Drinking water public right-to-know requirements in the United States.
The United States Environmental Protection Agency implements a national drinking-water program under the authority of the Federal Safe Drinking Water Act. Amendments to the Act in 1996 added new provisions to enhance consumer understanding of drinking-water issues. Notification requirements associated with annual consumer confidence reports, source water assessments and state compliance reports are intended to enhance the public's knowledge of the quality of their drinking water. Water utilities are also subject to public notification requirements to provide more timely information to consumers in response to violations of health standards. These right-to-know requirements are intended to build the public's confidence, but communicating with consumers can be challenging for both utility managers and government leaders. This paper discusses the need for timely communication, the challenge of providing information when there is uncertainty in the science and the importance of preparing to respond to critical incidents. Because surveys have shown that other members of the community may have better access to consumers or are more trusted, it is important for water utilities to establish relationships with the media and the local public health community.


Depression and anxiety in relation to cancer incidence and mortality: a systematic review and meta-analysis of cohort studies.
The link between depression and anxiety status and cancer outcomes has been well-documented but remains unclear. We comprehensively quantified the association between depression and anxiety defined by symptom scales or clinical diagnosis and the risk of cancer incidence, cancer-specific mortality, and all-cause mortality in cancer patients. Pooled estimates of the relative risks (RRs) for cancer incidence and mortality were performed in a meta-analysis by random effects or fixed effects models as appropriate. Associations were tested in subgroups stratified by different study and participant characteristics. Fifty-one eligible cohort studies involving 2,611,907 participants with a mean follow-up period of 10.3 years were identified. Overall, depression and anxiety were associated with a significantly increased risk of cancer incidence (adjusted RR: 1.13, 95% CI: 1.06-1.19), cancer-specific mortality (1.21, 1.16-1.26), and all-cause mortality in cancer patients (1.24, 1.13-1.35). The estimated absolute risk increases (ARIs) associated with depression and anxiety were 34.3 events/100,000 person years (15.8-50.2) for cancer incidence and 28.2 events/100,000 person years (21.5-34.9) for cancer-specific mortality. Subgroup analyses demonstrated that clinically diagnosed depression and anxiety were related to higher cancer incidence, poorer cancer survival, and higher cancer-specific mortality. Psychological distress (symptoms of depression and anxiety) was related to higher cancer-specific mortality and poorer cancer survival but not to increased cancer incidence. Site-specific analyses indicated that overall, depression and anxiety were associated with an increased incidence risks for cancers of the lung, oral cavity, prostate and skin, a higher cancer-specific mortality risk for cancers of the lung, bladder, breast, colorectum, hematopoietic system, kidney and prostate, and an increased all-cause mortality risk in lung cancer patients. These analyses suggest that depression and anxiety may have an etiologic role and prognostic impact on cancer, although there is potential reverse causality; Furthermore, there was substantial heterogeneity among the included studies, and the results should be interpreted with caution. Early detection and effective intervention of depression and anxiety in cancer patients and the general population have public health and clinical importance.


Experimental observation of Shapiro-steps in colloidal monolayers driven across time-dependent substrate potentials.
We experimentally study the motion of a colloidal monolayer which is driven across a commensurate substrate potential whose amplitude is periodically modulated in time. In addition to a significant reduction of the static friction force compared to an unmodulated substrate, we observe a Shapiro step structure in the force dependence of the mean particle velocity which is explained by the dynamical mode locking between the particle motion and the substrate modulation. In this regime, the entire crystal moves in a stick-slip fashion similar to what is observed when a single point contact is driven across a periodic surface. Contrary to numerical simulations, where typically a large number of Shapiro steps is found, only a single step is observed in our experiments. This is explained by the formation of kinks which weaken the synchronization between adjacent particles.


Telerehabilitation: an adjunct service delivery model for early intervention services.
Early Intervention (EI) services for children birth through two years of age are mandated by Part C of the Individuals with Disabilities Education Act (IDEA); however, personnel shortages, particularly in rural areas, limit access for children who qualify. Telerehabilitation has the potential to build capacity among caregivers and local providers as well as promote family-centered services through remote consultation. This article provides an overview of research related to telerehabilitation and early intervention services; discusses the feasibility of telerehabilitation within traditional EI service delivery models; examines telecommunications technology associated with telerehabilitation; and provides hypothetical case examples designed to illustrate potential applications of telerehabilitation in early intervention.


Biogeochemical controls on the product of microbial U(VI) reduction.
Biologically mediated immobilization of radionuclides in the subsurface is a promising strategy for the remediation of uranium-contaminated sites. During this process, soluble U(VI) is reduced by indigenous microorganisms to sparingly soluble U(IV). The crystalline U(IV) phase uraninite, or UO2, is the preferable end-product of bioremediation due to its relatively high stability and low solubility in comparison to biomass-associated nonuraninite U(IV) species that have been reported in laboratory and under field conditions. The goal of this study was to delineate the geochemical conditions that promote the formation of nonuraninite U(IV) versus uraninite and to decipher the mechanisms of its preferential formation. U(IV) products were prepared under varying geochemical conditions and characterized with X-ray absorption spectroscopy (XAS), scanning transmission X-ray microscopy (STXM), and various wet chemical methods. We report an increasing fraction of nonuraninite U(IV) species with decreasing initial U concentration. Additionally, the presence of several common groundwater solutes (sulfate, silicate, and phosphate) promote the formation of nonuraninite U(IV). Our experiments revealed that the presence of those solutes promotes the formation of bacterial extracellular polymeric substances (EPS) and increases bacterial viability, suggesting that the formation of nonuraninite U(IV) is due to a biological response to solute presence during U(VI) reduction. The results obtained from this laboratory-scale research provide insight into biogeochemical controls on the product(s) of uranium reduction during bioremediation of the subsurface.


Professional development themes in strength and conditioning coaches.
The purpose of this study was to explore professional development themes in experienced strength and conditioning coaches. Strength and conditioning coaches (N = 15, mean age = 34.3 years, SD = 5.2 years) with 11.4 (SD = 4.9) years experience working with elite, professional, or talented athletes were interviewed about their professional development. The interviews were transcribed verbatim and content analyzed. Over time, subjects' service-delivery practices became more flexible and client driven. Their role understanding also broadened to include various dimensions, such as the need to consider various stakeholders and the value of good relationships with athletes. The subjects shifted from relying on external justification for professional decision making to their experience-based knowledge. The subjects believed athlete work experience, interactions with senior strength and conditioning coaches and other colleagues, the professional literature, and nonprofessional experiences, such as their own athletic experience and sales or managerial training, were the primary influences on their professional development. Typically, the subjects experienced anxiety about their competence, both early in their careers and when working in new contexts or with new athlete groups, but over time, they developed increased confidence. In addition, the subjects experienced reduced narcissism over time about the control they had over athletes and their competitive results. The current results provide information about the characteristics of effective strength and conditioning coaches, the ways they develop their competencies to help athletes, and the emotions they experience throughout their careers. These results may help strength and conditioning practitioners in planning and optimizing their professional development and effectiveness with athletes.


A comparative analysis of pharmacists' perspectives on codeine use and misuse - a three country survey.
The misuse of codeine is of increasing concern in a number of countries, particularly as this relates to over -the-counter pain and cough relief medication, and is also supplied as a prescription medicine. The study aimed to obtain and analyse the opinions and experience of pharmacy staff with regard to codeine misuse. A cross-sectional web-based survey of pharmacy staff's perspectives on this issue was administered through professional or regulatory bodies and completed by samples drawn in South Africa (n = 124), Ireland (n = 464) and the United Kingdom (n = 129). The majority of participants reported combination codeine-containing products as most popular, but significantly more pharmacy staff in South Africa reported codeine-containing cough syrups as most commonly popular (X2 = 122.7(2), p < 0.001). Codeine use was also seen significantly more of a public health problem in South Africa than in the other two countries (X2 = 7.6(2), p = 0.02). There was no difference across countries in the level of codeine misuse reported by pharmacy staff. Further findings indicate that professional training and education is desired, with unequivocal findings for the need for greater codeine control (X2 = 12.0(2), p = 0.002). In conclusion, there were some inter-country differences, but overall the findings seem to suggest that pharmacists across all three countries view codeine misuse as a problem among their customers. Recommendations centre on risk management, surveillance and staff training.


Assessment of anti-inflammatory and antinociceptive activities of Olea europaea L.
Leaves and fruits of Olea europaea L. (Family Oleaceae) are used for the treatment of various kinds of diseases, i.e., rheumatism and hemorrhoids, and as a vasodilator in vascular disorders for ages in folk medicine. In order to evaluate this information, anti-inflammatory and antinociceptive activities of the ethanolic and n-hexane extracts prepared from the fruits of O. europaea were investigated. For the anti-inflammatory activity, the carrageenan-induced hind paw edema and acetic acid-induced increased capillary permeability models were used, whereas for the antinociceptive activity, the p-benzoquinone-induced writhing and hot plate tests in mice were used. The results revealed that the ethanolic extract did not show a significant anti-inflammatory or analgesic activity, whereas the n-hexane extract displayed 12.7-27.8% inhibition on the carrageenan-induced hind paw edema model at the 400 mg/kg dose, without inducing any apparent acute toxicity as well as gastric damage. Further studies are warranted to define and isolate the active anti-inflammatory and antinociceptive components from this plant, which may yield safe and effective agents to be used in the treatment of inflammatory disorders.


Kernel Clustering: Density Biases and Solutions.
Kernel methods are popular in clustering due to their generality and discriminating power. However, we show that many kernel clustering criteria have density biases theoretically explaining some practically significant artifacts empirically observed in the past. For example, we provide conditions and formally prove the density mode isolation bias in kernel K-means for a common class of kernels. We call it Breiman's bias due to its similarity to the histogram mode isolation previously discovered by Breiman in decision tree learning with Gini impurity. We also extend our analysis to other popular kernel clustering methods, e.g., average/normalized cut or dominant sets, where density biases can take different forms. For example, splitting isolated points by cut-based criteria is essentially the sparsest subset bias, which is the opposite of the density mode bias. Our findings suggest that a principled solution for density biases in kernel clustering should directly address data inhomogeneity. We show that density equalization can be implicitly achieved using either locally adaptive weights or locally adaptive kernels. Moreover, density equalization makes many popular kernel clustering objectives equivalent. Our synthetic and real data experiments illustrate density biases and proposed solutions. We anticipate that theoretical understanding of kernel clustering limitations and their principled solutions will be important for a broad spectrum of data analysis applications across the disciplines.


