Recent evaluations of the peer-led approach in adolescent sexual health education: a systematic review.
Peer-led interventions have become a popular method of providing sexual health education to adolescents, but the efficacy of this approach and the methodological quality of recent trials have not been systematically reviewed. Electronic and hand searches were conducted to identify quasi-randomized and randomized controlled trials of peer-led adolescent sexual health education published from 1998 to 2005. Studies were eligible if they had an appropriate comparison group, provided preintervention and postintervention data, and reported all outcomes. Study results were summarized and, where appropriate, pooled; in addition, 10 aspects of studies' methodological quality were assessed. Thirteen articles met the inclusion criteria. Pooled, adjusted results from seven trials that examined the effects of peer-led interventions on condom use at last sex found no overall benefit (odds ratio, 1.0). None of the three trials that assessed consistent condom use found a benefit. One study reported a reduced risk of chlamydia (0.2), but another found no impact on STI incidence. One study found that young women (but not young men) who received peer-led education were more likely than nonrecipients to have never had sex. Most interventions produced improvements in knowledge, attitudes and intentions. Only three studies fulfilled all 10 of the assessed quality criteria; two others met nine criteria. Despite promising results in some trials, overall findings do not provide convincing evidence that peer-led education improves sexual outcomes among adolescents. Future trials should build on the successful trials conducted to date and should strive to fulfill existing quality criteria.


Effects of lipoic acid and dihydrolipoic acid on 4-aminophenol-mediated erythrocytic toxicity in vitro.
The effects of the antioxidant lipoic acid and its reduced form, dihydrolipoic acid (DHLA), were studied on the process of the erythrocytic toxicity of 4-aminophenol in human erythrocytes in vitro. 4-Aminophenol alone caused a stepwise increase in methaemoglobin formation, along with a commensurate decrease in total thiols. At 10 min., in the presence of lipoic acid alone and the thiol depletor 1-chloro-2,4-dinitrobenzene (CDNB) alone, 4-aminophenol-mediated methaemoglobin formation was significantly increased, whilst thiol levels were significantly reduced compared with the 4-aminophenol alone. At 10 min., with DHLA and CDNB alone, 4-aminophenol was associated with significantly increased methaemoglobin formation. However, thiol levels were not significantly different in the presence of DHLA compared with 4-aminophenol alone, although thiol levels were different compared with control (4-aminophenol alone) in the incubations with CDNB alone. At 15 min., only CDNB/4-aminophenol methaemoglobin formation differed from control, whilst thiol levels were significantly lower in the presence of CDNB alone compared with 4-aminophenol alone. Lipoic acid enhanced the toxicity of 4-aminophenol in terms of increased methaemoglobin formation coupled with increased thiol depletion, whilst DHLA showed increased 4-aminophenol-mediated methaemoglobin formation without thiol depletion. Lipoic acid, and to a lesser extent its reduced derivative DHLA, acted as a prooxidant in the presence of 4-aminophenol, enhancing the oxidative stress effects of the amine in human erythrocytes.


Islet cell autotransplantation after subtotal pancreatectomy.
Six patients, ranging in age from 28 to 41 years, five men and one woman, underwent 80% to 95% pancreatectomy for chronic pancreatitis, with subsequent autotransplantation of pancreatic fragments. The technique for isolation of pancreatic fragments containing islets of Langerhans was extrapolated from previous experimental work. The follow-up period ranged from one to 25 months. Normal or near-normal carbohydrate metabolism was observed in each patient after the autotransplantation procedure; however, only two patients were insulin independent at 25 and 20 months. One patient died one month after pancreatectomy and autotransplantation of disseminated intravascular coagulation, and another died at three months of surgical complications and sepsis. The remaining two patients were alive and insulin dependent at nine and 25 months. Further developments in islet cell autotransplantation techniques are necessary to achieve, if possible, an insulin-independent status and avert surgically induced diabetes mellitus after total or subtotal pancreatectomy.


Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome.
Recombination-activating gene 1 (RAG1) deficiency results in severe combined immunodeficiency (SCID) caused by a complete lack of T and B lymphocytes. If untreated, patients succumb to recurrent infections. We sought to develop lentiviral gene therapy for RAG1-induced SCID and to test its safety. Constructs containing the viral spleen-focus-forming virus (SF), ubiquitous promoters, or cell type-restricted promoters driving sequence-optimized RAG1 were compared for efficacy and safety in sublethally preconditioned Rag1(-/-) mice undergoing transplantation with transduced bone marrow progenitors. Peripheral blood CD3(+) T-cell reconstitution was achieved with SF, ubiquitous promoters, and cell type-restricted promoters but 3- to 18-fold lower than that seen in wild-type mice, and with a compromised CD4(+)/CD8(+) ratio. Mitogen-mediated T-cell responses and T cell-dependent and T cell-independent B-cell responses were not restored, and T-cell receptor patterns were skewed. Reconstitution of mature peripheral blood B cells was approximately 20-fold less for the SF vector than in wild-type mice and often not detectable with the other promoters, and plasma immunoglobulin levels were abnormal. Two months after transplantation, gene therapy-treated mice had rashes with cellular tissue infiltrates, activated peripheral blood CD44(+)CD69(+) T cells, high plasma IgE levels, antibodies against double-stranded DNA, and increased B cell-activating factor levels. Only rather high SF vector copy numbers could boost T- and B-cell reconstitution, but mRNA expression levels during T- and B-cell progenitor stages consistently remained less than wild-type levels. These results underline that further development is required for improved expression to successfully treat patients with RAG1-induced SCID while maintaining low vector copy numbers and minimizing potential risks, including autoimmune reactions resembling Omenn syndrome.


Genetic linkage mapping of an annual x perennial ryegrass population.
Annual (Lolium multiflorum Lam.) and perennial ( L. perenne L.) ryegrass are two common forage and turfgrass species grown throughout the world. Perennial ryegrass is most commonly used for turfgrass purposes, and contamination by annual ryegrass, through physical seed mixing or gene flow, can result in a significant reduction in turfgrass quality. Seed certifying agencies in the United States currently use a test called seedling root fluorescence (SRF) to detect contamination between these species. The SRF test, however, can be inaccurate and therefore, the development of additional markers for species separation is needed. Male and female molecular-marker linkage maps of an interspecific annual x perennial ryegrass mapping population were developed to determine the map location of the SRF character and to identify additional genomic regions useful for species separation. A total of 235 AFLP markers, 81 RAPD markers, 16 comparative grass RFLPs, 106 SSR markers, 2 isozyme loci and 2 morphological characteristics, 8-h flowering, and SRF were used to construct the maps. RFLP markers from oat and barley and SSR markers from tall fescue and other grasses allowed the linkage groups to be numbered, relative to the Triticeae and the International Lolium Genome Initative reference population P150/112. The three-generation population structure allowed both male and female maps to be constructed. The male and female maps each have seven linkage groups, but differ in map length with the male map being 537 cm long and the female map 712 cm long. Regions of skewed segregation were identified in both maps with linkage groups 1, 3, and 6 of the male map showing the highest percentage of skewed markers. The (SRF) character mapped to linkage group 1 in both the male and female maps, and the 8-h flowering character was also localized to this linkage group on the female map. In addition, the Sod-1 isozyme marker, which can separate annual and perennial ryegrasses, mapped to linkage group 7. These results indicate that Lolium linkage groups 1 and 7 may provide additional markers and candidate genes for use in ryegrass species separation.


Thalamic field potentials during deep brain stimulation of periventricular gray in chronic pain.
Stimulation of the central gray matter areas has been used for the treatment of chronic pain for decades. To better understand the mechanism of action of such treatment we studied the effects of stimulation of the periventricular gray (PVG) on the sensory thalamus in two patients with chronic central pain. In each case, two electrodes were implanted in the PVG (Medtronic 3389) and the ventroposterolateral thalamic nucleus (Medtronic 3387), respectively, under guidance of CT/MRI image fusion. The PVG was stimulated in the frequency range of 2-100 Hz in alert patients while pain was assessed using the McGill-Melzack visual analogue scale. In addition, local field potentials (FPs) were recorded from the sensory thalamus during PVG stimulation. Maximum pain relief was obtained with 5-25 Hz stimulation while 50-100 Hz made the pain worse. This suggests that pain suppression was frequency dependent. Interestingly, we detected low frequency FPs at 0.2-0.4 Hz closely associated with the pain. During 5-25 Hz PVG stimulation the amplitude of this potential was significantly reduced and this was associated with marked pain relief. At the higher frequencies (50-100 Hz) however, there was no reduction in the FPs and no pain suppression. We have found an interesting correlation between thalamic activity and chronic pain. This curious low frequency potential may provide an objective index for quantifying chronic pain, and may hold further clues to the mechanism of action of PVG stimulation.


Metabolic Concomitants of Obese and Nonobese Women With Features of Polycystic Ovarian Syndrome.
Polycystic ovarian syndrome (PCOS) is often associated with obesity and diabetes. The present study measured body fat distribution and metabolic risk factors in women with features of PCOS. Cross-sectional, multiethnic study of cardiovascular risks. General community. 145 PCOS and 344 non-PCOS women. Body composition by dual x-ray absorptiometry; abdominal fat masses measured by magnetic resonance imaging and hepatic triglyceride by magnetic resonance spectroscopy. Body composition, liver fat content, homeostatic model assessment for insulin resistance (HOMA-IR), revised, and metabolic syndrome components. PCOS women had a higher free androgen index compared with the non-PCOS women. Nonobese PCOS and non-PCOS women had a similar body fat content and distribution, HOMA-IR, and hepatic triglyceride content. Obese PCOS women had a similar total body fat percentage compared with their non-PCOS counterparts (41.4% and 41.4% respectively). Both obese groups had similar intraperitoneal fat (1.4% of total body mass in PCOS vs 1.4% in non-PCOS). However, obese PCOS women had a greater ratio of truncal/lower body fat (1.42 vs 1.27; P < 0.016). They also had greater insulin resistance (HOMA-IR: PCOS, 2.24% vs non-PCOS, 1.91%; P < 0.016), higher liver triglyceride content (6.96% in PCOS vs 4.44% in non-PCOS; P < 0.016), and a greater incidence of hypertension (33% vs 24%; P < 0.05). No differences were observed in other metabolic risk factors. Both obese and nonobese women with PCOS features had a greater free androgen index compared with non-PCOS women, but neither had greater intraperitoneal fat or abnormal lipid levels. Obese, but not nonobese, women with PCOS had a greater truncal/lower extremity fat ratio, HOMA-IR, and liver triglyceride content.


