The intrinsic apoptotic pathway is required for lipopolysaccharide-induced lung endothelial cell death.
LPS has been implicated in the pathogenesis of endothelial cell death associated with Gram-negative bacterial sepsis. The binding of LPS to the TLR-4 on the surface of endothelial cells initiates the formation of a death-inducing signaling complex at the cell surface. The subsequent signaling pathways that result in apoptotic cell death remain unclear and may differ among endothelial cells in different organs. We sought to determine whether LPS and cycloheximide-induced cell death in human lung microvascular endothelial cells (HmVECs) was dependent upon activation of the intrinsic apoptotic pathway and the generation of reactive oxygen species. We found that cells overexpressing the anti-apoptotic protein Bcl-X(L) were resistant to LPS and cycloheximide-induced death and that the proapoptotic Bcl-2 protein Bid was cleaved following treatment with LPS. The importance of Bid was confirmed by protection of Bid-deficient (bid(-/-)) mice from LPS-induced lung injury. Neither HmVECs treated with the combined superoxide dismutase/catalase mimetic EUK-134 nor HmVECs depleted of mitochondrial DNA (rho(0) cells) were protected against LPS and cycloheximide-induced death. We conclude that LPS and cycloheximide-induced death in HmVECs requires the intrinsic cell death pathway, but not the generation of reactive oxygen species.


Tailored Web-Based Information for Younger and Older Patients with Cancer: Randomized Controlled Trial of a Preparatory Educational Intervention on Patient Outcomes.
Many patients with cancer, including older patients (aged ≥65 years), consult the Web to prepare for their doctor's visit. In particular, older patients have varying needs regarding the mode in which information is presented (eg, via textual, visual, or audiovisual modes) owing to age-related sensory (eg, impaired vision and hearing) and cognitive decline (eg, reduced processing speed). Therefore, Web-based information targeted at older patient populations is likely to be used and processed more effectively, and evaluated more positively, when tailored to age-related capabilities and preferences. This, in turn, may benefit patient outcomes. This randomized controlled trial tested the effects of a Web-based tailored educational intervention among newly diagnosed younger (<65 years) and older (≥65 years) patients with cancer. We compared the intervention group who viewed a mode-tailored website (ie, enabling patients to tailor information using textual, visual, and audiovisual modes) with 3 control groups view a nontailored website (ie, text only, text with images, and text with videos). We examined website experience outcomes (ie, website satisfaction, website involvement, knowledge, anxiety, and communication self-efficacy) and consultation experience outcomes (ie, question asking during consultation, anxiety, and information recall). Patients from a multidisciplinary outpatient clinic (N=232) viewed a mode-tailored or nontailored website as preparation before their hospital consultations to discuss diagnosis and treatment. Data were collected before (T1), during (T2), and after (T3) visitation. Website experience outcomes were assessed with questionnaires (T1). Patients' question asking was coded from videotaped consultations, and anxiety was assessed through a questionnaire (T2). Telephone interviews were conducted to assess knowledge acquired from the website before (T1) and after consultation (T3), and information recall from the consultation (T3). The preparatory website was well used across all conditions (mean 34 min). Younger patients viewing the mode-tailored website were more satisfied before consultation (P=.02) and reported lower anxiety after consultation (P=.046; vs text only). This pattern was not found in older patients. Mode tailoring yielded no other significant differences in patient outcomes. Regression analyses showed that website involvement (beta=.15; P=.03) and, to a lesser extent, website satisfaction (beta=.15; P=.05) positively associated with knowledge before consultation (T1). In turn, higher knowledge before consultation (beta=.39; P<.001), together with time on the website (beta=.21; P=.002; T1), predicted information recall from consultations (T3). Patients with higher knowledge before consultation (T1) also reported higher knowledge from the website afterward (T3; beta=.22; P=.003). Offering preparatory online information before consultations benefits information processing and patient outcomes of both younger and older newly diagnosed patients with cancer. Younger patients benefit even more when information is offered in a mode-tailored manner. We discuss the theoretical, methodological, and practical implications for patient-provider communication research in an electronic health era. Netherlands Trial Register NTR5904; https://www.trialregister.nl/trial/5750.


[The state and role of esophagus, stomach, intestinal microbiota in patients with ulcer disease, chronic gastritis, esophagitis.]
The microflora of 64 biopsies taken during fibrogastroduodenoscopy of the mucous membrane of the esophagus, stomach and duodenum in healthy volunteers and 1120 samples obtained from the same parts of the digestive tract in patients with esophagitis, chronic gastritis and peptic ulcer disease were studied. The patients ranged in age from 18 to 62 years. Traditional bacteriological method was used to isolate and identify microorganisms. Staphylococcus spp., Streptococcus spp., Lactobacillus spp., Bacteroides spp., Stomatococcus spp., Enterobacteriaceae, Corynebacterium spp., Micrococcus spp., Neisseria spp., Veilonella spp. were isolated from biopsies of healthy respondents in an average amount from 3.2 to 4.68 lg CFU/g. H.pylori was found in 60% (5.66 lg CFU/g) in the esophagus, in 33.3% of cases (5.12 lg CFU/g) from the fundal part of the stomach, in 44.4% (5.25 lg CFU/g) from the antral part of the stomach, in 5.5% (4.2 lg CFU/g) in the duodenal mucosa. In samples obtained from the inflamed and eroded mucous membrane of the esophagus, stomach and duodenum, opportunistic bacteria of the genera Klebsiella, Enterobacter, Proteus, Pseudomonas, Peptococcus, Actinomyces, yeast fungi of the genus Candida etc. were detected in an amount exceeding 4 lg CFU/g. H. pylori isolated in 6.3-16.7% of patients (4.25-4.6 lg CFU/g) and did not dominate in relation to other microorganisms, and in most cases had a low frequency of its occurrence. In patients with the recurrence of peptic ulcer disease, exacerbation of chronic gastritis and esophagitis, dysbiosis was developed, characterized by an increase in the species and quantitative composition of opportunistic microflora, an increase in its enzymatic and cytotoxic activity, which can contribute to the maintenance of inflammatory and necrotic processes and inhibit the elimination of the pathological process.


Antituberculosis activity of clarithromycin.
Antituberculosis activity of clarithromycin (CLA), a macrolide antibiotic, was investigated in vitro, in macrophages, and in C57BL/6 mice, CLA showed high in vitro MICs (4 to > 16 micrograms/ml) for several strains of Mycobacterium tuberculosis and caused slight enhancement of activity of rifampin (RIF) against H37Rv but failed to increase the activity of either RIF or isoniazid (INH) against other strains. However, inside J774A.1 macrophages, CLA showed high activity and was synergistic with RIF against some strains of tubercle bacilli susceptible or resistant to INH and RIF. In the in vivo studies with a drug-susceptible strain (H37Rv), CLA protected mice from mortality due to tuberculosis for up to 8 weeks of observation. The CFU data for lungs and spleens revealed that the antituberculosis activity of CLA is inferior to those of INH and streptomycin. However, the activity of CLA when used alone or in combination was comparable to that of thiacetazone, indicating its potential usefulness as a secondary drug for the treatment of tuberculosis.


Death Anxiety in the Context of Religion, Personality and Life Meanings.
Previous studies on the context between death anxiety and religion do not provide any clear evidence regarding "anxiety buffer" function. In this explorative study, death anxiety and attitude to death were determined in the context of mood, personality and meaning of life among groups of Muslims (n = 60) and Christian Protestants (n = 60). Death anxiety and attitude to death were assessed using the Bochum questionnaire for recording death anxiety and attitudes to death. Death anxiety was mild to moderate in our healthy Participants of Muslim and Christian faith. Attitude towards death was therefore much more pronounced among Muslim members than Christians. The influence of religious beliefs on the fear of death does not appear to be direct and linear. Sources that provide meaning in life and emotional stability can contribute to a reduction in death anxiety and a less problematic attitude towards death.


Exploring factors that affect hospital referral in rural settings: a case study from Norway.
A patient's needs and the seriousness of the disease are not the only factors that determine referral to hospital. The objective of this study was to analyse whether locum doctors (LDs) have a different pattern of referral to hospital from regular GPs (RGPs). All hospital referrals for one year (n = 5566 patients) from two Norwegian rural primary health care (PHC) centres to the nearby district hospital were analysed with regard to ICD-10 diagnosis groups. A major difference between the PHCs was that one had a continuous supply of LDs while the other had a stable group of RGPs. The equal-sized communities were demographically and socio-culturally similar. The PHC centre mainly operated by short-term LDs referred a relatively high number of patients to the district hospital within the diagnosis groups of chapter VI 'Diseases of the nervous system' (proportionate referral rate 210%; p = 0.010), and chapter IX 'Diseases of the circulatory system' (proportionate referral rate 130%; p = 0.048), and a comparatively low number of patients for the diagnostic groups in chapter X 'Diseases of the respiratory system' (p = 0.018), and chapter XIV 'Diseases of the genitourinary system' (p = 0.039), compared with the norm of the district hospital's total population. The number and proportion of the total number of referrals, adjusted for population size, did not differ between the two rural communities. The LD-run PHC centre differed significantly from the total norm in 5 out of 19 ICD chapters, equal to 41% of the patients. Only one significant difference in hospital referrals related to ICD-diagnoses groups were found between the studied rural PHC centres, but the LD-run PHC differed from the total norm. These differences could neither be explained from the district's consumption of somatic hospital care nor the demographical differences, but were related to staffing at the PHC, that is LDs or RGPs. The analysis also revealed that possible under- and/or over-diagnosing of certain diseases occurred, both having potential medical consequences for the patient, as well as increasing healthcare expenditure.


