Value of biomarkers in osteoarthritis: current status and perspectives.
Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the 'omics' (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.


Assessment of Animal-Based Pig Welfare Outcomes on Farm and at the Abattoir: A Case Study.
The study assessed the prevalence of animal-based pig welfare outcomes on one Chilean farm and one abattoir. A total of 198 pens of slaughter pigs (9,049 pigs) were observed on farm and 54 batches (8,843 pigs) were observed at the abattoir. All assessments were conducted from outside the pen on farm and from outside the corridor where pigs were unloaded from the truck at the abattoir. Batch size and number of pigs with ear, tail and skin lesions, hernias, rectal prolapse, bursitis, and lameness were recorded. Data were analyzed using generalized linear mixed models. There was a large variation among pens on farm and among batches at the abattoir for all outcomes. Bursitis was the most prevalent outcome recorded in both locations, followed by ear lesions recorded on farm and by tail lesions recorded at the abattoir. Ear lesions' prevalence was higher on farm (P < 0.001), while tail lesions, hernia, and bursitis prevalence were higher at the abattoir (P < 0.001). Ear lesions' prevalence on farm was higher in female and mixed-sex groups than in male groups (P < 0.01), but male groups tended to have a higher tail lesions' prevalence (P < 0.1). The results show a difference in welfare outcomes, suggesting that assessment of outcomes on farm could complement ante-mortem inspections at the abattoir. However, as the same animals were not inspected in the two locations and there is the possibility of a seasonal influence on the results, the findings should be interpreted with caution and further research is required.


A randomized, prospective pilot comparison of 3 atrial appendage elimination techniques: Internal ligation, stapled excision, and surgical excision.
Elimination of the left atrial appendage (LAA) attempts to reduce stroke in patients with atrial fibrillation (AF). A retrospective review suggests that various surgical techniques are often unsuccessful and may leave a stump or gap. In a pilot study, we prospectively evaluated 3 surgical techniques with long-term follow up to define effectiveness. At a single institution, 28 patients undergoing concomitant AF surgery were randomized prospectively into 1 of 3 techniques of LAA elimination: internal suture ligation (IL), external stapled excision (StEx), and surgical excision (SxEx). The success of LAA elimination was assessed by transesophageal echocardiography (TEE) in all patients at the time of surgery. Failure of LAA closure consisted of either a stump (residual appendage tissue >1 cm in maximum length) or a gap (persistent flow between the left atrium [LA] and the LAA). Failure was treated intraoperatively when recognized. Late follow-up was obtained using a TEE at a mean of 0.4 years in 21/28 (75%) of patients. Early failure was recognized and treated in 1 patient in the IL group (13%), 6 patients in the StEx group (60%), and 2 patients in the SxEx group (20%) (P = .06). On follow-up TEE, 4 of 7 patients in the IL group (57%) had developed gaps, 3 of whom (43%) with greater than mild flow. No patients in the StEx or SxEx groups had a gap (P = .03). In late follow-up, 1 of 7 patients in the IL group (14%) had a stump, compared with 2 of 8 (25%) in the StEx group and 3 of 6 (50%) in the SxEx group (P = .35). The overall failure rate was 57%: 5 of 8 (63%) in the IL group, 6 of 10 (60%) in the StEx group, and 5 of 10 (50%) in the SxEx group (P = .85). No patient had a stroke at any time during follow-up. LAA elimination is often incomplete and goes undetected. If the LAA is eliminated at the time of surgery, then TEE should be used intraoperatively to assess effectiveness and reintervention performed if warranted. Late assessment for completeness of closure should be considered before cessation of anticoagulation until more effective LAA techniques can be developed.


Sexual dimorphism in the subadult mandible: quantification using geometric morphometrics.
There have been numerous attempts, with varying degrees of success, to differentiate males from females on the basis of the immature skeleton. We investigate here whether the mandible can discriminate immature individuals by sex; the techniques we apply are from the field of geometric morphometrics. The application of these methods in forensic anthropology is still relatively new; thus, an important aspect of this research is that it demonstrates potential applications in this discipline. The sample comprises 96 known age and sex subadult individuals; the three-dimensional coordinates of 38 landmarks are analyzed using the shape analysis software morphologika. Multivariate regressions indicated no significant sexual dimorphism in the subadult sample; this result is supported by poor cross-validated classification accuracy (59%). Our results suggest that the subadult mandible is not dimorphic (to the extent that dimorphism is not evident within the sample we studied); thus, sex determination using previously described criteria is likely to yield poor results.