Integrative "omic" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes.
Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis. To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis. Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82). A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.


Regulation of calcification site pH is a polyphyletic but not always governing response to ocean acidification.
The response of marine-calcifying organisms to ocean acidification (OA) is highly variable, although the mechanisms behind this variability are not well understood. Here, we use the boron isotopic composition (δ11B) of biogenic calcium carbonate to investigate the extent to which organisms' ability to regulate pH at their site of calcification (pHCF) determines their calcification responses to OA. We report comparative δ11B analyses of 10 species with divergent calcification responses (positive, parabolic, threshold, and negative) to OA. Although the pHCF is closely coupled to calcification responses only in 3 of the 10 species, all 10 species elevate pHCF above pHsw under elevated pCO2. This result suggests that these species may expend additional energy regulating pHCF under future OA. This strategy of elevating pHCF above pHsw appears to be a polyphyletic, if not universal, response to OA among marine calcifiers-although not always the principal factor governing a species' response to OA.


Optimal moving angle of pusher plate in occlusive-type pulsatile blood pump.
Since the occlusive-type pulsatile extracorporeal blood pump (Twin-Pulse Life Support System; Seoul National University, Seoul, Korea) received the CE mark of the European Directives and Korea Food and Drug Administration approval (2004) for short-term applications as an extracorporeal life support system, the pump system has been tested for hemolysis. This pump system was recently upgraded with an ameliorated pusher plate to reduce hemolysis. In this study, numerical analysis and in vitro tests were performed to determine the optimal conditions for increasing the durability of the blood sac and pump output. During the simulation, the minimum sliding interface force (SIF) for the angle of the pusher plate movement (PPM) was calculated (40-70 degrees ). In the in vitro durability test, the angle of the PPM was increased gradually from 40 to 70 degrees in 10 degrees increments, and the mean time to failure (MTTF) of the blood sac was calculated. Fifteen tests were conducted for each case: 40, 50, 60, and 70 degrees (n = 15 each). The MTTF of the blood sac was defined as the time when a crack of the blood sac occurred. The longer lifetime of the blood sac at 60 degrees of the PPM (297.0 h) than that at 50 degrees (197.6 h) was attributed to the lower SIF value (-0.13, normalized value) at 60 degrees of the PPM.


Most randomized controlled trials for psoriasis used placebo comparators despite the availability of effective treatments.
The availability of effective treatments for psoriasis raises ethical questions about the use of a placebo group in therapeutic trials. We evaluated the use of the placebo over time in such trials. From trials in a living Cochrane review and network meta-analysis for psoriasis, we included trials comparing a biologic to a placebo or other systemic treatment. First, we tested the changes in placebo rate from 2001 to 2019 by linear regression, then constructed networks for 2004-2019 and evaluated the contribution of the placebo to the network meta-analysis estimates per trial and per comparison. We included 81 trials (36,774 patients). The placebo rate did not decrease significantly over time. The proportion contribution of trials with a placebo decreased from 100% in 2004 to 86% in 2008 and 75% in 2019. However, the proportion contribution of trials without a placebo remained low (from 0% in 2004 to 25% in 2019). The design of future psoriasis trials should be reviewed to improve the number of patients to be included in a placebo group.


[Transcranial magnetic stimulation as a treatment for depression].
The high incidence of depressive disorder in the Netherlands calls for additional forms of therapy. Transcranial magnetic stimulation (TMS) is a form of non-invasive brain stimulation that has been investigated in the last 15 years in order to find out whether this form of stimulation is effective in the treatment of depression. To discover whether TMS has proved effective in the treatment of depressed patients. Results show that tms treatment is safe when applied to the frontal lobes of the cerebral cortex and that the therapeutic effect is comparable to the effect of psychotherapy and antidepressants. Future studies should concentrate on an increase in efficiency by providing more insight into the working mechanisms and the effect of individual differences. Follow-up studies are needed to investigate the duration of the antidepressive effect. TMS seems to be a promising tool for the treatment of depressive disorders. However, there are many questions and uncertainties about the efficiency and applicability of TMS.


Pregnant women's knowledge about mother-to-child transmission (MTCT) of HIV infection through breast feeding.
The HIV and AIDS epidemic in South Africa has reached serious proportions. Over 5, 5 million South Africans are infected with HIV (Department of Health, 2004: 10). Mother to Child Transmission (MTCT) is a well-established mode of HIV transmission and these infections may occur during pregnancy, labour, delivery and breastfeeding. According to the Department of Health (2000: 2), breastfeeding constitutes a significant risk of MTCT HIV transmission. Studies in Africa have also shown that breast-feeding increases the risk of MTCT by 12%-43% (Department of Health, 2000: 13; Department of Health, 2000:3). Since breastfeeding is a significant and preventable mode of HIV transmission to infants, there is an urgent need to educate, counsel and support women and families to make informed decisions about how best to feed their infants in the context of HIV. To achieve a reduction in MTCT, there is an urgent need to empower women with information on MTCT for informed decision-making. However, cultural factors and the stigma associated with HIV and AIDS might contribute to limited knowledge about MTCT through breastfeeding. The aim of the study was to determine pregnant women's knowledge about MTCT of HIV/AIDS infection through breastfeeding. Findings of the study will be used to update the existing health education programmes in the field of Maternal and Child Health. The design was a descriptive research survey. The population consisted of 100 pregnant women. Convenience sampling was used to select mothers during antenatal visits at a particular clinic at Polokwane municipality. Self-constructed questionnaires were translated into Northern Sotho and distributed to the women. Data analysis used descriptive statistics. The findings of the study revealed a high level of awareness of HIV and AIDS and a low level of knowledge about MTCT of HIV and AIDS infection through breastfeeding. Based on the conclusions, a revised health education programme was proposed for the Maternal and Child Health field.


[Therapy for smoking: consensus in German-speaking countries].
The german speaking countries (Austria, Germany, Switzerland) are not the most advanced in the world when it comes to the control of tobacco related diseases. The medical system in these countries has yet to be convinced that smoking cessation is not only necessary but feasible. In order to provide a basic document for further activities, a consensus development process was initiated. The consensus development process forms part of the activities performed by the UICC (International Union Against Cancer) Project Smoking Cessation, which is a project within the framework of the UICC Tobacco and Cancer Programme. The 1988 Report of the US Surgeon General states very clearly, that the use of tobacco products is not a matter of free choice, but is the result of an addiction as scientifically valid as the addiction to heroin and other narcotics. The scientific literature provides informations on many methods and techniques for a smoking cessation, both pharmacological and non-pharmacological. Many pharmacological approaches have been tried to treat nicotine dependence in man. According to scientific standards and many controlled studies, nicotine has been the only drug found to be effective in treating nicotine dependence. Many techniques, ranging from self help to sophisticated combined therapeutic approaches including pharmacological interventions, are now available to deal with the nicotine addiction. Smoking cessation treatment uses time, effort and other resources and the question of reimbursement for these services has to be considered. As with any other form of treatment, costs needed to be paid either by the individual patient/client and/or by other sources including private and national health insurance systems.(ABSTRACT TRUNCATED AT 250 WORDS)


Functional characterization of the halogenase SpmH and discovery of new deschloro-tryptophan dimers.
The halogenase gene spmH was putatively involved in the biosynthesis of spiroindimicins/indimicins (SPMs/IDMs), a group of chlorinated tryptophan dimers (TDs) from deep-sea-derived Streptomyces sp. SCSIO 03032. Inactivation of spmH led to six deschloro-analogues of TDs, including four new compounds SPMs G (1) and H (2), and IDMs F (3) and G (4). The structures and absolute configurations of 1-4 were unambiguously determined by the combination of extensive spectroscopic analysis, single-crystal X-ray diffraction and quantum chemical ECD calculations. Compounds 1 and 2 exhibited moderate cytotoxic activities against four cancer cell lines. Additionally, SpmH was biochemically characterized in vitro as an l-tryptophan 5-halogenase.


Sodium-glucose Co-transporter 2 Inhibitors Reduce the Abdominal Visceral Fat Area and May Influence the Renal Function in Patients with Type 2 Diabetes.
Objective and Methods An SGLT2 inhibitor (ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin, or canagliflozin) was administered to 132 outpatients with type 2 diabetes mellitus with or without other antidiabetic drugs for 6 months to evaluate its efficacy, the incidence of adverse events, and its influence on the renal function. Results The patient's mean glycated hemoglobin level significantly improved from 7.52±1.16% to 6.95±0.98% (p<0.001). The body weight of the patients was significantly reduced from 78.0±15.3 kg to 75.6±15.1 kg (p<0.001). The estimated visceral fat area was also significantly reduced from 108.4±44.6 cm2 to 94.5±45.3 cm2 (p<0.001). The waist circumference, blood pressure, serum alanine aminotransferase, γ-glutamyl transpeptidase, and uric acid levels also showed a significant decrease. The urinary albumin/creatinine ratio (U-ACR) was significantly reduced in the patients whose U-ACR levels were 30-300 mg/gCr at the baseline. The mean eGFR significantly decreased in the patients with a pre-treatment eGFR value of ≥90 mL/min/1.73 m2 but remained unchanged in the patients with a pre-treatment value of <90 mL/min/1.73 m2. A total of 13 adverse events were noted, including systemic eruption (n=1), cystitis (n=2), pudendal pruritus (n=2), nausea (n=1), malaise (n=1), a strong hunger sensation and increased food ingestion (n=1), and non-serious hypoglycemia (n=5). Conclusion SGLT2 inhibitors seemed to be useful in the treatment of obese type 2 diabetes mellitus patients. Furthermore, these data suggest that SGLT2 inhibitors may protect the renal function.


