examined the effects of milkweed (Asclepias spp.) induced defenses on the resistance of monarch caterpillars (Danaus plexippus) to a protozoan parasite (Ophryocystis elektroscirrha). Milkweeds contain toxic secondary chemicals called cardenolides, higher concentrations of which are associated with reduced parasite growth. Previous work showed that declines in foliar cardenolides caused by aphid attack render monarch caterpillars more susceptible to infection. Here, we ask whether cardenolide induction by monarchs increases monarch resistance to disease. We subjected the high-cardenolide milkweed A. curassavica and the low-cardenolide A. syriaca to caterpillar grazing, and reared infected and uninfected caterpillars on these plants. As expected, monarchs suffered less parasite growth and disease when reared on A. curassavica than on A. syriaca. We also found that herbivory increased cardenolide concentrations in A. curassavica, but not A. syriaca. However, cardenolide induction in A. curassavica was insufficient to influence monarch resistance to the parasite. Our results suggest that interspecific variation in cardenolide concentration is a more important driver of parasite defense than plasticity via induced defenses in this tri-trophic system.


Effective management of epistaxis in athletes.
To review current management techniques and describe an alternative technique for managing epistaxis in athletes. Nosebleeds are not usually considered a serious medical condition, but management can be a challenge. Traditional management techniques may place opposing athletes at risk for blood exposure. DESCRPTION: The purpose of this article is to review the anatomy of the nasal blood supply, discuss various etiologies and outline the evaluation of epistaxis, and present various management techniques, including an alternative to traditional techniques. The alternative management technique presented allows effective management of epistaxis and quick return to play while reducing the risk of blood exposure for other competitors.


Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses.
Background: Chorioamnionitis, inflammation of the fetal membranes during pregnancy, is often caused by intra-amniotic (IA) infection with single or multiple microbes. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). Neonates with NEC have structural and functional damage to the intestinal mucosa and the enteric nervous system (ENS), with loss of enteric neurons and glial cells. Yet, the impact of acute, chronic, or repetitive antenatal inflammatory stimuli on the development of the intestinal mucosa and ENS has not been studied. The aim of this study was therefore to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs. Materials and Methods: A sheep model of pregnancy was used in which the ileal mucosa, submucosa, and ENS were assessed following IA exposure to lipopolysaccharide (LPS) for 2 or 7 days (acute), Ureaplasma parvum (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS). Results: IA LPS exposure for 7 days or IA UP exposure for 42 days caused intestinal injury and inflammation in the mucosal and submucosal layers of the gut. Repetitive microbial exposure did not further aggravate injury of the terminal ileum. Chronic IA UP exposure caused significant structural ENS alterations characterized by loss of PGP9.5 and S100β immunoreactivity, whereas these changes were not found after re-exposure of chronic UP-exposed fetuses to LPS for 2 or 7 days. Conclusion: The in utero loss of PGP9.5 and S100β immunoreactivity following chronic UP exposure corresponds with intestinal changes in neonates with NEC and may therefore form a novel mechanistic explanation for the association of chorioamnionitis and NEC.


Tailchaser (Tlc): a new mouse mutation affecting hair bundle differentiation and hair cell survival.
We have undertaken a phenotypic approach in the mouse to identifying molecules involved in inner ear function by N-ethyl-N-nitrosourea mutagenesis followed by screening for new dominant mutations affecting hearing or balance. The pathology and genetic mapping of the first of these new mutants, tailchaser (Tlc), is described here. Tlc/+ mutants display classic behavioural symptoms of a vestibular dysfunction, including head-shaking and circling. Behavioural testing of ageing mice revealed a gradual deterioration of both hearing and balance function, indicating that the pathology caused by the Tlc mutation is progressive, similar to many dominant nonsyndromic deafnesses in humans. Based on scanning electron microscopy (SEM) studies, Tlc clearly plays a developmental role in the hair cells of the cochlea since the stereocilia bundles fail to form the characteristic V-shape pattern around the time of birth. By young adult stages, Tlc/+ outer hair bundles are grossly disorganised although inner hair bundles appear relatively normal by SEM. Increased compound action potential thresholds revealed that the Tlc/+ cochlear hair cells were not functioning normally in young adults. Similar to inner hair cells, the hair bundles of the vestibular hair cells also do not appear grossly disordered. However, all types of hair cells in the Tlc/+ inner ear eventually degenerate, apparently regardless of the degree of organisation of their hair bundles. We have mapped the Tlc mutation to a 12 cM region of chromosome 2, between D2Mit164 and D2Mit423. Based on the mode of inheritance and map location, Tlc appears to be a novel mouse mutation affecting both hair cell survival and stereocilia bundle development.


"We want respect": adults with intellectual and developmental disabilities address respect in research.
Respect is central to ethical guidelines for research. The scientific community has long debated, and at times disagreed on, how to demonstrate respect in research with adults with intellectual and developmental disabilities. To illuminate the voices of those most affected, the author studies the views of adults with intellectual and developmental disabilities on respect in research. Findings are consistent with disability rights' ideas and indicate that adults with intellectual and developmental disabilities have much to contribute to the discussion, that they value participating, and that they agree with calls to focus on human rights and dignity. Notably, participants spoke at lengths about the nature of interactions between researchers and participants. Implications are discussed, including how to infuse research standards with community-supported values and preferences.


A closer look at the distribution of number needed to treat (NNT): a Bayesian approach.
In this paper, I present a Bayesian approach to estimation of the number needed to treat (NNT). The use of NNT as a measure of clinical benefit is now becoming commonplace. Various methods of estimation have been proposed, but none of them seem to provide entirely good estimates. Very little has been done to understand the statistical properties of NNT. Here, I derive the posterior distribution of NNT and use simulations to investigate the general behaviour of the distribution. The posterior mode of the distribution is proposed as a point estimate and results are compared with the conventional method of estimation of NNT done by inversion.


Calponin. Developmental isoforms and a low molecular weight variant.
Two-dimensional gel analysis of basic proteins in developing human smooth muscle identifies calponin as a prominent marker of the differentiated phenotype. Adult tissue (human and mouse) typically expresses up to four calponin isoforms, three of which appear sequentially during fetal development: adult myometrial cells express the same three isoforms in primary culture in vitro and these are down-regulated, in reverse order, during the subsequent modulation of phenotype. Monospecific, polyclonal antibodies against calponin identify a lower molecular weight variant of calponin (L-calponin) that is strongly and specifically expressed in adult smooth muscles of the human urogenital tract. L-calponin is down-regulated in benign smooth muscle derived tumors (leiomyoma) and is not expressed in primary cultures of normal uterine tissue.


Mechanisms of lead and manganese neurotoxicity.
Human exposure to neurotoxic metals is a global public health problem. Metals which cause neurological toxicity, such as lead (Pb) and manganese (Mn), are of particular concern due to the long-lasting and possibly irreversible nature of their effects. Pb exposure in childhood can result in cognitive and behavioural deficits in children. These effects are long-lasting and persist into adulthood even after Pb exposure has been reduced or eliminated. While Mn is an essential element of the human diet and serves many cellular functions in the human body, elevated Mn levels can result in a Parkinson's disease (PD)-like syndrome and developmental Mn exposure can adversely affect childhood neurological development. Due to the ubiquitous presence of both metals, reducing human exposure to toxic levels of Mn and Pb remains a world-wide public health challenge. In this review we summarize the toxicokinetics of Pb and Mn, describe their neurotoxic mechanisms, and discuss common themes in their neurotoxicity.


Echelette optical low-pass filter as a Bangerter filter for diagnosis and treatment of amblyopia and diplopia.
This paper presents a new echelette optical low-pass filter that serves as a Bangerter filter (BF) for diagnosis and treatment of amblyopia and diplopia. Theoretical analysis and experimental measurements showed that echelette BFs have several advantages over the modern BFs used in medicine. Four echelette BFs with different grating periods and one BF were manufactured, and image blurring in an optical visual system with an echelette BF was experimentally investigated. The experimentally measured modulation transfer function and line spread function demonstrated definite image blurring (line expansion) that is inversely proportional to the width of the grating period. The results of measurements of the angular resolution of the optical system with an echelette BF coincide well with the results obtained by theory.


Reliability of immunologic markers of celiac sprue in the assessment of mucosal recovery after gluten withdrawal.
We studied 47 adults (21 men, 26 women), with biopsy-proven celiac sprue and anti-endomysin antibody (EmA) positivity while untreated, to evaluate the usefulness of both serologic markers of celiac sprue [i.e., immunoglobulin A (IgA)-EmA and total Ig-anti-gliadin (AGA) antibodies] and of a detailed dietary inquiry in predicting the mucosal pattern after gluten withdrawal. A second biopsy was repeated 8-30 months after beginning a gluten-free diet, along with EmA and AGA determinations and the dietary inquiry. Both EmA and AGA were appraised by indirect immunofluorescence on monkey esophagus and rat kidney, respectively. Intestinal biopsy was graded according to Cooke's criteria. After gluten withdrawal, intestinal mucosa reverted to normal in only nine patients. Both EmA and AGA showed high positive but low negative predictive values on intestinal histologic outcome. The positive predictive value of admission of dietary lapses was 100%, whereas the negative predictive value was 39.1%. Neither serologic markers nor dietary inquiries are to be regarded as reliable predictors of intestinal outcome after a gluten-free diet. Biopsy remains the best means of ascertaining mucosal recovery.


