Lactational amenorrhea for family planning.
50 % of pregnancies are unwanted. For several reasons including difficulty in obtaining contraceptives, no or ineffective contraception is used to prevent these unwanted pregnancies. The Lactational Amenorrhoea Method(LAM) however is a contraceptive method available and accessible for many women. To assess in fully breastfeeding women, staying amenorrheic, the efficacy of the Lactational Amenorrhoea Method as a contraceptive method. The efficacy of LAM, as defined in 1988 in Bellagio, was compared with alternative definitions of LAM; the outcomes were measured using pregnancy and menstruation life tables. MEDLINE searches from 1966 until 2002 and EMBASE from 1988 until 2002; reference lists of studies and review articles; books related to LAM; published abstracts from breastfeeding, reproductive health, contraceptive conferences; and e-mail communication with coordinators of such studies. From 454 potentially relevant studies 154 investigated the risk of pregnancy during LAM or lactational amenorrhea. Two reviewers applied the following inclusion criteria: prospective study, cases and -if available- controls had to be sexually active, pregnancy had to be confirmed by physical examination or a pregnancy test. Life table menstruation rates and life table pregnancy rates were taken as endpoints. Thirteen publications, reporting on 9 intervention groups and 2 control groups, met the inclusion criteria and were included in this systematic review. Their quality was assessed. Two reviewers independently extracted data, disagreements were resolved through discussion. Because of the heterogeneity of the included studies, the studies were analyzed using narrative methods. For the outcome two controlled studies of LAM users reported life table pregnancy rates at 6 months of 0.45 and 2.45 percent and 5 uncontrolled studies of LAM users reported 0-7.5 percent. Life table pregnancy rates of women fully breastfeeding and amenorrheic but not using any contraceptive method were 0.88 in one study and 0.9-1.2 percent (95% CI 0. 0-2.4 ) in a second study, depending on the definition of menstruation used. The life table menstruation rate at 6 months in all studies varied between 11.1-39.4 percent. No clear difference in life table pregnancy rates was found between women using LAM and supported in doing so, and fully breastfeeding, amenorroic women not using any method. Because the length of lactation amenorrhoea of women using LAM is too different between populations studied, and population specific, it is uncertain whether LAM extends lactational amenorrhoea.


The appearance of dextranomer-hyaluronic acid copolymer implants on ultrasound may predict resolution of vesicoureteral reflux after injection therapy.
To investigate the correlation between implant appearance on ultrasound (US) and voiding cystourethrography (VCUG) results after dextranomer-hyaluronic acid copolymer (DxHA) injection in children with vesicoureteral reflux (VUR). Consecutive cases of primary VUR treated by endoscopic subureteral injection of DxHA were retrospectively reviewed. All children had postoperative bladder US and VCUG with a mean interval of 34 days and 47 days after injection, respectively. VUR resolution at postoperative VCUG was considered as treatment success. Implant appearance on US was graded according to the retained volume and its location by visual inspection; it was then correlated with VCUG results using the Spearman correlation coefficient. A total of 36 children (56 ureters) were identified in which 38 ureters (68%) had a clearly visualized implant on postoperative US and 40 ureters (71%) showed VUR resolution. The sensitivity of implant visualization on US for predicting reflux resolution was 73% (29/40), specificity 44% (7/16), positive predictive value 76% (29/38), and negative predictive value 39% (7/18). The grade 1, grade 2, and grade 3 implant appearances showed VUR resolution in 88% (22/25), 54% (7/13), and 61% (11/18), and showed persistent VUR in 8% (2/25), 15% (2/13), and 28% (5/18), respectively (p = 0.032). The implant appearance on postoperative US showed good correlation with VCUG results in the early post-injection period. Large retained implants were associated with treatment success, while small or non-visualized implants were related to the persistent reflux.


Evaluating the impact of hospitalists.
The hospital-based generalist physician is a recent organizational innovation in health care in the United States. Does the hospitalist model provide improved health care? The answer to this question lies in a rigorous evaluation of the hospitalist system in the clinical setting. This paper describes key outcomes that need to be assessed and methodologic issues that need to be addressed when conducting and interpreting the results of evaluations of the hospitalist model. To provide evidence about the value of the hospitalist model, quality of care should be evaluated through the measurement of both processes and outcomes. The clinical processes assessed may include diagnostic tests and treatments that are causally linked with outcomes. A variety of outcomes can be measured, such as death, clinical or physiologic status, physical function, and psychological well-being. The analysis of resource use data can aid in an assessment of the relative costs and effectiveness of clinical services. An evaluation of the hospitalist model requires an adequate research design, which should include a precise definition of the model being studied, the selection of an appropriate comparison group, the collection of clinical and demographic information on patients, the specification of both process and outcome measures, and the use of statistical techniques that are appropriate to the questions being asked and the data being collected. The design must distinguish between outcomes attributable to the introduction of hospitalists and those attributable to other changes in medical treatments and the organization of care.


Prognostic Value of Serum Lactate Levels in Critically Ill Patients in an Intensive Care Unit.
The patient in critical condition, regardless of the cause of admission, continues to be a challenge for health systems due to the high mortality that it reports. There is a need to identify some marker of early obtaining, easy to interpret and with high relevance in the prognosis of these patients. To determine the prognostic value of serum lactate in an Intensive Care Unit (ICU). One hundred and forty-five patients admitted to an ICU were enrolled in the study. The Acute Physiology and Chronic Health Evaluation II (APACHE) prognosis score, Sequential Organ Failure Assessment, hemodynamic support need, mechanical ventilation, cause of admission, stay in ICU, analytical and physiological variables were determined. The probability of survival of patients who had elevated and normal serum lactate levels was calculated. The risk of dying was determined using the Cox regression model. Twenty-eight patients died (19%) in the ICU. The serum lactate value was higher in the group of patients with trauma, infections, APACHE II and high creatinine levels; as well as with decreased mean arterial blood pressure, need for hemodynamic support and mechanical ventilation. The survival capacity was higher in patients who had normal serum lactate. Serum lactate was the sole independent predictor of mortality (AHR 1.28 [1.07-1.53], p = 0.008). Patient assessment through the determination of serum lactate levels provides useful information in the initial evaluation of the critical patient.


Defective MHC class II presentation by dendritic cells limits CD4 T cell help for antitumor CD8 T cell responses.
Cancer immunosurveillance failure is largely attributed to insufficient activation signals and dominant inhibitory stimuli for tumor Ag (TAg)-specific CD8 T cells. CD4 T cells have been shown to license dendritic cells (DC), thereby having the potential for converting CD8 T cell responses from tolerance to activation. To understand the potential cooperation of TAg-specific CD4 and CD8 T cells, we have characterized the responses of naive TCR transgenic CD8 and CD4 T cells to poorly immunogenic murine tumors. We found that whereas CD8 T cells sensed TAg and were tolerized, the CD4 T cells remained ignorant throughout tumor growth and did not provide help. This disparity in responses was due to normal TAg MHC class I cross-presentation by immature CD8alpha+ DC in the draining lymph node, but poor MHC class II presentation on all DC subsets due to selective inhibition by the tumor microenvironment. Thus, these results reveal a novel mechanism of cancer immunosubversion, in which inhibition of MHC-II TAg presentation on DC prevents CD4 T cell priming, thereby blocking any potential for licensing CD8alpha+ DC and helping tolerized CD8 T cells.


FLVCR1 promotes the proliferation and tumorigenicity of synovial sarcoma through inhibiting apoptosis and autophagy.
Feline leukemia virus subgroup C receptor 1 (FLVCR1) has been reported to have a crucial role in variety of biological processes, including cell proliferation, cell death, apoptosis, oxidative stress response, cellular differentiation and metabolism. However, little is known about its role in synovial sarcoma (SS). In the current study, FLVCR1 expression was analyzed in two SS cell lines (SW982 and HS-SY-II), and in eight SS tissues and paired adjacent non-tumor tissues using reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemistry. Lentivirus-mediated short hairpin RNAs were used to knock down FLVCR1 expression in SW982 and HS-SY-II cells. The effects of FLVCR1 knockdown on the cell proliferation, clonogenicity, cell cycle and apoptosis in SS cells were evaluated by MTT, colony formation assay, flow cytometry analysis, western blotting and in vivo tumorigenesis in nude mice. In the current study, gene expression of FLVCR1 was upregulated in SS cell lines (SW982 and HS-SY-II) and SS tissues from patients. The protein levels of FLVCR1 in SS tissues were also significantly higher than in adjacent non-tumor tissues. Furthermore, suppressing the expression of FLVCR1 in SS cells using short hairpin RNA effectively attenuated cell proliferation, colony formation and impaired the cell cycle, and also significantly induced apoptosis and autophagy. In accordance with this, an in vivo tumorigenicity assay in mice demonstrated that suppression of FLVCR1 expression inhibited the growth of SS tumors implanted subcutaneously. Collectively, these results demonstrated that FLVCR1 may act as an oncoprotein, and have key roles in promoting proliferation and tumorigenicity of SS, and this may shed new light on finding novel therapeutic strategies against SS.


Prevention of stent thrombosis with reduced dose of prasugrel in two patients undergoing treatment of cerebral aneurysms with pipeline embolisation devices.
Prevention of intracranial stent thrombosis with dual-antiplatelet therapy is widely used in neuroendovascular procedures. However, the rising incidence of inadequate platelet inhibition with clopidogrel may increase complications following stent placement, especially with newer devices that possess a larger total metal surface area. While there are recent reports of prasugrel as an alternative to clopidogrel, there is no clinical evidence in neurointerventional patients regarding the use of a lower maintenance dose as an alternative strategy to gain adequate platelet inhibition while possibly reducing the risk of bleeding. We present 6-month efficacy and safety outcomes of two patients undergoing elective pipeline embolisation that were found to have inadequate platelet response to clopidogrel and subsequently transitioned to prasugrel 5 mg daily for the prevention of stent thrombosis.