Pleomorphic adenoma of the epiglottis.
Pleomorphic adenoma is the most common benign tumor of the major salivary glands. A pleomorphic adenoma in the larynx constitutes a rarity. A small number of cases have been reported in the literature. We report on a case seen in our hospital, and have reviewed those cases published in the medical literature during the last 25 years.


Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis.
Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD. A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV(1)) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-alpha (TNF-alpha), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model. Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-alpha levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89)). Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.


Encapsulating (111)In in nanocontainers for scintigraphic imaging: synthesis, characterization, and in vivo biodistribution.
A new strategy for the radiolabeling of porous nanocontainers has been developed, and the first experiments in vivo are reported. Our approach consists of the use of nanometer-sized zeolites whose channels have been filled with the positively charged gamma-emitter (111)In(3+) via simple ion exchange. To avoid leaching of the isotope under physiological conditions, the entrances of the channels have been closed using a specifically designed molecular stopcock. This stopcock has a positively charged group that enters the channels and entraps the loaded radionuclides via electrostatic and steric repulsion. The other side of the stopcock is a bulky triethoxysilane group that can covalently bind to the walls of the zeolite entrances, thereby irreversibly closing the channels. The surface of the zeolites has been functionalized with different chemical groups in order to investigate the different biodistributions depending of the nature of the functionalizations. Preliminary in vivo experiments with Wistar rats have been performed and showed the potential of the approach. This strategy leads to a nanoimaging probe with a very high density of radioisotopes in a confined space, which is highly stable in physiological solution and could allow a large variety of functionalities on its external surface.


Variables Associated with Adherence to Stress Ulcer Prophylaxis in Patients Admitted to the General Hospital Wards: A Prospective Study.
Purpose: The dramatic increase in stress ulcer prophylaxis (SUP) prescribing patterns over the past several years has raised concerns regarding to their appropriate utilization. This prospective study attempted to evaluate the trend of adherence to stress ulcer prophylaxis from admission until discharge in non- Intensive care unit (ICU) setting. Additionally, we attempted to find those variables associated with appropriate SUP administration. Methods: Data collection was performed prospectively to evaluate 195 randomly selected adult patients who received SUP or had indication for that in non-ICU wards of one of the largest referral center in Iran, during 6 months. Adherence was studied according to widely accepted American Society of Health system Pharmacists (ASHP) guideline. Univariate and multivariate logistic regression was also performed to detect associations related to misuse of SUP. Results: We recognized total inappropriate use of SUP upon admission, during hospital stay and at discharge were somewhat identical at different time points (61%, 80% and 77.4% respectively). On the other hand, since small number of patients experienced SUP underutilization, unfortunately this was not possible to elucidate factors that may have effect on this flawed behavior. However, increasing age was identified to be significant variable in SUP overutilization. Conclusion: This prospective study highlighted inappropriate overutilization of SUP within non-critically ill patients and found factors which predicted this behavior. Adherence during hospital stay was also calculated for the first time in this study, which was related to SUP adherence upon hospital admission.


Role of the Mmr efflux pump in drug resistance in Mycobacterium tuberculosis.
Efflux pumps are membrane proteins capable of actively transporting a broad range of substrates from the cytoplasm to the exterior of the cell. Increased efflux activity in response to drug treatment may be the first step in the development of bacterial drug resistance. Previous studies showed that the efflux pump Mmr was significantly overexpressed in strains exposed to isoniazid. In the work to be described, we constructed mutants lacking or overexpressing Mmr in order to clarify the role of this efflux pump in the development of resistance to isoniazid and other drugs in M. tuberculosis. The mmr knockout mutant showed an increased susceptibility to ethidium bromide, tetraphenylphosphonium, and cetyltrimethylammonium bromide (CTAB). Overexpression of mmr caused a decreased susceptibility to ethidium bromide, acriflavine, and safranin O that was obliterated in the presence of the efflux inhibitors verapamil and carbonyl cyanide m-chlorophenylhydrazone. Isoniazid susceptibility was not affected by the absence or overexpression of mmr. The fluorometric method allowed the detection of a decreased efflux of ethidium bromide in the knockout mutant, whereas the overexpressed strain showed increased efflux of this dye. This increased efflux activity was inhibited in the presence of efflux inhibitors. Under our experimental conditions, we have found that efflux pump Mmr is mainly involved in the susceptibility to quaternary compounds such as ethidium bromide and disinfectants such as CTAB. The contribution of this efflux pump to isoniazid resistance in Mycobacterium tuberculosis still needs to be further elucidated.


River ecosystem conceptual models and non-perennial rivers: A critical review.
Conceptual models underpin river ecosystem research. However, current models focus on continuously flowing rivers and few explicitly address characteristics such as flow cessation and drying. The applicability of existing conceptual models to nonperennial rivers that cease to flow (intermittent rivers and ephemeral streams, IRES) has not been evaluated. We reviewed 18 models, finding that they collectively describe main drivers of biogeochemical and ecological patterns and processes longitudinally (upstream-downstream), laterally (channel-riparian-floodplain), vertically (surface water-groundwater), and temporally across local and landscape scales. However, perennial rivers are longitudinally continuous while IRES are longitudinally discontinuous. Whereas perennial rivers have bidirectional lateral connections between aquatic and terrestrial ecosystems, in IRES, this connection is unidirectional for much of the time, from terrestrial-to-aquatic only. Vertical connectivity between surface and subsurface water occurs bidirectionally and is temporally consistent in perennial rivers. However, in IRES, this exchange is temporally variable, and can become unidirectional during drying or rewetting phases. Finally, drying adds another dimension of flow variation to be considered across temporal and spatial scales in IRES, much as flooding is considered as a temporally and spatially dynamic process in perennial rivers. Here, we focus on ways in which existing models could be modified to accommodate drying as a fundamental process that can alter these patterns and processes across spatial and temporal dimensions in streams. This perspective is needed to support river science and management in our era of rapid global change, including increasing duration, frequency, and occurrence of drying.


Post-Amadori AGE inhibition as a therapeutic target for diabetic complications: a rational approach to second-generation Amadorin design.
Aminoguanidine and pyridoxamine (Pyridorintrade mark), two major inhibitors of advanced glycation end product (AGE) formation, have entered clinical trials for diabetic nephropathy. They share no structural similarity and are believed to inhibit AGE formation by entirely different mechanisms. Pyridoxamine is a post-Amadori AGE inhibitor-that is, an "Amadorin"-whereas aminoguanidine primarily scavenges reactive dicarbonyl precursors to AGEs. However, pyridoxamine also has a limited potential to react with dicarbonyls. We thus embarked on an effort to develop second-generation Amadorins with low nucleophilicity. Our hypothesis was that we could improve specificity for inhibiting the post-Amadori pathway by minimizing the potential for scavenging small dicarbonyl intermediates. This mechanism-based strategy has led to a rational drug design program that has successfully produced candidate Amadorins, among them the novel compound BST-4997. This Amadorin has greater post-Amadori potency than pyridoxamine but possess no dicarbonyl scavenging activity. Prototypical inhibitors like BST-4997 provide a unique tool to help identify relevant AGE pathways that contribute to diabetic complications. Targeting AGE inhibition differs significantly from traditional approaches to drug discovery and thus represents a new paradigm for the drug industry that should be recognized.


Circulating enterolactone and risk of endometrial cancer.
It has been suggested that phytoestrogens protect against hormone-dependent cancers. Lignans are the main class of phytoestrogens in Western diets. We conducted a prospective study of endometrial cancer and circulating levels of the main human lignan, enterolactone. The design was a case-control study nested within 3 prospective cohort studies, in New York, Sweden and Italy. Serum or plasma samples had been collected at enrollment and stored at -80 degrees C. A total of 153 cases, diagnosed a median of 5.3 years after blood donation, and 271 matched controls were included. No difference in circulating enterolactone was observed between cases (median, 19.2 nmol/L) and controls (18.5 nmol/L). Adjusting for body mass index, the odds ratio for the top tertile of enterolactone, as compared to the lowest was 1.2 (95% CI, 0.7-2.0; p for trend = 0.53). Lack of association was observed in both pre- and postmenopausal women. No correlation was observed between enterolactone and circulating estrogens or SHBG in healthy postmenopausal women. These results do not support a protective role of circulating lignans, in the range of levels observed, against endometrial cancer.


Biomimetic injectable HUVEC-adipocytes/collagen/alginate microsphere co-cultures for adipose tissue engineering.
Engineering adipose tissue that has the ability to engraft and establish a vascular supply is a laudable goal that has broad clinical relevance, particularly for tissue reconstruction. In this article, we developed novel microtissues from surface-coated adipocyte/collagen/alginate microspheres and human umbilical vein endothelial cells (HUVECs) co-cultures that resembled the components and structure of natural adipose tissue. Firstly, collagen/alginate hydrogel microspheres embedded with viable adipocytes were obtained to mimic fat lobules. Secondly, collagen fibrils were allowed to self-assemble on the surface of the microspheres to mimic collagen fibrils surrounding the fat lobules in the natural adipose tissue and facilitate HUVEC attachment and co-cultures formation. Thirdly, the channels formed by the gap among the microspheres served as the room for in vitro prevascularization and in vivo blood vessel development. The endothelial cell layer outside the microspheres was a starting point of rapid vascular ingrowth. Adipose tissue formation was analyzed for 12 weeks at 4-week intervals by subcutaneous injection into the head of node mice. The vasculature in the regenerated tissue showed functional anastomosis with host blood vessels. Long-term stability of volume and weight of the injection was observed, indicating that the vasculature formed within the constructs benefited the formation, maturity, and maintenance of adipose tissue. This study provides a microsurgical method for adipose regeneration and construction of biomimetic model for drug screening studies.