Targeting Nitric Oxide with Natural Derived Compounds as a Therapeutic Strategy in Vascular Diseases.
Within the family of endogenous gasotransmitters, nitric oxide (NO) is the smallest gaseous intercellular messenger involved in the modulation of several processes, such as blood flow and platelet aggregation control, essential to maintain vascular homeostasis. NO is produced by nitric oxide synthases (NOS) and its effects are mediated by cGMP-dependent or cGMP-independent mechanisms. Growing evidence suggests a crosstalk between the NO signaling and the occurrence of oxidative stress in the onset and progression of vascular diseases, such as hypertension, heart failure, ischemia, and stroke. For these reasons, NO is considered as an emerging molecular target for developing therapeutic strategies for cardio- and cerebrovascular pathologies. Several natural derived compounds, such as polyphenols, are now proposed as modulators of NO-mediated pathways. The aim of this review is to highlight the experimental evidence on the involvement of nitric oxide in vascular homeostasis focusing on the therapeutic potential of targeting NO with some natural compounds in patients with vascular diseases.


Description of four novel psychrophilic, ionizing radiation-sensitive Deinococcus species from alpine environments.
Five psychrophilic bacterial strains were isolated from soil samples collected above the treeline of alpine environments. Phylogenetic analysis based on 16S rRNA gene sequences indicated that these organisms represent four novel species of the genus Deinococcus; levels of sequence similarity to the type strains of recognized Deinococcus species were in the range 89.3-94.7 %. Strains PO-04-20-132T, PO-04-20-144, PO-04-19-125T, ME-04-01-32T and ME-04-04-52T grew aerobically, with optimum growth at 10 degrees C and at pH 6-9. The major respiratory menaquinone was MK-8. The fatty acid profiles of strains PO-04-20-132T, PO-04-20-144, PO-04-19-125T and ME-04-01-32T were dominated by 16 : 1omega7c, 17 : 0 iso and 15 : 1omega6c, whereas 16 : 1omega7c, 17 : 0 cyclo and 16 : 0 predominated in strain ME-04-04-52T. The DNA G+C contents of strains PO-04-20-132T, PO-04-19-125T, ME-04-01-32T and ME-04-04-52T were 63.2, 63.1, 65.9 and 62.6 mol%, respectively. Strains PO-04-20-132T, PO-04-19-125T, ME-04-01-32T and ME-04-04-52T had gamma radiation D10 (dose required to reduce the bacterial population by 10-fold) values of < or =4 kGy. These four strains showed sensitivity to UV radiation and extended desiccation as compared with Deinococcus radiodurans. On the basis of the phylogenetic analyses, and chemotaxonomic and phenotypic data, it is proposed that strains PO-04-20-132T (=LMG 24019T=NRRL B-41950T; Deinococcus radiomollis sp. nov.), PO-04-19-125T (=LMG 24282T=NRRL B-41949T; Deinococcus claudionis sp. nov.), ME-04-01-32T (=LMG 24022T=NRRL B-41947T; Deinococcus altitudinis sp. nov.) and ME-04-04-52T (=LMG 24283T=NRRL B-41948T; Deinococcus alpinitundrae sp. nov.) represent the type strains of four novel species of the genus Deinococcus.


Improving Temporal Consistency of Preferences: The Influence of Mental Construal.
Majority of the current literature on mental construal has focused on effects of varying construal levels on preference shifts whereas this research investigates the influence of mental construal on the change of preference consistency over time. Building on construal level theory, we propose that high-level construal, which creates abstract, and decontextualized mental representations, leads individuals to more consistent preferences than low-level construal, which creates concrete, and contextualized mental representations. Furthermore we examine the effect of having a matching versus non-matching construal level at two different evaluation instances, on achieving greater extents of consistency. To test this prediction a mixed experimental design is employed, in which participants evaluated electronic products at two different sessions. It is demonstrated that when participants have the same construal level at two points in time, their evaluations become similar since they mentally construe the objects in the same way whereas when the construal level differs at these two points, participants focus on different aspects of the products, form different evaluations and have less consistent preferences.


Anharmonic interaction signals for acoustic detection of analyte.
The challenges with frequency-based acoustic detection systems in sensitive, selective, and reliable quantitative estimation of surface-bound analyte are well-known. These systems are traditionally used in their linear incarnations; i.e., the measurement frequency is the same as the driving frequency. However, it was found in this work that interactions of adsorbents with sensor surface show significant anharmonicity even at low drive amplitudes. In particular, using streptavidin-coated polystyrene microbeads on an oscillating quartz surface in air, it has been demonstrated through modeling and experiments that the anharmonic signal from microparticle to surface interaction is significantly higher relative to that from bare quartz and orders of magnitude higher than relative shifts in resonant frequency. The signal is proportional to the number of microparticles and holds a well-defined functional relationship with the amplitude of oscillation, distinct to the nature of interaction with the surface for a given analyte. This approach, thus, can be used for ultrasensitive and quantitative detection of surface adsorbents and characterization of different kinds of surface interactions, distinguishing specific from nonspecific adsorbents. The modeling also reveals a direct functional relationship between the measured anharmonic signal and the interaction potential of the adsorbent with the surface.


The Effects of Repetitive Use and Pathological Remodeling on Channelrhodopsin Function in Cardiomyocytes.
Aim: Channelrhodopsins (ChRs) are a large family of light-gated ion channels with distinct properties, which is of great importance in the selection of a ChR variant for a given application. However, data to guide such selection for cardiac optogenetic applications are lacking. Therefore, we investigated the functioning of different ChR variants in normal and pathological hypertrophic cardiomyocytes subjected to various illumination protocols. Methods and Results: Isolated neonatal rat ventricular cardiomyocytes (NRVMs) were transduced with lentiviral vectors to express one of the following ChR variants: H134R, CatCh, ReaChR, or GtACR1. NRVMs were treated with phenylephrine (PE) to induce pathological hypertrophy (PE group) or left untreated [control (CTL) group]. In these groups, ChR currents displayed unique and significantly different properties for each ChR variant on activation by a single 1-s light pulse (1 mW/mm2: 470, 565, or 617 nm). The concomitant membrane potential (V m) responses also showed a ChR variant-specific profile, with GtACR1 causing a slight increase in average V m during illumination (V plateau: -38 mV) as compared with a V plateau > -20 mV for the other ChR variants. On repetitive activation at increasing frequencies (10-ms pulses at 1-10 Hz for 30 s), peak currents, which are important for cardiac pacing, decreased with increasing activation frequencies by 17-78% (p < 0.05), while plateau currents, which are critical for arrhythmia termination, decreased by 10-75% (p < 0.05), both in a variant-specific manner. In contrast, the corresponding V plateau remained largely stable. Importantly, current properties and V m responses were not statistically different between the PE and CTL groups, irrespective of the variant used (p > 0.05). Conclusion: Our data show that ChR variants function equally well in cell culture models of healthy and pathologically hypertrophic myocardium but show strong, variant-specific use-dependence. This use-dependent nature of ChR function should be taken into account during the design of cardiac optogenetic studies and the interpretation of the experimental findings thereof.


Isolation of a herpes simplex virus cDNA encoding the DNA repair enzyme uracil-DNA glycosylase.
Activity of the DNA repair enzyme uracil-DNA glycosylase has been shown to increase in herpes simplex virus type 2 (HSV-2)-infected cells. When mRNA derived from either HSV-1- or HSV-2-infected HeLa S3 cells was translated in an in vitro translation system, significant uracil-DNA glycosylase activity could be detected in the lysate. This activity was specific for the removal of uracil from DNA. Lysates from in vitro translation of mRNA derived from uninfected HeLa cells did not contain measurable glycosylase activity. A cDNA library was constructed with mRNA derived from HSV-2-infected cells 10 h postinfection. Pooled isolates from this library were used in hybrid-arrest and in vitro translation reactions to isolate a uracil-DNA glycosylase-specific cDNA. In vitro translation of hybrid-selected RNA, by using this cDNA, produced glycosylase activity in the lysate. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of radiolabeled products from this translation reaction showed a protein component with a molecular weight of 39,000. This is consistent with the molecular weight determinations of the purified glycosylase enzyme derived from either uninfected or HSV-infected HeLa cells. Northern (RNA blot) analysis of HSV-derived RNA, by using the glycosylase cDNA as a probe, revealed five overlapping transcripts of 3.4, 2.8, 2.4, 1.7, and 1.0 kilobases. Southern analysis indicated that the DNA sequence encoding the HSV-specific uracil-DNA glycosylase was located between 0.065 and 0.08 map units on the prototypic arrangement of the HSV genome.


