An analysis of the size and direction of the association between mental toughness and Olympic distance personal best triathlon times.
Athletes, coaches, sport psychology practitioners, and researchers suggest that mental toughness represents an important construct that is associated with athletic performance. Unfortunately, the absence of real-world performance as a dependent variable has limited our ability to substantiate this claim. The concern of a lack of ecologically valid measures of sports performance might be addressed by examining the relationship between mental toughness and sports performance using a standardized measure of personal best (PB) triathlon time and a validated unidimensional measure of mental toughness. Three hundred and sixteen triathletes completed the 8-item mental toughness index (MTI), reported their age, and provided a PB Olympic distance triathlon time and the total number of triathlons they had completed to date. Given that males are typically quicker than females, a standardized time was calculated by dividing the PB by the current Olympic record for gender; we also hypothesized that more experienced triathletes would report quicker PB times because of greater frequency and duration of training. Once we had controlled for gender and experience, we predicted that mental toughness would be negatively associated with triathlon time and the size of the relationship would be of a moderate magnitude. Results revealed small- to moderate-sized negative relationships between both completed number of triathlons and mental toughness with standardized PB time. The hierarchical regression analysis showed that mental toughness provided a unique contribution to the variability in standardized Olympic triathlon PB after controlling for the total number of triathlons completed.


Current Approaches to Vaccine Safety Using Observational Data: A Rationale for the EUMAEUS (Evaluating Use of Methods for Adverse Events Under Surveillance-for Vaccines) Study Design.
Post-marketing vaccine safety surveillance aims to detect adverse events following immunization in a population. Whether certain methods of surveillance are more precise and unbiased in generating safety signals is unclear. Here, we synthesized information from existing literature to provide an overview of the strengths, weaknesses, and clinical applications of epidemiologic and analytical methods used in vaccine monitoring, focusing on cohort, case-control and self-controlled designs. These designs are proposed to be evaluated in the EUMAEUS (Evaluating Use of Methods for Adverse Event Under Surveillance-for vaccines) study because of their widespread use and potential utility. Over the past decades, there have been an increasing number of epidemiological study designs used for vaccine safety surveillance. While traditional cohort and case-control study designs remain widely used, newer, novel designs such as the self-controlled case series and self-controlled risk intervals have been developed. Each study design comes with its strengths and limitations, and the most appropriate study design will depend on availability of resources, access to records, number and distribution of cases, and availability of population coverage data. Several assumptions have to be made while using the various study designs, and while the goal is to mitigate any biases, violations of these assumptions are often still present to varying degrees. In our review, we discussed some of the potential biases (i.e., selection bias, misclassification bias and confounding bias), and ways to mitigate them. While the types of epidemiological study designs are well established, a comprehensive comparison of the analytical aspects (including method evaluation and performance metrics) of these study designs are relatively less well studied. We summarized the literature, reporting on two simulation studies, which compared the detection time, empirical power, error rate and risk estimate bias across the above-mentioned study designs. While these simulation studies provided insights on the analytic performance of each of the study designs, its applicability to real-world data remains unclear. To bridge that gap, we provided the rationale of the EUMAEUS study, with a brief description of the study design; and how the use of real-world multi-database networks can provide insights into better methods evaluation and vaccine safety surveillance.


The cylindrical inclusion gene of Turnip mosaic virus encodes a pathogenic determinant to the Brassica resistance gene TuRB01.
The viral component of Turnip mosaic virus (TuMV) determining virulence to the Brassica napus TuRB01 dominant resistance allele has been identified. Sequence comparisons of an infectious cDNA clone of the UK 1 isolate of TuMV (avirulent on TuRB01) and a spontaneous mutant capable of infecting plants possessing TuRB01 suggested that a single nucleotide change in the cylindrical inclusion (CI) protein coding region (gene) of the virus was responsible for the altered phenotype. A second spontaneous mutation involved a different change in the CI gene. The construction of chimeric genomes and subsequent inoculations to plant lines segregating for TuRB01 confirmed the involvement of the CI gene in this interaction. Site-directed mutagenesis of the viral coat protein (CP) gene at the ninth nucleotide was carried out to investigate its interaction with TuRB01. The identity of this nucleotide in the CP gene did not affect the outcome of the viral infection. Both mutations identified in the CI gene caused amino acid changes in the C terminal third of the protein, outside any of the conserved sequences reported to be associated with helicase or cell-to-cell transport activities. This is the first example of a potyvirus CI gene acting as a determinant for a genotype-specific resistance interaction.


Implant Treatment in the Predoctoral Clinic: A Retrospective Database Study of 1091 Patients.
This retrospective study was conducted at the Marquette University School of Dentistry to (1) characterize the implant patient population in a predoctoral clinic, (2) describe the implants inserted, and (3) provide information on implant failures. The study cohort included 1091 patients who received 1918 dental implants between 2004 and 2012, and had their implants restored by a crown or a fixed dental prosthesis. Data were collected from patient records, entered in a database, and summarized in tables and figures. Contingency tables were prepared and analyzed by a chi-squared test. The cumulative survival probability of implants was described using a Kaplan-Meier survival curve. Univariate and multivariate frailty Cox regression models for clustered observations were computed to identify factors associated with implant failure. Mean patient age (±1 SD) at implantation was 59.7 ± 15.3 years; 53.9% of patients were females, 73.5% were Caucasians. Noble Biocare was the most frequently used implant brand (65.0%). Most implants had a regular-size diameter (59.3%). More implants were inserted in posterior (79.0%) than in anterior jaw regions. Mandibular posterior was the most frequently restored site (43%); 87.8% of implants were restored using single implant crowns. The overall implant-based cumulative survival rate was 96.4%. The patient-based implant survival rate was 94.6%. Implant failure risk was greater among patients than within patients (p < 0.05). Age (>65 years; hazard ratio [HR] = 3.2, p = 0.02), implant staging (two-stage; HR = 4.0, p < 0.001), and implant diameter (wide; HR = 0.4, p = 0.04) were statistically associated with implant failure. Treatment with dental implants in a supervised predoctoral clinic environment resulted in survival rates similar to published results obtained in private practice or research clinics. Older age and implant staging increased failure risk, while the selection of a wide implant diameter was associated with a lower failure risk.


Public health lives: Gro Harlem Brundtland.
Health has been a deeply personal, professional and political dimension of Gro Harlem Brundtland's life. Her decision to study breast feeding while an MPH student at Harvard in 1964, or her desire to tackle tobacco being influenced by her father sending her as a 10-year old girl to buy his cigarettes at the local store, or her deeply personal family experience of mental ill health all led her to take actions on the global stage to address these and other issues that evidence showed would have global impact. Her impact on global health started with a commitment to make a difference in the lives of people, particularly those in greatest need.


When 7 transmembrane receptors are not G protein-coupled receptors.
Classically, 7 transmembrane receptors transduce extracellular signals by coupling to heterotrimeric G proteins, although recent in vitro studies have clearly demonstrated that they can also signal via G protein-independent mechanisms. However, the physiologic consequences of this unconventional signaling, particularly in vivo, have not been explored. In this issue of the JCI, Zhai et al. demonstrate in vivo effects of G protein-independent signaling by the angiotensin II type 1 receptor (AT1R) (see the related article beginning on page 3045). In studies of the mouse heart, they compare the physiologic and biochemical consequences of transgenic cardiac-specific overexpression of a mutant AT1R incapable of G protein coupling with those of a wild-type receptor. Their results not only provide the first glimpse of the physiologic effects of this newly appreciated mode of signaling but also provide important and previously unappreciated clues as to the underlying molecular mechanisms.


Validation of the Dyadic Coping Inventory with Chinese couples: Factorial structure, measurement invariance, and construct validity.
The Dyadic Coping Inventory (DCI, Bodenmann, 2008) assesses how couples support each other when facing individual (e.g., workload) and common (e.g., parenting) stressors. Specifically, the DCI measures partners' perceptions of their own (Self) and their partners' behaviors (Partner) when facing individual stressors, and partners' common coping behaviors when facing common stressors (Common). To date, the DCI has been validated in 6 different languages from individualistic Western cultures; however, because culture can affect interpersonal interactions, it is unknown whether the DCI is a reliable measure of coping behaviors for couples living in collectivistic Eastern cultures. Based on data from 474 Chinese couples (N = 948 individuals), the current study examined the Chinese version of the DCI's factorial structure, measurement invariance (MI), and construct validity of test scores. Using 3 cultural groups (China, Switzerland, and the United States [U.S.]), confirmatory factor analysis revealed a 5-factor structure regarding Self and Partner and a 2-factor structure regarding Common dyadic coping (DC). Results from analyses of MI indicated that the DCI subscales met the criteria for configural, metric, and full/partial scalar invariance across cultures (Chinese-Swiss and Chinese-U.S.) and genders (Chinese men and women). Results further revealed good construct validity of the DCI test scores. In all, the Chinese version of the DCI can be used for measuring Chinese couples' coping behaviors, and is available for cross-cultural studies examining DC behaviors between Western and Eastern cultures. (PsycINFO Database Record


Do nutritional supplements lower the risk of stroke or hypertension?
Between 1986 and 1991, 29,584 persons took part in a randomized nutritional intervention trial in Linxian, China, an area whose residents had chronically low intakes of several nutrients and high rates of esophageal and gastric cardia cancer as well as stroke. Using a one-half replicate of a 2(4) factorial design, we randomized individuals to one of eight groups which received combinations of four supplements: retinol and zinc (factor A); riboflavin and niacin (factor B); vitamin C and molybdenum (factor C); and beta-carotene, alpha-tocopherol (vitamin E), and selenium (factor D). Deaths that occurred during 5 years of supplementation were ascertained and classified according to cause. At the end of the supplementation period, we measured blood pressure readings and determined the prevalence of hypertension. Participants who received factor D had reductions in total mortality (9%) and total cancer mortality (13%). These individuals also had the largest reduction in stroke mortality (relative risk = 0.91; 95% confidence interval = 0.76-1.07). End-of-trial hypertension, however, was not less prevalent among those receiving factor D. Our findings contrast with the larger reductions in stroke death and hypertension found in a parallel trial of Linxian subjects with esophageal dysplasia who received a multivitamin/mineral supplement, suggesting an effect largely derived from nutrients other than those received in the present study.