New methodologies in the construction of dendritic materials.
Dendritic polymers are highly branched polymer structures, with complex, secondary architectures and well-defined spatial location of functional groups. Due to their unique physical and chemical features, applications in areas such as targeted drug-delivery, macromolecular carriers, catalysis, sensors, light harvesting, surface engineering and biomimetic materials have been proposed. However, only a few dendritic materials have been exploited commercially due to time consuming syntheses and the generation of significant waste/presence of unreacted starting materials. This tutorial review describes traditional synthesis of dendritic materials as well as recent advances in synthetic strategies, for example the use of Click chemistry, as a tool to efficiently obtain complex, functional dendritic structures.


Cancer in adolescents and young adults: Who remains at risk of poor social functioning over time?
The objective of the current study was to examine social functioning among adolescents and young adults (AYAs) within the first 2 years after a cancer diagnosis and compare their scores with population norms and identify trajectories of social functioning over time and its correlates. A multicenter, longitudinal study was conducted among 215 AYA patients with cancer aged 14 to 39 years. A total of 141 patients completed a self-report measure of social functioning within the first 4 months of diagnosis and again at 12 months and 24 months later. AYA patients with cancer were found to have significantly worse social functioning scores around the time of diagnosis (52.0 vs 85.1; P<.001), at the 12-month follow-up (73.1 vs 85.1; P<.001), and at the 24-month follow-up (69.2 vs 85.1; P<.001) when compared with population norms. Significant improvements in social functioning from baseline to the 12-month follow-up were observed; however, social functioning levels remained stable thereafter. Among participants, 9% demonstrated consistently high/normal social functioning, 47% demonstrated improved social functioning, 13% were found to have worsening social functioning, and 32% demonstrated consistently low social functioning. AYA patients with cancer who had consistently low social functioning were more often off treatment at the time of follow-up, reported more physical symptoms and higher levels of distress at baseline and follow-up, and perceived less social support at baseline compared with the other 3 groups. Although improved over time, social functioning still was found to be compromised 24 months after the primary diagnosis. Nearly one-third of these patients remain at risk of poor social functioning. Reducing physical symptoms and psychological distress and enhancing social support by interventions during the period after treatment may potentially help these young survivors to better reintegrate into society. Cancer 2017;123:2743-51. © 2017 American Cancer Society.


Parity effects on maternal behaviour are not related to circulating oestradiol concentrations in two breeds of sheep.
Primiparous females of many species, including the sheep, do not show as competent maternal behaviour as multiparous mothers. In this study we investigated whether circulating concentrations of oestradiol might be related to this response, since breed differences in oestradiol concentrations have been shown to correlate with maternal behaviours. Oestradiol concentrations were measured in plasma collected at 2-weekly intervals from primiparous and multiparous ewes of two breeds (Scottish Blackface and Suffolk) throughout gestation, and maternal behaviour was recorded at parturition. Circulating oestradiol concentrations, and the ratio of oestradiol to progesterone concentration (O:P ratio) were higher in late pregnancy in Blackface ewes, but there were no significant effects of ewe parity. However, there was a significant interaction between breed and parity as O:P ratio was lower in primiparous Suffolk ewes compared to multiparous. This relationship was not seen in Blackface ewes. Blackface ewes of both parities groomed their lambs more frequently and made more low-pitched vocalisations than Suffolk ewes. Primiparous ewes were more likely to move as the lamb attempted to suck, and to show withdrawal or aggression towards the lamb. Primiparous Suffolk ewes also made more high pitched bleats than other classes of ewe. The data support previous studies which show an effect of breed on circulating oestradiol and O:P ratio but suggest that parity effects on maternal behaviour may be mediated by sensitivity to circulating concentration of oestradiol rather than variations in the plasma concentrations of this hormone.


Mind the gap: Performance metric evaluation in brain-age prediction.
Estimating age based on neuroimaging-derived data has become a popular approach to developing markers for brain integrity and health. While a variety of machine-learning algorithms can provide accurate predictions of age based on brain characteristics, there is significant variation in model accuracy reported across studies. We predicted age in two population-based datasets, and assessed the effects of age range, sample size and age-bias correction on the model performance metrics Pearson's correlation coefficient (r), the coefficient of determination (R2 ), Root Mean Squared Error (RMSE) and Mean Absolute Error (MAE). The results showed that these metrics vary considerably depending on cohort age range; r and R2 values are lower when measured in samples with a narrower age range. RMSE and MAE are also lower in samples with a narrower age range due to smaller errors/brain age delta values when predictions are closer to the mean age of the group. Across subsets with different age ranges, performance metrics improve with increasing sample size. Performance metrics further vary depending on prediction variance as well as mean age difference between training and test sets, and age-bias corrected metrics indicate high accuracy-also for models showing poor initial performance. In conclusion, performance metrics used for evaluating age prediction models depend on cohort and study-specific data characteristics, and cannot be directly compared across different studies. Since age-bias corrected metrics generally indicate high accuracy, even for poorly performing models, inspection of uncorrected model results provides important information about underlying model attributes such as prediction variance.


Effects of attention on neuroelectric correlates of auditory stream segregation.
A general assumption underlying auditory scene analysis is that the initial grouping of acoustic elements is independent of attention. The effects of attention on auditory stream segregation were investigated by recording event-related potentials (ERPs) while participants either attended to sound stimuli and indicated whether they heard one or two streams or watched a muted movie. The stimuli were pure-tone ABA--patterns that repeated for 10.8 sec with a stimulus onset asynchrony between A and B tones of 100 msec in which the A tone was fixed at 500 Hz, the B tone could be 500, 625, 750, or 1000 Hz, and--was a silence. In both listening conditions, an enhancement of the auditory-evoked response (P1-N1-P2 and N1c) to the B tone varied with Deltaf and correlated with perception of streaming. The ERP from 150 to 250 msec after the beginning of the repeating ABA- patterns became more positive during the course of the trial and was diminished when participants ignored the tones, consistent with behavioral studies indicating that streaming takes several seconds to build up. The N1c enhancement and the buildup over time were larger at right than left temporal electrodes, suggesting a right-hemisphere dominance for stream segregation. Sources in Heschl's gyrus accounted for the ERP modulations related to Deltaf-based segregation and buildup. These findings provide evidence for two cortical mechanisms of streaming: automatic segregation of sounds and attention-dependent buildup process that integrates successive tones within streams over several seconds.


Human Nbp35 is essential for both cytosolic iron-sulfur protein assembly and iron homeostasis.
The maturation of cytosolic iron-sulfur (Fe/S) proteins in mammalian cells requires components of the mitochondrial iron-sulfur cluster assembly and export machineries. Little is known about the cytosolic components that may facilitate the assembly process. Here, we identified the cytosolic soluble P-loop NTPase termed huNbp35 (also known as Nubp1) as an Fe/S protein, and we defined its role in the maturation of Fe/S proteins in HeLa cells. Depletion of huNbp35 by RNA interference decreased cell growth considerably, indicating its essential function. The deficiency in huNbp35 was associated with an impaired maturation of the cytosolic Fe/S proteins glutamine phosphoribosylpyrophosphate amidotransferase and iron regulatory protein 1 (IRP1), while mitochondrial Fe/S proteins remained intact. Consequently, huNbp35 is specifically involved in the formation of extramitochondrial Fe/S proteins. The impaired maturation of IRP1 upon huNbp35 depletion had profound consequences for cellular iron metabolism, leading to decreased cellular H-ferritin, increased transferrin receptor levels, and higher transferrin uptake. These properties clearly distinguished huNbp35 from its yeast counterpart Nbp35, which is essential for cytosolic-nuclear Fe/S protein assembly but plays no role in iron regulation. huNbp35 formed a complex with its close homologue huCfd1 (also known as Nubp2) in vivo, suggesting the existence of a heteromeric P-loop NTPase complex that is required for both cytosolic Fe/S protein assembly and cellular iron homeostasis.


Molecular characterization and adhesive properties of CF29K, an adhesin of Klebsiella pneumoniae strains involved in nosocomial infections.
We previously described a CS31A-related protein, CF29K, expressed by Klebsiella pneumoniae strains involved in nosocomial infections. In this study, we cloned and sequenced cf29A, the structural gene of the CF29K protein, and showed that CF29K is an antigenic subtype of CS31A. The CF29K protein was found to be identical to the CS31A-L protein on the basis of biochemical and immunological properties. In contrast, the CS31A-H protein presented a different apparent molecular mass during sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a different limited degradation pattern with endopeptidase V8, and a specific conformational epitope. We cloned and sequenced the CS31A-L structural gene and confirmed that CF29K and CS31A-L are identical, but their major subunits differ from ClpG (the CS31A-H subtype major subunit) by one amino acid at position 89 of the mature protein, which is a lysine in CF29K instead of the asparagine in ClpG. Site-directed mutagenesis experiments demonstrated that the biochemical and immunological differences between CS31A-H and CF29K or CS31A-L were dependent only on the amino acid at position 89 of the mature protein. To study the adhesive properties of CS31A-H and CF29K in the same Escherichia coli reference strain, we performed transcomplementation experiments with the cloned CS31A major-subunit structural genes or cloned cf29A gene and the clp accessory genes of the CS31A operon. We showed that CS31A-L, CF29K, and CS31A-H were involved in adhesion to Caco-2 and Int-407 cells but not to HEp-2 cells. Nevertheless, K. pneumoniae strains and corresponding E. coli transconjugants producing CF29K adhered to cultured Caco-2, Int-407, and HEp-2 cells, indicating the expression of another R-plasmid-encoded adhesin that mediated adhesion to HEp-2 cells. The carbohydrate part of the eucaryotic receptor of CF29K and CS31A-H adhesins was investigated by adhesion inhibition experiments with Int-407 cells. Although CS31A and CF29K belong to the K88 adhesin family, the receptor does not contain N-acetyl-D-galactosamine residues but contains N-acetylneuraminic acid and N-acetyl-D-glucosamine.