EXEL-8232, a small-molecule JAK2 inhibitor, effectively treats thrombocytosis and extramedullary hematopoiesis in a murine model of myeloproliferative neoplasm induced by MPLW515L.
About 10% of patients with essential thrombocythemia (ET) or myelofibrosis (MF) that lack mutations in JAK2 harbor an activating mutation in the thrombopoietin receptor, MPLW515L. Distinct from the JAK2V617F retroviral transplant model, the MPLW515L model recapitulates many features of ET and MF, including severe fibrosis and thrombocytosis. We have tested EXEL-8232, an experimental potent JAK2 inhibitor, for efficacy in suppression of thrombocytosis in vivo and for its ability to attenuate MPLW515L myeloproliferative disease. EXEL-8232 was administered for 28 days q12 h by oral gavage at doses of 30 or 100 mg/kg, prospectively. Animals treated with EXEL-8232 at 100 mg/kg had normalized high platelet counts, eliminated extramedullary hematopoiesis in the spleen and eliminated bone marrow fibrosis, whereas the wild-type controls did not develop thrombocytopenia. Consistent with a clinical response in this model, we validated surrogate end points for response to treatment, including a reduction of endogenous colony growth and signaling inhibition in immature erythroid and myeloid primary cells both in vitro and upon treatment in vivo. We conclude that EXEL-8232 has efficacy in treatment of thrombocytosis in vivo in a murine model of ET and MF, and may be of therapeutic benefit for patients with MPL-mutant MPN.


Evaluating HCV screening, linkage to care, and treatment across insurers.
We examined how a population susceptible to hepatitis C virus (HCV) moves through the HCV screening and linkage-to-care (SLTC) continuum across insurance providers (Medicare, Medicaid, commercial) and identified opportunities for increasing the number of patients who complete the SLTC process and receive treatment. Discrete-time Markov model. A cohort of 10,000 HCV-susceptible patients was simulated through the HCV SLTC process using a Markov model with parameters from published literature. Three scenarios were explored: baseline, in which each step required a separate visit and all infected saw a specialist; reflex, which reflexed antibody and RNA testing; and consolidated, which reflexed antibody, RNA, fibrosis staging, and genotype testing into 1 step, with an optional specialist visit. For each scenario, we estimated the number of patients lost at each stage, yield, and cost. Streamlining the SLTC process by reducing the number of required visits results in more patients completing the process and receiving treatment. Among antibody-positive patients, 76% of those with Medicaid and 71% of those with Medicare and commercial insurance are lost to follow-up in baseline. In reflex and consolidated, these proportions fall to 26% and 27% and 4% and 5%, respectively. The cost to identify and link 1 additional infected patient to care ranges from $1586 to $2546 in baseline and $212 to $548 in consolidated. Total cost, inclusive of treatment, ranges from $1.0 million to $3.1 million in baseline and increases to $3.8 million to $15.1 million in reflex and $5.3 million to $21.0 million in consolidated. Reducing steps in the HCV SLTC process increases the number of patients who learn their HCV status, receive appropriate care, and initiate treatment.


Appraisal process in sheep (Ovis aries): interactive effect of suddenness and unfamiliarity on cardiac and behavioral responses.
Appraisal theories state that an emotion results from an individual's evaluation of a stimulating event, which is based on a set of criteria. Each criterion triggers specific expressions that can be modulated by the outcome of other criteria. The authors analyzed the effects of the criteria of suddenness, unfamiliarity, and their combination on behavioral and cardiac responses in lambs (Ovis aries). Lambs were exposed to a visual stimulus that appeared either rapidly or slowly and was either unfamiliar or familiar. Suddenness induced a startle response and an increase in heart rate. Unfamiliarity induced an orientation response. The combination of suddenness and unfamiliarity enhanced both the heart rate increase and the behavioral orientation response. These results support the hypotheses of specificity and modulation of emotional expressions.


Low connector-to-connector loss through silicon photonic chips using ultra-low loss splicing of SMF-28 to high numerical aperture fibers.
Here we present extremely low connector-to-connector loss (≤3 dB) through silicon photonic chips using ultra-low loss (≤0.15 dB) splicing between SMF-28 and ultra-high numerical aperture (UHNA) fibers. The small MFD from the UHNA fibers enables strong coupling to hybrid TE/TM edge couplers achieving TM (TE) losses of 1.25 (2.35) dB per coupler and low polarization-dependent loss. Mode coupling simulations and tolerance are investigated to understand performance.


Comparison of microsatellites and isozymes in genetic diversity studies of Oryza glumaepatula (Poaceae) populations.
The study of the genetic structure of wild plant populations is essential for their management and conservation. Several DNA markers have been used in such studies, as well as isozyme markers. In order to provide a better comprehension of the results obtained and a comparison between markers which will help choose tools for future studies in natural populations of Oryza glumaepatula, a predominantly autogamous species, this study used both isozymes and microsatellites to assess the genetic diversity and genetic structure of 13 populations, pointing to similarities and divergences of each marker, and evaluating the relative importance of the results for studies of population genetics and conservation. A bulk sample for each population was obtained, by sampling two to three seeds of each plant, up to a set of 50 seeds. Amplified products of eight SSR loci were electrophoresed on non-denaturing polyacrylamide gels, and the fragments were visualized using silver staining procedure. Isozyme analyses were conducted in polyacrylamide gels, under a discontinuous system, using six enzymatic loci. SSR loci showed higher mean levels of genetic diversity (A=2.83, p=0.71, A(p)=3.17, H(o)=0.081, H(e)=0.351) than isozyme loci (A=1.20, p=0.20, A(p)=1.38, H(o)=0.006, H(e)=0.056). Interpopulation genetic differentiation detected by SSR loci (R(ST)=0.631, equivalent to F(ST)=0.533) was lower than that obtained with isozymes (F(ST)=0.772). However, both markers showed high deviation from Hardy-Weinberg expectations (F(IS)=0.744 and 0.899, respectively for SSR and isozymes). The mean apparent outcrossing rate for SSR (t(a)=0.14) was higher than that obtained using isozymes (t(a)=0.043), although both markers detected lower levels of outcrossing in Amazonia compared to the Pantanal. The migrant number estimation was also higher for SSR (Nm=0.219) than isozymes (Nm=0.074), although a small number for both markers was expected due to the mode of reproduction of this species, defined as mixed with predominance of self fertilization. No correlation was obtained between genetic and geographic distances with SSR, but a positive correlation was found between genetic and geographic distances with isozymes. We conclude that these markers are divergent in detecting genetic diversity parameters in O. glumaepatula and that microsatellites are powerful for detecting information at the intra-population level, while isozymes are more powerful for inter-population diversity, since clustering of populations agreed with the expectations based on the geographic distribution of the populations using this marker.


Management of patients with early-stage colon cancer: guidelines of the Italian Medical Oncology Association.
About 75% of colorectal cancers are diagnosed as early stage, in which radical surgery is achievable. In the last decade, in Italy, the overall incidence of colorectal cancer has remained stable, while mortality gradually decreased, which is attributable to early diagnosis and improved medical, surgical and locoregional treatments. The Italian Medical Oncology Association formulated guidelines to manage early-stage colon cancer, including screening, diagnosis, treatment and follow-up, which we herein present.


Multiscale binarization of gene expression data for reconstructing Boolean networks.
Network inference algorithms can assist life scientists in unraveling gene-regulatory systems on a molecular level. In recent years, great attention has been drawn to the reconstruction of Boolean networks from time series. These need to be binarized, as such networks model genes as binary variables (either "expressed" or "not expressed"). Common binarization methods often cluster measurements or separate them according to statistical or information theoretic characteristics and may require many data points to determine a robust threshold. Yet, time series measurements frequently comprise only a small number of samples. To overcome this limitation, we propose a binarization that incorporates measurements at multiple resolutions. We introduce two such binarization approaches which determine thresholds based on limited numbers of samples and additionally provide a measure of threshold validity. Thus, network reconstruction and further analysis can be restricted to genes with meaningful thresholds. This reduces the complexity of network inference. The performance of our binarization algorithms was evaluated in network reconstruction experiments using artificial data as well as real-world yeast expression time series. The new approaches yield considerably improved correct network identification rates compared to other binarization techniques by effectively reducing the amount of candidate networks.


Spectral prediction model for piles of nonscattering sheets.
The present paper investigates the reflection and transmission properties of piles of nonscattering sheets. Using a spectral prediction model, we perform a detailed analysis of the spectral and color variations induced by variations of the number of superposed sheets, the absorbance of the sheet material, the refractive index of the medium between the sheets, and the reflectance of the background. The spectral prediction model accounts for the multiple reflections and transmissions of light between the interfaces bounding the layers. We describe in detail the procedure for deducing model parameters from measured data. Tests performed with nonscattering plastic sheets demonstrate the excellent accuracy of the predictions. A large set of predicted spectra illustrate the different evolutions of reflected and transmitted spectra as well as the corresponding colors for various types of piles.


Effect of laser treatment on the attachment and viability of mesenchymal stem cell responses on shape memory NiTi alloy.
The objectives of this study were to investigate the effect of laser-induced surface features on the morphology, attachment and viability of mesenchymal stem cells (MSCs) at different periods of time, and to evaluate the biocompatibility of different zones: laser-melted zone (MZ), heat-affected zone (HAZ) and base metal (BM) in laser-treated NiTi alloy. The surface morphology and composition were studied by scanning electron microscope (SEM) and X-ray photoemission spectroscopy (XPS), respectively. The cell morphology was examined by SEM while the cell counting and viability measurements were done by hemocytometer and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. The results indicated that the laser-induced surface features, such as surface roughening, presence of anisotropic dendritic pattern and complete surface Ni oxidation were beneficial to improve the biocompatibility of NiTi as evidenced by the highest cell attachment (4 days of culture) and viability (7 days of culture) found in the MZ. The biocompatibility of the MZ was the best, followed by the BM with the HAZ being the worst. The defective and porous oxide layer as well as the coarse grained structure might attribute to the inferior cell attachment (4 days of culture) and viability (7 days of culture) on the HAZ compared with the BM which has similar surface morphology.


