Clinical Correlates of Initial Treatment Disengagement in First-Episode Psychosis.
Early engagement in care is thought to reduce disabling social losses related to the duration of untreated psychosis (DUP), such as school dropout, homelessness, and incarceration, which contribute to chronic disability. Early-intervention services that promote recovery will not be effective if eligible persons drop out of treatment after an initial hospitalization for a psychotic disorder. We had the unique opportunity to examine the treatment disengagement rate of patients with early psychosis after an initial hospitalization. In a predominantly male, African-American, and socioeconomically disadvantaged group of 33 participants with first-episode psychosis assessed at initial hospitalization and six months after discharge, we compared clinical characteristics (medication adherence attitudes and behaviors, knowledge about schizophrenia, insight, symptom severity, and persistence of alcohol and drug use) among those who disengaged and people who engaged in care. More than half (18, 54.5%) attended <3 outpatient appointments in the six months after hospital discharge and, of those, nearly all (15, 83.3%) attended no outpatient appointments. Disengaged people were much less adherent to medications in the past month and six months, and scored lower on medication adherence attitudes, knowledge about psychosis, and insight. They had greater positive symptom severity and a higher likelihood of continuing drug use. Clinical Relevancy: Initial treatment disengagement is very common among young people with first-episode psychosis and is associated with poorer clinical status. More research is needed on the causes of disengagement during this critical period and ways to improve initial treatment engagement among people with first-episode psychosis.


The relationship between vasectomy and angiographically determined atherosclerosis in men.
Long-term prospective studies in monkeys have shown that vasectomy is associated with an increase in atherosclerotic disease. The purpose of the present investigation is to evaluate whether vasectomy in men is associated with atherosclerotic disease in the coronary arteries. In this study information was obtained on the vasectomy status in a series of 7,420 men who had previously been referred for coronary angiography because of cardiovascular symptomatology and have been followed for as long as 9 years to evaluate coronary artery bypass surgery and the natural history of the disease. It was found that 5.0% had a vasectomy prior to angiography. Two different data analysis procedures were used to determine whether the vasectomized men had a greater degree of angiographically determined coronary occlusive disease than the nonvasectomized men. Subgroups with minimal and extensive coronary artery disease were also analyzed. Results of all analyses show that the vasectomized men did not have more coronary occlusive disease. Possible patient selection biases in this study are discussed.


Kisspeptin-10 enhanced egg production in quails associated with the increase of triglyceride synthesis in liver.
Our previous results showed that kisspeptin-10 (Kp-10) injections via intraperitoneal (i.p.) once daily for three weeks notably promoted the egg laying rate in quails. In order to investigate the mechanism behind the effects of Kp-10 on enhancing the egg laying rate in birds, this study focused on the alternations of lipids synthesis in liver after Kp-10 injections. 75 female quails (22 d of age) were allocated to three groups randomly, and subjected to 0 (control, Con), 10 nmol (low dosage, L) and 100 nmol (high dosage, H) Kp-10 injections via i.p. once daily for three weeks, respectively. At d 52, quails were sacrificed and sampled for further analyses. Serum E2 concentration was increased by Kp-10 injections, and reached statistical significance in H group. Serum triglyceride (TG) concentrations were increased by 46.7% in L group and 36.8% in H group, respectively, but did not reach statistical significance, and TG contents in liver were significantly elevated by Kp-10 injections in a dose-dependent manner. Serum total cholesterol (Tch) concentrations significantly decreased in H group, while in H group the hepatic Tch content was markedly increased. The level of non-esterified fatty acid (NEFA), apolipoprotein A1 and B (apoA1 and apoB) were not altered by Kp-10 injections. The genes expression of sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthetase (FAS), apolipoprotein VLDL-II (apoVLDL-II), cholesterol 7α-hydroxylase (CYP7A1) and vitellogenin II (VTG-II) were significantly up-regulated by high but not low dosage of Kp-10 injection compared to the control group. However, the expression of SREBP-2, acetyl-CoA carboxylase (ACCα), malic enzyme (ME), stearoyl-CoA (Δ9) desaturase 1 (SCD1), apolipoprotein A1 (apoA1), fatty acid binding protein 2 (FABP2), 3-hydroxyl-3-methyl glutaryl-coenzyme A reductases (HMGCR), estrogen receptor α, β (ERα and β) mRNA were not affected by Kp-10 treatment. In line with hepatic mRNA abundance, hepatic SREBP1 protein content was significantly higher in H group. Although the mRNA expression was not altered, the content of ERα protein in liver was also significantly increased in H group. However, SREBP-2 protein content in liver was not changed by Kp-10 treatment. In conclusion, exogenous Kp-10 consecutive injections during juvenile stage significantly advanced the tempo of egg laying in quails, which was associated with the significant elevation in hepatic lipids synthesis and transport.


The emotional distress in a community after the terrorist attack on the World Trade Center.
To examine psychological impact of the September 11th disaster on the immediate neighborhood of the New York World Trade Center. 555 residents from the local Chinatown community participated in the study. They were surveyed retrospectively on their emotional-distress immediately after the tragedy and five months later. Prevalent anxiety was found in general community residents and additional depression in those who lost family members or friends. The mental health condition of the community improved tremendously five months later, with the initial 59% of general residents having 4 or more emotional symptoms dropping to 17%. However, more than half of the community residents had persistently shown one or more symptoms of emotional distress. Those who had lost a family member or friend in the disaster showed significantly higher distress, with 90% of them had four or more major psychiatric symptoms during the first few weeks right after the disaster, and the rate dropped to 35% five months later. Overall, those in their 40s and 50s seemed to have had relatively higher emotional distress than both younger and older groups. Methodological limitations were discussed concerning retrospective reporting and sample characteristics.


Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction.
Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury. CrT-OE mice were selected for left ventricular (LV) creatine 20-100% above wild-type values and subjected to acute and chronic coronary artery ligation. Increasing myocardial creatine up to 100% was not detrimental even in ageing CrT-OE. In chronic heart failure, creatine elevation was neither beneficial nor detrimental, with no effect on survival, LV remodelling or dysfunction. However, CrT-OE hearts were protected against I/R injury in vivo in a dose-dependent manner (average 27% less myocardial necrosis) and exhibited greatly improved functional recovery following ex vivo I/R (59% of baseline vs. 29%). Mechanisms contributing to ischaemic protection in CrT-OE hearts include elevated PCr and glycogen levels and improved energy reserve. Furthermore, creatine loading in HL-1 cells did not alter antioxidant defences, but delayed mitochondrial permeability transition pore opening in response to oxidative stress, suggesting an additional mechanism to prevent reperfusion injury. Elevation of myocardial creatine by 20-100% reduced myocardial stunning and I/R injury via pleiotropic mechanisms, suggesting CrT activation as a novel, potentially translatable target for cardiac protection from ischaemia.


An exploration of young carers' experiences of school and their perceptions regarding their future career - a scoping review protocol.
Background: Young carers are young people who care for a relative or a friend with an illness, disability, frailty, a mental health issue or addiction. Across the world, it is challenging to calculate the exact numbers due to the invisible nature of their role that can exist due to stigmatisation and fear of authoritative intrusion. As young carers reach 16 years and over, future career prospects become more significant. Young carers are more likely than their peers not to be in education, employment, or training and are more likely to do poorly at school or college than their non-caregiving peers due to the demands of caring. Recognising that positive engagement at school is a vital correlate of positive employment outcomes, young carers are at risk as their caring role can limit the range of employment opportunities open to them. This paper outlines the protocol for a robust synthesis of the literature surrounding young carers and their career perceptions. The scoping review will address the research question 'What is known from the literature about young carers in school and their career perceptions?' The overall aim of this paper is to present a protocol for the scoping review to map the key concepts, types of evidence, and gaps in research related to young carers in school and their future careers. Methods: The review will follow Arksey and O'Malley (2005) and Levac et al.'s, (2010) scoping review framework. The steps involved include: (1) research question identification; (2) relevant studies identification; (3) selection of studies; (4) data charting; (5) collating, summarising and reporting the results; and (6) stakeholders' consultation. Conclusions: The scoping review is an appropriate first step to employ in presenting the literature to inform a larger research study on young carers' experiences in school and their perceptions regarding their future careers.


Redistribution of carbon flux toward 2,3-butanediol production in Klebsiella pneumoniae by metabolic engineering.
Klebsiella pneumoniae KCTC2242 has high potential in the production of a high-value chemical, 2,3-butanediol (2,3-BDO). However, accumulation of metabolites such as lactate during cell growth prevent large-scale production of 2,3-BDO. Consequently, we engineered K. pneumoniae to redistribute its carbon flux toward 2,3-BDO production. The ldhA gene deletion and gene overexpression (budA and budB) were conducted to block a pathway that competitively consumes reduced nicotinamide adenine dinucleotide and to redirect carbon flux toward 2,3-BDO biosynthesis, respectively. These steps allowed efficient glucose conversion to 2,3-BDO under slightly acidic conditions (pH 5.5). The engineered strain SGSB105 showed a 40% increase in 2,3-BDO production from glucose compared with that of the host strain, SGSB100. Genes closely related to 2,3-BDO biosynthesis were observed at the gene transcription level by cultivating the SGSB100, SGSB103, SGSB104, and SGSB105 strains under identical growth conditions. Transcription levels for budA, budB, and budC increased approximately 10% during the log phase of cell growth relative to that of SGSB100. Transcription levels of 2,3-BDO genes in SGSB105 remained high during the log and stationary phases. Thus, the carbon flux was redirected toward 2,3-BDO production. Data on batch culture and gene transcription provide insight into improving the metabolic network for 2,3-BDO biosynthesis for industrial applications.


