Understanding the Mechanisms of Gold Shell Growth onto Polymer Microcapsules to Control Shell Thickness.
Polymer microcapsules have been used commercially for decades, however they have an inherent flaw which renders them impractical as a carrier of small, volatile molecules. The porous nature of the polymer shell allows for diffusion of the encapsulated molecules into the bulk. The use of metal shells is an innovative way to prevent undesired loss of small molecules from the core of microcapsules, however it is important, particularly when using expensive metals to ensure that the resulting shell is as thin as possible. Here we investigate the fundamental mechanisms controlling the gold shell thickness when a fragrance oil is encapsulated in a poly(methyl methacrylate) shell. We consider the distribution of the nanoparticles on the capsule surface, and from quantification of the adsorbed nanoparticle (NP) density and resulting shell thickness, we propose mechanisms to describe the gold shell growth for systems with high and low NP surface coverage. We suggest from our observations that the gold grows to fill in the gaps between NPs. At low NP concentrations, thicker metal shells form. We postulate that this is due to the low NP density on the surface, forcing the gold clusters to grow larger before they meet the adjacent ones. Thus, to grow the thinnest possible shells a densely packed monolayer of platinum nanoparticles is required on the capsule surface.


Improving pharmacist-patient communications based on King's theory of goal attainment: Study protocol for a cluster randomized controlled trial.
Previous studies revealed widespread poor communications between pharmacists and patients in various settings. But little is known about how pharmacists communicate with patients and its impact on patient outcomes. King's theory of goal attainment (TGA) describes the dynamic interpersonal interactions in which a patient develops and attains certain goals. This study aims to: (i) test the TGA model in the interface between pharmacists and patients; and (ii) evaluate the effects of TGA-guided interventions. The study will be conducted in 30 community pharmacies recruited from three cities in China's Hubei province. It will start with a baseline cross-sectional survey on 640 patients to test the hypothesized TGA model in community pharmacies. An intervention program will then be developed based on the TGA model and will be evaluated in a matched-pair cluster randomized trial. The participating pharmacies will be pair-matched and randomly allocated to an intervention group and a control group. Pharmacists in the intervention group will receive three sessions of training in line with the TGA model over one year, compared with a pharmaceutical training program in the control group without a communication component. A double-blind procedure will apply. Changes in patient experience in communications and pharmaceutical care will be analyzed. Ethics and dissemination: The study was approved by the Research Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (IORG: IORG 0003571). ChiCTR1800014679.


Combined TRAM flap with latissimus dorsi myocutaneous flap for reconstruction of a large breast post-radiation induced necrosis.
Radiation therapy is a critical component of breast cancer management following breast-conserving surgery. Post-radiation sequelae are greater in women with larger breasts, given the need for higher doses and dosing heterogeneity. The goal of breast reconstruction post-mastectomy is to improve the quality of life and add no more health risk. The optimal reconstruction should make the patient feel as natural as possible. Reconstruction of a large-sized breast with aesthetically satisfactory outcome poses a challenge to the breast surgeon. The breast of most Egyptian women is of a large volume with variable degrees of ptosis, thus it is difficult to reconstruct such a large-ptotic breast using an implant. We describe the successful reconstruction of a large-sized breast after radiation-induced necrosis using a combined transverse myocutaneous rectus abdominis flap and latissimus dorsi myocutaneous flap reconstruction. The combined use of both flaps offered a more natural breast reconstruction and avoided the use of any implants.


Efficacy of four preventive measures against enamel demineralization at the bracket periphery-comparison of microhardness and confocal laser microscopy analysis.
The aim of this in-vitro study was to investigate the efficacy of four preventive measures against enamel demineralization and to compare the suitability of microhardness (MH) measurements and confocal laser microscopy (CLSM). A total of 80 teeth were randomly allocated into four groups. The effect against demineralization of two coating materials (group 1: resin-modified glass ionomer (RMGI) cement varnish (ClinproXT); group 2: composite sealant (ProSeal)) and that of two types of bracket-bonding material (group 3: amorphous calcium phosphate (ACP) composite (AegisOrtho); group 4: RMGI (FujiOrthoLC)) was compared after pH-cycling by MH and CLSM. Measurements were made at the edge of the coating/bracket as well as at 50, 100, 200, and 400 μm distance. The data were converted into values of mineralization (Vol%) and analyzed by parametric (ANOVA and Tukey's post hoc) or non-parametric (Kruskal-Wallis and Games-Howell post hoc) tests. ClinproXT and ProSeal were proved to protect the bracket periphery. However, the area next to them showed demineralizations. The mean area of lesion (CLSM-data) was significantly different between the groups (p < 0.0001). The smallest lesions were revealed for the RMGI-based materials. MH identified only for group 4 a significant difference between the area next to the bracket base and that at 200 and 400 µm distance. There was nearly no lesion under both coatings. A stagnation of demineralization was identified particularly for the RMGI. ProSeal showed an inferior protection of the untreated enamel. MH and CLSM analysis were suitable to detect subsurface lesions. A diverse efficacy of materials against enamel demineralization at bracket periphery has to be noticed.


Learning to construct sentences in Spanish: a replication of the Weird Word Order technique.
In the present study, children's early ability to organise words into sentences was investigated using the Weird Word Order procedure with Spanish-speaking children. Spanish is a language that allows for more flexibility in the positions of subjects and objects, with respect to verbs, than other previously studied languages (English, French, and Japanese). As in prior studies (Abbot-Smith et al., 2001; Chang et al., 2009; Franck et al., 2011; Matthews et al., 2005, 2007), we manipulated the relative frequency of verbs in training sessions with two age groups (three- and four-year-old children). Results supported earlier findings with regard to frequency: children produced atypical word orders significantly more often with infrequent verbs than with frequent verbs. The findings from the present study support probabilistic learning models which allow higher levels of flexibility and, in turn, oppose hypotheses that defend early access to advanced grammatical knowledge.


Identification of chicken intestinal microbiota correlated with the efficiency of energy extraction from feed.
The microbiota of the gastrointestinal tract is a complex community of many different species of microorganisms, dominated by bacteria. This diverse population provides the host with an extensive array of enzymes and substrates which, together with the host's metabolic capabilities, provides an extensive metabolome available for nutrient and energy collection. We investigated broiler chickens to determine whether the abundance of certain members of the microbiota was correlated with the relative ability to extract energy from a typical wheat soybean diet. A number of mostly uncultured phylotypes were identified that significantly differed in abundance between birds with high apparent metabolizable energy (AME), measured as the difference between energy consumed and energy excreted, and those with low AME. Among the phylotypes that were more prevalent in birds with high energy efficiency, most were closely associated with isolates of bacterial groups that are commonly recognized as producing enzymes that degrade cellulose and/or resistant starch. Phylotypes that were negatively correlated with performance were all unknown and uncultured, a significant number belonging to an unknown class of Firmicutes. The identification of bacterial phylotypes correlated with the efficiency of energy use opens up the possibility of harnessing these bacteria for the manipulation of the host's ability to utilize energy. Increasing the ability to convert food to body weight is of interest to the agricultural industries, while the opposite is applicable in weight management and obesity control in humans.


Development and validation of a spectrofluorimetric method for the quantification of ceftriaxone in pharmaceutical formulations and plasma.
We describe the development and validation of a new, simple, sensitive and cost-effective method for the determination of ceftriaxone in commercial formulations and spiked human plasma. The method proposes the conversion of ceftriaxone into a fluorescent product by reacting with ortho-phthalaldehyde (OPA) in the presence of sulfite at room temperature. The reaction medium is buffered to pH 10 using borate buffer. The derivatized reaction product is highly fluorescent and exhibits maximum fluorescence intensity at λ(em) = 386 nm after excitation at λ(ex) = 324 nm. The experimental parameters affecting progress of the derivatization reaction were carefully studied and optimized. Under optimum experimental conditions, the method has an excellent correlation coefficient of 0.9984 with a broad linear range of 0.4-20 µg/mL. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 1.30 × 10(-3) and 3.90 × 10(-3) µg/mL, respectively. The interference effects of common excipients on the quantification of drug were investigated and no interference effect was observed. The proposed method has been successfully applied to the determination of ceftriaxone in pharmaceutical formulations and spiked human plasma samples. The method has been validated statistically through percent recovery studies using standard addition and by comparison with a reference HPLC method. The developed method exhibits excellent inter- and intraday precision.


Modeling and acquisition of drug-drug interaction knowledge.
The effectiveness of computerized clinical decision support systems (CDSS) depends on the quality of the knowledge they refer to. In this article, we are interested in the acquisition, modeling and representation of the knowledge embedded in the "national reference framework of drug-drug interaction" published by the French Health Products Safety Agency. A model of drug-drug interactions has been designed using bottom-up and top-down approaches. This model is the basis for the design of an XML format to represent and extract information on drug interactions from the reference framework. A specific tool has been developed to extract the information from a corpus of 1053 drug monographs using a methodology similar to the one used by the GEM-Cutter tool to extract information from clinical guidelines. Strategies to integrate the XML files produced into CDDSSs are discussed. Modeling and acquisition of drug-drug interaction knowledge from a corpus of drug monographs is a potential approach to foster the development of CDSS and improve their specificity.


Validation of a probabilistic model of dietary exposure to selected pesticides in Dutch infants.
A probabilistic model for dietary exposure to pesticides was validated. For this, we evaluated the agreement of dietary exposure to six pesticides as estimated with the model with exposures measured in duplicate diet samples (='real intake') and those calculated with the point estimate. To calculate the exposure with the model and point estimate, consumption data of the duplicate diet survey and pesticide residue measurements from Dutch monitoring programmes in 2000 and 2001 were used. The model was considered validated when the outcome was both higher than the real intake and lower than the point estimate. Results showed that exposures estimated with the model were closer to the real intake than those of the point estimate, and that the model outcome was lower than the point estimate. Furthermore, it was shown that the probabilistic approach can address the exposure to a pesticide via the consumption of different food products, while the point estimate only estimates the exposure through the consumption of one product. The model validated is a valuable asset when estimating the dietary exposure to pesticides in both the authorization of new pesticides and the evaluation of exposures using monitoring data.