The 1:1 co-crystal of triphen-yl(2,3,5,6-tetra-fluoro-benz-yl)phospho-nium bromide and 1,1,2,2-tetra-fluoro-1,2-di-iodo-ethane.
The title compound, C25H18F4P(+)·Br(-)·C2F4I2, is a 1:1 co-crystal of triphen-yl(2,3,5,6-tetra-fluoro-benz-yl)phospho-nium (TTPB) bromide and 1,1,2,2-tetra-fluoro-1,2-di-iodo-ethane (TFDIE). The crystal structure consists of a framework of TTPB cations held together by C-H⋯Br inter-actions. In this framework, infinite channels along [100] are filled by TFDIE mol-ecules held together in infinite ribbons by short F⋯F [2.863 (2)-2.901 (2)Å] inter-actions. The structure contains halogen bonds (XB) and hydrogen bonds (HB) in the bromide coordination sphere. TFDIE functions as a monodentate XB donor as only one I atom is linked to the Br(-) anion and forms a short and directional inter-action [I⋯Br(-) 3.1798 (7) Å and C-I⋯Br(-) 177.76 (5)°]. The coordination sphere of the bromide anion is completed by two short HBs of about 2.8 Å (for H⋯Br) with the acidic methyl-ene H atoms and two longer HBs of about 3.0 Å with H atoms of the phenyl rings. Surprisingly neither the second iodine atom of TFDIE nor the H atom on the tetra-fluoro-phenyl group make any short contacts.


COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.


Solution and mechanochemical syntheses, and spectroscopic and structural studies in the silver(I) (bi-)carbonate: triphenylphosphine system.
Syntheses of a number of adducts of silver(I) (bi-)carbonate with triphenylphosphine, both mechanochemically, and from solution, are described, together with their infra-red spectra, (31)P CP MAS NMR and crystal structures. Ag(HCO(3)):PPh(3) (1:4) has been isolated in the ionic form [Ag(PPh(3))(4)](HCO(3))·2EtOH·3H(2)O. Ag(2)CO(3):PPh(3) (1:4) forms a binuclear neutral molecule [(Ph(3)P)(2)Ag(O,μ-O'·CO)Ag(PPh(3))(2)](·2H(2)O), while Ag(HCO(3)):PPh(3) (1:2) has been isolated in both mononuclear and binuclear forms: [(Ph(3)P)(2)Ag(O(2)COH)] and [(Ph(3)P)(2)Ag(μ-O·CO·OH)(2)Ag(PPh(3))(2)] (both unsolvated). A more convenient method for the preparation of the previously reported copper(I) complex [(Ph(3)P)(2)Cu(HCO(3))] is also reported.


Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice.
Mouse genetic models can be used to dissect molecular mechanisms that result in human disease. This approach requires detection and demonstration of compelling parallels between phenotypes in mouse and human. Ts65Dn mice are at dosage imbalance for many of the same genes duplicated in trisomy 21 or Down syndrome (DS), the most common live-born human aneuploidy. Analysis of the craniofacial skeleton of Ts65Dn mice using three-dimensional morphometric methods demonstrates an absolute correspondence between Ts65Dn and DS craniofacial dysmorphology, a distinctive and completely penetrant DS phenotype. The genes at dosage imbalance in Ts65Dn are localized to a small region of mouse chromosome 16 and, by comparative mapping, to the corresponding region of human Chromosome 21, providing independent experimental data supporting the contribution of genes in this region to this characteristic DS phenotype. This analysis establishes precise parallels in human and mouse skull phenotypes resulting from dosage imbalance for the same genes, revealing strong conservation of the evolved developmental genetic program that underlies mammalian skull morphology and validating the use of this mouse model in the analysis of this important DS phenotype. This evolutionary conservation further establishes the mouse as a valid model for a wide range of syndromes producing craniofacial maldevelopment.


Challenges in defining an optimal approach to formula-based allocations of public health funds in the United States.
Controversy and debate can arise whenever public health agencies determine how program funds should be allocated among constituent jurisdictions. Two common strategies for making such allocations are expert review of competitive applications and the use of funding formulas. Despite widespread use of funding formulas by public health agencies in the United States, formula allocation strategies in public health have been subject to relatively little formal scrutiny, with the notable exception of the attention focused on formula funding of HIV care programs. To inform debates and deliberations in the selection of a formula-based approach, we summarize key challenges to formula-based funding, based on prior reviews of federal programs in the United States. The primary challenge lies in identifying data sources and formula calculation methods that both reflect and serve program objectives, with or without adjustments for variations in the cost of delivering services, the availability of local resources, capacity, or performance. Simplicity and transparency are major advantages of formula-based allocations, but these advantages can be offset if formula-based allocations are perceived to under- or over-fund some jurisdictions, which may result from how guaranteed minimum funding levels are set or from "hold-harmless" provisions intended to blunt the effects of changes in formula design or random variations in source data. While fairness is considered an advantage of formula-based allocations, the design of a formula may implicitly reflect unquestioned values concerning equity versus equivalence in setting funding policies. Whether or how past or projected trends are taken into account can also have substantial impacts on allocations. Insufficient attention has been focused on how the approach to designing funding formulas in public health should differ for treatment or service versus prevention programs. Further evaluations of formula-based versus competitive allocation methods are needed to promote the optimal use of public health funds. In the meantime, those who use formula-based strategies to allocate funds should be familiar with the nuances of this approach.


Discordance of intraoperative frozen section analysis with definitive histology of sentinel lymph nodes in breast cancer surgery: complementary axillary lymph node dissection is irrelevant for subsequent systemic therapy.
In breast cancer surgery, intraoperative frozen section (FS) analysis of sentinel lymph nodes (SLNs) enables axillary lymph node dissection (ALND) during the same operative procedure. In case of discordance between a "negative" FS analysis and definitive histology, an ALND as a second operation is advocated since additional lymph node metastases may be present. The clinical implications of the subsequent ALND in these patients were evaluated. Between November 2000 and May 2008, 879 consecutive breast cancer patients underwent surgery including sentinel lymph node biopsy (SLNB) with intraoperative FS analysis of 2 central cuts from axillary SLNs. Following fixation and serial sectioning, SLNs were further examined postoperatively with hematoxylin and eosin (H&E) and immunohistochemical techniques. For patients with a discordant FS examination, the effect of the pathology findings of the subsequent ALND specimen on subsequent nonsurgical therapy were evaluated. FS analysis detected axillary metastases in the SLN(s) in 200 patients (23%), while the definitive pathology examination detected metastases in SLNs in another 151 patients (17%). A complementary ALND was performed in 108 of the 151 patients with discordant FS. Additional tumor positive axillary lymph nodes were found in 17 patients (16%), leading to "upstaging" in 7 (6%). Subsequent nonsurgical treatment was adjusted in 4 patients (4%): all 4 had more extensive locoregional radiotherapy; no patient received additional hormonal and/or chemotherapy. Discordance between intraoperative FS analysis and definitive histology of SLNs is common. In this selection of patients, a substantial proportion had additional lymph node metastases, but postsurgical treatment was rarely adjusted based on the findings of the complementary ALND.


Amphiphilic, thixotropic additives for extrusion-based 3D printing of silica-reinforced silicone.
The ability to utilize extrusion-based, direct ink write (DIW) 3D printing to create silica-reinforced silicones with complex structures could expand their utility in industrial and biomedical applications. Sylgard 184, a common Pt-cure silicone, lacks the thixotropic behavior necessary for effective printing and its hydrophobicity renders cured structures susceptible to biofouling. Herein, we evaluated the efficacy of various PEO-silane amphiphiles (PEO-SAs) as thixotropic and surface modifying additives in Sylgard 184. Eight amphiphilic PEO-SAs of varying architecture (e.g. linear, star, and graft), crosslinkability, and PEO content were evaluated. Modified formulations were also prepared with additional amounts of silica filler, both hexamethyldisilazane (HMDS)-treated and dimethyldichlorosilane (DiMeDi)-treated types. Numerous PEO-SA modified silicone formulations demonstrated effective water-driven surface hydrophilicity that was generally diminished with the addition of HMDS-treated silica filler. While increased yield stress was observed for PEO-SA modified silicones with added HMDS-treated filler, none achieved the initial target for 3D printing (>1000 Pa). Only the formulations containing the DiMeDi-treated filler (17.3 wt%) were able to surpass this value. These formulations were then tested for their thixotropic properties and all surpassed the targets for recovered storage modulus (G') (>1000 Pa) and loss factor (<0.8). In particular, the triblock linear PEO-SA produced exceptionally high recovered G', low loss factor, and substantial water-driven restructuring to form a hydrophilic surface. Combined, these results demonstrate the potential of silicones modified with PEO-SA surface-modifying additives (SMAs) for extrusion-based, DIW 3D printing applications.