Genome-wide association study identifies 30 loci associated with bipolar disorder.
Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.


Electric and near-field acoustic detection, a comparative study.
The acceleration fields in the vicinity of quietly moving prey are governed by the same mathematical equation as the bioelectric fields aquatic animals produce. Hence, to reach their prey, predatory fish may use the inertial sense organs of the inner ear in a similar fashion as sharks and rays use the electroreceptors, the ampullae of Lorenzini. Besides the acceleration fields, predatory fish may detect the velocity fields of the prey, responding to the accelerations the inner ear receives from the spatial differences in the velocity experienced over time due to the relative motion between predator and prey.


The effect of aquatic intervention on the gross motor function and aquatic skills in children with cerebral palsy.
The objective of this study was to investigate the effect of an aquatic intervention on the gross motor function and aquatic skills of children with cerebral palsy (CP). Twenty-nine children with CP, aged 5 to 14, were recruited. Fourteen children completed an aquatic intervention (EG), and 13 children served as controls (CG). Two participants dropped out due to events (illness) unrelated to the intervention. The aquatic intervention lasted 6 weeks (2 sessions per week at 55 minutes per session) with a follow-up period of 3 weeks. The outcome measures were the Gross Motor Function Measure (GMFM) for motor function and the Water Orientation Test Alyn 2 (WOTA 2) for aquatic skills assessment. A significant improvement was observed in the secondary assessment of GMFM and WOTA 2. In contrast to the aquatic skills improvement, the GMFM change was not maintained at follow-up. Our results indicate that children with CP can improve gross motor function on dry land and aquatic skills with a 6-week water intervention. The intervention period was too short for sustainable improvement in dry-land motor skills after intervention (follow-up), but time was sufficient to achieve sustainable improvements in aquatic skills.


Perioperative management of severe congenital protein C deficiency.
: Perioperative care of congenital protein C deficiency has not been well established. Here, we describe a patient with congenital protein C deficiency who underwent laparoscopic fundoplication and gastrostomy at 2 years of age. Preoperatively, we stopped warfarin, administered fresh frozen plasma, and activated protein C. These procedures were performed without bleeding or clotting events, and at 3 days after the procedures, we restarted warfarin. Several episodes of abdominal hemorrhage and purpura fulminans occurred 2-4 weeks postoperatively, and the events were managed conservatively. We conclude that an invasive procedure can be performed in patients with protein C deficiency with appropriate supportive therapy, and postoperative observation for a sufficient length of time is essential to minimize the risk of complications.


Genetic selection? A study of individual variation in the enzymes of folate metabolism.
Genetic variation in folate metabolism has been associated with survival in utero, the success of in vitro fertilisation, multiple pathologies and longevity. We have looked at the prevalence of genetic variants of the enzymes MTHFR and TYMS in 2,898 DNA samples derived from five cohorts collected in the United Kingdom. The simultaneous analysis of genetic variants of the MTHFR and TYMS loci was carried out to investigate a putative gene-gene interaction that was first observed in an elderly male population from Norfolk. We have made a consistent observation in five population cohorts; the proportion of individuals who are homozygous for the 2R allele of the 5'UTR TYMS polymorphism is less in individuals who are homozygous for the T allele of MTHFR 677 than in individuals homozygous for the C allele of MTHFR 677 (p = 0.02). These data may suggest a gene-gene interaction and could be evidence of genetic selection, with some pregnancies more or less viable as a consequence of genetic variation. If these genetic phenomena affect the way folate is handled at the cellular level in utero it is possible that maternal folic acid intake may over-ride such genetic selection.


Diurnal and nocturnal transcriptomic variation in the Caribbean staghorn coral, Acropora cervicornis.
Reef-building corals experience large diel shifts in their environment, both externally due to changes in light intensity, predator activity and prey availability, and internally as a result of diel fluctuations in photosynthesis by their endosymbiotic algae, Symbiodinium. Diel patterns of tentacle behaviour, skeletal growth and gene expression indicate reactions of the coral animal in response to light and through circadian regulation. Some corals, such as the Caribbean Acroporas, have strong within-colony division of labour, including specialized fast-growing apical polyps, accompanied by large gene expression differences. Here we use RNA-seq to evaluate how diel changes in gene expression vary within the branching Caribbean staghorn coral, Acropora cervicornis, between branch tips and branch bases. Multifactor generalized linear model analysis indicated that 6% (3005) of transcripts were differentially expressed between branch tips and bases, while 1% (441) of transcripts were differentially expressed between day and night. The gene expression patterns of 220 transcripts were affected by both time of day and location within the colony. In particular, photoreceptors, putative circadian genes, stress response genes and metabolic genes were differentially expressed between day and night, and some of these, including Amcry1, tef and hebp2, exhibited location-specific regulation within the coral colony as well. These findings indicate that the genetic response of the coral to day and night conditions varies within the colony. Both time of day and location within the colony are factors that should be considered in future coral gene expression experiments.


Monoclonal antibodies to the VP6 of porcine subgroup I rotaviruses reactive with subgroup I and non-subgroup I non-subgroup II strains.
A panel of 10 monoclonal antibodies produced after immunization with two porcine subgroup I rotavirus strains (OSU and A46), and directed against the major inner capsid protein (VP6), fell into six patterns of reactivity when tested against a collection of human and animal group A rotavirus strains. Monoclonal antibodies of pattern I recognized all rotavirus strains. Antibodies of patterns 2 and 3 recognized all subgroup II strains and some, but not all, subgroup I strains. Pattern 4 antibodies identified all subgroup I strains and two strains (H2, equine; CC117, porcine) not reactive with reference subgroup monoclonal antibodies (strains non-I non-II). Pattern 5 antibody exhibited the same reactivity as pattern 4 except for not recognizing the non-I non-II equine strain. Pattern 6 antibodies reacted exclusively with subgroup I and non-I non-II rotaviruses of porcine origin. By competitive binding assays, monoclonal antibodies of patterns 4, 5 and 6 appeared to recognize a single antigenic site, which included at least three overlapping epitopes. In immunoblots all monoclonal antibodies, except one, recognized only the trimeric, but not the monomeric form of VP6.


Programmed cell death in plant reproduction.
Reproductive development is a rich arena to showcase programmed cell death in plants. After floral induction, the first act of reproductive development in some plants is the selective killing of cells destined to differentiate into an unwanted sexual organ. Production of functional pollen grains relies significantly on deterioration and death of the anther tapetum, a tissue whose main function appears to nurture and decorate the pollen grains with critical surface molecules. Degeneration and death in a number of anther tissues result ultimately in anther rupture and dispersal of pollen grains. Female sporogenesis frequently begins with the death of all but one of the meiotic derivatives, with surrounding nucellar cells degenerating in concert with embryo sac expansion. Female tissues that interact with pollen undergo dramatic degeneration, including death, to ensure the encounter of compatible male and female gametes. Pollen and pistil interact to kill invading pollen from an incompatible source. Most observations on cell death in reproductive tissues have been on the histological and cytological levels. We discuss various cell death phenomena in reproductive development with a view towards understanding the biochemical and molecular mechanisms that underlie these processes.


Cdc42 reactivation at growth sites is regulated by local cell-cycle-dependent loss of its GTPase-activating protein Rga4 in fission yeast.
In fission yeast, polarized cell growth stops during division and resumes after cytokinesis completes and cells separate. It is unclear how growth reactivation is timed to occur immediately after cell separation. We uncoupled these sequential events by delaying cytokinesis with a temporary Latrunculin A treatment. Mitotic cells recovering from treatment initiate end growth during septation, displaying a polar elongation simultaneous with septation (PrESS) phenotype. PrESS cell ends reactivate Cdc42, a major regulator of polarized growth, during septation, but at a fixed time after anaphase B. A candidate screen implicates Rga4, a negative regulator of Cdc42, in this process. We show that Rga4 appears punctate at the cell sides during G2, but is diffuse during mitosis, extending to the ends. Although the Morphogenesis Orb6 (MOR) pathway is known to promote cell separation and growth by activating protein synthesis, we find that, for polarized growth, removal of Rga4 from the ends is also necessary. Therefore, we propose that growth resumes after division once the MOR pathway is activated and the ends lose Rga4 in a cell-cycle-dependent manner.


The neuroimaging of sacred values.
Sacred (or protected) values (SVs) constitute core beliefs that define primary reference groups. There is significant research on SVs at a behavioral level, but their neural underpinnings are just beginning to be discovered. In this paper, we highlight the current state of neuroimaging research concerning SVs. Given that SVs are considered to be strongly motivated by moral principles, we first provide an outline of the neural circuits that have been found to be involved in moral cognition. We then review various neuroimaging studies that have explored the notion of SVs. Specifically, we concentrate on neuroimaging studies dealing with intergroup bias and those that focus on social norms, since these are two basic dimensions of SVs that have been studied with neuroimaging techniques. Finally, we review two studies that have directly addressed SVs with neuroimaging techniques, and we offer suggestions for further avenues of study.