Mechanisms of sodium/calcium selectivity in sodium channels probed by cysteine mutagenesis and sulfhydryl modification.
A conserved lysine residue in the "P loop" of domain III renders sodium channels highly selective. Conversion of this residue to glutamate, to mimic the homologous position in calcium channels, enables Ca2+ to permeate sodium channels. Because the lysine-to-glutamate mutation converts a positively charged side chain to a negative one, it has been proposed that a positive charge at this position suffices for Na+ selectivity. We tested this idea by converting the critical lysine to cysteine (K1237C) in mu 1 rat skeletal sodium channels expressed in Xenopus oocytes. Selectivity of the mutant channels was then characterized before and after chemical modification to alter side-chain charge. Wild-type channels are highly selective for Na+ over Ca2+ (PCa/PNa < 0.01). The K1237C mutation significantly increases permeability to Ca2+ (PCa/PNa = 0.6) and Sr2+. Analogous mutations in domains I (D400C), II (E755C), and IV (A1529C) did not alter the selectivity for Na+ over Ca2+, nor did any of the domain IV mutations (G1530C, W1531C, and D1532C) that are known to affect monovalent selectivity. Interestingly, the increase in permeability to Ca2+ in K1237C cannot be reversed by simply restoring the positive charge to the side chain by using the sulfhydryl modifying reagent methanethiosulfonate ethylammonium. Single-channel studies confirmed that modified K1237C channels, which exhibit a reduced unitary conductance, remain permeable to Ca2+, with a PCa/PNa of 0.6. We conclude that the chemical identity of the residue at position 1237 is crucial for channel selectivity. Simply rendering the 1237 side chain positive does not suffice to restore selectivity to the channel.


Association Between Preoperative Fibrinogen-to-Albumin Ratio and All-Cause Mortality After Off-Pump Coronary Artery Bypass Grafting: A Retrospective Observational Study.
The fibrinogen-to-albumin ratio (FAR) is a recently introduced prognostic marker for patients with coronary artery disease. The present study investigated whether the FAR is associated with clinical outcome after off-pump coronary artery bypass grafting (OPCAB). We retrospectively reviewed 1759 patients who underwent OPCAB (median duration of follow-up, 46 months). To evaluate the association between FAR and mortality in OPCAB patients, time-dependent coefficient Cox regression analyses were used to assess the association between FAR and all-cause mortality. In multivariable time-dependent coefficient Cox regression analyses, preoperative FAR was an independent risk factor for all-cause mortality after OPCAB (adjusted hazard ratio, 1.051; 95% confidence interval, 1.021-1.082). In the restricted cubic spline function curve of the multivariable-adjusted relationship between the preoperative FARs, a linear increase in the relative hazard for all-cause mortality was observed as the FAR increased (P = .001). A higher FAR is associated with increased all-cause mortality after OPCAB. The preoperative FAR could be a prognostic factor for predicting higher mortality after OPCAB.


Reelin activates SRC family tyrosine kinases in neurons.
Reelin is a large signaling molecule that regulates the positioning of neurons in the mammalian brain. Transmission of the Reelin signal to migrating embryonic neurons requires binding to the very-low-density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor-2 (apoER2). This induces tyrosine phosphorylation of the adaptor protein Disabled-1 (Dab1), which interacts with a shared sequence motif in the cytoplasmic tails of both receptors. However, the kinases that mediate Dab1 tyrosine phosphorylation and the intracellular pathways that are triggered by this event remain unknown. We show that Reelin activates members of the Src family of non-receptor tyrosine kinases (SFKs) and that this activation is dependent on the Reelin receptors apoER2 and VLDLR and the adaptor protein Dab1. Dab1 is tyrosine phosphorylated by SFKs, and the kinases themselves can be further activated by phosphorylated Dab1. Increased Dab1 protein expression in fyn-deficient mice implies a response to impaired Reelin signaling that is also observed in mice lacking Reelin or its receptors. However, fyn deficiency alone does not compound the neuronal positioning defect of vldlr- or apoer2-deficient mice, and this finding suggests functional compensation by other SFKs. Our results show that Dab1 is a physiological substrate as well as an activator of SFKs in neurons. Based on genetic evidence gained from multiple strains of mutant mice with defects in Reelin signaling, we conclude that activation of SFKs is a normal part of the cellular Reelin response.


Decision support systems for personalized and participative radiation oncology.
A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models 'learn' using advanced and innovative information technologies (ideally in a distributed fashion - please watch the animation: http://youtu.be/ZDJFOxpwqEA) from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multi-faceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re-evaluated (through quality assurance procedures) in different patient datasets in order to refine and re-optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine.


A hydrodynamic comparison of solution and gas phase proteins and their complexes.
The extent to which protein structures are preserved on transfer from solution to gas phase is a central question for native mass spectrometry. Here we compare the collision cross sections (Ω) of a wide range of different proteins and protein complexes (15-500 kDa) with their corresponding Stokes radii (RS). Using these methods, we find that Ω and RS are well correlated, implying overall preservation of protein structure in the gas phase. Accounting for protein hydration, a scaling term is required to bring Ω and RS into parity. Interestingly, the magnitude of this scaling term agrees almost entirely with the drag factor proposed by Millikan. RS were then compared with various different predicted values of Ω taken from their atomic coordinates. We find that many of the approaches used to obtained Ω from atomic coordinates miscalculate the physical sizes of the proteins in solution by as much as 20%. Rescaling of Ω estimated from atomic coordinates may therefore seem appropriate as a general method to bring theoretical values in line with those observed in solution.


Pattern of depressive symptoms in Parkinson's disease.
Depressive symptoms are common in Parkinson's disease (PD); however, it is unclear whether there are specific depressive symptom patterns in patients with PD and comorbid depression (dPD). The goal of this study is to examine the frequency and correlates of specific depressive symptoms in PD. A sample of 158 individuals with PD completed the self-rated Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS). By multiple-regression analysis, the authors examined the association between HANDS total and subscale scores and various demographic variables. The frequency of depression was 37% (N=58). Patients with a history of depression before PD had significantly more serious depression than those who had no such history. Of those who were more depressed, the most common symptoms of depression endorsed were low energy, difficulty with concentration/making decisions, feeling blue, feeling hopeless, and having poor sleep. There is a relatively high prevalence of dPD. Items on the HANDS that discriminated best between depressed and nondepressed subjects with PD included feeling blue, feeling hopeless, feeling worthless, lack of interest, and self-blame. It remains to be defined whether dPD should be understood primarily as a psychological reaction to a physical disability or perceived impending one, or as a direct expression of the neuropathology of PD.