Appetitive Traits and Weight in Children: Evidence for Parents' Controlling Feeding Practices as Mediating Mechanisms.
Children's food approach and food avoidance are appetitive traits with genetic or biological bases. Nonetheless, parents play a critical role in children's dietary intake through parenting and feeding practices. The present study tested parents' controlling feeding practices (i.e., restriction and pressure to eat) as mediating mechanisms between child appetitive traits and child BMI in an economically and ethnically diverse sample. Participants were 139 children aged 4 to 6 years (51.8% males, M = 4.77 years, SD = 0.84) and their parents. Results showed that restriction and pressure to eat mediated the relation between child food approach or food avoidance and child BMI. Mediation effects did not differ across poverty status or racial/ethnic groups. Also, the type of controlling feeding that parents exert related to children's weight status in diametrically different or opposite ways. Thus, food-related parenting appears to be a promising point of entry for childhood obesity prevention programs. Findings are consistent with a biopsychosocial model of the development of eating and weight in childhood which takes into account both parent and child behavior and characteristics and links child biology and behavior with psychosocial processes and environment.


Piericidin A1 Blocks Yersinia Ysc Type III Secretion System Needle Assembly.
The type III secretion system (T3SS) is a bacterial virulence factor expressed by dozens of Gram-negative pathogens but largely absent from commensals. The T3SS is an attractive target for antimicrobial agents that may disarm pathogenic bacteria while leaving commensal populations intact. We previously identified piericidin A1 as an inhibitor of the Ysc T3SS in Yersinia pseudotuberculosis. Piericidins were first discovered as inhibitors of complex I of the electron transport chain in mitochondria and some bacteria. However, we found that piericidin A1 did not alter Yersinia membrane potential or inhibit flagellar motility powered by the proton motive force, indicating that the piericidin mode of action against Yersinia type III secretion is independent of complex I. Instead, piericidin A1 reduced the number of T3SS needle complexes visible by fluorescence microscopy at the bacterial surface, preventing T3SS translocator and effector protein secretion. Furthermore, piericidin A1 decreased the abundance of higher-order YscF needle subunit complexes, suggesting that piericidin A1 blocks YscF needle assembly. While expression of T3SS components in Yersinia are positively regulated by active type III secretion, the block in secretion by piericidin A1 was not accompanied by a decrease in T3SS gene expression, indicating that piericidin A1 may target a T3SS regulatory circuit. However, piericidin A1 still inhibited effector protein secretion in the absence of the T3SS regulator YopK, YopD, or YopN. Surprisingly, while piericidin A1 also inhibited the Y. enterocolitica Ysc T3SS, it did not inhibit the SPI-1 family Ysa T3SS in Y. enterocolitica or the Ysc family T3SS in Pseudomonas aeruginosa. Together, these data indicate that piericidin A1 specifically inhibits Yersinia Ysc T3SS needle assembly. IMPORTANCE The bacterial type III secretion system (T3SS) is widely used by both human and animal pathogens to cause disease yet remains incompletely understood. Deciphering how some natural products, such as the microbial metabolite piericidin, inhibit type III secretion can provide important insight into how the T3SS functions or is regulated. Taking this approach, we investigated the ability of piericidin to block T3SS function in several human pathogens. Surprisingly, piericidin selectively inhibited the Ysc family T3SS in enteropathogenic Yersinia but did not affect the function of a different T3SS within the same species. Furthermore, piericidin specifically blocked the formation of T3SS needles on the bacterial surface without altering the localization of several other T3SS components or regulation of T3SS gene expression. These data show that piericidin targets a mechanism important for needle assembly that is unique to the Yersinia Ysc T3SS.


Psychological characteristics in musician׳s dystonia: a new diagnostic classification.
Numerous studies suggest that dysfunctional basal ganglia-thalamo-cortical circuits are involved in both movement disorders and psychiatric impairments. The current exploratory investigation explored possible psychological differences, firstly between 24 healthy musicians (HM) and 24 musicians diagnosed with focal dystonia (FDM) (Study I), and secondly among 35 FDM patients only (Study II). Results revealed that FDM patients are six times more likely to exhibit elevated anxiety, perfectionistic and stress characteristics than HM. These psychological conditions might contribute as aggravating risk factors to the development of FDM. However, half of the FDM patients did not demonstrate any signs of anxiety, perfectionism or stress. The findings point to the clear existence of two different psychological profiles among FDM patients. We suggest that this psychological distinction might reflect two different mal-adaptive processes mediated via different circuits of the cortico-basal ganglia-thalamicloops. The new classification of FDM patients will contribute to the reinforcement of the diagnostic repertoire, necessary for the selection of more specific treatment methods.


Effect of Klebsiella pneumoniae enterotoxin on intestinal transport in the rat.
The effects on intestinal transport of either a semipurified preparation of enterotoxin elaborated by Klebsiella pneumoniae or similaryly prepared control material were tested by marker perfusion studies in the small intestine of rats. At a concentration of 2 mg/ml, the enterotoxin produced net secretion of water, Na, and Cl in both jejunal and ileal segments; HCO3 transport was not affected. Net secretion was evident within 30 min after intorduction of the toxin and was maximal after 90 min. The addition of 56 mM glucose to the enterotoxin-containing perfusion fluid resulted in reversal of water and Na transport to net absorption in both intestinal segments. The enterotoxin also produced a significant depression of xylose absorption in both the jejunum and ileum but did not affect the absorption of either glucose or L-leucine. Intestinal structure was not altered after perfusion of the toxin but insillation of approximately one-quarter of the total perfusion dose into a ligated jejunal loop for 18 h produced fluid secretion and structural abnormalities. These observations confirm the fact that other species of coliform bacteria in addition to tescherichia coli are capable of elaborating an enterotoxin. Such species commonly contaminate the small intestine of persons with tropical sprue and it is suggested that chronic exposure of the intestinal mucosa to the enterotoxin elaborated by these bacteria may be a factor in the pathogenesis of intestinal abnormalities in thid disorder.


Beta2-agonist administration increases sarcoplasmic reticulum Ca2+-ATPase activity in aged rat skeletal muscle.
Aging is associated with a slowing of skeletal muscle contractile properties, including a decreased rate of relaxation. In rats, the age-related decrease in the maximal rate of relaxation is reversed after 4-wk administration with the beta2-adrenoceptor agonist (beta2-agonist) fenoterol. Given the critical role of the sarcoplasmic reticulum (SR) in regulating intracellular Ca2+ transients and ultimately the time course of muscle contraction and relaxation, we tested the hypothesis that the mechanisms of action of fenoterol are mediated by alterations in SR proteins. Sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) kinetic properties were assessed in muscle homogenates and enriched SR membranes isolated from the red (RG) and white (WG) portions of the gastrocnemius muscle in adult (16 mo) and aged (28 mo) F344 rats that had been administered fenoterol for 4 wk (1.4 mg/kg/day ip, in saline) or vehicle only. Aging was associated with a 29% decrease in the maximal activity (Vmax) of SERCA in the RG but not in the WG muscles. Fenoterol treatment increased the Vmax of SERCA and SERCA1 protein levels in RG and WG. In the RG, fenoterol administration reversed an age-related selective nitration of the SERCA2a isoform. Our findings demonstrate that the mechanisms underlying age-related changes in contractile properties are fiber type dependent, whereas the effects of fenoterol administration are independent of age and fiber type.


Functional domains within the a sequence involved in the cleavage-packaging of herpes simplex virus DNA.
Newly replicated herpes simplex virus (HSV) DNA consists of head-to-tail concatemers which are cleaved to generate unit-length genomes bounded by the terminally reiterated a sequence. Constructed defective HSV vectors (amplicons) containing a viral DNA replication origin and the a sequence are similarly replicated into large concatemers which are cleaved at a sequences punctuating the junctions between adjacent repeat units, concurrent with the packaging of viral DNA into nucleocapsids. In the present study we tested the ability of seed amplicons containing specific deletions in the a sequence to become cleaved and packaged and hence be propagated in virus stocks. These studies revealed that two separate signals, located within the Ub and Uc elements of the a sequence, were essential for amplicon propagation. No derivative defective genomes were recovered from seed constructs which lacked the Uc signal. In contrast, propagation of seed constructs lacking the Ub signal resulted in the selection of defective genomes with novel junctions, containing specific insertions of a sequences derived from the helper virus DNA. Comparison of published sequences of concatemeric junctions of several herpesviruses supported a uniform mechanism for the cleavage-packaging process, involving the measurement from two highly conserved blocks of sequences (pac-1 and pac-2) which were homologous to the required Uc and Ub sequences. These results form the basis for general models for the mechanism of cleavage-packaging of herpesvirus DNA.


Colorectal cancer prognosis: is it all mutation, mutation, mutation?
For the 500,000 new cases of colorectal cancer in the world each year, identification of patients with a worse prognosis and those who are more likely to respond to treatment is a challenge. There is an increasing body of evidence correlating genetic mutations with outcome in tumours derived from human colorectal cancer cohorts. K-ras, but not p53 or APC, mutations appear to be associated with poorer overall survival in colorectal cancer patients.


Using Clinical Notes and Natural Language Processing for Automated HIV Risk Assessment.
Universal HIV screening programs are costly, labor intensive, and often fail to identify high-risk individuals. Automated risk assessment methods that leverage longitudinal electronic health records (EHRs) could catalyze targeted screening programs. Although social and behavioral determinants of health are typically captured in narrative documentation, previous analyses have considered only structured EHR fields. We examined whether natural language processing (NLP) would improve predictive models of HIV diagnosis. One hundred eighty-one HIV+ individuals received care at New York Presbyterian Hospital before a confirmatory HIV diagnosis and 543 HIV negative controls were selected using propensity score matching and included in the study cohort. EHR data including demographics, laboratory tests, diagnosis codes, and unstructured notes before HIV diagnosis were extracted for modeling. Three predictive algorithms were developed using machine-learning algorithms: (1) a baseline model with only structured EHR data, (2) baseline plus NLP topics, and (3) baseline plus NLP clinical keywords. Predictive models demonstrated a range of performance with F measures of 0.59 for the baseline model, 0.63 for the baseline + NLP topic model, and 0.74 for the baseline + NLP keyword model. The baseline + NLP keyword model yielded the highest precision by including keywords including "msm," "unprotected," "hiv," and "methamphetamine," and structured EHR data indicative of additional HIV risk factors. NLP improved the predictive performance of automated HIV risk assessment by extracting terms in clinical text indicative of high-risk behavior. Future studies should explore more advanced techniques for extracting social and behavioral determinants from clinical text.