An improved method for estimating surface fine particle concentrations using seasonally adjusted satellite aerosol optical depth.
Using satellite observations of aerosol optical depth (AOD) to estimate surface concentrations of fine particulate matter (PM2.5) is a well-established technique in the air quality community. In this study, the relationships between PM2.5 concentrations measured at five monitor locations in the Baltimore, MD/Washington, DC region and AOD from Moderate Resolution Imaging Spectroradiometer (MODIS), Multi-Angle Imaging Spectroradiometer (MISR), and Geostationary Operational Environmental Satellite (GOES) were calculated for the summer of 2004 and all of 2005. Linear regression methods were used to determine the direct quantitative relationships between the satellite AOD values and PM2.5 concentration measurements. Results show that correlations between AOD and surface PM2.5 concentrations range from 0.46 to 0.84 for the analyzed time period. Correlations with AOD from MODIS and MISR were higher than those from GOES, likely because of variations in the algorithms used by the different instruments. To determine the relative usefulness of platform- and season-specific AOD PM2.5 regression analysis, the results from this study were used to estimate surface PM2.5 concentrations for two representative case studies. This analysis of case studies demonstrates that it is necessary to include season and satellite platform information for more accurate estimates of surface PM2.5 concentrations from satellite AOD data. Consequently, tools that currently use a constant relationship to estimate surface PM2.5 concentrations from satellite AOD data, such as the Infusing satellite Data into Environmental Applications (IDEA) website, may need to be revised to include parameters that allow the relationships to vary with season and satellite platform to provide more accurate results.


On-chip interrogator based on Fourier transform spectroscopy.
In this paper, the design and the characterization of a novel interrogator based on integrated Fourier transform (FT) spectroscopy is presented. To the best of our knowledge, this is the first integrated FT spectrometer used for the interrogation of photonic sensors. It consists of a planar spatial heterodyne spectrometer, which is implemented using an array of Mach-Zehnder interferometers (MZIs) with different optical path differences. Each MZI employs a 3×3 multi-mode interferometer, allowing the retrieval of the complex Fourier coefficients. We derive a system of non-linear equations whose solution, which is obtained numerically from Newton's method, gives the modulation of the sensor's resonances as a function of time. By taking one of the sensors as a reference, to which no external excitation is applied and its temperature is kept constant, about 92% of the thermal induced phase drift of the integrated MZIs has been compensated. The minimum modulation amplitude that is obtained experimentally is 400 fm, which is more than two orders of magnitude smaller than the FT spectrometer resolution.


Cross-modal plasticity in specific auditory cortices underlies visual compensations in the deaf.
When the brain is deprived of input from one sensory modality, it often compensates with supranormal performance in one or more of the intact sensory systems. In the absence of acoustic input, it has been proposed that cross-modal reorganization of deaf auditory cortex may provide the neural substrate mediating compensatory visual function. We tested this hypothesis using a battery of visual psychophysical tasks and found that congenitally deaf cats, compared with hearing cats, have superior localization in the peripheral field and lower visual movement detection thresholds. In the deaf cats, reversible deactivation of posterior auditory cortex selectively eliminated superior visual localization abilities, whereas deactivation of the dorsal auditory cortex eliminated superior visual motion detection. Our results indicate that enhanced visual performance in the deaf is caused by cross-modal reorganization of deaf auditory cortex and it is possible to localize individual visual functions in discrete portions of reorganized auditory cortex.


Radiation Planning Assistant - A Streamlined, Fully Automated Radiotherapy Treatment Planning System.
The Radiation Planning Assistant (RPA) is a system developed for the fully automated creation of radiotherapy treatment plans, including volume-modulated arc therapy (VMAT) plans for patients with head/neck cancer and 4-field box plans for patients with cervical cancer. It is a combination of specially developed in-house software that uses an application programming interface to communicate with a commercial radiotherapy treatment planning system. It also interfaces with a commercial secondary dose verification software. The necessary inputs to the system are a Treatment Plan Order, approved by the radiation oncologist, and a simulation computed tomography (CT) image, approved by the radiographer. The RPA then generates a complete radiotherapy treatment plan. For the cervical cancer treatment plans, no additional user intervention is necessary until the plan is complete. For head/neck treatment plans, after the normal tissue and some of the target structures are automatically delineated on the CT image, the radiation oncologist must review the contours, making edits if necessary. They also delineate the gross tumor volume. The RPA then completes the treatment planning process, creating a VMAT plan. Finally, the completed plan must be reviewed by qualified clinical staff.


Effects of glucocorticoid treatment on bone strength.
Glucocorticoids (GCs) are prescribed for the treatment of several diseases, but their long-term use causes osteoporosis. Current research suggests that GCs suppress the canonical Wnt/beta pathway, resulting in decreased expression of critical bone proteins. This study examined how bone structure and strength of high bone mass (HBM) mice and low density lipoprotein receptor-related protein 5 (LRP5) knockout (KO+/-) mice are affected by GC treatment in comparison to wild-type (WT) mice, and if changes were specific to either trabecular or cortical bone. Mice were treated with either prednisone or placebo. The femurs and L4 vertebral bodies were analyzed by micro-CT for structure and mechanically tested to determine strength and apparent material strength properties. Differences in all measured variables corresponding to GC treatment and genotype were tested using two-way ANOVA. GC treatment caused decreased structural strength parameters, weakened apparent material strength properties, and disruption of bone structure in HBM, but not LRP5+/- or WT, mice. Despite treatment-related loss, trabecular bone structure and strength remained elevated as compared to LRP5+/- and WT mice. In HBM femurs, both cortical and trabecular structure, but not strength parameters, were negatively affected by treatment. In HBM vertebral bodies, both structural and strength parameters were negatively affected by treatment.


Pharmacoproteomic analysis of prechemotherapy and postchemotherapy plasma samples from patients receiving neoadjuvant or adjuvant chemotherapy for breast carcinoma.
In this study, proteomic changes were examined in response to paclitaxel chemotherapy or 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) chemotherapy in plasma from patients with Stage I-III breast carcinoma. The authors also compared the plasma profiles of patients with cancer with the plasma profiles of healthy women to identify breast carcinoma-associated protein markers. Sixty-nine patients and 15 healthy volunteers participated in the study. Plasma was sampled on Day 0 before chemotherapy and on Day 3 posttreatment in the 69 patients or 3 days apart in the 15 healthy women. Twenty-nine patients received preoperative chemotherapy, and 40 received postoperative chemotherapy. Surface-enhanced laser desorption/ionization mass spectrometry was used to generate protein mass profiles. Few changes were observed in plasma during treatment. Only 1 protein peak was identified (mass/charge ratio [m/z], 2790) that was induced by paclitaxel and, to a lesser extent, by FAC chemotherapy. This proteomic response was detectable in 80% of patients who were treated preoperatively but also was present with lesser intensity in approximately 40% of patients treated postoperatively. There was no clear correlation between induction of m/z 2790 during a single course of treatment and final tumor response to preoperative chemotherapy. Five other peaks also were identified that discriminated between plasma from patients with breast carcinoma and plasma from normal women. These same peaks also were detectable in a subset of patients who already had undergone surgery to remove their tumors. A single chemotherapy-inducible SELDI-MS peak and five other peaks that distinguished plasma obtained from patients with breast carcinoma from plasma obtained from normal, healthy women were identified. The (as yet unsequenced) proteins represented by these peaks are candidate markers of micrometastatic disease after surgery.


A meta-learning approach for genomic survival analysis.
RNA sequencing has emerged as a promising approach in cancer prognosis as sequencing data becomes more easily and affordably accessible. However, it remains challenging to build good predictive models especially when the sample size is limited and the number of features is high, which is a common situation in biomedical settings. To address these limitations, we propose a meta-learning framework based on neural networks for survival analysis and evaluate it in a genomic cancer research setting. We demonstrate that, compared to regular transfer-learning, meta-learning is a significantly more effective paradigm to leverage high-dimensional data that is relevant but not directly related to the problem of interest. Specifically, meta-learning explicitly constructs a model, from abundant data of relevant tasks, to learn a new task with few samples effectively. For the application of predicting cancer survival outcome, we also show that the meta-learning framework with a few samples is able to achieve competitive performance with learning from scratch with a significantly larger number of samples. Finally, we demonstrate that the meta-learning model implicitly prioritizes genes based on their contribution to survival prediction and allows us to identify important pathways in cancer.


Personality, dopamine receptor D4 exon III polymorphisms, and academic achievement in medical students.
This study investigated the relationships between genetic polymorphisms, personality traits, and academic achievement in medical school students. Study subjects were 220 1st-year medical students at Korea University Medical School during two consecutive academic years (2003-2004). Grade-point averages (GPA) during the second semester of the 1st year of the medical school were obtained as a measure of academic achievement. In addition, all participants completed the Temperament and Character Inventory and questionnaires on depression and anxiety. The polymorphisms in exon III of the dopamine D4 receptor (DRD4) were determined using the polymerase chain reaction. Our results revealed that both male and female subjects with a higher GPA may be characterized as having higher persistence and lower novelty seeking traits. In addition, male subjects with high GPA had higher scores in self directedness and female subjects with a higher GPA may be characterized as having higher scores in harm avoidance. Male students with 4-repeat alleles had a significantly lower GPA than male students without 4-repeat alleles. This relationship also remained after controlling for the personality variables, none of which showed a relationship with the polymorphism after Bonferroni correction. For females, however, no associations could be found between GPA and the polymorphism. Thus, the present study demonstrated for the first time a possible influence of the DRD4 48 bp variable number of tandem repeats polymorphism on academic achievement and proved that this was not mediated by performance-associated personality traits.