Effect of growth medium pH of Aeropyrum pernix on structural properties and fluidity of archaeosomes.
The influence of pH (6.0; 7.0; 8.0) of the growth medium of Aeropyrum pernix K1 on the structural organization and fluidity of archaeosomes prepared from a polar-lipid methanol fraction (PLMF) was investigated using fluorescence anisotropy and electron paramagnetic resonance (EPR) spectroscopy. Fluorescence anisotropy of the lipophilic fluorofore 1,6-diphenyl-1,3,5-hexatriene and empirical correlation time of the spin probe methylester of 5-doxylpalmitate revealed gradual changes with increasing temperature for the pH. A similar effect has been observed by using the trimethylammonium-6-diphenyl-1,3,5-hexatriene, although the temperature changes were much smaller. As the fluorescence steady-state anisotropy and the empirical correlation time obtained directly from the EPR spectra alone did not provide detailed structural information, the EPR spectra were analysed by computer simulation. This analysis showed that the archaeosome membranes are heterogeneous and composed of several regions with different modes of spin-probe motion at temperatures below 70°C. At higher temperatures, these membranes become more homogeneous and can be described by only one spectral component. Both methods indicate that the pH of the growth medium of A. pernix does not significantly influence its average membrane fluidity. These results are in accordance with TLC analysis of isolated lipids, which show no significant differences between PLMF isolated from A. pernix grown in medium with different pH.


Changes to the Fossil Record of Insects through Fifteen Years of Discovery.
The first and last occurrences of hexapod families in the fossil record are compiled from publications up to end-2009. The major features of these data are compared with those of previous datasets (1993 and 1994). About a third of families (>400) are new to the fossil record since 1994, over half of the earlier, existing families have experienced changes in their known stratigraphic range and only about ten percent have unchanged ranges. Despite these significant additions to knowledge, the broad pattern of described richness through time remains similar, with described richness increasing steadily through geological history and a shift in dominant taxa, from Palaeoptera and Polyneoptera to Paraneoptera and Holometabola, after the Palaeozoic. However, after detrending, described richness is not well correlated with the earlier datasets, indicating significant changes in shorter-term patterns. There is reduced Palaeozoic richness, peaking at a different time, and a less pronounced Permian decline. A pronounced Triassic peak and decline is shown, and the plateau from the mid Early Cretaceous to the end of the period remains, albeit at substantially higher richness compared to earlier datasets. Origination and extinction rates are broadly similar to before, with a broad decline in both through time but episodic peaks, including end-Permian turnover. Origination more consistently exceeds extinction compared to previous datasets and exceptions are mainly in the Palaeozoic. These changes suggest that some inferences about causal mechanisms in insect macroevolution are likely to differ as well.


The impact of an expanded genetic testing program and selective oophorectomy on the incidence of ovarian cancer in West Pomerania.
The aim of the study was to evaluate the impact of a regional population-based genetic testing program on the incidence of ovarian cancer in West Pomerania. Between 1999 and 2010, a total of 37,552 women ages 35 to 70 were tested for three BRCA1 founder mutations at the outpatient genetics clinic of the Pomeranian Medical University in Szczecin, Poland. A total of 641 women were found to carry a mutation (1.7%) and of these, 220 had a prophylactic oophorectomy (34.3%). A total of 12 women had an occult cancer diagnosed at the time of prophylactic oophorectomy (5.5%). We estimate that 26 more ovarian cancers would have been diagnosed by January 2015 in the absence of these oophorectomies and that an additional 25 cancers will be prevented in the future (total 51). During this period, 1611 ovarian cancers were diagnosed in the region; therefore we estimate that approximately 1.6% of ovarian cancers were prevented between 1999 and 2015 by our genetic testing program. We conclude that the prophylactic oophorectomies performed between 1999 and 2010 as a result of widespread BRCA1 mutation testing have reduced the incidence of ovarian cancer in Pomerania by a small amount (about 1.6%), and that the impact of genetic testing will increase in the coming years.


Lower doses of oral estrogen and progestogens as treatment for postmenopausal women.
Estrogen, with or without a progestin, is effective for the treatment of menopausal symptoms. Larger doses of estrogen/progestin have been used than required for the amelioration of menopausal symptoms. Both positive and negative outcomes of hormone therapy are reported in postmenopausal women. The positive aspects have been those associated with a reduction in menopausal symptoms such as hot flashes, and improvement in vulvovaginal atrophy with maintenance of bone mineral density. The problems have included an increased risk of venous thrombosis and breast cancer. The anticipation is that as the dose of oral estrogen and progestins is lowered, the benefits can be maintained and the side effects reduced. Recent clinical trials have found that lower doses of estrogen and/or progestin reduce or improve menopausal symptoms and maintain bone mineral density. The impact of lower doses of hormones on heart disease, and venous thromboembolism and stroke remain to be determined in future studies.


A solid-state NMR method for solution of zeolite crystal structures.
Since zeolites are notoriously difficult to prepare as large single crystals, structure determination usually relies on powder X-ray diffraction (XRD). However, structure solution (i.e., deriving an initial structural model) directly from powder XRD data is often very difficult due to the diffraction phase problem and the high degree of overlap between the individual reflections, particularly for materials with the structural complexity of most zeolites. Here, we report a method for structure determination of zeolite crystal structures that combines powder XRD and nuclear magnetic resonance (NMR) spectroscopy in which the crucial step of structure solution is achieved using solid-state (29)Si double-quantum dipolar recoupling NMR, which probes the distance-dependent dipolar interactions between naturally abundant (29)Si nuclei in the zeolite framework. For two purely siliceous zeolite blind test samples, we demonstrate that the NMR data can be combined with the unit cell parameters and space group to solve structural models that refine successfully against the powder XRD data.


Refinement of the Diatom Episome Maintenance Sequence and Improvement of Conjugation-Based DNA Delivery Methods.
Conjugation of episomal plasmids from bacteria to diatoms advances diatom genetic manipulation by simplifying transgene delivery and providing a stable and consistent gene expression platform. To reach its full potential, this nascent technology requires new optimized expression vectors and a deeper understanding of episome maintenance. Here, we present the development of an additional diatom vector (pPtPBR1), based on the parent plasmid pBR322, to add a plasmid maintained at medium copy number in Escherichia coli to the diatom genetic toolkit. Using this new vector, we evaluated the contribution of individual yeast DNA elements comprising the 1.4-kb tripartite CEN6-ARSH4-HIS3 sequence that enables episome maintenance in Phaeodactylum tricornutum. While various combinations of these individual elements enable efficient conjugation and high exconjugant yield in P. tricornutum, individual elements alone do not. Conjugation of episomes containing CEN6-ARSH4 and a small sequence from the low GC content 3' end of HIS3 produced the highest number of diatom exconjugant colonies, resulting in a smaller and more efficient vector design. Our findings suggest that the CEN6 and ARSH4 sequences function differently in yeast and diatoms, and that low GC content regions of greater than ~500 bp are a potential indicator of a functional diatom episome maintenance sequence. Additionally, we have developed improvements to the conjugation protocol including a high-throughput option utilizing 12-well plates and plating methods that improve exconjugant yield and reduce time and materials required for the conjugation protocol. The data presented offer additional information regarding the mechanism by which the yeast-derived sequence enables diatom episome maintenance and demonstrate options for flexible vector design.


The Assessment of Allostatic Overload in Patients with Congestive Heart Failure by Clinimetric Criteria.
The precipitating role of emotional stress in the development of congestive heart failure (CHF) is a long-standing clinical observation. We employed new clinimetric criteria for the assessment of allostatic overload (AO) in a sample of CHF patients, with regard to its associations with psychological distress and health status. Allostatic overload was assessed by a semi-structured interview based on clinimetric criteria in 70 consecutive outpatients with CHF. One observer-rated scale and two self-rating questionnaires for psychological distress were administered. Cardiac variables were also collected at intake. Twenty-three patients (32.9%) were classified as having AO according to clinimetric criteria. Significant differences were found with regard to gender, with women being more likely to report AO than men (23.5% versus 57.9%). Patients with AO presented significantly higher levels of psychological distress (based on scales administered) compared with those who did not. Among cardiac risk factors, hyperglycaemia was found to be significantly associated with the presence of AO. The use of the clinimetric criteria provides a global index for identifying distress that might adversely influence the course and progression of CHF. It may be of use in clinical practice, leading to therapeutic suggestions such as lifestyle modifications and psychotherapy to help patients deal with their difficulties.


Numerical simulation of the environmental impact of hydraulic fracturing of tight/shale gas reservoirs on near-surface groundwater: Background, base cases, shallow reservoirs, short-term gas, and water transport.
Hydrocarbon production from unconventional resources and the use of reservoir stimulation techniques, such as hydraulic fracturing, has grown explosively over the last decade. However, concerns have arisen that reservoir stimulation creates significant environmental threats through the creation of permeable pathways connecting the stimulated reservoir with shallower freshwater aquifers, thus resulting in the contamination of potable groundwater by escaping hydrocarbons or other reservoir fluids. This study investigates, by numerical simulation, gas and water transport between a shallow tight-gas reservoir and a shallower overlying freshwater aquifer following hydraulic fracturing operations, if such a connecting pathway has been created. We focus on two general failure scenarios: (1) communication between the reservoir and aquifer via a connecting fracture or fault and (2) communication via a deteriorated, preexisting nearby well. We conclude that the key factors driving short-term transport of gas include high permeability for the connecting pathway and the overall volume of the connecting feature. Production from the reservoir is likely to mitigate release through reduction of available free gas and lowering of reservoir pressure, and not producing may increase the potential for release. We also find that hydrostatic tight-gas reservoirs are unlikely to act as a continuing source of migrating gas, as gas contained within the newly formed hydraulic fracture is the primary source for potential contamination. Such incidents of gas escape are likely to be limited in duration and scope for hydrostatic reservoirs. Reliable field and laboratory data must be acquired to constrain the factors and determine the likelihood of these outcomes. Short-term leakage fractured reservoirs requires high-permeability pathways Production strategy affects the likelihood and magnitude of gas release Gas release is likely short-term, without additional driving forces.