Thinking inside the frame: A framing analysis of the humanities in Danish print news media.
The humanities, the natural and social sciences all represent advanced and systematic knowledge production-and they all receive public funding for doing so. However, although the field of public understanding of science has been well established for decades, similar research attention has not been directed at the humanities. The purpose of this study is to argue the case for further research of public understanding of the humanities and to take a first step in that direction by presenting a study of the framing of the humanities in Danish print news media. Different framings of the humanities are analyzed. Despite the differences in the issue-specific frames, the generic framing of the humanities shared by most articles is as follows: 75% explicitly frame the humanities as deficit, while the remaining 25% are more neutral. Consequently, if newspapers constitute the only source of information concerning the humanities, newsreaders may not be much wiser in understanding what the humanities might be-but they will know that whatever the humanities is, it is broken and useless.


Mastication in the oral myofunctional disorders.
The aim of this article is to show two ways of clinical work with mastication in Oral Myofunctional Disorders. Consideration is given to limitations that make direct treatment impossible: symptoms/signs of temporo-mandibular joint, occlusions alterations, types of orthodontics or orthopedics appliances and loosing teeth. The procedures suggested are named procedures WITH and WITHOUT LIMITATIONS.


Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial.
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively (P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group (P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.


Establishing a high yielding streptomyces-based cell-free protein synthesis system.
Cell-free protein synthesis (CFPS) has emerged as a powerful platform for applied biotechnology and synthetic biology, with a range of applications in synthesizing proteins, evolving proteins, and prototyping genetic circuits. To expand the current CFPS repertoire, we report here the development and optimization of a Streptomyces-based CFPS system for the expression of GC-rich genes. By developing a streamlined crude extract preparation protocol and optimizing reaction conditions, we were able to achieve active enhanced green fluorescent protein (EGFP) yields of greater than 50 μg/mL with batch reactions lasting up to 3 h. By adopting a semi-continuous reaction format, the EGFP yield could be increased to 282 ± 8 μg/mL and the reaction time was extended to 48 h. Notably, our extract preparation procedures were robust to multiple Streptomyces lividans and Streptomyces coelicolor strains, although expression yields varied. We show that our optimized Streptomyces lividans system provides benefits when compared to an Escherichia coli-based CFPS system for increasing percent soluble protein expression for four Streptomyces-originated high GC-content genes that are involved in biosynthesis of the nonribosomal peptides tambromycin and valinomycin. Looking forward, we believe that our Streptomyces-based CFPS system will contribute significantly towards efforts to express complex natural product gene clusters (e.g., nonribosomal peptides and polyketides), providing a new avenue for obtaining and studying natural product biosynthesis pathways. Biotechnol. Bioeng. 2017;114: 1343-1353. © 2017 Wiley Periodicals, Inc.


An antiinflammatory effect of salmeterol, a long-acting beta(2) agonist, assessed in airway biopsies and bronchoalveolar lavage in asthma.
The addition of long-acting beta(2) agonists to inhaled corticosteroid (ICS) therapy in symptomatic patients with asthma improves clinical status more than increasing the dose of ICS. It has been suggested that these benefits could be at the cost of an increase in airway inflammation, but few histopathological studies have been performed in the relevant group. In a double-blind, parallel-group, placebo-controlled study, we randomly assigned 50 symptomatic patients with asthma who were receiving ICS (range, 100 -500 microgram/d) to 12 wk of supplementary treatment with salmeterol (50 microgram twice daily) or fluticasone (100 microgram twice daily) or placebo. Bronchial biopsies and BAL were obtained from 45 patients before and after treatment and analyzed. After treatment with salmeterol there was no deterioration of airway inflammation as assessed by mast cells, lymphocytes, or macrophages in BAL or biopsies, but rather a significant fall in EG1-positive eosinophils in the lamina propria (from a median 18.3 to 7.6 cells/mm, p = 0.01), which was not seen after treatment with fluticasone. The only cellular effect of added fluticasone was a decrease in BAL lymphocyte activation. There was a concurrent improvement in clinical status, more marked with salmeterol than with increased ICS. Thus, adding salmeterol to ICS is not associated with increased "allergic" airway inflammation, but conversely with a complementary antieosinophil effect.


Naproxen: corticosteroid-sparing effect in rheumatoid arthritis.
Ambulatory patients with a diagnosis of "classical" or "definite" active adult rheumatoid arthritis were selected. They had been stabilized for at least six months previously with oral administration of paramethasone acetate plus various analgesics and/or nonsteroidal anti-inflammatory agents. During an initial period of two to five weeks, the paramethasone dosage was adjusted and other medications replaced by placebo to find the minimum required to keep the patient at a level similar to the one at the beginning of the study. Subsequently, with the double-blind method, the effect of 400 mg naproxen daily was compared with placebo, making periodic and progressive reductions in the corticosteroid dosage, unknown to the patient, until a tolerable minimum was found. The average total observation time was 14 weeks. Results obtained in the first 28 patients showed an average reduction of 57 per cent in paramethasone dose for the group treated with naproxen, versus 21 per cent for the control group. One patient experienced euphoria which could possibly have been related to the test drug. It is concluded that naproxen possesses a significant corticosteroid-sparing effect with negligible toxicity.


Management of portal vein thrombosis in cirrhosis: an update.
Portal vein thrombosis (PVT) is a complication of cirrhosis. However, whether PVT worsens cirrhosis outcome is a debated issue. To report an update on the management of PVT. A review was performed on the outcome, prevention, and treatment of PVT. Some studies suggest that PVT could worsen the rate of hepatic decompensation and survival of cirrhosis, whereas others report a non-negative impact of PVT in the outcome of cirrhosis. Therefore, the prognostic value of PVT in cirrhosis remains a gray zone. One single randomized-controlled trial reported that enoxaparin could prevent PVT, delay the occurrence of hepatic decompensation, and improve survival. However, no further study data confirmed this assumption and the issue is not actually generalizable. Numerous studies report that anticoagulation determines a relatively high rate of portal vein recanalization in cirrhotics PVT. However, further data are warranted to confirm the risk-to-benefit of anticoagulation, especially bleeding. Transjugular intrahepatic portosystemic shunt (TIPS) has been reported to be effective as a treatment of PVT in cirrhosis, with the advantage of avoiding the risk of bleeding linked to anticoagulation. However, there are no data comparing TIPS with anticoagulation as a treatment of PVT in cirrhosis. Furthermore, there is no evidence on whether both anticoagulation and TIPS improve survival. It is uncertain whether PVT affects cirrhosis outcome. Further data are needed to weigh the risk/benefit ratio of enoxaparin for the prevention of PVT in cirrhosis. Anticoagulation or TIPS should probably be indicated in liver transplantation candidates, but avoided in patients not suitable for liver transplantation and with an otherwise poor prognosis. Future studies should evaluate which subgroup of cirrhotics with PVT may benefit from treatment. Management of PVT in cirrhosis should be personalized.


Insulin receptors: differences in structural organization on adipocyte and liver plasma membranes.
Comparison was made of the distribution of the insulin receptor sites on adipocyte and liver plasma membranes by using ferritin-insulin. Two-thirds of the occupied insulin receptors on adipocytes occurred in groups of two or more whereas up to two-thirds of the receptors on liver occurred as single receptors. Ferritin-insulin did not cause aggregation of the receptor sites in either tissue. The naturally occurring groups of receptors on adipocyte membranes may play a role in the greater sensitivity of adipocytes to insulin.


Leptin signaling, adiposity, and energy balance.
A chronic minor imbalance between energy intake and energy expenditure may lead to obesity. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure. The cloning of the ob gene and the identification of its encoded protein, leptin, have provided a system signaling the amount of adipose energy stores to the brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic receptors to inhibit feeding and increase thermogenesis. A feedback regulatory loop with three distinct steps has been identified: (1) a sensor (leptin production by adipose cells) monitors the size of the adipose tissue mass; (2) hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors (LRb); (3) effector systems, including the sympathetic nervous system, control the two main determinants of energy balance-energy intake and energy expenditure. While this feedback regulatory loop is well established in rodents, there are many unsolved questions about its applicability to body weight regulation in humans. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Gender is an important factor determining plasma leptin, with women having markedly higher leptin concentrations than men for any given degree of fat mass. The ob mRNA expression is also upregulated by glucocorticoids, whereas stimulation of the sympathetic nervous system results in its inhibition. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides. The orexigenic neuropeptides that are downregulated by leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected responses (i.e., a reduction in food intake and an increase in energy expenditure). This suggests that obese humans are resistant to the effects of endogenous leptin. This resistance is also shown by the lack of effect of exogenous leptin administration to induce weight loss in obese patients. The mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Reduction of the leptin signal induces several neuroendocrine responses that tend to limit weight loss, such as hunger, food-seeking behavior, and suppression of plasma thyroid hormone levels. Conversely, it is unlikely that leptin has evolved to prevent obesity when plenty of palatable foods are available because the elevated plasma leptin levels resulting from the increased adipose tissue mass do not prevent the development of obesity. In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal (mutations of the leptin gene or of the leptin receptor gene), which produces an internal perception of starvation and results in a chronic stimulation of excessive food intake.


Is Oral Contrast Necessary for Multidetector Computed Tomography Imaging of Patients With Acute Abdominal Pain?
The purpose of our study was to validate the hypothesis that eliminating the use of oral contrast for multidetector computed tomography (MDCT) would not affect the detection of acute abdominal abnormalities in emergency room patients. We conducted a retrospective study to assess the effect of discontinuing oral contrast use for MDCT scans of the abdomen and pelvis for patients presenting with acute abdominal pain and body mass index (BMI) >25. Patients with BMI <25 continued to receive oral contrast. The medical records were reviewed to determine the rate of repeat imaging within 7 days from the initial CT scan, as well as delayed or missed diagnoses related to the absence of oral contrast. The study was approved by the research ethics board at our institution. A total of 1378 patients had an MDCT examination of the abdomen and pelvis between November 1, 2012, and October 31, 2013. 375 patients met the inclusion criteria (174 males and 201 females; mean age 57 years; range 18-97 years). Seven of 375 (1.9%) patients had a repeat CT examination with oral contrast within 7 days. Of these 7 patients, none had a change in the course of their management due to the utilization of oral contrast. No delayed or missed diagnoses related to the absence of oral contrast were identified. Omitting oral contrast for imaging patients with BMI >25 presenting with acute abdominal pain resulted in no delayed or missed diagnoses, in our retrospective study. The benefits of prompt imaging diagnosis outweigh the unlikely need for repeat imaging.