Treatment of anterior communicating artery aneurysms: complementary aspects of microsurgical and endovascular procedures.
Endovascular and surgical treatment must be clearly defined in the management of anterior communicating artery (ACoA) aneurysms. In this study the authors report their recent experience in using a combined surgical and endovascular team approach for ACoA aneurysms, and compare these results with those obtained during an earlier period in which surgical treatment was used alone. Morbidity and mortality rates, causes of unfavorable outcomes, and morphological results were also assessed. The prospective study included 223 patients who were divided into three groups: Group A (83 microsurgically treated patients, 1990-1995); Group B (103 microsurgically treated patients, 1996-2000); and Group C (37 patients treated with Guglielmi Detachable Coil [GDC] embolization, 1996-2000). Depending on the direction in which the aneurysm fundus projected, the authors attempted to apply microsurgical treatment to Type 1 aneurysms (located in front of the axis formed by the pericallosal arteries). They proposed the most adapted procedure for Type 2 aneurysms (located behind the axis of the pericallosal arteries) after discussion with the neurovascular team, depending on the physiological status of the patient, the treatment risk, and the size of the aneurysm neck. In accordance with the classification of Hunt and Hess, the authors designated those patients with unruptured aneurysms (Grade 0) and some patients with ruptured aneurysms (Grades I-III) as having good preoperative grades. Patients with Grade IV or V hemorrhages were designated as having poor preoperative grades. By performing routine angiography and computerized tomography scanning, the causes of unfavorable outcome (Glasgow Outcome Scale [GOS] score < 5) and the morphological results (complete or incomplete occlusion) were analyzed. Overall, the clinical outcome was excellent (GOS Score 5) in 65% of patients, good (GOS Score 4) in 9.4%, fair (GOS Score 3) in 11.6%, poor (GOS Score 2) in 3.6%, and fatal in 10.3% (GOS Score 1). Among 166 patients in good preoperative grades, an excellent outcome was observed in 134 patients (80.7%). The combined permanent morbidity and mortality rate accounted for up to 19.3% of patients. The rates of permanent morbidity and death that were related to the initial subarachnoid hemorrhage were 6.2 and 1.5% for Group A, 6.6 and 1.3% for Group B, and 4 and 4% for Group C, respectively. The rates of permanent morbidity and death that were related to the procedure were 15.4 and 1.5% for Group A, 3.9 and 0% for Group B, and 8 and 8% for Group C, respectively. When microsurgical periods were compared, the rate of permanent morbidity or death related to microsurgical complications decreased significantly (Group A, 11 patients [16.9%] and Group B, three patients [3.9%]); Fisher exact test, p = 0.011) from the period of 1990 to 1995 to the period of 1996 to 2000. The combined rate of morbidity and mortality that was related to the endovascular procedure (16%) explained the nonsignificance of the different rates of procedural complications for the two periods, despite the significant decrease in the number of microsurgical complications. Among 57 patients in poor preoperative grade, an excellent outcome was observed in 11 patients (19.3%); however, permanent morbidity (GOS Scores 2-4) or death (GOS Score 1) occurred in 46 patients (80.7%). With regard to the correlation between vessel occlusion (the primary microsurgical complication) and the morphological characteristics of aneurysms, only the direction in which the fundus projected appeared significant as a risk factor for the microsurgically treated groups (Fisher exact test: Group A, p = 0.03; Group B, p = 0.002). The difference between endovascular and microsurgical procedures in the achievement of complete occlusion was considered significant (chi2 = 6.13, p = 0.01). The direction in which the fundus projects was chosen as the morphological criterion between endovascular and surgical methods. The authors propose that microsurgical clip application should be the preferred option in the treatment of ACoA aneurysms with anteriorly directed fundi and that endovascular packing be selected for those lesions with posteriorly directed fundi, depending on morphological criteria.


The use of Stunkard's figure rating scale to identify underweight and overweight in Chinese adolescents.
To compare the performance of Stunkard's current body size (CBS) with self-reported body mass index (BMI), waist circumference (WC) and waist to stature ratio (WSR) in predicting weight status in Chinese adolescents, and to determine the CBS cutoffs for overweight/obesity and underweight. This cross-sectional study was conducted in a sample of 5,418 secondary school students (45.2% boys; mean age 14.7 years). Height and weight were measured by trained teachers or researchers. Subjects were classified as underweight, normal weight, or overweight/obese according to the International Obesity Task Force cutoffs. Subjects were asked to select the figure that best resembled their CBS on the Stunkard's figure rating scale. Self-reported height, weight, WC and WSR were also obtained. The performance of CBS, self-reported BMI, WC and WSR as a weight status indicator was analysed by sex-specific receiver operating characteristic curves. The optimal CBS cutoffs for underweight and overweight/obesity were determined based on the Youden Index. Apart from self-reported BMI, CBS had the greatest area under curve (AUC) for underweight in boys (0.82) and girls (0.81). For overweight/obesity, CBS also had a greater AUC (0.85) than self-reported WC and WSR in boys, and an AUC (0.81) comparable to self-reported WC and WSR in girls. In general, CBS values of 3 and 5 appeared to be the optimal cutoffs for underweight and overweight/obesity, respectively, in different sex-age subgroups. CBS is a potentially useful indicator to assess weight status of adolescents when measured and self-reported BMI are not available.


Reaction-diffusion analysis of the effects of temperature on high-energy phosphate dynamics in goldfish skeletal muscle.
Thermal acclimation results in dramatic changes in the fractional volume of mitochondria within skeletal muscle of teleost fish. We investigated the hypothesis that changes in mitochondrial volume represent a compensatory response to temperature-induced changes in intracellular diffusion coefficients (D) of the high-energy phosphate compounds ATP and creatine phosphate (PCr). Using 31P nuclear magnetic resonance spectroscopy, we determined DPCr and DATP in goldfish (Carassius auratus) skeletal muscle at 25 degrees C and 5 degrees C: DPCr was 3.28 +/- 0.18 x 10(-6) cm2s-1 at 25 degrees C and 2.00 +/- 0.90 x 10(-6) cm2s-1 at 5 degrees C: DATP was 2.13 +/- 0.16 x 10(-6) cm2s-1 at 25 degrees C and was estimated to be 1.30 x 10(-6) cm2s-1 at 5 degrees C. There was no evidence for an effect of acclimation temperature or fiber type on DATP or DPCr. A mathematical reaction-diffusion model was used to calculate profiles of [ATP], [PCr] and the free energy of ATP hydrolysis (delta GATP) in activated goldfish muscle fibers at 5 degrees C and 25 degrees C. The results showed spatial and temporal constancy of [ATP], [PCr] and delta GATP in red fibers at both temperatures, regardless of changes in acclimation temperature or mitochondrial density. The model also showed spatial and temporal constancy of [ATP] in white fibers at 5 degrees C and 25 degrees C, but gradients in [PCr] and delta GATP developed in white fibers under all conditions of temperature and acclimation temperature. These gradients were attenuated in cold-acclimated animals by cold-induced increases in mitochondrial density. However, the model shows that the proximal stimulus for temperature-induced changes in mitochondrial volume density in muscle is not a disruption in intracellular diffusion of high-energy phosphates.


Exploration of the cytochrome c oxidase pathway puzzle and examination of the origin of elusive mutational effects.
Gaining detailed understanding of the energetics of the proton-pumping process in cytochrome c oxidase (CcO) is a problem of great current interest. Despite promising mechanistic proposals, so far, a physically consistent model that would reproduce all the relevant barriers needed to create a working pump has not been presented. In addition, there are major problems in elucidating the origin of key mutational effects and in understanding the nature of the apparent pK(a) values associated with the pH dependencies of specific proton transfer (PT) reactions in CcO. This work takes a key step in resolving the above problems, by considering mutations, such as the Asn139Asp replacement, that blocks proton pumping without affecting PT to the catalytic site. We first introduce a formulation that makes it possible to relate the apparent pK(a) of Glu286 to different conformational states of this residue. We then use the new formulation along with the calculated pK(a) values of Glu286 at these different conformations to reproduce the experimentally observed apparent pK(a) of the residue. Next, we take the X-ray structures of the native and Asn139Asp mutant of the Paracoccus denitrificans CcO (N131D in this system) and reproduce for the first time the change in the primary PT pathways (and other key features) based on simulations that start with the observed structural changes. We also consider the competition between proton transport to the catalytic site and the pump site, as a function of the bulk pH, as well as the H/D isotope effect, and use this information to explore the relative height of the two barriers. The paper emphasizes the crucial role of energy-based considerations that include the PT process, and the delicate control of PT in CcO.


Identification of novel splicing variants of protein tyrosine phosphatase receptor type Z.
Protein tyrosine phosphatase receptor type Z (PTPRZ, also known as PTPζ or RPTPβ) is preferentially expressed in the central nervous system (CNS). PTPRZ plays important roles during development and adulthood in CNS myelination, learning and memory. Three splicing isoforms for PTPRZ have been identified to date: two receptor type isoforms, PTPRZ-A and PTPRZ-B, and one secretory isoform, PTPRZ-S. We herein identified novel PTPRZ receptor sub-isoforms without a seven-amino acid sequence encoded by exon 16. This sequence forms a part of the helix-turn-helix segment called the 'wedge' structure, which is located at the N-terminal region in the membrane-proximal protein tyrosine phosphatase domain. In contrast to conventional receptor isoforms with uniform expression, the deleted isoforms were expressed in the brain, but not in the retina, indicating the tissue-specific splicing of exon 16. Biochemical analyses of PTPRZ intracellular regions revealed differences in the characteristics of the deleted form, namely, stronger binding activity to postsynaptic density protein 95 (PSD95) and greater enrichment in the postsynaptic density fraction than the full-length form. Furthermore, the exon 16-deleted form exhibited higher catalytic efficiency in vitro. These results suggest that sub-isoforms of PTPRZ have different functions because of variations in the wedge structure.