Structure-activity relationships of the antimalarial agent artemisinin. 5. Analogs of 10-deoxoartemisinin substituted at C-3 and C-9.
Novel 3- and 9-substituted analogs (4-19) of 10-deoxoartemisinin, 3, were prepared from the corresponding known lactones by one-pot reduction with sodium borohydride and boron trifluoride etherate. Reproducibility problems associated with this heterogeneous reaction were encountered on small reaction scales, and thus alternative methodology was sought for this reduction. Conversion of the lactones to tetrahydropyrans via the corresponding intermediate lactols was made more reproducible using a two-step sequence involving low-temperature reduction with diisobutylaluminum hydride followed by deoxygenation with boron trifluoride etherate in the presence of triethylsilane. In this manner, 10-deoxoartemisinin (3) could be obtained from artemisinin (1) in greater than 95% overall yield. All analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs were much more active than the natural product (+)-artemisinin (1) or 10-deoxoartemisinin (3). Conventional structure-activity relationships are discussed in relation to the bioassay data.


[Metabolic characteristics of thermophilic microorganisms].
The maximum growth rate of thermophilic bacteria was found in the exponential growth phase during 2 to 3 hours, and the metabolism was aerobic. In the linear growth phase, the substrate (glucose) was metabolized both by the aerobic and anaerobic pathways during the cultivation of the thermophilic bacteria with shaking; this was confirmed by increasing values of the respiratory quotient and by the evolution of volatile acids. The mesophilic bacteria oxidized the substrate by the aerobic pathway under the same conditions of cultivation, both during the exponential and linear growth phases, and had the stable value of the respiratory quotient. The economic coefficient was lower in the thermophilic microorganisms (bacteria and thermotolerant yeasts) than in the mesophilic cultures.


When water interacts with temperature: Ecological and evolutionary implications of thermo-hydroregulation in terrestrial ectotherms.
The regulation of body temperature (thermoregulation) and of water balance (defined here as hydroregulation) are key processes underlying ecological and evolutionary responses to climate fluctuations in wild animal populations. In terrestrial (or semiterrestrial) ectotherms, thermoregulation and hydroregulation closely interact and combined temperature and water constraints should directly influence individual performances. Although comparative physiologists traditionally investigate jointly water and temperature regulation, the ecological and evolutionary implications of these coupled processes have so far mostly been studied independently. Here, we revisit the concept of thermo-hydroregulation to address the functional integration of body temperature and water balance regulation in terrestrial ectotherms. We demonstrate how thermo-hydroregulation provides a framework to investigate functional adaptations to joint environmental variation in temperature and water availability, and potential physiological and/or behavioral conflicts between thermoregulation and hydroregulation. We extend the classical cost-benefit model of thermoregulation in ectotherms to highlight the adaptive evolution of optimal thermo-hydroregulation strategies. Critical gaps in the parameterization of this conceptual optimality model and guidelines for future empirical research are discussed. We show that studies of thermo-hydroregulation refine our mechanistic understanding of physiological and behavioral plasticity, and of the fundamental niche of the species. This is illustrated with relevant and recent examples of space use and dispersal, resource-based trade-offs, and life-history tactics in insects, amphibians, and nonavian reptiles.


Spotlight on bicalutamide 150mg in the treatment of locally advanced prostate cancer.
Bicalutamide (Casodex) is a competitive androgen receptor antagonist that inactivates androgen-regulated prostate cell growth and function, leading to cell apoptosis and inhibition of prostate cancer growth. It is administered orally as a once-daily dose. In the EU and a number of other countries, bicalutamide 150 mg/day is approved in men with locally advanced nonmetastatic prostate cancer as immediate therapy either as an adjuvant to active treatment or as monotherapy as an alternative to surgical or medical castration. Combined analysis of the three trials that comprise the bicalutamide Early Prostate Cancer programme showed that bicalutamide administered in conjunction with standard care in men with locally advanced prostate cancer offers disease-free survival benefits over standard care alone and is generally well tolerated. Overall survival was improved to a greater extent in the subgroup of patients who received bicalutamide plus radiation therapy compared with radiation therapy alone. Men with localised prostate cancer do not benefit from the addition of bicalutamide to standard care. Combined analysis of two other studies in men with locally advanced prostate cancer show that bicalutamide monotherapy offers better tolerability and higher health-related quality-of-life scores for sexual interest and physical capacity compared with surgical or medical castration, while achieving disease-free and overall survival durations that were not significantly different. Thus, when treatment options are being evaluated, bicalutamide as adjuvant therapy or monotherapy should be considered as an alternative to other available hormonal therapies in men with locally advanced prostate cancer, especially in those who wish to maintain an active lifestyle.


Psychological interventions for grief in adults: A systematic review and meta-analysis of randomized controlled trials.
The present meta-analysis evaluates the efficacy of psychological interventions for grief in bereaved adults and explores the possible moderating influence of various study characteristics. A systematic literature search was conducted by two reviewers who independently searched electronic databases, reviewed and selected eligible studies, and evaluated their methodological quality. A total of 31 randomized controlled trials (RCTs) were included in the meta-analysis. Statistically significant pooled effects of psychological intervention on grief symptoms were found for both post-intervention (Hedges's g = 0.41, p > .001, K = 31) and follow-up (g = 0.45, p > .001, K = 18). While generally robust, the effect was smaller at post-intervention when adjusting for possible publication bias (g = 0.31). Compared with the remaining studies, larger post-intervention effect sizes were found for studies with (1) individually delivered interventions (Beta = 0.49, p < .001), (2) the ICG-(R)/PG-13 questionnaire as the grief instrument (Beta = 0.46, p < .001), (3) participants who were ≥6 months post-loss (Beta = 0.58, p < .001), (4) participants included based on high baseline symptom levels (Beta = 0.40, p = .002) and (5) higher study quality (Beta = 0.06, p = .013). The included studies were methodologically heterogeneous and their methodological quality varied considerably. Moreover, there were some indications of publication bias. Given the recent introduction of Prolonged Grief Disorder in the ICD-11, the results of the present meta-analysis are timely and of clinical relevance. Based on our results, psychological intervention appears efficacious for alleviating grief symptoms in bereaved adults, with several study characteristics as possible moderators of the effect. The interpretability of the results, however, is challenged by some limitations of the available research, including possible publication bias.


Decursinol and decursin protect primary cultured rat cortical cells from glutamate-induced neurotoxicity.
We previously reported six neuroprotective decursinol derivatives, coumarins from Angelica gigas (Umbelliferae) roots. To elucidate the action patterns of decursinol derivatives, we investigated the neuroprotective effects of decursinol and decursin, which showed highly significant activity and were major constituents of A. gigas, using primary cultures of rat cortical cells in-vitro. At concentrations of 0.1-10.0 microM, both decursinol and decursin exerted a significant neuroprotective activity pretreatment and throughout treatment. In addition, decursin had a neuroprotective impact in the post-treatment paradigm implying that decursin might possess different action mechanisms from that of decursinol in the protection of neurons against glutamate injury. Both decursinol and decursin effectively reduced the glutamate-induced increased intracellular calcium ([Ca(2+)](i)) in cortical cells, suggesting that these two coumarins may exert neuroprotection by reducing calcium influx by overactivation of glutamate receptors. This suggestion was supported by the result that decursinol and decursin protected neurons against kainic acid (KA)-induced neurotoxicity better than against that induced by N-methyl-D-aspartate (NMDA). Moreover, both decursinol and decursin significantly prevented glutamate-induced decreases in glutathione, a cellular antioxidant, and glutathione peroxidase activity. In addition, both compounds efficiently reduced the overproduction of cellular peroxide in glutamate-injured cortical cells. These results suggested that both decursinol and decursin protected primary cultured rat cortical cells against glutamate-induced oxidative stress by both reducing calcium influx and acting on the cellular antioxidative defence system. Moreover, decursin is considered to probably have a different action mechanism from that of decursinol in protecting cortical cells against glutamate injury.


Generation of Earth's first-order biodiversity pattern.
The first-order biodiversity pattern on Earth today and at least as far back as the Paleozoic is the latitudinal diversity gradient (LDG), a decrease in richness of species and higher taxa from the equator to the poles. LDGs are produced by geographic trends in origination, extinction, and dispersal over evolutionary timescales, so that analyses of static patterns will be insufficient to reveal underlying processes. The fossil record of marine bivalve genera, a model system for the analysis of biodiversity dynamics over large temporal and spatial scales, shows that an origination and range-expansion gradient plays a major role in generating the LDG. Peak origination rates and peak diversities fall within the tropics, with range expansion out of the tropics the predominant spatial dynamic thereafter. The origination-diversity link occurs even in a "contrarian" group whose diversity peaks at midlatitudes, an exception proving the rule that spatial variations in origination are key to latitudinal diversity patterns. Extinction rates are lower in polar latitudes (> or =60 degrees ) than in temperate zones and thus cannot create the observed gradient alone. They may, however, help to explain why origination and immigration are evidently damped in higher latitudes. We suggest that species require more resources in higher latitudes, for the seasonality of primary productivity increases by more than an order of magnitude from equatorial to polar regions. Higher-latitude species are generalists that, unlike potential immigrants, are adapted to garner the large share of resources required for incumbency in those regions. When resources are opened up by extinctions, lineages spread chiefly poleward and chiefly through speciation.