Photobleaching in STED nanoscopy and its dependence on the photon flux applied for reversible silencing of the fluorophore.
In STED (stimulated emission depletion) nanoscopy, the resolution and signal are limited by the fluorophore de-excitation efficiency and photobleaching. Here, we investigated their dependence on the pulse duration and power of the applied STED light for the popular 750 nm wavelength. In experiments with red- and orange-emitting dyes, the pulse duration was varied from the sub-picosecond range up to continuous-wave conditions, with average powers up to 200 mW at 80 MHz repetition rate, i.e. peak powers up to 1 kW and pulse energies up to 2.5 nJ. We demonstrate the dependence of bleaching on pulse duration, which dictates the optimal parameters of how to deliver the photons required for transient fluorophore silencing. Measurements with the dye ATTO647N reveal that the bleaching of excited molecules scales with peak power with a single effective order ~1.4. This motivates peak power reduction while maintaining the number of STED-light photons, in line with the superior resolution commonly achieved for nanosecond STED pulses. Other dyes (ATTO590, STAR580, STAR635P) exhibit two distinctive bleaching regimes for constant pulse energy, one with strong dependence on peak power, one nearly independent. We interpret the results within a photobleaching model that guides quantitative predictions of resolution and bleaching.


Hard evidence on soft skills.
This paper summarizes recent evidence on what achievement tests measure; how achievement tests relate to other measures of "cognitive ability" like IQ and grades; the important skills that achievement tests miss or mismeasure, and how much these skills matter in life. Achievement tests miss, or perhaps more accurately, do not adequately capture, soft skills-personality traits, goals, motivations, and preferences that are valued in the labor market, in school, and in many other domains. The larger message of this paper is that soft skills predict success in life, that they causally produce that success, and that programs that enhance soft skills have an important place in an effective portfolio of public policies.


Cost of individual peer counselling for the promotion of exclusive breastfeeding in Uganda.
Exclusive breastfeeding (EBF) for 6 months is the recommended form of infant feeding. Support of mothers through individual peer counselling has been proved to be effective in increasing exclusive breastfeeding prevalence. We present a costing study of an individual peer support intervention in Uganda, whose objective was to raise exclusive breastfeeding rates at 3 months of age. We costed the peer support intervention, which was offered to 406 breastfeeding mothers in Uganda. The average number of counselling visits was about 6 per woman. Annual financial and economic costs were collected in 2005-2008. Estimates were made of total project costs, average costs per mother counselled and average costs per peer counselling visit. Alternative intervention packages were explored in the sensitivity analysis. We also estimated the resources required to fund the scale up to district level, of a breastfeeding intervention programme within a public health sector model. Annual project costs were estimated to be US$56,308. The largest cost component was peer supporter supervision, which accounted for over 50% of total project costs. The cost per mother counselled was US$139 and the cost per visit was US$26. The cost per week of EBF was estimated to be US$15 at 12 weeks post partum. We estimated that implementing an alternative package modelled on routine public health sector programmes can potentially reduce costs by over 60%. Based on the calculated average costs and annual births, scaling up modelled costs to district level would cost the public sector an additional US$1,813,000. Exclusive breastfeeding promotion in sub-Saharan Africa is feasible and can be implemented at a sustainable cost. The results of this study can be incorporated in cost effectiveness analyses of exclusive breastfeeding promotion programmes in sub-Saharan Africa.


Protocol for a randomised controlled feasibility study examining the efficacy of brief cognitive therapy for the Treatment of Anxiety Disorders in Adolescents (TAD-A).
Anxiety disorders affect a quarter of the population during their lifetime, and typically emerge in childhood or adolescence. Anxiety disorders disrupt young people's social, emotional and academic development and in the absence of treatment, often follow a chronic course. Although effective treatments, such as Cognitive Behaviour Therapy (CBT), exist, only a small proportion of adolescents with anxiety disorders who need treatment receive them. Barriers to treatment provision include the fact that CBT typically requires 14-16 sessions by a highly qualified therapist and services are stretched - resulting in lengthy waiting lists and limited access to treatment. This highlights the importance of developing new ways of providing effective treatments for adolescent anxiety disorders. This study aims to assess the feasibility of a future, large-scale trial. This will give a clear indication of the likely success of running a randomised controlled trial to compare a new, brief cognitive therapy treatment to an existing CBT group therapy for adolescents with anxiety disorders. The study will examine whether a definitive trial can be conducted on the basis of a feasibility RCT using a number of well-defined criteria. The feasibility RCT is a single-centre, randomised control trial. Forty-eight Young people (age 11-17.5 years) attending a university research clinic, who meet the diagnostic criteria for a DSM-5 anxiety disorder, will be randomly allocated to receive either (1) Adolescent Cognitive Therapy for Anxiety (ACTA), which involves six 60-90-min sessions and a booster session or (2) group CBT, which involves eight 2-h sessions and a booster session. As part of the feasibility indicators, patient outcomes, expectations and experiences, as well as health economic factors, will be assessed before, at the end of treatment and at a 3-month follow-up. The successful delivery of a future, definitive trial has the potential to bring direct benefits to young people and their families, adolescent mental health service providers, as well as benefits to adult mental health services and society more broadly by disrupting the negative trajectory commonly associated with adolescent anxiety disorders. ISRCTN, ID: ISRCTN86123204 . Retrospectively registered on 23 November 2017.


Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB.
Angiotensin II type 2 (AT(2)) receptors can be regarded as an endogenous repair system, because the AT(2) receptor is upregulated in tissue damage and mediates tissue protection. A potential therapeutic use of this system has only recently come within reach through synthesis of the first selective, orally active, nonpeptide AT(2) receptor agonist, compound 21 (C21; dissociation constant for AT(2) receptor: 0.4 nM; dissociation constant for angiotensin II type 1 receptor: >10,000 nM). This study tested AT(2) receptor stimulation with C21 as a potential future therapeutic approach for the inhibition of proinflammatory cytokines and of nuclear factor kappaB. C21 dose-dependently (1 nM to 1 micromol/L) reduced tumor necrosis factor-alpha-induced interleukin 6 levels in primary human and murine dermal fibroblasts. AT(2) receptor specificity was controlled for by inhibition with the AT(2) receptor antagonist PD123319 and by the absence of effects in AT(2) receptor-deficient cells. AT(2) receptor-coupled signaling leading to reduced interleukin 6 levels involved inhibition of nuclear factor kappaB, activation of protein phosphatases, and synthesis of epoxyeicosatrienoic acid. Inhibition of interleukin 6 promoter activity by C21 was comparable in strength to inhibition by hydrocortisone. C21 also reduced monocyte chemoattractant protein 1 and tumor necrosis factor-alpha in vitro and in bleomycin-induced toxic cutaneous inflammation in vivo. This study is the first to show the anti-inflammatory effects of direct AT(2) receptor stimulation in vitro and in vivo by the orally active, nonpeptide AT(2) receptor agonist C21. These data suggest that pharmacological AT(2) receptor stimulation may be an orally applicable future therapeutic approach in pathological settings requiring the reduction of interleukin 6 or inhibition of nuclear factor kappaB.


Risk factors of neonatal sepsis in India: A systematic review and meta-analysis.
The incidence of neonatal sepsis in India is the highest in the world. Evidence regarding its risk factors can guide clinical practice and prevention strategies. To review, assess and synthesize the available literature from India on the risk factors of sepsis among neonates. A systematic review was conducted. We searched PubMed, CINAHL, Scopus, Web of Science, Popline, IndMed, Indian Science Abstracts and Google Scholar from inception up to March 23, 2018 to identify observational analytical studies reporting on risk factors of laboratory-confirmed neonatal sepsis in India. Two authors independently screened studies (title, abstract and full-text stages), extracted data, and assessed quality. A random-effects meta-analysis was performed as substantial heterogeneity was anticipated. Subgroup and sensitivity analyses were additionally performed. Effect size in our review included odds ratio and standardized mean difference. Fifteen studies were included from 11,009 records, of which nine were prospective in design. Birthweight and gestational age at delivery were the most frequently reported factors. On meta-analyses, it was found that male sex (OR: 1.3, 95% CI: 1.02, 1.68), out born neonates (OR: 5.5, 95% CI: 2.39, 12.49), need for artificial ventilation (OR: 5.61; 95% CI: 8.21, 41.18), gestational age <37 weeks (OR: 2.05; 95% CI:1.40, 2.99) and premature rupture of membranes (OR:11.14, 95% CI: 5.54, 22.38) emerged as risk factors for neonatal sepsis. Included studies scored lowest on exposure assessment and confounding adjustment, which limited comparability. Inadequacy and variation in definitions and methodology affected the quality of included studies and increased heterogeneity. Male neonates, outborn admissions, need for artificial ventilation, gestational age <37 weeks and premature rupture of membranes are risk factors for sepsis among neonates in India. Robustly designed and reported research is urgently needed to confirm the role of other risk factors of neonatal sepsis in India.


Thrombophilic mutations are a main risk factor for placental abruption.
The aim of the present study was to evaluate inherited thrombophilic factor V Leiden and factor II A20210 mutations in women presenting with abruption of a normally implanted placenta. In a multi-center, case-control study, 50 consecutive women requiring immediate delivery because of abruption of the placenta were enrolled. Inclusion criteria were: abruptio placentae requiring immediate delivery, normally implanted placenta, Caucasian ethnic background, parity <3, delivery performed at Institutions. Exclusion criteria were: history of thromboembolism, history of 2 or more spontaneous abortions, uterine leiomyomas with a diameter >5 cm, illicit drug abuse, premature rupture of membranes, multiple pregnancy. One hundred Caucasian women with uneventful pregnancies carried to term, matched for parity and age, served as controls. Heterozygotes were found to be significantly more prevalent among women with abruptio placentae than among controls. The carriership of the FV Leiden mutation confers a OR of 9.12 (95% C.I.: 2.18-31.7; p=0.0005). Women carrying F II A20210 mutation have a OR of 12.25 (95% C.I.: 2.36-29.6; p=0.0004). No homozygotes or double heterozygotes were found. Twenty-three patients (46%) also met the criteria for a diagnosis of pre-eclampsia (PE). In such cases the prevalence of mutations (factor V: 6 cases, 26.1%; factor II: 5 cases, 21.7%) was similar to that in women without pre-eclampsia (factor V: 5 cases, 18.7%; factor II: 5 cases, 18.5%). The presence of either of the above reported thrombophilic mutations represents a relevant risk factor for the occurrence of placental abruption in Caucasians. This risk is independent of the development of pre-eclampsia. Patients who have had dramatic abruption of a normally implanted placenta should undergo evaluation for the presence of genetic mutations of coagulation factors V and II.