In the early phase of programmed cell death in Tobacco Bright Yellow 2 cells the mitochondrial adenine nucleotide translocator, adenylate kinase and nucleoside diphosphate kinase are impaired in a reactive oxygen species-dependent manner.
To investigate whether and how mitochondria can change in plant programmed cell death (PCD), we used the non-photosynthetic Tobacco Bright Yellow 2 (TBY-2) cells. These can be synchronized to high levels, stand out in terms of growth rate and homogeneity and undergo PCD as a result of heat shock. Using these cells we investigated the activity of certain mitochondrial proteins that have a role in providing ATP and/or other nucleoside triphosphates (NTPs). We show that, already after 2 h from the heat shock, when cell viability remains unaffected, the rate of ADP/ATP exchange due to adenine nucleotide translocator (ANT) activity, and the rate of the reactions catalysed by adenylate kinase (ADK; EC 184.108.40.206) and nucleoside diphosphate kinase (NDPK; EC 126.96.36.199) are inhibited in a non-competitive-like manner. In all cases, externally added ascorbate partially prevented the inhibition. These effects occurred in spite of minor (for ANT) or no changes in the mitochondrial protein levels as immunologically investigated. Interestingly, a decrease of both the steady state level of the ascorbate pool and of the activity of l-galactono-gamma-lactone dehydrogenase (GLDH) (EC 126.96.36.199), the mitochondrial enzyme catalysing the last step of ascorbate biosynthesis, were also found.


Transition from Birth to Ten to Birth to Twenty: the South African cohort reaches 13 years of age.
Birth to Ten now Birth to Twenty (BT20), is the largest and longest running longitudinal birth cohort study in Africa. In this paper, the methods, magnitude and significance of recruitment, follow-up and attrition are described. Although more than 5000 births were notified in the area in the 7-week enrollment period in early 1990, only 3275 children were established to have been born to women who were residents in the Greater Johannesburg Metropolitan area for at least the first 6 months of the child's life. Seventy per cent of these children and their families have been followed up for more than 12 years, indicating an average attrition rate of less than 3% per annum, with most attrition occurring in the first 2 years of the study. The most common reason for attrition was movement out of the study area, although detailed follow-up, and the extent of contact re-established at later points, indicate very high levels of circular migration among women and young children between urban and rural areas, as well as very high levels of residential mobility within urban areas. There has been no differential loss of vulnerable families and children. African women living in Soweto are the most consistent participants in the study. A bias, by population group membership and residential area, was introduced in the recruitment phases of the project by the difficulty of enrolling the small proportion of people in the metropolis, largely Whites, who used private delivery services in 1989-90.


[Low pressure trocar resection versus Iglesias suction resection].
Trocar resection is superior to Iglesias' backwash resection. The main criteria on which this assessment is based are the larger operative specimen obtained, the shorter duration of the operation, and the much smaller intraoperative infiltration volume. This last was determined using a glycine irrigation solution, by measuring the increase in glycine in the serum by means of column chromatography. This showed that the intravesical irrigation pressure determines the absorption volume after opening of the venous sinus, while the duration of the resection and the volume of irrigation solution employed perioperatively are of less importance. In the case of alcohol-based irrigation solutions these results can be confirmed by measuring the "standby" alcohol in the respiratory air.


A 51-item calcium-focused food frequency questionnaire is a reliable tool to assess dietary calcium intake in postmenopausal women.
Given the lack in a valid biomarker to assess dietary calcium intake (dCai), reproducible estimation of usual dCai is crucial for better understanding of its interaction with health outcomes in specific populations. This study tested the hypothesis that a calcium-focused food frequency questionnaire (FFQ) may be used to estimate dCai of women ≥50 years residing in a multicultural environment (Montreal, Canada). One hundred and eight women (age, 63.1±7.7 years; 98% postmenopausal) completed the FFQ twice and 4 nonconsecutive 24-hour recalls (24HRs) over 1 month. Medians of dCai were compared by Wilcoxon signed rank test. Reproducibility and relative validity of the FFQ were assessed by Spearman correlation (rs) and Cohen's weighted kappa (κw). Agreement was further assessed by cross-classification by quartiles, Bland-Altman plot, and sensitivity and specificity analyses. The median (interquartile range) dCai estimated by the FFQ and 24HRs were 723 (524-1033) mg/d and 854 (666-1068) mg/d, respectively (P<.001). The FFQs had a strong correlation (rs=0.72, P<.001) and moderate agreement (κw=0.55). The FFQ and 24HRs were moderately correlated (rs=0.65, P<.001). Cross-classification showed moderate agreement (κw=0.42), with 85% of the participants classified into identical or contiguous quartiles and 2.8% into extreme opposite quartiles. According to the Bland-Altman plot, the FFQ underestimated dCai with a bias of 99 mg/d (95% limits of agreement, -677 to +480 mg/d). Sensitivity and specificity of identifying intakes <1000 mg/d were 90% and 57%, respectively. This FFQ is a useful tool to discriminate dCai <600 and ≥1000 mg/d in postmenopausal women and to rank dCai in epidemiological studies.


Interaction of 16 alpha-[125I]iodo-estradiol with estrogen receptor and other steroid-binding proteins.
This communication describes the synthesis of 16 alpha-[125I]iodo-estradiol (125I-E2) with specific activities greater than 1000 Ci/mmol (1 Ci = 3.7 x 10(10) becquerels). We show that it binds to the same specific estrogen receptor sites as does [3H]estradiol and that it does so with an affinity that is indistinguishable from that for the latter steroid. This is true for receptor obtained from calf uterus and from a pool of human mammary carcinomas. There is no significant binding of 125 I-E2 to the testosterone-estradiol-binding globulin of human plasma. 125I-E2 also binds tightly to anti-estradiol antibodies raised against estradiol derivatized at carbons 3, 6, and 17. Finally, we show that unlabeled I-E2 is an active estrogen in vivo as demonstrated by its ability to increase uterine weight in ovariectomized rats.


Clinical spectrum of chronic rheumatic heart disease in India.
The study aim was to determine prevalence and patterns of chronic rheumatic heart disease (RHD) in developing countries, where it remains a major cause of mortality and morbidity. The incidence of different valvular lesions and complications in chronic RHD were analyzed. The study design was a retrospective case series analysis in the setting of a tertiary care institution in southern India. Participants were consecutive patients registered under 'chronic RHD' in the cardiology department of the authors' institution over the past 20 years. Data are presented for 10,000 cases in two age groups: group I, aged < or = 18 years (n = 2,910); and group II, aged > 18 years (n = 7,090). Mitral regurgitation was the single most common lesion (n = 1,007) in group I, while the dominant lesion in group II was mitral stenosis (n = 2,943). Isolated aortic valve disease was seen in 130 (4.5%) and 195 (2.8%) cases in groups I and II, respectively. Tricuspid stenosis was seen in 45 cases, and rheumatic involvement of all four cardiac valves was documented in four cases. Pulmonary hypertension was present in 42.4% and 80.8% in groups I and II, respectively, and functional tricuspid regurgitation in 38.9% and 77.2%, respectively. Overall, 5.9% of patients had atrial fibrillation, 0.9% had left atrial thrombus (seen on transthoracic echocardiography) and 0.4% had embolic cerebrovascular events. Pericardial effusion was present in 0.7% cases, and infective endocarditis was noted at presentation in 0.6%. Chronic RHD in developing countries is associated with major complications and high mortality. The critical evaluation of individual lesions must be combined with frequent overall clinical evaluation in order to time appropriate medical and surgical interventions.


Mechanism of transcriptional activation by the proto-oncogene Twist1.
Mammalian Twist1, a master regulator in development and a key factor in tumorigenesis, is known to repress transcription by several mechanisms and is therefore considered to mediate its function mainly through inhibition. A role of Twist1 as transactivator has also been reported but, so far, without providing a mechanism for such an activity. Here we show that heterodimeric complexes of Twist1 and E12 mediate E-box-dependent transcriptional activation. We identify a novel Twist1 transactivation domain that coactivates together with the less potent E12 transactivation domain. We found three specific residues in the highly conserved WR domain to be essential for the transactivating function of murine Twist1 and suggest an alpha-helical structure of the transactivation domain.


Gun carrying by high school students in Boston, MA: does overestimation of peer gun carrying matter?
This paper investigates: (1) whether high school students overestimate gun carrying by their peers, and (2) whether those students who overestimate peer gun carrying are more likely to carry firearms. Data come from a randomly sampled survey conducted in 2008 of over 1,700 high school students in Boston, MA. Over 5% of students reported carrying a gun, 9% of boys and 2% of girls. Students substantially overestimated the percentage of their peers who carried guns; the likelihood that a respondent carried a gun was strongly associated with their perception of the level of peer gun carrying. Most respondents believed it was easier for other youth to obtain guns than it was for them. Social marketing campaigns designed to lower young people's perceptions about the prevalence of peer gun carrying may be a promising strategy for reducing actual gun carrying among youth.


[Importance of anesthetic management for the patients with systolic anterior motion after mitral valve plasty].
Systolic anterior motion (SAM) after mitral valve plasty (MVP) occurs at an incidence of 1 to 4%. The management is related to this condition. Three patients developed SAM just after MVP. In the first patient, a 51-year-old man, volume loading and methoxamine were employed, which elevated arterial pressure, but led to a severer catastrophe. This suggested the indication of mitral valve replacement to the surgeons. The second patient, a 75-year-old woman, underwent re-annuloplasty after the first MVP because of incomplete correction. Before the separation from the second CPB, continuous dopamine infusion was started because we feared that the long CPB time would have impaired LV function. The TEE showed the catastrophe, but it disappeared just after the discontinuation of the dopamine infusion and the administration of propranolol and norepinephrine. The last patient was a 72-year-old woman. For the catastrophe, propranolol was given and an immediate improvement followed with TEE showing no evidence of the catastrophe. The goal for anesthetic management of the catastrophe after MVP is to decrease the hyperdynamic ventricular contraction. We managed SAM by volume loading and discontinuation of beta-stimulants and/or administration of beta-blockers.


Effects of habitat on individual reproductive success of mature male parr of Atlantic salmon Salmo salar.
The effect of the presence of stone blocks in the spawning habitat on the reproductive success of mature male parr of Atlantic salmon Salmo salar of various sizes and ages was tested in an artificial channel. Shelters allowed smaller individuals to contribute to egg fertilization as much as large parr, suggesting that the size-based dominance observed in a shelterless habitat was not maintained in a more complex habitat.