ACE gene and physical activity, blood pressure, and hypertension: a population study in Finland.
The study evaluated the association of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene (ACE I/D) with self-reported moderate-intensity leisure time physical activity (MILTPA), arterial blood pressure (BP) and history of hypertension (HT). A representative population-based sample of 721 middle-aged adults (358 women) from two areas of Finland was genotyped for the ACE I/D. After exclusion criteria were applied, 455 subjects (288 women) were selected for the analysis. The distribution of the ACE I/D genotypes did not differ significantly among frequent vs. nonfrequent MILTPA groups (chi(2) = 2.556; df = 2; P value = 0.279). The main predictors of BP were male gender, age, body mass index, and arterial pulse. Additionally, tobacco smoking and alcohol consumption also had a significant main effect on diastolic BP. HT was significantly more frequent in subjects with obesity, family history of cardiovascular disease, or lower educational level. As for BP, neither ACE I/D nor MILTPA was associated with HT. The study confirmed recent reports from population-based studies of no association between ACE I/D and physical fitness. The study also confirmed a lack of association between ACE I/D and BP or HT.


In vitro colonic metabolism of coffee and chlorogenic acid results in selective changes in human faecal microbiota growth.
Coffee is a relatively rich source of chlorogenic acids (CGA), which, as other polyphenols, have been postulated to exert preventive effects against CVD and type 2 diabetes. As a considerable proportion of ingested CGA reaches the large intestine, CGA may be capable of exerting beneficial effects in the large gut. Here, we utilise a stirred, anaerobic, pH-controlled, batch culture fermentation model of the distal region of the colon in order to investigate the impact of coffee and CGA on the growth of the human faecal microbiota. Incubation of coffee samples with the human faecal microbiota led to the rapid metabolism of CGA (4 h) and the production of dihydrocaffeic acid and dihydroferulic acid, while caffeine remained unmetabolised. The coffee with the highest levels of CGA (P<0·05, relative to the other coffees) induced a significant increase in the growth of Bifidobacterium spp. relative to the control vessel at 10 h after exposure (P<0·05). Similarly, an equivalent quantity of CGA (80·8 mg, matched with that in high-CGA coffee) induced a significant increase in the growth of Bifidobacterium spp. (P<0·05). CGA alone also induced a significant increase in the growth of the Clostridium coccoides-Eubacterium rectale group (P<0·05). This selective metabolism and subsequent amplification of specific bacterial populations could be beneficial to host health.


Slow [Ca2+]i oscillations induced by ketoisocaproate in single mouse pancreatic islets.
The effect of alpha-ketoisocaproate (KIC), the first catabolic metabolite of the amino acid leucine, on [Ca2+]i, insulin release, and membrane potential was measured in mouse pancreatic islets of Langerhans. Stimulatory concentrations of KIC (2.5-10 mmol/l) caused slow oscillations of [Ca2+]i and cyclic variations of the membrane potential. Slow [Ca2+]i oscillations depended on extracellular calcium. Simultaneous measurements of [Ca2+]i and insulin release resolved pulsatile insulin secretion that paralleled slow [Ca2+]i oscillations. Whereas 11 mmol/l glucose induced a significant increase in cAMP, KIC was unable to modify it. Glucagon (10 nmol/l), which significantly increased cAMP in mouse islets, also increased the frequency of glucose-induced fast [Ca2+]i oscillations. However, neither glucagon (10 nmol/l) nor dibutyryl cAMP (1 mmol/l) was able to change the slow oscillation pattern into a fast pattern. Imaging of Ca2+ showed that KIC-induced slow oscillations were synchronic throughout the whole islet. It is suggested that beta-cell electrical activity plays a role in the origin of slow [Ca2+]i oscillations.


Development of an Algorithm to Distinguish Smoldering Versus Symptomatic Multiple Myeloma in Claims-Based Data Sets.
The distinction of patients with symptomatic multiple myeloma (MM) from those with smoldering MM poses a challenge for researchers who use administrative databases. Historically, researchers either have included all patients or used treatment receipt as the distinguishing factor; both methods have drawbacks. We present an algorithm for distinguishing between symptomatic and smoldering MM using ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes for the classic defining events of symptomatic MM commonly referred to as the CRAB criteria (hypercalcemia, renal impairment, anemia, and bone lesions). SEER-Medicare-linked data from 4,187 patients with MM diagnosed between 2007 and 2011 were used for this analysis. Eighty-four percent had ICD-9-CM codes consistent with CRAB criteria, whereas only 57% received treatment. Overall survival of patients with symptomatic MM defined as receipt of treatment was 32.3 months versus 26.6 months for the overall population and 22.9 months for patients with symptomatic MM defined by CRAB criteria. Conceptually, removal of patients with smoldering MM should result in a reduction in overall survival; however, the cohort of patients who received treatment tended to be younger and healthier than the overall population, which could have skewed the results. The algorithm we present resulted in a larger and more representative sample than classification by treatment status and reduced potential bias that could result from including all patients with smoldering MM in the analysis. Although this study was performed using the SEER-Medicare database, the methodology was broad enough that the algorithm could be extended to additional claims-based data sets with relative ease.