Molecular Mechanism of the Flexible Glycan Receptor Recognition by Mumps Virus.
Mumps virus (MuV) is an important aerosol-transmitted human pathogen causing epidemic parotitis, meningitis, encephalitis, and deafness. MuV preferentially uses a trisaccharide containing α2,3-linked sialic acid as a receptor. However, given the MuV tropism toward glandular tissues and the central nervous system, an additional glycan motif(s) may also serve as a receptor. Here, we performed a large-scale glycan array screen with MuV hemagglutinin-neuraminidase (MuV-HN) attachment proteins by using 600 types of glycans from The Consortium for Functional Glycomics Protein-Glycan Interaction Core in an effort to find new glycan receptor motif(s). According to the results of the glycan array, we successfully determined the crystal structures of MuV-HN proteins bound to newly identified glycan motifs, sialyl LewisX (SLeX) and the oligosaccharide portion of the GM2 ganglioside (GM2-glycan). Interestingly, the complex structures showed that SLeX and GM2-glycan share the same configuration with the reported trisaccharide motif, 3'-sialyllactose (3'-SL), at the binding site of MuV-HN, while SLeX and GM2-glycan have several unique interactions compared with those of 3'-SL. Thus, MuV-HN protein can allow an additional spatial modification in GM2-glycan and SLeX at the second and third carbohydrates from the nonreducing terminus of the core trisaccharide structure, respectively. Importantly, MuV entry was efficiently inhibited in the presence of 3'-SL, SLeX, or GM2-glycan derivatives, which indicates that these motifs can serve as MuV receptors. The α2,3-sialylated oligosaccharides, such as SLeX and 3'-sialyllactosamine, are broadly expressed in various tissues, and GM2 exists mainly in neural tissues and the adrenal gland. The distribution of these glycan motifs in human tissues/organs may have bearing on MuV tropism.IMPORTANCE Mumps virus (MuV) infection is characterized by parotid gland swelling and can cause pancreatitis, orchitis, meningitis, and encephalitis. MuV-related hearing loss is also a serious complication because it is usually irreversible. MuV outbreaks have been reported in many countries, even in high-vaccine-coverage areas. MuV has tropism toward glandular tissues and the central nervous system. To understand the unique MuV tropism, revealing the mechanism of receptor recognition by MuV is very important. Here, using a large-scale glycan array and X-ray crystallography, we show that MuV recognizes sialyl LewisX and GM2 ganglioside as receptors, in addition to a previously reported MuV receptor, a trisaccharide containing an α2,3-linked sialic acid. The flexible recognition of these glycan receptors by MuV may explain the unique tropism and pathogenesis of MuV. Structures will also provide a template for the development of effective entry inhibitors targeting the receptor-binding site of MuV.


Electrophysiological features in dogs with peripheral nerve sheath tumors: 51 cases (1993-2010).
To determine the electrophysiological changes in dogs with peripheral nerve sheath tumors (PNSTs), evaluate the prevalence of these changes, assess the correlation between spontaneous activity in epaxial muscles and proximal invasion by the tumor, and evaluate whether knowledge of electrophysiological changes could be helpful in the imaging diagnosis via CT or MRI. Retrospective case series. 51 dogs with a histologic (n = 18) or a suspected (33) diagnosis of PNST. Clinical, postmortem, and histologic reports and details of electrodiagnostic procedures and CT or MRI reports were studied. Twenty-four CT and 6 MRI reports for dogs with PNSTs were reviewed by a single observer blinded to the diagnosis. Only 2 of the 51 dogs had no electrophysiological changes. The most commonly affected muscles were those innervated by the radial, ulnar, median, tibial-sciatic, and peroneal nerves. Abnormal spontaneous epaxial muscle activity was significantly more frequent in the group with foraminal or spinal invasion by the tumors. Knowledge of the electrophysiological changes increased diagnostic accuracy of CT. Results suggested that electrophysiological studies may be sensitive for the detection of PNST and helpful in the imaging diagnosis. Epaxial electromyographic abnormalities appeared to be predictive for intervertebral or vertebral canal invasion by PNSTs in dogs.


Socioeconomic disparities in tobacco-related health outcomes across racial/ethnic groups in the United States: National Health Interview Survey 2010.
Existing research documents strong inverse socioeconomic gradients in current smoking and lung cancer morbidity and mortality; these gradients appear stronger among non-Hispanic Whites and Blacks compared with Hispanics. We sought to examine a broader range of outcomes across the tobacco use continuum, examining socioeconomic gradients separately among the 3 largest racial/ethnic groups in the United States. We used data from the 2010 National Health Interview Survey (n = 17,284) Cancer Control Supplement to calculate prevalences and means for outcomes across the tobacco use continuum by educational attainment and income separately among non-Hispanic Black, Hispanic/Latino, and non-Hispanic White adults. Findings demonstrate that current smoking, age at initiation, cigarettes per day, years quit, and secondhand smoke all exhibit strong inverse educational gradients and moderately strong inverse income gradients, especially among Whites and Blacks. Hispanics/Latinos generally have more favorable outcomes along the tobacco use continuum and less evident socioeconomic gradients. Educational attainment is strongly associated with indicators across the tobacco use continuum among non-Hispanic Whites and Blacks. More research is needed to determine whether policies and programs to increase educational attainment may also reduce tobacco-related health disparities.


TIMP-3 facilitates binding of target metalloproteinases to the endocytic receptor LRP-1 and promotes scavenging of MMP-1.
Matrix metalloproteinases (MMPs) and the related families of disintegrin metalloproteinases (ADAMs) and ADAMs with thrombospondin repeats (ADAMTSs) play a crucial role in extracellular matrix (ECM) turnover and shedding of cell-surface molecules. The proteolytic activity of metalloproteinases is post-translationally regulated by their endogenous inhibitors, known as tissue inhibitors of metalloproteinases (TIMPs). Several MMPs, ADAMTSs and TIMPs have been reported to be endocytosed by the low-density lipoprotein receptor-related protein-1 (LRP-1). Different binding affinities of these proteins for the endocytic receptor correlate with different turnover rates which, together with differences in their mRNA expression, determines their nett extracellular levels. In this study, we used surface plasmon resonance to evaluate the affinity between LRP-1 and a number of MMPs, ADAMs, ADAMTSs, TIMPs and metalloproteinase/TIMP complexes. This identified MMP-1 as a new LRP-1 ligand. Among the proteins analyzed, TIMP-3 bound to LRP-1 with highest affinity (KD = 1.68 nM). Additionally, we found that TIMP-3 can facilitate the clearance of its target metalloproteinases by bridging their binding to LRP-1. For example, the free form of MMP-1 was found to have a KD of 34.6 nM for LRP-1, while the MMP-1/TIMP-3 complex had a sevenfold higher affinity (KD = 4.96 nM) for the receptor. TIMP-3 similarly bridged binding of MMP-13 and MMP-14 to LRP-1. TIMP-1 and TIMP-2 were also found to increase the affinity of target metalloproteinases for LRP-1, albeit to a lesser extent. This suggests that LRP-1 scavenging of TIMP/metalloproteinase complexes may be a general mechanism by which inhibited metalloproteinases are removed from the extracellular environment.


Patients' beliefs about the causes, persistence and control of psychotic experiences predict take-up of effective cognitive behaviour therapy for psychosis.
There is evidence that patients with schizophrenia benefit from standard cognitive behaviour therapy (CBT) only if active techniques are used ('full therapy'). By contrast, attending sessions but not proceeding beyond engagement and assessment strategies ('partial therapy'), or simply not attending sessions ('no therapy'), is not associated with better outcomes. The factors leading to full therapy are unknown. We hypothesized that patients' initial ideas about the nature and extent of their problems would predict use of CBT. A match between patients' views of their problems and the principles underlying treatment would lead to better outcomes. Ninety-two patients with a recent relapse of psychosis completed the Illness Perception Questionnaire (IPQ) before receiving CBT. We examined whether their illness perceptions predicted the take-up of therapy. Patients who did not attend sessions believed their problems would not last as long as those who attended them. Those who attended sessions but did not proceed to full therapy had a lower sense of control over their problems and a more biological view of their causes. Patients who took up full therapy were more likely to attribute the cause of their problems to their personality and state of mind. The take-up of therapy was predicted neither by levels of psychiatric symptoms nor by insight. People with psychosis who have psychologically orientated views of their problems, including the potential to gain control over them, may be more likely to engage fully and do well with standard CBT for psychosis, irrespective of the severity of their problems.


Gum mastic inhibits the expression and function of the androgen receptor in prostate cancer cells.
Accumulating evidence suggests that the androgen receptor (AR) may play an important role in the development and progression of prostate cancer. To find new, useful compounds that effectively may attenuate the function of AR in prostate cancer cells, the authors investigated the effect of gum mastic, a natural resin, on AR activity. An androgen-responsive prostate cancer cell line LNCaP was used as a model for this study. Gene transfer, reverse transcriptase-polymerase chain reaction analysis, electrophoretic mobility shift assay, and Western blot analysis were used to test the effect of gum mastic on the expression and function of the AR. To demonstrate the inhibitory effect of gum mastic on the function of the AR, the expression of androgen-regulated genes, including prostate-specific antigen (PSA), human kallikrein 2 (hK2), and NKX3.1 were measured. In addition, transient transfection assays with the PSA promoter and the AR promoter also were used to test the effects of mastic. The results showed that gum mastic inhibited the expression of the AR at the transcriptional level, resulting in the down-regulation of both AR messenger RNA and protein levels. Therefore, the function of the AR was inhibited, as reflected by the reduced expression of NKX3.1 and PSA and by androgen-stimulated growth. Because gum mastic exhibited a strong in vitro potency to attenuate the expression and function of the AR, further investigation will be required to determine whether this naturally occurring substance has in vivo potency to inhibit prostate cancer development.


