Brown clouds over South Asia: biomass or fossil fuel combustion?
Carbonaceous aerosols cause strong atmospheric heating and large surface cooling that is as important to South Asian climate forcing as greenhouse gases, yet the aerosol sources are poorly understood. Emission inventory models suggest that biofuel burning accounts for 50 to 90% of emissions, whereas the elemental composition of ambient aerosols points to fossil fuel combustion. We used radiocarbon measurements of winter monsoon aerosols from western India and the Indian Ocean to determine that biomass combustion produced two-thirds of the bulk carbonaceous aerosols, as well as one-half and two-thirds of two black carbon subfractions, respectively. These constraints show that both biomass combustion (such as residential cooking and agricultural burning) and fossil fuel combustion should be targeted to mitigate climate effects and improve air quality.


Do fit kids have fit parents?
Physical fitness is an important indicator of current and future health status. This analysis examines the relationships among child-parent dyads in physical fitness measures. The analysis is based on biological child-parent dyads from three cycles of the Canadian Health Measures Survey (Cycle 1: 2007 to 2009, Cycle 2: 2009 to 2011, and Cycle 5: 2016 to 2017). Physical fitness components-cardiorespiratory (CRF) (n = 615), muscular strength (n = 1,319) and flexibility (n = 1,295)-were measured at mobile examination centres using standardized fitness tests. Descriptive, correlation and regression analyses were used to examine relationships among child-parent dyads. CRF (R = 0.12), muscular strength (R = 0.23) and flexibility (R = 0.22) measures were weakly correlated among child-parent dyads. Modest increases in the physical fitness levels of children were observed with increases in the fitness rating scores of their parents. According to unadjusted and adjusted regression models, CRF (p< 0.05), muscular strength (p< 0.001) and flexibility (p< 0.001) were positively associated among child-parent dyads. When examined by sex of parent and child, CRF was significantly associated in mother-son dyads only, grip strength was associated in all dyad types except father-son pairings, and flexibility was associated in mother-son and father-son pairings only. A significant and positive association was evident in measured physical fitness among parents and children. Some variation in the presence and strength of associations existed according to child and parent sex.


Endothelin-dependent vasoconstriction in human uterine artery: application to preeclampsia.
Reduced uteroplacental perfusion, the initiating event in preeclampsia, is associated with enhanced endothelin-1 (ET-1) production which feeds the vasoconstriction of uterine artery. Whether the treatments of preeclampsia were effective on ET-1 induced contraction and could reverse placental ischemia is the question addressed in this study. We investigated the effect of antihypertensive drugs used in preeclampsia and of ET receptor antagonists on the contractile response to ET-1 on human uterine arteries. Experiments were performed, ex vivo, on human uterine artery samples obtained after hysterectomy. We studied variations in isometric tension of arterial rings in response to the vasoconstrictor ET-1 and evaluated the effects of various vasodilators and ET-receptor antagonists on this response. Among antihypertensive drugs, only dihydropyridines were effective in blocking and reversing the ET-1 contractile response. Their efficiency, independent of the concentration of ET-1, was only partial. Hydralazine, alpha-methyldopa and labetalol had no effect on ET-1 induced contraction which is mediated by both ET(A) and ET(B) receptors in uterine artery. ET receptors antagonists, BQ-123 and BQ-788, slightly reduced the amplitude of the response to ET-1. Combination of both antagonists was more efficient, but it was not possible to reverse the maximal ET-1-induced contraction with antagonists used alone or in combination. Pharmacological drugs currently used in the context of preeclampsia, do not reverse ET-1 induced contraction. Only dihydropyridines, which partially relax uterine artery previously contracted with ET-1, might offer interesting perspectives to improve placental perfusion.


Taurine regulation of short term synaptic plasticity in fragile X mice.
Fragile X Syndrome is the most common known genetic cause of autism. The Fmr1-KO mouse, lacks the fragile X mental retardation protein (FMRP), and is used as a model of the syndrome. The core behavioral deficits of autism may be conceptualized either as excessive adherence to patterns as seen in repetitive actions and aberrant language, or as insensitivity to subtle but socially important changes in patterns. The hippocampus receives information from the entorhinal cortex and plays a crucial role in the processing of patterned information. To gain more insight into the physiological function of FMRP and the neuronal mechanisms underlying fragile X syndrome, we examined the electrophysiological response of the hippocampus to pair pulse stimulation as a measure of patterned information processing and how it is affected in the Fmr1-KO mouse. In this study, we used paired-pulse stimulation of the afferent perforant path and recorded from the CA1 region of the hippocampus. Two-month-old FVB/NJ male mice and age-matched Fmr1-KO mice were used in this study. Hippocampal slices were prepared, equilibrated in artificial cerebrospinal fluid (aCSF), and excitatory post synaptic potentials (EPSPs) measured by stimulating the perforant path of the dentate gyrus (DG) while recording from the molecular layer of CA1. Stimulation occurred by setting current and pulse width to evoke a fixed percentage of maximal EPSP amplitude. This stimulation paradigm allowed us to examine the processing capabilities of the hippocampus as a function of increasing interstimulus intervals (ISI) and how taurine, a GABAA receptor agonist, affects such information processing. We found that hippocampal slices from wild type (WT) showed pair-pulse facilitation at ISI of 100-300 ms whereas slices from Fmr1-KO brains showed a consistent pair-pulse depression at a comparable ISI. Addition of 10 muM taurine to WT slices resulted in a drastic decrease of the peak response to the second stimulus, resulting in an initial depression at 100 ms ISI followed by potentiation at higher ISI (150 ms and above). In the presence of taurine, the amplitude of the second response remained significantly lower than in its absence. Fmr1-KO mice however, were completely insensitive to taurine application and pair-pulse stimulation always resulted in a depression of the response to the second stimulus. Previously we reported that Fmr1-KO mice have reduced beta subunits of the GABAA receptors. We also showed as well as others that taurine acts as an agonist or a modulator for GABAA receptors. Therefore, the insensitivity of Fmr1-KO slices to taurine application could be due to the reduced binding sites on the GABAA receptors in the Fmr1-KO mice.


Relationship of on Admission Hypocalcaemia and Illness Severity as Measured by APACHE-II and SOFA Score in Intensive Care Patients'.
Hypocalcaemia is very much prevalent in critically ill patients yet very less is known about its association with severity of illness. Acute Physiology and Chronic Health Evaluation (APACHE) and Sequential Organ Failure Assessment (SOFA) are two commonly used and validated scoring tool used to assess the severity of illness in critically ill patients. To analyze the relation of on admission hypocalcaemia with severity of illness as measured by APACHE-II and SOFA scores. After institute approval, 111 patients admitted during May to June 2016 were evaluated. Age, sex, on admission, ionized calcium (iCa0) levels, first day APACHE-II and SOFA scores were collected. Data were then divided in different classes based on iCa0 levels (i.e., normocalcaemic, mild, moderate and severe hypocalcaemic), APACHE-II and SOFA scores and their relationship was assessed using INSTAT software (GraphPad Software, Inc, La Zolla, CA, USA) with appropriate statistical tests. Seventy eight (70.27%) patients were having hypocalcaemia on admission (<1.15 mmol/L). The mean APACHE-II score of normocalcaemic patients were significantly (p<0.05) lower as compared to moderate and severe hypocalcaemic patients (15.57±6.85 versus 21.72±6.37 and 15.57±6.85 versus 22.34±7.53, respectively). The mean iCa0 level in patients with APACHE-II > 20 were significantly lower than patients with APACHE-II < 9 (0.88±0.26 versus 1.09±0.24, p <0.05) but the mean iCa0 level in patients with SOFA > 9 were not significantly lower than patients with SOFA < 4 (0.99±0.41 versus 1.04±0.23, p > 0.05). The relative risk of on admission hypocalcaemia across increasing illness severity was also not statistically significant. Both relative risk of mortality and length of ICU stay were higher in on admission moderate hypocalcaemic patients as compared to normocalcaemic but the difference was not statistically significant. On admission, hypocalcaemia has inconsistent correlation with increasing illness severity in adult intensive care patients. iCa0 of 0.81-0.90 mmol/L appears to have maximum deleterious effect with regard to mortality and length of ICU stay.


Prescribed intensity in 3D rotational geometry for extended sources by using a conversion function in 2D design.
To obtain a prescribed intensity in three-dimensional (3D) rotationally symmetric geometry for an extended source, a two-dimensional (2D) intensity design method is often used. The 3D entity of the lens can be gained by rotating the profile of the lens obtained by the 2D design method. However, the intensity we set in 2D design is quite different from the one we obtain through ray-tracing by the Monte Carlo method in the 3D rotational geometry. Noting the differences of intensity patterns between 2D and 3D, a 3D conversion function (3DCF) should be deduced to convert the prescribed 3D intensity into a 2D intensity in the 2D design process. The extended Lambertian source properties are taken into account during the derivation process. Using the 3DCF, we can quickly obtain the prescribed intensity in 3D rotationally symmetric geometry for an LED extended source without the fussy feedback strategy. The error is small enough for most general illumination. Three examples are presented to demonstrate the correction effectiveness of the proposed conversion function.