Nitrospira-like bacteria associated with nitrite oxidation in freshwater aquaria.
Oxidation of nitrite to nitrate in aquaria is typically attributed to bacteria belonging to the genus Nitrobacter which are members of the alpha subdivision of the class Proteobacteria. In order to identify bacteria responsible for nitrite oxidation in aquaria, clone libraries of rRNA genes were developed from biofilms of several freshwater aquaria. Analysis of the rDNA libraries, along with results from denaturing gradient gel electrophoresis (DGGE) on frequently sampled biofilms, indicated the presence of putative nitrite-oxidizing bacteria closely related to other members of the genus Nitrospira. Nucleic acid hybridization experiments with rRNA from biofilms of freshwater aquaria demonstrated that Nitrospira-like rRNA comprised nearly 5% of the rRNA extracted from the biofilms during the establishment of nitrification. Nitrite-oxidizing bacteria belonging to the alpha subdivision of the class Proteobacteria (e.g., Nitrobacter spp.) were not detected in these samples. Aquaria which received a commercial preparation containing Nitrobacter species did not show evidence of Nitrobacter growth and development but did develop substantial populations of Nitrospira-like species. Time series analysis of rDNA phylotypes on aquaria biofilms by DGGE, combined with nitrite and nitrate analysis, showed a correspondence between the appearance of Nitrospira-like bacterial ribosomal DNA and the initiation of nitrite oxidation. In total, the data suggest that Nitrobacter winogradskyi and close relatives were not the dominant nitrite-oxidizing bacteria in freshwater aquaria. Instead, nitrite oxidation in freshwater aquaria appeared to be mediated by bacteria closely related to Nitrospira moscoviensis and Nitrospira marina.


Electron microprobe analysis of lunar samples.
Plagioclase feldspar, clinopyroxene, and ilmenite in a polished thin section of a type A crystalline rock were analyzed. The clinopyroxene grains are compositionally variable, and both high Ca and low Ca phases are present. The plagioclase is compositionally homogeneous. The ilmenite is chemically homogeneous except for occasional, small areas of high local chromium concentration. Accessory minerals are: apatite (containing Cl, F, Y, and Ce), troilite, and metallic iron. Glassy spherules from the lunar soil are for the most part similar in composition to the crystalline rocks; however, some appear to have been monomineralic. The crystalline rock has apparently formed by relatively rapid cooling of a silicate melt under conditions of low oxygen partial pressure. Many components of the soil appear to have formed by meteoritic impact.


Recurrent renal stone disease-advances in pathogenesis and clinical management.
Kidney stones are common in industrialised nations: up to 15% of white men and 6% of all women will develop one stone, with recurrence in about half these people. Risk factors for formation of stones include urinary promoters (calcium, urate, cystine, and sodium) and urinary inhibitors (magnesium, citrate, and nephrocalcin). Acute renal colic can be precipitated by dehydration and reduced urine output, increased protein intake, heavy physical exercise, and various medicines. Such colic manifests as severe loin pain and can be accompanied by frequent urination, dysuria, oliguria, and haematuria. Documentation of stone characteristics is extremely important: type, size, location, and underlying metabolic abnormalities. Such details can be obtained with a combination of biochemical investigations, microscopic examination of urine under polarised light, and an intravenous pyelogram. Ultrasonography and plain abdominal radiographs are also useful, especially for patients unable to tolerate an intravenous pyelogram. Acute therapy includes complete pain relief, rehydration, and encouragement of diuresis. Long-term management encompasses education of patients with regard to diet and fluid intake, control of calciuria, citrate replacement, and treatment of any underlying urinary-tract infection or metabolic abnormality. Stones smaller than 5 mm normally pass spontaneously, whereas larger stones, as big as 2 cm, are best treated with extracorporeal shock-wave lithotripsy. All physicians should have a clear understanding of the pathogenesis and clinical management (acute treatment and prevention of recurrence) of renal stone disease.


New genetic evidence for involvement of the dopamine system in migraine with aura.
In order to systematically test the hypothesis that genetic variation in the dopamine system contributes to the susceptibility to migraine with aura (MA), we performed a comprehensive genetic association study of altogether ten genes from the dopaminergic system in a large German migraine with aura case-control sample. Based on the genotyping results of 53 variants across the ten genes in 270 MA cases and 272 controls, three genes-DBH, DRD2 and SLC6A3-were chosen to proceed to additional genotyping of 380 MA cases and 378 controls. Four of the 26 genotyped polymorphisms in these three genes displayed nominally significant allelic P-values in the sample of 650 MA patients and 650 controls. Three of these SNPs [rs2097629 in DBH (uncorrected allelic P value = 0.0012, OR = 0.77), rs7131056 in DRD2 (uncorrected allelic P value = 0.0018, OR = 1.28) and rs40184 in SLC6A3 (uncorrected allelic P value = 0.0082, OR = 0.81)] remained significant after gene-wide correction for multiple testing by permutation analysis. Further consideration of imputed genotype data from 2,937 British control individuals did not affirm the association with DRD2, but supported the associations with DBH and SLC6A3. Our data provide new evidence for an involvement of components of the dopaminergic system-in particular the dopamine-beta hydroxylase and dopamine transporter genes-to the pathogenesis of migraine with aura.


Community-based Mental Healthcare: A Case Study in a Cross-border Region of Germany and the Netherlands.
Community-based mental healthcare (CBMH) aims at supplying psychiatric patients with rehabilitative care outside the hospital. The aim of this study was to compare the organization of CBMH in a cross-border region of Germany and the Netherlands. Semi-structured interviews gave insight into characteristics of CBMH approaches applied in the German region of Aachen (IHP) and the Dutch Province of Limburg (FACT). We applied a Delphi technique to select a performance indicator (PI) set for CBMH, which served as a conceptual model to allow comparison. Both approaches are flexible, patient-centred and include the evaluation of quality. Both provide financial and administrative support for the access. CBMH approaches appear to be equally valid from several perspectives even if they revealed, at the same time, important differences related to scope, integration with non-CBMH care resources and geographic coverage. Secondarily, the study provides a contribution to the development of a PI set to compare and evaluate CBMH approaches.


Independent and joint effects of the MAPT and SNCA genes in Parkinson disease.
We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects.


cis-to-trans isomerization of azobenzene investigated by using thin films of metal-organic frameworks.
The activation barrier for cis-to-trans isomerization is a key parameter for governing the properties of photoswitchable molecules. This quantity can be computed by using theoretical methods, but experimental determination is not straightforward. Photoswitchable molecules typically do not change their conformation in the pure crystalline state. When the molecules are in solution, the switching is affected by the viscosity and polarity of the solvent and when embedded in polymers, the conformational change is affected by the polymer matrix. Here, we describe a novel approach where the photoswitchable group is integrated in a highly crystalline, porous molecular framework. Sufficiently large pore sizes in such metal-organic frameworks, MOFs, allow unhindered switching and the strictly periodic structure of the lattice eliminates virtually all contributions from inhomogeneities. Using IR spectroscopy to probe the conformational state of azobenzene, the energy barrier separating the cis and the trans state could be determined by an Arrhenius analysis of the data accumulated in a temperature regime between 314 K and 385 K. The result, 1.09 ± 0.09 eV, is in very good agreement with the activation energy reported for the thermal cis-to-trans isomerization of free azobenzene as computed by DFT calculations.


[Italian consensus on EULAR recommendations 2005 for the management of hip osteoarthritis].
The recommendations for the management of osteoarthritis (OA) of the hip were proposed by EULAR in 2005. Among the most important objectives of the expert charged to provide these recommendations were their wide dissemination and implementation. Thus, the information generated can be used by each individual country to produce their own set of management guidelines and algorithms for treatment in primary care. According with that previously executed for the EU-LAR recommendation 2003 for the knee, the Italian Society of Rheumatology (SIR) has organised a Consensus on the EULAR recommendations 2005 for the management of hip OA. To obtain an acceptability as large as possible, the group of experts was composed by many physicians interested in the management of hip OA, including Orthopaedics, Rheumatologists, Physiatrists, and General Practitioners. Main aim of the Consensus was to analyse the acceptability and applicability of the recommendations according to own experience and local situations in the Italy. The results of this Consensus have demonstrated that a large majority of the EULAR recommendations are endorsed by the Italian experts. Furthermore, the final document of the Italian Consensus clearly indicated the need that the specialists involved in the management of hip OA strongly encourage the dissemination of the EULAR 2005 recommendations also in Italy.


The association between water-borne fluoride and bone mineral density in older adults.
While the benefit of fluoridation in the prevention of dental caries has been overwhelmingly substantiated, the effect of fluoride on bone mineral density is less clear. This cross-sectional study was designed to compare the bone mineral densities of older adults exposed to various levels of fluoride from community water systems. Participants were recruited from 3 rural communities with naturally occurring fluoride in their water systems at 0.03, 0.7, and 2.5 mg/L. All adults, age 60 and over, were eligible if they were ambulatory and had a long-term history (> or = 20 yrs) of ingesting city water. Bone mineral density (BMD) was measured by means of dual-energy x-ray absorptiometry at 3 anatomical sites: lumbar spine, proximal femur, and forearm. A total of 353 white non-Hispanic women and 317 white non-Hispanic men took part in the study. When the data were stratified by city of residence and gender, men and women living in the community with high levels of fluoride in their community water system had significantly higher lumbar spine BMD than their counterparts from the communities with low and moderate fluoride levels. The women in the high-fluoride community had significantly higher proximal femur BMD, but there were no statistically significant differences among men in either proximal femur or forearm BMD. Long-term exposure (> or = 20 yrs) to higher levels of fluoride appears to have a positive impact on lumbar spine and proximal femur BMD. Based on the results of this study, exposure to fluoride at levels considered "optimal" for the prevention of dental caries (from 0.7 to 1.2 mg/L) appears to have no significant impact on bone mineral density. The relationship between higher levels of fluoride exposure and bone mineral density requires further investigation.