A double blind community-based randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged 2-59 months in Karachi, Pakistan (RETAPP).
Fast breathing pneumonia is characterized by tachypnoea in the absence of danger signs and is mostly viral in etiology. Current guidelines recommend antibiotic therapy for all children with fast breathing pneumonia in resource limited settings, presuming that most pneumonia is bacterial. High quality clinical trial evidence to challenge or support the continued use of antibiotics, as recommended by the World Health Organization is lacking. This is a randomized double blinded placebo-controlled non-inferiority trial using parallel assignment with 1:1 allocation ratio, to be conducted in low income squatter settlements of urban Karachi, Pakistan. Children 2-59 months old with fast breathing, without any WHO-defined danger signs and seeking care at the primary health care center are randomized to receive either three days of placebo or amoxicillin. From prior studies, a sample size of 2430 children is required over a period of 28 months. Primary outcome is the difference in cumulative treatment failure between the two groups, defined as a new clinical sign based on preset definitions indicating illness progression or mortality and confirmed by two independent primary health care physicians on day 0, 1, 2 or 3 of therapy. Secondary outcomes include relapse measured between days 5-14. Modified per protocol analysis comparing hazards of treatment failure with 95% confidence intervals in the placebo arm with hazards in the amoxicillin arm will be done. This study will provide evidence to support or refute the use of antibiotics for fast breathing pneumonia paving a way for guideline change. Clinical Trials (NIH) Register NCT02372461.


The effect of access and satisfaction on regular mammogram and Papanicolaou test screening in a multiethnic population.
Access and satisfaction are determinants of preventive service use, but few studies have evaluated their role in breast and cervical cancer screening in multiethnic populations. We sought to investigate the relationship between race/ethnicity, access, satisfaction, and regular mammogram and Papanicolaou test receipt in 5 racial/ethnic groups. We conducted a telephone survey in 4 languages. Our subjects were black, Chinese, Filipino, Latino, or white women aged 40 to 74 residing in Alameda County, California. regular mammograms (last test within 15 months and another within 2 years prior) and Papanicolaou tests (36 months and 3 years, respectively). Independent: race/ethnicity, sociodemographic variables, access (health insurance, usual site of care, regular doctor, check-up within 12 months, knowing where to go, copayment for tests), and satisfaction (overall satisfaction scale, waiting times, test-related pain and embarrassment, test satisfaction). Among women who had ever had a mammogram or Papanicolaou test, 54% and 77%, respectively, received regular screening. In multivariate analyses, regular mammography was positively associated with increased age (odds ratio [OR] 1.05 per year), private insurance (OR 1.7), check-up in the past year (OR 2.3), knowing where to go for mammography (OR 3.0), and greater satisfaction with processes of care (OR 1.04 per unit), and negatively with not knowing copayment amount (OR 0.4), too many forms to fill out (OR 0.5), embarrassment at the last mammogram (OR 0.6), and Filipino race/ethnicity. Similar results were found for regular Papanicolaou tests. Access and satisfaction are important predictors of screening but do little to explain racial/ethnic variation. Tailored interventions to improve regular mammography and Papanicolaou test screening in multiethnic populations are needed.


Planning clinically relevant biomarker validation studies using the "number needed to treat" concept.
Despite an explosion of translational research to exploit biomarkers in diagnosis, prediction and prognosis, the impact of biomarkers on clinical practice has been limited. The elusiveness of clinical utility may partly originate when validation studies are planned, from a failure to articulate precisely how the biomarker, if successful, will improve clinical decision-making for patients. Clarifying what performance would suffice if the test is to improve medical care makes it possible to design meaningful validation studies. But methods for tackling this part of validation study design are undeveloped, because it demands uncomfortable judgments about the relative values of good and bad outcomes resulting from a medical decision. An unconventional use of "number needed to treat" (NNT) can structure communication for the trial design team, to elicit purely value-based outcome tradeoffs, conveyed as the endpoints of an NNT "discomfort range". The study biostatistician can convert the endpoints into desired predictive values, providing criteria for designing a prospective validation study. Next, a novel "contra-Bayes" theorem converts those predictive values into target sensitivity and specificity criteria, to guide design of a retrospective validation study. Several examples demonstrate the approach. In practice, NNT-guided dialogues have contributed to validation study planning by tying it closely to specific patient-oriented translational goals. The ultimate payoff comes when the report of the completed study includes motivation in the form of a biomarker test framework directly reflecting the clinical decision challenge to be solved. Then readers will understand better what the biomarker test has to offer patients.


Performance of guidelines for the screening and diagnosis of gestational diabetes mellitus during the COVID-19 pandemic: A scoping review of the guidelines and diagnostic studies evaluating the recommended testing strategies.
The COVID-19 pandemic has necessitated less resource-intensive testing guidelines to identify gestational diabetes mellitus (GDM). We performed a scoping review of the international evidence reporting the ability of diagnostic tests recommended during the pandemic to accurately identify patients with GDM, compared to pre-pandemic reference standards, and associated test and clinical outcomes. A comprehensive search of the literature was carried out in Embase, LitCovid, Cochrane Covid-19 study register, and medRxiv on 14th June 2021. 145 unique citations were returned; after screening according to pre-specified inclusion criteria by title and abstract and then full text, 13 studies involving 40,836 pregnant people and an additional 52,884 instances of OGTT were included. Thresholds defined in the Australian pandemic guideline appear adequate to identify most GDM cases; false negative cases appeared at lower risk of hyperglycaemia-in-pregnancy(HIP)-related events. For UK and Canadian guidelines, a larger proportion would be misdiagnosed as non-GDM; these false negative cases had broadly equivalent HIP-related event rates as true positives. The OGTT remains the most effective test to identify abnormal glucose processing in pregnancy, supporting the prompt return to standard guidelines post-pandemic. Cohort studies investigating the impact of the change in guidelines on GDM pregnancies and associated outcomes are needed.


The European Union Emissions Trading System reduced CO2 emissions despite low prices.
International carbon markets are an appealing and increasingly popular tool to regulate carbon emissions. By putting a price on carbon, carbon markets reshape incentives faced by firms and reduce the value of emissions. How effective are carbon markets? Observers have tended to infer their effectiveness from market prices. The general belief is that a carbon market needs a high price in order to reduce emissions. As a result, many observers remain skeptical of initiatives such as the European Union Emissions Trading System (EU ETS), whose price remained low (compared to the social cost of carbon). In this paper, we assess whether the EU ETS reduced [Formula: see text] emissions despite low prices. We motivate our study by documenting that a carbon market can be effective if it is a credible institution that can plausibly become more stringent in the future. In such a case, firms might cut emissions even though market prices are low. In fact, low prices can be a signal that the demand for carbon permits weakens. Thus, low prices are compatible with successful carbon markets. To assess whether the EU ETS reduced carbon emissions even as permits were cheap, we estimate counterfactual carbon emissions using an original sectoral emissions dataset. We find that the EU ETS saved about 1.2 billion tons of [Formula: see text] between 2008 and 2016 (3.8%) relative to a world without carbon markets, or almost half of what EU governments promised to reduce under their Kyoto Protocol commitments. Emission reductions in sectors covered under the EU ETS were higher.


Distinct regulation of tonsillar immune response in virus infection.
The relationships between tonsillar immune responses, and viral infection and allergy are incompletely known. To study intratonsillar/nasopharyngeal virus detections and in vivo expressions of T-cell- and innate immune response-specific cytokines, transcription factors, and type I/II/III interferons in human tonsils. Palatine tonsil samples were obtained from 143 elective tonsillectomy patients. Adenovirus, bocavirus-1, coronavirus, enteroviruses, influenza virus, metapneumovirus, parainfluenza virus, rhinovirus, and respiratory syncytial virus were detected using PCR. The mRNA expression levels of IFN-α, IFN-β, IFN-γ, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-β, FOXP3, GATA3, RORC2, and Tbet were directly analyzed by quantitative RT-PCR. Fifty percentage of subjects reported allergy, 59% had ≥1 nasopharyngeal viruses, and 24% had ≥1 intratonsillar viruses. Tonsillar virus detection showed a strong negative association with age; especially rhinovirus or parainfluenza virus detection showed positive association with IFN-γ and Tbet expressions. IL-37 expression was positively associated with atopic dermatitis, whereas IFN-α, IL-13, IL-28, and Tbet expressions were negatively associated with allergic diseases. Network analyses demonstrated strongly polarized clusters of immune regulatory (IL-10, IL-17, TGF-β, FOXP3, GATA3, RORC2, Tbet) and antiviral (IFN-α, IFN-β, IL-28, IL-29) genes. These two clusters became more distinctive in the presence of viral infection or allergy. A negative correlation between antiviral cytokines and IL-10, IL-17, IL-37, FOXP3, and RORC2 was observed only in the presence of viruses, and interestingly, IL-13 strongly correlated with antiviral cytokines. Tonsillar cytokine expression is closely related to existing viral infections, age, and allergic illnesses and shows distinct clusters between antiviral and immune regulatory genes.


Surface chemistry and catalysis confined under two-dimensional materials.
Two-dimensional (2D) materials are characterised by their strong intraplanar bonding but weak interplanar interaction. Interfaces between neighboring 2D layers or between 2D overlayers and substrate surfaces provide intriguing confined spaces for chemical processes, which have stimulated a new area of "chemistry under 2D cover". In particular, well-defined 2D material overlayers such as graphene, hexagonal boron nitride, and transition metal dichalcogenides have been deposited on solid surfaces, which can be used as model systems to understand the new chemistry. In the present review, we first show that many atoms and molecules can intercalate ultrathin 2D materials supported on solid surfaces and the space under the 2D overlayers has been regarded as a 2D nanocontainer. Moreover, chemical reactions such as catalytic reactions, surface adlayer growth, chemical vapor deposition, and electrochemical reactions occur in the 2D confined spaces, which further act as 2D nanoreactors. It has been demonstrated that surface chemistry and catalysis are strongly modulated by the 2D covers, resulting in weakened molecule adsorption and enhanced surface reactions. Finally, we conclude that the confinement effect of the 2D cover leads to new chemistry in a small space, such as "catalysis under cover" and "electrochemistry under cover". These new concepts enable us to design advanced nanocatalysts encapsulated with 2D material shells which may present improved performance in many important processes of heterogeneous catalysis, electrochemistry, and energy conversion.