Testing the performance of secondary anvils shaped with focused ion beam from the single-crystal diamond for use in double-stage diamond anvil cells.
The success of high-pressure research relies on the inventive design of pressure-generating instruments and materials used for their construction. In this study, the anvils of conical frustum or disk shapes with flat or modified culet profiles (toroidal or beveled) were prepared by milling an Ia-type diamond plate made of a (100)-oriented single crystal using the focused ion beam. Raman spectroscopy and synchrotron x-ray diffraction were applied to evaluate the efficiency of the anvils for pressure multiplication in different modes of operation: as single indenters forced against the primary anvil in diamond anvil cells (DACs) or as pairs of anvils forced together in double-stage DACs (dsDACs). All types of secondary anvils performed well up to about 250 GPa. The pressure multiplication factor of single indenters appeared to be insignificantly dependent on the shape of the anvils and their culets' profiles. The enhanced pressure multiplication factor found for pairs of toroidally shaped secondary anvils makes this design very promising for ultrahigh-pressure experiments in dsDACs.


Schizophrenia patients demonstrate a distinctive pattern of decision-making impairment on the Iowa Gambling Task.
Although dorsolateral prefrontal cortex (DLPFC) abnormalities in schizophrenia are well established, several lines of evidence suggest the orbitofrontal cortex (OFC) may also be dysfunctional in this disorder. We examined the performance of schizophrenia patients and nonpatient controls on the Iowa Gambling Task [Cognition 50 (1994) 7], a decision-making task sensitive to OFC damage that involves a series of selections from four decks of cards that vary in their reward/punishment profiles. Patients also completed neuropsychological tests assessing DLPFC functions and clinical symptom assessments. The schizophrenic patients demonstrated a pattern of impaired performance that differed both from healthy controls and from the "non-conservative" pattern typically found in patients with OFC lesions. The patients selected from the two card decks that had low frequency and high magnitude punishments significantly more often than the decks with high frequency and low magnitude punishments. Performance on the task was not strongly related to tests sensitive to DLPFC dysfunction but was correlated with negative symptoms. Results suggest that individuals with schizophrenia display a pattern of compromised decision-making that is somewhat distinct from that found in OFC lesion patients and that may be linked to certain clinical symptoms.


Wound infections following spinal fusion with posterior segmental spinal instrumentation.
Twenty-three of 238 patients (9.7%) developed wound infections following segmental spinal instrumentation. When the infected group and a matched control group were compared, the infected group had a significantly higher number of patients with cerebral palsy and myelodysplasia (nonambulatory), patients with wound hematomas, patients with fusions that extended into the sacral region, and patients who were incontinent of urine. A high incidence of infections with gram-negative aerobic bacilli correlated with the extension of the surgery into the sacral region and bowel and/or bladder incontinence. Prophylactic antibiotics with broader coverage for gram-negative bacilli may be warranted for these procedures. Postoperative wound infections were managed by surgical drainage and debridement as well as antibiotics. Removal of the hardware was not necessary to control the infection in these patients who underwent segmental spinal instrumentation.


Layer-by-layer deposition of silver/gold nanoparticles for catalytic reduction of nitroaromatics.
A general method has been fabricated to achieve normal as well as inverted core-shell architectures of silver/gold through a layer-by-layer deposition technique on a commercial anion exchange resin. Electrostatic field force of the charged resin beads supports immobilization of anionic metal precursors [MX(n)]-, in turn deposition of silver/gold nanoparticles onto the solid resin matrix and reduction of 2-nitrobenzoic acid to obtain the corresponding amines through effective catalysis. The shell thickness has been tailored made by exploiting a new method of cyclic and repetitive deposition of the desired metal precursors. Thermodynamic parameters for the reduction reaction have been presented. Kinetic study reveals a comparative account of rates between the mono- and bi-metallic nanoparticles where silver stands to be a better catalyst for the reduction of nitroaromatics.


Beta2* nicotinic acetylcholine receptors modulate pain sensitivity in acutely abstinent tobacco smokers.
Nicotine and tobacco smoking administration have demonstrated antinociceptive effects that are mediated by the nicotinic acetylcholine receptor containing the beta2* subunit (beta(2)*-nAChR). In this study, we examined the relationship between beta(2)*-nAChR availability and nociception during acute withdrawal in human tobacco smokers using [(123)I]5-IA-85380 ([(123)I]5-IA) and single photon emission computed tomography (SPECT) brain imaging. Tobacco smokers (n = 24, aged 34 +/- 11 years) participated in the cold pressor task during acute withdrawal (up to 3 hr) and a second cold pressor task following 7-13 days of smoking abstinence on the day they were imaged with [(123)I]5-IA SPECT. The cold pressor task is used to measure pain sensitivity (when subjects first feel pain) and pain tolerance (when subjects cannot withstand pain). Following 7-13 days of tobacco smoking abstinence, increased pain sensitivity, for example, shorter time to first feel pain, was significantly associated with higher beta(2)*-nAChR availability in the thalamus (r = -.43), parietal (r = -.50), frontal (r = -.55), anterior cingulate (r = -.44), temporal (r = -.43), and occipital (r = -.48) cortices. The percent change in pain sensitivity from the first to second cold pressor task was significantly correlated with beta(2)*-nAChR availability in the thalamus (r = -.57), cerebellum (r = -.50), striatum (r = -.057), parietal (r = -.46), anterior cingulate (r = -.48), temporal (r = -.55), and occipital (r = -.57) cortices. Similar associations were not observed with pain tolerance. This suggests that beta(2)*-nAChRs play a role in pain sensitivity but not pain tolerance during tobacco smoking withdrawal. If individuals are more likely to relapse in response to painful stimuli, lower beta(2)*-nAChR availability during acute abstinence may be protective.


Soft-Tissue Reconstruction at Anterior Implant Sites With Soft-Tissue Dehiscences.
The treatment of a peri-implant soft-tissue dehiscence (PSTD) can be quite challenging for many clinicians and leave gravely disappointing esthetic remarks for patients to bear. The present article describes the treatment of two adjacent PSTDs in the forefront of the anterior region, where papilla deficiency also was exhibited. The case was treated with a coronally advanced flap and connective tissue graft (CTG) with submerged healing. The implant-supported crowns and abutments were removed, and soft-tissue augmentation was performed using a CTG that was sutured to the buccal site of the implants. The flap was released and sutured over the implants, which were submerged aiming for a closure by primary intention. After 3 months, a combination of an apically positioned flap and roll flap was performed to increase keratinized mucosa width around the implants and augment the peri-implant papilla. Clinical and esthetic satisfactory outcomes were obtained at 1 year.


The Role of Low-Dose Oral Methotrexate in Increasing Anti-TNF Drug Levels and Reducing Immunogenicity in IBD.
Concomitant immunomodulation is utilised in combination with anti-TNF therapy for IBD primarily to increase drug levels and prevent anti-drug antibody formation. Whilst thiopurines have traditionally been the immunomodulator of choice in IBD populations, there are concerns regarding the long-term safety of the prolonged use of these agents: particularly an association with lymphoproliferative disorders. Given this, we have explored the existing literature on the use of low-dose oral methotrexate as an alternative immunomodulator for this indication. Although there is a lack of data directly comparing the efficacies of methotrexate and thiopurines as concomitant immunomodulators, the available literature supports the use of methotrexate in improving the pharmacokinetics of anti-TNF agents. Furthermore, low-dose oral methotrexate regimens appear to have comparable efficacies to higher-dose parenteral administration and are better tolerated. We suggest that clinicians should consider the use of low-dose oral methotrexate as an alternative to thiopurines when the primary purpose of concomitant immunomodulation is to improve anti-TNF pharmacokinetics.


Effects of ethionine on digestive enzyme synthesis and discharge by mouse pancreas.
The earliest changes noted during the evolution of pancreatitis induced by feeding mice a choline-deficient ethionine-supplemented (CDE) diet are an increase in the number of zymogen granules in pancreatic acinar cells and an increase in digestive enzyme content of the pancreas. We have studied the processes of protein and digestive enzyme synthesis and discharge at varying times after institution of the CDE diet, a choline-deficient diet (CD), and a diet containing ethionine but not choline-deficient (E). Both the CDE and E diets increased digestive enzyme content within 12 h of their institution. Both the CDE and E diets reduced the rate of protein and amylase synthesis and caused a marked reduction in the rate of protein and amylase discharge from the pancreas. These changes were greatest and were noted earliest in the CDE diet group. A marked reduction in secretagogue-induced in vivo and in vitro amylase discharge followed ingestion of either the CDE or E diet. These studies indicate that the increased pancreatic content of digestive enzymes noted after ingestion of the CDE and E diets results from an ethionine-induced decrease in the rat of digestive enzyme discharge. This phenomenon is enhanced by simultaneous choline deficiency. Subsequent intrapancreatic activation of zymogens may couple these changes in enzyme content to the development of hemorrhagic pancreatitis.


On the properties of immobilized elongation factor Tu from Thermus thermophilus HB8.
Elongation factor Tu from Thermus thermophilus was coupled to cyanogen-bromide-activated Sepharose 4B and its properties were investigated. The immobilized elongation factor retained its ligand binding properties. It specifically binds GDP and GTP but does not interact with other nucleotide 5'-phosphates. A conversion of immobilized EF-Tu . GDP to EF-Tu . GTP can be achieved by simple equilibration with GTP. The immobilized EF-Tu . GTP specifically binds aminoacyl-tRNAs and allows a facile purification of aminoacyl-tRNA species from bulk tRNA. It is stable at room temperature for several months and can be repeatedly used for aminoacyl-tRNA isolation.


A spectroscopic study of some of the peptidyl radicals formed following hydroxyl radical attack on beta-amyloid and alpha-synuclein.
There is clear evidence implicating oxidative stress in the pathology of many neurodegenerative diseases. Reactive oxygen species (ROS) are the primary mediators of oxidative stress, and hydrogen peroxide, a key ROS, is generated during aggregation of the amyloid proteins associated with some of these diseases. Hydrogen peroxide is catalytically converted to the aggressive hydroxyl radical in the presence of Fe(II) and Cu(I), which renders amyloidogenic proteins such as beta-amyloid and alpha-synuclein (implicated in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively) vulnerable to self-inflicted hydroxyl radical attack. Here, we report some of the peptide-derived radicals, detected by electron spin resonance spectroscopy employing sodium 3,5-dibromo-4-nitrosobenzenesulfonate as a spin-trap, following hydroxyl radical attack on Abeta(1-40), alpha-synuclein and some other related peptides. Significantly, we found that sufficient hydrogen peroxide was self-generated during the early stages of aggregation of Abeta(1-40) to produce detectable peptidyl radicals, on addition of Fe(II). Our results support the hypothesis that oxidative damage to Abeta (and surrounding molecules) in the brain in AD could be due, at least in part, to the self-generation of ROS. A similar mechanism could operate in PD and some other "protein conformational" disorders.