Searching for best practices of youth friendly services - a study protocol using qualitative comparative analysis in Sweden.
Swedish youth clinics constitute one of the most comprehensive and consolidated examples of a nationwide network of health care services for young people. However, studies evaluating their 'youth-friendliness' and the combination of factors that makes them more or less 'youth-friendly' have not been conducted. This protocol will scrutinise the current youth-friendliness of youth clinics in northern Sweden and identify the best combination of conditions needed in order to implement the criteria of youth-friendliness within Swedish youth clinics and elsewhere. In this study, we will use qualitative comparative analysis to analyse the conditions that are sufficient and/or necessary to implement Youth Friendly Health Services in 20 selected youth-clinics (cases). In order to conduct Qualitative Comparative Analysis, we will first identify the outcomes and the conditions to be assessed. The overall outcome - youth-friendliness - will be assessed together with specific outcomes for each of the five domains - accessible, acceptable, equitable, appropriate and effective. This will be done using a questionnaire to be applied to a sample of young people coming to the youth clinics. In terms of conditions, we will first identify what might be the key conditions, to ensure the youth friendliness of health care services, through literature review, interviews with professionals working at youth clinics, and with young people. The combination of conditions and outcomes will form the hypothesis to be further tested later on in the qualitative comparative analysis of the 20 cases. Once information on outcomes and conditions is gathered from each of the 20 clinics, it will be analysed using Qualitative Comparative Analysis. The added value of this study in relation to the findings is twofold: on the one hand it will allow a thorough assessment of the youth-friendliness of northern Swedish youth clinics. On the other hand, it will extract lessons from one of the most consolidated examples of differentiated services for young people. Methodologically, this study can contribute to expanding the use of Qualitative Comparative Analysis in health systems research.


Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice.
Protective effects of curcumin (U1), one of the major yellow pigments in turmeric and its derivative, tetrahydrocurcumin (THU1), against ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage were studied in male ddY mice. Single Fe-NTA treatment (5 mg Fe/kg body intraperitoneally) transiently causes oxidative stress, as shown by the accumulation of lipid peroxidation products and 8-hydroxy-2'-deoxyguanosine in the kidney. Mice were fed with a diet containing 0.5 g/100 g U1 or THU1 for 4 wk. THU1 significantly inhibited 2-thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine formation in the kidney; U1 inhibited only 4-hydroxy-2-nonenal-modified protein formation. To elucidate the mechanisms of protection by U1 and THU1, the pharmacokinetics and radical-scavenging capacities of U1 and THU1 were investigated by HPLC and electron spin resonance spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide, respectively. Induction of antioxidant enzymes was also investigated. The amounts of THU1 and its conjugates (as sulfates and glucuronides) in the liver and serum were larger in the THU1 group than in the U1 group. The amounts of U1 and its conjugates were small even in the U1 group. These results suggest that THU1 is more easily absorbed from the gastrointestinal tract than U1. Furthermore, THU1 induced antioxidant enzymes, such as glutathione peroxidase, glutathione S-transferase and NADPH: quinone reductase, as well as or better than U1 and scavenged Fe-NTA-induced free radicals in vitro better than U1. These results suggest that U1 is converted to THU1 in vivo and that THU1 is a more promising chemopreventive agent.


Targeting Tregs in Malignant Brain Cancer: Overcoming IDO.
One of the hallmark features of glioblastoma multiforme (GBM), the most common adult primary brain tumor with a very dismal prognosis, is the accumulation of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Regulatory T cells (Tregs) segregate into two primary categories: thymus-derived natural Tregs (nTregs) that develop from the interaction between immature T cells and thymic epithelial stromal cells, and inducible Tregs (iTregs) that arise from the conversion of CD4(+)FoxP3(-) T cells into FoxP3 expressing cells. Normally, these Treg subsets complement one another's actions by maintaining tolerance of self-antigens, thereby suppressing autoimmunity, while also enabling effective immune responses toward non-self-antigens, thus promoting infectious protection. However, Tregs have also been shown to be associated with the promotion of pathological outcomes, including cancer. In the setting of GBM, nTregs appear to be primary players that contribute to immunotherapeutic failure, ultimately leading to tumor progression. Several attempts have been made to therapeutically target these cells with variable levels of success. The blood brain barrier-crossing chemotherapeutics, temozolomide, and cyclophosphamide (CTX), vaccination against the Treg transcriptional regulator, FoxP3, as well as mAbs against Treg-associated cell surface molecules CD25, CTLA-4, and GITR are all different therapeutic approaches under investigation. Contributing to the poor success of past approaches is the expression of indoleamine 2,3-dioxygenase 1 (IDO), a tryptophan catabolizing enzyme overexpressed in GBM, and critically involved in regulating tumor-infiltrating Treg levels. Herein, we review the current literature on Tregs in brain cancer, providing a detailed phenotype, causative mechanisms involved in their pathogenesis, and strategies that have been used to target this population, therapeutically.


Association of 17 Definitions of Remission with Functional Status in a Large Clinical Practice Cohort of Patients with Rheumatoid Arthritis.
To compare the association between different remission criteria and physical function in patients with rheumatoid arthritis followed in clinical practice. Longitudinal data from the METEOR database were used. Seventeen definitions of remission were tested: American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based; Simplified/Clinical Disease Activity Index (SDAI/CDAI); and 14 Disease Activity Score (DAS)-based definitions. Health Assessment Questionnaire (HAQ) ≤ 0.5 was defined as good functional status. Associations were investigated using generalized estimating equations. Potential confounders were tested and sensitivity analyses performed. Data from 32,915 patients (157,899 visits) were available. The most stringent definition of remission was the ACR/EULAR Boolean-based definition (1.9%). The proportion of patients with HAQ ≤ 0.5 was higher for the most stringent definitions, although it never reached 100%. However, this also meant that, for the most stringent criteria, many patients in nonremission had HAQ ≤ 0.5. All remission definitions were associated with better function, with the strongest degree of association observed for the SDAI (adjusted OR 3.36, 95% CI 3.01-3.74). The 17 definitions of remission confirmed their validity against physical function in a large international clinical practice setting. Achievement of remission according to any of the indices may be more important than the use of a specific index. A multidimensional approach, targeted at wider goals than disease control, is necessary to help all patients achieve the best possible functional status.


Nigella sativa oil with a calorie-restricted diet can improve biomarkers of systemic inflammation in obese women: A randomized double-blind, placebo-controlled clinical trial.
Inflammation is one of the primary mechanisms in the development of metabolic complications. Although anti-inflammatory characteristics of Nigella sativa (NS) have been indicated in animal models, clinical trials related to the effects of NS on inflammatory parameters are relatively scarce. The aim of the present study was to determine the effects of NS oil combined with a calorie-restricted diet on systemic inflammatory biomarkers in obese women. In this double-blind placebo-controlled randomized clinical trial, 90 volunteer obese (body mass index = 30-34.9 kg/m(2)) women aged 25-50 years were recruited. Participants were randomly divided into two groups, an intervention group (n = 45) and a placebo group (n = 45). Each group received either: (1) a low-calorie diet with 3 g/day of NS oil or (2) a low-calorie diet with 3 g/day placebo for 8 weeks. A total of 84 females (intervention group = 43; placebo group = 41) completed the trial. Subjects in the intervention group did not report any side effects with the NS oil supplementation. NS oil decreased serum levels of tumor necrosis factor-alpha (-40.8% vs -16.1%, P = .04) and high-sensitivity C-reactive protein (-54.5% vs -21.4%, P = .01) compared to the placebo group. However, there were no significant changes in interleukin-6 levels (-8.6 vs -2.4%, P = .6) in the NS group compared to the placebo group. NS oil supplementation combined with a calorie-restricted diet may modulate systemic inflammatory biomarkers in obese women. However, more studies are needed to clarify the efficacy of NS oil as an adjunct therapy to improve inflammatory parameters in obese subjects.


Properties of perhalogenated {closo-B10} and {closo-B11} multiply charged anions and a critical comparison with {closo-B12} in the gas and the condensed phase.
closo-Borate anions [closo-BnXn]2- are part of the most famous textbook examples of polyhedral compounds. Substantial differences in their reactivity and interactions with other compounds depending on the substituent X and cluster size n have been recognized, which favor specific closo-borates for different applications in cancer treatment, chemical synthesis, and materials science. Surprisingly, a fundamental understanding of the molecular properties underlying these differences is lacking. Here, we report our study comparing the electronic structure and reactivity of closo-borate anions [closo-BnXn]2- (X = Cl, Br, I, n = 10, 11, 12 in all combinations) in the gas phase and in solution. We investigated the free dianions and the ion pairs [nBu4N]+[closo-BnXn]2- by gas phase anion photoelectron spectroscopy accompanied by theoretical investigations. Strong similarities in electronic structures for n = 10 and 11 were observed, while n = 12 clusters were different. A systematic picture of the development in electronic stability along the dimension X is derived. Collision induced dissociation shows that fragmentation of the free dianions is mainly dependent on the substituent X and gives access to a large variety of boron-rich molecular ions. Fragmentation of the ion pair depends strongly on n. The results reflect the high chemical stability of clusters with n = 10 and 12, while those with n = 11 are much more prone to dissociation. We bridge our study to the condensed phase by performing comparative electrochemistry and reactivity studies on closo-borates in solution. The trends found at the molecular level are also reflected in the condensed-phase properties. We discuss how the gas phase values allow evaluation of the influence of the condensed phase on the electronic stability of closo-borates. A synthetic method via an oxidation/chlorination reaction yielding [closo-B10Cl10]2- from highly chlorinated {closo-B11} clusters is introduced, which underlines the intrinsically high reactivity of the {closo-B11} cage.