Innervation and vasculature of human sweat glands: an immunohistochemistry-laser scanning confocal fluorescence microscopy study.
Secreting tubules, nerves fibers, and blood vessels in human sweat glands (SGs) were fluorescently stained by immunohistochemical and lectin methods for examination with a laser scanning confocal microscope (LSCM). Using these techniques, the three-dimensional distribution of up to three substances within a single specimen was investigated by collecting a series of optical sections for each of three fluorophores. Each SG received several nerve fibers. These branched into delicate bands of one or more axons that ran longitudinal to the sweat tubule then encircled the tubule. A heavy complement of capillaries was interwoven among the sweat tubules. Sweat ducts were accompanied from the SG toward the skin surface by one or two longitudinally oriented nerve fibers and capillaries. Immunoreactive staining of nerves was heaviest with protein gene product 9.5 antibody, but triple labeling showed that immunoreactivity to calcitonin gene-related peptide, vasoactive intestinal polypeptide, and synaptophysin was also present in the same axons. Substance P-immunoreactive axons were sparse in SGs but were present in other areas of the skin. The techniques used have considerable potential in examination of human skin biopsies for diagnosis of disorders affecting the somatic and autonomic nervous systems.


Clinical experience of single-session percutaneous aspiration and OK-432 sclerotherapy for treatment of simple renal cysts: 1-year follow-up.
To evaluate the efficacy and safety of single-session OK-432 sclerotherapy for the treatment of renal cysts. From October 2005 to November 2006, 48 patients (61 simple renal cysts) were included in the study. Indications were determined as flank discomfort (n = 37) or patient reassurance due to increasing size (n = 11). The simple renal cysts were aspirated under ultrasonography (US), at which point OK-432 was injected into the cyst. Follow-up was performed with US or computed tomography scan every 3 months until 1 year. Complete regression of the renal cyst or more than 70% reduction in size with no symptoms indicated a successful treatment. Among 61 renal cysts of 48 patients, the overall success rate was 98.4%. Complete regression occurred in 46 cysts (75.4%), and more than 90% reduction in size occurred in 6 cysts (9.8%). A size reduction of 80% to 90% and 70% to 80% occurred in five (8.2%) and three cysts (4.9%), respectively. A size reduction less than 70% occurred in only one cyst (1.6%). The success of cyst regression was correlated with cyst volume. Clinical symptoms resolved in 100% of patients with symptomatic cysts, and there was no enlargement of the aspirated cysts at the 1-year follow-up. After the procedure, there were only some minor complications, such as mild fever, flank pain, and leukocytosis, which subsided with the conservative treatment. Percutaneous OK-432 sclerotherapy is simple, safe, and effective, and it can be an alternative first-line therapy for simple renal cysts.


Sirolimus for Recurrent Giant Cell Myocarditis After Heart Transplantation: A Unique Therapeutic Strategy.
Giant cell myocarditis (GCM) is a rare and a rapidly progressive disorder with fatal outcomes such that patients often require heart transplantation. We present a case of recurrent GCM in a transplanted patient with a history of Crohn disease requiring a novel therapeutic approach. After the orthotopic heart transplantation, GCM recurred on aggressive immunosuppression over the months, which included corticosteroids, basiliximab, tacrolimus, antithymocyte globulin, and rituximab. Although combination immunosuppressive therapy containing cyclosporine and 2-4 additional drugs including corticosteroids, azathioprine, mycophenolate mofetil, muromonab, gammaglobulin, or methotrexate have shown to prolong the transplant-free survival by keeping the disease under control, its role in preventing and treating recurrence posttransplantation is unclear. We added sirolimus, a macrolide antibiotic, with properties of T- and B-lymphocyte proliferation inhibition on the above immunosuppressive treatment postrecurrence of GCM. After sirolimus initiation and continuation, the patient has remained disease free.


A novel deep learning based automatic auscultatory method to measure blood pressure.
It is clinically important to develop innovative techniques that can accurately measure blood pressures (BP) automatically. This study aimed to present and evaluate a novel automatic BP measurement method based on deep learning method, and to confirm the effects on measured BPs of the position and contact pressure of stethoscope. 30 healthy subjects were recruited. 9 BP measurements (from three different stethoscope contact pressures and three repeats) were performed on each subject. The convolutional neural network (CNN) was designed and trained to identify the Korotkoff sounds at a beat-by-beat level. Next, a mapping algorithm was developed to relate the identified Korotkoff beats to the corresponding cuff pressures for systolic and diastolic BP (SBP and DBP) determinations. Its performance was evaluated by investigating the effects of the position and contact pressure of stethoscope on measured BPs in comparison with reference manual auscultatory method. The overall measurement errors of the proposed method were 1.4 ± 2.4 mmHg for SBP and 3.3 ± 2.9 mmHg for DBP from all the measurements. In addition, the method demonstrated that there were small SBP differences between the 2 stethoscope positions, respectively at the 3 stethoscope contact pressures, and that DBP from the stethoscope under the cuff was significantly lower than that from outside the cuff by 2.0 mmHg (P < 0.01). Our findings suggested that the deep learning based method was an effective technique to measure BP, and could be developed further to replace the current oscillometric based automatic blood pressure measurement method.


Human indolethylamine N-methyltransferase: cDNA cloning and expression, gene cloning, and chromosomal localization.
Indolethylamine N-methyltransferase (INMT) catalyzes the N-methylation of tryptamine and structurally related compounds. We recently cloned and characterized the rabbit INMT cDNA and gene as a step toward cloning the cDNA and gene for this enzyme in humans. We have now used a PCR-based approach to clone a human INMT cDNA that had a 792-bp open reading frame that encoded a 263-amino-acid protein 88% identical in sequence to rabbit INMT. Northern blot analysis of 35 tissues showed that a 2.7-kb INMT mRNA species was expressed in most tissues. When the cDNA was expressed in COS-1 cells, the recombinant enzyme catalyzed the methylation of tryptamine with an apparent K(m) value of 2.9 mM. The human cDNA was then used to clone the human INMT gene from a human genomic BAC library. The gene was 5471 bp in length, consisted of three exons, and was structurally similar to the rabbit INMT gene as well as genes for nicotinamide N-methyltransferase and phenylethanolamine N-methyltransferase in several species. All INMT exon-intron splice junctions conformed to the "GT-AG" rule, and no canonical TATA or CAAT sequences were present within the 5'-flanking region of the gene. Human INMT mapped to chromosome 7p15.2-p15.3 on the basis of both PCR analysis and fluorescence in situ hybridization. Finally, two possible single nucleotide polymorphisms were identified within exon 3, both of which altered the encoded amino acid. The cloning and expression of a human INMT cDNA, as well as the cloning, structural characterization, and mapping of its gene represent steps toward future studies of the function and regulation of this methyltransferase enzyme in humans.


Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
The cellular and molecular mechanisms mediating histamine-independent itch in primary sensory neurons are largely unknown. Itch induced by chloroquine (CQ) is a common side effect of this widely used antimalarial drug. Here, we show that Mrgprs, a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons, function as itch receptors. Mice lacking a cluster of Mrgpr genes display significant deficits in itch induced by CQ but not histamine. CQ directly excites sensory neurons in an Mrgpr-dependent manner. CQ specifically activates mouse MrgprA3 and human MrgprX1. Loss- and gain-of-function studies demonstrate that MrgprA3 is required for CQ responsiveness in mice. Furthermore, MrgprA3-expressing neurons respond to histamine and coexpress gastrin-releasing peptide, a peptide involved in itch sensation, and MrgprC11. Activation of these neurons with the MrgprC11-specific agonist BAM8-22 induces itch in wild-type but not mutant mice. Therefore, Mrgprs may provide molecular access to itch-selective neurons and constitute novel targets for itch therapeutics.


Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunts.
The technique of peritoneovenous shunting for the alleviation of abdominal pain and distension in malignant ascites due to inoperable cancer, returns the fluid to the circulation via a one-way, valved, anastomosis between the peritoneum and the jugular vein. Surprisingly, although the patients treated with this technique receive direct infusions of malignant tumor cells into the blood, this study of 29 patients, 15 of whom came to autopsy, shows that they did not all develop metastases, some being completely free of such lesions despite long survival. Even when metastases do form, they are small and clinically asymptomatic, and the technique is therefore not hazardous. In some patients, inert tumor cells identifiable by natural markers were recognized in the tissues, but no growing metastases were observed. In others, the distribution of secondary deposits was unexpected in that metastases did not form in the organ containing the first capillary bed encountered, although hematogenous metastases had formed in other organs. Despite the fact that various factors such as (a) the small numbers of patients treated with the technique; (b) the sensitive nature of studies on terminally ill patients; and (c) the absence of consistency in the sample population with regard to factors such as length of survival and site of neoplasm, combine to reduce the number of suitable cases for study, the approach has unrivaled power and interest for those seeking to understand mechanisms underlying tumor metastasis in humans.


A meta-analysis of the association between induced abortion and breast cancer risk among Chinese females.
To evaluate the association between induced abortion (IA) and breast cancer risk among Chinese females. We searched three English databases (PubMed, ScienceDirect, and Wiley) and three Chinese databases (CNKI, WanFang, and VIP) for studies up to December 2012, supplemented by manual searches. Two reviewers independently conducted the literature searching, study selection, and data extraction and quality assessment of included studies. Random effects models were used to estimate the summary odds ratios (ORs) and the 95 % confidence intervals (CIs). A total of 36 articles (two cohort studies and 34 case-control studies) covering 14 provinces in China were included in this review. Compared to people without any history of IA, an increased risk of breast cancer was observed among females who had at least one IA (OR = 1.44, 95 % CI 1.29-1.59, I (2) = 82.6 %, p < 0.001, n = 34). No significant publication bias was found among the included studies (Egger test, p = 0.176). The risk increased to 1.76 (95 % CI 1.39-2.22) and 1.89 (95 % CI 1.40-2.55) for people who had at least two IAs and at least three IAs, respectively. Subgroup analyses showed similar results to the primary results. Meta-regression analysis of the included studies found that the association between IA and breast cancer risk attenuated with increasing percent of IA in the control group (β = -0.022, p < 0.001). IA is significantly associated with an increased risk of breast cancer among Chinese females, and the risk of breast cancer increases as the number of IA increases. If IA were to be confirmed as a risk factor for breast cancer, high rates of IA in China may contribute to increasing breast cancer rates.