Estimating the richness of a population when the maximum number of classes is fixed: a nonparametric solution to an archaeological problem.
Estimating assemblage species or class richness from samples remains a challenging, but essential, goal. Though a variety of statistical tools for estimating species or class richness have been developed, they are all singly-bounded: assuming only a lower bound of species or classes. Nevertheless there are numerous situations, particularly in the cultural realm, where the maximum number of classes is fixed. For this reason, a new method is needed to estimate richness when both upper and lower bounds are known. Here, we introduce a new method for estimating class richness: doubly-bounded confidence intervals (both lower and upper bounds are known). We specifically illustrate our new method using the Chao1 estimator, rarefaction, and extrapolation, although any estimator of asymptotic richness can be used in our method. Using a case study of Clovis stone tools from the North American Lower Great Lakes region, we demonstrate that singly-bounded richness estimators can yield confidence intervals with upper bound estimates larger than the possible maximum number of classes, while our new method provides estimates that make empirical sense. Application of the new method for constructing doubly-bound richness estimates of Clovis stone tools permitted conclusions to be drawn that were not otherwise possible with singly-bounded richness estimates, namely, that Lower Great Lakes Clovis Paleoindians utilized a settlement pattern that was probably more logistical in nature than residential. However, our new method is not limited to archaeological applications. It can be applied to any set of data for which there is a fixed maximum number of classes, whether that be site occupancy models, commercial products (e.g. athletic shoes), or census information (e.g. nationality, religion, age, race).


Color Vision Deficiency and Functional Disorders Among Israeli Male Adolescents Between 2007 and 2013.
Color vision deficiency has been associated with educational difficulties among male children, as well as attention-deficit hyperactivity disorder (ADHD). We examined the association of color vision deficiency with functional conditions, including ADHD, irritable bowel syndrome, enuresis and somatoform disorders, in a large population of male adolescents. We included all Israeli male adolescents that underwent medical and cognitive examinations during conscription between the years 2007 and 2013. The prevalence of ADHD, irritable bowel syndrome, enuresis, and somatoform disorders among color vision deficiency patients was compared to a control group. The study included 305 964 males aging 17 ± 0.6, of which 7584 (2.5%) had color vision deficiency. Using a multivariable analysis, the probability for irritable bowel syndrome, enuresis, and somatoform disorders among color vision deficiency patients was increased by 1.41, 1.94, and 3.87, respectively (P < .05). No significant association was found between ADHD and color vision deficiency. Color vision abnormalities are associated with functional disorders in male adolescents, including irritable bowel syndrome, enuresis, and somatoform disorders.


Strongyloides stercoralis infection presenting as an unusual cause of massive upper gastrointestinal bleeding in an immunosuppressed patient: a case report.
Strongyloidiasis caused by Strongyloides stercoralis is a rare but well documented cause of massive upper gastrointestinal (GI) bleeding especially in endemic areas. However, oesophagogastroduodenoscopic findings and extractions of S. stercoralis, in the adult worm form, from the duodenum is even rarer. We report a case of a 27-year-old Tanzanian woman with HIV who presented with massive upper GI bleeding. She had S. stercoralis, in the adult worm form, traversing the stomach and duodenum and extracted by oesophagogastroduodenoscopy (OGD). She was treated successfully with Ivermectine and antiretroviral therapy for HIV was initiated. Strongyloidiasis should be included in the differential diagnosis of mass upper GI bleeding in immunosuppressive patients living in, or originating from, endemic areas. We believe this to be the first case to be reported from our environment.


The Efficacy and Safety of 12 Weeks of Sofosbuvir and Ledipasvir versus Sofosbuvir, Ledipasvir, and Ribavirin in Patients with Chronic Hepatitis C, Genotype 1, Who Have Cirrhosis and Have Failed Prior Therapy: A Systematic Review and Meta-Analysis.
Background. The recommended therapy for patients with chronic hepatitis C (CHC), genotype 1, who have cirrhosis and have failed prior therapy is 12 weeks of sofosbuvir (SOF), ledipasvir (LDV), and ribavirin (RBV). This recommendation is based on expert opinion, and the efficacy of 12 weeks of SOF/LDV compared to SOF/LDV/RBV in this patient population has not yet been established. Methods. We conducted a systematic review and meta-analysis. Two investigators independently searched electronic databases and relevant conference proceedings for randomized controlled trials comparing rates of sustained virologic response 12 weeks after therapy (SVR12) when using 12 weeks of SOF/LDV versus 12 weeks of SOF/LDV/RBV in patients with CHC, genotype 1, who have cirrhosis and failed previous therapy. Results. Our search strategy yielded 596 studies of which four met criteria for inclusion. The pooled RR of not achieving SVR12 with SOF/LDV versus SOF/LDV/RBV was 1.21 (95% CI: 0.42-3.48). Adverse events were lower in the SOF/LDV compared to the SOF/LDV/RBV arms (pooled RR: 0.11, 95% CI: 0.04-0.29). Conclusions. Our findings suggest that 12 weeks of SOF/LDV cannot be considered noninferior to 12 weeks of SOF/LDV/RBV to achieve SVR12 in patients with CHC who have cirrhosis and failed prior therapy.


Potency of testicular somatic environment to support spermatogenesis in XX/Sry transgenic male mice.
The sex-determining region of Chr Y (Sry) gene is sufficient to induce testis formation and the subsequent male development of internal and external genitalia in chromosomally female mice and humans. In XX sex-reversed males, such as XX/Sry-transgenic (XX/Sry) mice, however, testicular germ cells always disappear soon after birth because of germ cell-autonomous defects. Therefore, it remains unclear whether or not Sry alone is sufficient to induce a fully functional testicular soma capable of supporting complete spermatogenesis in the XX body. Here, we demonstrate that the testicular somatic environment of XX/Sry males is defective in supporting the later phases of spermatogenesis. Spermatogonial transplantation analyses using XX/Sry male mice revealed that donor XY spermatogonia are capable of proliferating, of entering meiosis and of differentiating to the round-spermatid stage. XY-donor-derived round spermatids, however, were frequently detached from the XX/Sry seminiferous epithelia and underwent cell death, resulting in severe deficiency of elongated spermatid stages. By contrast, immature XY seminiferous tubule segments transplanted under XX/Sry testis capsules clearly displayed proper differentiation into elongated spermatids in the transplanted XY-donor tubules. Microarray analysis of seminiferous tubules isolated from XX/Sry testes confirmed the missing expression of several Y-linked genes and the alterations in the expression profile of genes associated with spermiogenesis. Therefore, our findings indicate dysfunction of the somatic tubule components, probably Sertoli cells, of XX/Sry testes, highlighting the idea that Sry alone is insufficient to induce a fully functional Sertoli cell in XX mice.


Insights on vitamin D's role in cardiovascular disease: investigating the association of 25-hydroxyvitamin D with the dimethylated arginines.
Accumulating evidence has stipulated a strong correlation between vitamin D (vitD) deficiency and cardiovascular disease (CVD); however, a mechanistic link is missing. This study investigated the association of vitD with endothelial dysfunction parameters. Subjects comprised male patients with verified coronary artery disease (CAD) (n=69) and age- and sex-matched controls (n=20). 25-Hydroxyvitamin D [25(OH)D] was determined using high performance liquid chromatography with ultraviolet detection whereas asymmetric and symmetric dimethylarginine (ADMA and SDMA, respectively) were determined by liquid chromatography-mass spectrometry. Nitric oxide (NO) was determined spectrophotometrically and high-sensitivity C-reactive protein (hs-CRP) was determined using enzyme-linked immunosorbent assay (ELISA). Comparison of mean 25(OH)D concentrations of patients and controls yielded a significant result (p=0.0002). 25(OH)D2 was dominant in patients whereas 25(OH)D3 was dominant in controls (p=0.003 and 0.001, respectively). Comparison of mean ADMA and SDMA concentrations of patients exhibiting normal and suboptimal vitD yielded insignificant results (p=0.692 and 0.998, respectively). Significant results were obtained from the comparison of mean hs-CRP and NO concentrations of patients exhibiting normal and suboptimal vitD (p=0.035 and 0.031, respectively). Results suggest involvement of vitD with the NO system, however not via modulation of the dimethylated arginines. A potential anti-inflammatory activity for vitD is also raised.


New insights into tumor dormancy: Targeting DNA repair pathways.
Over the past few decades, major strides have advanced the techniques for early detection and treatment of cancer. However, metastatic tumor growth still accounts for the majority of cancer-related deaths worldwide. In fact, breast cancers are notorious for relapsing years or decades after the initial clinical treatment, and this relapse can vary according to the type of breast cancer. In estrogen receptor-positive breast cancers, late tumor relapses frequently occur whereas relapses in estrogen receptor-negative cancers or triple negative tumors arise early resulting in a higher mortality risk. One of the main causes of metastasis is tumor dormancy in which cancer cells remain concealed, asymptomatic, and untraceable over a prolonged period of time. Under certain conditions, dormant cells can re-enter into the cell cycle and resume proliferation leading to recurrence. However, the molecular and cellular regulators underlying this transition remain poorly understood. To date, three mechanisms have been identified to trigger tumor dormancy including cellular, angiogenic, and immunologic dormancies. In addition, recent studies have suggested that DNA repair mechanisms may contribute to the survival of dormant cancer cells. In this article, we summarize the recent experimental and clinical evidence governing cancer dormancy. In addition, we will discuss the role of DNA repair mechanisms in promoting the survival of dormant cells. This information provides mechanistic insight to explain why recurrence occurs, and strategies that may enhance therapeutic approaches to prevent disease recurrence.