Eschar removal by bromelain based enzymatic debridement (Nexobrid®) in burns: An European consensus.
Early debridement and/or eschar removal is regarded as a significant step in the treatment of deep partial and full thickness burns. It aims to control wound bioburden and allows early wound closure by conservative treatment or skin grafting. Preservation of viable dermis accompanied by early wound closure, is regarded as a necessary step to reduce scar related complication, e.g. functional limitations and/or unaesthetic scar formation. Aside from the classical techniques of surgical excision as tangential excision for eschar removal, hydro-surgery, maggot therapy, laser, enzymatic debridement have been described as additional techniques in the burn surgeon's armamentarium. It is widely accepted that early eschar removal within 72h improves the outcome of burn wound treatment by reducing bacterial wound colonization, infection and length of hospital stay. In contrast, the right technique for eschar removal is still a matter of debate. There is increasing evidence that enzymatic debridement is a powerful tool to remove eschar in burn wounds, reducing blood loss, the need for autologous skin grafting and the number of wounds requiring surgical excision. In order to assess the role and clinical advantages of enzymatic debridement by a mixture of proteolytic enzymes enriched in Bromelain (Nexobrid®) beyond the scope of the literature and in view of users' experience, a European Consensus Meeting was scheduled. The aim was to provide statements for application, based on the mutual experience of applying enzymatic debridement in more than 500 adult and pediatric patients by the consensus panelists. Issues to be addressed were: indications, pain management and anesthesia, timing of application, technique of application, after-intervention care, skin grafting after enzymatic debridement, blood loss, training strategies and learning curve and areas of future research needs. Sixty-eight (68) consensus statements were provided for the use of enzymatic debridement. The degree of consensus was remarkably high, with a unanimous consensus in 88.2% of statements, and lowest degree of consensus of 70% in only 3 statements. This consensus document may serve as preliminary guideline for the use of enzymatic debridement with user-oriented recommendations until further evidence and systematic guidelines are available.


Single-channel analysis of a K channel at basolateral membrane of rabbit proximal convoluted tubule.
The basolateral membrane of the rabbit proximal convoluted tubule (PCT) is known to be largely permeable to K ions. The patch-clamp technique was used to investigate the molecular basis of this K permeability. At room temperature and with a high-K solution (127 mM) in both the bathing medium and the patch pipette, current jumps associated with an inward-rectifying channel could be detected in every active cell-attached experiment. When the K concentration in the pipette was changed from 200 to 5 mM KCl (NaCl replacement), the single-channel conductance for inward currents changed from 54 to 10 pS. The observed shift in the zero current potential measured as a function of the patch pipette K concentration could be fitted using the Goldman-Hodgkin-Katz equation with a permeability ratio PNa/PK = 0.06. The channel was found to be moderately voltage dependent (e-fold per 56 mV depolarization). For instance, the open-channel probability (Po) increased from 0.06 to 0.16 following a membrane depolarization from -50 to +50 mV. A time interval distribution analysis showed for the open state a dominant single time constant of 14 and 10 ms at 50 and -50 mV, respectively. Two time constants equal to 1 (flickering) and 26 ms at +50 mV and to 0.6 and 300 ms at -50 mV were obtained for the closed-state interval distribution. Based on this analysis, it was concluded that the decrease of Po at negative potentials was due more to the appearance of prolonged silent periods than from a change in the channel mean open time.


[Echographic screening of the abdominal aorta in older men is not useful].
Aneurysm of the abdominal aorta (AAA) is a normal symptom of old age, the prevalence and chance of rupture of which are highly exaggerated, and which very seldom leads to death. The result of screening is that many men (5%) are medicalised unjustly and exposed to the severe risks of a surgical intervention. The mortality during open surgery is 5-6%. Screening has no effect on the total mortality.


New animal model of extrinsic dental erosion-Erosive effect on the mouse molar teeth.
Consumption of acidic food and drinks is considered as important risk factor for development of dental erosion. There are several in vitro and in situ studies focusing on the risk indicators and preventive treatment, however, the need for a standardized animal model has been emphasised for many years. The aim was to establish an animal model of extrinsic dental erosion, which may serve as a standard for future studies to improve our understanding of the erosion. Two acidic drinks, sports drink and cola drink, were given to young mice for six weeks. Experimental and control (water) molars and incisors were dissected out and observed by scanning electron microscopy (SEM). Mandibular first molars were subsequently ground transversely and observed again by SEM. The tooth height and enamel thickness were measured on the SEM images. The lingual surface of the mandibular molars was most eroded after consumption of acidic drinks. The cola drink exhibited higher erosive effect on mandibular molars compared to sports drink. The lingual tooth height, compared to control, was about 34% and 18% lower in the cola drink and sports drink molars, respectively. Compared to the control molars, the lingual enamel was about 23% thinner in the sports drink molars and totally eroded on the certain lingual areas of the cola drink molars. This new animal model of extrinsic dental erosion and the presented method with ground molars observed in SEM are suitable for further studies, which will gain deeper insights into the erosive disease.


Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar.
Whole exome sequencing (WES) has greatly facilitated the identification of causal mutations for diverse human genetic disorders. We applied WES as a molecular diagnostic tool to identify disease-causing genes in consanguineous families in Qatar. Seventeen consanguineous families with diverse disorders were recruited. Initial mutation screening of known genes related to the clinical diagnoses did not reveal the causative mutations. Using WES approach, we identified the definitive disease-causing mutations in four families: (i) a novel nonsense homozygous (c.1034C>G) in PHKG2 causing glycogen storage disease type 9C (GSD9C) in a male with initial diagnosis of GSD3; (ii) a novel homozygous 1-bp deletion (c.915del) in NSUN2 in a male proband with Noonan-like syndrome; (iii) a homozygous SNV (c.1598C>G) in exon 11 of IDUA causing Hurler syndrome in a female proband with unknown clinical diagnosis; (iv) a de novo known splicing mutation (c.1645+1G>A) in PHEX in a female proband with initial diagnosis of autosomal recessive hypophosphatemic rickets. Applying WES as a diagnostic tool led to the unambiguous identification of disease-causing mutations in phenotypically complex disorders or correction of the initial clinical diagnosis in ˜25% of our cases.


Assessing the Validity and Reliability of a New Pressure Ulcer Risk Assessment Scale for Patients in Intensive Care Units.
The high incidence of pressure ulcers/injuries (PU/Is) among patients in intensive care units (ICUs) suggests a need for improved risk assessment. The study aimed to develop and assess the validity and reliability of a new PU/I risk assessment scale. The authors developed the Efteli Günes (EFGU) Pressure Ulcer Risk Assessment Scale based on a conceptual framework of risk factors developed by Coleman et al. These factors comprised direct (immobility, skin/PU status, poor perfusion) and indirect (poor sensory perception and response, diabetes, moisture, poor nutrition, low albumin) factors, as well as factors that could potentially influence risk (older age, medications, pitting edema, chronic wound infection, acute illness, increased body temperature. These factors were operationalized into 8 scale variables: skin status in areas exposed to pressure, discomfort and pain sensation in areas exposed to pressure, incontinence, diastolic blood pressure, age, diabetes, ability to make small position shifts in areas exposed to pressure, and skin tolerance test. The presence and/or extent of each factor was assigned a value; the total score ranged from 0 to 15, with higher values indicating increased risk. Intraclass correlation (ICC) was used to assess interrater agreement. To test the instrument's validity and reliability, a prospective, methodological study was conducted from September 1, 2015 to November 1, 2016, in the Neurology, Internal Medicine, Neurosurgery, Orthopedics, and Traumatology ICUs of a university hospital in Turkey. Eligible participants had to be bedbound ICU patients at least 18 years old, without a PU/I on admission, not receiving inotropic and/or vasopressor medications, and with a minimum ICU stay of 6 days. Demographic and clinical data were collected upon admission and daily thereafter until ICU discharge (maximum stay 12 weeks) or death. Descriptive statistics and Student's t and chi-squared tests were used to analyze the data. Reliability was determined using Cronbach's alpha. The Kaiser-Meyer-Olkin coefficient was used to determine validity, and the diagnostic and Youden indices were used to establish the cutoff value for risk. Of the 207 patients included in this study 117 [56.5%] were male, mean age was 60.85 ± 16.45 years, the majority of participants (88 [42.5%]) were in the Neurology ICU), and 56 (27.1%) developed a PU/I. The presence of diabetes was found not to be a risk factor (r = 0.18), but the inability to make small position shifts (r = 0.79) was found to be a significant risk factor. After removing the diabetes variable (maximum score 14), 97.1% of patients with a score of 6 or greater on the EFGU scale score developed a PU/I. The Cronbach alpha coefficient for reliability was 0.81, sensitivity of the scale was 0.97, specificity was 0.83, positive predictive value was 0.69, and negative predictive value was 0.99. The ICC coefficient was 0.99. The validity and reliability of the EFGU Scale seem to indicate a high predictive value for PU/I occurrence among ICU patients involved in the study. Multicenter studies involving larger samples of ICU patients are needed to validate the results.