Online learning with hidden markov models.
We present an online version of the expectation-maximization (EM) algorithm for hidden Markov models (HMMs). The sufficient statistics required for parameters estimation is computed recursively with time, that is, in an online way instead of using the batch forward-backward procedure. This computational scheme is generalized to the case where the model parameters can change with time by introducing a discount factor into the recurrence relations. The resulting algorithm is equivalent to the batch EM algorithm, for appropriate discount factor and scheduling of parameters update. On the other hand, the online algorithm is able to deal with dynamic environments, i.e., when the statistics of the observed data is changing with time. The implications of the online algorithm for probabilistic modeling in neuroscience are briefly discussed.


Nuclear scaffold-associated protease: in situ nuclear localization and effects of a protease inhibitor on growth and morphology of a ras-transformed hepatocyte cell line.
We have previously identified a multicatalytic protease (MCP) activity associated with the nuclear scaffold (NS) in hepatocytes and fibroblasts. When we used the chloromethylketone protease inhibitor AAPFcmk, which is targeted to chymotrypsinlike protease activity, we observed a dramatic inhibition of transformation of fibroblasts, with effects that were relatively selective for the NS fraction. Here, we undertook experiments to determine the effects of AAPFcmk on Simian Virus 40-immortalized CWSV1 cells compared with a ras-transformed hepatocyte cell line (NR4) derived from CWSV1. We used biotinAAPFcmk and fluorescent reagents to demonstrate a nuclear chymotrypsinlike protease activity, which is most prominent at the nuclear envelope. The ras-transformed NR4 cells were highly susceptible to growth inhibition in a dose-dependent manner, showing 85% growth inhibition at 50 mumol/LAAPFcmk. In contrast, the immortalized CWSV1 cells were not sensitive at the concentrations (10 to 50 mumol/L) of AAPFcmk tested. In subcellular fractionation studies, the inhibitory effects of AAPFcmk were confined to the NS fraction. The AAPFcmk-induced growth inhibition was accompanied by marked morphological changes in ras-transformed cells, without evidence of overt toxicity. No change in DNA content was observed, but a marked increase in organization of actin cytoskeletal elements was seen. These results suggest that a protease activity associated with the nuclear scaffold has important functions in controlling cytoskeletal filament organization and cell replication.


A study of Y-chromosome microsatellite variation in sub-Saharan Africa: a comparison between F(ST) and R(ST) genetic distances.
Seven Y-chromosome microsatellite loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, and DYS393) were analyzed in three populations from sub-Saharan Africa: the Bamileke and Ewondo populations from Cameroon and the Hutu from Rwanda. Complete typing was obtained for 112 individuals, and a total of 53 different haplotypes was observed. The single-locus gene diversity, averaged across populations, ranges from 0.100 for the DYS392 locus to 0.610 for the DYS389I locus. The haplotype diversity ranges from 0.832 (Ewondo) to 0.965 (Hutu), with an intermediate value of 0.918 in the Bamileke. The diversity among Bamileke, Ewondo, Hutu, and other sub-Saharan populations selected from the literature was analyzed using both a classical (F(ST)) and a stepwise-based (R(ST)) genetic distance method. The pattern of interpopulational diversity based on F(ST) was congruent with anthropological knowledge, while that based on R(ST) revealed unexpected and unconvincing population affinities. From a practical point of view, our study indicates that Y-chromosome microsatellite data may provide useful information for analyses of interpopulational diversity among sub-Saharan populations if an adequate number of loci and individuals along with an appropriate genetic distance method are used. On a theoretical ground, we propose that the lesser performance of R(ST) compared to F(ST) could be explained by the important role played by genetic drift in shaping the relationships among examined populations.


MeCP2 mutant protein is expressed in astrocytes as well as in neurons and localizes in the nucleus.
The MECP2 gene, located at Xq28, encodes methyl-CpG-binding protein 2 (MeCP2), which is frequently mutated (up to 90%) in Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder, which affects primarily girls during early childhood and it is one of the most common causes of mental retardation in females. R270X is one of the most frequent recurrent MECP2 mutations among RTT cohorts. The R270X mutation resides within the TRD-NLS (Transcription Repression Domain-Nuclear Localization Signal) region of MeCP2 and causes a more severe clinical phenotype with increased mortality as compared to other mutations. To evaluate the functional role of the R270X mutation, we generated a transgenic mouse model expressing MeCP2(270_EGFP) (human mutation equivalent) by BAC recombineering. The expression pattern of MeCP2(270_EGFP) was similar to that of endogenous MeCP2. Strikingly, MeCP2(270_EGFP) localizes in the nucleus, contrary to the conjecture that R270X could cause disruption of the NLS. In primary hippocampal cells, we show that MeCP2(270_EGFP) was expressed in astrocytes by colocalization with the astrocyte-specific marker glial fibrillary acidic protein. Our data showing expression of MeCP2(270_EGFP) in transgenic mice astrocytes further reinforce the recent findings concerning the expression of MeCP2 in the glial cells.


Structural basis of the CD8 alpha beta/MHC class I interaction: focused recognition orients CD8 beta to a T cell proximal position.
In the immune system, B cells, dendritic cells, NK cells, and T lymphocytes all respond to signals received via ligand binding to receptors and coreceptors. Although the specificity of T cell recognition is determined by the interaction of T cell receptors with MHC/peptide complexes, the development of T cells in the thymus and their sensitivity to Ag are also dependent on coreceptor molecules CD8 (for MHC class I (MHCI)) and CD4 (for MHCII). The CD8alphabeta heterodimer is a potent coreceptor for T cell activation, but efforts to understand its function fully have been hampered by ignorance of the structural details of its interactions with MHCI. In this study we describe the structure of CD8alphabeta in complex with the murine MHCI molecule H-2D(d) at 2.6 A resolution. The focus of the CD8alphabeta interaction is the acidic loop (residues 222-228) of the alpha3 domain of H-2D(d). The beta subunit occupies a T cell membrane proximal position, defining the relative positions of the CD8alpha and CD8beta subunits. Unlike the CD8alphaalpha homodimer, CD8alphabeta does not contact the MHCI alpha(2)- or beta(2)-microglobulin domains. Movements of the CD8alpha CDR2 and CD8beta CDR1 and CDR2 loops as well as the flexibility of the H-2D(d) CD loop facilitate the monovalent interaction. The structure resolves inconclusive data on the topology of the CD8alphabeta/MHCI interaction, indicates that CD8beta is crucial in orienting the CD8alphabeta heterodimer, provides a framework for understanding the mechanistic role of CD8alphabeta in lymphoid cell signaling, and offers a tangible context for design of structurally altered coreceptors for tumor and viral immunotherapy.


Dynamic generation of surgery specific simulators -- a feasibility study.
Most of the current surgical simulators rely on preset anatomical virtual environments (VE). The functionality of a simulator is typically fixed to anatomy-based specific tasks. This rigid design principle makes it difficult to reuse an existing simulator for different surgeries. It also makes it difficult to simulate procedures for specific patients, since their anatomical features or anomalies cannot be easily replaced in the VE. In this paper, we demonstrate the reusability of a modular skill-based simulator, LapSkills, which allows dynamic generation of surgery-specific simulations. Task and instrument modules are easily reused from LapSkills and the three-dimensional VE can be replaced with other anatomical models. We build a nephrectomy simulation by reusing the simulated vessels and the clipping and cutting task modules from LapSkills. The VE of the kidney is generated with our anatomical model generation tools and then inserted into the simulation (while preserving the established tasks and evaluation metrics). An important benefit for the created surgery and patient-specific simulations is that reused components remain validated. We plan to use this faster development process to generate a simulation library containing a wide variety of laparoscopic surgical simulations. Incorporating the simulations into surgical training programs will help collect data for validating them.


Relating results of chronic toxicity responses to population-level effects: modeling effects on wild Chinook salmon populations.
Standard toxicity tests assess the physiological responses of individual organisms to exposure to toxic substances under controlled conditions. Time and space restrictions often prohibit the assessment of population-level responses to a toxic substance. Compounds affecting various toxicity endpoints, such as growth, fecundity, behavior, or immune function, alter different demographic traits and produce different impacts on the population. Chronic effects of immune suppression, reproductive impairment, and growth reduction were examined using life history models for Chinook salmon (Oncorhynchus tshawytscha). Modeled immune suppression acted through reductions in age-specific survival, with first- and second-year survival producing the greatest changes in the population growth rate (lamda). A 10% reduction in various reproductive parameters all produced a similar lamda, but different sensitivity and stable age distributions. Growth reduction models incorporated effects to both survival and reproduction and produced additive effects. Overall, model output indicated that for Chinook salmon, alteration of first-year survival has the greatest relative impact on lamda. Results support the importance of linking toxicity endpoints to the demographic traits that they influence and help generate toxicity tests that are more relevant for the species. Life history modeling provides a useful tool to develop testable hypotheses regarding specific and comparative population-level impacts.


C subunit of the ATP synthase is an amyloidogenic calcium dependent channel-forming peptide with possible implications in mitochondrial permeability transition.
The c subunit is an inner mitochondrial membrane (IMM) protein encoded by three nuclear genes. Best known as an integral part of the F0 complex of the ATP synthase, the c subunit is also present in other cytoplasmic compartments in ceroid lipofuscinoses. Under physiological conditions, this 75 residue-long peptide folds into an α-helical hairpin and forms oligomers spanning the lipid bilayer. In addition to its physiological role, the c subunit has been proposed as a key participant in stress-induced IMM permeabilization by the mechanism of calcium-induced permeability transition. However, the molecular mechanism of the c subunit participation in IMM permeabilization is not completely understood. Here we used fluorescence spectroscopy, atomic force microscopy and black lipid membrane methods to gain insights into the structural and functional properties of unmodified c subunit protein that might make it relevant to mitochondrial toxicity. We discovered that c subunit is an amyloidogenic peptide that can spontaneously fold into β-sheets and self-assemble into fibrils and oligomers in a Ca2+-dependent manner. C subunit oligomers exhibited ion channel activity in lipid membranes. We propose that the toxic effects of c subunit might be linked to its amyloidogenic properties and are driven by mechanisms similar to those of neurodegenerative polypeptides such as Aβ and α-synuclein.