Illuminating CO2 reduction on frustrated Lewis pair surfaces: investigating the role of surface hydroxides and oxygen vacancies on nanocrystalline In2O(3-x)(OH)y.
Designing catalytic nanostructures that can thermochemically or photochemically convert gaseous carbon dioxide into carbon based fuels is a significant challenge which requires a keen understanding of the chemistry of reactants, intermediates and products on surfaces. In this context, it has recently been reported that the reverse water gas shift reaction (RWGS), whereby carbon dioxide is reduced to carbon monoxide and water, CO2 + H2 → CO + H2O, can be catalysed by hydroxylated indium oxide nanocrystals, denoted In2O(3-x)(OH)y, more readily in the light than in the dark. The surface hydroxide groups and oxygen vacancies on In2O(3-x)(OH)y were both shown to assist this reaction. While this advance provides a first step toward the rational design and optimization of a single-component gas-phase CO2 reduction catalyst for solar fuels generation, the precise role of the hydroxide groups and oxygen vacancies in facilitating the reaction on In2O(3-x)(OH)y nanocrystals has not been resolved. In the work reported herein, for the first time we present in situ spectroscopic and kinetic observations, complemented by density functional theory analysis, that together provide mechanistic information into the surface reaction chemistry responsible for the thermochemical and photochemical RWGS reaction. Specifically, we demonstrate photochemical CO2 reduction at a rate of 150 μmol gcat(-1) hour(-1), which is four times better than the reduction rate in the dark, and propose a reaction mechanism whereby a surface active site of In2O(3-x)(OH)y, composed of a Lewis base hydroxide adjacent to a Lewis acid indium, together with an oxygen vacancy, assists the adsorption and heterolytic dissociation of H2 that enables the adsorption and reaction of CO2 to form CO and H2O as products. This mechanism, which has its analogue in molecular frustrated Lewis pair (FLP) chemistry and catalysis of CO2 and H2, is supported by preliminary kinetic investigations. The results of this study emphasize the importance of engineering the surfaces of nanostructures to facilitate gas-phase thermochemical and photochemical carbon dioxide reduction reactions to energy rich fuels at technologically significant rates.


Intermediate- and long-term earthquake prediction.
Progress in long- and intermediate-term earthquake prediction is reviewed emphasizing results from California. Earthquake prediction as a scientific discipline is still in its infancy. Probabilistic estimates that segments of several faults in California will be the sites of large shocks in the next 30 years are now generally accepted and widely used. Several examples are presented of changes in rates of moderate-size earthquakes and seismic moment release on time scales of a few to 30 years that occurred prior to large shocks. A distinction is made between large earthquakes that rupture the entire downdip width of the outer brittle part of the earth's crust and small shocks that do not. Large events occur quasi-periodically in time along a fault segment and happen much more often than predicted from the rates of small shocks along that segment. I am moderately optimistic about improving predictions of large events for time scales of a few to 30 years although little work of that type is currently underway in the United States. Precursory effects, like the changes in stress they reflect, should be examined from a tensorial rather than a scalar perspective. A broad pattern of increased numbers of moderate-size shocks in southern California since 1986 resembles the pattern in the 25 years before the great 1906 earthquake. Since it may be a long-term precursor to a great event on the southern San Andreas fault, that area deserves detailed intensified study.


Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality.
Defining what represents a macronutritionally balanced diet remains an open question and a high priority in nutrition research. Although the amount of protein may have specific effects, from a broader dietary perspective, the choice of protein sources will inevitably influence other components of diet and may be a critical determinant for the health outcome. To examine the associations of animal and plant protein intake with the risk for mortality. This prospective cohort study of US health care professionals included 131 342 participants from the Nurses' Health Study (1980 to end of follow-up on June 1, 2012) and Health Professionals Follow-up Study (1986 to end of follow-up on January 31, 2012). Animal and plant protein intake was assessed by regularly updated validated food frequency questionnaires. Data were analyzed from June 20, 2014, to January 18, 2016. Hazard ratios (HRs) for all-cause and cause-specific mortality. Of the 131 342 participants, 85 013 were women (64.7%) and 46 329 were men (35.3%) (mean [SD] age, 49 [9] years). The median protein intake, as assessed by percentage of energy, was 14% for animal protein (5th-95th percentile, 9%-22%) and 4% for plant protein (5th-95th percentile, 2%-6%). After adjusting for major lifestyle and dietary risk factors, animal protein intake was not associated with all-cause mortality (HR, 1.02 per 10% energy increment; 95% CI, 0.98-1.05; P for trend = .33) but was associated with higher cardiovascular mortality (HR, 1.08 per 10% energy increment; 95% CI, 1.01-1.16; P for trend = .04). Plant protein was associated with lower all-cause mortality (HR, 0.90 per 3% energy increment; 95% CI, 0.86-0.95; P for trend < .001) and cardiovascular mortality (HR, 0.88 per 3% energy increment; 95% CI, 0.80-0.97; P for trend = .007). These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors. Replacing animal protein of various origins with plant protein was associated with lower mortality. In particular, the HRs for all-cause mortality were 0.66 (95% CI, 0.59-0.75) when 3% of energy from plant protein was substituted for an equivalent amount of protein from processed red meat, 0.88 (95% CI, 0.84-0.92) from unprocessed red meat, and 0.81 (95% CI, 0.75-0.88) from egg. High animal protein intake was positively associated with cardiovascular mortality and high plant protein intake was inversely associated with all-cause and cardiovascular mortality, especially among individuals with at least 1 lifestyle risk factor. Substitution of plant protein for animal protein, especially that from processed red meat, was associated with lower mortality, suggesting the importance of protein source.


Containment Studies of Transgenic Mosquitoes in Disease Endemic Countries: The Broad Concept of Facilities Readiness.
Genetic strategies for large scale pest or vector control using modified insects are not yet operational in Africa, and currently rely on import of the modified strains to begin preliminary, contained studies. Early involvement of research teams from participating countries is crucial to evaluate candidate field interventions. Following the recommended phased approach for novel strategies, evaluation should begin with studies in containment facilities. Experiences to prepare facilities and build international teams for research on transgenic mosquitoes revealed some important organizing themes underlying the concept of "facilities readiness," or the point at which studies in containment may proceed, in sub-Saharan African settings. First, "compliance" for research with novel or non-native living organisms was defined as the fulfillment of all legislative and regulatory requirements. This is not limited to regulations regarding use of transgenic organisms. Second, the concept of "colony utility" was related to the characteristics of laboratory colonies being produced so that results of studies may be validated across time, sites, and strains or technologies; so that the appropriate candidate strains are moved forward toward field studies. Third, the importance of achieving "defensible science" was recognized, including that study conclusions can be traced back to evidence, covering the concerns of various stakeholders over the long term. This, combined with good stewardship of resources and appropriate funding, covers a diverse set of criteria for declaring when "facilities readiness" has been attained. It is proposed that, despite the additional demands on time and resources, only with the balance of and rigorous achievement of each of these organizing themes can collaborative research into novel strategies in vector or pest control reliably progress past initial containment studies.


Evidence from pupillometry and fMRI indicates reduced neural response during vicarious social pain but not physical pain in autism.
Autism spectrum disorder (ASD) is characterized by substantial social deficits. The notion that dysfunctions in neural circuits involved in sharing another's affect explain these deficits is appealing, but has received only modest experimental support. Here we evaluated a complex paradigm on the vicarious social pain of embarrassment to probe social deficits in ASD as to whether it is more potent than paradigms currently in use. To do so we acquired pupillometry and fMRI in young adults with ASD and matched healthy controls. During a simple vicarious physical pain task no differences emerged between groups in behavior, pupillometry, and neural activation of the anterior insula (AIC) and anterior cingulate cortex (ACC). In contrast, processing complex vicarious social pain yielded reduced responses in ASD on all physiological measures of sharing another's affect. The reduced activity within the AIC was thereby explained by the severity of autistic symptoms in the social and affective domain. Additionally, behavioral responses lacked correspondence with the anterior cingulate and anterior insula cortex activity found in controls. Instead, behavioral responses in ASD were associated with hippocampal activity. The observed dissociation echoes the clinical observations that deficits in ASD are most pronounced in complex social situations and simple tasks may not probe the dysfunctions in neural pathways involved in sharing affect. Our results are highly relevant because individuals with ASD may have preserved abilities to share another's physical pain but still have problems with the vicarious representation of more complex emotions that matter in life.


Styrene oxide metabolism in rhesus monkey liver: enzyme activities in subcellular fractions and in isolated hepatocytes.
The activity and the kinetic behavior of expoxide hydrolase were studied in various subcellular fractions of rhesus monkey liver isolated by differential centrifugation. The purity of the fractions was estimated by morphometric electron microscopy. Hydrolase activity was measured by a specific radiometric assay with [7-3H]styrene oxide as substrate. All isolated subcellular fractions catalyzed the hydration of styrene oxide at a significant rate. With a saturating concentration of substrate (1 mM), the enzymatic activity (nanomole of product per minute per milligram of protein; mean +/- S.E.) turned out to be 1.51 +/- 0.45 (nuclear fraction), 3.50 +/- 1.11 (mitochondrial fraction), 14.8 +/- 2.26 (microsomal fraction) and 1.69 +/- 0.37 (soluble fraction). The hydrolase obeyed Michaelis-Menten kinetics in each fraction. Vmax (nanomole per minute per milligram; mean +/- S.E.) was 1.64 +/- 0.65 (nuclear fraction) 3.87 +/- 1.71 (mitochondrial fraction), 19.8 +/- 5.4 (microsomal fraction) and 2.72 +/- 1.36 (soluble fraction). The Km (millimole; mean +/- S.E.) values in the fractions were 0.09 +/- 0.02, 0.07 +/- 0.01, 0.23 +/- 0.15 and 0.64 +/- 0.40, respectively. The metabolism of styrene oxide was also studied in isolated hepatocytes from rhesus monkey. These cells hydrated the substrate easily whereas the conjugation of styrene oxide with glutathione was not measurable. Our results show that epoxide hydrolase is present in all subcellular fractions of the rhesus monkey liver. Styrene oxide is preferentially metabolized by hydration to styrene glycol in the isolated hepatocytes of this species and no conjugation with glutathione was found under the incubation conditions used.