[Diagnostic value of radionuclide visualization of the reticuloendothelial system of macrophages in multiple sclerosis].
Scintigraphic examination of the liver, spleen, bone marrow and retroperitoneal lymph nodes with the help of colloidal radiopharmaceutical 113mIn was conducted in 55 patients with multiple sclerosis (MS) and in 13 patients with other diseases of the nervous system. The authors ascertained dysfunction of cells of the mononuclear phagocytic system (MPS) in the MS patients. Clinical manifestations of the disease were found to correlate with the findings of radionuclide imaging of the parenchymatous organs and lymph nodes. A conclusion was drawn about the total disruption of the functional activity of MPS cells in MS and the inevitable involvement of the liver in the pathogenesis of the disease.


[Localization and distribution of human olfactory mucosa in the nasal cavities].
The exact distribution of the human olfactory mucosa can only be determined in studies that evaluate the entire olfactory region. The purpose of this study is to determine the distribution of human olfactory mucosa in the nasal cavities, by performing the histological analysis, by light microscopy, of anatomical specimens of the olfactory region obtained from cadavers. The specimens were taken during the autopsy of fresh cadavers. In each of the specimens, the distance between the cribiform plate and the lower limit of the olfactory region was determined in three different locations of the septal and lateral walls. Of the 230 anatomical specimens available, 217 were excluded for medical or technical reasons. Morphometric studies were performed on 13 specimens (total 156 measurements). The lower limit of the olfactory mucosa in the nasal septum was 15.9 ± 3.2 mm, 15.3 mm ± 3 and 16 ± 2.8 mm in the anterior, middle and posterior olfactory regions. The lower limit of the olfactory mucosa in the turbinate wall was 15.3 ± 2.4 mm, 14.8 ± 2.3 mm and 12.3 ± 1.9 mm in the equivalent regions. The minimum value observed was 12 mm. The olfactory mucosa extends through the upper and middle turbinates and the confronting nasal septum in a minimum distance of 12 mm and that may exceed 16 mm. Knowing the exact distribution of the olfactory mucosa can guide the collection of this tissues in humans, for diagnostic or therapeutic purposes.


Marginal leakage of class V cavities restored with silorane-based and methacrylate-based resin systems.
The aim of this study was to compare the microleakage of class V cavities restored by silorane resin with those restored by the methacrylate resin system. Sixty standardized class V cavities were prepared on premolars. The teeth were restored with Filtek(TM) Silorane and Silorane(TM) System Adhesive, Filtek(TM) Silorane and Adper(TM) Easy One and Filtek(TM) Supreme XT and Adper(TM) Easy One. The area and the depth of dye leakage were measured. Considering dye leakage area, the best results were achieved in group I (mean-M=0.114±0.083 mm(2)), then in group III (M=0.384±0.480 mm(2)) and finally in group II (M=5.389±6.587 mm(2)). Considering the depth of dye leakage, there was a significant difference between group I (mean rank-m.r.=1.23±0.44 mm) and II (1.98±0.83 mm), group II and III (1.23±0.40 mm). In this study silorane composite and its adhesive showed less microleakage than the methacrylate composite, and it showed compatibility only with its assigned adhesive. Less microleakage of silorane restorations could provide better and long lasting composite fillings.


Swelling-induced structural changes and microparticle uptake of gelatin gels probed by NMR and CLSM.
Gelatin gels are increasingly involved in many industrial applications due to several advantages including cost efficiency and biocompatibility. Generally, their production requires the use of aqueous solvents, which cause significant swelling, due to the ability of solvent molecules to penetrate through the gel microstructure and increase its volume. Since swelling mechanisms and their effect on the gel structure are not fully understood, further investigations are required. In this work, we combine macroscopic measurements of the swelling ratio (SR) with Nuclear Magnetic Resonance (NMR) and Confocal Laser Scanning Microscopy (CLSM) to investigate changes in the gelatin structure as a function of both polymer concentration and swelling time. SR values increase as a function of time until a maximum is reached and then show a slight drop for all the gelatin concentrations after 24 h swelling time, probably due to a network relaxation process. NMR allows determination of mass transport and molecular dynamics of water inside the gelatin pores, while CLSM is used to visualize the penetration of tracers (polystyrene microbeads) with a diameter much larger than the gel pores. Structural parameters, such as average pore size and tortuosity, are estimated. In particular, the pore size decreases for higher polymer concentration and increases during swelling, until reaching a maximum, and then dropping at longer times. The penetration of tracers provides evidence of the heterogeneity of the gel structure and shows that single microcarriers can be loaded in gelatin gels upon swelling.


Model-Based and Data-Driven Control of Event- and Self-Triggered Discrete-Time Linear Systems.
The present paper considers the model-based and data-driven control of unknown discrete-time linear systems under event-triggering and self-triggering transmission schemes. To this end, we begin by presenting a dynamic event-triggering scheme (ETS) based on periodic sampling, and a discrete-time looped-functional approach, through which a model-based stability condition is derived. Combining the model-based condition with a recent data-based system representation, a data-driven stability criterion in the form of linear matrix inequalities (LMIs) is established, which also offers a way of co-designing the ETS matrix and the controller. To further alleviate the sampling burden of ETS due to its continuous/periodic detection, a self-triggering scheme (STS) is developed. Leveraging precollected input-state data, an algorithm for predicting the next transmission instant is given, while achieving system stability. Finally, numerical simulations showcase the efficacy of ETS and STS in reducing data transmissions as well as practicality of the proposed co-design methods.


Phytochemical Screening by LC-ESI-MS/MS and Effect of the Ethyl Acetate Fraction from Leaves and Stems of Jatropha macrantha Müll Arg. on Ketamine-Induced Erectile Dysfunction in Rats.
Jatropha macrantha Müll Arg. L is also known as "huanarpo macho" and used in the Peruvian traditional medicine as an aphrodisiac and erectile dysfunction (ED). The aim of this study was to determine the phytochemical constituents in leaves and stems ethyl acetate fraction (LEAF and SEAF) of J. macrantha and to compare the antioxidant activity and the ameliorative effect on ketamine-induced erectile dysfunction in rats. The phytochemical constituents were determined by LC-ESI-MS/MS, the total phenolic compounds and total flavonoids (TPC and TF) by Folin-Ciocalteu and aluminum chloride, respectively. The antioxidant activity was determined by DPPH, ABTS, and FRAP assays. Experimental groups were divided as follows: I: negative control; II: positive control (ketamine at 50 mg/ kg/d); III: sildenafil 5 mg/kg; IV, V, VI: LEAF at 25, 50 and 100 mg/kg, respectively, and VII, VIII, IX: SEAF at 25, 50, and 100 mg/kg, respectively. The phytochemical analysis revealed the presence mainly of coumarins, flavonoids, phenolic acids, and terpenes. TPC of LEAF and SEAF were 359 ± 5.21 mg GAE/g and 306 ± 1.93 mg GAE/g, respectively; TF in LEAF and SEAF were 23.7 ± 0.80 mg EQ/g, and 101 ± 1.42 mg EQ/g, respectively. The DPPH, ABTS, FRAP in SEAF were 647 ± 3.27; 668 ± 2.30; and 575 ± 2.86 μmol TE/g, respectively, whilst LEAF showed 796 ± 3.15; 679 ± 0.85; and 806 ± 3.42 μmol TE/g, respectively. Regarding sexual behavior, LEAF showed a better effect in mount frequency, intromission frequency, ejaculation frequency, mount latency, intromission latency, ejaculatory latency, and post ejaculatory latency than SEAF. As conclusion, LEAF of J. macrantha at 50 mg/kg showed a better effect on sexual behavior in male rats with erectile dysfunction than SEAF but not higher than sildenafil.


Late arrhythmias after surgery for transposition of the great arteries.
The evolution of surgical techniques for transposition of the great arteries (TGA) provides a moving target for the assessment of late arrhythmias. Imposed on varying anatomical substrates are progressive surgical interventions, each with its own set of sequelae. Analysis of the risk of arrhythmia development requires division into which arrhythmia is present, for which form of transposition, undergoing what type of surgery, and in which surgical era. For purposes of this review, available data on d-TGA undergoing Senning repairs, Mustard repairs, and arterial switch repairs and congenitally corrected TGA undergoing double switch repairs are reviewed.


Human mesenchymal stem cells increase anti-oxidant defences in cells derived from patients with Friedreich's ataxia.
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disorder which is, at present, incurable. Oxidative damage and inhibition of mitochondrial function are key determinants of cellular damage in FRDA, since there is greater sensitivity to oxidative stress in cells with frataxin deficiency. In addition, frataxin-deficient cells have an impaired ability to recruit antioxidant defences against endogenous oxidative stress. We have recently shown that factors derived from bone marrow-derived mesenchymal stem cells (MSCs) increase hydrogen peroxide scavenging enzymes and offer protection against hydrogen peroxide-mediated injury in cells derived from patients with FRDA. Here we extend these studies and have performed a series of experiments showing that expression of superoxide dismutase (1 and 2) enzymes is reduced in FRDA cells but can be restored by treatment with conditioned medium from human MSCs. Furthermore, we have demonstrated that exposure to factors secreted by MSCs increases resistance to nitric oxide-induced oxidative stress in FRDA fibroblasts through, at least in part, restoring the expression of the superoxide dismuting enzymes and via modulation of PI(3) kinase/Akt pathways. These findings suggest that MSCs secrete factors that improve the cellular homeostasis of cells derived from FRDA patients and provide suitable support for their enhanced survival. This study further suggests the potential therapeutic use of MSCs in patients with FRDA.