Molecular markers in sex hormone pathway genes associated with the efficacy of androgen-deprivation therapy for prostate cancer.
Although most advanced prostate cancer patients respond to androgen-deprivation therapy (ADT), the efficacy is widely variable. We investigated whether the host genetic variations in sex hormone pathway genes are associated with the efficacy of ADT. A cohort of 645 patients with advanced prostate cancer treated with ADT was genotyped for 18 polymorphisms across 12 key genes involved in androgen and estrogen metabolism. We found that after adjusting for known risk factors in multivariate Cox regression models, AKR1C3 rs12529 and AR-CAG repeat length remained significantly associated with prostate cancer-specific mortality (PCSM) after ADT (P ≤ 0.041). Furthermore, individuals carrying two unfavorable genotypes at these loci presented a 13.7-fold increased risk of PCSM compared with individuals carrying zero (P<0.001). Our results identify two candidate molecular markers in key genes of androgen and estrogen pathways associated with PCSM after ADT, establishing the role of pharmacogenomics in this therapy.


Dual inhibitors of LSD1 and spermine oxidase.
We have previously described the synthesis and evaluation of 3,5-diamino-1,2,4-triazole analogues as inhibitors of the flavin-dependent histone demethylase LSD1. These compounds are potent inhibitors of LSD1 without activity against monoamine oxidases A and B, and promote the elevation of H3K4me2 levels in tumor cells in vitro. We now report that the cytotoxicity of these analogues in pancreatic tumor cells correlates with the overexpression of LSD1 in each tumor type. In addition, we show that a subset of these 3,5-diamino-1,2,4-triazole analogues inhibit a related flavin-dependent oxidase, the polyamine catabolic enzyme spermine oxidase (SMOX) in vitro.


Agricultural diversification as an important strategy for achieving food security in Africa.
Farmers in Africa have long adapted to climatic and other risks by diversifying their farming activities. Using a multi-scale approach, we explore the relationship between farming diversity and food security and the diversification potential of African agriculture and its limits on the household and continental scale. On the household scale, we use agricultural surveys from more than 28,000 households located in 18 African countries. In a next step, we use the relationship between rainfall, rainfall variability, and farming diversity to determine the available diversification options for farmers on the continental scale. On the household scale, we show that households with greater farming diversity are more successful in meeting their consumption needs, but only up to a certain level of diversity per ha cropland and more often if food can be purchased from off-farm income or income from farm sales. More diverse farming systems can contribute to household food security; however, the relationship is influenced by other factors, for example, the market orientation of a household, livestock ownership, nonagricultural employment opportunities, and available land resources. On the continental scale, the greatest opportunities for diversification of food crops, cash crops, and livestock are located in areas with 500-1,000 mm annual rainfall and 17%-22% rainfall variability. Forty-three percent of the African cropland lacks these opportunities at present which may hamper the ability of agricultural systems to respond to climate change. While sustainable intensification practices that increase yields have received most attention to date, our study suggests that a shift in the research and policy paradigm toward agricultural diversification options may be necessary.


A systematic review of lateral wedge orthotics--how useful are they in the management of medial compartment osteoarthritis?
Studies on the use of lateral wedge orthotics in the conservative management of medial compartment osteoarthritis are widely quoted. This approach, however, does not consider the disruption of the interaction between lower limb and foot and ankle function that lateral wedges would produce. This comprehensive, systematic review was therefore undertaken to evaluate all available literature to determine whether evidence exists to support their use. MEDLINE, EMBASE, CINAHL, Allied and Complimentary Medicine, PubMed, EBSCO HOST and PEDro, Abstracts of Reviews of Effects in the National Electronic Library for Health for Cochrane Reviews and manual searching were used to identify studies. was searched for trials in progress. Data extraction was performed by the three authors using a paper data extraction form which was based on the CONSORT statement and Critical Skills Appraisal Programme (CASP) guidelines. Overall, the results of this review suggest that, based on current evidence there are no major or long-term beneficial effects with the use of lateral wedges.


Leaf movement in Calathea lutea (Marantaceae).
Calathea lutea is a broad-leaved, secondary successional plant which shows complex leaf movements involving both elevation and folding of the leaf surface about the pulvinus. In the plants studied, mean leaf elevation increased from approximately 34 degrees in the early morning to 70 degrees at noon while the angle of leaf folding increased from 13 degrees to 50 degrees over the same time period. During the period from early morning to noon, these movements resulted in a significant decrease in the cosine of the angle of incidence, a measure of the direct solar radiation intercepted. The observed changes in elevational angle significantly reduce the cosine of angle of incidence while folding does not significantly reduce the fraction of direct solar radiation intercepted during the period of direct exposure of the leaf surface to the solar beam. Since elevational changes seem to account for the reduction in exposure to direct solar radiation, the role of folding remains unclear.


Fish biodiversity patterns of a mesophotic-to-subphotic artificial reef complex and comparisons with natural substrates.
Artificial reefs act as high-rugosity habitats and are often deployed to enhance fishing; however, the effects of man-made features on fish communities can be unpredictable and are poorly understood in deeper waters. In this study, we used a submersible to describe a deep-water artificial reef complex (93-245 m) off of Ewa Beach, Oahu, Hawaii, USA, and evaluated possible conservation and/or fisheries-related contributions. Sixty-eight species were recorded, with larger features supporting greater diversity of species. Species composition changed strongly with depth and a faunal break was detected from 113-137 m. While the features supported diverse fish communities, they were not similar to those on natural substrates, and were numerically dominated by only two species, Lutjanis kasmira and Chromis verater. Depth-generalist and endemic species were present at levels comparable to natural substrates, but were less abundant and species-rich than at biogenic Leptoseris reefs at similar depths. While the non-native L. kasmira was highly abundant, its presence and abundance were not associated with discernable changes in the fish community, and was not present deeper than 120 m. Finally, five species of commercially- and recreationally-important 'Deep 7' fisheries species were also observed, but the artificial reef complex was mostly too shallow to provide meaningful benefits.


Bioinformatic analysis of the nucleolus.
The nucleolus is a plurifunctional, nuclear organelle, which is responsible for ribosome biogenesis and many other functions in eukaryotes, including RNA processing, viral replication and tumour suppression. Our knowledge of the human nucleolar proteome has been expanded dramatically by the two recent MS studies on isolated nucleoli from HeLa cells [Andersen, Lyon, Fox, Leung, Lam, Steen, Mann and Lamond (2002) Curr. Biol. 12, 1-11; Scherl, Coute, Deon, Calle, Kindbeiter, Sanchez, Greco, Hochstrasser and Diaz (2002) Mol. Biol. Cell 13, 4100-4109]. Nearly 400 proteins were identified within the nucleolar proteome so far in humans. Approx. 12% of the identified proteins were previously shown to be nucleolar in human cells and, as expected, nearly all of the known housekeeping proteins required for ribosome biogenesis were identified in these analyses. Surprisingly, approx. 30% represented either novel or uncharacterized proteins. This review focuses on how to apply the derived knowledge of this newly recognized nucleolar proteome, such as their amino acid/peptide composition and their homologies across species, to explore the function and dynamics of the nucleolus, and suggests ways to identify, in silico, possible functions of the novel/uncharacterized proteins and potential interaction networks within the human nucleolus, or between the nucleolus and other nuclear organelles, by drawing resources from the public domain.


Filaggrin mutations and atopy: consequences for future therapeutics.
Filaggrin is a key component of the epidermal differentiation complex of the stratum corneum in the epidermal layer of human skin. Loss-of-function mutations in filaggrin have been described in patients with atopic eczema and are associated with an increased risk of atopic sensitization in these individuals. Atopic eczema is the first stage of the atopic march that describes the phenomenon of increased rates of allergic rhinitis and allergic asthma observed in individuals with early atopic dermatitis. The skin barrier disruptions of atopic eczema associated with loss-of-function mutations in filaggrin are thought to provide a nidus for allergic sensitization to food and aeroallergens, which can then lead to increased allergic disease. It is on this foundation that therapies aimed at restoration of barrier function are thought to play a role, not only in the effective treatment of atopic eczema, but also in the prevention of further allergic disease development.


Revisiting transthyretin related cardiac amyloidosis: Case report and review of literature.
Amyloidosis is a complex group of disorders that can involve many organs and cause their dysfunction. Cardiac involvement indicates worse prognosis and influences treatment strategies. Cardiac amyloidosis is an under-diagnosed entity and high index of clinical suspicion and careful interpretation of basic diagnostic tools such as electrocardiogram and echocardiography is needed for early detection. Congestive heart failure due to restrictive pattern and/or conduction system abnormality, in absence of coronary artery disease should raise suspicion. We present a case of transthyretin related cardiac amyloidosis and discuss the key clinical and diagnostic findings along with review of existing literature regarding its management and outcomes.


Arginine vasopressin-induced hypertrophy of cultured rat aortic smooth muscle cells.
Recently we reported that the contractile agonist angiotensin II induces hypertrophy, not hyperplasia, in cultured rat aortic smooth muscle cells (Geisterfer AAT, Peach MJ, Owens GK: Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res 1988;62:749-756). We have further explored the hypothesis that contractile agonists are important regulators of smooth muscle cell growth by examining the effects of another contractile agonist, arginine vasopressin, on growth of cultured rat aortic smooth muscle cells. Autoradiographic analysis as well as cell number determinations showed that arginine vasopressin (1 microM) did not stimulate proliferation in cells made quiescent in a defined serum-free media nor did it augment proliferation in 0.4% fetal bovine serum. However, flow cytometric analysis of cellular protein content demonstrated that arginine vasopressin (1 microM) did induce cellular hypertrophy in quiescent cultures after 4 days of treatment, increasing smooth muscle cell protein content by 35% as compared with vehicle-treated controls. The increase in protein content showed a concentration dependence. Cellular hypertrophy was accompanied by an increase in [35S]methionine incorporation, which was elevated 45% by 24 hours. Both the increase in [35S]methionine incorporation and the increase in protein content could be prevented by the specific arginine vasopressin receptor antagonist. [1-beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine] arginine vasopressin. An increase in [35S]methionine incorporation was observed between 12 and 24 hours after treatment of quiescent smooth muscle cells for only 5 minutes with arginine vasopressin (1 microM). Arginine vasopressin-induced increases in [35S]methionine incorporation was increased within 6 hours after treatment. These studies show that arginine vasopressin, like angiotensin II, induces hypertrophy but not hyperplasia of cultured rat aortic smooth muscle cells.