Orthostatic hypotension and mortality risk: a meta-analysis of cohort studies.
Orthostatic hypotension (OH) has been found to be related to increased risk of mortality, although results of previous cohort studies were not always consistent. The aim of this meta-analysis was to investigate the association between OH and mortality risk. Medline, Embase and references cited in related reviews and studies. Cohort studies evaluating the association between OH and mortality risk were identified. Two investigators read all papers and extracted all relevant information. A total of 56 125 subjects with 11 580 mortality cases from nine cohorts were included in the meta-analysis. Pooled results indicated that the presence of OH at baseline was significantly associated with an increased risk of all-cause mortality (adjusted risk ratio (RR) = 1.40, p<0.001). Subgroup analysis suggested that the association between OH and all-cause mortality was less strong for the studies in which classic risk factors were adequately adjusted compared with those in which they were not adequately controlled. In addition, although our meta-analysis failed to reveal a significant association between OH and cardiovascular (CV) mortality (RR=1.20, p=0.47), we did find that subjects with OH had an increased risk of non-CV mortality (RR=1.18, p=0.05). The presence of OH is associated with a significantly increased risk of all-cause mortality, which may partially be mediated by classic risk factors. Further research is needed to determine whether the association between OH and mortality risk is causal.


Non-equilibrium effects evidenced by vibrational spectra during the coil-to-globule transition in poly(N-isopropylacrylamide) subjected to an ultrafast heating-cooling cycle.
Molecular dynamics simulations in conjunction with finite element calculations are used to explore the conformational dynamics of a thermo-sensitive oligomer, namely poly(N-isopropylacrylamide) (PNIPAM), subjected to an ultra-fast heating-cooling cycle. Finite element (FE) calculations were used to predict the temperature profile resulting from laser-induced heating of the polymer-aqueous system. The heating rate (∼0.6 K ps(-1)) deduced from FE calculations was used to heat an aqueous solution of PNIPAM consisting of 30 monomeric units (30-mer) from 285 K to 315 K. Non-equilibrium effects arising from the ultra-fast heating-cooling cycle results in a hysteresis during the coil-to-globule transition. The corresponding atomic scale conformations were characterized by monitoring the changes in the vibrational spectra, which provided a reliable metric to study the coil-to-globule transition in PNIPAM and vice-versa across the LCST. The vibrational spectra of bonds involving atoms from the oligomer backbone and the various side-groups (amide I, amide II, and the isopropyl group of PNIPAM) of the oligomers were analyzed to study the conformational changes in the oligomer corresponding to the observed hysteresis. The differences in the vibrational spectra calculated at various temperatures during heating and cooling cycles were used to understand the coil-to-globule and globule-to-coil transitions in the PNIPAM oligomer and identify the changes in the relative interactions between various atoms in the backbone and in the side groups of the oligomer with water. The shifts in the computed vibrational spectral peaks and the changes in the intensity of peaks for the different regions of PNIPAM, seen across the LCST during the heating cycle, are in good agreement with previous experimental studies. The changes in the radius of gyration (Rg) and vibrational spectra for amide I and amide II regions of PNIPAM suggest a clear coil-to-globule transition at ∼301 K during the heating cycle from 285 K to 315 K. During the heating cycle, a comparison of the vibrational spectra of isopropyl groups in PNIPAM at 285 K and 315 K suggests dehydration of the isopropyl moieties at 315 K. This implies that the oligomer-water interactions are dominant below the LCST whereas oligomer-oligomer interactions pre-dominate above the LCST. On the other hand, during the cooling cycle minor changes in the Rg and vibrational spectra of the PNIPAM oligomer in going from 315 K to 285 K indicate that the interactions between oligomer-oligomer and between the oligomer and water are less perturbed during the cooling cycle. Our simulations suggest that the observed hysteresis is a consequence of ultrafast heating-cooling kinetics, which allows insufficient relaxation times for the solvated oligomer.


Evaluation of carbonic anhydrase IX as a therapeutic target for inhibition of breast cancer invasion and metastasis using a series of in vitro breast cancer models.
Triple negative, resistant or metastatic disease are major factors in breast cancer mortality, warranting novel approaches. Carbonic anhydrase IX (CAIX) is implicated in survival, migration and invasion of breast cancer cells and inhibition provides an innovative therapeutic strategy. The efficacy of 5 novel ureido-substituted sulfamate CAIX inhibitors were assessed in increasingly complex breast cancer models, including cell lines in normoxia and hypoxia, 3D spheroids and an ex-vivo explant model utilizing fresh biopsy tissue from different breast cancer subtypes. CAIX expression was evaluated in a tissue microarray (TMA) of 92 paired lymph node and primary breast cancers and 2 inhibitors were appraised in vivo using MDA-MB-231 xenografts. FC11409B, FC9398A, FC9403, FC9396A and S4 decreased cell proliferation and migration and inhibited 3D spheroid invasion. S4, FC9398A and FC9403A inhibited or prevented invasion into collagen. FC9403A significantly reversed established invasion whilst FC9398A and DTP348 reduced xenograft growth. TMA analysis showed increased CAIX expression in triple negative cancers. These data establish CAIX inhibition as a relevant therapeutic goal in breast cancer, targeting the migratory, invasive, and metastatic potential of this disease. The use of biopsy tissue suggests efficacy against breast cancer subtypes, and should provide a useful tool in drug testing against invasive cancers.


Comparison of a new slender 6 Fr sheath with a standard 5 Fr sheath for transradial coronary angiography and intervention: RAP and BEAT (Radial Artery Patency and Bleeding, Efficacy, Adverse evenT), a randomised multicentre trial.
The 6 Fr Glidesheath Slender (GSS6Fr) is a recently developed thin-walled radial sheath with an outer diameter (OD) that is smaller than the OD of standard 6 Fr sheaths. The purpose of this trial was to clarify whether the use of this new slender sheath would result in similar rates of RAO to a standard 5 Fr sheath in unselected patients undergoing transradial (TR) coronary angiography and/or intervention, and to assess the relative importance of sheath size and haemostasis protocol on the rate of RAO. We conducted a randomised, multicentre, non-inferiority trial comparing the GSS6Fr against the standard GS5Fr in patients undergoing TR coronary angiography and/or intervention. Patients in each group were subsequently randomised to undergo patent haemostasis or the institutional haemostasis protocol. The primary endpoint was the occurrence of RAO at discharge. A total of 1,926 patients were randomised in 12 centres. The incidence of RAO was 3.47% with GSS6Fr compared with 1.74% with GS5Fr (risk difference 1.73%, 95% CI: 0.51-2.95%; pnon-inferiority=0.150). Patients randomised to patent haemostasis had a similar rate of RAO compared with institutional haemostasis (2.61% vs. 2.61%, p=1). There was no difference with regard to all secondary endpoints, including vascular access-site complications, local bleeding and spasm. In this large multicentre randomised trial, the GSS6Fr was associated with a low event rate for the primary endpoint (RAO), although non-inferiority to the GS5Fr was not met, due to a lower than expected rate of RAO in the GS5Fr group. As compared to institutional haemostasis, the use of patent haemostasis was not associated with a reduced rate of RAO.


Early repair of trauma-related full-thickness rotator cuff tears does not eliminate the problem of healing failure.
Failure of healing is a well-known problem after repair of the rotator cuff. This study aimed to investigate if early repair of trauma-related full-thickness rotator cuff tears (FTRCTs) could prevent this failure. In this prospective trial, 62 consecutive patients (14 women (23%), 48 men (77%); median age 61 years (interquartile range (IQR) 54 to 65)) with trauma-related FTRCT underwent arthroscopic single-row repair within six weeks of trauma. Tendon integrity was assessed one year after surgery using the Sugaya score on MR images. Patients were followed up with Western Ontario Rotator Cuff (WORC) index, EuroQol visual analogue scale (EQ VAS), and the Constant-Murley score (CS) two years after repair. A total of 57 patients (92%) had MR images available at one year; 59 patients (95%) had CS (one year), WORC (two years), and EQ VAS scores (two years). Intact repair was found on MRI in 36 patients (63%); 13 patients (23%) displayed healing failure of at least one repaired tendon and eight patients (14%) displayed total healing failure. Median WORC index and relative CS improved from 30.8 points (IQR 20.1 to 38.6) at baseline to 85.0 points (IQR 60.6 to 95.7) at two years and 26.5 points (IQR 21.2 to 37.4) to 83.2 points (IQR 71.9 to 97.5) at one year, respectively. The relative CS at one year was significantly better among those with intact repairs compared with those with healing failure (91.6 vs 78.1 points; p = 0.031). Although early repair of trauma-related FTRCT improved patient relevant outcomes over two years for the entire cohort, only two out of three repaired rotator cuffs displayed intact structural integrity on MRI after one year. Consequently, early repair did not seem to prevent healing failure after trauma-related FTRCT. Cite this article: Bone Joint J 2019;101-B:603-609.


Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: an experimental study.
As ischemic stroke is associated with an excessive release of glutamate into the neuronal extracellular space, a decrease in blood glutamate levels could provide a mechanism to remove it from the brain tissue, by increasing the brain-blood gradient. In this regard, the ability of glutamate oxaloacetate transaminase (GOT) to metabolize glutamate in blood could represent a potential neuroprotective tool for ischemic stroke. This study aimed to determine the neuroprotective effects of GOT in an animal model of cerebral ischemia by means of a middle cerebral arterial occlusion (MCAO) following the Stroke Therapy Academic Industry Roundtable (STAIR) group guidelines. In this animal model, oxaloacetate-mediated GOT activation inhibited the increase of blood and cerebral glutamate after MCAO. This effect is reflected in a reduction of infarct size, smaller edema volume, and lower sensorimotor deficits with respect to controls. Magnetic resonance spectroscopy confirmed that the increase of glutamate levels in the brain parenchyma after MCAO is inhibited after oxaloacetate-mediated GOT activation. These findings show the capacity of the GOT to remove glutamate from the brain by means of blood glutamate degradation, and suggest the applicability of this enzyme as an efficient and novel neuroprotective tool against ischemic stroke.