Histamine responsiveness of isolated gastric glands.
Gastric glands isolated from rabbit were employed to perform a pharmacological characterization of the histamine receptor associated with physiological and biochemical responses in gastric cells. Five separate response parameters were characterized using histamine analogues and histamine antagonists. The following parameters were studied: respiration, accumulation of the weak base aminopyrine, adenylate cyclase activity, cAMP accumulation, and the uptake of histamine. All parameters were examined for agonist and antagonist potency using dose-response curves, ED50 and pA2 values. Comparison of the ED50-agonist and pA2-cimetidine values showed a remarkable similarity for respiration, aminopyrine accumulation, adenylate cyclase activity, and cAMP accumulation. The agonist potency sequence and pA2 values for H2- vs. H1-receptor antagonists characterized the histamine receptor associated with these four parameters as being of the H2 type. Moreover, the similarity of pharmacological characteristics provides evidence for a similar, if not common, receptor for these responses. The histamine uptake system shows a generally lower affinity for most agonists. Although the general agonist potency sequence is similar to the other parameters, notable exceptions were found for antagonists and the typical H2-agonist, dimaprit. Thus, the uptake system does not appear to be related directly to the activation of secretion and the carrier binding site cannot be simply defined by H1 or H2 properties.


Topical nifedipine with lidocaine ointment versus active control for pain after hemorrhoidectomy: results of a multicentre, prospective, randomized, double-blind study.
Spasm through the internal anal sphincter is one of the supposed causes for pain after hemorrhoidectomy, a common and distressing experience. We hypothesized that the addition of topical nifedipine to lidocaine would improve pain control by causing a relaxation of the smooth muscle of the internal anal sphincter. We conducted a multicentre randomized, double-blind trial to compare the efficacy of 0.3% nifedipine and 1.5% lidocaine ointment versus 1.5% lidocaine ointment alone in reducing pain after hemorrhoidectomy. A physician unaware of the treatment arm measured pain by use of the Analogue Chromatic Continuous Scale (ACCS) at baseline; soon after surgery; at 2, 4, 6, 8 and 24 hours after surgery; on day 7 after surgery; and at a final visit 14 days after surgery. The physician also noted the time to first analgesic administration within 24 hours after surgery. In all, 135 patients per group participated (270 total). Evaluation of the delta ACCS score versus basal value, a covariate for rescue analgesic administration time, revealed better pain control in the group that received nifedipine with lidocaine at 6 hours after surgery and on day 7 (p < 0.011 and p < 0.054, respectively). We noticed no difference between groups for time of administration of rescue analgesic, blood pressure, heart rate or frequency of headache. Although there was no difference between groups for time of administration of rescue analgesic after open hemorrhoidectomy, the patients' assessment of pain using ACCS showed that the use of topical nifedipine with lidocaine may provide a slight significant difference in favour of the study group at 6 hours and at day 7 after surgery. Narcotic analgesics and nonsteroidal anti-inflammatory drug administration should continue to be recommended. Further research focusing on these outcomes is warranted.


Evaluation of Six Aromatic Amines in the Mainstream Smoke of Commercial Cigars.
Aromatic amines are a class of carcinogenic compounds present in tobacco smoke that are listed on the U.S. Food and Drug Administration (FDA) list of harmful and potentially harmful constituents (HPHCs) in tobacco products and tobacco smoke. The yields of six aromatic amines (1-aminonaphthalene [1-AN], 2-aminonaphthalene [2-AN], 3-aminobiphenyl [3-ABP], 4-aminobiphenyl [4-ABP], ortho-toluidine [o-TOL], and o-anisidine [o-ANI]) in the mainstream smoke from 23 commercial filtered cigars, 16 cigarillos, and 11 large cigars were determined using solid-phase microextraction coupled to gas chromatography triple quadrupole mass spectrometry (SPME headspace GC-MS/MS). The commercial cigars were smoked under the Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) Recommended Method 64 using a linear cigar smoking machine. The aromatic amine yields in the mainstream smoke from 50 commercial cigars show high levels of variation within and between the products. The average yields of the aromatic amines in the filtered cigars, cigarillos, and large cigars were 108, 371, and 623 ng/cigar for o-TOL; 6, 14, and 22 ng/cigar for o-ANI; 65, 114, and 174 ng/cigar for 1-AN; 25, 59, and 87 ng/cigar for 2-AN; 6, 17, and 27 ng/cigar for 3- ABP; and 8, 11, and 17 ng/cigar for 4-ABP, respectively. The relationships between aromatic amines and (1) total particulate matter (TPM), (2) water-soluble proteins, and (3) water-insoluble proteins were evaluated. We found that the aromatic amines showed a good linear response with TPM on a per cigar basis and showed significant positive correlations with proteins. In addition, the water-insoluble proteins make a greater contribution to the formation of aromatic amines compared to the water-soluble proteins.


Hepatocyte transplantation.
Numerous laboratory studies have shown that hepatocyte transplantation may serve as an alternative to organ transplantation for patients with life-threatening liver disease. Because of the successes of experimental hepatocyte transplantation, institutions have attempted to use this therapy in the clinic for the treatment of a variety of hepatic diseases. Unfortunately, unequivocal evidence of transplanted human hepatocyte function has been obtained in only one patient with Crigler-Najjar syndrome type I, and, even then, the amount of bilirubin-UGT enzyme activity derived from the transplanted cells was not sufficient to eliminate the patient's eventual need for organ transplantation. A roadmap for improving patient outcome following hepatocyte transplantation can be obtained by a re-examination of previous animal research. A better understanding of the factors that allow hepatocyte integration and survival in the liver and spleen is needed to help reduce the need for repeated cell infusions and multiple donors. Although clinical evidence of hepatocyte function can be used to indicate function of transplanted hepatocytes, definitive histologic evidence is difficult to obtain. In order to assess whether rejection is taking place in a timely fashion, a reliable way of detecting donor hepatocytes will be needed. The most important issue affecting transplantation, however, relates to donor availability. Alternatives to the transplantation of allogeneic human hepatocytes include transplantation of hepatocytes derived from fetal, adult or embryonic stem cells, engineered immortalized cells, or hepatocytes derived from other animal species.


Increased formation of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, in human breast cancer tissue and its relationship to GSTP1 and COMT genotypes.
Reactive oxygen species (ROS) induced damage to DNA plays a major role in carcinogenesis. In order to estimate the level of oxidative damage and its role in breast cancer, 8-hydroxy-2'-deoxyguanosine (8-OHdG) was determined in DNA isolated from human breast tissue. Furthermore, we investigated whether polymorphisms in genes for enzymes involved in generation and elimination of ROS had any association with the level of 8-OHdG in breast tissue. In this study, the level of 8-OHdG in DNA was measured by the high performance liquid chromatography-electrochemical detector (HPLC-ECD) method. Genotypes of cytochrome P450 (CYP)1A1, glutathione S-transferase (GST)M 1, GSTP1 and catechol O-methyltransferase (COMT) were determined by PCR-based restriction fragment length polymorphism analysis. A total of 61 Japanese patients were included in the study. The mean level of 8-OHdG in DNA of breast cancer tissues was 2.07 +/- 0.95 per 10(5) dG residues, while the mean level of 8-OHdG in DNA of non-cancerous breast tissues was 1.34 +/- 0.46 per 10(5) dG residues. The 8-OHdG levels in DNA of breast cancer tissues were significantly higher than those of their corresponding non-cancerous breast tissues (P < 0.0001). There was negative correlation between the clinical stage and the mean level of 8-OHdG in DNA of breast cancer tissues. Furthermore, patients with genotype of high GSTP1 activity had lower level of 8-OHdG in DNA of breast cancer tissues than others. On the contrary, the mean level of 8-OHdG in DNA of breast cancer tissues was higher among patients with genotype of high COMT activity. Our findings support the assumption that cancer cells are more exposed to oxidative stress than adjacent non-cancerous tissue. Genetic polymorphisms in enzymes involved in ROS metabolism may have a role in individual susceptibility to oxidant-related breast disease. At the same time, reduction of oxidative stress is thought to be a very important measure for primary prevention of breast cancer.


"Organic brain syndrome" secondary to 5-fluorouracil toxicity.
A 68-year-old woman, who was treated with 5-fluorouracil (5-FU) intravenous therapy weekly for variable periods following hemicolectomy for adenocarcinoma of the cecum, had at least two well-described episodes of mental confusion, disorientation, and deterioration, in the absence of cerebellar tract signs. The sensorium cleared after cessation of 5-FU, only to deteriorate following readministration of the drug. She was thought to have organic brain syndrome during her most recent mental relapse. Her mental status has now been intact for more than one year since her last exposure to 5-FU. This is believed to be the third patient who has shown mental changes which could be attributable to 5-FU toxicity. Since 5-FU is the most frequently used chemotherapy for the treatment of colonic cancer, it is important that this form of toxicity be recognized lest subject patients be judged to have irreversible organic brain syndrome or metastatic carcinoma.