Supporting the Health Care Transition From Adolescence to Adulthood in the Medical Home.
Risk and vulnerability encompass many dimensions of the transition from adolescence to adulthood. Transition from pediatric, parent-supervised health care to more independent, patient-centered adult health care is no exception. The tenets and algorithm of the original 2011 clinical report, "Supporting the Health Care Transition from Adolescence to Adulthood in the Medical Home," are unchanged. This updated clinical report provides more practice-based quality improvement guidance on key elements of transition planning, transfer, and integration into adult care for all youth and young adults. It also includes new and updated sections on definition and guiding principles, the status of health care transition preparation among youth, barriers, outcome evidence, recommended health care transition processes and implementation strategies using quality improvement methods, special populations, education and training in pediatric onset conditions, and payment options. The clinical report also includes new recommendations pertaining to infrastructure, education and training, payment, and research.


Determining predominating histologic component in malignant mixed müllerian tumors: is it worth it?
Malignant mixed müllerian tumors (MMMT) are highly aggressive tumors, usually diagnosed in advanced stage. Cases of MMMT derive from either ovary or uterus. In our study, we investigated the role of carcinomatous and sarcomatous component on response to chemotherapy and disease outcome. We retrospectively analyzed 25 patients with MMMT who were treated in our outpatient clinic from 1998 to 2003. All the paraffin specimens were reevaluated according to the histopathologic features (primary site and percentages of carcinomatous and sarcomatous component) and the effect of predominant histologic type on response to treatment. Primary tumor sites were ovary and endometrium in 36% and 64% of patients, respectively. Ten of 25 patients (40%) were treated with a combination chemotherapy regimen of cisplatin-ifosfamide (PI) and 7 patients (28%) were treated with paclitaxel-carboplatin (PC) protocol. Despite chemotherapy, 17.6% of patients had progressive disease. The remaining 13 patients (54.2%) responded to chemotherapy. Response rates of patients treated with PC (100%) were remarkably higher than the response rates of patients treated with PI (66.6%). Moreover, patients with predominating carcinomatous component had a higher response rate (87.5%) than patients with predominating sarcomatous component (66.6%). MMMT are highly chemoresponsive tumors, irrespective of primary site. One of the best predictors to response is the histologic pattern. Predominating histopathologic feature (carcinoma or sarcoma) should be taken into consideration in predicting the response and planning the chemotherapy regimen.


Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis.
Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. The primary authors provided individual participant data that were analyzed using mixed-effects models. The primary outcome was preterm birth (<37 weeks' gestational age). From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.


Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties.
In recent years, several inhibitors that prevent caspase activation and apoptosis have emerged. At high doses, however, these inhibitors can have nonspecific effects and/or become cytotoxic. In this study, we determined the effectiveness of broad spectrum caspase inhibitors to prevent apoptosis. A carboxy terminal phenoxy group conjugated to the amino acids valine and aspartate (Q-VD-OPh) potently inhibited apoptosis. Q-VD-OPh was significantly more effective in preventing apoptosis than the widely used inhibitors, ZVAD-fmk and Boc-D-fmk, and was also equally effective in preventing apoptosis mediated by the three major apoptotic pathways, caspase 9/3, caspase 8/10, and caspase 12. In addition to the increased effectiveness, Q-VD-OPh was not toxic to cells even at extremely high concentrations. Our data indicate that the specificity, effectiveness, and reduced toxicity of caspase inhibitors can be significantly enhanced using carboxyterminal o-phenoxy groups and may have important uses in vivo.


Realizations of the abstract regular H3 polyhedra.
Regular polyhedra and related structures such as complexes and nets play a prominent role in the study of materials such as crystals, nanotubes and viruses. An abstract regular polyhedron {\cal P} is the combinatorial analog of a classical regular geometric polyhedron. It is a partially ordered set of elements called faces that are completely characterized by a string C-group (G, T), which consists of a group G generated by a set T of involutions. A realization R is a mapping from {\cal P} to a Euclidean G space that is compatible with the associated real orthogonal representation of G. This work discusses an approach to the theory of realizations of abstract regular polyhedra with an emphasis on the construction of a realization and its decomposition as a blend of subrealizations. To demonstrate the approach, it is applied to the polyhedra whose automorphism groups are abstractly isomorphic to the non-crystallographic Coxeter group H3.


Nonparticipation in a population-based trial to increase colorectal cancer screening.
Many trials have tested different strategies to increase colorectal cancer (CRC) screening. Few describe whether participants are representative of the population from which they are recruited. To determine risk factors related to nonparticipation among patients enrolled in an integrated health plan and not up to date for CRC testing, in a trial to increase screening rates. Between July 2008 and October 2009, a total of 15,000 adults aged 50-74 years from 21 clinics in Washington State who were due for CRC screening were contacted. Nonparticipants were defined as English-speaking patients who did not engage in the call or refused participation while still potentially eligible. Log-binomial regression models were used to estimate the relative risk of nonparticipation. Analyses were completed between October 2010 and June 2011. Patients who were nonwhite, had less education, used tobacco, had less continuity of care, and had lower rates of preventive care and cancer screening were more likely to be nonparticipants. Patients reporting never having received any type of CRC testing or screening were also more likely not to participate (62% of nonparticipants vs 46% of participants; adjusted RR=1.58, 95% CI=1.47, 1.70). Reasons for refusal included costs, risks of procedures, and not wanting their medical records reviewed. Patients eligible for but not participating in the trial were more likely to be from minority socioeconomic and racial groups and had behaviors that can negatively affect cancer outcomes. Additional efforts are needed to recruit patients who need CRC screening the most. This trial is registered at clinicaltrials.gov NCT 00697047.


Laparoscopic systemic devascularization of uterine cornu for cornual resection in interstitial pregnancy.
Cornual pregnancies carry a greater maternal mortality risk than ampullary ectopic pregnancies and they may cause significant hemorrhage. A woman aged 36 years with a six-week history of amenorrhea, slight vaginal bleeding, and low abdominal pain of three days duration presented to our clinic. A diagnosis of right cornual ectopic pregnancy was made using ultrasonographic findings. Laparoscopic exploration confirmed the diagnosis. We occluded the uterine artery at its origin and also transected vessels within the mesosalpinx and uteroovarian ligament to successfully accomplish avascularization of a cornual pregnancy. Occlusion of the uterine arteries is reported to be a safe and blood-sparing technique. Severe hemorragia may occur during the operation; therefore, techniques to minimize blood loss are reported. In our case, occlusion of the uterine artery and transection of the mesosalpinx and uteroovarian vessels provided a bloodless operation and there was no need to bilaterally occlude vessels.


Homoeologous chromosome pairing: frequency differences in inbred and intraspecific hybrid polyploid ferns.
The homosporous fern Ceratopteris thalictroides (Parkeriaceae) has evolved a polyploid genetic system that serves to store and release genetic variability in spite of self-fertilization and Mendelian homozygosity. This is demonstrated by the segregation of a gametophyte mutant within two inbred tetraploid lines and in their intraspecific hybrid. The segregation behavior can be explained by a model involving a duplicated locus and regular homoeologous chromosome pairing. Homoeologous pairing occurs at low levels in the inbred lines and at a high level in the hybrid, indicating intraspecific differences in chromosome pairing affinities.


Field trials of an asexual blood stage malaria vaccine: studies of the synthetic peptide polymer SPf66 in Thailand and the analytic plan for a phase IIb efficacy study.
Several years ago the Walter Reed Army Institute of Research (WRAIR) initiated an independent analysis of the candidate malaria blood stage vaccine SPf66. WRAIR contracted for the synthesis and formulation of SPf66 in United States Food and Drug Administration (FDA) inspected laboratories within the U.S., and in 1992, filed an Investigational New Drug (IND) application with the FDA. Preclinical studies indicated that the vaccine could be synthesized to meet its release specifications, and when adjuvanted with alum, was essentially equivalent to Colombian produced SPf66 in regards to immunogenicity in preclinical studies of rodents and primates, and in human volunteers in Phase I studies. The goal of these efforts was ultimately to conduct a Phase IIb field trial to determine the safety and efficacy of SPf66 produced under current Good Manufacturing Practices (cGMP). Such a trial is currently underway in a malaria endemic refugee camp along the Thai-Burmese border. Here we briefly describe the study and present the formal analytic plan that was submitted to regulatory authorities in the United States for analysis of the study results. We believe such independent confirmatory studies are an essential part of the vaccine development process and are required to provide important data regarding the safety and efficacy of candidate vaccines in diverse geographical regions, and as a means to assess their role in the context of broader malaria control programmes.


"The challenge of managing insecurities": Parents' experiences with the care for their child with congenital diaphragmatic hernia.
Last decennia remarkable advances have been made in decreasing the mortality rate of children with congenital diaphragmatic hernia (CDH), resulting in a relatively growing patient group with long-term complications and complex care needs. These consequences have a huge impact on the quality of life of both children and their families. To provide practical recommendations for improving the quality of care for this patient group, the present study sought to obtain insights into the experiences and needs of parents with a child with CDH. A qualitative study was conducted on the experiences and needs of parents with a child with CDH living in the Netherlands. Data was obtained by means of a discourse analyses of 17 weblogs written by parents and three online focus groups with 8-12 parents per group (n = 29). The data was analysed thematically and structured by using the model of Lawoko (2007) on parental satisfaction with care. Although parents were generally satisfied with the delivered care, they frequently encountered challenges in managing insecurities throughout the care process. Besides the unpredictable disease progress, insecurities were exacerbated by: (a) limited specialized knowledge of long-term consequences, (b) logistical problems, and (c) nontransparent communication. Providing security through, for instance, a clear care plan and by engaging parents in the decision-making process helped them feel more in control. This study showed that parents' main challenge was to manage insecurities. Creating securities by providing a care plan and involving parents in the decision-making process helped parents to feel more in control. To improve quality of care for children with CDH, future measures should, therefore, focus on reducing insecurities by managing expectations, improving transparency and stimulating engagement.