Plasminogen activator inhibitor-1 activity in type 2 diabetes: a different relationship with coronary heart disease and diabetic retinopathy.
Plasminogen activator inhibitor (PAI)-1, a key regulator of fibrinolysis, is associated with increased risk of coronary heart disease (CHD) and is a potential therapeutic target for CHD. However, the relationship between PAI-1 and the most common diabetic microvascular complication, retinopathy, is unclear. The purpose of this study was to assess the relationship between PAI-1 activity and both retinopathy and CHD in type 2 diabetes. We determined PAI-1 activity and both retinopathy (assessed by masked grading of 3-field retinal photographs) and CHD status (assessed by ECG and standard questionnaires) in 147 men and women with type 2 diabetes, mean age (SD) 64 (7) years, in a cross-sectional setting. Plasma PAI-1 activity was inversely associated with prevalent retinopathy (P=0.006) and severity of retinopathy (P=0.022), and was associated with lower risk of diabetic retinopathy, independent of major retinopathy risk factors (duration of diabetes and HbA1c) and determinants of PAI-1 (obesity and triglyceride level) (OR 0.74 [0.60 to 0.92], P=0.006). Conversely, higher plasma PAI-1 activity was independently associated with greater risk of CHD, after adjusting for the major CHD risk factors and determinants of PAI-1 (OR 1.31 [1.06 to 1.62], P=0.001). These data support mounting evidence that a higher PAI-1 plasma level is independently associated with a lower risk of retinopathy but a higher risk of CHD in type 2 diabetes.


Selective effects of selenium selenite on 7,12-dimethylbenz(a)anthracene-DNA binding in fetal mouse cell cultures.
Sodium selenite inhibits the binding of 7,12-dimethylbenz(a)anthracene (DMBA) to DNA in tertiary cultures of fetal mouse cells in a rather selective fashion. Inhibition can be demonstrated at 6 but not at 3 h after DMBA addition to the cells. Inhibition is seen after treatment of the cells with DMBA concentrations of 0.05 or 0.1 micrograms/ml but not after treatment at 0.01 micrograms/ml. Furthermore the inhibition seen with up to 1 microgram selenium/ml is selective in that products from the anti bay region dihydrodiol epoxide metabolite (where the epoxide oxygen is trans to the 4-hydroxy group) are suppressed while those from the syn-dihydrodiol-epoxide (where the epoxide oxygen is cis to the 4-hydroxy group) are not affected. In the absence of selenite, it was found that syn-dihydrodiol epoxide-DNA adducts are formed in a roughly linear fashion with time over a range of DMBA concentration. In contrast, the capacity of the cells to generate anti-dihydrodiol-epoxide adducts in a 3-h interval is saturated at concentrations of DMBA above 0.025 micrograms/ml and after the initial 3-h period the cells generate these adducts at up to a 6-fold greater rate than during the initial 3 h. This increase in rate of formation of anti-dihydrodiol-epoxide products is inhibited by actinomycin D and appears to be a consequence of DMBA inducing an enzyme activity which selectively generates the anti-dihydrodiol-epoxide and not the syn-dihydrodiol-epoxide. The selective action of sodium selenite in inhibiting only anti-dihydrodiol-epoxide product formation and doing this only at certain times and at certain doses of DMBA is a result of the fact that it inhibits the induction process. Once induction has occurred, sodium selenite is no longer inhibitory of DMBA-DNA binding. The chemopreventive action of selenium in chemical carcinogenesis could be partially attributable to effects such as those described herein on carcinogen-DNA binding. It is also possible, however, that the chemopreventive actions of selenium might be attributable to effects on the expression of genes other than those involved in carcinogen metabolism.


Estradiol induces a shift in cultured cells that release prolactin or growth hormone.
The process by which estradiol induces an increase in the percentage of prolactin cells in the rat pituitary requires clarification. In this study the effect of estradiol treatment on growth hormone and prolactin cells in monolayer cultures of male rat pituitaries was assessed by use of reverse hemolytic plaque assays. Treatment of cultures with 17 beta-estradiol (10 nM) for 6 days elevated significantly (P less than 0.01) the percentage of all cells in culture that released prolactin without affecting the percentage of growth hormone secretors. However, by sequentially assaying single cells for growth hormone and prolactin, we found that estradiol caused a marked increase (P less than 0.01) in the proportion of individual cells that released both growth hormone and prolactin and a commensurate decrease in the proportion that released growth hormone alone. These results demonstrate that estradiol acts directly on cultures of male pituitary cells to shift the proportions of cells that released growth hormone, prolactin, or both hormones and indicate that estradiol may convert cells that release only growth hormone to those that release both growth hormone and prolactin.


Effect of saline loading during heat acclimatization on adrenocortical hormone levels.
Six male subjects were acclimatized to heat; once they were given sufficient 1% saline to prevent the occurrence of a salt deficit during acclimatization, and another time they were given no saline. Plasma aldosterone (PA), plasma cortisol (PC), plasma renin activity (PRA), and plasma electrolytes were measured before, during, and after and sweat electrolytes before and after the 11-day acclimatization program. PRA and PA were significantly increased by the acute stress of heat and exercise but were unaffected by acclimatization. These increases were attenuated, but not prevented, by drinking saline, whereas sweat [Na] and PC were reduced by acclimatization but were unaffected by saline. Thus adrenocortical activity has been shown not to be increased after heat acclimatization, and mineralocorticoid activity, although potentiated by a Na deficit, appears to be determined primarily by the acute stress of heat and of exercise. Hence, the increased Na conservation with acclimatization is likely to be a normal response to heat and exercise even in the absence of a negative Na balance.


A whole-of-population study of the prevalence and patterns of criminal offending in people with schizophrenia and other mental illness.
Large epidemiological studies are needed to better understand the prevalence and profile of offending by people with mental illness. This study used a whole-of-population design to examine the prevalence, type and pattern of offending across all psychiatric diagnoses, including schizophrenia, compared to the general population. Method We used whole-of-population longitudinal record-linked data for a cohort of all Western Australians born 1955-1969 to determine arrest history over the period 1985-1996 and to ascertain recorded history of psychiatric illness. Of the cohort, 116 656 had been arrested and 40 478 were on the psychiatric case register. The period prevalence of arrest for people with any psychiatric illness was 32.1%. The highest arrest prevalence, by diagnostic category, was for substance use disorders (59.4%); the prevalence for schizophrenia was 38.7%. Co-morbid substance use disorders significantly increased risk of arrest in people with schizophrenia. The prevalence of mental illness among offenders was 11.1%: 6.5% of offenders had substance use disorders and 1.7% had schizophrenia. For the majority of offenders with a psychiatric illness, first arrest preceded first contact with mental health services; for schizophrenia only, this proportion was increasing over time. The mean percentage annual change in the number of arrests during 1985-1996 rose significantly for offenders with a psychiatric illness other than schizophrenia and dropped significantly for those with no mental illness. Compared to non-psychiatric offenders, offenders with schizophrenia were more likely to offend alone, to offend in open places and to target strangers. Our findings open the way to an informed approach to the management of offenders with mental illness.


Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data.
Lenalidomide has been linked to second primary malignancies in myeloma. We aimed to pool and analyse available data to compare the incidence of second primary malignancies in patients with and without lenalidomide exposure. We identified relevant studies through a search of PubMed and abstracts from the American Society of Clinical Oncology, American Society of Hematology, and the International Myeloma Workshop. Randomised, controlled, phase 3 trials that recruited patients with newly diagnosed multiple myeloma between Jan 1, 2000, and Dec 15, 2012, and in which at least one group received lenalidomide were eligible for inclusion. We obtained individual patient data (age, sex, date of diagnosis, allocated treatment and received treatment, duration of treatment and cause of discontinuation, maintenance treatment, date of first relapse, date of second primary malignancy diagnosis, type of second primary malignancy, date of death or last contact, and cause of death) by direct collaboration with the principal investigators of eligible trials. Primary outcomes of interest were cumulative incidence of all second primary malignancies, solid second primary malignancies, and haematological second primary malignancies, and were analysed by a one-step meta-analysis. We found nine eligible trials, of which seven had available data for 3254 patients. 3218 of these patients received treatment (2620 had received lenalidomide and 598 had not), and were included in our analyses. Cumulative incidences of all second primary malignancies at 5 years were 6·9% (95% CI 5·3-8·5) in patients who received lenalidomide and 4·8% (2·0-7·6) in those who did not (hazard ratio [HR] 1·55 [95% CI 1·03-2·34]; p=0·037). Cumulative 5-year incidences of solid second primary malignancies were 3·8% (95% CI 2·7-4·9) in patients who received lenalidomide and 3·4% (1·6-5·2) in those that did not (HR 1·1 [95% CI 0·62-2·00]; p=0·72), and of haematological second primary malignancies were 3·1% (95% CI 1·9-4·3) and 1·4% (0·0-3·6), respectively (HR 3·8 [95% CI 1·15-12·62]; p=0·029). Exposure to lenalidomide plus oral melphalan significantly increased haematological second primary malignancy risk versus melphalan alone (HR 4·86 [95% CI 2·79-8·46]; p<0·0001). Exposure to lenalidomide plus cyclophosphamide (HR 1·26 [95% CI 0·30-5·38]; p=0·75) or lenalidomide plus dexamethasone (HR 0·86 [95% CI 0·33-2·24]; p=0·76) did not increase haematological second primary malignancy risk versus melphalan alone. Patients with newly diagnosed myeloma who received lenalidomide had an increased risk of developing haematological second primary malignancies, driven mainly by treatment strategies that included a combination of lenalidomide and oral melphalan. These results suggest that alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma. Celgene Corporation.