From extracellular to intracellular: the establishment of a symbiosis.
The colonization of host cells by modern symbionts is surveyed. The morphological distinction between extracellular and intracellular symbionts is not sharp, and the various kinds of association can be arranged in a graded series of increasing morphological integration of the symbiont into the host cell. Apart from some aggressive parasitic infections, the great majority of symbionts are enclosed by a host membrane in a vacuole. Those not enclosed in a host vacuole usually cannot be cultivated outside the cell. It is therefore surmised that encirclement by a vacuolar membrane would only disappear, if at all, in the later stages of the evolution of intracellular symbiosis. Recognition mechanisms between host and symbiont occur, but have been little studied. In some associations, recognition at surface contact occurs, and there is evidence for the involvement of lectins in certain cases. In other associations, recognition may occur wholly or in part after the entry of symbiont into host cells. After entry, special mechanisms for the biotrophic transfer of nutrients from symbiont to host develop. Both the symbiont population size and its rate of increase are strictly regulated by the host cell; symbiont metabolism may be controlled likewise. Rates of evolution of intracellular symbionts are probably very rapid, owing in part to responses of the host cell to its symbiont.


Universal expressions of population change by the Price equation: Natural selection, information, and maximum entropy production.
The Price equation shows the unity between the fundamental expressions of change in biology, in information and entropy descriptions of populations, and in aspects of thermodynamics. The Price equation partitions the change in the average value of a metric between two populations. A population may be composed of organisms or particles or any members of a set to which we can assign probabilities. A metric may be biological fitness or physical energy or the output of an arbitrarily complicated function that assigns quantitative values to members of the population. The first part of the Price equation describes how directly applied forces change the probabilities assigned to members of the population when holding constant the metrical values of the members-a fixed metrical frame of reference. The second part describes how the metrical values change, altering the metrical frame of reference. In canonical examples, the direct forces balance the changing metrical frame of reference, leaving the average or total metrical values unchanged. In biology, relative reproductive success (fitness) remains invariant as a simple consequence of the conservation of total probability. In physics, systems often conserve total energy. Nonconservative metrics can be described by starting with conserved metrics, and then studying how coordinate transformations between conserved and nonconserved metrics alter the geometry of the dynamics and the aggregate values of populations. From this abstract perspective, key results from different subjects appear more simply as universal geometric principles for the dynamics of populations subject to the constraints of particular conserved quantities.


Influence of noncircular chainring on male physiological parameters in hand cycling.
The purpose of this study was to examine the influence of a noncircular chainring (NCC) compared with a conventional circular chainring (CC) on hand cycling performance. Eleven nondisabled male participants with no hand cycling experience initially completed an incremental exercise test. Afterward, the participants completed two 20 s sprint tests, followed by a 20 min endurance test and then another two 20 s sprint tests. An NCC and a CC were used in random order on two separate occasions. To compare the effects of the NCC and CC on power data of the sprint tests and metabolic response during the endurance test, a two-way analysis of variance for repeated measures was used. Average power values of the sprint tests showed no significant difference between NCC and CC, but over time, values of the first and third sprint tests were higher than those of the second and fourth sprint tests for both chainrings. Values of energy expenditure (kilojoules), gross efficiency (percentage), and net efficiency (percentage) after 10 and 20 min during the endurance test using NCC and CC showed no significant differences (p > 0.05) either between tests or over time. Under the current test conditions and focusing on physiological parameters, a performance optimization using an NCC in hand cycling could not be proven.


Adipose Tissue Inflammation Is Not Related to Adipose Insulin Resistance in Humans.
The role of adipose tissue (AT) inflammation in AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression, and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC50). We studied 86 volunteers with normal weight or obesity at baseline and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong positive relationship between IC50 and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC50 and abdominal AT inflammatory markers CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6, and TNF-α mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC50; however, there was no reduction in adipose ATM content, senescent cells, or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.


Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing.
The design and production of an oral dual-compartmental dosage unit (dcDU) was examined in vitro and in vivo with the purpose of physically isolating and modulating the release profile of an anti-tuberculosis drug combination. Rifampicin (RIF) and isoniazid (ISO) are first line combination drugs for treatment of tuberculosis (TB) that negatively interact with each other upon simultaneous release in acidic environment. The dcDUs were designed in silico by computer aided design (CAD) and fabricated in two steps; first three-dimensional (3D) printing of the outer structure, followed by hot-melt extrusion (HME) of the drug-containing filaments. The structure of the fabricated dcDUs was visualized by scanning electron microscopy (SEM). The 3D printed compartmentalized shells were loaded with filaments containing active pharmaceutical ingredient (API) and selectively sealed to modulate drug dissolution. The drug release profile of the dcDUs was characterized by pH-transfer dissolution in vitro and pharmacokinetics studies in rats, and resulted in modified release of the APIs from the dcDUs as compared to the free filaments. Furthermore, the selective physical sealing of the compartments resulted in an effective retardation of the in vitro API release. The findings of this study support the development of controllable-by-design dcDU systems for combination therapies to enable efficient therapeutic translation of oral dosage forms.


Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity.
Excitotoxic neuronal death underlies many neurodegenerative disorders. Because cannabinoid receptor agonists act presynaptically to inhibit glutamate release, we examined the effects of Win 55212-2, a full agonist at CB(1) receptors, and Delta(9)-tetrahydrocannabinol (THC), a partial agonist, on the survival of neurons exposed to an excitotoxic pattern of synaptic activity. Reducing the extracellular Mg(2+) concentration ([Mg(2+)](o)) to 0.1 mM evoked an aberrant pattern of glutamatergic activity that produced synaptically mediated death of rat hippocampal neurons in culture. Neuronal viability was quantified with a multiwell fluorescence plate scanner equipped to detect propidium iodide fluorescence. Win 55212-2 (100 nM) and THC (100 nM) significantly reduced 0.1 mM [Mg(2+)](o)-induced cell death by 77 +/- 11% and 84 +/- 8%, respectively. Interestingly, the protection afforded by THC was not significantly different from that produced by Win 55212-2, suggesting that attenuation without a complete block of excitatory activity is sufficient for neuroprotection. The effect of prolonged drug exposure on the neuroprotection afforded by cannabinoid receptor agonists was also studied. When cultures were pretreated for 24 h with Win 55212-2 (100 nM) or THC (100 nM), inhibition of 0.1 mM [Mg(2+)](o)-induced toxicity was significantly reduced to 39 +/- 19% and 45 +/- 13%, respectively. Thus, desensitization of CB(1) receptors diminishes the neuroprotective effects of cannabinoids. This study demonstrates the importance of agonist efficacy and the duration of treatment on the neuroprotective effects of cannabinoids. It will be important to consider these effects on neuronal survival when evaluating pharmacologic treatments that modulate the endocannabinoid system.


Management of a child with vomiting.
Vomiting is a protective reflex that results in forceful ejection of stomach contents up to and out of the mouth. It is a common complaint and may be the presenting symptom of several life-threatening conditions. It can be caused by a variety of organic and nonorganic disorders; gastrointestinal (GI) or outside of GI. Acute gastritis and gastroenteritis (AGE) are the leading cause of acute vomiting in children. Important life threatening causes in infancy include congenital intestinal obstruction, atresia, malrotation with volvulus, necrotizing enterocolitis, pyloric stenosis, intussusception, shaken baby syndrome, hydrocephalus, inborn errors of metabolism, congenital adrenal hypoplasia, obstructive uropathy, sepsis, meningitis and encephalitis, and severe gastroenteritis, and in older children appendicitis, intracranial mass lesion, diabetic ketoacidosis, Reye's syndrome, toxic ingestions, uremia, and meningitis. Initial evaluation is directed at assessment of airway, breathing and circulation, assessment of hydration status and red flag signs (bilious or bloody vomiting, altered sensorium, toxic/septic/apprehensive look, inconsolable cry or excessive irritability, severe dehydration, concern for symptomatic hypoglycemia, severe wasting, Bent-over posture). The history and physical examination guides the approach in an individual patient. The diverse nature of causes of vomiting makes a "routine" laboratory or radiologic screen impossible. Investigations (Serum electrolytes and blood gases,renal and liver functions and radiological studies) are required in any child with dehydration or red flag signs, to diagnose surgical causes. Management priorities include treatment of dehydration, stoppage of oral fluids/feeds and decompression of the stomach with nasogastric tube in patients with bilious vomiting. Antiemetic ondansetron(0.2 mg/kg oral; parenteral 0.15 mg/kg; maximum 4 mg) is indicated in children unable to take orally due to persistent vomiting, post-operative vomiting, chemotherapy induced vomiting, cyclic vomiting syndrome and acute mountain sickness.


Aldose Reductase Mediates Transforming Growth Factor β2 (TGF-β2)-Induced Migration and Epithelial-To-Mesenchymal Transition of Lens-Derived Epithelial Cells.
Cataract surgery involves removal of lens tissue, but is associated with a high complication rate due to regrowth of residual lens epithelial cells to produce posterior capsule opacification (PCO) and diminished visual acuity. As inhibitors of aldose reductase (AR) have been shown to suppress markers of PCO, our studies were designed to identify a role for AR in the pathogenesis of PCO. Sorbinil-mediated AR inhibition was determined by measuring sorbitol accumulation. Cell migration was measured using both transwell and scratch assays. Proteins in the SMAD signaling pathway were measured by Western blotting. The interactions of AR and SMADs were demonstrated by co-immunoprecipitation (Co-IP) and proximity ligation assay (PLA). Epithelial-to-mesenchymal transition (EMT) expression was measured by Western blot and quantitative PCR (q-PCR). Matrix metalloproteinase (MMP)-2 and MMP-9 activities were measured in conditioned medium by zymography. We observed that either Sorbinil-mediated AR inhibition or siRNA-mediated AR gene knockdown prevented migration of lens epithelial cells following exposure to TGF-β2. AR inhibition or AR knockdown reduced SMAD and MMP activation triggered by TGF-β2. In addition, we demonstrated AR inhibition or AR knockdown decreased TGF-β2-induced expression of EMT markers. Co-IP studies and PLA were used to demonstrate that AR and SMAD2 interact either directly or in close concert with additional factor(s) in a nonenzymatic manner. This study demonstrates that AR participates in the response of lens epithelial cells to TGF-β2. Our studies raise the possibility that AR inhibition may be effective in preventing development of PCO by disrupting the TGF-β2/SMAD pathway.