Clear cell odontogenic carcinoma of the mandible: a treatment strategy.
Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic tumor of the jaws, histologically characterized by the presence of agglomerates of cells with eosinophilic cytoplasm. The patient, a 62-year-old Caucasian woman, presented an intraosseous lesion in the mandibular symphysis. A clinical examination revealed a discrete volumetric increase with a hard consistency, palpable to extraoral and intraoral examinations. Imaging studies revealed an extensive radiolucent area, without defined limits, extending from the region of the right second premolar to the left canine. Incisional biopsy analysis indicated a diagnosis of CCOC. The treatment proposed was segmental resection of the mandible with a safety margin. After six months without recurrence, definitive mandibular reconstruction was performed using an iliac crest graft, followed by rehabilitation with implant-supported denture after five months. After three years of post-resection follow-up, the patient has shown no evidence of recurrence or metastasis. She continues to be under follow-up. To conclude, CCOC must be considered a malignant tumor with aggressive behavior. Previous studies have shown that resection with free margins is a treatment with a lower rate of recurrence. Nevertheless, long-term follow-up is necessary for such patients.


Disease-specific genomic analysis: identifying the signature of pathologic biology.
Genomic high-throughput technology generates massive data, providing opportunities to understand countless facets of the functioning genome. It also raises profound issues in identifying data relevant to the biology being studied. We introduce a method for the analysis of pathologic biology that unravels the disease characteristics of high dimensional data. The method, disease-specific genomic analysis (DSGA), is intended to precede standard techniques like clustering or class prediction, and enhance their performance and ability to detect disease. DSGA measures the extent to which the disease deviates from a continuous range of normal phenotypes, and isolates the aberrant component of data. In several microarray cancer datasets, we show that DSGA outperforms standard methods. We then use DSGA to highlight a novel subdivision of an important class of genes in breast cancer, the estrogen receptor (ER) cluster. We also identify new markers distinguishing ductal and lobular breast cancers. Although our examples focus on microarrays, DSGA generalizes to any high dimensional genomic/proteomic data.


Generalist solutions to complex problems: generating practice-based evidence--the example of managing multi-morbidity.
A growing proportion of people are living with long term conditions. The majority have more than one. Dealing with multi-morbidity is a complex problem for health systems: for those designing and implementing healthcare as well as for those providing the evidence informing practice. Yet the concept of multi-morbidity (the presence of >2 diseases) is a product of the design of health care systems which define health care need on the basis of disease status. So does the solution lie in an alternative model of healthcare? Strengthening generalist practice has been proposed as part of the solution to tackling multi-morbidity. Generalism is a professional philosophy of practice, deeply known to many practitioners, and described as expertise in whole person medicine. But generalism lacks the evidence base needed by policy makers and planners to support service redesign. The challenge is to fill this practice-research gap in order to critically explore if and when generalist care offers a robust alternative to management of this complex problem. We need practice-based evidence to fill this gap. By recognising generalist practice as a 'complex intervention' (intervening in a complex system), we outline an approach to evaluate impact using action-research principles. We highlight the implications for those who both commission and undertake research in order to tackle this problem. Answers to the complex problem of multi-morbidity won't come from doing more of the same. We need to change systems of care, and so the systems for generating evidence to support that care. This paper contributes to that work through outlining a process for generating practice-based evidence of generalist solutions to the complex problem of person-centred care for people with multi-morbidity.


Psychological risk factors for chronic post-surgical pain after inguinal hernia repair surgery: a prospective cohort study.
A significant proportion of patients experience chronic post-surgical pain (CPSP) following inguinal hernia surgery. Psychological models are useful in predicting acute pain after surgery, and in predicting the transition from acute to chronic pain in non-surgical contexts. This is a prospective cohort study to investigate psychological (cognitive and emotional) risk factors for CPSP after inguinal hernia surgery. Participants were asked to complete questionnaires before surgery and 1 week and 4 months after surgery. Data collected before surgery and 1 week after surgery were used to predict pain at 4 months. Psychological risk factors assessed included anxiety, depression, fear-avoidance, activity avoidance, catastrophizing, worry about the operation, activity expectations, perceived pain control and optimism. The study included 135 participants; follow-up questionnaires were returned by 119 (88.1%) and 115 (85.2%) participants at 1 week and 4 months after surgery respectively. The incidence of CPSP (pain at 4 months) was 39.5%. After controlling for age, body mass index and surgical variables (e.g. anaesthetic, type of surgery and mesh type used), lower pre-operative optimism was an independent risk factor for CPSP at 4 months; lower pre-operative optimism and lower perceived control over pain at 1 week after surgery predicted higher pain intensity at 4 months. No emotional variables were independently predictive of CPSP. Further research should target these cognitive variables in pre-operative psychological preparation for surgery.