Modeling Urban Hydrology and Green Infrastructure Using the AGWA Urban Tool and the KINEROS2 Model.
Urban hydrology and green infrastructure (GI) can be modeled using the Automated Geospatial Watershed Assessment (AGWA) Urban tool and the Kinematic Runoff and Erosion (KINEROS2) model. The KINEROS2 model provides an urban modeling element with nine overland flow components that can be used to represent various land cover types commonly found in the built environment while treating runoff-runon and infiltration processes in a physically based manner. The AGWA Urban tool utilizes a Geographic Information System (GIS) framework to prepare parameters required for KINEROS2, executes the model, and imports results for visualization in the GIS. The AGWA Urban tool was validated on a residential subdivision in Arizona, USA, using 47 rainfall events (June 2005 to September 2006) to compare observed runoff volumes and peak flow rates with simulated results. Comparison of simulated and observed runoff volumes resulted in a slope of 1.00 for the regression equation with an R2 value of 0.80. Comparison of observed and simulated peak flows had a slope of 1.12 with an R 2 value of 0.83. A roof runoff analysis was simulated for 787 events, from January 2006 through December 2015, to analyze the water availability from roof runoff capture. Simulation results indicated a 15% capture of the average monthly rainfall volume on the watershed. Additionally, rainwater captured from roofs has the potential to provide for up to 70% of the domestic annual per capita water use in this region. Five different scenarios (S1 - base, S2 - with retention basins, S3 - with permeable driveways, S4 - with rainwater harvesting cisterns, and S5 - all GI practices from S2, S3, and S4) were simulated over the same period to compare the effectiveness of GI implementation at the parcel level on runoff and peak flows at the watershed outlet. Simulation results indicate a higher runoff volume reduction for S2 (53.41 m3 average capacity, average 30% reduction) as compared to S3 (average 14% reduction), or S4 (3.78 m3 capacity, average 6% reduction). Analysis of peak flows reveal larger peak flow reduction for S2. S3 showed more reduction of smaller peak flows as compared to S4.


Solar Radiation Exposure and Outdoor Work: An Underestimated Occupational Risk.
A considerably high number of outdoor workers worldwide are constantly exposed for the majority of their working life to solar radiation (SR); this exposure is known to induce various adverse health effects, mainly related to its ultraviolet (UV) component. The skin and the eye are the principal target organs for both acute and long-term exposure. Actinic keratosis, non-melanoma skin cancers, and malignant melanoma are the main long-term adverse skin effects, whereas in the eye pterygium, cataracts, and according to an increasing body of evidence, macular degeneration may be induced. Despite this, SR exposure risk is currently undervalued, if not neglected, as an occupational risk factor for outdoor workers. SR exposure is influenced by various environmental and individual factors, and occupation is one of the most relevant. For a better understanding of this risk and for the development of more effective prevention strategies, one of the main problems is the lack of available and adequate methods to estimate SR worker exposure, especially long-term exposure. The main aims of this review were to provide a comprehensive overview of SR exposure risk of outdoor workers, including the UV exposure levels and the main methods recently proposed for short-term and cumulative exposure, and to provide an update of knowledge on the main adverse eye and skin effects. Finally, we also outline here preventive interventions to reduce occupational risk.


Modulation of Hydra attenuata rhythmic activity: phase response curve.
We investigated the effect of photic stimulation on the frequency of Hydra attenuata column contractions. We used positive or negative abrupt light transitions, single or repetitive light or darkness pulses, and alternation of light and darkness periods. The main results are: (a) The frequency of the contraction pulse trains (CPTs) varies transiently in response to an abrupt variation of the light intensity. (b) CPTs in progress can be inhibited by different types of photic stimuli. (c) The response time to a single photic stimulus varies during the inter-CPT interval and depends also on the polarity of the stimulus. (d) The CPTs are entrainable with repetitive light stimulation of various frequencies. (e) Long-lasting variations of the frequency of CPTs occur after the end of a repetitive light stimulation. We suggest that the mechanism responsible for the rhythym of column contractions is quite similar to that on which other biological rhythmic phenomena are based.


Interaction of stilbene disulphonates with cloned K(ATP) channels.
In this study, we tested the effects of the stilbene disulphonates DIDS and SITS on three different types of cloned K(ATP) channel (Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2DeltaC) heterologously expressed in Xenopus oocytes, with the aim of identifying the part of the channel which is involved in mediating disulphonate inhibition. We found that the inhibitory site(s) for these drugs lies within the Kir6.2 subunit of the channel, although its properties are further modulated by the sulphonylurea (SUR) subunit. In particular, SUR2A reduces both the rate and extent of block, by impairing the ability of DIDS binding to produce channel closure. The disulphonate-binding site interacts with the ATP inhibitory site on Kir6.2 because ATP is able to protect against irreversible channel inhibition by disulphonates. This effect is not mimicked by tolbutamide (at a concentration that interacts with Kir6.2) and is abolished by mutations that render the channel ATP insensitive. A number of point mutations in both the N and C termini of Kir6.2 reduced the extent and reversibility of channel inhibition by SITS. The results are consistent with the idea that residue C42 of Kir6.2 is likely to be involved in covalently linking of SITS to the channel. Other types of Kir channel (Kir1.1, Kir2.1 and Kir4.1) were also irreversibly blocked by DIDS, suggesting that these channels may share common binding sites for these stilbene disulphonates.


Genotype x environment interaction for age at first calving in Brazilian and Colombian Holsteins.
The objective was to determine whether there is a genotype x environment interaction for age at first calving (AFC) in Holstein cattle in Brazil and Colombia. Data included 51,239 and 25,569 first-lactation records from Brazil and Colombia, respectively. Of 4230 sires in the data, 530 were North American sires used in both countries. Analyses were done using the REML bi-trait animal model, and AFC was considered as a distinct characteristic in each country. Fixed effects of contemporary group (herd-calving year), sire genetic group, and cow genetic group, and random effects of animal and residual variation were included in the model. Average AFC in Brazil and Colombia were 29.5 +/- 4.0 and 32.1 +/- 3.5 mo, respectively. Additive and residual genetic components and heritability coefficient for AFC in Brazil were 2.21 mo2, 9.41 mo2, and 0.19, respectively, whereas for Colombia, they were 1.02 mo2, 6.84 mo2, and 0.13, respectively. The genetic correlation of AFC between Brazil and Colombia was 0.78, indicating differences in ranking of sires consistent with a genotype x environment interaction. Therefore, in countries with differing environments, progeny of Holstein sires may calve at relatively younger or older ages compared with contemporary herdmates in one environment versus another.


Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound.
Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling, interfering with its control of glucose homeostasis and metabolism. PTP1B activity is elevated in obesity and type 2 diabetes and is a major cause of insulin resistance. Trodusquemine (MSI-1436) is a "first-in-class" highly selective inhibitor of PTP1B that can cross the blood-brain barrier to suppress feeding and promote insulin sensitivity and glycemic control. Trodusquemine is a naturally occurring cholestane that can be purified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured synthetically by a fairly laborious process that requires several weeks. Here, we tested a novel easily and rapidly (2 days) synthesized polyaminosteroid derivative (Claramine) containing a spermino group similar to Trodusquemine for its ability to inhibit PTP1B. Like Trodusquemine, Claramine displayed selective inhibition of PTP1B but not its closest related phosphatase TC-PTP. In cultured neuronal cells, Claramine and Trodusquemine both activated key components of insulin signaling, with increased phosphorylation of insulin receptor-β (IRβ), Akt and GSK3β. Intraperitoneal administration of Claramine or Trodusquemine effectively restored glycemic control in diabetic mice as determined by glucose and insulin tolerance tests. A single intraperitoneal dose of Claramine, like an equivalent dose of Trodusquemine, suppressed feeding and caused weight loss without increasing energy expenditure. In summary, Claramine is an alternative more easily manufactured compound for the treatment of type II diabetes.


Angiomatous involvement of an extremity. A spectrum of syndromes.
Congenital diffuse hemangiomatous involvement of the entire left thigh and knee joint in a 12-year-old girl was complicated by a Kasabach-Merrit type of consumptive coagulopathy. Repeated pathologic fractures of the left femur resulted in a nonunion. She also had a progressively increasing leg-length discrepancy, a stiff contracted knee, and leg atrophy distal to the knee. She was misdiagnosed originally as a Klippel-Trenauney syndrome, the progress of which is usually self-limited progression and involution. Despite steroid treatment, femoral artery banding, and intramedullary fixation of her femur, the hemangioma caused progressive debilitation of her left lower limb. At age nine, nonunion progressed to marked osteolysis and was treated by a through-knee amputation. A review of the literature revealed much confusion about multiple syndromes associated with angiomatous involvement of the lower limb. Prognostically, the depth and extent of the lesion were the most significant characteristics. This is well illustrated in this long-term follow-up study showing diffuse deep involvement that led to eventual amputation. Furthermore, this patient presents a multitude of complications developing from large angiomas.


A Fast and Scalable Approach for Synthesis of Hierarchical Porous Zeolitic Imidazolate Frameworks and One-Pot Encapsulation of Target Molecules.
A trimethylamine (TEA)-assisted synthesis approach that combines the preparation of hierarchical porous zeolitic imidazolate framework ZIF-8 nanoparticles and one-pot encapsulation of target molecules is presented. Two dye molecules, rhodamine B (RhB) and methylene blue (MB), and one protein (bovine serum albumin, BSA) were tested as the target molecules. The addition of TEA into the solution of zinc nitrate promoted the formation of ZnO nanocrystals, which rapidly transformed to ZIF-8 nanoparticles after the addition of the linker 2-methylimidazole (Hmim). Hierarchical porous dye@ZIF-8 nanoparticles with high crystallinity, large BET surface areas (1300-2500 m2/g), and large pore volumes (0.5-1.0 cm3/g) could be synthesized. The synthesis procedure was fast (down to 2 min) and scalable. The Hmim/Zn ratio could be greatly reduced (down to 2:1) compared to previously reported ones. The surface areas, and the mesopore size, structure, and density could be modified by changing the TEA or dye concentrations, or by postsynthetic treatment using reflux in methanol. This synthesis and one-pot encapsulation approach is simple and can be readily scaled up. The photophysical properties such as lifetime and photostability of the dyes could be tuned via encapsulation. The lifetimes of the encapsulated dyes were increased by 3-27-fold for RhB@ZIF-8 and by 20-fold for MB@ZIF-8, compared to those of the corresponding free dyes. The synthesis approach is general, which was successfully applied for encapsulation of protein BSA. It could also be extended for the synthesis of hierarchical porous cobalt-based ZIF (dye@ZIF-67).