Technical nuances of awake brain tumor surgery and the role of maximum safe resection.
Awake craniotomy is a valuable surgical approach to aide in the identification and preservation of functional areas of the brain during the removal of intrinsic brain tumors. We reviewed the current literature for evidence in support of extent of resection to improve survival, symptom management, and time to malignant transformation in low- and high-grade glioma, as well as methods and technical nuances to maximize safety and extent of resection during awake brain tumor surgery. We found 22 studies involving low-grade glioma and 33 studies of high-grade glioma that examined the role of extent of resection to improve outcome. Though there are no randomized clinical trials on the subject, there is a growing body of evidence supporting improved overall and progression-free survival with greater extent of resection. Additionally, patients benefit from longer malignant progression-free survival in addition to superior seizure control. Techniques in awake brain tumor surgery have evolved to allow a greater degree of safety, even in patients who were previously considered high risk. Based on the current practice described in this review, we conclude that awake brain tumor surgery can be safely performed to improve extent of tumor resection and survival, with the added benefit of low failure rates and excellent long-term functional outcomes.


Association of cigarette smoking and CRP levels with DNA methylation in α-1 antitrypsin deficiency.
Alpha-1 antitrypsin (AAT) deficiency and tobacco smoking are confirmed risk factors for Chronic Obstructive Pulmonary Disease. We hypothesized that variable DNA methylation would be associated with smoking and inflammation, as reflected by the level of C-Reactive Protein (CRP) in AAT-deficient subjects. Methylation levels of 1,411 autosomal CpG sites from the Illumina GoldenGate Methylation Cancer Panel I were analyzed in 316 subjects. Associations of five smoking behaviors and CRP levels with individual CpG sites and average methylation levels were assessed using non-parametric testing, linear regression and linear mixed effect models, with and without adjustment for age and gender. Univariate linear regression analysis revealed that methylation levels of 16 CpG sites significantly associated with ever-smoking status. A CpG site in the TGFBI gene was the only site associated with ever-smoking after adjustment for age and gender. No highly significant associations existed between age at smoking initiation, pack-years smoked, duration of smoking, and time since quitting smoking as predictors of individual CpG site methylation levels. However, ever-smoking and younger age at smoking initiation associated with lower methylation level averaged across all sites. DNA methylation at CpG sites in the RUNX3, JAK3 and KRT1 genes associated with CRP levels. The most significantly associated CpG sites with gender and age mapped to the CASP6 and FZD9 genes, respectively. In summary, this study identified multiple potential candidate CpG sites associated with ever-smoking and CRP level in AAT-deficient subjects. Phenotypic variability in Mendelian diseases may be due to epigenetic factors.


Association of intravenous administration of human Muse cells with deficit amelioration in a rat model of spinal cord injury.
Multilineage-differentiating stress-enduring (Muse) cells are pluripotent stem cells, which can be harvested from the bone marrow. After transplantation, Muse cells can migrate to an injured site of the body and exert repair effects. However, it remains unknown whether Muse cell transplantation can be an effective treatment in spinal cord injury (SCI). The authors used a rat model of thoracic spinal cord contusion injury. For Muse cell transplantation, the clinical product CL2020 containing 300,000 Muse cells was administered intravenously 1 day after midthoracic SCI. Animals were divided into CL2020 (n = 11) and vehicle-treated (n = 15) groups. Behavioral and histological evaluations were conducted over a period of 8 weeks to see whether intravenous CL2020 administration provided therapeutic effects for SCI. The effects of human-selective diphtheria toxin on reversion of the therapeutic effects of CL2020 were also investigated. Hindlimb motor function significantly improved after CL2020 transplantations. Importantly, the effects were reverted by the human-selective diphtheria toxin. In immunohistochemical analyses, the cystic cavity formed after the injury was smaller in the CL2020 group. Furthermore, higher numbers of descending 5-hydroxytryptamine (5-HT) fibers were preserved distal to the injury site after CL2020 administration. Eight weeks after the injury, Muse cells in CL2020 were confirmed to differentiate most predominantly into neuronal cells in the injured spinal cord. Following SCI, Muse cells in CL2020 can reach the injured spinal cord after intravenous administration and differentiate into neuronal cells. Muse cells in CL2020 facilitated nerve fiber preservation and exerted therapeutic potential for severe SCI.


Estimated and measured BMI and self-perceived body image of adolescents in Germany: part 1 - general implications for correcting prevalence estimations of overweight and obesity.
This study examines the degree of divergence between BMI calculated from subjective assessments and BMI calculated from measured height and weight as a function of gender and body image. In the German National Health Interview and Examination Survey for Children and Adolescents (KiGGS) the height and weight of 17,641 children and adolescents aged 0-18 years were measured. Participants were also questioned about their subjective body image (whether they considered themselves much too thin, a bit too thin, exactly the right weight, too fat or much too fat). A representative subsample of adolescents between 11 and 17 years old (N = 3,436: 1,663 boys and 1,773 girls) was asked additionally to self-report their body weight and height before being measured. The bias in the self-reported BMI yielded an underestimation of overweight and obesity prevalence. Girls who considered themselves much too fat or too fat and boys who considered themselves as much too fat underestimated their BMI. This was taken into account using a correction procedure for prevalence estimates of overweight and obesity based on the concept of conditional probabilities. The proposed correction formula using data from the KiGGS study can be applied to other German studies of adolescents in which weight, height and body image are only determined by self-report. Furthermore the correction procedure in principle can be transferred to other studies in other countries as long as a parallel validation study has been conducted to assess both subjective and objective BMI and body image.


Is smartphone addiction really an addiction?
Aims In light of the rise in research on technological addictions and smartphone addiction in particular, the aim of this paper was to review the relevant literature on the topic of smartphone addiction and determine whether this disorder exists or if it does not adequately satisfy the criteria for addiction. Methods We reviewed quantitative and qualitative studies on smartphone addiction and analyzed their methods and conclusions to make a determination on the suitability of the diagnosis "addiction" to excessive and problematic smartphone use. Results Although the majority of research in the field declares that smartphones are addictive or takes the existence of smartphone addiction as granted, we did not find sufficient support from the addiction perspective to confirm the existence of smartphone addiction at this time. The behaviors observed in the research could be better labeled as problematic or maladaptive smartphone use and their consequences do not meet the severity levels of those caused by addiction. Discussion and conclusions Addiction is a disorder with severe effects on physical and psychological health. A behavior may have a similar presentation as addiction in terms of excessive use, impulse control problems, and negative consequences, but that does not mean that it should be considered an addiction. We propose moving away from the addiction framework when studying technological behaviors and using other terms such as "problematic use" to describe them. We recommend that problematic technology use is to be studied in its sociocultural context with an increased focus on its compensatory functions, motivations, and gratifications.


Comparative study of the cytolytic activity of snake venoms from African spitting cobras (Naja spp., Elapidae) and its neutralization by a polyspecific antivenom.
Venoms of several Naja species found in Sub-Saharan Africa, and commonly known as "spitting cobras", induce a predominantly cytotoxic pattern of envenomings that may evolve into tissue necrosis and gangrene. Cytotoxic components of their venoms have been identified as members of the three-finger toxin and phospholipase A(2) protein families. In this study, an in vitro assay using the myogenic cell line C2C12, was utilized to compare the cytolytic activities of venoms from five species of spitting cobras: Naja nigricollis, Naja katiensis, Naja pallida, Naja nubiae, and Naja mossambica. These venoms were strongly cytotoxic, causing a 50% effect at ~1.5 μg/well (15 μg/ml), except for N. katiensis venom, which required nearly twice this amount. Using the cell-based assay, the ability of an equine polyspecific antivenom (EchiTab-Plus-ICP) to neutralize cytotoxicity was assessed. The antivenom completely inhibited the cytotoxic activity of all five venoms, although high antivenom/venom ratios were needed. Neutralization curves displayed the following decreasing order of efficiency: N. nubiae > N. pallida > N. mossambica > N. nigricollis > N. katiensis. Results indicate that neutralizing antibodies toward toxins responsible for this particular effect are present in the antivenom, albeit in low titers. Fucoidan, a natural sulfated polysaccharide known to inhibit the toxic effects of some basic snake venom components, was unable to reduce cytotoxicity of Naja venoms. Results emphasize the need of enhancing the immunogenicity of low molecular mass toxins during antivenom production, as well as to search for useful toxin inhibitors which could complement antivenom therapy.


An epigenetic trap stabilizes singular olfactory receptor expression.
The molecular mechanisms regulating olfactory receptor (OR) expression in the mammalian nose are not yet understood. Here, we identify the transient expression of histone demethylase LSD1 and the OR-dependent expression of adenylyl cyclase 3 (Adcy3) as requirements for initiation and stabilization of OR expression. As a transcriptional coactivator, LSD1 is necessary for desilencing and initiating OR transcription, but as a transcriptional corepressor, it is incompatible with maintenance of OR expression, and its downregulation is imperative for stable OR choice. Adcy3, a sensor of OR expression and a transmitter of an OR-elicited feedback, mediates the downregulation of LSD1 and promotes the differentiation of olfactory sensory neurons (OSNs). This novel, three-node signaling cascade locks the epigenetic state of the chosen OR, stabilizes its singular expression, and prevents the transcriptional activation of additional OR alleles for the life of the neuron.


Expression and characterization of an RNA capping enzyme encoded by Chlorella virus PBCV-1.
We report that the A103R protein of Chlorella virus PBCV-1 is an mRNA capping enzyme that catalyzes the transfer of GMP from GTP to the 5' diphosphate end of RNA. This is a two-step reaction in which the enzyme first condenses with GTP to form a covalent enzyme-GMP intermediate and then transfers the GMP to an RNA acceptor to form a GpppN cap. Purified recombinant Al03R is a 38-kDa monomer that lacks RNA (guanine-7-) methyltransferase activity. With respect to its size, amino acid sequence, and biochemical properties, A103R is more closely related to the yeast RNA guanylyltransferases than it is to the multifunctional capping enzymes coded for by other large DNA viruses--the poxviruses and African swine fever virus. We surmise that in order to cap its transcripts, PBCV-l must either encode additional 5' processing activities or else rely on the host alga to provide these functions.