Stereoselective pharmacodynamic and pharmacokinetic analysis of sec-Butylpropylacetamide (SPD), a new CNS-active derivative of valproic acid with unique activity against status epilepticus.
sec-Butylpropylacetamide (racemic-SPD) is a chiral CNS-active amide derivative of valproic acid (VPA). This study describes synthesis and stereospecific comparative pharmacodynamics (PD, anticonvulsant activity and teratogenicity) and pharmacokinetic (PK) analysis of four individual SPD stereoisomers. SPD stereoisomers' anticonvulsant activity was comparatively evaluated in several anticonvulsant animal models including the benzodiazepine-resistant status epilepticus (SE). SPD stereoisomers' PK-PD relationship was evaluated in rats. Teratogenicity of SPD stereoisomers was evaluated in SWV mice strain, susceptible to VPA-induced neural tube defect (NTD). SPD stereoisomers (141 or 283 mg/kg) did not cause NTD. SPD has stereoselective PK and PD. (2R,3S)-SPD and (2S,3R)-SPD higher clearance led to a 50% lower plasma exposure that may contribute to their relative lower activity in the pilocarpine-induced SE model. (2S,3S)-SPD, (2R,3R)-SPD, and racemic-SPD have similar anticonvulsant activity and a PK profile that are better than those of (2R,3S)-SPD and (2S,3R)-SPD, making them good candidates for development as new, potent antiepileptics with a potential in benzodiazepine-resistant SE.


Argemone mexicana decoction for the treatment of uncomplicated falciparum malaria.
A prospective, dose-escalating, quasi-experimental clinical trial was conducted with a traditional healer using a decoction of Argemone mexicana for the treatment of malaria in Mali. The remedy was prescribed in three regimens: once daily for 3 days (Group A; n=23); twice daily for 7 days (Group B; n=40); and four times daily for the first 4 days followed by twice daily for 3 days (Group C; n=17). Thus, 80 patients were included, of whom 80% were aged<5 years and 25% were aged<1 year. All presented to the traditional healer with symptoms of malaria and had a Plasmodium falciparum parasitaemia>2000/microl but no signs of severe malaria. The proportions of adequate clinical response (ACR) at Day 14 were 35%, 73% and 65% in Groups A, B and C, respectively (P=0.011). At Day 14, overall proportions of ACR were lower in children aged<1 year (45%) and higher in patients aged>5 years (81%) (P=0.027). Very few patients had complete parasite clearance, but at Day 14, 67% of patients with ACR had a parasitaemia<2000/microl. No patient needed referral for severe disease. Only minor side effects were observed. Further research should determine whether this local resource could represent a first-aid home treatment in remote areas.


Aortic dissection associated with aortitis syndrome.
A 50-year-old woman with aortitis syndrome complicated by aortic dissection, is reported. The dissection was observed at the level of the descending thoracic aorta by aortography and at the intimal side of the dilated aorta on CT. An aneurysm of the right subclavian artery and a diffusely thick wall of the abdominal aorta were also observed. This case suggests that the uneven wall of the aorta in aortitis syndrome might be dissected at the intimal side by dilatation.


Enzymatic Hydrolysis of Alginate to Produce Oligosaccharides by a New Purified Endo-Type Alginate Lyase.
Enzymatic hydrolysis of sodium alginate to produce alginate oligosaccharides has drawn increasing attention due to its advantages of containing a wild reaction condition, excellent gel properties and specific products easy for purification. However, the efficient commercial enzyme tools are rarely available. A new alginate lyase with high activity (24,038 U/mg) has been purified from a newly isolated marine strain, Cellulophaga sp. NJ-1. The enzyme was most active at 50 °C and pH 8.0 and maintained stability at a broad pH range (6.0-10.0) and temperature below 40 °C. It had broad substrate specificity toward sodium alginate, heteropolymeric MG blocks (polyMG), homopolymeric M blocks (polyM) and homopolymeric G blocks (polyG), and possessed higher affinity toward polyG (15.63 mM) as well as polyMG (23.90 mM) than polyM (53.61 mM) and sodium alginate (27.21 mM). The TLC and MS spectroscopy analysis of degradation products suggested that it completely hydrolyzed sodium alginate into oligosaccharides of low degrees of polymerization (DPs). The excellent properties would make it a promising tool for full use of sodium alginate to produce oligosaccharides.


Different interaction between the agonist JN403 and the competitive antagonist methyllycaconitine with the human alpha7 nicotinic acetylcholine receptor.
The interaction of the agonist JN403 with the human (h) alpha7 nicotinic acetylcholine receptor (AChR) was compared to that for the competitive antagonist methyllycaconitine (MLA). The receptor selectivity of JN403 was studied on the halpha7, halpha3beta4, and halpha4beta2 AChRs. The results established that the cationic center and the hydrophobic group found in JN430 and MLA are important for the interaction with the AChRs. MLA preincubation inhibits JN403-induced Ca(2+) influx in GH3-halpha7 cells with a potency 160-fold higher than that when MLA is co-injected with JN403. The most probable explanation, based on our dynamics results, is that MLA (more specifically the 3-methyl-2,5-dioxopyrrole ring and the B-D rings) stabilizes the resting conformational state. The order of receptor specificity for JN403 is as follows: halpha7 > halpha3beta4 ( approximately 40-fold) > halpha4beta2 ( approximately 500-fold). This specificity is based on a larger number of hydrogen bonds between the carbamate group (another pharmacophore) of JN403 and the halpha7 sites, the electrostatic repulsion between the positively charged residues around the halpha3beta4 sites and the cationic center of JN403, fewer hydrogen bonds for the interaction of JN403 with the halpha3beta4 AChR, and an unfavorable van der Waals interaction between JN403 and the alpha4-beta2 interface. The higher receptor specificity for JN403 could be important for the treatment of alpha7-related disorders, including dementias, pain-related ailments, depression, anxiety, and wound healing.


Preparation and release kinetics of microencapsulated cisplatin with ethylcellulose.
Several kinds of microcapsules containing cisplatin were prepared by the ethylcellulose coacervation process in an attempt to administer cisplatin with chemoembolization. Microcapsules made either with mechanical stirring or with sonication showed similar properties; the chemical structure of cisplatin was not affected by the micro-encapsulation process. The release kinetics of cisplatin from ethylcellulose-walled microcapsules followed different patterns, according to the wall thickness. In each case, the release kinetics did not depend on the stirring rate of the surrounding medium. Only microcapsules with a cisplatin release ratio from 80 to 100% within 24 h were selected for later clinical use.


The preservative efficacy testing method for powdered eye shadows.
Preservative efficacy testing is based on a sample inoculation using a microbial suspension with a determined amount of colony-forming units (CFU). After that, the number of survivors is investigated by periodic evaluations, and the results are compared with specifications. When liquid cosmetics are evaluated, it is easy to obtain homogeneity between the inoculum and the sample, but for a powder sample it cannot be guaranteed. In this context, freeze-dried microorganisms could be used to help the homogenization. In this research, the preservative efficacy is evaluated using a powdered eye shadow. The microorganisms used were Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger. The challenge tests were performed in samples with (P) or without (NP) added preservative. The methods used to evaluate the results were the ones described in the official compendia and in the cosmetics guides of international associations, also using linear regression in calculating the D-value. The results showed that it is possible to use freeze-dried microorganisms instead of suspension to evaluate the preservative efficacy of cosmetic solids. The microorganism stability was verified by the determination of the microbial load and the minimum inhibitory concentration after freeze-drying and during the following six months.


Metabolic utilization of linoleate and alpha-linolenate in cultured Sertoli cells.
1. The capacity of cultured Sertoli cells to synthesize long-chain polyunsatured fatty acids (PUFA) from the essential fatty acid (EFA) precursors 18:2 n-6 and 18:3 n-3 was tested, and the concentrations of each EFA required to obtain maximal incorporation into membrane lipids were determined. 2. The two EFA were added to the culture medium as free fatty acids complexed to albumin in a molar ratio of 12:1. 3. When the substrates were added individually, the maximal levels of biosynthesis were obtained with 0.7 micrograms/ml of 18:2 n-6 and 2 micrograms/ml of 18:3 n-3. 4. When the two EFA were added together, clear alterations in the behavior of the desaturases with regard to the n-6 and n-3 fatty acids were observed. 5. It was found that a concentration of 0.35 micrograms/ml of each EFA represented the "ideal" required level in order to ensure optimal incorporation of 22-carbon PUFA into the membrane lipids. 6. These results provide the first data on the definition of EFA requirements for Sertoli cells in culture.


Predictors of shorter- and longer-term mortality after COVID-19 presentation among dialysis patients: parallel use of machine learning models in Latin and North American countries.
We developed machine learning models to understand the predictors of shorter-, intermediate-, and longer-term mortality among hemodialysis (HD) patients affected by COVID-19 in four countries in the Americas. We used data from adult HD patients treated at regional institutions of a global provider in Latin America (LatAm) and North America who contracted COVID-19 in 2020 before SARS-CoV-2 vaccines were available. Using 93 commonly captured variables, we developed machine learning models that predicted the likelihood of death overall, as well as during 0-14, 15-30, > 30 days after COVID-19 presentation and identified the importance of predictors. XGBoost models were built in parallel using the same programming with a 60%:20%:20% random split for training, validation, & testing data for the datasets from LatAm (Argentina, Columbia, Ecuador) and North America (United States) countries. Among HD patients with COVID-19, 28.8% (1,001/3,473) died in LatAm and 20.5% (4,426/21,624) died in North America. Mortality occurred earlier in LatAm versus North America; 15.0% and 7.3% of patients died within 0-14 days, 7.9% and 4.6% of patients died within 15-30 days, and 5.9% and 8.6% of patients died > 30 days after COVID-19 presentation, respectively. Area under curve ranged from 0.73 to 0.83 across prediction models in both regions. Top predictors of death after COVID-19 consistently included older age, longer vintage, markers of poor nutrition and more inflammation in both regions at all timepoints. Unique patient attributes (higher BMI, male sex) were top predictors of mortality during 0-14 and 15-30 days after COVID-19, yet not mortality > 30 days after presentation. Findings showed distinct profiles of mortality in COVID-19 in LatAm and North America throughout 2020. Mortality rate was higher within 0-14 and 15-30 days after COVID-19 in LatAm, while mortality rate was higher in North America > 30 days after presentation. Nonetheless, a remarkable proportion of HD patients died > 30 days after COVID-19 presentation in both regions. We were able to develop a series of suitable prognostic prediction models and establish the top predictors of death in COVID-19 during shorter-, intermediate-, and longer-term follow up periods.