Mechanical and physical responses to stretching with and without preisometric contraction in human skeletal muscle.
To examine electromyography (EMG) activity, passive torque, and stretch perception during static stretch and contract-relax stretch. Two separate randomized crossover protocols: (1) a constant angle protocol on the right side, and (2) a variable angle protocol on the left side. 10 male volunteers. Stretch-induced mechanical response in the hamstring muscles during passive knee extension was measured as knee flexion torque (Nm) while hamstring surface EMG was measured. Final position was determined by extending the knee to an angle that provoked a sensation similar to a stretch maneuver. Constant angle stretch: The knee was extended to 10 degree below final position, held 10sec, then extended to the final position and held for 80 sec. Variable angle stretch: The knee was extended from the starting position to 10 degrees below the final position, held 10sec, then extended to the onset of pain. Subjects produced a 6-sec isometric contraction with the hamstring muscles 10 degrees below the final position in the contract-relax stretch, but not in the static stretch. Passive torque, joint range of motion, velocity, and hamstring EMG were continuously recorded. Constant angle contract-relax and static stretch did not differ in passive torque or EMG response. In the final position, passive torque declined 18% to 21% in both contract-relax and static stretch (p<.001), while EMG activity was unchanged. In the variable angle protocol, maximal joint angle and corresponding passive torque were significantly greater in contract-relax compared with static stretch(p<.01), while EMG did not differ. At a constant angle the viscoelastic and EMG response was unaffected by the isometric contraction. The variable angle protocol demonstrated that PNF stretching altered stretch perception.


Negative regulation of αS1-casein (CSN1S1) improves β-casein content and reduces allergy potential in goat milk.
Compared with other milk proteins, αS1-casein (encoded by CSN1S1) is associated with higher rates of allergies in humans. Although some studies have revealed that CSN1S1 affects a variety of cellular physiological processes such as immune response and proliferation in various cells, whether CSN1S1 regulates other milk proteins in ruminants is not known. In this study, we observed a negative Pearson correlation between the contents of αS1-casein and β-casein in goat milk. Thus, we used isolated primary goat mammary epithelial cells along with adenoviral infection or small interference RNA to alter abundance of CSN1S1 and examine its role in milk protein synthesis regulation. Overexpressing CSN1S1 through adenoviral transfection decreased β-casein mRNA (CSN2) and protein abundance, whereas interference of CSN1S1 resulted in a significant increase in β-casein abundance. CSN1S1 reduced phosphorylation level of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5a (STAT5a). The transcription factor STAT5a activates CSN2 transcription by binding with its promoter region and then promotes β-casein synthesis. Furthermore, CSN1S1 inhibited CSN2 promoter activity and β-casein synthesis by modulating the JAK2/STAT5a signaling pathway. No changes in abundance were detected for αS2-casein (CSN1S2), κ-casein (CSN3) and major whey proteins (LALBA, BLG). Overall, our results underscored a mechanism whereby CSN1S1 inhibits β-casein synthesis via inhibition of STAT5a. The data suggested that knocking down CSN1S1 not only reduced the content of αS1-casein, but also increased the abundance of major milk proteins including β-casein. Thus, the present study provides a theoretical basis for manipulating αS1-casein mRNA to improve quality of ruminant milk for human consumption.


Ultrasonography of the normal fetal brain.
Since the early 1960s it has been possible to identify the fetal head using A-mode ultrasound. The introduction of high-resolution, real-time, gray-scale ultrasound in the mid-to-late 1970s first enabled the routine display of subtle internal anatomy. Using presently available equipment, the fetus can be imaged from 7 weeks after the last menstrual period until term and the internal anatomy of the fetal head can be detected after 11-12 weeks. The ultrasonic anatomy of the normal fetal head throughout the second and third trimesters is discussed, as are the normal changes taking place with growth.


Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning/memory deficits in juveniles followed by progressive functional recovery in adults.
Administration of ethanol to rodents during the synaptogenesis period induces extensive apoptotic neurodegeneration in the developing brain. This neurotoxicity may explain the reduced brain mass and neurobehavioral disturbances in human Fetal Alcohol Syndrome (FAS). Here, we report binge-like exposure of infant mice to ethanol on a single postnatal day triggered apoptotic death of neurons from diencephalic structures that comprise an extended hippocampal circuit important for spatial learning and memory. The ethanol exposure paradigm yielding these neuronal losses caused profound impairments in spatial learning and memory at 1 month of age. This impairment was significantly attenuated during subsequent development, indicating recovery of function. Recovery was not associated with increased neurogenesis, suggesting plastic reorganization of neuronal networks compensated for early neuronal losses. We hypothesize that neuroapoptotic damage in homologous regions of human brain underlies cognitive deficits in FAS and the human brain of FAS victims has a similar capacity to effect functional recovery.


Thrombocytosis in a patient with upper gastrointestinal bleeding.
Reported here is a case of upper gastrointestinal bleeding secondary to a peptic ulcer involving an extremely high platelet count of 989 × 109/L. Myeloproliferative neoplasms were ruled out on the basis of gene mutation testing and a bone marrow biopsy. After the cessation of index bleeding, the platelet count decreased markedly. Thus, reactive thrombocytosis was considered as a possibility.


Active LINE-1 retrotransposons in human testicular cancer.
An antibody to the protein encoded by the first open reading frame of the human LINE-1 (L1Hs) element was used to examine immunohistochemically 59 formalin-fixed, human testicular germ cell tumors. Six tumors were positive for L1Hs expression. In all cases the L1Hs-positive cells were epithelial and most had the very characteristic, undifferentiated appearance of embryonal carcinoma or yolk sac tumor cells. One L1Hs-positive tumor had metastasized to the lung and lymph nodes and the metastatic cells also expressed L1Hs. This is the first observation of widespread retrotransposon expression in human tissue. These observations raise the possibility that L1Hs-encoded proteins may function as oncoproteins in some cancers.


Factors associated with the compliance of standard precaution; review article.
Compliance with standard precautions is very important for healthcare workers because studies have shown that it helps in minimising the transmission of infectious diseases and healthcare-associated infections which is directly proportional to the patient cost and stay of the patient in hospitals. As healthcare associated infections increase, the cost and the stay of the patient will increase. Researchers suggest that all healthcare workers need to follow the standard precautions guideline and it can be possible with the help of health education, training, provision of equipment and supervision by the management. Barriers to the compliance identified are lack of education, heavy workload, unavailability of equipment, lack of resources and lack of access to supplies. The lack of education and heavy workload are the major factors faced by the nurses.


The association between pregnancy weight gain and birthweight: a within-family comparison.
Excessive weight gain during pregnancy seems to increase birthweight and the offspring's risk of obesity later in life. However, this association might be confounded by genetic and other shared effects. We aimed to examine the association between maternal weight gain and birthweight using state-based birth registry data that allowed us to compare several pregnancies in the same mother. In this population-based cohort study, we used vital statistics natality records to examine all known births in Michigan and New Jersey, USA, between Jan 1, 1989, and Dec 31, 2003. From an initial sample of women with more than one singleton birth in the database, we made the following exclusions: gestation less than 37 weeks or 41 weeks or more; maternal diabetes; birthweight less than 500 g or more than 7000 g; and missing data for pregnancy weight gain. We examined how differences in weight gain that occurred during two or more pregnancies for each woman predicted the birthweight of her offspring, using a within-subject design to reduce confounding to a minimum. Our analysis included 513 501 women and their 1 164 750 offspring. We noted a consistent association between pregnancy weight gain and birthweight (β 7·35, 95% CI 7·10-7·59, p<0·0001). Infants of women who gained more than 24 kg during pregnancy were 148·9 g (141·7-156·0) heavier at birth than were infants of women who gained 8-10 kg. The odds ratio of giving birth to an infant weighing more than 4000 g was 2·26 (2·09-2·44) for women who gained more than 24 kg during pregnancy compared with women who gained 8-10 kg. Maternal weight gain during pregnancy increases birthweight independently of genetic factors. In view of the apparent association between birthweight and adult weight, obesity prevention efforts targeted at women during pregnancy might be beneficial for offspring. US National Institutes of Health.


Deficiency of a protein-repair enzyme results in the accumulation of altered proteins, retardation of growth, and fatal seizures in mice.
L-Asparaginyl and L-aspartyl residues in proteins are subject to spontaneous degradation reactions that generate isomerized and racemized aspartyl derivatives. Proteins containing L-isoaspartyl and D-aspartyl residues can have altered structures and diminished biological activity. These residues are recognized by a highly conserved cytosolic enzyme, the protein L-isoaspartate(D-aspartate) O-methyltransferase (EC 18.104.22.168). The enzymatic methyl esterification of these abnormal residues in vitro can lead to their conversion (i.e., repair) to normal L-aspartyl residues and should therefore prevent the accumulation of potentially dysfunctional proteins in vivo as cells and tissues age. Particularly high levels of the repair methyltransferase are present in the brain, although enyzme activity is present in all vertebrate tissues. To define the physiological relevance of this protein-repair pathway and to determine whether deficient protein repair would cause central nervous system dysfunction, we used gene targeting in mouse embryonic stem cells to generate protein L-isoaspartate(D-aspartate) O-methyltransferase-deficient mice. Analyses of tissues from methyltransferase knockout mice revealed a striking accumulation of protein substrates for this enzyme in the cytosolic fraction of brain, heart, liver, and erythrocytes. The knockout mice showed significant growth retardation and succumbed to fatal seizures at an average of 42 days after birth. These results suggest that the ability of mice to repair L-isoaspartyl- and D-aspartyl-containing proteins is essential for normal growth and for normal central nervous system function.


Udonella myliobati n. comb. (Platyhelminthes:Udonellidae) and its occurrence in eastern Australia.
A total of 2,571 of the copepod Caligus epidemicus Hewitt from the yellow-fin bream, Acanthopagrus australis Günther, was examined for udonellids. Calinella myliobati Guberlet, 1936 was found on 3.3% of male copepods and 10.1% of female copepods. A new combination, Udonella myliobati (Guberlet, 1936) is proposed and its description emended. It differs from the type species Udonella caligorum Johnston, 1835 (as described by Price [1938]) in having a short egg filament and a median genital aperture. Only 1 of 102 chalimus larvae was infected, by a single adult worm. Juvenile udonellids common on mature copepods, were not found on any of the chalimus larvae. The highest number of U. myliobati (Guberlet, 1936), including hatching and unhatched eggs on 1 copepod, was 159. Adult and juvenile worms were attached mainly along the margins of the carapace and to the genital complex, whereas the majority of the eggs were attached to the ventral surface of the genital complex. The transfer of an adult worm from a male copepod to a female copepod was observed while the copepods were copulating. The large number of udonellids on a small population of mostly female copepods from the Brisbane River suggested that this was an aging population of copepods compared to the copepods collected from a semi-enclosed pond.