Patient-specific academic detailing for smoking cessation: feasibility study.
To describe and to determine the feasibility of a patient-specific academic detailing (PAD) smoking cessation (SC) program in a primary care setting. Descriptive cohort feasibility study. Hamilton, Ont. Pharmacists, physicians, nurse practitioners, and their patients. Integrated pharmacists received basic academic detailing training and education on SC and then delivered PAD to prescribers using structured verbal education and written materials. Data were collected using structured forms. Five main feasibility criteria were generated based on Canadian academic detailing programs: PAD coordinator time to train pharmacists less than 40 hours; median time of SC education per pharmacist less than 20 hours; median time per PAD session less than 60 minutes for initial visit; percentage of prescribers receiving PAD within 3 months greater than 50%; and number of new SC referrals to pharmacists at 6 months more than 10 patients per 1.0 full-time equivalent (FTE) pharmacist (total of approximately 30 patients). Eight pharmacists (5.8 FTE) received basic academic detailing training and education on SC PAD. Forty-eight physicians and 9 nurse practitioners consented to participate in the study. The mean PAD coordinator training time was 29.1 hours. The median time for SC education was 3.1 hours. The median times for PAD sessions were 15 and 25 minutes for an initial visit and follow-up visit, respectively. The numbers of prescribers who had received PAD at 3 and 6 months were 50 of 64 (78.1%) and 57 of 64 (89.1%), respectively. The numbers of new SC referrals at 3 and 6 months were 11 patients per FTE pharmacist (total of 66 patients) and 34 patients per FTE pharmacist (total of 200 patients), respectively. This study met the predetermined feasibility criteria with respect to the management, resources, process, and scientific components. Further study is warranted to determine whether PAD is more effective than conventional academic detailing.


Genetic variants associated with non-typhoidal Salmonella bacteraemia in African children.
Non-typhoidal Salmonella (NTS) causes invasive and frequently fatal disease in African children. Existing strategies to prevent, diagnose, and treat NTS disease are inadequate. An improved understanding of the biology of invasive Salmonella infection will facilitate the development of novel NTS control measures. Despite evidence in mice and man showing a clear role for host genetics in NTS susceptibility, there are no published studies investigating host genetic susceptibility to NTS in African populations. We conducted a genome-wide association study (SNP Array 6.0, Affymetrix, CA, USA) of NTS bacteraemia in Kenyan children, with replication in Malawian children. We assessed the function of NTS-associated variants in an expression quantitative trait locus (eQTL) dataset of interferon γ (IFNγ) and lipopolysaccharide-stimulated monocytes from 432 healthy European adults. Serum IFNγ (Bio-Plex immunoassay, Bio-Rad Laboratories, CA, USA) in Malawian NTS cases (n=106) during acute disease was correlated with genotype by linear regression. After whole-genome imputation and quality control, 180 Kenyan cases and 2677 controls were included in an association analysis at 7 951 614 (additive model) and 4 669 537 (genotypic model) loci. After quality control, 143 Malawian cases and 336 controls were included in the replication analysis. An intronic variant in STAT4 was associated (recessive model) with NTS in both Kenyan and Malawian children (Kenya p=5·6 × 10(-9), Malawi p=0·02, combined p=1·4 × 10(-9); odds ratio 7·2, 95% CI 3·8-13·5). The NTS-associated variant was an eQTL for STAT4 expression in IFNγ-stimulated monocytes (p=9·59 × 10(-6)), the NTS risk allele being associated with lower STAT4 expression. In Malawian children with NTS bacteraemia, the same NTS risk allele was associated with lower serum concentrations of IFNγ (p=0·02) at presentation. STAT4 is highly plausible as a susceptibility locus for invasive NTS disease. STAT4 mediates IFNγ release in T cells and natural killer cells in response to interleukin 12 (IL12). Individuals with rare mutations elsewhere in the IL12-IFNγ axis are at risk of disseminated NTS infection. We provide the first evidence, to our knowledge, of a host genetic determinant of NTS disease in African children, and of a STAT4 variant conferring susceptibility to an infectious disease in man. Wellcome Trust.


Alternative astronomy: experiment in self-sufficiency blossoms.
Half a dozen astronomy graduate students facing meager job prospects decide they would rather fight than switch. They drop out of the postdoctoral rat race, move to California, and establish a close-knit if impoverished community centered around astronomy. They build their own observatory complete with a telescope superior to those of many universities and incorporating the latest in modern electronic instruments, all the while maintaining their independence and doing without government grants. They undertake an ambitious research effort and win the respect, admiration, and even envy of prominent astronomers.


Fusion of classic P300 detection methods' inferences in a framework of fuzzy labels.
Designing a reliable and accurate brain-computer interface (BCI) is one of the most challenging fields in biomedical signal processing. To achieve this goal, different methods have been adopted in different blocks of a typical BCI system (i.e., in preprocessing, feature extraction, feature classification and feature selection blocks). Since BCI's speed plays a crucial role in its success in real-life applications, using mathematically simple techniques with accurate and reliable performance can improve this aspect of BCI systems' design. In this paper, a new method is introduced, which combines information from different classic time series similarity measures, using a simple fuzzy fusion framework. This method is accurate and reliable in P300 (a positive event-related component occurring 300 ms after stimulus onset) detection. This framework is used to combine two computationally simple signal detection methods: "peak picking" and "template matching". Fusion takes place in the last step (decision-making step) by means of a fuzzy rule-base. Compared to similar works on electroencephalogram-based (EEG-based) BCI datasets, in spite of being computationally simple, this new technique's performance is comparable to very complicated methods, like support vector machines. This research indicates that, using both spatial and temporal information content of EEG trials (from all electrodes or a subset of them), even under a non-complicated mathematical framework can yield an accurate and powerful classification.


Neural correlates of perceptual color inferences as revealed by #thedress.
Color constancy involves disambiguating the spectral characteristics of lights and surfaces, for example to distinguish red in white light from white in red light. Solving this problem appears especially challenging for bluish tints, which may be attributed more often to shading, and this bias may underlie the individual differences in whether people described the widely publicized image of #thedress as blue-black or white-gold. To probe these higher-level color inferences, we examined neural correlates of the blue-bias, using frequency-tagging and high-density electroencephalography to monitor responses to 3-Hz alternations between different color versions of #thedress. Specifically, we compared relative neural responses to the original "blue" dress image alternated with the complementary "yellow" image (formed by inverting the chromatic contrast of each pixel). This image pair produced a large modulation of the electroencephalography amplitude at the alternation frequency, consistent with a perceived contrast difference between the blue and yellow images. Furthermore, decoding topographical differences in the blue-yellow asymmetries over occipitoparietal channels predicted blue-black and white-gold observers with over 80% accuracy. The blue-yellow asymmetry was stronger than for a "red" versus "green" pair matched for the same component differences in L versus M or S versus LM chromatic contrast as the blue-yellow pair and thus cannot be accounted for by asymmetries within either precortical cardinal mechanism. Instead, the results may point to neural correlates of a higher-level perceptual representation of surface colors.


Exploring genomes with a game engine.
More and more evidence indicates that the 3D conformation of eukaryotic genomes is a critical part of genome function. However, due to the lack of accurate and reliable 3D genome structural data, this information is largely ignored and most of these studies have to use information systems that view the DNA in a linear structure. Visualizing genomes in real time 3D can give researchers more insight, but this is fraught with hardware limitations since each element contains vast amounts of information that cannot be processed on the fly. Using a game engine and sophisticated video game visualization techniques enables us to construct a multi-platform real-time 3D genome viewer. The game engine-based viewer achieves much better rendering speed and can handle much larger amounts of data compared to our previous implementation using OpenGL. Combining this viewer with 3D genome models from experimental data could provide unprecedented opportunities to gain insight into the conformation-function relationships of a genome.


Esculetin, a Coumarin Derivative, Prevents Thrombosis: Inhibitory Signaling on PLCγ2-PKC-AKT Activation in Human Platelets.
Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in human platelet activation and experimental mouse models. At 10-80 μM, esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619. Esculetin inhibited adenosine triphosphate release, P-selectin expression, hydroxyl radical (OH·) formation, Akt activation, and phospholipase C (PLC)γ2/protein kinase C (PKC) phosphorylation, but did not diminish mitogen-activated protein kinase phosphorylation in collagen-activated human platelets. Platelet function analysis indicated that esculetin substantially prolonged the closure time of whole blood. In experimental mice, esculetin significantly increased the occlusion time in thrombotic platelet plug formation and reduced mortality associated with acute pulmonary thromboembolism. However, it did not prolong the bleeding time. This study demonstrates that esculetin inhibits human platelet activation via hindering the PLCγ2-PKC cascade, hydroxyl radical formation, Akt activation, and ultimately suppressing platelet activation. Therefore, esculetin may act as an essential therapeutic agent for preventing thromboembolic diseases.