Root-specific transcript profiling of contrasting rice genotypes in response to salinity stress.
Elevated salinity imposes osmotic and ion toxicity stresses on living cells and requires a multitude of responses in order to enable plant survival. Building on earlier work profiling transcript levels in rice (Oryza sativa) shoots of FL478, a salt-tolerant indica recombinant inbred line, and IR29, a salt-sensitive cultivar, transcript levels were compared in roots of these two accessions as well as in the roots of two additional salt-tolerant indica genotypes, the landrace Pokkali and the recombinant inbred line IR63731. The aim of this study was to compare transcripts in the sensitive and the tolerant lines in order to identify genes likely to be involved in plant salinity tolerance, rather than in responses to salinity per se. Transcript profiles of several gene families with known links to salinity tolerance are described (e.g. HKTs, NHXs). The putative function of a set of genes identified through their salt responsiveness, transcript levels, and/or chromosomal location (i.e. underneath QTLs for salinity tolerance) is also discussed. Finally, the parental origin of the Saltol region in FL478 is further investigated. Overall, the dataset presented appears to be robust and it seems likely that this system could provide a reliable strategy for the discovery of novel genes involved in salinity tolerance.


Derivation of human embryonic stem cell lines from biopsied blastomeres on human feeders with minimal exposure to xenomaterials.
In a continuous effort to improve the generation of therapeutic grade human embryonic stem cell (hESC) lines, we focused on preserving developmental capacity of the embryos, minimizing the exposure to xenomaterials, increasing derivation efficacy, and reducing the complexity of the derivation procedure. In this study, we describe an improved method for efficient derivation of hESC lines from blastomeres of biopsied embryos. Our protocol substituted feeder cells of mouse origin with human foreskin fibroblasts (HFFs), limited serum exposure of cells to formation of the initial outgrowth, and increased derivation efficacy from 12.5% (one hESC line out of 13 biopsies) to 50% (3 out of 6 biopsies) by using early population doubling (PD) HFFs. In addition, it eliminated a need for embryo-blastomere coculture, thus reducing the complexity of the culture and enabling continued development of the biopsied embryo under optimal conditions. All derived lines maintained normal karyotype and expressed totipotent phenotype including the ability to differentiate into trophectoderm and all three germ layers.


Physical activity energy expenditure and cardiometabolic health in three rural Kenyan populations.
Physical activity is beneficial for metabolic health but the extent to which this may differ by ethnicity is still unclear. Here, the objective was to characterize the association between physical activity energy expenditure (PAEE) and cardiometabolic risk among the Luo, Kamba, and Maasai ethnic groups of rural Kenya. In a cross-sectional study of 1084 rural Kenyans, free-living PAEE was objectively measured using individually-calibrated heart rate and movement sensing. A clustered metabolic syndrome risk score (zMS) was developed by averaging the sex-specific z-scores of five risk components measuring central adiposity, blood pressure, lipid levels, glucose tolerance, and insulin resistance. zMS was 0.08 (-0.09; -0.06) SD lower for every 10 kJ/kg/day difference in PAEE after adjustment for age and sex; this association was modified by ethnicity (interaction with PAEE P < 0.05). When adjusted for adiposity, each 10 kJ/kg/day difference in PAEE was predicted to lower zMS by 0.04 (-0.05, -0.03) SD, without evidence of interaction by ethnicity. The Maasai were predicted to have higher cardiometabolic risk than the Kamba and Luo at every quintile of PAEE, with a strong dose-dependent decreasing trend among all ethnicities. Free-living PAEE is strongly inversely associated with cardiometabolic risk in rural Kenyans. Differences between ethnic groups in this association were observed but were explained by differences in central adiposity. Therefore, targeted interventions to increase PAEE are more likely to be effective in subgroups with high central adiposity, such as Maasai with low levels of PAEE.


Artificial Intelligence in Lung Cancer Pathology Image Analysis.
Accurate diagnosis and prognosis are essential in lung cancer treatment selection and planning. With the rapid advance of medical imaging technology, whole slide imaging (WSI) in pathology is becoming a routine clinical procedure. An interplay of needs and challenges exists for computer-aided diagnosis based on accurate and efficient analysis of pathology images. Recently, artificial intelligence, especially deep learning, has shown great potential in pathology image analysis tasks such as tumor region identification, prognosis prediction, tumor microenvironment characterization, and metastasis detection. In this review, we aim to provide an overview of current and potential applications for AI methods in pathology image analysis, with an emphasis on lung cancer. We outlined the current challenges and opportunities in lung cancer pathology image analysis, discussed the recent deep learning developments that could potentially impact digital pathology in lung cancer, and summarized the existing applications of deep learning algorithms in lung cancer diagnosis and prognosis. With the advance of technology, digital pathology could have great potential impacts in lung cancer patient care. We point out some promising future directions for lung cancer pathology image analysis, including multi-task learning, transfer learning, and model interpretation.


USING PARTICIPATORY METHODS AND GEOGRAPHIC INFORMATION SYSTEMS (GIS) TO PREPARE FOR AN HIV COMMUNITY-BASED TRIAL IN VULINDLELA, SOUTH AFRICA (Project Accept-HPTN 043).
Recent attempts to integrate geographic information systems (GIS) and participatory techniques, have given rise to terminologies such as participatory GIS and community-integrated GIS. Although GIS was initially developed for physical geographic application, it can be used for the management and analysis of health and health care data. Geographic information systems, combined with participatory methodology, have facilitated the analysis of access to health facilities and disease risk in different populations. Little has been published about the usefulness of combining participatory methodologies and GIS technology in an effort to understand and inform community-based intervention studies, especially in the context of HIV. This article attempts to address this perceived gap in the literature. The authors describe the application of participatory research methods with GIS in the formative phase of a multisite community-based social mobilization trial, using voluntary counseling and testing and post-test support as the intervention.