Characterization of an Endophytic Gloeosporium sp. and Its Novel Bioactivity with "Synergistans".
Gloeosporium sp. (OR-10) was isolated as an endophyte of Tsuga heterophylla (Western hemlock). Both ITS and 18S sequence analyses indicated that the organism best fits either Hypocrea spp. or Trichoderma spp., but neither of these organisms possess conidiophores associated with acervuli, in which case the endophytic isolate OR-10 does. Therefore, the preferred taxonomic assignment was primarily based on the morphological features of the organism as one belonging to the genus Gloeosporium sp. These taxonomic observations clearly point out that limited ITS and 18S sequence information can be misleading when solely used in making taxonomic assignments. The volatile phase of this endophyte was active against a number of plant pathogenic fungi including Phytophthora palmivora, Rhizoctonia solani, Ceratocystis ulmi, Botrytis cinerea, and Verticillium dahliae. Among several terpenes and furans, the most abundantly produced compound in the volatile phase was 6-pentyl-2H-pyran-2-one, a compound possessing antimicrobial activities. When used in conjunction with microliter amounts of any in a series of esters or isobutyric acid, an enhanced inhibitory response occurred with each test fungus that was greater than that exhibited by Gloeosporium sp. or the compounds tested individually. Compounds behaving in this manner are hereby designated "synergistans." An expression of the "median synergistic effect," under prescribed conditions, has been termed the mSE50. This value describes the amount of a potential synergistan that is required to yield an additional median 50% inhibition of a target organism. In this report, the mSE50s are reported for a series of esters and isobutyric acid. The results indicated that isoamyl acetate, allyl acetate, and isobutyric acid generally possessed the lowest mSE50 values. The value and potential importance of these microbial synergistic effects to the microbial environment are also discussed.


Anemia, testosterone, and pituitary adenoma in men.
Older men with clinically nonfunctioning pituitary tumors have been noted to be anemic, to have hypopituitarism, and to have low serum levels of testosterone. The authors hypothesized that men with pituitary adenomas and hypogonadism have a physiologically related decrease in hematocrit. A retrospective analysis was conducted of 216 patients older than 50 years of age who harbored pituitary adenomas. In 100 men serum testosterone levels and a complete blood (cell) count (CBC) were obtained before treatment; a CBC was also acquired in a series of women with pituitary adenomas. Using clinical laboratory standards, anemia was defined as a hematocrit less than 40% in men and less than 35% in women. Thirty-one (46.3%) of 67 men with low serum concentrations of testosterone were anemic. In men with low levels of testosterone, the average hematocrit was 39.9%, compared with 45.6% for men with normal testosterone levels (p < 0.001). Men with macroadenomas were most likely to have both anemia and a low serum concentration of testosterone. Anemia was associated with a low level of testosterone, adjusting for tumor size (odds ratio 19, 95% confidence interval 4.86-77.03). Of patients with anemia, 84% were men and 16% were women (p < 0.001). The prevalence of anemia in women was low and was not correlated with tumor size. Men receiving testosterone replacement therapy had a significantly higher hematocrit value than men with low or normal testosterone levels. These findings support a direct relationship between serum testosterone levels and hematopoiesis in men, and demonstrate that hematopoiesis is compromised in men who have low concentrations of testosterone due to a pituitary adenoma.


Influence of diet on calcium metabolism, tissue calcification and urinary sludge in rabbits (Oryctolagus cuniculus).
Rabbits absorb more calcium (Ca) from their diet than they require, and excrete surplus via urine, which therefore contains a typical 'sludge'. This makes rabbits susceptible to Ca-containing uroliths. But given the Ca content of diets of free-ranging specimens, and the limited reports of urinary sludge and Ca contents in free-ranging lagomorphs, we can suspect that rabbits are naturally adapted to high urinary Ca loads. We fed four groups of New Zealand hybrid rabbits [n = 28, age at start 5-6 weeks) pelleted diets consisting of lucerne hay only (L, Ca 2.32% dry matter (DM)], lucerne:oats 1:1 (LG, Ca 1.36%), grass hay only (G, Ca 1.04%), or grass:oats 1:1 (GG, 0.83%) for 25 weeks, with water available ad libitum. Diets were not supplemented with Ca, phosphorus, or vitamin D. Rabbits on diets LG and GG had lower food and water intakes, lower faeces and urine output, grew faster and had higher body mass at slaughter (mainly attributable to adipose tissue). Apparent Ca digestibility decreased in the order L-LG-G/GG. Rabbits on L had larger and heavier kidneys, more urinary sediment at sonography, and a higher urinary Ca content than the other groups. No animal showed signs of urolithiasis/calcinosis at X-ray, sonography, or gross pathology. Kidney/aorta histology only sporadically indicated Ca deposits, with no systematic difference between groups. Under the conditions of the experiment, dietary Ca loads in legume hay do not appear problematic for rabbits, and other factors, such as water supply and level of activity may be important contributors to urolithiasis development in veterinary patients. However, due to the lower Ca content of grass hay, the significantly lower degree of urinary sludge formation, and the significantly higher water intake related with grass hay feeding, grass hay-dominated diets are to be recommended for rabbits in which urolithiasis prevention is an issue.


The effect of body mass index on high versus low administered activity protocol myocardial perfusion imaging scan time and effective dose using a cadmium zinc telluride camera in clinical practice.
Cadmium Zinc Telluride (CZT) crystal-based myocardial perfusion imaging (MPI) cameras have increased count sensitivity compared to Anger cameras and can be used to lower either the injected activity or the image acquisition time. Institutions adopting CZT cameras need to decide whether to lower the injected activity or imaging time or attempt to lower both with a compromise. The aim of our study was to compare the scan time required to obtain similar count images using high activity protocol (HAP) versus low activity protocol (LAP) stratified by body mass index (BMI) and assess the impact on effective dose and our clinic workflow. Using a CZT camera, a cohort of 100 consecutive clinical patients imaged with LAP rest-stress MPI with approximately 185 MBq and 555 MBq activity was retrospectively compared to a similar cohort of 100 consecutive clinical patients imaged with HAP rest-stress MPI using approximately 370 MBq and 1110 MBq. Administered activity and BMI both had a statistically significant effect on scan time and radiation effective dose. LAP scans took an average of 9 min longer than HAP scans overall, P < 0.0001 and larger BMIs took longer than smaller BMIs, P < 0.0001. In addition, scan times were longer in men than women, P = 0.007. Effective dose was inversely proportional to BMI with an overall decrease of approximately 50% comparing LAP to HAP. For the same CZT camera, the LAP increased scan time while lowering the radiation effective dose when compared to HAP. The increase in scan time increased proportionally to BMI. The effective dose was inversely proportional to BMI. This increase in time did not have a significant impact on our local workflow, but its implications should be considered in the setting of LAP implementation, especially in obese or high patient volume practices.


The impact of Janus nanoparticles on the compatibilization of immiscible polymer blends under technologically relevant conditions.
Several hundred grams of Janus nanoparticles (d ≈ 40 nm) were synthesized from triblock terpolymers as compatibilizers for blending of technologically relevant polymers, PPE and SAN, on industry-scale extruders. The Janus nanoparticles (JPs) demonstrate superior compatibilization capabilities compared to the corresponding triblock terpolymer, attributed to the combined intrinsic properties, amphiphilicity and the Pickering effect. Straightforward mixing and extrusion protocols yield multiscale blend morphologies with "raspberry-like" structures of JPs-covered PPE phases in a SAN matrix. The JPs densely pack at the blend interface providing the necessary steric repulsion to suppress droplet coagulation during processing. We determine the efficiency of JP-compatibilization by droplet size evaluation and find the smallest average droplet size of d ≈ 300 nm at 10 wt % of added compatibilizer, whereas at 2 wt %, use of JPs is most economic with reasonable small droplets and narrow dispersity. In case of excess JPs, rheological properties of the system is changed by a droplet network formation. The large-scale synthesis of JPs, the low required weight fractions and their exceptional stability against extensive shear and temperature profiles during industrial extrusion process make JP promising next generation compatibilizers.


Antibacterial action of honey on oral streptococci.
The antibacterial properties of honey against medically important bacteria have been well documented but this information is not available for the oral bacteria and specifically for the oral streptococci. We determined the minimal inhibitory concentration (MIC) of honey for oral streptococci. Honey had a MIC of 25 per cent (vol/vol) for the bacteria tested with the exception of Streptococcus anginosus and Streptococcus oralis which were inhibited by 17 per cent (vol/vol) and 12 per cent (vol/vol) honey respectively. The hypertonic sugar control had a MIC of 25 per cent (vol/vol) for all the bacteria tested. Although the results of this study indicate that there could be other antibacterial agents present in the honey, it may be assumed that the hypertonic sugar concentration played an important role in this activity.


Identification of two murine loci homologous to the v-cbl oncogene.
The virally transduced oncogene v-cbl transforms fibroblasts in vitro and induces early B-cell-lineage lymphomas in vivo. A series of probes derived from a molecular clone of v-cbl were used to map related sequences in the mouse genome. Analyses of Chinese hamster x mouse somatic-cell hybrids showed that two related genes, cbl-1 and cbl-2, were located on chromosomes 6 and 9, respectively. Restriction enzyme studies of DNA from hybrid cells containing either chromosome 6 or 9 suggested that cbl-1 resembles v-cbl and may be a processed gene, whereas cbl-2 has a complex genomic structure. Analyses of Mus domesticus/M. spretus interspecific backcross mice showed that Cbl-1 maps between the immunoglobulin kappa light chain and T-cell receptor beta chain loci and that Cbl-2 is tightly linked to Thy-1.