Conformational changes of blood ACE in chronic uremia.
The pattern of binding of monoclonal antibodies (mAbs) to 16 epitopes on human angiotensin I-converting enzyme (ACE) comprise a conformational ACE fingerprint and is a sensitive marker of subtle protein conformational changes. Toxic substances in the blood of patients with uremia due to End Stage Renal Disease (ESRD) can induce local conformational changes in the ACE protein globule and alter the efficacy of ACE inhibitors. The recognition of ACE by 16 mAbs to the epitopes on the N and C domains of ACE was estimated using an immune-capture enzymatic plate precipitation assay. The precipitation pattern of blood ACE by a set of mAbs was substantially influenced by the presence of ACE inhibitors with the most dramatic local conformational change noted in the N-domain region recognized by mAb 1G12. The "short" ACE inhibitor enalaprilat (tripeptide analog) and "long" inhibitor teprotide (nonapeptide) produced strikingly different mAb 1G12 binding with enalaprilat strongly increasing mAb 1G12 binding and teprotide decreasing binding. Reduction in S-S bonds via glutathione and dithiothreitol treatment increased 1G12 binding to blood ACE in a manner comparable to enalaprilat. Some patients with uremia due to ESRD exhibited significantly increased mAb 1G12 binding to blood ACE and increased ACE activity towards angiotensin I accompanied by reduced ACE inhibition by inhibitory mAbs and ACE inhibitors. The estimation of relative mAb 1G12 binding to blood ACE detects a subpopulation of ESRD patients with conformationally changed ACE, which activity is less suppressible by ACE inhibitors. This parameter may potentially serve as a biomarker for those patients who may need higher concentrations of ACE inhibitors upon anti-hypertensive therapy.


A Comprehensive Phylogenomic Platform for Exploring the Angiosperm Tree of Life.
The tree of life is the fundamental biological roadmap for navigating the evolution and properties of life on Earth, and yet remains largely unknown. Even angiosperms (flowering plants) are fraught with data gaps, despite their critical role in sustaining terrestrial life. Today, high-throughput sequencing promises to significantly deepen our understanding of evolutionary relationships. Here, we describe a comprehensive phylogenomic platform for exploring the angiosperm tree of life, comprising a set of open tools and data based on the 353 nuclear genes targeted by the universal Angiosperms353 sequence capture probes. The primary goals of this article are to (i) document our methods, (ii) describe our first data release, and (iii) present a novel open data portal, the Kew Tree of Life Explorer (https://treeoflife.kew.org). We aim to generate novel target sequence capture data for all genera of flowering plants, exploiting natural history collections such as herbarium specimens, and augment it with mined public data. Our first data release, described here, is the most extensive nuclear phylogenomic data set for angiosperms to date, comprising 3099 samples validated by DNA barcode and phylogenetic tests, representing all 64 orders, 404 families (96$\%$) and 2333 genera (17$\%$). A "first pass" angiosperm tree of life was inferred from the data, which totaled 824,878 sequences, 489,086,049 base pairs, and 532,260 alignment columns, for interactive presentation in the Kew Tree of Life Explorer. This species tree was generated using methods that were rigorous, yet tractable at our scale of operation. Despite limitations pertaining to taxon and gene sampling, gene recovery, models of sequence evolution and paralogy, the tree strongly supports existing taxonomy, while challenging numerous hypothesized relationships among orders and placing many genera for the first time. The validated data set, species tree and all intermediates are openly accessible via the Kew Tree of Life Explorer and will be updated as further data become available. This major milestone toward a complete tree of life for all flowering plant species opens doors to a highly integrated future for angiosperm phylogenomics through the systematic sequencing of standardized nuclear markers. Our approach has the potential to serve as a much-needed bridge between the growing movement to sequence the genomes of all life on Earth and the vast phylogenomic potential of the world's natural history collections. [Angiosperms; Angiosperms353; genomics; herbariomics; museomics; nuclear phylogenomics; open access; target sequence capture; tree of life.].


Cellular uptake mediated off/on responsive near-infrared fluorescent nanoparticles.
Fluorescence imaging, utilizing molecular fluorophores, often acts as a central tool for the investigation of fundamental biological processes and offers huge future potential for human imaging coupled to therapeutic procedures. An often encountered limitation with fluorescence imaging is the difficulty in discriminating nonspecific background fluorophore emission from a fluorophore localized at a specific region of interest. This limits imaging to individual time points at which background fluorescence has been minimized. It would be of significant advantage if the fluorescence output could be modulated from off to on in response to specific biological events as this would permit imaging of such events in real time without background interference. Here we report our approach to achieve this for the most fundamental of cellular processes, i.e. endocytosis. We describe a new near-infrared off to on fluorescence switchable nanoparticle construct that is capable of switching its fluorescence on following cellular uptake but remains switched off in extracellular environments. This permits continuous real-time imaging of the uptake process as extracellular particles are nonfluorescent. The principles behind the fluorescence off/on switch can be understood by encapsulation of particles in cellular organelles which effect a microenvironmental change establishing a fluorescence signal.


Distribution of proteins within different compartments of tendon varies according to tendon type.
Although the predominant function of all tendons is to transfer force from muscle to bone and position the limbs, some tendons additionally function as energy stores, reducing the energetic cost of locomotion. To maximise energy storage and return, energy-storing tendons need to be more extensible and elastic than tendons with a purely positional function. These properties are conferred in part by a specialisation of a specific compartment of the tendon, the interfascicular matrix, which enables sliding and recoil between adjacent fascicles. However, the composition of the interfascicular matrix is poorly characterised and we therefore tested the hypothesis that the distribution of elastin and proteoglycans differs between energy-storing and positional tendons, and that protein distribution varies between the fascicular matrix and the interfascicular matrix, with localisation of elastin and lubricin to the interfascicular matrix. Protein distribution in the energy-storing equine superficial digital flexor tendon and positional common digital extensor tendon was assessed using histology and immunohistochemistry. The results support the hypothesis, demonstrating enrichment of lubricin in the interfascicular matrix in both tendon types, where it is likely to facilitate interfascicular sliding. Elastin was also localised to the interfascicular matrix, specifically in the energy-storing superficial digital flexor tendon, which may account for the greater elasticity of the interfascicular matrix in this tendon. A differential distribution of proteoglycans was identified between tendon types and regions, which may indicate a distinct role for each of these proteins in tendon. These data provide important advances into fully characterising structure-function relationships within tendon.


"Pee-in-a-Pot": acceptability and uptake of on-site chlamydia screening in a student population in the Republic of Ireland.
The aim of the study was to explore the acceptability and uptake of on-campus screening using a youth friendly approach in two Third Level higher education institutions (HEIs). This study is part of wider research exploring the optimal setting for chlamydia screening in Ireland. Male and female students were given the opportunity to take a free anonymous test for chlamydia during a one week programme of "pee-in-a-pot" days at two HEI campuses in the West of Ireland. The study was set up after extensive consultation with the two HEIs and advertised on the two campuses using a variety of media in the two weeks preceding the screening days. Screening involved the provision and distribution of testing packs at communal areas and in toilet facilities. In Ireland, chlamydia notifications are highest amongst 20-29 year olds and hence the screening criterion was aimed at 18-29 year olds. Urine samples were tested using a nucleic acid amplification test (NAAT). Following the screening days, qualitative in-depth interviews were conducted with participants about their experiences of the event. Out of 1,249 test kits distributed in two HEIs, 592 specimens were collected giving a return rate of 47.5%. Tests excluded (54) were due to labelling errors or ineligibility of participants' age. Two thirds of those tested were females and the mean age was 21 years. Overall, 3.9% (21/538) of participants tested positive, 5% (17/336) among females and 2% (4/191) among males. Participant interviews identified factors which enhanced student participation such as anonymity, convenience, accessibility of testing, and the informal and non-medical approach to testing. Screening for chlamydia using on-campus "pee-in-a-pot" days is an acceptable strategy in this population. This model can detect and treat asymptomatic cases of chlamydia and avoid many of the barriers associated with testing for sexually transmitted infections (STIs) in clinical settings.


Department Wide Validation in Digital Pathology-Experience from an Academic Teaching Hospital Using the UK Royal College of Pathologists' Guidance.
we describe our experience of validating departmental pathologists for digital pathology reporting, based on the UK Royal College of Pathologists (RCPath) "Best Practice Recommendations for Implementing Digital Pathology (DP)," at a large academic teaching hospital that scans 100% of its surgical workload. We focus on Stage 2 of validation (prospective experience) prior to full validation sign-off. twenty histopathologists completed Stage 1 of the validation process and subsequently completed Stage 2 validation, prospectively reporting a total of 3777 cases covering eight specialities. All cases were initially viewed on digital whole slide images (WSI) with relevant parameters checked on glass slides, and discordances were reconciled before the case was signed out. Pathologists kept an electronic log of the cases, the preferred reporting modality used, and their experiences. At the end of each validation, a summary was compiled and reviewed with a mentor. This was submitted to the DP Steering Group who assessed the scope of cases and experience before sign-off for full validation. A total of 1.3% (49/3777) of the cases had a discordance between WSI and glass slides. A total of 61% (30/49) of the discordances were categorised as a minor error in a supplementary parameter without clinical impact. The most common reasons for diagnostic discordances across specialities included identification and grading of dysplasia, assessment of tumour invasion, identification of small prognostic or diagnostic objects, interpretation of immunohistochemistry/special stains, and mitotic count assessment. Pathologists showed similar mean diagnostic confidences (on Likert scale from 0 to 7) with a mean of 6.8 on digital and 6.9 on glass slide reporting. we describe one of the first real-world experiences of a department-wide effort to implement, validate, and roll out digital pathology reporting by applying the RCPath Recommendations for Implementing DP. We have shown a very low rate of discordance between WSI and glass slides.


Thickness and refractive-index measurement of birefringent material by laser feedback technique.
We introduce a technique for simultaneous measurement of thickness and refractive index of birefringent materials. The principle is based on the laser feedback effect that laser polarization states flip between two orthogonal directions when a birefringent material is placed into the external cavity. The position of polarization flipping is determined by the phase-retardation magnitude of the birefringent material. Some feature points in the laser intensity curve can be used to calculate phase retardation. We derive an expression for phase retardation and rotation angle of a birefringent material to calculate thickness and refractive index. This technique is noncontact and compatible with in situ thickness and refractive-index measurement. The measurement precision of thickness is 59 nm and of refractive index is 0.0006.