Phytochemicals: cancer chemoprevention and suppression of tumor onset and metastasis.
Carcinogenesis is a multi-step process which could be prevented by phytochemicals. Phytochemicals from dietary plants and other plant sources such as herbs are becoming increasingly important sources of anticancer drugs or compounds for cancer chemoprevention or adjuvant chemotherapy. Phytochemicals can prevent cancer initiation, promotion, and progression by exerting anti-inflammatory and anti-oxidative stress effects which are mediated by integrated Nrf2, NF-kappaB, and AP-1 signaling pathways. In addition, phytochemicals from herbal medicinal plants and/or some dietary plants developed in recent years have been shown to induce apoptosis in cancer cells and inhibition of tumor growth in vivo. In advanced tumors, a series of changes involving critical signaling molecules that would drive tumor cells undergoing epithelial-mesenchymal transition and becoming invasive. In this review, we will discuss the potential molecular targets and signaling pathways that mediate tumor onset and metastasis. In addition, we will shed light on some of the phytochemicals that are capable of targeting these signaling pathways which would make them potentially applicable to cancer chemoprevention, treatment and control of cancer progression.


Implications of pannexin 1 and pannexin 3 for keratinocyte differentiation.
Pannexin (Panx) 1 and Panx3 are integral membrane proteins that share some sequence homology with the innexin family of invertebrate gap junctions. They are expressed in mammalian skin. Pannexins have been reported to form functional mechanosensitive single-membrane channels, but their importance in regulating cellular function is poorly understood. In this study, Panx1 and Panx3 were detected in the epidermis of 13.5 day embryonic mice. Compared with newborn mice, there was less Panx1 expression in both thin and thick murine skin, whereas Panx3 expression was unchanged. To investigate the role of pannexins in keratinocyte differentiation, we employed rat epidermal keratinocytes (REKs) that have the capacity to differentiate into organotypic epidermis, and engineered them to overexpress Panx1, Panx1-GFP or Panx3. The expression of Panx1 or Panx3 resulted in the increased ability of REKs to take up dye, suggesting that cell-surface channels were formed. Compared with monolayer REKs, endogenous Panx1 levels remained unchanged, whereas the 70 kDa immunoreactive species of Panx3 was greatly increased in the organotypic epidermis. In monolayer cultures, ectopic Panx1 and Panx1-GFP localized to the plasma membrane, whereas Panx3 displayed both intracellular and plasma-membrane profiles. Although both pannexins reduced cell proliferation, only Panx1 disrupted the architecture of the organotypic epidermis and markedly dysregulated cytokeratin 14 expression and localization. Furthermore, ectopic expression of only Panx1 reduced the vital layer thickness of the organotypic epidermis. In summary, Panx1 and Panx3 are coexpressed in the mammalian epidermis, and the regulation of Panx1 plays a key role in keratinocyte differentiation.


Technique for the Characterization of Phospholipid Microbubbles Coatings by Transmission Electron Microscopy.
Gas microbubbles stabilized by a surfactant or polymer coating are of considerable clinical interest because of their imaging and drug delivery potential under ultrasound exposure. The utility of microbubbles for a given application is intrinsically linked to their structure and stability. These in turn are highly sensitive to coating composition and fabrication techniques. Various methods including fluorescence and atomic force microscopy have been applied to characterize microbubble properties, but direct observation of coating structure at the nanoscale still poses a considerable challenge. Here we describe a transmission electron microscopy (TEM) technique to observe the surface of microbubbles. Images from a series of phospholipid-coated microbubble systems, including those decorated with nanoparticles, are presented. They indicate that the technique enables visualization of the coating structure, in particular lipid discontinuities and nanoparticle distribution. This information can be used to better understand how microbubble surface structure relates to formulation and/or processing technique and ultimately to functionality.


Assessing delivery and quantifying efficacy of small interfering ribonucleic acid therapeutics in the skin using a dual-axis confocal microscope.
Transgenic reporter mice and advances in imaging instrumentation are enabling real-time visualization of cellular mechanisms in living subjects and accelerating the development of novel therapies. Innovative confocal microscope designs are improving their utility for microscopic imaging of fluorescent reporters in living animals. We develop dual-axis confocal (DAC) microscopes for such in vivo studies and create mouse models where fluorescent proteins are expressed in the skin for the purpose of advancing skin therapeutics and transdermal delivery tools. Three-dimensional image volumes, through the different skin compartments of the epidermis and dermis, can be acquired in several seconds with the DAC microscope in living mice, and are comparable to histologic analyses of reporter protein expression patterns in skin sections. Intravital imaging with the DAC microscope further enables visualization of green fluorescent protein (GFP) reporter gene expression in the skin over time, and quantification of transdermal delivery of small interfering RNA (siRNA) and therapeutic efficacy. Visualization of transdermal delivery of nucleic acids will play an important role in the development of innovative strategies for treating skin pathologies.