Serum biomarkers in patients with stable and exacerbated COPD-bronchiectasis overlap syndrome.
Bronchiectasis (B), commonly seen in patients with chronic obstructive pulmonary disease (COPD), is associated with exacerbations and predicts mortality. To differentiate patient groups with COPD-(B+) or COPD-(B-) and their exacerbations by using inflammatory markers. Consecutive COPD patients were divided into two groups according to findings on high resolution thorax CT (HRCT) images using Smith and modified Reiff scores. Patients were prospectively followed for possible future exacerbations. Serum fibrinogen, C-reactive protein (CRP), soluble urokinase-type plasminogen activator receptor (suPAR) and Plasminogen activator inhibitor-1 (PAI-1) levels were studied during exacerbation and stable periods. Eighty-seven patients were included and (85 M, 2 F), mean aged was 68.1 ± 9 (46-87). HRCT confirmed bronchiectasis in 38 (43.7%) patients, most commonly in tubular form (89.4%) and in lower lobes. COPD-B(+) group had lower body mass index (P = 0.036), more advanced stage of disease (P = 0.004) and more frequent exacerbation (P = 0.01). The HRCT scores were correlated with exacerbation rate (r = 0.356, P < 0.05). Fibrinogen and CRP values were higher in exacerbation (P = 0.01, P = 0.013, respectively) especially in COPD-B(+) patients. suPAR and PAI-1 levels were also higher in COPD-B(+) patients although it was not statistically significant. Bronchiectasis is common and causes frequent exacerbations in COPD. Identifying of COPD-B(+) phenotype by HRCT scoring systems has considerable importance for both therapeutic options and clinical outcome of the disease. In addition to fibrinogen and CRP, high serum levels of suPAR and PAI-1 suggest us their significant roles in increased systemic inflammation associated with coexisting of COPD and bronchiectasis.


Neuropathic itch.
Chronic itch can be caused by dysfunctions of itch-sensing neurons that produce sensory hallucinations of pruritogenic stimuli. The cellular and molecular mechanisms are still unknown. All neurological disease categories have been implicated, and neurological causes should be considered for patients with otherwise-unexplained itch. The same neurological illnesses that cause neuropathic pain can also or instead cause itch. These include shingles (particularly of the head or neck), small-fiber polyneuropathies, radiculopathies (eg, notalgia paresthetica and brachioradial pruritis), and diverse lesions of the trigeminal nerve, root, and central tracts. Central nervous system lesions affecting sensory pathways, including strokes, multiple sclerosis, and cavernous hemangiomas, can cause central itch. Neuropathic itch is a potent trigger of reflex and volitional scratching although this provides only fleeting relief. Rare patients whose lesion causes sensory loss as well as neuropathic itch can scratch deeply enough to cause painless self-injury. The most common location is on the face (trigeminal trophic syndrome). Treating neuropathic itch is difficult; antihistamines, corticosteroids, and most pain medications are largely ineffective. Current treatment recommendations include local or systemic administration of inhibitors of neuronal excitability (especially local anesthetics) and barriers to reduce scratching.


Are religion and spirituality barriers or facilitators to treatment for HIV: a systematic review of the literature.
Much attention has been given to the relationship between religion/spirituality (R/S) and HIV in recent years, but comparatively little has been explored in regard to R/S and HIV testing, retention in care, and adherence to medication. Religious views concerning HIV risk behavior pose challenges to communication and education about sexual health in religious communities and may serve as barriers to HIV treatment and care. Conversely, religious coping and spiritual well-being, as well as social support could serve as facilitators to HIV treatment and care. This study aims to fill a gap in the literature by addressing the following questions: (1) what dimensions of R/S have been found to be factors associated with HIV outcomes?; (2) which R/S factors function as barriers or facilitators to care among people living with HIV (PLWH)?; and (3) which R/S factors, if any, vary across socio-demographic groups? Thirty-three empirical articles were identified for systematic review. Of the 33 empirical studies included, 24 studies found that at least one measure of R/S was associated with better adherence and clinical health outcomes. Twelve studies found at least one measure of R/S to be associated with poorer adherence and clinical health outcomes. Seven of the studies found at least one R/S measure to have no significant association with outcomes. Though all of the studies included in this review focused on R/S experiences of PLWH, there was very little consistency in regard to measurement of R/S. Studies in this review included a wide range of R/S measures, including beliefs, religious/spiritual practices, R/S coping, organizational religion, and many more. Of the 33 studies reviewed, only 9 focused on unique populations such as women, people with histories of substance abuse, immigrants, etc. Findings from this review highlight opportunities for more studies in various populations using standardized R/S measures.


Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects.
Appropriate antibiotic exposure at the site of infection is important for clinically effective therapy. This study compared the epithelial lining fluid (ELF) penetration of ceftolozane/tazobactam, which has potent in vitro activity against many Gram-negative pathogens causing nosocomial pneumonia, with that of piperacillin/tazobactam in healthy adult volunteers. In this Phase 1, open-label trial, 51 healthy adult subjects were randomized to receive three doses of either ceftolozane/tazobactam 1.5 g administered every 8 h via a 60 min infusion or piperacillin/tazobactam 4.5 g administered every 6 h via a 30 min infusion. Serial blood samples were obtained for determination of plasma drug concentrations. Bronchoscopy and bronchoalveolar lavage were performed at pre-specified timepoints in five subjects per timepoint in each treatment group to determine the ELF drug concentration. The penetration of individual analytes into the ELF was determined from the ratio of the area under the plasma concentration-time curve in ELF to that in plasma (AUC(ELF)/AUC(plasma)). Plasma and ELF concentrations of ceftolozane, piperacillin and tazobactam increased rapidly, reaching maximal concentrations at the end of the infusion. Mean maximum concentration and AUC from time 0 to the end of the dosing interval (AUC(0-τ)) for ceftolozane in ELF were 21.8 mg/L and 75.1 mg·h/L, respectively. Corresponding values for piperacillin were 58.8 mg/L and 94.5 mg·h/L. The ELF/plasma AUC ratio for ceftolozane was 0.48 compared with 0.26 for piperacillin. This study demonstrated that ceftolozane penetrated well into the ELF following parenteral administration of ceftolozane/tazobactam.


Adherence to dietary recommendations is not associated with depression in two Swiss population-based samples.
Little is known about adherence to dietary recommendations and depression. Furthermore, dietary habits may differ among depression subtypes, which has not been evaluated previously. Two population-based Swiss studies, including 3620 individuals from PsyCoLaus and 11,032 individuals from the Swiss Health Survey 2012 (SHS), were used to examine the associations between adherence to common dietary guidelines and odds of depressive disorders. In both studies, depression was assessed by validated instruments. Adherence to dietary recommendations were assessed by a semi-quantitative food frequency questionnaire (PsyCoLaus) and by single item questions (SHS). Logistic regression analyses were used to assess the association of adhering to dietary recommendations with depression. For the analyses of diet with depression subtypes maximum-likelihood multinomial (polytomous) logistic regression analyses were conducted. No association of adherence to dietary recommendations with current major depressive disorder (MDD) was observed in any of the two study populations except for adherence to fish consumption, which was positively associated with MDD in the SHS. For depression subtypes, statistically significantly positive associations of vegetable consumption and adherence to the 5-a-day recommendation with current unspecified and current melancholic MDD were found. In conclusion, we don't see consistent associations between adherence to dietary recommendations and MDD or subtypes of depression.


Probing O-H Bonding through Proton Detected 1H-17O Double Resonance Solid-State NMR Spectroscopy.
The ubiquity of oxygen in organic, inorganic, and biological systems has stimulated the application and development of 17O solid-state NMR spectroscopy as a probe of molecular structure and dynamics. Unfortunately, 17O solid-state NMR experiments are often hindered by a combination of broad NMR signals and low sensitivity. Here, it is demonstrated that fast MAS and proton detection with the D-RINEPT pulse sequence can be generally applied to enhance the sensitivity and resolution of 17O solid-state NMR experiments. Complete 2D 17O → 1H D-RINEPT correlation NMR spectra were typically obtained in less than 10 h from less than 10 mg of material, with low to moderate 17O enrichment (less than 20%). Two-dimensional 1H-17O correlation solid-state NMR spectra allow overlapping oxygen sites to be resolved on the basis of proton chemical shifts or by varying the mixing time used for 1H-17O magnetization transfer. In addition, J-resolved or separated local field (SLF) blocks can be incorporated into the D-RINEPT pulse sequence to allow the direct measurement of one-bond 1H-17O scalar coupling constants (1 JOH) or 1H-17O dipolar couplings ( DOH), respectively, the latter of which can be used to infer 1H-17O bond lengths. 1 JOH and DOH calculated from plane-wave density functional theory (DFT) show very good agreement with experimental values. Therefore, the 2D 1H-17O correlation experiments, 1H-17O scalar and dipolar couplings, and plane-wave DFT calculations provide a method to precisely determine proton positions relative to oxygen atoms. This capability opens new opportunities to probe interactions between oxygen and hydrogen in a variety of chemical systems.


Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. Duration of Anticoagulation Trial.
The length of time after an episode of venous thromboembolism during which the risk of newly diagnosed cancer is increased is not known, and whether vitamin K antagonists have an antineoplastic effect is controversial. In a prospective, randomized study of the duration of oral anticoagulation (six weeks or six months) after a first episode of venous thromboembolism, patients were questioned annually about any newly diagnosed cancer. After a mean follow-up of 8.1 years, we used the Swedish Cancer Registry to identify all diagnoses of cancer and causes of death in the study population. The observed numbers of cases of cancer were compared with expected numbers based on national incidence rates, and the standardized incidence ratios were calculated. A first cancer was diagnosed in 111 of 854 patients (13.0 percent) during follow-up. The standardized incidence ratio for newly diagnosed cancer was 3.4 (95 percent confidence interval, 2.2 to 4.6) during the first year after the thromboembolic event and remained between 1.3 and 2.2 for the following five years. Cancer was diagnosed in 66 of 419 patients (15.8 percent) who were treated for six weeks with oral anticoagulants, as compared with 45 of 435 patients (10.3 percent) who were treated for six months (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.4). The difference was mainly due to the occurrence of new urogenital cancers, of which there were 28 cases in the six-week group (6.7 percent) and 12 cases in the six-month group (2.8 percent) (odds ratio, 2.5; 95 percent confidence interval, 1.3 to 5.0). The difference in the incidence of cancer between the treatment groups became evident only after two years of follow-up, and it remained significant after adjustment for sex, age, and whether the thromboembolism was idiopathic or nonidiopathic. Older age at the time of the venous thrombosis and an idiopathic thromboembolism were also independent risk factors for a diagnosis of cancer. No difference in the incidence of cancer-related deaths was detected. The risk of newly diagnosed cancer after a first episode of venous thromboembolism is elevated during at least the following two years. Subsequently, the risk seems to be lower among patients treated with oral anticoagulants for six months than among those treated for six weeks.


Local differentiation and plasticity in size and sex expression in jack-in-the-pulpit, Arisaema triphyllum (Araceae).
The size advantage hypothesis suggests that natural selection will favor size-dependent sex expression when one sex gains more than the other by being large. But members of a minority sex will also have a higher reproductive value, on average. Thus, an individual's reproductive success depends on the reproductive decisions made by neighboring individuals. As a result, the optimal relationship between size and sex may differ among populations. In Arisaema triphyllum, the probability for an individual to be female increases with size, regardless of the character measured. A reciprocal transplant experiment showed the relationship between size and sexual expression is environmentally plastic. Plants originating from our two study sites became female at a larger average size when grown at one site than when grown at the other. In addition to environmental influence on sex expression, the experiment demonstrated genetic differences in the relationship between size and sex. Plants collected from one site became female at a larger size than those from the other, regardless of where they were grown. Thus, while the environment in which an individual was grown had a substantial influence on its sex expression, populations only a few kilometers apart have genetically different relationships between size and sex.


Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.
Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH. Fourteen patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes. Liraglutide reduced BMI (-1.9 vs. +0.04kg/m(2); p<0.001), HbA1c (-0.3 vs. +0.3%; p<0.01), cholesterol-LDL (-0.7 vs. +0.05mmol/L; p<0.01), ALT (-54 vs. -4.0IU/L; p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01). Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.


Cerebral white matter integrity mediates adult age differences in cognitive performance.
Previous research has established that age-related decline occurs in measures of cerebral white matter integrity, but the role of this decline in age-related cognitive changes is not clear. To conclude that white matter integrity has a mediating (causal) contribution, it is necessary to demonstrate that statistical control of the white matter-cognition relation reduces the magnitude of age-cognition relation. In this research, we tested the mediating role of white matter integrity, in the context of a task-switching paradigm involving word categorization. Participants were 20 healthy, community-dwelling older adults (60-85 years), and 20 younger adults (18-27 years). From diffusion tensor imaging tractography, we obtained fractional anisotropy (FA) as an index of white matter integrity in the genu and splenium of the corpus callosum and the superior longitudinal fasciculus (SLF). Mean FA values exhibited age-related decline consistent with a decrease in white matter integrity. From a model of reaction time distributions, we obtained independent estimates of the decisional and nondecisional (perceptual-motor) components of task performance. Age-related decline was evident in both components. Critically, age differences in task performance were mediated by FA in two regions: the central portion of the genu, and splenium-parietal fibers in the right hemisphere. This relation held only for the decisional component and was not evident in the nondecisional component. This result is the first demonstration that the integrity of specific white matter tracts is a mediator of age-related changes in cognitive performance.


Strategies and limitations in app usage and human mobility.
Cognition has been found to constrain several aspects of human behaviour, such as the number of friends and the number of favourite places a person keeps stable over time. This limitation has been empirically defined in the physical and social spaces. But do people exhibit similar constraints in the digital space? We address this question through the analysis of pseudonymised mobility and mobile application (app) usage data of 400,000 individuals in a European country for six months. Despite the enormous heterogeneity of apps usage, we find that individuals exhibit a conserved capacity that limits the number of applications they regularly use. Moreover, we find that this capacity steadily decreases with age, as does the capacity in the physical space but with more complex dynamics. Even though people might have the same capacity, applications get added and removed over time. In this respect, we identify two profiles of individuals: app keepers and explorers, which differ in their stable (keepers) vs exploratory (explorers) behaviour regarding their use of mobile applications. Finally, we show that the capacity of applications predicts mobility capacity and vice-versa. By contrast, the behaviour of keepers and explorers may considerably vary across the two domains. Our empirical findings provide an intriguing picture linking human behaviour in the physical and digital worlds which bridges research studies from Computer Science, Social Physics and Computational Social Sciences.


Interaction of the poliovirus receptor CD155 with the dynein light chain Tctex-1 and its implication for poliovirus pathogenesis.
The cellular receptor for poliovirus CD155 (or PVR) is the founding member of a new class of membrane-associated immunoglobulin-like proteins, which include the mouse tumor-associated antigen E4 (Tage4) and three proteins termed "nectins." Using a yeast two-hybrid screen we have discovered that the cytoplasmic domain of CD155 associates strongly and specifically with Tctex-1, a light chain of the dynein motor complex, the latter representing the major driving force for retrograde transport of endocytic vesicles and membranous organelles. We confirmed the interaction biochemically and by co-immunoprecipitation, and we mapped the Tctex-1 binding site to a SKCSR motif within the juxtamembrane region of CD155. Tctex-1 immunoreactivity was detected in mouse sciatic nerve and spinal cord (two tissues of central importance for poliovirus pathogenesis) in punctate, possibly vesicular, patterns. We propose that the cytoplasmic domain may target CD155-containing endocytic vesicles to the microtubular network. Neurotropic viruses like poliovirus, herpesvirus, rabies virus, and pseudorabies virus all utilize neuronal retrograde transport to invade the central nervous system. Association with Tctex-1 and, hence, with the dynein motor complex may offer an explanation for how poliovirus hijacks the cellular transport machinery to retrogradely ascend along the axon to the neuronal cell body.


Metals in proteins: correlation between the metal-ion type, coordination number and the amino-acid residues involved in the coordination.
Metal ions are constituents of many metalloproteins, in which they have either catalytic (metalloenzymes) or structural functions. In this work, the characteristics of various metals were studied (Cu, Zn, Mg, Mn, Fe, Co, Ni, Cd and Ca in proteins with known crystal structure) as well as the specificity of their environments. The analysis was performed on two data sets: the set of protein structures in the Protein Data Bank (PDB) determined with resolution <1.5 A and the set of nonredundant protein structures from the PDB. The former was used to determine the distances between each metal ion and its electron donors and the latter was used to assess the preferred coordination numbers and common combinations of amino-acid residues in the neighbourhood of each metal. Although the metal ions considered predominantly had a valence of two, their preferred coordination number and the type of amino-acid residues that participate in the coordination differed significantly from one metal ion to the next. This study concentrates on finding the specificities of a metal-ion environment, namely the distribution of coordination numbers and the amino-acid residue types that frequently take part in coordination. Furthermore, the correlation between the coordination number and the occurrence of certain amino-acid residues (quartets and triplets) in a metal-ion coordination sphere was analysed. The results obtained are of particular value for the identification and modelling of metal-binding sites in protein structures derived by homology modelling. Knowledge of the geometry and characteristics of the metal-binding sites in metalloproteins of known function can help to more closely determine the biological activity of proteins of unknown function and to aid in design of proteins with specific affinity for certain metals.


Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry.
Variants within the gene cluster encoding α3, α5, and β4 nicotinic receptor subunits are major risk factors for substance dependence. The strongest impact on risk is associated with variation in the CHRNA5 gene, where at least two mechanisms are at work: amino acid variation and altered mRNA expression levels. The risk allele of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele. In populations of European ancestry, there are approximately 50 highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and the adjacent PSMA4 gene region that are associated with CHRNA5 mRNA levels. It is not clear which of these variants contribute to the changes in CHRNA5 transcript level. Because populations of African ancestry have reduced linkage disequilibrium among variants spanning this gene cluster, eQTL mapping in subjects of African ancestry could potentially aid in defining the functional variants that affect CHRNA5 mRNA levels. We performed quantitative allele specific gene expression using frontal cortices derived from 49 subjects of African ancestry and 111 subjects of European ancestry. This method measures allele-specific transcript levels in the same individual, which eliminates other biological variation that occurs when comparing expression levels between different samples. This analysis confirmed that substance dependence associated variants have a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortices of African and European ancestry and identified 10 highly correlated variants, located in a 9 kb region, that are potential functional variants modifying CHRNA5 mRNA expression levels.


A novel and effective inhibitor combination involving bortezomib and OTSSP167 for breast cancer cells in light of label-free proteomic analysis.
The 26S proteasome plays important roles in many intracellular processes and is therefore a critical intracellular cellular target for anticancer treatments. The primary aim of the current study was to identify critical proteins that may play roles in opposing the antisurvival effect of the proteasome inhibitor bortezomib together with the calcium-chelator BAPTA-AM in cancer cells using label-free LC-MS/MS. In addition, based on the results of the proteomic technique, a novel and more effective inhibitor combination involving bortezomib as well as OTSSP167 was developed for breast cancer cells. Using label-free LC-MS/MS, it was found that expressions of 1266 proteins were significantly changed between the experimental groups. Among these proteins were cell division cycle 5-like (Cdc5L) and drebrin-like (DBNL). We then hypothesized that inhibition of the activities of these two proteins may lead to more effective anticancer inhibitor combinations in the presence of proteasomal inhibition. In fact, as presented in the current study, Cdc5L phosphorylation inhibitor CVT-313 and DBNL phosphorylation inhibitor OTSSP167 were highly cytotoxic in 4T1 breast cancer cells and their IC50 values were 20.1 and 43 nM, respectively. Under the same experimental conditions, the IC50 value of BAPTA-AM was found 19.9 μM. Using WST 1 cytotoxicity assay, it was determined that 10 nM bortezomib + 10 nM CVT-313 was more effective than the control, the single treatments, or than 5 nM bortezomib + 5 nM CVT-313. Similarly, 10 nM bortezomib + 10 nM OTSSP167 was more cytotoxic than the control, the monotherapies, 5 nM bortezomib + 5 nM OTSSP167, or than 5 nM bortezomib + 10 nM OTSSP167, indicating that bortezomib + OTSSP167 was also more effective than bortezomib + CVT-313 in a dose-dependent manner. Furthermore, the 3D spheroid model proved that bortezomib + OTSSP167 was more effective than the monotherapies as well as bortezomib + CVT-313 and bortezomib + BAPTA-AM combinations. Finally, the effect of bortezomib + OTSSP167 combination was tested on MDA-MB-231 breast cancer cells, and it similarly determined that 20 nM bortezomib +40 nM OTSSP167 combination completely blocked the formation of 3D spheroids. Altogether, the results presented here indicate that bortezomib + OTSSP167 is a novel and effective combination and may be tested further for cancer treatment in vivo and in clinical settings.


UVC-induced stress granules in mammalian cells.
Stress granules (SGs) are well characterized cytoplasmic RNA bodies that form under various stress conditions. We have observed that exposure of mammalian cells in culture to low doses of UVC induces the formation of discrete cytoplasmic RNA granules that were detected by immunofluorescence staining using antibodies to RNA-binding proteins. UVC-induced cytoplasmic granules are not Processing Bodies (P-bodies) and are bone fide SGs as they contain TIA-1, TIA-1/R, Caprin1, FMRP, G3BP1, PABP1, well known markers, and mRNA. Concomitant with the accumulation of the granules in the cytoplasm, cells enter a quiescent state, as they are arrested in G1 phase of the cell cycle in order to repair DNA damages induced by UVC irradiation. This blockage persists as long as the granules are present. A tight correlation between their decay and re-entry into S-phase was observed. However the kinetics of their formation, their low number per cell, their absence of fusion into larger granules, their persistence over 48 hours and their slow decay, all differ from classical SGs induced by arsenite or heat treatment. The induction of these SGs does not correlate with major translation inhibition nor with phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). We propose that a restricted subset of mRNAs coding for proteins implicated in cell cycling are removed from the translational apparatus and are sequestered in a repressed form in SGs.


Evolution of body-wall musculature in the Platyhelminthes (Acoelomorpha, Catenulida, Rhabditophora).
In an effort to understand the phylogeny of the Platyhelminthes, the patterns of body-wall musculature of flatworms were studied using fluorescence microscopy and Alexa-488-labeled phalloidin. Species of the Catenulida have a simple orthogonal gridwork of longitudinal and circular muscles. Members of the Rhabditophora have the same gridwork of musculature, but also have diagonal muscles over their entire body. Although a few species of Acoelomorpha possessed a simple orthogonal grid of musculature, most species typically have distinctly different patterns of dorsal and ventral body-wall musculature that include sets of longitudinal, circular, U-shaped, and several kinds of diagonal muscles. Several distinct patterns of musculature were identified, including 8 patterns in 11 families of acoels. These patterns have proven to be useful in clarifying the phylogeny of the Acoelomorpha, particularly with regard to the higher acoels. Patterns of musculature as well as other morphological characters are used here for revisions of acoel systematics, including the return of Eumecynostomum sanguineum (Mecynostomidae) to the genus Aphanostoma (Convolutidae), the revision of the family Childiidae, and the formation of a new family, Actinoposthiidae.


Stretchy and strong polyurethane-urea supramolecular (PUUS) hydrogels with various stimulus-responsive behaviours: the effect of chain-extenders.
The development of an easy synthetic strategy combined with straightforward tailoring of physical properties and functionalities, such that optimal performance can be targeted for various applications, still remains challenging. Previously, we reported the construction of thermo- and water-responsive strong and tough supramolecular hydrogels based on the cooperatively enhancing effect between H-bonding and hydrophobic forces. Recently, the strategy was greatly simplified to a one-pot two-step approach. In this work, by simply changing the chain extenders used in the second step, different kinds of functional units are easily introduced into the hard segments in the main chain of the copolymers to endow the resultant strong and tough supramolecular hydrogels with various stimulus-responsive properties. A dynamic covalent bond (disulphide or imine bond, e.g.-S-S- or -C[double bond, length as m-dash]N-) in the main chain provides the resulting hydrogels with reduction or pH responsive degradation (gel-to-sol transition) on demand behaviors, respectively; the azobenzene unit endows the yielding hydrogels with UV-Vis controlled stiffness; the pyridine group containing supramolecular hydrogel shows metal ion responsive mechanical and fluorescent behavior. These results provide progress toward addressing the challenges of achieving structural and synthetic simplicity married with sophisticated functionalities.


The Diagnostic Shift of SIDS to Undetermined: Are There Unintended Consequences?
Over the last two decades, a diagnostic shift in regards to the certification of sudden deaths in infancy has emerged with reassignment of deaths previously certified as sudden infant death syndrome (SIDS) to a trend utilizing the classification of undetermined or asphyxia. The consequences of this shift outside the medicolegal death investigation (MDI) community is unknown. We surveyed US organizations working in the field of sudden infant death as well as bereaved parents to understand their perceptions of the current diagnostic trends. Two online anonymous surveys were utilized. Sixty-seven organizations and 55 parents with an infant death diagnosis of SIDS, sudden unexplained infant death (SUID), undetermined, or asphyxia participated. Just over 50% (34/67) of the organizations perceived the shift had an effect on their organization including barriers to bereavement support and education. Forty percent (22/55) of parent respondents stated they did not understand the final diagnosis of their infant's death. The highest frequency of themes elicited from parents were frustration that the diagnosis (regardless of terminology) did not fully explain the death, detrimental mental health effects, and negative perceptions towards the medical and public health communities. However, parents of children whose death was classified as SIDS were spared from negative perceptions towards the medical field, described the least amount of confusion, and reported the most instances of positives effects. Legal implications, perceived social stigmas, and research obstacles were also described. Recommendations from this study include the integration of collaborative efforts to combat sudden infant death with all stakeholders, in and outside of MDI, to achieve better understanding and eradication of these tragedies, improved public education, and effective care of all bereaved.


Preservation of motor programs in paraplegics as demonstrated by attempted and imagined foot movements.
Execution and imagination of movement activate distinct neural circuits, partially overlapping in premotor and parietal areas, basal ganglia and cerebellum. Can long-term deafferented/deefferented patients still differentiate attempted from imagined movements? The attempted execution and motor imagery network of foot movements have been investigated in nine chronic complete spinal cord-injured (SCI) patients using fMRI. Thorough behavioral assessment showed that these patients were able to differentiate between attempted execution and motor imagery. Supporting the outcome of the behavioral assessment, fMRI disclosed specific patterns of activation for movement attempt and for motor imagery. Compared with motor execution data of healthy controls, movement attempt in SCI patients revealed reduced primary motor cortex activation at the group level, although activation was found in all single subjects with a high variability. Further comparisons with healthy subjects revealed that during attempt and motor imagery, SCI patients show enhanced activation and recruitment of additional regions in the parietal lobe and cerebellum that are important in sensorimotor integration. These findings reflect central plastic changes due to altered input and output and suggest that SCI patients may require additional cognitive resources to perform these tasks that may be one and the same phenomenon, or two versions of the same phenomenon, with quantitative differences between the two. Nevertheless, the retained integrity of movement attempt and motor imagery networks in SCI patients demonstrates that chronic paraplegics can still dispose of the full motor programs for foot movements and that therefore, attempted and imagined movements should be integrated in rehabilitative strategies.