Predominance of Lactobacillus plantarum Strains in Peruvian Amazonian Fruits.
The objective of this research was the identification and characterization of lactic acid bacteria (LAB) isolated from Peruvian Amazonian fruits. Thirty-seven isolates were obtained from diverse Amazonian fruits. Molecular characterization of the isolates was performed by ARDRA, 16S-23S ITS RFLP and rep-PCR using GTG5 primers. Identification was carried out by sequencing the 16S rDNA gene. Phenotypic characterization included nutritional, physiological and antimicrobial resistance tests. Molecular characterization by Amplified Ribosomal DNA Restriction Analysis (ARDRA) and 16S-23S ITS RFLP resulted in four restriction profiles while GTG5 analysis showed 14 banding patterns. Based on the 16S rDNA gene sequence, the isolates were identified as Lactobacillus plantarum (75.7%), Weissella cibaria (13.5%), Lactobacillus brevis (8.1%), and Weissella confusa (2.7%). Phenotypic characterization showed that most of the isolates were homofermentative bacilli, able to ferment glucose, maltose, cellobiose, and fructose and grow in a broad range of temperatures and pH. The isolates were highly susceptible to ampicillin, amoxicillin, clindamycin, chloramphenicol, erythromicyn, penicillin, and tetracycline and showed great resistance to kanamycin, gentamycin, streptomycin, sulfamethoxazole/trimethoprim, and vancomycin. No proteolytic or amylolytic activity was detected. L. plantarum strains produce lactic acid in higher concentrations and Weissella strains produce exopolymers only from sucrose. Molecular methods allowed to accurately identify the LAB isolates from the Peruvian Amazonian fruits, while phenotypic methods provided information about their metabolism, physiology and other characteristics that may be useful in future biotechnological processes. Further research will focus especially on the study of L. plantarum strains. The objective of this research was the identification and characterization of lactic acid bacteria (LAB) isolated from Peruvian Amazonian fruits. Thirty-seven isolates were obtained from diverse Amazonian fruits. Molecular characterization of the isolates was performed by ARDRA, 16S-23S ITS RFLP and rep-PCR using GTG5 primers. Identification was carried out by sequencing the 16S rDNA gene. Phenotypic characterization included nutritional, physiological and antimicrobial resistance tests. Molecular characterization by Amplified Ribosomal DNA Restriction Analysis (ARDRA) and 16S-23S ITS RFLP resulted in four restriction profiles while GTG5 analysis showed 14 banding patterns. Based on the 16S rDNA gene sequence, the isolates were identified as Lactobacillus plantarum (75.7%), Weissella cibaria (13.5%), Lactobacillus brevis (8.1%), and Weissella confusa (2.7%). Phenotypic characterization showed that most of the isolates were homofermentative bacilli, able to ferment glucose, maltose, cellobiose, and fructose and grow in a broad range of temperatures and pH. The isolates were highly susceptible to ampicillin, amoxicillin, clindamycin, chloramphenicol, erythromicyn, penicillin, and tetracycline and showed great resistance to kanamycin, gentamycin, streptomycin, sulfamethoxazole/trimethoprim, and vancomycin. No proteolytic or amylolytic activity was detected. L. plantarum strains produce lactic acid in higher concentrations and Weissella strains produce exopolymers only from sucrose. Molecular methods allowed to accurately identify the LAB isolates from the Peruvian Amazonian fruits, while phenotypic methods provided information about their metabolism, physiology and other characteristics that may be useful in future biotechnological processes. Further research will focus especially on the study of L. plantarum strains.


Out-patient chronic pain service in Hong Kong: prospective study.
To examine the profile and referral pattern of patients attending an out-patient pain management service in Hong Kong. Prospective cross-sectional survey. Regional public hospitals, Hong Kong. All patients attending out-patient pain management clinics in the New Territories East public hospitals between 1 September and 31 December 2002. Demographic profiles, referring specialty, pain diagnosis, pain sites, duration and severity of pain, treatment modality, litigation, compensation, and social welfare status. Data were collected using a standardised questionnaire. Two hundred and forty-eight patients were interviewed. Most patients (70%) were middle-aged, with 21% over 60 years. Seventy-nine percent of patients were referred to the clinics either from orthopaedic surgeons (64.1%), general and other surgeons (14.9%), or general practitioners (3.6%). The median (range) duration of pain was 2.3 (0.08-26.7) years. The most common pain diagnoses were musculoskeletal back pain (46.4%) and neuropathic pain (27.8%). A total of 11.3% of the patients had two pain diagnoses, while 40.7% complained of pain in more than one location. Pain in the limbs was the most frequent complaint followed by the head, neck, and back. Approximately 38% of patients had tried four or more treatment modalities. Oral medication was the most common method (86.7%) of pain-relief treatment. More than half of the patients had also tried physiotherapy and traditional Chinese medicine. Approximately 37% of the patients were unemployed, while 31% were receiving social security subsidy. Eighty-six patients had pain associated with a work-related injury, and of these patients, 80% were involved in compensation claims. The profile of patients referred to the pain management clinics was complex. Patients were mainly referred from specialists. The economic implication in this group of patients is likely to be significant as many patients utilised multiple treatment modalities, were unemployed and on social welfare benefits, and were involved in compensation and litigation proceedings.


Haverhill fever with spine involvement.
Haverhill fever and rat-bite fever are closely-related syndromes caused by Streptobacillus moniliformis. This infection is characterized by the abrupt onset of fever with rigors, myalgias, headache, polyarthritis, and rash. We report a case of infection with S. moniliformis that manifested as acute polyarthritis with involvement of the spine. To our knowledge, involvement of the spine has not been reported previously with this infection. Diagnosis can be particularly difficult in the absence of fever or obvious exposure to rodents, as in our case. A high degree of awareness is necessary to make the diagnosis of this potentially fatal infection, which is easily treatable.


Severe mental illness and risk of sexual offending in men: a case-control study based on Swedish national registers.
To examine the comorbidity of severe mental illness with sexual offending in men. A case-control design was used to investigate psychiatric hospitalization and sexual offending. Data were obtained from Swedish national registers for crime, hospital discharge diagnoses (based on International Classification of Diseases revisions 9 and 10), demographic, and socioeconomic factors for the years 1988 through 2000. All male sexual offenders (N = 8495) in Sweden were included and compared with a random sample of male controls taken from the general population (N = 19,935). The population attributable risk fraction (the proportion of all sexual crimes throughout the study period that were committed by patients with a history of psychiatric hospitalization) was also estimated. After adjustment for demographic and socioeconomic confounders, sexual offenders were 6 times more likely to have a history of psychiatric hospitalization compared with the general population (OR = 6.3, 95% CI = 5.7 to 6.9). Sexual offenders were significantly more likely to have a severe mental illness than the general population, whether this was schizophrenia (OR = 4.8, 95% CI = 3.4 to 6.7), other psychoses (OR = 5.2, 95% CI = 3.9 to 6.8), or bipolar affective disorder (OR = 3.4, 95% CI = 1.8 to 6.4). The proportion of all sexual crimes committed by hospitalized psychiatric patients (the population attributable risk fraction) was 20.1%. The increased relative risk of psychiatric hospitalization and severe mental illness in sexual offenders is contrary to much expert opinion in the field. If these findings are replicated in other settings, policies in the criminal justice system regarding the assessment, management, and treatment of sexual offenders may need review.


Socioeconomic status and cognitive functioning: moving from correlation to causation.
A growing body of cognitive research uses sophisticated behavioral and neuroimaging measurements to demonstrate associations between family socioeconomic status (SES) and specific cognitive functions. We argue for the value in these kinds of studies of increased sophistication in the measurement and modeling of SES. With regard to measurement, SES combines several components, each of which represents distinct resources that might benefit children's cognitive development in different ways. Policy implications of studies using omnibus SES composites are problematic because there are no 'treatments' for enhancing overall SES, although policies abound for enhancing specific components of SES such as family income. Past literature offers guidance regarding how best to measure each of the SES components. With regard to modeling, we point out that the manipulability of economic, educational, and occupational components of SES varies, which provides opportunities for generating experimental or quasi-experimental variation in some components but not others. Evidence on the causal connections between SES components and child outcomes is summarized. Both experimental and quasi-experimental studies involving manipulation of family income have demonstrated consistent associations with a number of cognitive measures. Quasi-experimental increases in maternal education have also shown associations with child achievement. We end with a discussion of useful directions in SES-related cognitive research. WIREs Cogn Sci 2012, 3:377-386. doi: 10.1002/wcs.1176 For further resources related to this article, please visit the WIREs website.


A prospective observational study with dose volume parameters predicting rectosigmoidoscopic findings and late rectosigmoid bleeding in patients with uterine cervical cancer treated by definitive radiotherapy.
We assessed the value of dose-volumetric parameters predicting rectosigmoid mucosal changes (RMC) and late rectosigmoid complications (LRC). Between January 2004 and February 2006, 77 patients with stage IB-IIIB cervical cancer underwent external beam radiotherapy and computed tomography (CT)-based intracavitary irradiation. Total dose to the rectal point and several dose-volumetric parameters for rectosigmoid colon (D20cc, D15cc, D10cc, D5cc, D2cc, D1cc, and D0.1cc , defined as the minimal doses received by the highest irradiated volumes of 20, 15, 10, 5, 2, 1, and 0.1 cc, respectively), were calculated using the equivalent dose in 2 Gy fractions (α/β = 3, Gy3). The RMC and LRC were graded by rectosigmoidoscopy and Radiation Therapy Oncology Group criteria every 6 months, respectively. Of 77 patients, 27 (35.1%) patients developed RMC ≥ score 3 and 22 (28.6 %) patients developed LRC ≥ grade 2. There was a positive correlation between RMC score and LRC grade (r = 0.728, p < 0.001). In multivariate analyses, D5cc, among the dose-volumetric parameters, was significant parameter for the risks of RMC ≥ score 3 and LRC ≥ grade 2 (p < 0.05). D5cc may be a more reliable estimate than other dose-volumetric parameters for predicting the risk of RMC ≥ score 3 and LRC ≥ grade 2 in CT-based brachytherapy.


Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression.
MicroRNAs (miRNAs) from the gene cluster miR-143-145 are diminished in cells of colorectal tumor origin when compared with normal colon epithelia. Until now, no report has addressed the coordinate action of these miRNAs in colorectal cancer (CRC). In this study, we performed a comprehensive molecular and functional analysis of the miRNA cluster regulatory network. First, we evaluated proliferation, migration, anchorage-independent growth and chemoresistance in the colon tumor cell lines after miR-143 and miR-145 restoration. Then, we assessed the contribution of single genes targeted by miR-143 and miR-145 by reinforcing their expression and checking functional recovery. Restoring miR-143 and miR-145 in colon cancer cells decreases proliferation, migration and chemoresistance. We identified cluster of differentiation 44 (CD44), Kruppel-like factor 5 (KLF5), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) as proteins targeted by miR-143 and miR-145. Their re-expression can partially revert a decrease in transformation properties caused by the overexpression of miR-143 and miR-145. In addition, we determined a set of mRNAs that are diminished after reinforcing miR-143 and miR-145 expression. The whole transcriptome analysis ascertained that downregulated transcripts are enriched in predicted target genes in a statistically significant manner. A number of additional genes, whose expression decreases as a direct or indirect consequence of miR-143 and miR-145, reveals a complex regulatory network that affects cell signaling pathways involved in transformation. In conclusion, we identified a coordinated program of gene repression by miR-143 and miR-145, in CRC, where either of the two miRNAs share a target transcript, or where the target transcripts share a common signaling pathway. Major mediators of the oncosuppression by miR-143 and miR-145 are genes belonging to the growth factor receptor-mitogen-activated protein kinase network and to the p53 signaling pathway.


Coordinative trends of a tridentate thiosemicarbazone ligand: synthesis, characterization, luminescence studies and desulfurization processes.
The coordinative chemistry of the tridentate thiosemicarbazone ligand 2-pyridinecarboxaldehyde 4-N-ethylthiosemicarbazone (HL(Et)) has been explored by using an electrochemical methodology. All the complexes have been characterized using analytical and spectroscopic techniques. In the case of copper we have isolated two different complexes, with Cu(L(Et))(2).4H(2)O (6) and [Cu(2)(L(Et))(2)(SO(4))] (7) formulae. The sulfate group coordinated to the copper atoms in was probably released to the media as a consequence of a desulfurization process. Single X-ray crystallography has been carried out for the ligand HL(Et) and the complexes , [Ag(6)(L(Et))(6)].CH(3)CN (9) and [Pb(L(Et))(2)] (2). The copper(ii) complex is a dimer compound in which two antiparallel monodeprotonated ligands are coordinated to two copper centres by establishment of mu(2)-thiolate bridges and the additional coordination of a sulfate group bridging the two metal atoms. The silver complex is an unusual hexanuclear cluster compound with a wheel-type conformation, while the lead complex is a monomer which exhibits the lone pair effect. A structural comparative study of the electrochemically obtained complexes derived from HL(X) ligands (X= Me, Et and Ph) have been performed. Finally, the solution behaviour of the complexes was checked by NMR, UV and fluorescence studies.


Epigenetic silencing of miR-145-5p contributes to brain metastasis.
Brain metastasis is a major cause of morbidity and mortality of lung cancer patients. We assessed whether aberrant expression of specific microRNAs could contribute to brain metastasis. Comparison of primary lung tumors and their matched metastatic brain disseminations identified shared patterns of several microRNAs, including common down-regulation of miR-145-5p. Down-regulation was attributed to methylation of miR-145's promoter and affiliated elevation of several protein targets, such as EGFR, OCT-4, MUC-1, c-MYC and, interestingly, tumor protein D52 (TPD52). In line with these observations, restored expression of miR-145-5p and selective depletion of individual targets markedly reduced in vitro and in vivo cancer cell migration. In aggregate, our results attribute to miR-145-5p and its direct targets pivotal roles in malignancy progression and in metastasis.


Acoustic radiation force impulse imaging of mechanical stiffness propagation in myocardial tissue.
Acoustic radiation force impulse (ARFI) imaging has been shown to be capable of imaging local myocardial stiffness changes throughout the cardiac cycle. Expanding on these results, the authors present experiments using cardiac ARFI imaging to visualize and quantify the propagation of mechanical stiffness during ventricular systole. In vivo ARFI images of the left ventricular free wall of two exposed canine hearts were acquired. Images were formed while the heart was externally paced by one of two electrodes positioned on the epicardial surface and either side of the imaging plane. Two-line M-mode ARFI images were acquired at a sampling frequency of 120 Hz while the heart was paced from an external stimulating electrode. Two-dimensional ARFI images were also acquired, and an average propagation velocity across the lateral field of view was calculated. Directions and speeds of myocardial stiffness propagation were measured and compared with the propagations derived from the local electrocardiogram (ECG), strain, and tissue velocity measurements estimated during systole. In all ARFI images, the direction of myocardial stiffness propagation was seen to be away from the stimulating electrode and occurred with similar velocity magnitudes in either direction. When compared with the local epicardial ECG, the mechanical stiffness waves were observed to travel in the same direction as the propagating electrical wave and with similar propagation velocities. In a comparison between ARFI, strain, and tissue velocity imaging, the three methods also yielded similar propagation velocities.


A profiling analysis of contributions of cigarette smoking, dietary calcium intakes, and physical activity to fragility fracture in the elderly.
Fragility fracture and bone mineral density (BMD) are influenced by common and modifiable lifestyle factors. In this study, we sought to define the contribution of lifestyle factors to fracture risk by using a profiling approach. The study involved 1683 women and 1010 men (50+ years old, followed up for up to 20 years). The incidence of new fractures was ascertained by X-ray reports. A "lifestyle risk score" (LRS) was derived as the weighted sum of effects of dietary calcium intake, physical activity index, and cigarette smoking. Each individual had a unique LRS, with higher scores being associated with a healthier lifestyle. Baseline values of lifestyle factors were assessed. In either men or women, individuals with a fracture had a significantly lower age-adjusted LRS than those without a fracture. In men, each unit lower in LRS was associated with a 66% increase in the risk of total fracture (non-adjusted hazard ratio [HR] 1.66; 95% CI, 1.26 to 2.20) and still significant after adjusting for age, weight or BMD. However, in women, the association was uncertain (HR 1.30; 95% CI, 1.11 to 1.53). These data suggest that unhealthy lifestyle habits are associated with an increased risk of fracture in men, but not in women, and that the association is mediated by BMD.


Structure of a non-psychrophilic trypsin from a cold-adapted fish species.
The crystal structure of cationic trypsin (CST) from the Atlantic salmon (Salmo salar) has been refined at 1.70 A resolution. The crystals are orthorhombic, belong to space group P212121, with lattice parameters a = 65.91, b = 83.11 and c = 154.79 A, and comprise four molecules per asymmetric unit. The structure was solved by molecular replacement with AMoRe and refined with X-PLOR to an R value of 17.4% and Rfree of 21.5% for reflections |F| > 3sigmaF between 8.0 and 1.7 A resolution. The four non-crystallographic symmetry (NCS) related molecules in the asymmetric unit display r.m.s. deviations in the range 0.31-0.74 A for main-chain atoms, with the largest differences confined to two loops. One of these is the calcium-binding loop where the electron-density indicates a calcium ion for only one of the four molecules. In order to find structural rationalizations for the observed difference in thermostability and catalytic efficiency of CST, anionic salmon trypsin (AST) and bovine trypsin (BT), the three structures have been extensively compared. The largest deviations for the superimposed structures occur in the surface loops and particularly in the so-called 'autolysis loop'. Both the salmon enzymes possess a high methionine content, lower overall hydrophobicity and enhanced surface hydrophilicity, compared with BT. These properties have so far been correlated to cold-adaptation features, while in this work it is shown that the non-psychrophilic cationic salmon trypsin shares these features with the psychrophilic anionic salmon trypsin.


Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis.
Apolipoprotein (apo) E, a constituent of several lipoproteins, is a ligand for the low density lipoprotein receptor, and this interaction is important for maintaining cholesterol and triglyceride homeostasis. We have used a gene replacement strategy to generate mice that express the human apoE3 isoform in place of the mouse protein. The levels of apoE mRNA in various tissues are virtually the same in the human apoE3 homozygous (3/3) mice and their littermates having the wild type mouse allele (+/+). Total cholesterol and triglyceride levels in fasted plasma from the 3/3 mice were not different from those in the +/+ mice, when maintained on a normal (low fat) chow diet. We found, however, notable differences in the distribution of plasma lipoproteins and apolipoprotein E between the two groups: beta-migrating lipoproteins and plasma apoB100 levels are decreased in the 3/3 mice, and the apoE distribution is shifted from high density lipoproteins to larger lipoprotein particles. In addition, the fractional catabolic rate of exogenously administered remnant particles without apoE was 6-fold slower in the 3/3 mice compared with the +/+ mice. When the 3/3 and +/+ animals were fed a high fat/high cholesterol diet, the 3/3 animals responded with a dramatic increase (5-fold) in total cholesterol compared with the +/+ mice (1.5-fold), and after 12 weeks on this same diet the 3/3 animals developed significantly (at least 13-fold) larger atherosclerotic plaques in the aortic sinus area than the +/+ animals. Thus the structural differences between human APOE3 and mouse ApoE proteins are sufficient to cause an increased susceptibility to dietary-induced hypercholesterolemia and atherosclerosis in the 3/3 mice.


Lightning in superconductors.
Crucially important for application of type-II superconductor films is the stability of the vortex matter--magnetic flux lines penetrating the material. If some vortices get detached from pinning centres, the energy dissipated by their motion will facilitate further depinning, and may trigger a massive electromagnetic breakdown. Up to now, the time-resolved behaviour of these ultra-fast events was essentially unknown. We report numerical simulation results revealing the detailed dynamics during breakdown as within nanoseconds it develops branching structures in the electromagnetic fields and temperature, with striking resemblance of atmospheric lightning. During a dendritic avalanche the superconductor is locally heated above its critical temperature, while electrical fields rise to several kV/m as the front propagates at instant speeds near up to 100 km/s. The numerical approach provides an efficient framework for understanding the ultra-fast coupled non-local dynamics of electromagnetic fields and dissipation in superconductor films.