Cross-cultural comparison of the perceptions and experiences of dementia care mapping "mappers" in the United States and the United Kingdom.
Survey results from 161 respondents trained in dementia care mapping (DCM) in the United States and United Kingdom (82 and 79 respondents, respectively) addressed the following: (a) To what extent are mappers using DCM? (b) How satisfied are mappers with DCM? (c) What affect does DCM have on mappers' attitudes toward their dementia practice? and (d) What challenges are encountered by mappers in the use of DCM? Analyses using odds ratios were used to make international and training-level (basic vs. advanced) comparisons. Differences across countries were found in use of DCM and lack of satisfaction using DCM codes. Similarities were found with positive affects of DCM on attitudes and lack of time for DCM. Differences in mappers' experiences and perceptions exist across the two countries, warranting increased attention to the cultural contexts within which mappers are situated and how these affect the implementation of DCM within a country.


[Fever after a tick bite: clinical manifestations and diagnosis of acute tick bite-associated infections in northeastern Switzerland].
Different tick-borne infections can cause an acute febrile illness. The study objectives were to investigate the clinical manifestations and diagnosis of infections among patients who presented with fever after a tick-bite, and to detect newly described pathogens, including Ehrlichia, Babesia and Rickettsia helvetica, in North-Eastern Switzerland. : We studied 75 patients (41 male, 34 female, median age 38 years, among them 10 children) who had fever within 3 weeks after a tick-bite. Paired sera were tested for antibodies to Borrelia burgdorferi, tick-borne encephalitis virus, Anaplasma (Ehrlichia) phagocytophila, Babesia microti, B. divergens, and Rickettsia helvetica. In addition, microscopy and polymerase chain reaction was used to detect Ehrlichia. Clinical data were obtained at baseline and at 1 and 2 year follow-up. Tick-borne infections were confirmed or possible in 36 (48 %) patients: 7 (9 %) Erythema migrans, 6 (8 %) other specific manifestations of Lyme borreliosis, 6 (8 %) Lyme borreliosis presenting as non-specific febrile illness, 8 (11 %) tick-borne encephalitis, 7 (10 %) granulocytic ehrlichiosis, 1 B. microti infection in a traveler from the US and 6 (8 %) dual infections. In 8 (11 %) patients serological findings were suggesting possible acute or past R. helvetica infection. Among patients with fever after a tick-bite, Lyme borreliosis was most frequently found. There was no evidence for babesiosis among the resident population. Serologic data suggest that human granulocytic ehrlichiosis and R. helvetica infections may be endemic in Switzerland. Among 50 % of the patients no tick-borne infections could be diagnosed.


BRCA1 germline mutations and polymorphisms in a clinic-based series of ovarian cancer cases: a Gynecologic Oncology Group study.
The aims of this study were to determine the frequency of BRCA1 gene alterations in an unselected, clinic-based series of ovarian cancer cases; to evaluate the usefulness of family history in predicting the likelihood of a disease-causing mutation; and to document the occurrence of polymorphic variants in BRCA1 and to determine their distribution among families accordingly to history of breast and/or ovarian cancer. Two hundred fifty-eight women with primary epithelial ovarian cancer, entered onto a nonclinical protocol of the Gynecologic Oncology Group, were analyzed for BRCA1 germline alterations by single-strand conformation polymorphism analysis. Protein-truncating mutations in BRCA1 were identified in 12 patients (4.6%). The median age of cancer diagnosis in BRCA1 mutation carriers was 47 years compared to 57 years in patients without mutations (P = 0.02). All but 1 of the patients with BRCA1 mutations reported a family history of breast and/or ovarian cancer and 8 had a first-degree relative with cancer. Twelve mutations of unknown significance were also identified. An association was also noted between the presence of common polymorphisms in BRCA1 and family history of cancer. Polymorphisms were present at higher frequency among women without a family history of cancer compared to women with positive family histories, suggesting they are associated with reduced risk. In a clinic-based series of ovarian cancer patients, germline BRCA1 mutations were detected in 12 of 258 (4.6%) patients. A strong correlation was noted between the presence of mutations and family history of breast and/or ovarian cancer, indicating that these women are most likely to benefit from genetic susceptibility testing.


Physiologic benefits of mechanical insufflation-exsufflation in children with neuromuscular diseases.
To analyze the physiologic effects and tolerance of mechanical insufflation-exsufflation (MI-E) by means of mechanical cough assistance (Cough Assist; JH Emerson Company; Cambridge, MA) for children with neuromuscular disease. Prospective clinical trial. Physiology laboratory of a pediatric pulmonary department of a university hospital. Seventeen children with Duchenne muscular dystrophy (n = 4), spinal muscular atrophy (n = 4), or other congenital myopathy (n = 9) who were in a stable state. Pressures of 15, 30, and 40 cm H(2)O were cycled to each patient, with 2 s for insufflation and 3 s for exsufflation. One application consisted of six cycles at each pressure for a total of three applications. Airway pressure and airflow were measured during every application. Breathing pattern, vital capacity (VC), sniff nasal inspiratory pressure (SNIP), peak expiratory flow (PEF), and respiratory comfort were evaluated at baseline and after each application. The tolerance of the patients was excellent, with a significant increase in the respiratory comfort score in all of the patients (p = 0.02). Expired volume during the MI-E application increased significantly to reach twice the VC at 40 cm H(2)O. Mean and maximal inspiratory and expiratory flows increased in a pressure-dependent manner. Breathing pattern did not change after the MI-E applications and pulse oximetric saturation remained stable within normal values, but the mean end-tidal carbon dioxide pressure decreased significantly. VC did not change, but the mean SNIP and PEF improved significantly after MI-E applications. Our results confirm the good tolerance and physiologic short-term benefit of the MI-E in children with neuromuscular disease who were in a stable state.