Risk factors for clinical anastomotic leakage following the resection of sigmoid and rectal cancer.
The aim of the study was to determine the risk factors for the leakage after sigmoid and rectal cancer resections depending on the height of anastomoses. Data of 269 patients, who underwent primary resection of colorectal cancer, were analyzed retrospectively: 21 patients underwent proctectomy with Parks coloanal anastomosis, 78--low anterior resection of rectum, 67--high anterior resection of rectum and 103--resection of sigmoid colon with colorectal anastomosis. Preoperative radiotherapy was performed on 61 patients. Anastomotic leakage occurred in 20 (7.4%) patients. Multivariate analysis of the overall population showed that the risk of anastomotic leakage was 3.9 times higher for males (p=0.02) and 3.5 times higher for anastomoses situated at or below 10 cm from the anal verge (p=0.01). Multivariate analysis of low colorectal and coloanal anastomoses (n=99) showed that only male sex was an independent factor. Multivariate analysis of patients with anastomosis situated higher than 10 cm from the anal verge (n=170) showed that the preoperative condition of the patient was as independent factor for the development of anastomotic leakage. Low rectal anastomoses are at risk for anastomotic leakage, especially in males and in generally unfit patients.


Exploring Enzymatic Conformational Dynamics at Surfaces through μ-FTIR Spectromicroscopy.
Immobilization of proteins onto solid supports has critical industrial, technological, and medical applications, and is a daily task in chemical research. Significant conformational rearrangements often occur due to enzyme-surface interactions, and it is of broad interest to develop methods to probe and better understand these molecular-level changes that contribute to the enzyme's catalytic activity and stability. While circular dichroism is a common method for solution-phase conformational study, the application to surface-supported proteins is not trivial and spatial mapping is not viable. On the other hand, a nonlinear laser spectroscopy technique used to analyze surfaces and interfaces is not often found in most laboratories, therefore requiring an alternative and reliable method. Here, we employed high-dimensional data spectromicroscopy analysis in the infrared region (μ-FTIR) to investigate the enzyme's conformational change when adsorbed onto solid matrices, across a ca. 20 mm2 area. Alcohol dehydrogenase (ADH) enzyme was adopted as a model enzyme to interact with CaF2, Au, and Au-thiol model substrates, strategically chosen for mapping the enzyme dynamics on solid surfaces with different polarity/hydrophobicity properties and extendable to other materials. Two-dimensional chemical maps indicate that the enzyme adsorbs with different patterns in which secondary structures dynamically adjust to optimize interprotein and enzyme-surface interactions. The results suggest an experimental approach to identify and map enzyme conformational dynamics onto different solid surfaces across space and provide insights into immobilized protein structure investigations for areas such as biosensing and bioenergy.


Synthesis and characterization of two novel mixed metal tellurates: KGaTeO5 x H2O and K3GaTe2O8(OH)2 x H2O.
Single crystals of KGaTeO5 x H2O and K3GaTe2O8(OH)2 x H2O have been synthesized by supercritical hydrothermal techniques using Te(OH)6, Ga2O3 and KOH as reagents, and characterized by single crystal X-ray diffraction, thermal analysis, IR and Raman spectroscopy. Ion-exchange studies revealed KGaTeO5 x H2O, with its open-framework structure, is capable of exchanging both smaller (Na+) and larger (Rb+) ions. In addition, higher thermal stability and reversible hydration properties were observed for KGaTeO5 x H2O.


Model averaging for robust extrapolation in evidence synthesis.
Extrapolation from a source to a target, eg, from adults to children, is a promising approach to utilize external information when data are sparse. In the context of meta-analyses, one is commonly faced with a small number of studies, whereas potentially relevant additional information may also be available. Here, we describe a simple extrapolation strategy using heavy-tailed mixture priors for effect estimation in meta-analysis, which effectively results in a model-averaging technique. The described method is robust in the sense that a potential prior-data conflict, ie, a discrepancy between source and target data, is explicitly anticipated. The aim of this paper is to develop a solution for this particular application to showcase the ease of implementation by providing R code, and to demonstrate the robustness of the general approach in simulations.


[Over-expression of human S-phase kinase-associated protein 2 (Skp2) promotes proliferation of MCF-7 breast cancer cells and increases the number of S phase cells].
To construct a eukaryotic expression vector for the human gene S-phase kinase-associated protein 2 (Skp2) with a FLAG tag (pcDNA3-FLAG-Skp2) and detect the effect of Skp2 over-expression on the cell growth and cell cycle in MCF-7 breast cancer cells. Skp2 was amplified from MDA-MB-231 breast cancer cells by reverse-transcription polymerase chain reaction (RT-PCR) and then used to construct the eukaryotic expression vector pcDNA3-FLAG-Skp2. Integration of Skp2 into the vector was confirmed via restriction digest and sequencing; The pcDNA3-FLAG-Skp2 was then transfected into MCF-7 breast cancer cells. Expression of Skp2 protein was verified by Western blotting. Cell growth was assessed by Alamar blue proliferation assay, cell cycle analysis was carried out by flow cytometry. The PCR amplified fragment was matched up with the anticipated result and its sequence was the same as the data published on GenBank, indicating that the recombinant plasmid pcDNA3-FLAG-Skp2 was constructed successfully. Western blotting revealed that the expression of Skp2 protein was markedly up-regulated in the pcDNA3-FLAG-Skp2 transfected MCF-7 cells at 48 hours. Furthermore, cell growth was significantly promoted in Skp2 over-expressed MCF-7 cells, and the cell count in S phase were also raised. The recombinant eukaryotic expression vector pcDNA3-FLAG-Skp2 has been constructed and expressed in MCF-7 breast cancer cells successfully. Over-expression of Skp2 resulted in the increased cell growth and number of S phase cells in Skp2 transfected MCF-7 cells.


Molecular Mechanism of Lead-Induced Superoxide Dismutase Inactivation in Zebrafish Livers.
Lead toxicity has been proved to be related with inducing oxidative stress of organisms and causing inactivation of antioxidant enzymes, the mechanism of which remains unknown. This study investigated and compared superoxide dismutase (Cu/Zn SOD) activity inhibited in lead-treated zebrafish livers and explored the mechanism of SOD inactivation by lead at the molecular level using multiple spectroscopic techniques, isothermal titration calorimetric (ITC) measurement, molecular docking study and ICP-AES detection. Results showed lead exposure decreased SOD activities in zebrafish livers due to direct interactions between lead and SOD, resulting in conformational and functional changes of the enzyme. To be specific, Studies at the molecular level indicated that lead bound into the active site channel of SOD, hindered the path of the catalytic substrate (O(2)(-•)), damaged its skeleton conformation and secondary structure, and interacted with the enzymatically related residue (Arg 141) through electrostatic forces (ΔH < 0, ΔS > 0), and caused the release of Cu(2+) and Zn(2+) from the catalytic pocket of SOD. This work shows a correlation between results on organismal and molecular levels, and obtains a possible model hypothesizing mechanisms of lead toxicity using in vitro experiments instead of in vivo ones.


GTP is the primary activator of the anti-HIV restriction factor SAMHD1.
SAMHD1 (SAM domain- and HD domain-containing protein 1) is a dGTP-dependent dNTP triphosphohydrolase that converts dNTPs into deoxyribonucleosides and triphosphates. Therefore, SAMHD1 expression, particularly in non-dividing cells, can restrict retroviral infections such as HIV and simian immunodeficiency virus by limiting cellular dNTPs, which are essential for reverse transcription. It has previously been established that dGTP acts as both an activator and a substrate of this enzyme, suggesting that phosphohydrolase activity of SAMHD1 is regulated by dGTP availability in the cell. However, we now demonstrate biochemically that the NTP GTP is equally capable of activating SAMHD1, but GTP is not hydrolyzed by the enzyme. Activation of SAMHD1 phosphohydrolase activity was tested under physiological concentrations of dGTP or GTP found in either dividing or non-dividing cells. Because GTP is 1000-fold more abundant than dGTP in cells, GTP was able to activate the enzyme to a greater extent than dGTP, suggesting that GTP is the primary activator of SAMHD1. Finally, we show that SAMHD1 has the ability to hydrolyze base-modified nucleotides, indicating that the active site of SAMHD1 is not restrictive to such modifications, and is capable of regulating the levels of non-canonical dNTPs such as dUTP. This study provides further insights into the regulation of SAMHD1 with regard to allosteric activation and active site specificity.


Global trends in pancreas cancer among Asia-Pacific population.
The incidence of pancreatic cancer is rising. Understanding trends of pancreatic cancer is crucial prior to putting policies and interventions in place. Countries with a high human development index (HDI) have a higher incidence, prevalence and mortality due to pancreatic cancer. This global trend is replicated in the Asia-Pacific countries with high HDI having higher incidence, prevalence and mortality due to pancreatic cancer. The incidence of pancreatic cancer is rising in the Asia-Pacific population as life expectancy increases with a rising HDI. Lack of good cancer registries has resulted in under reporting of pancreatic cancer in developing countries in the Asia-Pacific region. The mortality still remains high as in the Western world as most pancreatic cancers are diagnosed in an advanced stage of the disease due to non-availability of cost-effective screening tools with few patients receiving definitive care. Smoking, alcohol consumption, poor diet and obesity are significant modifiable risk factors contributing to the development of pancreatic cancer. Population based screening for pancreatic cancer is not cost-effective. Identification of hereditary and genetic factors in the Asia-Pacific population can help in targeted screening of high-risk individuals. Policies and interventions aimed at primary prevention have the greatest potential to be cost-effective yet impactful and reduce the disease burden.


Effect of thiol status on nitric oxide metabolism in the circulation.
To elucidate the dynamics of nitric oxide (NO) metabolism in the circulation and its relationship with glutathione metabolism, formation of nitrosylhemoglobin (NO-Hb), S-nitrosothiols (RSNO), and nitrite+nitrate (NOx) was determined in blood samples from normal rats and animals that were treated with a loading dose of GSH or L-buthionine-[S,R]-sulfoximine (BSO), a specific inhibitor of GSH synthesis. When incubated in vitro with 0.2 mM NOC7, an NO donor, NO-Hb levels increased rapidly, peaked at 10 min, and decreased thereafter with a half-life of 35 min in blood samples from control, BSO-treated, or GSH-loaded animals. Levels of low-molecular-weight RSNO in plasma samples from the three animal groups also increased transiently, peaked at 10 min, and decreased thereafter. However, the amount of RSNO formed in GSH-loaded rat plasma was significantly greater than in control and BSO-treated animals. Plasma levels of NOx rapidly and similarly increased in all animal groups. Intravenously injected NOC7 also generated NO-Hb in circulating erythrocytes. In control animals, blood levels of NO-Hb increased maximally at 30 min and decreased thereafter with a half-life of 100 min. NO-Hb formed in the GSH-loaded group was significantly lower than in the control group. In contrast, the rate of NO-Hb formation was significantly higher with the BSO-treated group than with the control group. Although NOC7 did not affect the plasma levels of low-molecular-weight RSNO in plasma of both control and BSO-treated groups, it significantly increased RSNO in the GSH-loaded group. Thirty minutes after administration of NOC7, about 20% of the dose was recovered as plasma NOx in all animal groups. These results suggested that GSH status in animals might affect the metabolism of NO.