Supervised machine learning model to predict mortality in patients undergoing venovenous extracorporeal membrane oxygenation from a nationwide multicentre registry.
Existing models have performed poorly when predicting mortality for patients undergoing venovenous extracorporeal membrane oxygenation (VV-ECMO). This study aimed to develop and validate a machine learning (ML)-based prediction model to predict 90-day mortality in patients undergoing VV-ECMO. This study included 368 patients with acute respiratory failure undergoing VV-ECMO from 16 tertiary hospitals across South Korea between 2012 and 2015. The primary outcome was the 90-day mortality after ECMO initiation. The inputs included all available features (n=51) and those from the electronic health record (EHR) systems without preprocessing (n=40). The discriminatory strengths of ML models were evaluated in both internal and external validation sets. The models were compared with conventional models, such as respiratory ECMO survival prediction (RESP) and predicting death for severe acute respiratory distress syndrome on VV-ECMO (PRESERVE). Extreme gradient boosting (XGB) (areas under the receiver operating characteristic curve, AUROC 0.82, 95% CI (0.73 to 0.89)) and light gradient boosting (AUROC 0.81 (95% CI 0.71 to 0.88)) models achieved the highest performance using EHR's and all other available features. The developed models had higher AUROCs (95% CI 0.76 to 0.82) than those of RESP (AUROC 0.66 (95% CI 0.56 to 0.76)) and PRESERVE (AUROC 0.71 (95% CI 0.61 to 0.81)). Additionally, we achieved an AUROC (0.75) for 90-day mortality in external validation in the case of the XGB model, which was higher than that of RESP (0.70) and PRESERVE (0.67) in the same validation dataset. ML prediction models outperformed previous mortality risk models. This model may be used to identify patients who are unlikely to benefit from VV-ECMO therapy during patient selection.


Evidence for a high-spin Fe(IV) species in the catalytic cycle of a bacterial phenylalanine hydroxylase.
Phenylalanine hydroxylase is a mononuclear non-heme iron protein that uses tetrahydropterin as the source of the two electrons needed to activate dioxygen for the hydroxylation of phenylalanine to tyrosine. Rapid-quench methods have been used to analyze the mechanism of a bacterial phenylalanine hydroxylase from Chromobacterium violaceum. Mössbauer spectra of samples prepared by freeze-quenching the reaction of the enzyme-(57)Fe(II)-phenylalanine-6-methyltetrahydropterin complex with O(2) reveal the accumulation of an intermediate at short reaction times (20-100 ms). The Mössbauer parameters of the intermediate (δ = 0.28 mm/s, and |ΔE(Q)| = 1.26 mm/s) suggest that it is a high-spin Fe(IV) complex similar to those that have previously been detected in the reactions of other mononuclear Fe(II) hydroxylases, including a tetrahydropterin-dependent tyrosine hydroxylase. Analysis of the tyrosine content of acid-quenched samples from similar reactions establishes that the Fe(IV) intermediate is kinetically competent to be the hydroxylating intermediate. Similar chemical-quench analysis of a reaction allowed to proceed for several turnovers shows a burst of tyrosine formation, consistent with rate-limiting product release. All three data sets can be modeled with a mechanism in which the enzyme-substrate complex reacts with oxygen to form an Fe(IV)═O intermediate with a rate constant of 19 mM(-1) s(-1), the Fe(IV)═O intermediate hydroxylates phenylalanine with a rate constant of 42 s(-1), and rate-limiting product release occurs with a rate constant of 6 s(-1) at 5 °C.


Metal-metal bonding in tetracyanometalates (M=PtII, PdII, NiII) of monovalent thallium. Crystallographic and spectroscopic characterization of the new compounds Tl2Ni(CN)4 and Tl2Pd(CN)4.
The new crystalline compounds Tl2Ni(CN)4 and Tl2Pd(CN)4 were synthesized by several procedures. The structures of the compounds were determined by single-crystal X-ray diffraction. The compounds are isostructural with the previously reported platinum analogue, Tl2Pt(CN)4. A new synthetic route to the latter compound is also suggested. In contrast to the usual infinite columnar stacking of [M(CN)4]2- ions with short intrachain M-M separations, characteristic of salts of tetracyanometalates of NiII, PdII, and PtII, the structure of the thallium compounds is noncolumnar with the two TlI ions occupying axial vertices of a distorted pseudo-octahedron of the transition metal, [MTl2C4]. The Tl-M distances in the compounds are 3.0560(6), 3.1733(7), and 3.140(1) A for NiII, PdII, and PtII, respectively. The short Tl-Ni distance in Tl2Ni(CN)4 is the first example of metal-metal bonding between these two metals. The strength of the metal-metal bonds in this series of compounds was assessed by means of vibrational spectroscopy. Rigorous calculations, performed on the molecules in D4h point group symmetry, provide force constants for the Tl-M stretching vibration constants of 146.2, 139.6, and 156.2 N/m for the NiII, PdII, and PtII compounds, respectively, showing the strongest metal-metal bonding in the case of the Tl-Pt compound. Amsterdam density-functional calculations for isolated Tl2M(CN)4 molecules give Tl-M geometry-optimized distances of 2.67, 2.80, and 2.84 A for M = NiII, PdII, and PtII, respectively. These distances are all substantially shorter than the experimental values, most likely because of intermolecular Tl-N interactions in the solid compounds. Time-dependent density-functional theory calculations reveal a low-energy, allowed transition in all three compounds that involves excitation from an a1g orbital of mixed Tl 6pz-M ndz2 character to an a2u orbital of dominant Tl 6pz character.


[Anomalous pregnancies in ancient medicine].
In ancient Greek medicine female physiology is determined by a particular state of non-steady equilibrium, largely based on pregnancy and lactation, presented as the only balanced and healthy periods in women's life. Nonetheless, pregnancy can be also a pathological moment, in particular referring to specific alterations of its 'normal time' ('seven-months', 'eight-months' and 'ten-months' children). The article analyzes the well-known case of myle, an abnormal pregnancy developing in three and sometimes four years, non resolving in a normal delivery, but often in a dramatic haemorrhagic flux. The author compares Hippocratic and Aristotelic testimonies about myle and abnormal pregnancies with the evidence fournished by the historical-religious recent studies about Hera and her parthenogenetic, monstrous children.


The Transition-State Structure for Human MAT2A from Isotope Effects.
Human methionine S-adenosyltransferase (MAT2A) catalyzes the formation of S-adenosylmethionine (SAM) from ATP and methionine. Synthetic lethal genetic analysis has identified MAT2A as an anticancer target in tumor cells lacking expression of 5'-methylthioadenosine phosphorylase (MTAP). Approximately 15% of human cancers are MTAP-/-. The remainder can be rendered MTAP- through MTAP inhibitors. We used kinetic isotope effect (KIE), commitment factor (Cf), and binding isotope effect (BIE) measurements combined with quantum mechanical (QM) calculations to solve the transition state structure of human MAT2A. The reaction is characterized by an advanced SN2 transition state. The bond forming from the nucleophilic methionine sulfur to the 5'-C of ATP is 2.03 Å at the transition state (bond order of 0.67). Departure of the leaving group triphosphate of ATP is well advanced and forms a 2.32 Å bond between the 5'-C of ATP and the oxygen of the triphosphate (bond order of 0.23). Interaction of MAT2A with its MAT2B regulatory subunit causes no change in the intrinsic KIEs, indicating the same transition state structure. The transition state for MAT2A is more advanced along the reaction coordinate (more product-like) than that from the near-symmetrical transition state of methionine adenosyltransferase from E. coli.


The first clinical case of a mutation at residue K185 of Kir6.2 (KCNJ11): a major ATP-binding residue.
Closure of the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel plays a key role in insulin secretion from the pancreatic beta-cells. Many mutations in KCNJ11 and ABCC8, which respectively encode the pore-forming (Kir6.2) and regulatory (SUR1) subunits of the K(ATP) channel, cause neonatal diabetes. All such mutations impair the ability of metabolically generated ATP to close the channel. Although lysine 185 is predicted to be a major contributor to the ATP-binding site of Kir6.2, no mutations at this residue have been found to cause neonatal diabetes to date. We report a 3-year-old girl with permanent neonatal diabetes (PNDM) caused by a novel heterozygous mutation (K185Q) at residue K185 of KCNJ11. The patient presented with marked hyperglycaemia and ketoacidosis at 70 days after birth, and insulin therapy was commenced. Wild-type and mutant K(ATP) channels were expressed in Xenopus oocytes and the effects of intracellular ATP on macroscopic K(ATP) currents in inside-out membrane patches were measured. In the simulated heterozygous state, the K185Q mutation caused a substantial reduction in the ability of MgATP to inhibit the channel. Heterozygous K185Q channels were still blocked effectively by the sulphonylurea tolbutamide. We report the first clinical case of a PNDM caused by a mutation at K185. Functional studies indicate that the K185Q mutation causes PNDM by reducing the ATP sensitivity of the K(ATP) channel, probably via a reduction in ATP binding to Kir6.2. Based on the experimental data, the patient was successfully transferred to sulphonylurea therapy.


(1)H, (13)C and (15)N resonance assignments of σ(S) activating protein Crl from Salmonella enterica serovar Typhimurium.
The general stress response in Enterobacteria, like Escherichia coli or Salmonella, is controlled by the transcription factor σ(S), encoded by the rpoS gene, which accumulates during stationary phase growth and associates with the core RNA polymerase enzyme (E) to promote transcription of genes involved in cell survival. Tight regulation of σ(S) is essential to preserve the balance between self-preservation under stress conditions and nutritional competence in the absence of stress. Whereas σ factors are generally inactivated upon interaction with anti-sigma proteins, σ(S) binding by the Crl protein facilitates the formation of the holoenzyme Eσ(S), and therefore σ(S)-controlled transcription. Previously, critical residues in both Crl and σ(S) were identified and assigned to the binding interface in the Crl-σ(S) complex. However, high-resolution structural data are missing to fully understand the molecular mechanisms underlying σ(S) activation by Crl, in particular the possible role of Crl in triggering domain rearrangements in the multi-domain protein σ(S). Here we provide the (1)H, (13)C and (15)N resonance assignments of Salmonella enterica serovar Typhimurium Crl, as a starting point for CrlSTM structure determination and further structural investigation of the CrlSTM-σ STM (S) complex.