Which antiretroviral regimen is associated with higher adherence in Brazil? A comparison of single, multi, and dolutegravir-based regimens.
We evaluated adherence to highly active antiretroviral therapy (HAART) and its associated factors according to the type of regimen in patients initiating treatment in Belo Horizonte, Minas Gerais State, Brazil. We measured adherence using the eight items Morisky Therapeutic Adhesion Scale (MMAS-8) and compared the use of "backbone" tenofovir/lamivudine plus efavirenz one tablet once-daily (STR) or dolutegravir in multi-tablet once-daily (MTR-DTG), or other multi-tablet regimens (MTR-other). We conducted a multivariate logistic regression analysis to address factors associated with adherence. A total of 393 patients were included, 254 used STR, 106 MTR-DTG, and 33 MTR-other. The overall adhesion rate was 44.8% (95%CI: 39.4; 50.1), 50% for MTR-DTG, 43.3% for STR and 39.4% for MTR-other. Multivariate analysis showed a higher chance of adherence among patients using MTR-DTG, those who received and understood counseling about their treatment and with a higher quality of life. Prior use of illicit drugs in the lifetime was associated with poorer adherence. Overall adherence was low, highlighting the need for strategies focusing on counseling about medicines and substance use. Pill burden was not an issue for patients using MTR-DTG once-daily, who achieved better results.


Safety, feasibility, and optimization of intra-arterial mitoxantrone delivery to gliomas.
Mitoxantrone is a highly cytotoxic antineoplastic drug, however, its poor penetration of the blood-brain barrier has limited its role in the treatment of brain cancers. We hypothesize that intra-arterial (IA) delivery of mitoxantrone may enhance its capacity for regional brain deposition thus expanding its potential as a brain tumor therapy agent. In this study we assessed the dose-response characteristics as well as the feasibility and safety of mitoxantrone delivery to the brain and specifically to gliomas in a rodent model. We show that delivery optimization utilizing the technique of intra-arterial transient cerebral hypoperfusion (IA-TCH) facilitates achieving the highest peak- and end- brain drug concentrations as compared to intravenous and IA delivery without hypoperfusion. Additionally, we observed significant tumor-specific uptake of mitoxantrone when delivered by the IA-TCH method. No untoward effects of IA-TCH delivery of mitoxantrone were observed. The IA-TCH method is shown to be a safely tolerated and feasible strategy for delivering mitoxantrone to tumors in the glioma model tested. Additional investigation is warranted to determine if IA-TCH delivery of mitoxantrone produces clinically relevant benefit.


What is the Source of Hypnotic Responses?
The author proposes that hypnosis is a culture-bound concept that has misattributed - to suggestion and hypnosis - the functioning of a natural, freestanding, human ability to alter personal experience. The 18th-century attribution of these phenomena (to the suggestions of a magnetizer) continues today because science and Western culture still do not explicitly acknowledge that humans possess a natural capacity to intentionally alter their own experiences. Like every other human ability (e.g. athletic, artistic, musical, mathematical, etc.), utilization of the natural human ability to intentionally alter one's personal experience does not require suggestion, trance, or hypnotic induction. This ability has been studied for over 200 years under the conceptual aegis of suggestibility and hypnosis. As a consequence, the phenomena of this freestanding ability have been veiled and conflated with hypnosis, suggestion, suggestibility, and hypnotizability. One serious consequence of this conflation is an underdeveloped, nomological network of hypnosis-centric concepts that has impeded the integration of hypnosis with the rest of science.


The impact of genetic background and sex on the phenotype of IL-23 induced murine spondyloarthritis.
Overexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated. We compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8-12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA. Male B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight. The phenotype of IL-23 induced disease in mice is controlled by genetic background and sex of the animals. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests that organ-specificity of IL-23 driven inflammation is genetically determined. The mechanisms behind the strain-specific differences and the sexual dimorphism observed in this study may be relevant for human spondyloarthritis and warrant further exploration.


Understanding Consumer Experiences and Insurance Outcomes Following Plan Disenrollment in the Nongroup Insurance Market.
Disenrollment from health plans purchased on Affordable Care Act (ACA) Marketplaces is frequent; little is known whether disenrollment from off-Marketplace plans is as common or about the experiences and consequences of disenrollment. Using longitudinal administrative data on 2017-2018 nongroup plan enrollment linked with survey data, we analyze plan disenrollment in one regional insurance carrier servicing three states. Overall, 71% of enrollees disenrolled from their 2017 plan. Disenrollment was associated with purchasing through an ACA Marketplace, the carrier making significant changes to an enrollee's plan benefit design, being healthier, being younger, and paying a higher premium for their 2017 plan in 2018. Experiencing financial burden or poor access to preferred providers was not associated with disenrollment. Most disenrollees (93.2%) enrolled in other coverage, often at a lower premium, but lacked confidence that they could afford needed care. These results can inform policy to support enrollees through coverage transitions and foster stability in the nongroup market.


Increasing confidence in mass discharge estimates using geostatistical methods.
Mass discharge is one metric rapidly gaining acceptance for assessing the performance of in situ groundwater remediation systems. Multilevel sampling transects provide the data necessary to make such estimates, often using the Thiessen Polygon method. This method, however, does not provide a direct estimate of uncertainty. We introduce a geostatistical mass discharge estimation approach that involves a rigorous analysis of data spatial variability and selection of an appropriate variogram model. High-resolution interpolation was applied to create a map of measurements across a transect, and the magnitude and uncertainty of mass discharge were quantified by conditional simulation. An important benefit of the approach is quantified uncertainty of the mass discharge estimate. We tested the approach on data from two sites monitored using multilevel transects. We also used the approach to explore the effect of lower spatial monitoring resolution on the accuracy and uncertainty of mass discharge estimates. This process revealed two important findings: (1) appropriate monitoring resolution is that which yielded an estimate comparable with the full dataset value, and (2) high-resolution sampling yields a more representative spatial data structure descriptor, which can then be used via conditional simulation to make subsequent mass discharge estimates from lower resolution sampling of the same transect. The implication of the latter is that a high-resolution multilevel transect needs to be sampled only once to obtain the necessary spatial data descriptor for a contaminant plume exhibiting minor temporal variability, and thereafter less spatially intensely to reduce costs.


Menin: the protein behind the MEN1 syndrome.
The cloning of the MEN1 gene in 1997 led to the characterization of menin, the protein behind the multiple endocrine neoplasia Type 1 syndrome. Menin, a novel nuclear protein with no homology to other gene products, is expressed ubiquitously. MEN1 missense mutations are dispersed along the coding region of the gene but are more common in the most conserved regions. Likewise, domains of protein interaction often correspond to the more conserved segments of menin. These protein interactions are generally facilitated by multiple domains or encompass a large portion of menin. The exception to this rule is a small stretch of amino acids mediating the interaction of menin with the mSin3A corepressor and histone deacetylase complexes. The C-terminal region of menin harbors several nuclear localization signals that play redundant functions in the localization of menin to the nuclear compartment. The nuclear localization signals are also important for the interaction of menin with the nuclear matrix. Menin is the target of several kinases and a candidate substrate of the ATM/ATR kinases, implying a role for this tumor suppressor in the DNA damage response. Menin is highly conserved from Drosophila to human but is absent in the nematode and in yeast.


Assessing basophil functional measures during monoclonal anti-IgE therapy.
Assessing the impact of therapeutic interventions on the clinical and immunologic responses of allergic subjects is a topic of extensive investigation. Available approaches include the measurement of in vivo allergen challenge responses, serologic measures, or in vitro studies of cells that participate in the allergic reaction. Several decades of work support that measures of allergen responses of IgE-bearing peripheral blood basophils can reflect clinical expression of allergic disease. In the last decade, an immune-based therapy targeting IgE, omalizumab, has emerged as an adjunct treatment for a variety of allergic diseases. This monoclonal humanized IgG antibody specifically binds circulating IgE at a region in the Fc tail that prevents IgE attachment to high affinity IgE receptor (FcεRI) bearing cell types such as tissue mast cells and blood basophils. This review focuses on methods to monitor changes of basophil allergen reactivity with a focus on omalizumab therapy and the implications for clinical disease management.


Psychiatric adult-onset of urea cycle disorders: A case-series.
Adult onset urea cycle disorders (UCD) may present with psychiatric symptoms, occasionally as the initial presentation. We aimed to describe the characteristics of patients presenting with a psychiatric adult-onset of UCDs, to discuss which signs could suggest this diagnosis in such a situation, and to determine which tests should be conducted. A survey of psychiatric symptoms occurring in teenagers or adults with UCD was conducted in 2010 among clinicians involved in the French society for the study of inborn errors of metabolism (SFEIM). Fourteen patients from 14 to 57 years old were reported. Agitation was reported in 10 cases, perseveration in 5, delirium in 4, and disinhibition in 3 cases. Three patients had pre-existing psychiatric symptoms. All patients had neurological symptoms associated with psychiatric symptoms, such as ataxia or dysmetria, psychomotor slowing, seizures, or hallucinations. Fluctuations of consciousness and coma were reported in 9 cases. Digestive symptoms were reported in 7 cases. 9 patients had a personal history suggestive of UCD. The differential diagnoses most frequently considered were exogenous intoxication, non-convulsive status epilepticus, and meningoencephalitis. Hyperammonemia (180-600 μmol/L) was found in all patients. The outcome was severe: mechanical ventilation was required in 10 patients, 5 patients died, and only 4 patients survived without sequelae. Adult onset UCDs can present with predominant psychiatric symptoms, associated with neurological involvement. These patients, as well as patients presenting with a suspicion of intoxication, must have UCD considered and ammonia measured without delay.