[Safety of term birth and cesarean birth rates].
This was a parallel of the rate of caesarean section and neurological morbidity of the term newborn. This study was performed on all infants born at a gestational age of 37 weeks or greater in 1981 and 1982 at the Baudelocque Maternity Hospital. The results show a stable caesarean section rate during these two years: 21% in 1981, 20% in 1982; as for the safety of term birth there was only one case of perinatal insult during a vaginal birth responsible for cerebral dysfunction of moderate degree. There was a 18% operative maternal morbidity and there were no deaths. We concluded that a caesarean section rate of 20% in a University Hospital is justified by the virtual absence of neonatal morbidity with an acceptable maternal risk. This rate should not increase. The possible ways of decreasing this rate, while maintaining neonatal safety, must be studied. The original aspect of this work concerns the monitoring of the caesarean section rate by the incidence of neurological complications of all term births during a fixed period of time.


Immunophenotypic characterisation of peripheral blood lymphocytes in autoimmune polyglandular syndrome type 1: clinical study and review of the literature.
Autoimmune endocrinopathies are characterised by an increased number of peripheral blood lymphocytes (PBL) expressing activation/ memory markers on their surface. The aim of this study was to determine whether a similar finding could be detected in a group of 11 paediatric and young adult patients suffering from autoimmune polyglandular syndrome type 1 (APS1), also called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), as very few data have previously been reported in this field. The control group was made up of 11 sex- and age-matched healthy subjects. Fifteen lymphocyte subsets were compared, in terms of percentage and absolute number, and statistical analysis was performed by the Mann-Whitney test. Measurement of T (CD3+), B (CD19+), natural killer (NK, CD3-CD16/56+), CD4+ and CD8+ T lymphocytes showed that patients with APS1 had a higher percentage and absolute count of T lymphocytes: this was entirely due to the statistically larger CD3+CD4+ fraction. Patients with APS1 also had slightly fewer B and NK lymphocytes, but the difference was negligible. Comparison of CD4+ subpopulations bearing activation and naive/memory antigens (marked by CD69, CD25, anti-HLA-DR, CD45RA and CD45RO) showed that patients with APS1 had generally larger percentages and absolute counts of these subsets: however, only the percentage and absolute size of the CD4+CD25+ subset (p = 0.0354 and p = 0.0151, respectively), and the absolute number of the CD4+ anti-HLA-DR+ and CD4+ CD45RO+ subsets (p = 0.0193 and p = 0.0209, respectively) were significantly higher. Interestingly, patients with APS1 also had significantly fewer CD8+CD11b+ and CD3-CD8+ cells. In conclusion, PBL distribution in APS1 resembles that of other autoimmune diseases. Further studies are needed to confirm and possibly extend these data.


Trout vascular and renal responses to atrial natriuretic factor and heart extracts.
Dorsal aortic pressure (DAP), urine flow rate, and urinary K+, Na+, and Cl- were monitored in chronically catheterized unanesthetized rainbow trout before and after injection of saline, tissue extracts, or synthetic (rat, Ile-26) atrial natriuretic factor (ANF). Synthetic ANF (1.0 and 10.0 micrograms/kg body wt) and extracts from trout atria and ventricles increased DAP, urine flow rate, and electrolyte excretion. Saline, skeletal muscle extracts, and 0.1 microgram/kg body wt synthetic ANF had no effect on DAP and only minor effects on renal water and ion excretion. The slow-onset long-duration pressor response to ANF and heart extracts contrasted with a rapid short-acting pressor effect of epinephrine. Synthetic ANF (10 micrograms/kg body wt) and ventricular extracts produced marked increases in Na+ and Cl- excretion but only a mild diuresis. Much of the increase in urine flow rate appears to be due to solvent injection. These results show that trout hearts contain an ANF-like material and that mammalian and piscine ANF produce hemodynamic and renal effects upon intra-arterial injection.


Theoretical investigations of energy harvesting efficiency from structural vibrations using piezoelectric and electromagnetic oscillators.
Conversion of ambient vibrational energy into electric power has been the impetus of much modern research. The traditional analysis has focused on absolute electrical power output from the harvesting devices and efficiency defined as the convertibility of an infinite resource of vibration excitation into power. This perspective has limited extensibility when applying resonant harvesters to host resonant structures when the inertial influence of the harvester is more significant. Instead, this work pursues a fundamental understanding of the coupled dynamics of a main mass-spring-damper system to which an electromagnetic or piezoelectric mass-spring-damper is attached. The governing equations are derived, a metric of efficiency is presented, and analysis is undertaken. It is found that electromagnetic energy harvesting efficiency and maximum power output is limited by the strength of the coupling such that no split system resonances are induced for a given mass ratio. For piezoelectric harvesters, only the coupling strength and certain design requirements dictate maximum power and efficiency achievable. Since the harvesting circuitry must "follow" the split resonances as the piezoelectric harvesters become more massive, the optimum design of piezoelectric harvesters appears to be more involved than for electromagnetic devices.


[A patient in a methoxetamine-induced dissociative psychosis].
The international drug market has dramatically changed with the emergence of various new psychoactive substances that are mostly being sold on the internet. One of those new psychoactive substances is methoxetamine (MXE), a structural analogue of ketamine. A 30-year-old man with no history of illness was presented to the accident and emergency department. He had lost his balance and could not move. He was in a dissociative psychosis, felt he had no control over his body and was extremely frightened. Most of this symptoms disappeared within two hours of arrival. The next day there were no indications of a psychosis, and only headache and nausea remained. The state of dissociative psychosis was caused by MXE, which was sold to him as an ecstasy tablet. Whether mixed with alcohol and other drugs or not, MXE can cause serious feelings of dissociation resulting in extreme anxiety and psychosis. This might cause severely lowered consciousness in these patients. Currently, use of MXE in the Netherlands is limited, but ketamine or MXE intoxication should be considered in patients with these symptoms.


Obesity is associated with altered mid-insula functional connectivity to limbic regions underlying appetitive responses to foods.
Obesity is fundamentally a disorder of energy balance. In obese individuals, more energy is consumed than is expended, leading to excessive weight gain through the accumulation of adipose tissue. Complications arising from obesity, including cardiovascular disease, elevated peripheral inflammation, and the development of Type II diabetes, make obesity one of the leading preventable causes of morbidity and mortality. Thus, it is of paramount importance to both individual and public health that we understand the neural circuitry underlying the behavioral regulation of energy balance. To this end, we sought to examine obesity-related differences in the resting state functional connectivity of the dorsal mid-insula, a region of gustatory and interoceptive cortex associated with homeostatically sensitive responses to food stimuli. Within the present study, obese and healthy weight individuals completed resting fMRI scans during varying interoceptive states, both while fasting and after a standardized meal. We examined group differences in the pre- versus post-meal functional connectivity of the mid-insula, and how those differences were related to differences in self-reported hunger ratings and ratings of meal pleasantness. Obese and healthy weight individuals exhibited opposing patterns of eating-related functional connectivity between the dorsal mid-insula and multiple brain regions involved in reward, valuation, and satiety, including the medial orbitofrontal cortex, the dorsal striatum, and the ventral striatum. In particular, healthy weight participants exhibited a significant positive relationship between changes in hunger and changes in medial orbitofrontal functional connectivity, while obese participants exhibited a complementary negative relationship between hunger and ventral striatum connectivity to the mid-insula. These obesity-related alterations in dorsal mid-insula functional connectivity patterns may signify a fundamental difference in the experience of food motivation in obese individuals, wherein approach behavior toward food is guided more by reward-seeking than by homeostatically relevant interoceptive information from the body.


An RNA polymerase II transcription factor inactivated in poliovirus-infected cells copurifies with transcription factor TFIID.
Inhibition of host cell RNA polymerase II-mediated transcription by poliovirus infection was studied in vitro. Whole-cell extracts prepared from poliovirus-infected HeLa cells at 3 h postinfection were shown to be deficient in a factor required for specific transcription from the adenovirus major late promoter. Three lines of evidence suggest that transcription factor TFIID is deficient in poliovirus-infected cells. First, the activity required to specifically restore transcription in poliovirus-infected cell extracts was shown to copurify with TFIID through three chromatographic steps. Second, transcription reactions reconstituted with phosphocellulose-derived chromatographic fractions revealed a fourfold decrease in the specific activity of the TFIID-containing fraction prepared from poliovirus-infected cells compared with that of the same fraction prepared from mock-infected cells. Finally, TFIID and the activity required to specifically restore transcription in virus-infected cell extracts were shown to have the same kinetics of heat inactivation. Together, these results suggest that inactivation of TFIID is an early event in the inhibition of host cell RNA polymerase II transcription by poliovirus.