Carvedilol increases ciclosporin bioavailability by inhibiting P-glycoprotein-mediated transport.
Carvedilol is often used to treat hypertension and for prophylaxis in vascular sclerosis in renal transplant recipients, who require concomitant treatment with ciclosporin. However, there are few reports regarding the pharmacokinetic interactions between carvedilol and ciclosporin. We have investigated the potential effects of carvedilol on the pharmacokinetics of ciclosporin, and examined the inhibitory effects of carvedilol on P-glycoprotein-mediated transcellular transport using Caco2 cells. Ciclosporin alone or with carvedilol was orally or intravenously administered to rats. The oral administration of carvedilol (10 mg kg(-1)) with ciclosporin (10 mg kg(-1)) increased the whole blood concentration of ciclosporin. When ciclosporin (3 mg kg(-1)) was intravenously administered with carvedilol (3 mg kg(-1)), there was no difference in the whole blood ciclosporin concentration between administration with and without carvedilol. Co-administration with carvedilol increased ciclosporin bioavailability from 33% to 70%. In Caco2 cells, carvedilol caused a concentration-dependent increase in the intracellular accumulation of ciclosporin, and its effect was comparable with that of verapamil. Carvedilol considerably raised the concentration of ciclosporin in the blood and this interaction was associated with the absorption phase of ciclosporin. This interaction was caused by the inhibition of P-glycoprotein-mediated transport by carvedilol in the intestine.


Finger force vectors in multi-finger prehension.
In a majority of studies on grasp, only normal forces were measured and only when a zero torque was exerted on a hand-held object. This study concerns finger force vectors during the torque production tasks. Subjects (n=8) stabilized a handle with an attachment that allowed for change of external torque from -1.5 to 1.5 Nm. Forces and moments exerted by the digit tips on the object were recorded. At the large (>-0.375 Nm) supination torques the index/middle and ring/little pairs of fingers generated oppositely directed tangential forces. The index and middle finger produced forces in a downward direction and therefore did not support the load. At a zero torque and pronation torques, the middle, ring and little fingers produced forces along nearly the same direction. The vector of the index finger force was always directed differently from the vectors of other finger forces, the angles ranged from 19 degrees 30' to 47 degrees 40'. The points of force application were systematically displaced with the torque, with the exception of the little finger. Tangential finger forces contributed substantially to the total torque exerted on the hand-held object.


Artificial evolution of coumarin dyes for dye sensitized solar cells.
The design and discovery of novel molecular structures with optimal properties has been an ongoing effort for materials scientists. This field has in general been dominated by experiment driven trial-and-error approaches that are often expensive and time-consuming. Here, we investigate if a de novo computational design methodology can be applied to the design of coumarin-based dye sensitizers with improved properties for use in Grätzel solar cells. To address the issue of synthetic accessibility of the designed compounds, a fragment-based assembly is employed, wherein the combination of chemical motifs (derived from the existing databases of structures) is carried out with respect to user-adaptable set of rules. Rather than using computationally intensive density functional theory (DFT)/ab initio methods to screen candidate dyes, we employ quantitative structure-property relationship (QSPR) models (calibrated from empirical data) for rapid estimation of the property of interest, which in this case is the product of short circuit current (Jsc) and open circuit voltage (Voc). Since QSPR models have limited validity, pre-determined applicability domain criteria are used to prevent unacceptable extrapolation. DFT analysis of the top-ranked structures provides supporting evidence of their potential for dye sensitized solar cell applications.


Expression of klotho and β-catenin in esophageal squamous cell carcinoma, and their clinicopathological and prognostic significance.
Esophageal carcinoma is one of the most common types of cancers in the world; the molecular mechanism underlying its tumorigenesis is still not well understood. This study was aimed at investigating the expression of klotho and β-catenin in patients with esophageal squamous cell carcinoma (ESCC) and analyzing their association with clinicopathological variables and their effects on prognosis. The expression patterns of klotho and β-catenin were determined by tissue microarray and immunohistochemical technique in ESCC and normal tissues, and their correlations with clinicopathological characteristics were investigated using univariate and multivariate analysis. The serum klotho levels in 40 ESCC patients and controls were measured by sandwich enzyme-linked immunosorbent assay system (ELISA). The expression level of klotho was significantly lower in ESCC than in the adjacent noncancerous tissues (30 vs. 50%, P < 0.000), and the protein level was negative correlated with clinical staging, histological grade, lymph node metastasis, and invasion depth (P < 0.05). Whereas, the expression of β-catenin was much higher in ESCC than their corresponding normal mucosa tissues (78.3 vs. 11.5%, P < 0.000), and the level of protein correlated only with histological grade and invasion depth (P < 0.05). Correlation analysis showed the expression level of klotho inversely correlated with that of β-catenin (r = -0.214, P < 0.01). Patients with klotho-positive tumors had longer survival than those with klotho-negative tumors (P < 0.01). Cox proportional hazards model analysis demonstrated that positive expression of klotho was an important factor indicating good prognosis (hazard ratio, 0.371; 95% confidence interval, 0.201-0.685; P < 0.01). ELISA showed that the level of serum klotho was markedly higher (461.50 ± 43.30 pg/mL) than control group (239.37 ± 20.65 pg/mL) (P < 0.001). Receiver operating characteristic analysis gave a cut-off value of 327.031 of serum klotho with a sensitivity of 81.3% and specificity of 81.2% (P < 0.000). Our present study demonstrated for the first time that klotho might be a novel biomarker candidate for predicting progression and prognosis in patients with ESCC.


Oxidation of linoleic and palmitic acid in pre-hibernating and hibernating common noctule bats revealed by 13C breath testing.
Mammals fuel hibernation by oxidizing saturated and unsaturated fatty acids from triacylglycerols in adipocytes, yet the relative importance of these two categories as an oxidative fuel may change during hibernation. We studied the selective use of fatty acids as an oxidative fuel in noctule bats (Nyctalus noctula). Pre-hibernating noctule bats that were fed 13C-enriched linoleic acid (LA) showed 12 times higher tracer oxidation rates compared with conspecifics fed 13C-enriched palmitic acid (PA). After this experiment, we supplemented the diet of bats with the same fatty acids on five subsequent days to enrich their fat depots with the respective tracer. We then compared the excess 13C enrichment (excess atom percentage, APE) in breath of bats for torpor and arousal events during early and late hibernation. We observed higher APE values in breath of bats fed 13C-enriched LA than in bats fed 13C-enriched PA for both states (torpor and arousal), and also for both periods. Thus, hibernating bats selectively oxidized endogenous LA instead of PA, probably because of faster transportation rates of polyunsaturated fatty acids compared with saturated fatty acids. We did not observe changes in APE values in the breath of torpid animals between early and late hibernation. Skin temperature of torpid animals increased by 0.7°C between early and late hibernation in bats fed PA, whereas it decreased by -0.8°C in bats fed LA, highlighting that endogenous LA may fulfil two functions when available in excess: serving as an oxidative fuel and supporting cell membrane functionality.


[Resected case of pulmonary mucormycosis].
A 62-year-old man, with chronic renal failure and receiving hemodialysis, pointed out to have an abnormal shadow on a chest X-ray. A chest computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose-positron emission tomography (FDG-PET) examination showed a 6 cm size mass lesion in the middle of left thoracic cavity. Confirmed diagnosis was not obtained by needle biopsies. Left upper lobectomy was performed on suspicion of a lung cancer. Histopathologically, fungal hyphae were detected in these surgical specimens and it was diagnosed as pulmonary mucormycosis caused by Rhizopus species.


An all-atom force field for metallocenes.
A new all-atom force field, for the molecular modeling of metallocenes was constructed. Quantum chemical calculations were performed to obtain several force field terms not yet defined in the literature. The remainder were transferred from the OPLS-AA/AMBER framework. The parametrization work included the obtention of geometrical parameters, torsion energy profiles, and distributions of atomic charges that blend smoothly with the OPLS-AA specification for a variety of organic molecular fragments. Validation was carried out by comparing simulated and experimental data for five different ferrocene derivatives in the crystalline phase. The present model can be regarded as a step toward a general force field for metallocenes, built in a systematic way, easily integrated with OPLS-AA, and transferable between different metal-ligand combinations.


Mendelian Randomization Studies in Stroke: Exploration of Risk Factors and Drug Targets With Human Genetic Data.
Elucidating the causes of stroke is key to developing effective preventive strategies. The Mendelian randomization approach leverages genetic variants related to an exposure of interest to investigate the effects of varying that exposure on disease risk. The random allocation of genetic variants at conception reduces confounding from environmental factors and thus strengthens causal inference, analogous to treatment allocation in a randomized controlled trial. With the recent explosion in the availability of human genetic data, Mendelian randomization has proven a valuable tool for studying risk factors for stroke. In this review, we provide an overview of recent developments in the application of Mendelian randomization to unravel the pathophysiology of stroke subtypes and identify therapeutic targets for clinical translation. The approach has offered novel insight into the differential effects of risk factors and antihypertensive, lipid-lowering, and anticoagulant drug classes on risk of stroke subtypes. Analyses have further facilitated the prioritization of novel drug targets, such as for inflammatory pathways underlying large artery atherosclerotic stroke and for the coagulation cascade that contributes to cardioembolic stroke. With continued methodological advances coupled with the rapidly increasing availability of genetic data related to a broad range of stroke phenotypes, the potential for Mendelian randomization in this context is expanding exponentially.


Comparative study of dimensional accuracy of different impression techniques using addition silicone impression material.
This study compared dimensional accuracy of the single, double with spacer, double with cut-out and double mix impression technique using addition silicone impression material. A typhodont containing Ivorine teeth model with six (6) full-crown tooth preparations were used as the positive control. Two stone replication models for each impression technique were made as test materials. Accuracy of the techniques were assessed by measuring four dimensions on the stone dies poured from the impression of the Ivorine teeth model. Results indicated that most of the measurements for the height, width and diameter slightly decreased and a few increased compared with the Ivorine teeth model. The double with cut-out and double mix technique presents the least difference from the master model as compared to the two latter impression techniques.