Employment and weight status: The extreme case of body concern in South Korea.
For an industrialized nation, obesity rates in South Korea are extremely low. Yet, reflecting an extremely fat-averse, thin-positive society, efforts to lose weight are now reportedly very common. Since the 1980s, South Korea has experienced an increasingly flexible and insecure labor market which was exacerbated by the 1997 economic recession. In this social and economic setting, body shape and weight status, as human capital, may have gained significant bargaining power in the labor market. Consequently, we propose that Koreans, particularly those who are employed in "stable" jobs (i.e., non-manual and regular jobs), would increasingly engage in intense weight management and reduction activities even when not technically overweight or obese as a means to job security and upward mobility. Using nationally-representative data from the Korean Nutrition and Health Examination Survey (KNHANES), we identify the changing role of weight concerns versus actual body weight in predicting South Korean efforts to lose weight between 2001 (KNHANES-phase 1) and 2007-2009 (phase 4). The patterns were examined by occupation type (manual and non-manual jobs) and status (regular and non-regular jobs). Oaxaca decomposition analysis supported that people's perception of being "fat," rather than actual weight status, was crucial to explaining accelerated weight management efforts in South Korea over the decade (coef. = 0.062 and p-value < .0001 for male with regular work; coef. = 0.031 and p-value = .002 for female with regular work). Occupation status, rather than employment in itself, mattered. Job stability predicted increased effort; the pattern of change through time suggests efforts to invest high levels of effort in appearance positively impacts both employment opportunity and stability.


Transglutaminase activity in the eye: cross-linking in epithelia and connective tissue structures.
To assess the distribution of transglutaminase (TGase) activity in ocular tissues and the target structures for cross-linking. Cryosections from human and cynomolgus monkey eyes were incubated with the biotinylated amine donor substrate cadaverine (biotC), which was subsequently visualized with streptavidin-peroxidase. Confocal laser scanning was used to colocalize biotC and fibrillin, a major component of elastic microfibrils and the zonular fibers in particular. Cryosections and isolated bovine zonules were treated with purified TGase 2 and biotC. The distribution of different TGases (1, 2, 3, and factor XIII) was confirmed immunohistochemically. Virtually all ocular tissues showed TGase activity with a remarkable preponderance for the ciliary body, zonular fibers, and blood vessel walls. Confocal laser scanning revealed fibrillin-containing microfibrils as a major target for TGase activity, in particular the ciliary zonules. Corneal epithelium and basement membrane showed a TGase cross-linking pattern similar to skin. Treatment of cryosections and isolated bovine zonular fibers with purified TGase 2 led to additional incorporation of biotC into extracellular matrix, particularly zonular fibers. The immunohistochemically predominant TGase 2 was associated with epithelia and particularly with connective tissue fibers. TGase 1 was restricted to the corneal epithelium, whereas factor XIII was found to be associated only with blood vessels. TGase 3 was absent. TGase 2 appears to be an important cross-linker and thus stabilizer of ocular connective tissue. In particular, the zonular fibers are a major target for TGase 2. This is of relevance in hereditary microfibrillopathies such as Marfan syndrome, which exhibits distinct ocular manifestations such as elongated bulbus, retinal detachment, and subluxation of the lens. Purified or recombinant TGase might be of therapeutic use in the future.


Concentrations of dioxins and dioxin-like PCBs in feed materials in the Netherlands, 2001-11.
This study aimed to obtain insights into contamination of feed materials used in the Netherlands with dioxins (polychlorinated dibenzo-p-dioxins and dibenzofurans) and dioxin-like polychlorinated biphenyls (PCBs). Monitoring results from the period 2001-11, covering in total 4938 samples, were statistically analysed and evaluated against the statutory limits set at the beginning or during this period. The percentage of samples exceeding maximum levels set within the European Union for either dioxins or the sum of dioxins and dioxin-like PCBs were below 1% for most feed categories, except for fish meal (4.1%), clay minerals (binders and anti-caking agents) (3.4%), and vegetable oils and byproducts (1.7%). For most feed categories, non-compliance with the action threshold (roughly 33% lower than maximum levels) for either dioxins or dioxin-like PCBs was up to three times higher than non-compliance with the respective maximum levels. Exceedance of action thresholds was just above 1% for animal fat, pre-mixtures and feed materials of plant origin excluding vegetable oils. For the categories fish meal, clay minerals, and vegetable oils and byproducts, the action thresholds were exceeded by 5.0%, 9.8% and 3.0% of the samples, respectively. In general, the percentages of samples that exceeded the action thresholds and maximum levels were lower than those reported for the European Union by the European Food Safety Authority (EFSA). In most of the feed materials, there seems to be a decreasing trend in concentrations of dioxins or dioxin-like PCBs over the years. However, a lowering of the limits of quantification during this period and the low concentrations in most samples precludes drawing strong conclusions.


Synthesis and secretion of gamma-globulin by lymph node cells, VIII. Order of synthesis of the interchain disulfide linkages of immunoglobulins.
Murine myeloma cells (ADJ-PC-5), incubated in vitro with (3)H-leucine, secrete (3)H-immunoglobulin G as a single molecular species as judged by the migration characteristics of the labeled product on sodium dodecyl sulfateacrylamide gel electrophoresis. However, the fact that some of the interchain disulfide linkages of intracellular immunoglobulins had not been acquired permitted the identification of the following intracellular species: LHHL (identical to immunoglobulin G), HHL, HH, and L (H and L refer to heavy and light polypeptide chains, respectively). Although HH and HHL were readily observed, radioactivity was not detected in the region of the gel where HL would be expected. The time course for the appearance of the intermediates indicates that in these cells the first interchain disulfide bond to be formed occurs between heavy chains. In contrast, the interchain disulfide bonds of immunoglobulins derived from rabbit lymph node cells were acquired in a different order. The principal intracellular species observed were LHHL and HL, whereas HHL and HH were not detectable. These findings indicate that in this species the first interchain disulfide bond to be formed is that between the heavy and light chains of immunoglobulin G.


Fast and slow nerve growth factor binding sites in human neuroblastoma and rat pheochromocytoma cell lines: relationship of sites to each other and to neurite formation.
We studied (a) the distribution and properties of fast and slow 125I-nerve growth factor (125I-NGF) binding sites in cultured human neuroblastoma (NB) cell lines that were categorized as responsive (N+) or unresponsive (N-) to NGF by neurite outgrowth, (b) whether fast or slow sites mediate actions of NGF, and (c) whether NGF-mediated conversion of fast to slow sites occurs in human NB and pheochromocytoma PC 12 cells. In human NB SH-SY5Y cells, the slow sites were trypsin resistant and binding was of high affinity. Loss of binding to the slow sites had a half-time of 25 to 30 min at 37 degrees C and was very slow at 4 degrees C. In contrast, the fast sites were trypsin sensitive and binding was of lower affinity; its dissociation half-time was less than 1 min at 4 degrees C and 37 degrees C. The association rate constants of both sites were about 0.8 to 1.2 X 10(7) M-1 sec-1. Some human NB cells had both fast and slow sites. The N+ human NB lines SH-SY5Y and LA-N-5 had only slow sites. Despite the virtual elimination of fast sites by trypsin in NB MC-IXC cells, remaining slow sites could still efficiently bind 125I-NGF. These observations showed that fast sites are not required for slow site binding, neurite outgrowth, or other demonstrated actions of NGF in some NB cells. In PC 12 cells, 125I-NGF initially bound to fast sites was not directly transferred to slow sites as required for NGF-mediated conversion. The association rate constants of fast and slow sites in PC12 cells were both about 2 X 10(7) M-1 sec-1. The association kinetics were consistent with simple bimolecular reactions in both NB and PC12 cells. The combined evidence in NB and PC12 cells did not support the hypothesis of NGF-mediated conversion of fast to slow sites.


The N-terminal peptide of the transglutaminase-activating metalloprotease inhibitor from Streptomyces mobaraensis accommodates both inhibition and glutamine cross-linking sites.
Streptomyces mobaraensis is a key player for the industrial production of the protein cross-linking enzyme microbial transglutaminase (MTG). Extra-cellular activation of MTG by the transglutaminase-activating metalloprotease (TAMP) is regulated by the TAMP inhibitory protein SSTI that belongs to the large Streptomyces subtilisin inhibitor (SSI) family. Despite decades of SSI research, the binding site for metalloproteases such as TAMP remained elusive in most of the SSI proteins. Moreover, SSTI is a MTG substrate, and the preferred glutamine residues for SSTI cross-linking are not determined. To address both issues, that is, determination of the TAMP and the MTG glutamine binding sites, SSTI was modified by distinct point mutations as well as elongation or truncation of the N-terminal peptide by six and three residues respectively. Structural integrity of the mutants was verified by the determination of protein melting points and supported by unimpaired subtilisin inhibitory activity. While exchange of single amino acids could not disrupt decisively the SSTI TAMP interaction, the N-terminally shortened variants clearly indicated the highly conserved Leu40-Tyr41 as binding motif for TAMP. Moreover, enzymatic biotinylation revealed that an adjacent glutamine pair, upstream from Leu40-Tyr41 in the SSTI precursor protein, is the preferred binding site of MTG. This extension peptide disturbs the interaction with TAMP. The structure of SSTI was furthermore determined by X-ray crystallography. While no structural data could be obtained for the N-terminal peptide due to flexibility, the core structure starting from Tyr41 could be determined and analysed, which superposes well with SSI-family proteins. ENZYMES: Chymotrypsin, EC220.127.116.11; griselysin (SGMPII, SgmA), EC18.104.22.168; snapalysin (ScNP), EC22.214.171.124; streptogrisin-A (SGPA), EC22.214.171.124; streptogrisin-B (SGPB), EC18.104.22.168; subtilisin BPN', EC188.8.131.52; transglutaminase, EC220.127.116.11; transglutaminase-activating metalloprotease (TAMP), EC3.4.-.-; tri-/tetrapeptidyl aminopeptidase, EC3.4.11.-; trypsin, EC126.96.36.199. DATABASES: The atomic coordinates and structure factors (PDB 6I0I) have been deposited in the Protein Data Bank (http://www.rcsb.org).