Current and Optimal Training in High-Value Care in the Internal Medicine Clerkship: A National Curricular Needs Assessment.
The clinical skills needed to practice high-value care (HVC) are core to all medical disciplines. Medical students form practice habits early, and HVC instruction is essential to this formation. The purpose of this study was to describe the state of HVC instruction and assessment in internal medicine clerkships and identify needs for additional curricula. In 2014, the Clerkship Directors in Internal Medicine conducted its annual survey of 121 U.S. and Canadian medical schools. The authors evaluated a subset of questions from that survey asking clerkship directors about the perceived importance of HVC instruction, type and amount of formal instruction and assessment, achievement of student competence, prioritization of topics, and barriers to curriculum implementation. Descriptive statistics were used to summarize responses, and chi-square tests were used to examine associations between response categories. The overall response rate was 77.7% (94/121). The majority (85; 91.4%) agreed that medical schools have a responsibility to teach about HVC across all phases of the curriculum. Of respondents, 31 (32.9%) reported their curricula as having some formal instruction on HVC, and 66 (70.2%) felt the amount was inadequate. Highest-priority topics for inclusion included overuse of diagnostic tests and treatments, defining value and its application to clinical reasoning, and balancing benefit and harm. Only 11 (17.8%) assessed students' competence in HVC. Internal medicine clerkship directors reported that HVC is insufficiently taught and assessed in medical school, despite relevance to practice. Developing generalizable curricular materials, faculty development, and dedicated curricular time may enhance HVC education.


The ExPeCT (Examining Exercise, Prostate Cancer and Circulating Tumour Cells) trial: study protocol for a randomised controlled trial.
Prostate cancer (PrCa) is the second most common cancer in Ireland. Many men present with locally advanced or metastatic cancer for whom curative surgery is inappropriate. Advanced cancer patients are encouraged to remain physically active and therefore there is a need to investigate how patients with metastatic disease tolerate physical activity programmes. Physical activity reduces levels of systemic inflammatory mediators and so an aerobic exercise intervention may represent an accessible and cost-effective means of ameliorating the pro-inflammatory effects of obesity and subsequently decrease poor cancer-specific outcomes in this patient population. This study will assess the feasibility and safety of introducing a structured aerobic exercise intervention to an advanced cancer population. This study will also examine if the evasion of immune editing by circulating tumour cells (CTCs) is an exercise-modifiable mechanism in obese men with prostate cancer. This international multicentre prospective study will recruit men with metastatic prostate cancer. Participants will be recruited from centres in Dublin (Ireland) and London (UK). Participants will be divided into exposed and non-exposed groups based on body mass index (BMI) ≥ 25 kg/m2 and randomised to intervention and control groups. The exercise group will undertake a regular supervised aerobic exercise programme, whereas the control group will not. Exercise intensity will be prescribed based on a target heart rate monitored by a polar heart rate monitor. Blood samples will be taken at recruitment and at 3 and 6 months to examine the primary endpoint of platelet cloaking of CTCs. Participants will complete a detailed questionnaire to assess quality of life (QoL) and other parameters at each visit. The overall aim of the ExPeCT trial is to examine the relationship between PrCa, exercise, obesity, and systemic inflammation, and to improve the overall QoL in men with advanced disease. Results will inform future work in this area examining biological markers of prognosis in advanced prostate cancer. Clinicaltrials.gov NLM identifier: NCT02453139 . Registered on 12 May 2015. This document contains excerpts from the ExPeCT trial protocol Version 1.5, 28 July 2016.


Processing and proliferative effects of human progastrin in transgenic mice.
Incompletely processed gastrins have been postulated to play a role in growth of the gastrointestinal tract, but few studies have examined the effects of progastrin on mucosal proliferation in vivo. Human gastrin gene expression and progastrin processing were therefore studied in transgenic mice containing a human gastrin (hGAS) minigene, and compared to processing in mice bearing an insulin gastrin (INS-GAS) transgene that overexpresses amidated gastrin. Progastrin processing was studied using region-specific antisera and radioimmunoassays, biosynthetic labeling, immunoprecipitation, and HPLC. Proliferative effects due to overexpression of processed and unprocessed gastrin in INS-GAS and hGAS mice, respectively, were determined using routine histology and BrdU incorporation. The pancreatic islets of INS-GAS mice were able to produce carboxyamidated G-17, resulting in a twofold elevation of serum amidated gastrin, marked thickening of the oxyntic mucosa, and an increased BrdU labeling index (LI) of the gastric body. In contrast, livers of adult hGAS mice expressed abundant human gastrin mRNA and human progastrin but were unable to process this peptide to the mature amidated form, resulting in markedly elevated serum progastrin levels and normal amidated gastrin levels. Nevertheless, there was a marked increase in the BrdU labeling index of the colon in hGAS mice (LI 7.46+/-1.90%), as well as in INS-GAS mice (LI 6.16+/-1.17%), compared to age-matched, wild type control mice (LI 4.01+/-0.98%, P < 0.05). These studies suggest that incompletely processed gastrin precursors may contribute to colonic mucosal proliferation in vivo.


Etiology of drinking and driving among adolescents: implications for primary prevention.
A prospective study was conducted to investigate what factors are predictive of self-reported drinking and driving (DD) among adolescents. The study employs a theoretical framework taken from Problem Behavior Theory; environmental, personality, and behavioral factors are explored for their predictability of DD. A cohort of 1482 high school students completed a written survey in spring of 1986 and again in fall of 1986. The findings confirm that Problem Behavior Theory provides a useful theoretical framework with which to identify etiological factors predictive of DD among adolescents. Identified personality, perceived environmental, behavioral, and demographic factors accounted for approximately 50% of the reported variance in DD at baseline. The same factors accounted for approximately 40% percent of the variance in follow-up DD and were predictive both among the students who did not drink and drive at baseline (incidence cases), and among those students who did drink and drive at baseline (continuation versus discontinuation of the behavior). Based on these etiological data, we recommend that school-based, peer-led educational prevention programs be designed to reach young adolescents prior to the age at which a driver's license is obtained. We further recommend that the programs be broad-based and consider DD within the larger context of drinking and driving related behaviors and traffic safety in general.


Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection.
ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistance in vitro. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log10 IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥ 40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.).


Reducing emergency room utilization in end-stage COPD - feasible or fantasy?
The emergency room (ER) is a common point of care transition for patients with end-stage chronic obstructive pulmonary disease. Many of these patients present to the ER because of dyspnea, anxiety and caregiver burden that is precipitated by fragmented and reactive systems of care that fail to meet their needs. This article uses an illustrative case report to outline the challenges patients and caregivers face and presents the core elements of care required to improve quality of care and decrease reliance on the ER.


Covalent grafting of chitosan onto stainless steel through aryldiazonium self-adhesive layers.
Although the conventional methods for strong attachment of chitosan onto stainless steel require many steps in different solvents, it has been demonstrated in this work that covalent grafting of chitosan on a steel surface can be easily achieved through the formation of a self-adhesive surface based on aryldiazonium seed layers. Initially, a polyaminophenyl layer is grafted on a stainless steel surface by means of the one-step GraftFast(TM) process (diazonium induced anchoring process). The grafted aminophenyl groups are then converted to an aryldiazonium seed layer by simply dipping the substrate in a sodium nitrite acidic solution. That diazonium-rich grafted layer can be used as a self-adhesive surface for subsequent spontaneous coating of chitosan onto the steel surface. X-ray photoelectron and impedance electrochemical spectroscopies were used to characterize the pristine and modified steel samples. As evidenced from impedance and linear polarization results, the primary polyaminophenyl layer characterized by a high charge transfer resistance contributed to better protection against corrosion of the resulting chitosan-coated steel in sulfuric acid medium.


Development of a Japanese version of the Epworth Sleepiness Scale (JESS) based on item response theory.
Various Japanese versions of the Epworth Sleepiness Scale (ESS) have been used, but none was developed via standard procedures. Here we report on the construction and testing of the developer-authorized Japanese version of the ESS (JESS). Developing the JESS involved translations, back translations, a pilot study, and psychometric testing. We identified questions in the ESS that were difficult to answer or were inappropriate in Japan, proposed possible replacements for those questions, and tested them with analyses based on item response theory (IRT) and classical test theory. The subjects were healthy people and patients with narcolepsy, idiopathic hypersomnia, or obstructive sleep apnea syndrome. We identified two of our proposed questions as appropriate replacements for two problematic questions in the ESS. The JESS had very few missing data. Internal consistency reliability and test-retest reliability were high. The patients had significantly higher JESS scores than did the healthy people, and higher JESS scores were associated with worse daytime function, as measured with the Pittsburgh Sleep Quality Index. In Japan, the JESS provides reliable and valid information on daytime sleepiness. Researchers who use the ESS with other populations should combine their knowledge of local conditions with the results of psychometric tests.