Emotional reactions of peers influence decisions about fairness in adolescence.
During adolescence, peers take on increasing importance, while social skills are still developing. However, how emotions of peers influence social decisions during that age period is insufficiently known. We therefore examined the effects of three different emotional responses (anger, disappointment, happiness) on decisions about fairness in a sample of 156 adolescents aged 12-17 years. Participants received written emotional responses from peers in a version of the Dictator Game to a previous unfair offer. Adolescents reacted with more generous offers after disappointed reactions compared to angry and happy reactions. Furthermore, we found preliminary evidence for developmental differences over adolescence, since older adolescents differentiated more between the three emotions than younger adolescents. In addition, individual differences in social value orientation played a role in decisions after happy reactions of peers to a previous unfair offer, such that participants with a "proself" orientation made more unfair offers to happy peers than "prosocial" participants. Taken together, our findings demonstrate that adolescents take emotions of peers into account when making social decisions, while individual differences in social value orientation affect these decisions, and age seems to influence the nature of the reaction.


Initial events in the formation of immune deposits in passive Heymann nephritis. gp330-anti-gp330 immune complexes form in epithelial coated pits and rapidly become attached to the glomerular basement membrane.
The nephritogenic antigen of Heymann's nephritis (HN), gp330, was previously demonstrated (4-9) to be a resident glycoprotein of coated pits in the glomerular and proximal tubule epithelium of rats, and anti-gp330 IgG given intravenously was found to form IDs in glomeruli (passive HN). The purpose of this study was to investigate the detailed events that occur in the formation of IDs in passive HN. HN was induced by the injection of either 125I-labeled or unlabeled anti-gp330 IgG. At various times after injection (15 min to 8 d) the kidneys of some of the injected rats were fixed by perfusion, and the distribution of the rabbit IgG was determined by immunofluorescence and by immunoelectron microscopy. Glomeruli were isolated from the kidneys of injected rats and used for isolation of GBM fractions or for elution of the bound IgG. At 15 min to 1 h after injection, the rabbit IgG was localized by immunocytochemistry exclusively in coated pits along the podocyte plasmalemma facing the GBM. By 1-8 d, anti-gp330 IgG was detected in larger electron-dense IDs often located under the slit diaphragms. Serial sectioning revealed that each of the IDs maintained contact with a coated pit at some level. When GBMs isolated from rats given radiolabeled anti-gp330 IgG were examined by electron microscopy, the IDs were found to remain attached to the GBMs as early as 15 min after injection and coisolated with them at all time points. By double-immunolabeling of the isolated GBMs with two sizes of gold particles, both the antigen (gp330) and the anti-gp330 IgG could be demonstrated in IDs at all time points. When the amount of radiolabeled anti-gp330 bound to GBM fractions was compared with that of isolated glomeruli, it was found that 20% of the radiolabel remained bound to the purified GBMs at 15 min after injection, and 90% at 3 d. The bound IgG was released only by treatments that disrupt antibody-antigen complexes (high and low pH), but not by the other treatments we tried (detergent, high salt, heparinase, or collagenase digestion). When the IgG bound to glomeruli was eluted with acid citrate buffer 3 d after injection, it was found to specifically immunoprecipitate only gp330 from detergent-solubilized 125I-labeled kidney microvillar vesicles. By isoelectric focusing the eluate was found to be enriched in IgGs with acidic isoelectric points.(ABSTRACT TRUNCATED AT 400 WORDS)


Transmembrane domain of CD44 is required for its detergent insolubility in fibroblasts.
The hyaluronan receptor CD44 is an abundant glycoprotein expressed on a variety of different cell types. In fibroblasts a significant portion of receptor molecules remain in the detergent-insoluble fraction after Triton X-100 extraction. Detergent insolubility of these CD44 molecules has been interpreted to reflect their association with the cytoskeleton. In this study we examined the structural features of CD44 required for its Triton X-100 insolubility in murine fibroblasts. We expressed in L cells the wild-type hematopoietic form of CD44, a mutant CD44 lacking the cytoplasmic domain, and two mutant CD44 molecules with substituted transmembrane domains. Immunofluorescence and cell surface iodination were performed and the detergent extraction profile of the transfected CD44 molecules was determined. No difference in detergent solubility was observed between wild-type and tailless mutant-transfected molecules. However, both CD44 mutants with a heterologous transmembrane domain, derived from either the CD3 zeta chain or CD45, were completely soluble in Triton X-100. These results demonstrate that the transmembrane region but not the cytoplasmic domain of CD44 is required for the detergent-insolubility in these cells. No obvious colocalization of CD44 and actin stress fibers was observed before or after treatment with cytochalasin D, and no change in the detergent extraction profile of wild-type and mutant CD44 molecules was effected by cytochalasin D. In equilibrium density sucrose gradients the Triton-insoluble CD44 component was found in the low density fractions, indicating an association with Triton X-100-insoluble lipids.(ABSTRACT TRUNCATED AT 250 WORDS)


Multimodal plasmonic optical fiber grating aptasensor.
Tilted fiber Bragg gratings (TFBGs) are now a well-established technology in the scientific literature, bringing numerous advantages, especially for biodetection. Significant sensitivity improvements are achieved by exciting plasmon waves on their metal-coated surface. Nowadays, a large part of advances in this topic relies on new strategies aimed at providing sensitivity enhancements. In this work, TFBGs are produced in both single-mode and multimode telecommunication-grade optical fibers, and their relative performances are evaluated for refractometry and biosensing purposes. TFBGs are biofunctionalized with aptamers oriented against HER2 (Human Epidermal Growth Factor Receptor-2), a relevant protein biomarker for breast cancer diagnosis. In vitro assays confirm that the sensing performances of TFBGs in multimode fiber are higher or identical to those of their counterparts in single-mode fiber, respectively, when bulk refractometry or surface biosensing is considered. These observations are confirmed by numerical simulations. TFBGs in multimode fiber bring valuable practical assets, featuring a reduced spectral bandwidth for improved multiplexing possibilities enabling the detection of several biomarkers.


Nonparametric permutation tests for functional neuroimaging: a primer with examples.
Requiring only minimal assumptions for validity, nonparametric permutation testing provides a flexible and intuitive methodology for the statistical analysis of data from functional neuroimaging experiments, at some computational expense. Introduced into the functional neuroimaging literature by Holmes et al. ([1996]: J Cereb Blood Flow Metab 16:7-22), the permutation approach readily accounts for the multiple comparisons problem implicit in the standard voxel-by-voxel hypothesis testing framework. When the appropriate assumptions hold, the nonparametric permutation approach gives results similar to those obtained from a comparable Statistical Parametric Mapping approach using a general linear model with multiple comparisons corrections derived from random field theory. For analyses with low degrees of freedom, such as single subject PET/SPECT experiments or multi-subject PET/SPECT or fMRI designs assessed for population effects, the nonparametric approach employing a locally pooled (smoothed) variance estimate can outperform the comparable Statistical Parametric Mapping approach. Thus, these nonparametric techniques can be used to verify the validity of less computationally expensive parametric approaches. Although the theory and relative advantages of permutation approaches have been discussed by various authors, there has been no accessible explication of the method, and no freely distributed software implementing it. Consequently, there have been few practical applications of the technique. This article, and the accompanying MATLAB software, attempts to address these issues. The standard nonparametric randomization and permutation testing ideas are developed at an accessible level, using practical examples from functional neuroimaging, and the extensions for multiple comparisons described. Three worked examples from PET and fMRI are presented, with discussion, and comparisons with standard parametric approaches made where appropriate. Practical considerations are given throughout, and relevant statistical concepts are expounded in appendices.


Diagnostic interpretation of array data using public databases and internet sources.
The range of commercially available array platforms and analysis software packages is expanding and their utility is improving, making reliable detection of copy-number variants (CNVs) relatively straightforward. Reliable interpretation of CNV data, however, is often difficult and requires expertise. With our knowledge of the human genome growing rapidly, applications for array testing continuously broadening, and the resolution of CNV detection increasing, this leads to great complexity in interpreting what can be daunting data. Correct CNV interpretation and optimal use of the genotype information provided by single-nucleotide polymorphism probes on an array depends largely on knowledge present in various resources. In addition to the availability of host laboratories' own datasets and national registries, there are several public databases and Internet resources with genotype and phenotype information that can be used for array data interpretation. With so many resources now available, it is important to know which are fit-for-purpose in a diagnostic setting. We summarize the characteristics of the most commonly used Internet databases and resources, and propose a general data interpretation strategy that can be used for comparative hybridization, comparative intensity, and genotype-based array data.


Analysis of nitroxide spin label motion in a protein-protein complex using multiple frequency EPR spectroscopy.
X- and W-band EPR spectra, at room and low temperatures, are reported for nitroxide spin labels attached to cysteine residues selectively introduced into two proteins, the DNase domain of colicin-E9 and its immunity protein, Im9. The dynamics of each site of attachment on the individual proteins and in the tight DNase-Im9 complex have been analysed by computer simulations of the spectra using a model of Brownian dynamics trajectories for the spin label and protein. Ordering potentials have been introduced to describe mobility of labels restricted by the protein domain. Label mobility varies with position from completely immobilised, to motionally restricted and to freely rotating. Bi-modal dynamics of the spin label have been observed for several sites. We show that W-band spectra are particularly useful for detection of anisotropy of spin label motion. On complex formation significant changes are observed in the dynamics of labels at the binding interface region. This work reveals multi-frequency EPR as a sensitive and valuable tool for detecting conformational changes in protein structure and dynamics especially in protein-protein complexes.


Modulation of striatal projection systems by dopamine.
The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems--so-called direct and indirect pathways--form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D(1) and D(2) DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.