Prolonged protection against methacholine-induced bronchoconstriction by the inhaled beta 2-agonist formoterol.
Formoterol fumarate is a new, high-affinity, beta 2-adrenergic receptor agonist that causes bronchodilation for at least 12 h. The purpose of this study was to compare the magnitude and duration of the effect of inhalation of formoterol (12 and 24 micrograms), albuterol (200 micrograms), and placebo in terms of protection against methacholine-induced bronchoconstriction. The 16 stable adult asthmatic subjects were studied on four separate study days. On each study day the subjects inhaled 2 puffs of the study medication, and methacholine tests were performed at 30 min and 4, 8, and 12 h later. Results were expressed as the provocative concentration of methacholine required to cause a 20% fall in FEV1 (PC20). At 30 min, 12 and 24 micrograms formoterol caused a mean 14- to 20-fold decrease in responsiveness, and albuterol a 12-fold decrease. However, albuterol had no significant protective effect at 4 h or thereafter, whereas there was still an 8-fold decrease in responsiveness for 24 micrograms formoterol and a 6-fold decrease for 12 micrograms formoterol at 12 h. This study has shown that both doses of formoterol were still actively protective against induced bronchoconstriction 12 h after inhalation, with minimal side effects. This suggests that formoterol may prove to be a very useful bronchodilator for the treatment of patients with asthma who have significant airway hyperresponsiveness or nocturnal symptoms and who require inhaled beta 2-agonists at least twice daily.


Coping style and substance use intention and behavior patterns in a cohort of BC adolescents.
Adolescence is a developmental period during which young teenagers are particularly susceptible to shifting from well-defined behavioral intentions to abstain from substance use to intentions that include experimentation with substance use and in many cases engagement substance use. Coping mechanisms are often an important determinant of adolescent well-being, and the style of coping adopted by the individual can influence positive or negative health behavior. The goal of this study was to examine how the levels of positive coping style (i.e., engagement) and negative coping style (i.e., disengagement) associated with increased risk for tobacco and marijuana use, and intentions to use among those who have never tried. Higher levels of engagement coping were associated with lower odds of tobacco and marijuana use (AOR=0.96 (95% CI: 0.94-0.98), p<0.001 and AOR=0.95 (95% CI: 0.93-0.97) p<0.001, respectively). Higher levels of disengagement coping were associated with greater odds of tobacco and marijuana use (AOR=1.03 (95% CI: 1.01-1.05), p<0.001 and AOR=1.05 (95% CI: 1.03-1.07), p<0.001, respectively). Engagement coping was also protective against the intention to use tobacco (AOR=0.97 (95% CI: 0.96-0.99), p<0.001) or marijuana (AOR=0.98 (95% CI: 0.96-0.99), p<0.01). These findings suggest that psychoeducational programs supporting the development of engagement oriented coping strategies may contribute not only to reductions in adolescents' use of tobacco and marijuana, but also to reductions in adolescents' intentions to use in the future.


Fluorescence correlation spectroscopy at micromolar concentrations without optical nanoconfinement.
Fluorescence correlation spectroscopy (FCS) is an important technique for studying biochemical interactions dynamically that may be used in vitro and in cell-based studies. It is generally claimed that FCS may only be used at nM concentrations. We show that this general consensus is incorrect and that the limitation to nM concentrations is not fundamental but due to detector limits as well as laser fluctuations. With a high count rate detector system and applying laser fluctuation corrections, we demonstrate FCS measurements up to 38 μM with the same signal-to-noise as at lower concentrations. Optical nanoconfinement approaches previously used to increase the concentration range of FCS are not necessary, and further increases above 38 μM may be expected using detectors and detector arrays with higher saturation rates and better laser fluctuation corrections. This approach greatly widens the possibilities of dynamic measurements of biochemical interactions using FCS at physiological concentrations.


Noise-Induced Hearing Threshold Shift Correlated with Body Weight and External-Ear Amplification in Chinchilla: a Preliminary Analysis.
External-ear amplification (EEA) has been shown to vary from 5-19 dB-A in large datasets of pediatric, adolescent, and adult human participants. However, variable EEA is an overlooked characteristic that likely plays a role in individual noise-induced hearing loss (NIHL) susceptibility. A noise exposure varying 5-19 dB-A translates to high-EEA individuals theoretically experiencing 3-4 times greater NIHL risk than low-EEA individuals. The purpose of this preliminary analysis was to test the hypothesis that higher EEA is correlated with increased noise-induced threshold shift susceptibility. Nine chinchillas were exposed to 4-kHz octave-band noise at 89 dB-SPL for 24 h. Auditory brainstem response thresholds were obtained pre-exposure, 24-h post-exposure, and 4-week post-exposure. Relationships between EEA and threshold shift were analyzed. Open-ear EEA ranged 11-19 dB-SPL, and occluded-ear EEA ranged 10-21 dB-SPL. Higher occluded-ear EEA was correlated with increased NIHL susceptibility (p = 0.04), as was lower body weight (p = 0.01). Male animals exhibited more threshold shift than female animals (p = 0.02), lower body weight than female animals (p = 0.02), and higher occluded-ear EEA (male mean = 18 dB; female mean = 15 dB). Taken together, increased threshold shift susceptibility was observed in the smallest animals, animals with the highest occluded-ear EEA, and in male animals (which tended to have higher occluded-ear EEA). Given the established relationship between smaller body size and higher occluded-ear EEA, these preliminary results suggest that body size (and occluded-ear EEA; a function of body size) could be a potential, underlying driver of NIHL susceptibility differences, rather than true sex differences.


Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.
IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.


Developmentally sensitive diagnostic criteria for mental health disorders in early childhood: the diagnostic and statistical manual of mental disorders-IV, the research diagnostic criteria-preschool age, and the diagnostic classification of mental health and developmental disorders of infancy and early childhood-revised.
As the infant mental health field has turned its focus to the presentation, course, and treatment of clinically significant mental health disorders, the need for reliable and valid criteria for identifying and assessing mental health symptoms and disorders in early childhood has become urgent. In this article we offer a critical perspective on diagnostic classification of mental health disorders in young children. We place the issue of early childhood diagnosis within the context of classification of psychopathology at other ages and describe, in some detail, diagnostic classifications that have been developed specifically for young children, including the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood (DC:0-3R; ZERO TO THREE, 2005), a diagnostic classification for mental health symptoms and disorders in infants, toddlers, and preschoolers. We briefly outline the role of diagnostic classification in clinical assessment and treatment planning. Last, we review the limitations of current approaches to the diagnostic classification of mental health disorders in young children.


Runx1 binds as a dimeric complex to overlapping Runx1 sites within a palindromic element in the human GM-CSF enhancer.
Runx1 is a developmentally regulated transcription factor that is essential for haemopoiesis. Runx1 can bind as a monomer to the core consensus sequence TGTGG, but binds more efficiently as a hetero-dimer together with the non-DNA binding protein CBFβ as a complex termed core binding factor (CBF). Here, we demonstrated that CBF can also assemble as a dimeric complex on two overlapping Runx1 sites within the palindromic sequence TGTGGCTGCCCACA in the human granulocyte macrophage colony-stimulating factor enhancer. Furthermore, we demonstrated that binding of Runx1 to the enhancer is rigidly controlled at the level of chromatin accessibility, and is dependent upon prior induction of NFAT and AP-1, which disrupt a positioned nucleosome in this region. We employed in vivo footprinting to demonstrate that, upon activation of the enhancer, both sites are efficiently occupied. In vitro binding assays confirmed that two CBF complexes can bind this site simultaneously, and transfection assays demonstrated that both sites contribute significantly to enhancer function. Computer modelling based on the Runx1/CBFβ/DNA crystal structure further revealed that two molecules of CBF could potentially bind to this class of palindromic sequence as a dimeric complex in a conformation whereby both Runx1 and CBFβ within the two CBF complexes are closely aligned.


Circadian misalignment, reward-related brain function, and adolescent alcohol involvement.
Developmental changes in sleep and circadian rhythms that occur during adolescence may contribute to reward-related brain dysfunction, and consequently increase the risk of alcohol use disorders (AUDs). This review (i) describes marked changes in circadian rhythms, reward-related behavior and brain function, and alcohol involvement that occur during adolescence, (ii) offers evidence that these parallel developmental changes are associated, and (iii) posits a conceptual model by which misalignment between sleep-wake timing and endogenous circadian timing may increase the risk of adolescent AUDs by altering reward-related brain function. The timing of sleep shifts later throughout adolescence, in part due to developmental changes in endogenous circadian rhythms, which tend to become more delayed. This tendency for delayed sleep and circadian rhythms is at odds with early school start times during secondary education, leading to misalignment between many adolescents' sleep-wake schedules and their internal circadian timing. Circadian misalignment is associated with increased alcohol use and other risk-taking behaviors, as well as sleep loss and sleep disturbance. Growing evidence indicates that circadian rhythms modulate the reward system, suggesting that circadian misalignment may impact adolescent alcohol involvement by altering reward-related brain function. Neurocognitive function is also subject to sleep and circadian influence, and thus circadian misalignment may also impair inhibitory control and other cognitive processes relevant to alcohol use. Specifically, circadian misalignment may further exacerbate the cortical-subcortical imbalance within the reward circuit, an imbalance thought to explain increased risk-taking and sensation-seeking during adolescence. Adolescent alcohol use is highly contextualized, however, and thus studies testing this model will also need to consider factors that may influence both circadian misalignment and alcohol use. This review highlights growing evidence supporting a path by which circadian misalignment may disrupt reward mechanisms, which may in turn accelerate the transition from alcohol use to AUDs in vulnerable adolescents.