High pH instability of quaternary ammonium surfactant coatings in capillary electrophoresis.
The two-tailed cationic surfactant dioctadecyldimethyl ammonium bromide (DODAB) produces semi-permanent coatings that yield strongly reversed electroosmotic flow (EOF), for example -0.31 ± 0.01 cm2 kV-1 s-1 at pH 3.5. Moreover, these coatings are easy to prepare, regenerable, cost effective, and yield high efficiency (520 000-900 000 plates per m) separations of cationic proteins over many runs under acidic (pH 3.5) conditions. Given the quaternary amine functionality of DODAB, we were surprised to observe that DODAB coatings become unstable at pH > 7. At pH 7.2, the EOF of a DODAB coated capillary drifted from reversed to cathodic over only 5 runs, and protein separations became severely compromised. By pH 12, no EOF reversal was observed. Electrophoretic and mass spectrometric studies demonstrate that the coating decomposition involves a surface conversion of the quaternary amine in DODAB to a variety of products, although the exact mechanism remains elusive. Regardless, the results herein demonstrate that semi-permanent coatings based on cationic two-tailed surfactants such as DODAB are limited to separations using acidic buffers.


Production Temperature Effects on the Structure of Hydrochar-Derived Dissolved Organic Matter and Associated Toxicity.
Hydrochar is a carbonaceous material derived from hydrothermal liquefaction, and it carries good potential as a new material for environmental applications. However, little is known about the dissolved organic matter (DOM) associated with hydrochar and the consequences of its release. The relationship between the production temperature and the characteristics of DOM released from hydrochar as well as the associated biotoxicity was investigated using a suite of advanced molecular and spectroscopic tools. With the increase in production temperature, the resulted hydrochar-based DOM contained a higher content of phenols and organic acids but less sugars and furans. Meanwhile, the molecular structure of DOM shifted to lower molecular weight with higher organic contents containing <6 O atoms per compound, aromatics, and N-containing substances. While low-temperature hydrochar-derived DOM showed minimal biotoxicity, increase in production temperature to 330 °C led to a great rise in toxicity. This might be attributed to the increased contents of phenols, organic acids, and organics containing <6 O atoms and 1 N atom per compound. These results suggest that hydrochar-derived DOM have more negative impacts on the environment than the organics associated with biochar production. Such understanding highlights the importance of controlling the hydrochar production process.


Advances in fetal surgery.
Historically, the gold standard for the treatment of congenital malformations has been planned delivery at tertiary care center with attempted post-natal repair or amelioration of the lesion. Over the last few decades however, rapid advances in imaging and instrumentation technology combined with superior knowledge of fetal pathophysiology has led to the development of novel intrauterine interventions for most common fetal anomalies. Great success has already been seen the treatment of previous devastating anomalies such as myelomeningocele (MMC), congenital cystic malformations of the lung, twin-twin transfusion, and sacrococcygeal teratomas. Although still limited, these innovative techniques have unique potential to improve outcomes in the most devastating fetal anomalies.


Performance and characteristics of a high pressure, high temperature capillary cell with facile construction for operando x-ray absorption spectroscopy.
We demonstrate the use of commercially available fused silica capillary and fittings to construct a cell for operando X-ray absorption spectroscopy (XAS) for the study of heterogeneously catalyzed reactions under high pressure (up to 200 bars) and high temperature (up to 280 °C) conditions. As the first demonstration, the cell was used for CO2 hydrogenation reaction to examine the state of copper in a conventional Cu/ZnO/Al2O3 methanol synthesis catalyst. The active copper component of the catalyst was shown to remain in the metallic state under supercritical reaction conditions, at 200 bars and up to 260 °C. With the coiled heating system around the capillary, one can easily change the length of the capillary and control the amount of catalyst under investigation. With precise control of reactant(s) flow, the cell can mimic and serve as a conventional fixed-bed micro-reactor system to obtain reliable catalytic data. This high comparability of the reaction performance of the cell and laboratory reactors is crucial to gain insights into the nature of actual active sites under technologically relevant reaction conditions. The large length of the capillary can cause its bending upon heating when it is only fixed at both ends because of the thermal expansion. The degree of the bending can vary depending on the heating mode, and solutions to this problem are also presented. Furthermore, the cell is suitable for Raman studies, nowadays available at several beamlines for combined measurements. A concise study of CO2 phase behavior by Raman spectroscopy is presented to demonstrate a potential of the cell for combined XAS-Raman studies.


Advances in open microsurgery for cerebral aneurysms.
Endovascular techniques introduced strong extrinsic forces that provoked reactive changes in aneurysm surgery. Microsurgery has become less invasive, more appealing to patients, lower risk, and efficacious for complex aneurysms, particularly those unfavorable for or failing endovascular therapy. To review specific advances in open microsurgery for aneurysms. A university-based, single-surgeon practice was examined for the use of minimally invasive craniotomies, surgical management of recurrence after coiling, the use of intracranial-intracranial bypass techniques, and cerebrovascular volume-outcome relationships. The mini-pterional, lateral supraorbital, and orbital-pterional craniotomies are minimally invasive alternatives to standard craniotomies. Mini-pterional and lateral supraorbital craniotomies were used in one-fourth of unruptured patients, increasing from 22% to 28%, whereas 15% of patients underwent orbital-pterional craniotomies and trended upward from 11% to 20%. Seventy-four patients were treated for coil recurrences (2.3% of all aneurysms) with direct clip occlusion (77%), clip occlusion after coil extraction (7%), or parent artery occlusion with bypass (16%). Intracranial-intracranial bypass (in situ bypass, reimplantation, reanastomosis, and intracranial grafts) transformed the management of giant aneurysms and made the surgical treatment of posterior inferior cerebellar artery aneurysms competitive with endovascular therapy. Centralization maximized the volume-outcome relationships observed with clipping. Aneurysm microsurgery has embraced minimalism, tailoring the exposure to the patient's anatomy with the smallest possible craniotomy that provides adequate exposure. The development of intracranial-intracranial bypasses is an important advancement that makes microsurgery a competitive option for complex and recurrent aneurysms. Trends toward centralizing aneurysm surgery in tertiary centers optimize results achievable with open microsurgery.


Dynorphin-immunoreactive neurons in the rat nucleus accumbens: ultrastructure and synaptic input from terminals containing substance P and/or dynorphin.
The endogenous opioid peptide dynorphin is enriched in neurons in the nucleus accumbens, for which coexistence and synaptic interactions with substance P have been postulated. We examined the immunogold-silver localization of dynorphin and immunoperoxidase labeling for substance P in single coronal sections through the core subregion of the nucleus accumbens of acrolein-fixed rat brain tissue. Dynorphin-immunoreactive somata were more prevalent than substance P-containing neurons throughout the region sampled for ultrastructural analysis. Dynorphin-labeled cells were spherical, contained unindented nuclei, and were closely apposed to other somata and dendrites, some of which also contained dynorphin immunoreactivity. The appositions were characterized by the absence of glial processes and contiguous contacts between the plasma membranes. Smooth endoplasmic reticulum and coated vesicles could also be identified in the cytoplasms on either side of the somatic or dendritic appositions. The dynorphin somata and dendrites received synaptic input from numerous unlabeled as well as dynorphin- and/or substance P-labeled axon terminals. Both types of terminals were morphologically similar in their content of small and large dense core vesicles and their formation of mainly symmetric synaptic specializations. In addition to dynorphin-immunoreactive targets, numerous dynorphin- and substance P-labeled terminals also formed synapses with unlabeled somata and dendrites. In some cases, terminals separately labeled for dynorphin and substance P converged on common targets with or without detectable dynorphin immunoreactivity. Terminals colocalizing both peptides were also found to synapse on unlabeled or dynorphin-labeled somata and dendrites. Additionally, presynaptic interactions were suggested by close appositions between dynorphin- and/or substance P-labeled terminals and other terminals that were unlabeled, dynorphin labeled, or substance P labeled. These results provide morphological data suggesting nonsynaptic communication between dynorphin-immunoreactive neurons and other neurons possibly mediated through receptive sites or second messengers associated with smooth endoplasmic reticulum in the nucleus accumbens. They also indicate that, in this region, 1) the activity of dynorphin neurons may be dependent on activation of autoreceptors for dynorphin as well as substance P and 2) additional neurons lacking dynorphin immunoreactivity are most likely inhibited (symmetric junctions) by terminals containing either one or both peptides. The findings may have implications for motor and analgesic responses to aversive tonic pain transmitted through dynorphin and substance P pathways within the nucleus accumbens.


A C-repeat binding factor transcriptional activator (CBF/DREB1) from European bilberry (Vaccinium myrtillus) induces freezing tolerance when expressed in Arabidopsis thaliana.
Freezing stress affects all plants from temperate zones to the poles. Global climate change means such freezing events are becoming less predictable. This in turn reduces the ability of plants to predict the approaching low temperatures and cold acclimate. This has consequences for crop yields and distribution of wild plant species. C-repeat binding factors (CBFs) are transcription factors previously shown to play a vital role in the acclimation process of Arabidopsis thaliana, controlling the expression of hundreds of genes whose products are necessary for freezing tolerance. Work in other plant species cements CBFs as key determinants in the trait of freezing tolerance in higher plants. To test the function of CBFs from highly freezing tolerant plants species we cloned and sequenced CBF transcription factors from three Vaccinium species (Vaccinium myrtillus, Vaccinium uliginosum and Vaccinium vitis-idaea) which we collected in the Arctic. We tested the activity of CBF transcription factors from the three Vaccinium species by producing transgenic Arabidopsis lines overexpressing them. Only the Vaccinium myrtillus CBF was able to substantially activate COR (CBF-target) gene expression in the absence of cold. Correspondingly, only the lines expressing the Vaccinium myrtillus CBF were constitutively freezing tolerant. The basis for the differences in potency of the three Vaccinium CBFs was tested by observing cellular localisation and protein levels. All three CBFs were correctly targeted to the nucleus, but Vaccinium uliginosum CBF appeared to be relatively unstable. The reasons for lack of potency for Vaccinium vitis-idaea CBF were not due to stability or targeting, and we speculate that this was due to altered transcription factor function.