Quantifying climatic and socioeconomic drivers of urban malaria in Surat, India: a statistical spatiotemporal modelling study.
Cities are becoming increasingly important habitats for mosquito vectors of disease. The pronounced heterogeneity of urban landscapes challenges our understanding of the effects of climate and socioeconomic factors on mosquito-borne disease dynamics at different spatiotemporal scales. Here, we quantify the impact of climatic and socioeconomic factors on urban malaria risk, using an extensive dataset in both space and time for reported Plasmodium falciparum cases in the city of Surat, northwest India. We analysed 10 years of monthly P falciparum cases resolved at three nested spatial resolutions (seven zones, 32 units, and 478 worker units) with a Bayesian hierarchical mixed model that incorporates the effects of population density, poverty, relative humidity, and temperature, in addition to random effects (structured and unstructured). To reduce dimensionality and avoid correlation of covariates, socioeconomic variables from survey data were summarised into main axes of variation using principal component analysis. With model selection, we identified the main drivers of spatiotemporal variation in malaria incidence rates at each of the three spatial resolutions. We also compared observations to model-fitted cases by quantifying the percentage of predictions within five discrete levels of malaria risk. The spatial variation of urban malaria cases was stationary over time, whereby locations with high and low yearly cases remained largely consistent across years. Local socioeconomic variation could be summarised with three principal components accounting for approximately 80% of the variance. The model that incorporated local temperature and relative humidity together with two of these principal components, largely representing population density and poverty, best explained monthly malaria patterns in models formulated at the three different spatial scales. As model resolution increased, the effect size of humidity decreased, whereas those of temperature and the principal component associated with population density increased. Model predictions accurately captured aggregated total monthly cases for the city; in space-time, they more closely matched observations at the intermediate scale, with around 57% of units estimated to fall in the observed category on average across years. The mean absolute error was lower at the intermediate level, showing that this is the best aggregation level to predict the space-time dynamics of malaria incidence rates across the city with the selected model. This statistical modelling framework provides a basis for development of a climate-driven early warning system for urban malaria for the units of Surat, including spatially explicit prediction of malaria risk several weeks to months in advance. Results indicate environmental and socioeconomic covariates for which further measurement at high resolution should lead to model improvement. Advanced warning combined with local surveillance and knowledge of disease hotspots within the city could inform targeted intervention as part of urban malaria elimination efforts. US National Institutes of Health.


[The present state and the future perspective of immunotherapy of renal cell carcinoma].
In extremely rare cases, the metastatic lesions of renal cell carcinoma (RCC) spontaneously regress after removal of the primary disease, and thus RCC has been considered to be immunogenic. Thus far, several immunotherapies including cytokine therapy, peptide vaccine and recent immune checkpoints inhibitors have been employed to treat patients with metastatic RCC. In this review, the recent progress in immunotherapy against RCC is surveyed and its future perspective is discussed. Our experimental research on galectin 9 and PINCH as promising immunotherapy targets is also mentioned.


Versatile family of modular aurora and airglow photometers.
A photometer system has been designed that incorporates the concepts of modularity and fully digitized control and data recording electronics. Modularity allows field substitution of background subtraction techniques, filter choice, and choice of input optical configuration. Novel features include a trichroic filtering module that allows simultaneous monitoring of auroral or airglow emission intensities in three spectral regions with the same field of view and input optics. Also described is a novel three-beam adaptation that allows monitoring of the emission intensity from three closely spaced regions in the upper atmosphere in the same spectral region. The digital counting and control electronics described are compatible with NIMBIN plug-in modules and allow expansion of the system to many photon-counting channels as well as ready interfacing with other data sources.


Photocatalytic activity and charge carrier dynamics of TiO2 powders with a binary particle size distribution.
The effects of the particle size distribution on the charge carrier dynamics and the photocatalytic activity of mixed titanium dioxide (TiO2) powder samples were investigated in this work. Instead of the synthesis of the small semiconductor particles, the binary particle size distributions of the powders were obtained by mixing commercially available TiO2 powders with different particle sizes. The pure anatase samples (average diameters: 7, 20, and 125 nm, respectively) were created via ultrasound treatment and discreet drying. The photocatalytic activity of the powder samples was assessed by the degradation of nitric oxide (NO) and acetaldehyde in the gas phase. Furthermore, the charge carrier kinetics was determined using transient absorption spectroscopy following pulsed laser excitation. Importantly, a recently published model based on fractal dimensions was used to fit the transient signals of the photo generated charge carriers in the TiO2 powder samples. The effects of the particle size on the acetaldehyde degradation could be explained by the formation of agglomerates, which reduce the available surface area of smaller particles. The fast oxidation of acetaldehyde on the surface of TiO2 by direct hole transfer was further independent of the observed charge carrier lifetimes on the microsecond time scale. The photocatalytic NO degradation, on the other hand, increased for samples containing larger amounts of small particles. The corresponding photonic efficiencies correlated well with the charge carrier lifetimes determined by the time-resolved studies. Hence, it was concluded that a long charge carrier lifetime generally leads to higher fractional conversions of NO. The employed fractal fit function was proved to be beneficial for the kinetic analysis of charge carrier recombination in TiO2, in direct comparison with a second order fit function.


Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors.
To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of the 24-h continuous intravenous (CIV) infusion of MK-0457, a novel pan-Aurora kinase inhibitor, in patients with advanced solid tumors and to determine the bioavailability of an oral dose of 100 mg MK-0457. MK-0457 was administered as a 24-h CIV infusion every 21 days. Dose escalation proceeded per toxicity criteria. A 100-mg oral dose was administered to seven patients 48 h prior to the CIV infusion dose of 64 mg/m(2)/h. Twenty-seven patients received a total of 86 infusions of MK-0457. Dose-limiting toxicity at 96 mg/m(2)/h included grade 4 neutropenia and grade 3 herpes zoster. The MTD was identified as 64 mg/m(2)/h. The most common adverse events were nausea, vomiting, diarrhea, and fatigue. Pharmacokinetic analyses revealed that CIV infusion MK-0457 had an estimated mean terminal half-life of approximately 6.6-10.2 h and that end-of-infusion concentrations and mean AUCs were approximately dose proportional. The estimated mean oral bioavailability of MK-0457 was 7.9%. One patient with advanced ovarian cancer attained prolonged stable disease for 11 months. MK-0457 was well tolerated in this schedule. Almost half the patients attained stable disease. Further development of this class of agents will likely occur in combination with other anti-cancer treatments.


In Situ Characterization for Boosting Electrocatalytic Carbon Dioxide Reduction.
The electrocatalytic reduction of carbon dioxide into organic fuels and feedstocks is a fascinating method to implement the sustainable carbon cycle. Thus, a rational design of advanced electrocatalysts and a deep understanding of reaction mechanisms are crucial for the complex reactions of carbon dioxide reduction with multiple electron transfer. In situ and operando techniques with real-time monitoring are important to obtain deep insight into the electrocatalytic reaction to reveal the dynamic evolution of electrocatalysts' structure and composition under experimental conditions. In this paper, the reaction pathways for the CO2 reduction reaction (CO2 RR) in the generation of various products (e.g., C1 and C2 ) via the proposed mechanisms are introduced. Moreover, recent advances in the development and applications of in situ and operando characterization techniques, from the basic working principles and in situ cell structure to detailed applications are discussed. Suggestions and future directions of in situ/operando analysis are also addressed.


Radium isotopes in Estonian groundwater: measurements, analytical correlations, population dose and a proposal for a monitoring strategy.
In some areas of Estonia, groundwater contains a significant number of natural radionuclides, especially radium isotopes, which may cause radiation protection concern depending on the geological structure of the aquifer. Indeed, the parametric value of 0.1 mSv y⁻¹ for the total indicative dose established by European Directive 98/83/EC, adopted as a limit value in Estonian national legislation, is often exceeded. A Twinning Project between Estonia and Italy was carried out within the framework of the Estonian Transition Facility Programme, sponsored by the European Union. Its aims were to assess the radiological situation of Estonian groundwater and related health consequences. The first step was a study of Estonian aqueducts and the population served by them, and a thorough analysis of the radiological database for drinking water, from which the relevant effective doses for the population were obtained. Particular attention was devoted to doses to children and infants. Correlations between the chemical parameters were investigated, in order to suggest the best possible analytical approach. Lastly, a monitoring strategy, i.e. sampling points and sampling frequencies, was proposed.


Proteomic characterization of novel alternative splice variant proteins in human epidermal growth factor receptor 2/neu-induced breast cancers.
Multifaceted alternative splicing in cancer cells greatly diversifies protein structure independently of genome changes, but the characterization of cancer-associated splice variants is quite limited. In this study, we used mass spectrometric data to interrogate a custom-built database created with three-frame translations of mRNA sequences from Ensembl and ECgene to find alternative splice variant proteins. In mass spectrometric files from liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses of normal mouse mammary glands or mammary tumors derived from conditional human epidermal growth factor receptor 2 (Her2)/neu transgenic mice, we identified a total of 608 alternative splice variants, of which peptides from 216 proteins were found only in the tumor sample. Among the 608 splice variants were 68 novel proteins that were not completely matched to any known protein sequence in mice, for which we found known functional motifs. Biological process enrichment analysis of the splice variants identified suggested the involvement of these proteins especially in cell motility and translation initiation. The cancer-associated differentially expressed splice variant proteins offer novel biomarker candidates that may function in breast cancer progression or metastasis.