Do negative symptoms of schizophrenia change over time? A meta-analysis of longitudinal data.
Negative symptoms are a core component of schizophrenia which can severely impact quality of life and functional outcomes. These symptoms are understood to be highly stable but this has not been tested in a meta-analysis, despite the wealth of longitudinal data available. A systematic review of the literature was conducted, with eligible studies pooled into a random-effects meta-analysis. Planned meta-regressions were conducted to evaluate the impact of factors known to induce secondary negative symptoms, in addition to other possible sources of heterogeneity. The main analysis included 89 samples from 41 studies, totalling 5944 participants. Negative symptoms were found to significantly reduce in all treatment interventions, including in placebo and treatment as usual conditions, with a medium effect size (ES) present across all study conditions (ES = 0.66, 95% confidence interval 0.56-0.77, I(2) = 94.0%). In a multivariate meta-regression, only the type of scale used was found to significantly influence negative symptom change. No difference in outcome was found between studies that excluded patients with a high level of positive or depressive symptoms, compared to those that did not. Negative symptoms were found to reduce in almost all schizophrenia outpatient samples. A reduction was found across all conditions, with effect sizes ranging from small to large depending upon the condition type. These findings challenge the convention that negative symptoms are highly stable and suggest that they may improve to a greater extent than what has previously been assumed.


Comparison of robotic and laparoscopic hysterectomy for benign gynecologic disease.
Use of robotically assisted hysterectomy for benign gynecologic conditions is increasing. Using the most recent, available nationwide data, we examined clinical outcomes, safety, and cost of robotic compared with laparoscopic hysterectomy. Women undergoing robotic or laparoscopic hysterectomy for benign disease were identified from the United States 2009 and 2010 Nationwide Inpatient Sample. Propensity scores derived from a logistic regression model were used to assemble matched cohorts of patients undergoing robotic and laparoscopic hysterectomy. Differences in in-hospital complications, hospital length of stay, and hospital charges were assessed between the matched groups. Of the 804,551 hysterectomies for benign conditions performed in 2009 and 2010, 20.6% were laparoscopic and 5.1% robotically assisted. Among minimally invasive hysterectomies, the use of robotic hysterectomy increased from 9.5% to 13.6% (P=.002). In a propensity-matched analysis, the overall complication rates were similar between robotic and laparoscopic hysterectomy (8.80% compared with 8.85%, relative risk 0.99, 95% confidence interval [CI] 0.89-1.09, P=.910). There was a lower incidence of blood transfusions in robotic cases (2.1% compared with 3.1%; P<.001), but patients undergoing robotic hysterectomy were more likely to experience postoperative pneumonia (relative risk 2.2, 95% CI 1.24-3.78, P=.005). The median cost of hospital care was $9,788 (interquartile range $7,105-12,780) for robotic hysterectomy and $7,299 (interquartile range $5,650-9,583) for laparoscopic hysterectomy (P<.001). Hospital costs were on average $2,489 (95% CI $2,313-2,664) higher for patients undergoing robotic hysterectomy. The use of robotic hysterectomy has increased. Perioperative outcomes are similar between laparoscopic and robotic hysterectomy, but robotic cases cost substantially more. : II.


Individual differences in metabolomics: individualised responses and between-metabolite relationships.
Many metabolomics studies aim to find 'biomarkers': sets of molecules that are consistently elevated or decreased upon experimental manipulation. Biological effects, however, often manifest themselves along a continuum of individual differences between the biological replicates in the experiment. Such differences are overlooked or even diminished by methods in standard use for metabolomics, although they may contain a wealth of information on the experiment. Properly understanding individual differences is crucial for generating knowledge in fields like personalised medicine, evolution and ecology. We propose to use simultaneous component analysis with individual differences constraints (SCA-IND), a data analysis method from psychology that focuses on these differences. This method constructs axes along the natural biochemical differences between biological replicates, comparable to principal components. The model may shed light on changes in the individual differences between experimental groups, but also on whether these differences correspond to, e.g., responders and non-responders or to distinct chemotypes. Moreover, SCA-IND reveals the individuals that respond most to a manipulation and are best suited for further experimentation. The method is illustrated by the analysis of individual differences in the metabolic response of cabbage plants to herbivory. The model reveals individual differences in the response to shoot herbivory, where two 'response chemotypes' may be identified. In the response to root herbivory the model shows that individual plants differ strongly in response dynamics. Thereby SCA-IND provides a hitherto unavailable view on the chemical diversity of the induced plant response, that greatly increases understanding of the system. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-012-0414-8) contains supplementary material, which is available to authorized users.


The Case for Ancient Hot Springs in Gusev Crater, Mars.
The origin and age of opaline silica deposits discovered by the Spirit rover adjacent to the Home Plate feature in the Columbia Hills of Gusev crater remains debated, in part because of their proximity to sulfur-rich soils. Processes related to fumarolic activity and to hot springs and/or geysers are the leading candidates. Both processes are known to produce opaline silica on Earth, but with differences in composition, morphology, texture, and stratigraphy. Here, we incorporate new and existing observations of the Home Plate region with observations from field and laboratory work to address the competing hypotheses. The results, which include new evidence for a hot spring vent mound, demonstrate that a volcanic hydrothermal system manifesting both hot spring/geyser and fumarolic activity best explains the opaline silica rocks and proximal S-rich materials, respectively. The opaline silica rocks most likely are sinter deposits derived from hot spring activity. Stratigraphic evidence indicates that their deposition occurred before the emplacement of the volcaniclastic deposits comprising Home Plate and nearby ridges. Because sinter deposits throughout geologic history on Earth preserve evidence for microbial life, they are a key target in the search for ancient life on Mars.


[Exercise therapy in hip or knee osteoarthritis].
"Exercise is medicine": exercise therapy reduces pain and activity limitations in osteoarthritis of the knee and is likely to have the same effects in osteoarthritis of the hip. Further research into exercise therapy is needed, since disease-modifying drugs are not available, pain medication can cause side effects, and surgical interventions are preferably applied in an advanced stage of disease. Classical exercise therapy is aimed at improving muscle strength, aerobic capacity, range of joint motion, and training of walking and activities of daily living. New modalities of targeted exercise therapy are currently being developed, aimed at the correction of low levels of activity and to correct instability of the knee. Weight loss, preferably combined with exercise therapy, reduces pain and activity limitations in osteoarthritis patients who are overweight. Modalities of exercise therapy adapted to comorbid conditions are currently being developed.


PET in the clinical management of glioma: evidence map.
Several studies have assessed PET to complement the anatomic information obtained from other imaging modalities in various clinical contexts for the management of glioma. We constructed an evidence map of clinical evidence on the use of PET in glioma and identified research gaps. We searched PubMed and Scopus (from inception through June 30, 2011) to identify studies assessing the use of PET for glioma regardless of setting of care or indication. We extracted test objectives, study characteristics, and phases of diagnostic evidence and then assessed research diversity and temporal trends in the literature. We excluded studies assessing only technical feasibility and optimization of PET. A total of 129 studies were considered eligible; the number of articles published annually has greatly increased over time (p for trend < 0.001). Most studies (n = 118, 91%) assessed diagnostic or prognostic performance; fewer studies reported on the impact of PET on diagnostic thinking (n = 4, 3%), therapeutic decisions (n = 4, 3%), or patient-relevant clinical outcomes (n = 3; 2%). Fluorine-18 FDG (n = 73, 57%) or (11)C-methionine (n = 44, 34%) were the two most commonly evaluated PET tracers. Pretherapy assessment (n = 72, 56%) and monitoring of treatment response (n = 48, 37%) were the most common settings of test use assessed in the research studies. More primary studies, particularly studies of newer tracers focusing on biopsy or treatment planning, are needed to better characterize the role of PET in specific contexts.


White Rice Intake and Incident Diabetes: A Study of 132,373 Participants in 21 Countries.
Previous prospective studies on the association of white rice intake with incident diabetes have shown contradictory results but were conducted in single countries and predominantly in Asia. We report on the association of white rice with risk of diabetes in the multinational Prospective Urban Rural Epidemiology (PURE) study. Data on 132,373 individuals aged 35-70 years from 21 countries were analyzed. White rice consumption (cooked) was categorized as <150, ≥150 to <300, ≥300 to <450, and ≥450 g/day, based on one cup of cooked rice = 150 g. The primary outcome was incident diabetes. Hazard ratios (HRs) were calculated using a multivariable Cox frailty model. During a mean follow-up period of 9.5 years, 6,129 individuals without baseline diabetes developed incident diabetes. In the overall cohort, higher intake of white rice (≥450 g/day compared with <150 g/day) was associated with increased risk of diabetes (HR 1.20; 95% CI 1.02-1.40; P for trend = 0.003). However, the highest risk was seen in South Asia (HR 1.61; 95% CI 1.13-2.30; P for trend = 0.02), followed by other regions of the world (which included South East Asia, Middle East, South America, North America, Europe, and Africa) (HR 1.41; 95% CI 1.08-1.86; P for trend = 0.01), while in China there was no significant association (HR 1.04; 95% CI 0.77-1.40; P for trend = 0.38). Higher consumption of white rice is associated with an increased risk of incident diabetes with the strongest association being observed in South Asia, while in other regions, a modest, nonsignificant association was seen.