Levels of insulin, corticosterone, T3, T4 and insulin sensitivity in fat and lean chickens.
The late generations of fat (FL) and lean (LL) chickens were compared. In the fasted state, plasma glucose was lower in FL chickens, whereas insulin, T3, T4 and corticosterone were unchanged. In the fed state, plasma insulin and T4 were increased in FL chickens whereas glucose, T3 and corticosterone were unchanged. During ad libitum refeeding both plasma glucose and insulin, and to a lesser degree T3, were lower and T4 higher in FL chickens whereas corticosterone remained unchanged between lines. The low glucose and insulin levels observed in FL during refeeding, which were not observed in the F4 generation, were also found after force-feeding. In contrast, during oral glucose tolerance test, as in previous generations, a better glucose tolerance, higher plasma insulin and slightly higher free fatty acid levels were found in FL chickens. The hypoglycemic effect of exogenous insulin was very similar (and poor) in both lines in the fed state and was higher in FL than in LL chickens in the fasted state. From the present and previous studies, a change in the glucose-insulin balance and possibly, in T3, could account for the differences in fattening of both lines.


Observation of electron-antineutrino disappearance at Daya Bay.
The Daya Bay Reactor Neutrino Experiment has measured a nonzero value for the neutrino mixing angle θ(13) with a significance of 5.2 standard deviations. Antineutrinos from six 2.9 GWth reactors were detected in six antineutrino detectors deployed in two near (flux-weighted baseline 470 m and 576 m) and one far (1648 m) underground experimental halls. With a 43,000 ton-GWth-day live-time exposure in 55 days, 10,416 (80,376) electron-antineutrino candidates were detected at the far hall (near halls). The ratio of the observed to expected number of antineutrinos at the far hall is R=0.940±0.011(stat.)±0.004(syst.). A rate-only analysis finds sin(2)2θ(13)=0.092±0.016(stat.)±0.005(syst.) in a three-neutrino framework.


Screening infants for neuroblastoma: the parents' perspective.
Health visitors collected urine samples from 6-month-old infants in a feasibility study of infant screening for neuroblastoma. As part of the project's evaluation, a study was conducted of the parents' views and experiences of screening. Parents of the most recently screened infants were contacted: 85 (68% of those contacted) were interviewed. Despite intermittent media coverage and written and verbal information being available, parents' overall knowledge of neuroblastoma screening was poor. Thirteen percent reported that they did not know the purpose of the test. Approximately one-third of parents reported initial anxiety about the test. Where samples were repeated because of unsatisfactory results, this percentage increased to 41% for a first-repeat sample. Parents were willing to make considerable effort to provide samples for screening but worried unnecessarily because the information they were given was either inadequate or in an inappropriate format (ie, verbal instead of written).


Can diabetes patients seeking a second hospital get better care? Results from nested case-control study.
This study investigates the effects of the number of medical institutions visited on risk of death. This study conducted a nested case-control design using the National Health Insurance Service-Senior database from 2002 to 2013. Cases were defined as those with death among outpatients who had first diagnosis of diabetes mellitus (E10-E14) after entry into the base cohort and controls were selected by incidence density sampling and matched to cases based on age, and sex. Our main results were presented by conditional logistic regression for nested case-controls design. Of total 55,558 final study samples, there were 9,313 (16.8%) cases and 46,245 (83.2%) controls. With an increase by one point in the number of hospitals per medical utilization, risk of death significantly increased by 4.1% (odds ratio (OR): 1.041, 95% confidence interval [CI]: 1.039-1.043). In both medical utilization and number of hospitals, those with high medical utilization (OR: 1.065, 95% CI: 1.059-1.070) and number of hospitals (OR: 1.049, 95% CI: 1.041-1.058) for risk of death were significantly higher than those with low medical utilization (OR: 1.040, 95% CI: 1.037-1.043) and number of hospitals (OR: 1.029, 95% CI: 1.027-1.032), respectively. The number of medical institution visited was significantly associated with risk of death. Therefore, diabetics should be warned about the potential of risk of death incurred from excessive access to medical utilizations.


Balancing Constraints and Objectives by Considering Problem Types in Constrained Multiobjective Optimization.
Constrained multiobjective optimization problems widely exist in real-world applications. To handle them, the balance between constraints and objectives is crucial, but remains challenging due to non-negligible impacts of problem types. In our context, the problem types refer particularly to those determined by the relationship between the constrained Pareto-optimal front (PF) and the unconstrained PF. Unfortunately, there has been little awareness on how to achieve this balance when faced with different types of problems. In this article, we propose a new constraint handling technique (CHT) by taking into account potential problem types. Specifically, inspired by the prior work, problems are classified into three primary types: 1) I; 2) II; and 3) III, with the constrained PF being made up of the entire, part and none of the unconstrained counterpart, respectively. Clearly, any problem must be one of the three types. For each possible type, there exists a tailored mechanism being used to handle the relationships between constraints and objectives (i.e., constraint priority, objective priority, or the switch between them). It is worth mentioning that exact problem types are not required because we just consider their possibilities in the new CHT. Conceptually, we show that the new CHT can make a tradeoff among different types of problems. This argument is confirmed by experimental studies performed on 38 benchmark problems, whose types are known, and a real-world problem (with unknown types) in search-based software engineering. Results demonstrate that within both decomposition-based and nondecomposition-based frameworks, the new CHT can indeed achieve a good tradeoff among different problem types, being better than several state-of-the-art CHTs.


Long chain oxoaldehydes and oxoalcohols from esters as major constituents of the surface lipids of Manduca sexta pupae in diapause.
Lipid constitutents of diapausing pupae of the tobacco hornworm, Manduca sexta (L), were identified by thin layer and gas-liquid chromatography, IR spectroscopy, and gas-liquid chromatography-mass spectrometry. Surface wax was a mixture of long chain polar compounds: oxoalcohol esters, oxoaldehydes, primary alcohol esters, and oxoalcohols, as listed in descending order of abundance. The distribution of the alcohols and aldehydes was C28 (75-85%), C27 (5%), and C26 (10-15%). The C26 compounds were largely 11-oxo isomers, but the C28 compounds consisted of similar amounts of 11- and 12-oxo isomers. The identities of the oxoaldehydes were confirmed by selective and complete NaBH4 reductions to yield oxoalcohols and diols, respectively. Mass spectral interpretations were verified with mass spectra of the oxoaldehyde, oxoalcohol, and diol synthesized from 12-hydroxystearic acid. Reduction of the total lipids with NaBH4 and hydrolysis of the product with ethanolic KOH gave oxoalcohols (85%), primary alcohols (8%), and oxoacids (5%); 30-40% of the oxoalcohols were derived from NaBH4-reduced oxoaldehydes, 5-10% were from free oxoalcohols, and 50% were from esters. Primary alcohols only existed as esters. Large quantities of fatty oxoalcohols relative to fatty oxoacids in the saponified mixture suggested the presence of esters other than those composed of long chain acids and alcohols. Oxoacids appeared to be mainly oxidation products of the oxoaldehydes.


Solid-state nuclear magnetic resonance evidence for parallel and antiparallel strand arrangements in the membrane-associated HIV-1 fusion peptide.
The HIV-1 fusion peptide serves as a useful model system for understanding viral/target cell fusion, at least to the lipid-mixing stage. Previous solid-state NMR studies have shown that the membrane-bound HIV-1 fusion peptide adopts an extended conformation in a lipid mixture close to that of host cells of the virus. In the present study, solid-state NMR REDOR methods were applied for detection of oligomeric beta strand structure. The samples were prepared under fusogenic conditions and contained equimolar amounts of two peptides, one with selective [(13)C]carbonyl labeling and the other with selective [(15)N]amide labeling. In the REDOR measurements, observation of reduced (13)C intensity due to hydrogen-bonded amide (15)N provides strong experimental evidence of oligomer formation by the membrane-associated peptide. Comparison of REDOR spectra on samples that were labeled at different residue positions suggests that there are both parallel and antiparallel arrangements of peptide strands. In the parallel arrangement, interpeptide hydrogen bonding decreases toward the C-terminus, while in the antiparallel arrangement, hydrogen bonds are observed along the entire length of residues which was probed (Gly-5 to Gly-16). For the parallel arrangement, these observations are consistent with the model in which the apolar N-terminal and central regions of the peptides penetrate into the membrane and hydrogen bond with one another while the polar C-terminus of the peptide is outside the membrane and hydrogen bonds with water. These measurements show that, at least at the end state of fusion, the peptide can adopt an oligomeric beta strand structure.


Differential effect of carbamazepine and valproate monotherapy on plasma levels of oestrone sulphate and dehydroepiandrosterone sulphate in male epileptic patients.
Steroid sulphates such as oestrone sulphate (OE1S) and dehydroepiandrosterone sulphate (DHEAS) have been suggested to be of biological importance in different disease states such as breast cancer and atherosclerosis. Previous studies have shown that drugs such as aminoglutethimide and rifampicin that induce P450-dependent mixed-function oxygenases selectively suppress plasma OE1S levels. The aim of this study was to evaluate the influence of treatment with carbamazepine, an antiepileptic drug known to stimulate mixed-function oxygenases, on plasma levels of OE1S and DHEAS. We measured plasma OE1S and DHEAS together with other plasma oestrogens and androgens in male epileptic patients before and during carbamazepine monotherapy. Patients treated with valproate monotherapy acted as a control group. Treatment with carbamazepine decreased plasma OE1S levels from a mean value of 810.8 to 411.6 pmol/l (mean suppression to 50.7% of pretreatment levels, P < 0.001). Similarly, the ratio of OE1S to OE1 fell to 59.9% of pretreatment levels (P < 0.001)). DHEAS decreased from a mean level of 4.9 mumol/l before treatment to 3.0 mumol/l during carbamazepine therapy (mean reduction to 62.7% of pretreatment levels (P < 0.001), while the ratio of DHEAS to DHEA fell to 63.0% of pretreatment values (P < 0.01). No significant change in plasma levels of the other oestrogens or androgens measured was observed. Treatment with valproate caused a slight decrease in FSH levels (P < 0.05), but no change in any of the other hormones measured was observed. Studies are warranted to evaluate the possible effects of long-term treatment with carbamazepine on the risk of developing endocrine-sensitive tumours and cardiovascular disease and also the possible effects of alterations in plasma DHEAS on epileptic activity.