[Health services utilization by the immigrant and native-born populations in the autonomous region of Murcia (Spain)].
To analyze the patterns of utilisation for three types of public health services (outpatient specialist visits, emergency visits and hospitalisations) in the Comunidad Autónoma de la Región de Murcia. We examine the differences between the average rates of utilization of these services among natives and non-Spanish immigrants, and whether these differences are due to differences in demographic structure, or to different behaviour between these groups. We use econometric models for utilisation to exploit administrative records on health care utilisation and the well established Oaxaca decomposition method. This splits average rates of utilisation and/or average health expenditure into two components: the first one stands for the part of the difference that can be attributed to differential patterns of behaviour among the two groups; the second one represents the part of the difference in average expenditure that can be attributed to the fact that average demographic characteristics among both groups differ. The rates of use of outpatient specialist visits, emergencies and hospital nights by the native population are greater than the corresponding rates for the immigrant population. For individuals aged between 20 to 40 years old, the utilisation rates of African and Latin-American females are higher than those for native females. The average health expenditure of native males is greater than that of immigrants. The difference is mainly due to different demographic features among the native and immigrant populations, except for the <<rest of Europe>> group, whose individuals show a different behaviour. In fact, among the 20 to 40 age group, the average health expenditure of native females equals that of Latin-American women, which is in turn below that of African females. In this paper we show that the remarkable differences in the age-gender balance among different (in terms of nationality) groups of insured residents in Murcia has a considerable effect on consumption of health services and therefore on the average health care expenditure attributable to these groups.


Specific association between bacteria and buoyant Microcystis colonies compared with other bulk bacterial communities in the eutrophic Lake Taihu, China.
The diversity of buoyant Microcystis colony-associated, settling particle-associated and free-living freshwater bacteria in the eutrophic Lake Taihu in China was compared by the polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) of 16S rRNA genes and by clone library analysis. The cluster analysis of DGGE profiles revealed that the buoyant Microcystis colony associates collected in summer and winter were clustered together and were distinct from settling particle-associated and free-living bacteria. In contrast, the bacterial communities of the latter two populations collected in summer were clustered together and varied from those collected in winter. The diversity indices of the Microcystis-associated bacterial population were significantly lower than those of the other two bulk bacterial communities (P < 0.05). Clone library analysis revealed that no shared operational taxonomic units were found in the three populations. Phylogenetic analysis confirmed that buoyant Microcystis-associated bacteria were distinct from the other communities and that they were dominated by Alphaproteobacteria, Betaproteobacteria and Gammaproteobacteria. Proteobacteria, Bacteroidetes and Actinobacteria were prevalent in all three habitats. Other bacterial taxa such as Planctomycetes, Verrucomicrobia, Gemmatimonadetes and Acidobacteria were associated with settling particles and with the water column. Buoyant Microcystis colonies, settling particles and the water column in the eutrophic lake are thus inhabited by different bacterial flora. In addition, specific bacterial communities are associated with buoyant Microcystis colonies.


Pulmonary problems in pregnancy.
Pregnant women with asthma and pulmonary infections should be treated essentially the same as nonpregnant women with similar disease severity. Definitive diagnosis and prompt treatment with heparin should be used for patients with pulmonary thromboembolism.


Pancreatitis as a medical emergency.
Pancreatitis in its acute form, whether from alcohol or gallstones, can be a severe, devastating illness. Patients presumed to have the disease require aggressive fluid therapy and imaging of the pancreas by ultrasound and computed tomography (CT). They should be managed in an intensive care setting until the course of the illness is determined. Surgical intervention is reserved for cases in which extensive pancreatic necrosis or infection is demonstrated by CT scan.


Gametophytic self-incompatibility reexamined.
The conventional hypothesis of gametophytic self-incompatibility in the angiosperms involves one to four multiallelic incompatibility loci and the positive inhibition of incompatible pollen tubes. However, this concept does not accommodate recent experimental data indicating that there may be many loci. An alternative hypothesis which incorporates many loci and complementary pollen-style interactions suggests that there may be no S gene, as previously thought, and that gametophytic self-incompatibility is perhaps merely one aspect of extensive pollen-style interactions.


Algorithm for identification of undifferentiated peripheral inflammatory arthritis: a multinational collaboration through the 3e initiative.
To develop an algorithm for identification of undifferentiated peripheral inflammatory arthritis (UPIA). An algorithm for identification of UPIA was developed by consensus during a roundtable meeting with an expert panel. It was informed by systematic reviews of the literature used to generate 10 recommendations for the investigation and followup of UPIA through the 3e initiative. The final recommendations from the 3e UPIA Initiative were made available to the panel to guide development of the algorithm. The algorithm drew on the clinical experience of the consensus panel and evidence from the literature where available. In patients presenting with joint swelling a thorough evaluation is required prior to diagnosing UPIA. After excluding trauma, the differential diagnosis should be formulated based on history and physical examination. A minimum set of investigations is suggested for all patients, with additional ones dependent on the most probable differential diagnoses. The diagnosis of UPIA can be made if, following these evaluations, a more specific diagnosis is not reached. Once a diagnosis of UPIA is established, patients should be closely followed as they may progress to a specific diagnosis, remit, or persist as UPIA, and additional investigations may be required over time. Our algorithm presents a diagnostic approach to identifying UPIA in patients presenting with joint swelling, incorporating the dynamic nature of the condition with the potential to evolve over time.


Nordic Specialist Course in Palliative Medicine: Evaluation and Impact on the Development of Palliative Medicine in the Nordic Countries: A Survey among Participants from Seven Courses 2003-2017.
Background: The five Nordic Associations for palliative medicine (PM) have since 2003 organized a common specialist course for six weeks in two years. Aim: To describe the course: participants, evaluations, impact on participants' careers, and on the development of PM in the Nordic countries. Methods: Information on participants taken from the course archive and national registries. A web survey sent to graduates from the courses 2003-2013 (n = 150) and 2013-2017 (n = 72). Results: Mean age at course start was 46.9 years; 66% were women. Mean overall evaluation score 5.7 (range 5.4-6.0, max 7.0). Survey response rate 84% (n = 186); 80% of respondents were working in PM, the majority as leaders, >90% engaged in teaching PM. About 40% were active in PM associations, lobbying, and guideline development. Conclusion: The Nordic Specialist Course in PM has had a profound impact on the participants' postcourse careers, influencing the development of PM in the Nordic countries.


Comparison of three methods for eliciting phonological processes.
Eight articulatory disordered children were studied to compare the occurrence of phonological processes using three elicitation methods, including single-word productions, imitated sentences, and continuous speech sampling. A total of 11 phonological processes were shown by the subjects, with only the process of gliding indicative of significantly different rates of occurrence among the three procedures. These subjects were relatively consistent in their use of phonological processes under different speaking conditions.


Restless legs syndrome. How to provide symptom relief with drug and nondrug therapies.
Restless legs syndrome (RLS) is a perplexing, debilitating, and fairly common condition that can be challenging to manage. Hallmark symptoms include an increase in the severity of sensations during rest and an irresistible urge to move the affected limbs. RLS often occurs concomitantly with periodic limb movement disorder. There are no known causes of RLS, but likely triggers include heredity, iron and vitamin deficiencies, caffeine, and alcohol. Chronic conditions such as diabetes, peripheral neuropathy, and Parkinson's disease can worsen and prolong RLS symptoms. Symptom management begins by establishing proper nutrition intake and improved sleep hygiene. If these fail, conservative pharmacologic treatment is appropriate, with regimens chosen from dopaminergic agents, benzodiazepines, opioids, and anticonvulsants.


Quantitation by enzyme-immunoassay of antibodies against Bothrops myotoxins in four commercially-available antivenoms.
An enzyme-immunoassay (EIA) for the quantitation of antibodies against myotoxins present in the venoms of Bothrops asper (Costa Rica), B. atrox (Colombia) and B. moojeni (Brazil), was developed. This EIA was utilized for the evaluation of four antivenoms produced in Mexico (Laboratorios Myn; MYN), Costa Rica (Instituto Clodomiro Picado; ICP), Colombia (Instituto Nacional de Salud; INS) and Brazil (Instituto Butantan; IB). Antivenoms ICP, IB and INS showed a higher titer of antibodies against the three myotoxins tested, with only slight differences between them, depending on the antigen utilized. In contrast, MYN antivenom had very low levels of antibodies to the three myotoxins. Seventeen batches of ICP antivenom were analyzed by EIA, using B. asper myotoxin II as antigen. Although all batches had high anti-myotoxin titers, these varied significantly. Batches produced after 1988 had, in general, higher titers than older (1986-1987) ones. Antivenom stored for one year at 37 degrees C had a slight, but significant (P less than 0.002) decrease of anti-myotoxin activity, compared to antivenom stored at 4 degrees C or 23 degrees C. No correlation was found between anti-myotoxin concentration and lethality-neutralizing ability of the ICP antivenom.


The contribution of twins to the study of cognitive ageing and dementia: the Older Australian Twins Study.
The Older Australian Twins Study (OATS) is a major longitudinal study of twins, aged ≥ 65 years, to investigate genetic and environmental factors and their interactions in healthy brain ageing and neurocognitive disorders. The study collects psychiatric, neuropsychological, cardiovascular, metabolic, biochemical, neuroimaging, genomic and proteomic data, with two-yearly assessments, and is currently in its third wave. The initial cohort comprises 623 individuals (161 monozygotic and 124 dizygotic twin pairs; 1 MZ triplets; 27 single twins and 23 non-twin siblings), of whom 426 have had wave 2 assessment. A number of salient findings have emerged thus far which assist in the understanding of genetic contributions to cognitive functions such as processing speed, executive ability and episodic memory, and which support the brain reserve hypothesis. The heritability of brain structures, both cortical and subcortical, brain spectroscopic metabolites and markers of small vessel disease, such as lacunar infarction and white matter hyperintensities, have been examined and can inform future genetic investigations. Work on amyloid imaging and functional magnetic resonance imaging is proceeding and epigenetic studies are progressing. This internationally important study has the potential to inform research into cognitive ageing in the future, and offers an excellent resource for collaborative work.