Basic consideration of research strategies for head and neck cancer.
Head and neck cancer (HNC) consists of a group of malignancies affecting closely related anatomical regions of the upper aerodigestive tract (UADT), including the oral cavity, salivary glands, upper and lower jaw bones and facial skin; the nasal cavity, paranasal sinuses, pharynx, larynx and thyroid gland (although the latter is often excluded and considered as part of endocrine neoplasms). Of these, 90% of HNCs are histologically squamous cell carcinomas originating from the mucosal lining. These malignancies are strongly associated with certain environmental and life-style risk factors, principally tobacco in both smoked and smokeless forms, excessive alcohol consumption, diets poor in antioxidants and essential micronutrients, UV light, chemicals used in certain workplaces, and viruses, principally certain strains of human papillomavirus (HPV) and Epstein-Barr virus (EBV). These cancers are frequently aggressive in their biological behaviour with local invasion and metastasis to lymph nodes in the neck. Since most patients are already at late stages of disease at the time of diagnosis, the desirable practice of early diagnosis (first sign of the malignant lesion at an initial stage) and early treatment, a critical priority to save lives and retain quality of life, is difficult to implement. Thus, primary prevention has been set as a key goal. This article aims to reinforce the basic knowledge of aetiology, key risk factors related to the development of head and neck cancer, basic features of clinical appearance of this group of cancers, and strategies for prevention and early detection.We also suggest basic research strategies on the basis of current knowledge, which should ultimately lead to the improvement of clinical management.


Rethinking the sustainability of Israel's irrigation practices in the Drylands.
Broad utilization of drip irrigation technologies in Israel has contributed to the 1600 percent increase in the value of produce grown by local farmers over the past sixty-five years. The recycling of 86% of Israeli sewage now provides 50% of the country's irrigation water and is the second, idiosyncratic component in Israel's strategy to overcome water scarcity and maintain agriculture in a dryland region. The sustainability of these two practices is evaluated in light of decades of experience and ongoing research by the local scientific community. The review confirms the dramatic advantages of drip irrigation over time, relative to flood, furrow and sprinkler irrigation and its significance as a central component in agricultural production, especially under arid conditions. In contrast, empirical findings increasingly report damage to soil and to crops from salinization caused by irrigation with effluents. To be environmentally and agriculturally sustainable over time, wastewater reuse programs must ensure extremely high quality treated effluents and ultimately seek the desalinization of recycled sewage.


Combinatorial Therapy of Zinc Metallochaperones with Mutant p53 Reactivation and Diminished Copper Binding.
Chemotherapy and radiation are more effective in wild-type (WT) p53 tumors due to p53 activation. This is one rationale for developing drugs that reactivate mutant p53 to synergize with chemotherapy and radiation. Zinc metallochaperones (ZMC) are a new class of mutant p53 reactivators that restore WT structure and function to zinc-deficient p53 mutants. We hypothesized that the thiosemicarbazone, ZMC1, would synergize with chemotherapy and radiation. Surprisingly, this was not found. We explored the mechanism of this and found the reactive oxygen species (ROS) activity of ZMC1 negates the signal on p53 that is generated with chemotherapy and radiation. We hypothesized that a zinc scaffold generating less ROS would synergize with chemotherapy and radiation. The ROS effect of ZMC1 is generated by its chelation of redox active copper. ZMC1 copper binding (K Cu) studies reveal its affinity for copper is approximately 108 greater than Zn2+ We identified an alternative zinc scaffold (nitrilotriacetic acid) and synthesized derivatives to improve cell permeability. These compounds bind zinc in the same range as ZMC1 but bound copper much less avidly (106- to 107-fold lower) and induced less ROS. These compounds were synergistic with chemotherapy and radiation by inducing p53 signaling events on mutant p53. We explored other combinations with ZMC1 based on its mechanism of action and demonstrate that ZMC1 is synergistic with MDM2 antagonists, BCL2 antagonists, and molecules that deplete cellular reducing agents. We have identified an optimal Cu2+:Zn2+ binding ratio to facilitate development of ZMCs as chemotherapy and radiation sensitizers. Although ZMC1 is not synergistic with chemotherapy and radiation, it is synergistic with a number of other targeted agents.


Trends of antenatal care during pregnancy in low- and middle-income countries: Findings from the global network maternal and newborn health registry.
Antenatal care (ANC) is an important opportunity to diagnose and treat pregnancy-related complications and to deliver interventions aimed at improving health and survival of both mother and the infant. Multiple individual studies and national surveys have assessed antenatal care utilization at a single point in time across different countries, but ANC trends have not often been studied in rural areas of low-middle income countries (LMICs). The objective of this analysis was to study the trends of antenatal care use in LMICs over a seven-year period. Using a prospective maternal and newborn health registry study, we analyzed data collected from 2011 to 2017 across five countries (Guatemala, India [2 sites], Kenya, Pakistan, and Zambia). Utilization of any ANC along with use of select services, including vitamins/iron, tetanus toxoid vaccine and HIV testing, were assessed. We used a generalized linear regression model to examine the trends of women receiving at least one and at least four antenatal care visits by site and year, controlling for maternal age, education and parity. Between January 2011 and December 2017, 313,663 women were enrolled and included in the analysis. For all six sites, a high proportion of women received at least one ANC visit across this period. Over the years, there was a trend for an increasing proportion of women receiving at least one and at least four ANC visits in all sites, except for Guatemala where a decline in ANC was observed. Regarding utilization of specific services, in India almost 100% of women reported receiving tetanus toxoid vaccine, vitamins/iron supplementation and HIV testing services for all study years. In Kenya, a small increase in the proportion of women receiving tetanus toxoid vaccine was observed, while for Zambia, tetanus toxoid use declined from 97% in 2011 to 89% in 2017. No trends for tetanus toxoid use were observed for Pakistan and Guatemala. Across all countries an increasing trend was observed for use of vitamins/iron and HIV testing. However, HIV testing remained very low (<0.1%) for Pakistan. In a range of LMICs, from 2011 to 2017 nearly all women received at least one ANC visit, and a significant increase in the proportion of women who received at least four ANC visits was observed across all sites except Guatemala. Moreover, there were variations regarding the utilization of preventive care services across all sites except for India where rates were generally high. More research is required to understand the quality and influences of ANC.


Assessing male condom failure and incorrect use.
It has not been well established whether common indices of male condom failure are valid predictors of biologically meaningful exposure during condom use. To address this gap, the authors compared self-reported condom malfunctions (i.e., breakage and slippage) and incorrect condom practices to 2 following objective measures of failure: prostate-specific antigen (PSA) detected in vaginal swabs collected after condom use and structural integrity of used condoms. The study, conducted in 2000-2001, evaluated 635 male condoms used by 77 women attending an outpatient, reproductive-health clinic in Birmingham, AL. Women reported breakage or slippage for 7.9% of condoms; 3.5% of postcoital swabs had moderate or high levels of PSA; and laboratory testing of used condoms revealed breaks (1.1%) and leaks (2.0%). Self-reported breakage and slippage was associated with moderate/high PSA concentrations in postcoital swabs only when the malfunctions were not accompanied by reports of corrective actions to reduce exposure (adjusted odds ratio [aOR], 6.9; 95% confidence interval [CI], 1.8-26.2). Defects observed in postcoital laboratory testing were related to PSA detection (aOR, 8.0; 95% CI, 1.5-42.6). Incorrect practices defined on the condom label were frequent, but not all types were associated with semen exposure. Furthermore, other practices not currently label-defined were associated with semen exposure: touching the tip of the penis with his hands (aOR, 6.2; 95% CI, 2.3-17.0) or with her hands (aOR, 2.8; 95% CI, 1.1-72) before donning the condom. Used correctly, male condoms afforded good protection based on objective measures of failure.


A late Holocene pollen record from proglacial Oblong Tarn, Mount Kenya.
High-elevation ecosystems, such as those on Mount Kenya are undergoing significant changes, with accelerated glacial ice losses over the twentieth century creating new space for alpine plants to establish. These ecosystems respond rapidly to climatic variability and within decades of glacial retreat, Afroalpine pioneering taxa stabilize barren land and facilitate soil development, promoting complex patches of alpine vegetation. Periglacial lake sediment records can be used to examine centennial and millennial scale variations in alpine and montane vegetation compositions. Here we present a 5300-year composite pollen record from an alpine tarn (4370 m asl) in the Hausberg Valley of Mount Kenya. Overall, the record shows little apparent variation in the pollen assemblage through time with abundant montane forest taxa derived and transported from mid elevations, notably high abundances of aerophilous Podocarpus pollen. Afroalpine taxa included Alchemilla, Helichrysum and Dendrosenecio-type, reflecting local vegetation cover. Pollen from the ericaceous zone was present throughout the record and Poaceae percentages were high, similar to other high elevation pollen records from eastern Africa. The Oblong Tarn record pollen assemblage composition and abundances of Podocarpus and Poaceae since the late Holocene (~4000 cal yr BP-present) are similar to pollen records from mid-to-high elevation sites of nearby high mountains such as Mount Elgon and Kilimanjaro. These results suggest a significant amount of uphill pollen transport with only minor apparent variation in local taxa. Slight decreasing trends in alpine and ericaceous taxonomic groups show a long-term response to global late Holocene cooling and a step decrease in rate of change estimated from the pollen assemblages at 3100 cal yr BP in response to regional hydroclimatic variability. Changes in the principal component axis scores of the pollen assemblage were coherent with an independent mid-elevation temperature reconstruction, which supported the strong influence of uphill pollen transport from montane forest vegetation and association between temperatures and montane vegetation dynamics. Pollen accumulation rates showed some variability related to minerogenic sediment input to the lake. The Oblong Tarn pollen record provides an indication of long term vegetation change atop Mount Kenya showing some decreases in local alpine and ericaceous taxa from 5300-3100 cal yr BP and minor centennial-scale variability of montane taxa from mid elevation forests. The record highlights potentials, challenges and opportunities for the use of proglacial lacustrine sediment to examine vegetation change on prominent mountain massifs.