Disruption of the Saccharomyces cerevisiae YAP3 gene reduces the proteolytic degradation of secreted recombinant human albumin.
Expression of recombinant human albumin (rHA) in Saccharomyces cerevisiae resulted in secretion of both mature albumin and a 45 kDa degradation product, comprising an N-terminal fragment of rHA with heterogeneous C-termini between residues 403 and 409 (Geisow et al., 1991). Site-directed mutagenesis of the human albumin gene (HA) to change Arg410 to Ala (R410A) caused a significant reduction in the amount of fragment produced. Mutation of the adjacent dibasic site Lys413 Lys414 had little effect in isolation, but in combination with the R410A mutation resulted in a further reduction in the amount of rHA fragment produced. This reduction could be duplicated with nature-identical rHA by disruption of the gene for an aspartyl protease (YAP3), alone or in conjunction with disruption of the KEX2 gene. Disruption of KEX2 alone did not result in any improvement in the degree of degradation of the rHA. Reduced degradation was also observed when an rHA-human growth hormone fusion protein was secreted from a yap3 strain, suggesting that such strains may have a general utility for heterologous protein secretion.


Tick-borne Great Island Virus: (II) Impact of age-related acquired immunity on transmission in a natural seabird host.
Tick-borne pathogen transmission is dependent upon tick number per host and the physical and temporal distribution of each feeding stage. Age-related acquired immunity to tick and pathogen may also be important but has received less attention. In this study we evaluate which of these parameters has the greatest impact on Great Island Virus (GIV) transmission between Ixodes uriae ticks and common guillemots (Uria aalge). The study system is well suited to investigate age-related effects because the guillemot population is naturally divided into 2 groups, older breeding and younger pre-breeding adult birds. The physical distribution and timing of adult and nymphal tick feeding was similar for both guillemot age groups. However, breeding birds were parasitized by significantly more ticks (mainly nymphs). Calculations based on tick number predict virus prevalence should be higher in ticks that have fed on breeding rather than pre-breeding birds. However, empirical evidence indicates the reverse. Protective acquired immunity to GIV infection may be the reason why GIV prevalence is actually significantly lower in ticks that have fed on breeders. Far more breeding (74%) than pre-breeding (12%) guillemots had antibodies that neutralized 1 or more GIV strains. Estimates of the force of infection support the view that pre-breeding birds experience higher rates of virus infection than breeding birds. The results indicate age-related acquired immunity is a key factor in GIV transmission and highlight the need to consider age-related effects and host immunity when undertaking quantitative studies of tick-borne pathogen transmission.


Lung cancer inhibitory effect of epigallocatechin-3-gallate is dependent on its presence in a complex mixture (polyphenon E).
Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. However, (-)-epigallocatechin-3-gallate (EGCG) alone was shown to be ineffective in preventing lung tumorigenesis in mice by aerosol administration. In this study, Polyphenon E and Polyphenon E without EGCG were administered by aerosol delivery to A/J mice 2 weeks after carcinogen treatment and continuing daily throughout the remainder of the study (20 weeks). An improved aerosol delivery system with a custom-built atomizer, an efficient solvent remove system, and a nose-only exposure chamber was used to provide aerosols with stable size distribution. There were no significant differences in the size distributions of Polyphenon E and Polyphenon E without EGCG. With a relatively low dose level (4.19 mg/kg), Polyphenon E decreased tumor multiplicity by 53%, whereas Polyphenon E without EGCG at the same dose failed to inhibit lung carcinogenesis. These results indicate that aerosol administration can be an effective approach in chemoprevention study, and aerosolized Polyphenon E can significantly inhibit pulmonary adenoma formation and growth in A/J mice. Furthermore, in aerosolized form, EGCG, which is thought to be the most active component of Polyphenon E, has to be present with other tea catechins to show chemopreventive activity on lung tumorigenesis.


Effects of sequestration on signal transduction cascades.
The building blocks of most signal transduction pathways are pairs of enzymes, such as kinases and phosphatases, that control the activity of protein targets by covalent modification. It has previously been shown [Goldbeter A & Koshland DE (1981) Proc Natl Acad Sci USA 78, 6840-6844] that these systems can be highly sensitive to changes in stimuli if their catalysing enzymes are saturated with their target protein substrates. This mechanism, termed zero-order ultrasensitivity, may set thresholds that filter out subthreshold stimuli. Experimental data on protein abundance suggest that the enzymes and their target proteins are present in comparable concentrations. Under these conditions a large fraction of the target protein may be sequestrated by the enzymes. This causes a reduction in ultrasensitivity so that the proposed mechanism is unlikely to account for ultrasensitivity under the conditions present in most in vivo signalling cascades. Furthermore, we show that sequestration changes the dynamics of a covalent modification cycle and may account for signal termination and a sign-sensitive delay. Finally, we analyse the effect of sequestration on the dynamics of a complex signal transduction cascade: the mitogen-activated protein kinase (MAPK) cascade with negative feedback. We show that sequestration limits ultrasensitivity in this cascade and may thereby abolish the potential for oscillations induced by negative feedback.


Avoiding the Major Causes of Death: Does Childhood Misfortune Reduce the Likelihood of Being Disease Free in Later Life?
Although previous research reveals the detrimental effects of early misfortune on the development of chronic diseases in later life, few studies have investigated its effects on remaining disease free. This study draws on cumulative inequality theory to investigate whether experiencing childhood misfortune reduces the likelihood of remaining disease free over time. This study utilizes five waves of data from the Health and Retirement Study to test whether five domains of childhood misfortune predict being disease free at baseline (2004) and developing disease over time (2004-2012). Respondents reporting risky parental behaviors during childhood were less likely to be disease free at baseline and had an increased risk of disease onset over time, the latter driven by having a guardian who smoked in combination with more pack-years smoked in adulthood. Furthermore, we find that adult resources, that is wealth, help to mitigate the noxious effects of other misfortunes, notably poor socioeconomic conditions. Consistent with cumulative inequality theory, these findings reveal that experiencing multiple types of misfortune during childhood decreases the likelihood of remaining disease free in later life, but engaging in health behaviors, such as physical activity, can help to ameliorate some of the noxious effects of early misfortune.


Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.
Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.


Evaluation of resident attitudes and self-reported competencies in health advocacy.
The CanMEDS Health Advocate role, one of seven roles mandated by the Royal College of Physicians and Surgeons Canada, pertains to a physician's responsibility to use their expertise and influence to advance the wellbeing of patients, communities, and populations. We conducted our study to examine resident attitudes and self-reported competencies related to health advocacy, due to limited information in the literature on this topic. We conducted a pilot experience with seven internal medicine residents participating in a community health promotion event. The residents provided narrative feedback after the event and the information was used to generate items for a health advocacy survey. Face validity was established by having the same residents review the survey. Content validity was established by inviting an expert physician panel to review the survey. The refined survey was then distributed to a cohort of core Internal Medicine residents electronically after attendance at an academic retreat teaching residents about advocacy through didactic sessions. The survey was completed by 76 residents with a response rate of 68%. The majority agreed to accept an advocacy role for societal health needs beyond caring for individual patients. Most confirmed their ability to identify health determinants and reaffirmed the inherent requirements for health advocacy. While involvement in health advocacy was common during high school and undergraduate studies, 76% of residents reported no current engagement in advocacy activity, and 36% were undecided if they would engage in advocacy during their remaining time as residents, fellows or staff. The common barriers reported were insufficient time, rest and stress. Medical residents endorsed the role of health advocate and reported proficiency in determining the medical and bio-psychosocial determinants of individuals and communities. Few residents, however, were actively involved in health advocacy beyond an individual level during residency due to multiple barriers. Further studies should address these barriers to advocacy and identify the reasons for the discordance we found between advocacy endorsement and lack of engagement.


Acute inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome associated with COVID-19: a case report.
Coronavirus disease 2019 (COVID-19) is a global pandemic. The disease, typically characterized by bilateral pulmonary infiltrates and profound elevation of inflammatory markers, can range in severity from mild or asymptomatic illness to a lethal cytokine storm and respiratory failure. A number of recognized complications of COVID-19 infection are described in the literature. Common neurological complications include headache and anosmia. Guillain-Barré syndrome (GBS) is an uncommon complication described in isolated case reports. However, a causal relationship has yet to be established. This case report adds to the growing body of evidence that GBS is a potential COVID-19 complication. A 70-year-old Caucasian woman with recently diagnosed COVID-19 infection presented to the emergency department with 4 days of gradually worsening ascending lower extremity weakness. Exam revealed bilateral lower extremity weakness, mute reflexes, and sensory loss. Soon after starting intravenous administration of immunoglobulin (IVIG), the patient developed respiratory distress, eventually requiring intubation. She remained intubated for the duration of her IVIG treatment. After five rounds of treatment, the patient was successfully extubated and transferred to acute rehab. Following 4 weeks of intense physical therapy, she was able to walk with assistance on room air. At the present time, this is one of the few reports of acute inflammatory demyelinating polyneuropathy (AIDP) or GBS associated with COVID-19 in the United States. It is unclear whether a causal relationship exists given the nature of the syndrome. However, in light of the growing number of reported cases, physicians should be aware of this possible complication when evaluating COVID-19 patients.