The upper limit pH in the dye-binding method for the determination of serum protein via measurements of the absorbance increase produced by protein error.
In the dye-binding method for determining the albumin concentration, the absorbance increase due to the change of the color shade by protein error of a pH indicator can be measured by a spectrophotometer. This absorbance increase is observed only in a restricted pH region, but this pH region is not theoretically studied yet. Thus, the author investigated the upper limit pH (pHUL) at which the absorbance increase occurs by the theoretical calculation, and compared these results with those obtained experimentally using four pH indicators. The pHUL is not affected by the dye or protein concentrations, or by the formation constant of the dye-protein complex; but the value changes according to the acid-dissociation constant of the dye (KD) and the ratio of the molar absorptivities of the proton-dissociated dye anion (epsilonD) and the dye-protein complex (epsilonPD). The pHUL value can be calculated by the equation, found theoretically. The calculated pHUL values of BPB, BCG, BCP and BTB were 5.1, 4.8, 6.2 and 5.5, respectively. These values correlated with the experimental results of 4.5 for BPB, 4.7 for BCG, 5.9 for BCP and 5.2 for BTB, but were not associated with the pKD values of each dye. The pHUL of these dyes did not change significantly for various dye and protein concentrations, as was expected from the thoretical calculation.


High-intensity training and cardiopulmonary exercise testing in patients with chronic obstructive pulmonary disease and non-small-cell lung cancer undergoing lobectomy.
Peak VO2, as measure of physical performance is central to a correct preoperative evaluation in patients with both non-small-cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) because it is closely related both to operability criteria and the rate of postoperative complications. Strategies to improve peak VO2, as a preoperative pulmonary rehabilitation programme (PRP), should be considered favourably in these patients. In order to clarify the role of pulmonary rehabilitation, we have evaluated the effects of 3-week preoperative high-intensity training on physical performance and respiratory function in a group of patients with both NSCLC and COPD who underwent lobectomy. We studied 40 patients with both NSCLC and COPD, age < 75 years, TNM stages I-II, who underwent lobectomy. Patients were randomly divided into two groups (R and S): Group R underwent an intensive preoperative PRP, while Group S underwent only lobectomy. We evaluated peak VO2 in all patients at Time 0 (T0), after PRP/before surgery in Group R/S (T1) and 60 days after surgery, respectively, in both groups (T2). There was no difference between groups in peak VO2 at T0, while a significant difference was observed both at T1 and T2. In Group R, peak VO2 improves significantly from T0 to T1: 14.9 ± 2.3-17.8 ± 2.1 ml/kg/min ± standard deviation (SD), P < 0.001 (64.5 ± 16.5-76.1 ± 14.9% predicted ± SD, P < 0.05) and deteriorates from T1 to T2: 17.8 ± 2.1-15.1 ± 2.4, P < 0.001 (76.1 ± 14.9-64.6 ± 15.5, P < 0.05), reverting to a similar value to that at T0, while in Group S peak VO2 did not change from T0 to T1 and significantly deteriorates from T1 to T2: 14.5 ± 1.2-11.4 ± 1.2 ml/kg/min ± SD, P < 0.00001 (60.6 ± 8.4-47.4 ± 6.9% predicted ± SD, P < 0.00001). PRP was a valid preoperative strategy to improve physical performance in patients with both NSCLC and COPD and this advantage was also maintained after surgery.


Early detection of retinal thickness changes in diabetes using Optical Coherence Tomography.
Diabetic Retinopathy (DR) is a severe and widely spread eye disease. Thus, an objective test for the early diagnosis and evaluation of treatment in DR is certainly needed. In this study, the ability of intraretinal layer segmentation to locally detect early retinal changes in diabetic patients is assessed using optical coherence tomography (OCT). Fifty diabetic patients with no or minimal DR underwent ophthalmic examination, OCT and fundus photography. Automated segmentation of intraretinal layers of the OCT images was performed using a custom-built algorithm. Mean thickness of the macula and intraretinal layers of patients with no DR (DM) was calculated in the fovea, pericentral and peripheral regions and compared with those in patients with mild DR (MDR). We found reduced retinal nerve fiber layer (RNFL) thickness in the pericentral and peripheral regions (27 + or - 2 versus 18 + or - 5 microm and 42 + or - 3 versus 33 + or - 9 microm, respectively, p<0.001) and reduced thickness of ganglion cell/inner plexiform layer (GCL+IPL) complex in the pericentral region of the macula (92 + or - 7 microm versus 80 + or - 10 microm, p<0.001) in the MDR group. Accordingly, macular thickness was reduced in the pericentral and peripheral region of the macula in the MDR group. Our results support the view of neurodegeneration in diabetes in the early stage of retinopathy which seems to involve the ganglion cells and cells of the inner plexiform layers (RNFL+GCL+IPL) mostly. Local retinal thickness measures can be obtained from OCT scans using an intraretinal layer segmentation procedure, and these measures could be helpful in finding a surrogate for following development of retinopathy that could affect vision.


Prevalence of enteric pathogens among community based asymptomatic individuals.
The objective of this study was to describe the prevalence of pathogenic microorganisms in asymptomatic individuals in a community study in Melbourne, Australia. The study population was a subset of 2803 individuals participating in the Water Quality Study; a community based randomized trial. Faecal specimens (1091) were collected over a 3-month period from asymptomatic individuals. Specimens were tested for a range of bacteria including Salmonella, Shigella and Campylobacter species. Rotavirus and adenovirus were detected using a Rota-Adeno latex kit, and protozoa were detected using a permanent stain (modified iron-haemotoxylin). Twenty-eight known pathogens were identified from the 1091 faecal specimens, a total carriage rate of 2.6%. Giardia species were present in 18 specimens (1.6%), Salmonella in four (0.4%), Campylobacter in one (0.1%), Cryptosporidium in four (0.4%) and adenovirus in one (0.1%). Blastocystis hominis was found in 65 specimens. The median age of those without a pathogen was 12.5 years compared with 6.6 years for those with a pathogen (P=0.02). Except for Giardia, pathogens were rarely found in asymptomatic individuals in the community. The prevalence of pathogens was higher in children than adults.


Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain.
Data on comparative safety of opioid analgesics are limited, but some reports suggest disproportionate mortality risk associated with methadone. Our objective was to compare mortality rates among patients who received prescribed methadone or long-acting morphine for pain. This is a retrospective observational cohort drawn from Department of Veterans Affairs (VA) health care databases, January 1, 2000, to December 31, 2007. We included 28,554 patients who received methadone and 79,938 who received long-acting morphine from VA pharmacies. Compared with those who received long-acting morphine, patients who received methadone were younger, less likely to have some medical comorbidities, and more likely to have psychiatric and substance use disorders. Patients were stratified into quintiles according to propensity score; the probability of receiving methadone was conditional on demographic, clinical, and VA service area variables. Overall propensity-adjusted mortality was lower for methadone than for morphine. Hazard ratios varied across propensity score quintiles; the magnitude of the between-drug difference in mortality decreased as the propensity to receive methadone increased. Mortality was significantly lower for methadone in all but the last quintile, in which there was no between-drug difference in mortality (hazard ratio=0.92, 95% confidence interval=0.74, 1.16). Multiple sensitivity analyses found either no difference in mortality between methadone and long-acting morphine or lower mortality rates among patients who received methadone. In summary, we found no evidence of excess all-cause mortality among VA patients who received methadone compared with those who received long-acting morphine. Randomized trials and prospective observational research are needed to better understand the relative safety of long-acting opioids.


Electric current-assisted manipulation of liquid metals using a stylus at micro-and nano-scales.
A novel methodology, based on wetting and electromigration, for transporting liquid metal, over long distances, at micro-and nano-scale using a stylus is reported. The mechanism is analogous to a dropper that uses 'suction and release' actions to 'collect and dispense' liquid. In our methodology, a stylus coated with a thin metal film acts like the dropper that collects liquid metal from a reservoir upon application of an electric current, holds the liquid metal via wetting while carrying the liquid metal over large distances away from the reservoir and drops it on the target location by reversing the direction of electric current. Essentially, the working principle of the technique relies on the directionality of electromigration force and adhesive force due to wetting. The working of the technique is demonstrated by using an Au-coated Si micropillar as the stylus, liquid Ga as the liquid metal to be transported, and a Kleindiek-based position micro-manipulator to traverse the stylus from the liquid reservoir to the target location. For demonstrating the potential applications, the technique is utilized for closing a micro-gap by dispensing a minuscule amount of liquid Ga and conformally coating the desired segment of the patterned thin films with liquid Ga. This study confirms the promising potential of the developed technique for reversible, controlled manipulation of liquid metal at small length scales.


Pharmacogenomic testing and antithrombotic therapy: ready for prime time?
Pharmacogenomics is the study of an individual's interaction with a specific drug based upon the genetic make-up of the individual. Pharmacogenomic testing can be a powerful tool in testing a drug's potential efficacy and toxicity on an individual patient. For this tool to be used correctly, certain criteria have to be met. First and foremost is the strength of association between the genetic variation and the drug's interaction. The predictiveness of pharmacogenomics for the individual patient must be factored in as well. If these criteria are not met, requiring pharmacogenomic testing is at best a waste of money and in some cases can endanger the patient's life. Stent thrombosis is a serious and many times fatal outcome in a small minority of patients who have received drug-eluting stents. Here, we discuss a case in which the FDA issued a "boxed warning" about the use of the anti-clotting medication, clopidogrel, used to prevent stent thrombosis, the pharmacogenomic data available at the time the warning was issued, and the medical community's response to the FDA's warning. This article also discusses developments in the field of anti-clotting therapy since the FDA's warning.