Overwintering hosts for the exotic leafroller parasitoid, Colpoclypeus florus: implications for habitat manipulation to augment biological control of leafrollers in pome fruits.
Thirty sites of managed and native habitats were surveyed for leafrollers (Lepidoptera: Tortricidae) in the apple producing region of central Washington State and northern Oregon from September through November 1997-2000 to discover species that supported overwintering by the parasitoid Colpoclypeus florus (Walker) (Hymenoptera: Eulophidae). C. florus, a species introduced from Europe, requires medium to large host larvae late in autumn on which to overwinter, and few leafroller species display this biology. Over the four years, five potential C. florus hosts were collected, including: Ancylis comptana (Froelich), Xenotemna pallorana (Robinson), and Syndemis sp. (Tortricidae), Filatima sp. (Gelechiidae), and Caloptilia burgessiellia (Zeller) (Gracillariidae). Of these, A. comptana, Syndemis sp., and Filatima sp. have been confirmed as overwintering hosts for C. florus. During the four years, the Syndemis sp. was rare and observed at only one location feeding on redosier dogwood, Cornus sericea L. (Cornales: Cornaceae) although, at this location, many of the larvae collected were parasitized by C. florus. Filatima sp. was common in the Yakima valley feeding on balsam poplar, Populus balsamifera L. ssp. trichocarpa (Torr. & Gray ex Hook) Brayshaw (Malpighiales: Salicaceae) but was rarely parasitized. A. comptana, however, was collected at many locations in central Washington and was frequently found as an overwintering host for C. florus. A. comptana was found feeding on two Rosaceae: Wood's rose, Rosa woodsii Lindl., and strawberry, Fragaria ananassa Duchesne (Rosales: Rosaceae). Based on the number of host larvae collected, A. comptana appears to be the primary overwintering host for C. florus in Washington. Introduction of A. comptana populations to near-orchard habitats may facilitate biological control of leafrollers that are orchard pests.


High-efficiency cogeneration boiler bagasse-ash geochemistry and mineralogical change effects on the potential reuse in synthetic zeolites, geopolymers, cements, mortars, and concretes.
Sugarcane bagasse ash re-utilisation has been advocated as a silica-rich feed for zeolites, pozzolans in cements and concretes, and geopolymers. However, many papers report variable success with the incorporation of such materials in these products as the ash can be inconsistent in nature. Therefore, understanding what variables affect the ash quality in real mills and understanding the processes to characterise ashes is critical in predicting successful ash waste utilisation. This paper investigated sugarcane bagasse ash from three sugar mills (Northern NSW, Australia) where two are used for the co-generation of electricity. Data shows that the burn temperatures of the bagasse in the high-efficiency co-generation boilers are much higher than those reported at the temperature measuring points. Silica polymorph transitions indicate the high burn temperatures of ≈1550 °C, produces ash dominated α -quartz rather than expected α-cristobilite and amorphous silica; although α-cristobilite, and amorphous silica are present. Furthermore, burn temperatures must be ≤1700 °C, because of the absence of lechatelierite where silica fusing and globulisation dominates. Consequently, silica-mineralogy changes deactivate the bagasse ash by reducing silica solubility, thus making bagasse ash utilisation in synthetic zeolites, geopolymers, or a pozzolanic material in mortars and concretes more difficult. For the ashes investigated, use as a filler material in cements and concrete has the greatest potential. Reported mill boiler temperatures discrepancies and the physical characteristics of the ash, highlight the importance of accurate temperature monitoring at the combustion seat if bagasse ash quality is to be prioritised to ensure a usable final ash product.


Chitosan and hyaluronan coated liposomes for pulmonary administration of curcumin.
Aiming at improving the nebulization performances and lung antioxidant protection of curcumin, chitosan or hyaluronan-coated liposomes were prepared and their characteristics and performances were compared with that of uncoated liposomes. Curcumin loaded liposomes displayed a diameter lower than 100nm, the coating with both polymers led to a small increase of vesicle size around 130nm and the zeta potential turned to positive values using chitosan while remained negative using hyaluronan. Chitosan allowed the formation of more lamellar and stiffer vesicles with a higher bilayer thickness (dB∼59Ǻ) with respect to the uncoated liposomes, whereas hyaluronan allowed the interdigitation of the bilayers (dB∼47Ǻ) due to the polymer intercalation between phospholipid head groups resulting in vesicles mainly organized in uncorrelated bilayers. Both polymer coatings, especially hyaluronan, greatly improved the stability of the vesicles, especially during the nebulization process, promoting the deposition of the phytodrug in the furthest stages of the impactor in high amount (≥50%). Polymer coated vesicles were biocompatible and improved the curcumin ability to protect A549 cells from the oxidative stress induced by hydrogen peroxide, restoring healthy conditions (cell relative metabolic activity 100%). In particular, a synergic effect of curcumin and hyaluronan was observed resulting in a proliferative effect and a subsequent further enhancement of cell relative metabolic activity up to 120%.


[The role of proto-oncogenes in fundamental manifestations of life].
Problems of the origin, structure and functions, in the cells and tissues, of the so-called proto-oncogenes (c-onc)--cell genes, homologues and oncogene foreparents (v-onc)--are considered in the review. Up-to-date data are given to show the participation of the main groups of proto-oncogenes in the processes of cell division, proliferation and differentiation. The role of c-onc genes is found to be important for fundamental manifestations of the cell life activity. Special attention is paid to the problem of interrelation of the proto-oncogenes with growth factors and their receptors.


Cell-type-related segregation of surface galactosyl-containing components at an early developmental stage in hemopoietic bone marrow cells in the rabbit.
The avidin-biotin complex was used for the selective ultrastructural labeling of terminal cell surface galactosyl residues. Rabbit bone marrow cells were treated with the enzyme galactose oxidase in the presence of biotin hydrazide. Subsequent treatment with ferritin-avidin conjugates enabled the electron microscopic visualization of terminal membrane-based galactose and/or N-acetylgalactosamine on these cells. All stages of erythroid development were characterized by high levels of exposed cell surface galactose, whereas all leukoid cells in the same preparations were virtually unlabeled by the above method. Modulations in the distribution of these surface determinants during differentiation and maturation of rabbit erythroid cells were found to concur in inverse fashion with respect to that of terminal sialic acids. Neuraminidase treatment, before the above labeling procedure, resulted in the exposure of additional galactosyl residues on the surface of all bone marrow cell types. The results indicate that a galactose-bearing glycoconjugate(s) may comprise an erythroid-specific membrane constituent of rabbit bone marrow cells. The high density of galactose on the surface of even the earliest erythroid precursors may eventually enable the identification and isolation of a stem cell, which already contains the erythroid-specific galactoconjugate(s). The results suggest that variations in the spectrum of cell surface carbohydrates may serve as recognition signals in the complex set of intercellular interactions which occur during the development and maturation of the erythrocyte. The occurrence of similar but species-specific variations in the complement of surface heterosaccharides during erythroid development of humans and other mammals supports this contention.


Prenatal ontogeny as a susceptibility period for cortical GABA neuron disturbances in schizophrenia.
Cognitive deficits in schizophrenia have been linked to disturbances in GABA neurons in the prefrontal cortex (PFC). Furthermore, cognitive deficits in schizophrenia appear well before the onset of psychosis and have been reported to be present during early childhood and even during the first year of life. Taken together, these data raise the following question: Does the disease process that produces abnormalities in prefrontal GABA neurons in schizophrenia begin prenatally and disrupt the ontogeny of cortical GABA neurons? Here, we address this question through a consideration of evidence that genetic and/or environmental insults that occur during gestation initiate a pathogenetic process that alters cortical GABA neuron ontogeny and produces the pattern of GABA neuron abnormalities, and consequently cognitive difficulties, seen in schizophrenia. First, we review available evidence from postmortem human brain tissue studies characterizing alterations in certain subpopulations of prefrontal GABA neuron that provide clues to a prenatal origin in schizophrenia. Second, we review recent discoveries of transcription factors, cytokine receptors, and other developmental regulators that govern the birth, migration, specification, maturation, and survival of different subpopulations of prefrontal GABA neurons. Third, we discuss recent studies demonstrating altered expression of these ontogenetic factors in the PFC in schizophrenia. Fourth, we discuss the potential role of disturbances in the maternal-fetal environment such as maternal immune activation in the development of GABA neuron dysfunction. Finally, we propose critical questions that need to be answered in future research to further investigate the role of altered GABA neuron ontogeny in the pathogenesis of schizophrenia.


Reinforced Ross operation and intermediate to long term follow up.
The Ross operation for aortic valve replacement continues to be a controversial option because of concerns related to late autograft dilation and progressive neo-aortic regurgitation. We described a technique in 2005 to address this problem, in which we place the entire autograft in a Dacron tube which makes it theoretically unlikely, if not impossible, for it to dilate-the reinforced Ross procedure. Since 2004, we have operated on 25 patients using this technique. Median length of follow-up in our cohort was 6 years, with 14 patients having 5 years or more of follow-up. Our data demonstrate the externally supported, or reinforced Ross technique using a straight graft is a safe and effective technique in older children, adolescents, and young adult patients. At intermediate follow-up, patients who underwent a reinforced Ross technique were less likely to have neoaortic root dilatation.