Evolution of woodcutting behaviour in Early Pliocene beaver driven by consumption of woody plants.
Modern beavers (Castor) are prolific ecosystem engineers and dramatically alter the landscape through tree harvesting and dam building. Little is known, however, about the evolutionary drivers of their woodcutting behaviour. Here we investigate if early woodcutting behaviour in Castoridae was driven by nutritional needs. We measured stable carbon and nitrogen isotopes (δ13C and δ15N) of coeval subfossil plants and beaver collagen (Dipoides sp.) from the Early Pliocene, High Arctic Beaver Pond fossil locality (Ellesmere Island), in order to reconstruct Dipoides sp. diet. Isotopic evidence indicates a diet of woody plants and freshwater macrophytes, supporting the hypothesis that this extinct semiaquatic beaver engaged in woodcutting behaviour for feeding purposes. In a phylogenetic context, the isotopic evidence implies that woodcutting and consumption of woody plants can be traced back to a small-bodied, semiaquatic Miocene castorid, suggesting that beavers have been consuming woody plants for over 20 million years. We propose that the behavioural complex (swimming, woodcutting, and consuming woody plants) preceded and facilitated the evolution of dam building. Dam building and food caching behaviours appear to be specializations for cold winter survival and may have evolved in response to late Neogene northern cooling.


Effects of Age and Estradiol on Gene Expression in the Rhesus Macaque Hypothalamus.
The hypothalamus plays a key role in mediating the effects of estrogen on many physiological functions, including reproduction, metabolism, and thermoregulation. We have previously observed marked estrogen-dependent gene expression changes within the hypothalamus of rhesus macaques during aging, especially in the KNDy neurons of the arcuate-median eminence (ARC-ME) that produce kisspeptin, neurokinin B, and dynorphin A. Little is known, however, about the mechanisms involved in mediating the feedback from estrogen onto these neurons. We used quantitative real-time PCR to profile age- and estrogen-dependent gene expression changes in the rhesus macaque hypothalamus. Our focus was on genes that encode steroid receptors (ESR1, ESR2, PGR, and AR) and on enzymes that contribute to the local synthesis of 17β-estradiol (E2; STS, HSD3B1/2, HSD17B5, and CYP19A). In addition, we used RT(2) Profiler™ PCR Arrays to profile a larger set of genes that are integral to hypothalamic function. KISS1, KISS1R, TAC3, and NPY2R mRNA levels increased in surgically menopausal (ovariectomized) old females relative to age-matched ovariectomized animals that received E2 hormone therapy. In contrast, PGR, HSD17B, GNRH2, SLC6A3, KISS1, TAC3, and NPY2R mRNA levels increased after E2 supplementation. The rhesus macaque ARC-ME expresses many genes that are responsive to changes in circulating estrogen levels, even during old age, and these may contribute to causing the normal and pathophysiological changes that occur during menopause.


DNA Methylation of Telomere-Related Genes and Cancer Risk.
Researchers hypothesized that telomere shortening facilitates carcinogenesis. Previous studies found inconsistent associations between blood leukocyte telomere length (LTL) and cancer. Epigenetic reprogramming of telomere maintenance mechanisms may help explain this inconsistency. We examined associations between DNA methylation in telomere-related genes (TRG) and cancer. We analyzed 475 participants providing 889 samples 1 to 3 times (median follow-up, 10.1 years) from 1999 to 2013 in the Normative Aging Study. All participants were cancer-free at each visit and blood leukocytes profiled using the Illumina 450K array. Of 121 participants who developed cancer, 34 had prostate cancer, 10 melanoma, 34 unknown skin malignancies, and 43 another cancer. We examined 2,651 CpGs from 80 TRGs and applied a combination of Cox and mixed models to identify CpGs prospectively associated with cancer (at FDR < 0.05). We also explored trajectories of DNA methylation, logistic regression stratified by time to diagnosis/censoring, and cross-sectional models of LTL at first blood draw. We identified 30 CpGs on 23 TRGs whose methylation was positively associated with cancer incidence (β = 1.0-6.93) and one protective CpG in MAD1L1 (β = -0.65), of which 87% were located in TRG promoters. Methylation trajectories of 21 CpGs increased in cancer cases relative to controls; at 4 to 8 years prediagnosis/censoring, 17 CpGs were positively associated with cancer. Three CpGs were cross-sectionally associated with LTL. TRG methylation may be a mechanism through which LTL dynamics reflect cancer risk. Future research should confirm these findings and explore potential mechanisms underlying these findings, including telomere maintenance and DNA repair dysfunction. Cancer Prev Res; 11(8); 511-22. ©2018 AACR.


Genetic and environmental contributions to carotid intima-media thickness and obesity phenotypes in the Northern Manhattan Family Study.
Both carotid intima-media thickness (IMT) and obesity are independent determinants of stroke and cardiovascular disease. The prevalence of obesity is higher in Hispanics. The genetic basis of IMT and obesity has not been well-characterized in Caribbean Hispanics. The purpose of this study was to examine the genetic and environmental contributions to IMT and obesity in this population. The data included 440 subjects from 77 Caribbean Hispanic families. Mean IMT and maximum IMT were measured in the internal carotid artery, common carotid artery, and carotid bifurcation. The total IMT was calculated as the mean value of IMT at all segments. Obesity phenotypes included body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), and skin-fold thickness. Variance component methods were used to estimate age-adjusted and sex-adjusted heritability. Bivariate analyses were conducted to test for genetic and environmental correlations between IMT and obesity. Heritabilities for IMT ranged from 9% to 40%, with the highest for total maximum IMT and lowest for internal carotid artery maximum IMT. Heritabilities for BMI, waist circumference, WHR, and skin-fold thickness were 44%, 47%, 5%, and 36%, respectively. There were significant genetic, but not environmental, correlations between IMT and BMI, waist circumference, and skin-fold thickness. There were no genetic or environmental correlations between IMT and WHR. We found a substantial genetic contribution to IMT, BMI, waist circumference, and skin-fold thickness. Obesity and IMT may share common genetic factors. Future gene mapping studies are warranted to identify genes predisposing to IMT and obesity in this population.


Preoperative magnetic resonance imaging predicts eligibility for arthroscopic primary anterior cruciate ligament repair.
To assess the role of preoperative magnetic resonance imaging (MRI) on the eligibility for arthroscopic primary anterior cruciate ligament (ACL) repair. All patients undergoing ACL surgery between 2008 and 2017 were included. Patients underwent arthroscopic primary repair if sufficient tissue length and quality were present, or they underwent single-bundle ACL reconstruction. Preoperative MRI tear locations were graded with the modified Sherman classification: type I (>90% distal remnant length), type II (75-90%), or type III (25-75%). MRI tissue quality was graded as good, fair, or poor. Arthroscopy videos were reviewed for tissue length and quality, and final treatment. Sixty-three repair patients and 67 reconstruction patients were included. Repair patients had more often type I tears (41 vs. 4%, p < 0.001) and good tissue quality (89 vs. 12%, p < 0.001). Preoperative MRI tear location and tissue quality predicted eligibility for primary repair: 90% of all type I tears and 88% of type II tears with good tissue quality were repaired, while only 23% of type II tears with fair tissue quality, 0% of type II tears with poor tissue quality, and 14% of all type III tears could be repaired. This study showed that tear location and tissue quality on preoperative MRI can predict eligibility for arthroscopic primary ACL repair. These findings may guide the orthopaedic surgeon on the preoperative assessment for arthroscopic primary repair of proximal ACL tears. Level IV.


Consensus statement on unicompartmental knee replacement: A collaboration between BASK and EKS.
The aim of this study was to deliver consensus recommendations for the clinical practice of unicompartmental knee arthroplasty (UKA). Members of the British Association for Surgery of the Knee (BASK) and European Knee Society (EKS) were invited to attend a joint meeting in London, UK (December 2019). A formal consensus process was undertaken at the meeting incorporating a multiple round Delphi exercise, with group discussion of areas of agreement and disagreement between rounds. Eighty delegates attended the meeting and five consensus statements were considered and revised, with a threshold level of 80% agreement required as the definition consensus. Five consensus statements with accompanying supporting evidence and text were agreed following two rounds of the process: (1) UKA should be offered as a successful alternative to TKA in patients undergoing arthroplasty who meet agreed indications; (2) When consenting a patient for UKA, information including the benefits and risks that are specific to UKA, should be tailored to and discussed with the individual patient; (3) Evidence suggests that surgeons should avoid low-volume use of UKA to optimise outcomes for their patients; (4) Surgeons should use the contemporary evidence-based indications and contraindications for medial UKA; (5) Knee arthroplasty surgeons should have exposure to and training in UKA. The agreed joint BASK-EKS consensus statements on UKA practice are recommended as the contemporary basis of optimal care for these patients and should inform future training and service developments.


Polycystic liver disease presenting as pruritus.
Polycystic liver disease (PCLD) is a rare autosomal dominant disorder which usually occurs in association with autosomal dominant polycystic kidney disease. Biliary obstruction is a rare complication of PCLD. Treatment options include percutaneous aspiration and sclerosis, surgical deroofing of cysts, liver resection or liver transplantation. Medical treatment involves the use of somatostatin analogues or mTOR inhibitors. We present a case of PCLD presenting for the first time with longstanding pruritus as the only symptom.


Parenting Stress, Social Support, and Depression for Ethnic Minority Adolescent Mothers: Impact on Child Development.
Rates of teenage pregnancies are higher for African American and Latina adolescents compared to their White peers. African American and Latina adolescent mothers also experience more adversities than their White peers, such as higher rates of depression, school dropout, and economic disadvantage. Furthermore, children of adolescent mothers are at higher risk for adverse development. Parenting stress and social support can impact outcomes experienced by adolescent parents and their children. The present study examined the influence of adolescent mothers' parenting stress and perceived social support on maternal depression at baseline (six months after birth), and its impact on infant development one year later (18 months after birth). Participants were 180 adolescent mothers of African American or Latino/Hispanic descent. Results suggest that higher levels of parenting stress and less perceived social support were associated with higher levels of depression in the adolescent mothers at baseline. Higher levels of maternal depression were also associated with more developmental delays in infants one year post-baseline. Additionally, depression mediated the relationship between parenting stress and later child outcomes. These findings highlight the importance of examining parenting factors such as parenting stress, social support, and maternal depression in ethnic minority adolescent parents, and provide valuable information regarding unique risk and protective factors associated with positive maternal outcomes for ethnic minority adolescent parents and healthy development for their children.