InnateDB: systems biology of innate immunity and beyond--recent updates and continuing curation.
InnateDB (http://www.innatedb.com) is an integrated analysis platform that has been specifically designed to facilitate systems-level analyses of mammalian innate immunity networks, pathways and genes. In this article, we provide details of recent updates and improvements to the database. InnateDB now contains >196 000 human, mouse and bovine experimentally validated molecular interactions and 3000 pathway annotations of relevance to all mammalian cellular systems (i.e. not just immune relevant pathways and interactions). In addition, the InnateDB team has, to date, manually curated in excess of 18 000 molecular interactions of relevance to innate immunity, providing unprecedented insight into innate immunity networks, pathways and their component molecules. More recently, InnateDB has also initiated the curation of allergy- and asthma-related interactions. Furthermore, we report a range of improvements to our integrated bioinformatics solutions including web service access to InnateDB interaction data using Proteomics Standards Initiative Common Query Interface, enhanced Gene Ontology analysis for innate immunity, and the availability of new network visualizations tools. Finally, the recent integration of bovine data makes InnateDB the first integrated network analysis platform for this agriculturally important model organism.


The soy effect in the disease models of nonbacterial prostatitis and obstructive voiding.
The goal of this study was to improve the understanding of the potential significance of dietary soy for human health by investigating its effects in the animal models of nonbacterial prostatitis and urethral obstruction. Nonbacterial prostatitis was induced in adult Noble rats with the combined treatment of testosterone and 17beta-estradiol. The inflammatory foci categorized into three forms were counted and correlated with expression of an estrogen-responsive gene, progesterone receptor (PR), in the dorsolateral lobes of the rats on soy (+) and soy (-) diets. Development of obstructive voiding after neonatal estrogenization of Noble rats (NeoDES rats) was followed with urodynamic measurements in rats on soy (+) and soy (-) diets. The amounts of genistein and daidzein, two major soy-derived isoflavones, were measured in the urine of Noble rats by the high-performance liquid chromatography-photodiodearray method. Dietary soy decreased the total number of inflammatory foci while no demonstrable effects were seen on the cellular composition of the infiltrates. Soy did not increase the weights of the pituitary gland, testes, or sex accessory glands, but it did increase the number of PR-positive epithelial cells in the dorsolateral prostate. It also decreased the bladder pressures in NeoDES rats but did not increase the flow rates. The soy effects may be mediated by the strong estrogen influence involved in the animal models. Dietary soy had anti-inflammatory effects in the prostate but only marginal effects on the development of obstructive voiding in Noble rats. The anti-inflammatory effects of soy may contribute to the lower prevalence of prostatitis-like symptoms and the historically lower risk of benign prostatic hyperplasia in Japan; however, no evidence was found that regular consumption of soy influences the age-related development of lower urinary tract symptoms or decline of flow rate.


Using complex networks to characterize international business cycles.
There is a rapidly expanding literature on the application of complex networks in economics that focused mostly on stock markets. In this paper, we discuss an application of complex networks to study international business cycles. We construct complex networks based on GDP data from two data sets on G7 and OECD economies. Besides the well-known correlation-based networks, we also use a specific tool for presenting causality in economics, the Granger causality. We consider different filtering methods to derive the stationary component of the GDP series for each of the countries in the samples. The networks were found to be sensitive to the detrending method. While the correlation networks provide information on comovement between the national economies, the Granger causality networks can better predict fluctuations in countries' GDP. By using them, we can obtain directed networks allows us to determine the relative influence of different countries on the global economy network. The US appears as the key player for both the G7 and OECD samples. The use of complex networks is valuable for understanding the business cycle comovements at an international level.


Consensus statement on the pathology of IgG4-related disease.
IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and-often but not always-elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4-7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4⁺ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.


Circadian typology is related to resilience and optimism in healthy adults.
The relationships between circadian typology and several aspects related to mental health, such as satisfaction with life, emotional intelligence, perceived well-being and psychopathological symptomatology have been documented. However, their relationships with two psychological strengths such as resilience and optimism have not been examined yet. Therefore, the purpose of the present study was to explore whether circadian typology is related to both measures, taking into consideration the possible influence of sex. A sample of 1922 participants (978 men), aged between 18 and 60 yrs (30.08 ± 10.53) completed the reduced Morningness-Eveningness Questionnaire (rMEQ), the 10-item Connor-Davidson Resilience Scale (10-item CD-RISC) and the Life Orientation Test-Revised (LOT-R). Circadian typology was associated with different values in resilience (F(2,1915) = 45.89; p < 0.001; [Formula: see text]( )= 0.046) and optimism (F(2,1915) = 37.74; p < 0.001; [Formula: see text]( )= 0.038), independently of the sex. Morning-type subjects showed the highest resilience and optimism scores while the lowest scores were shown by evening-type, exhibiting the neither-type subjects intermediate scores (p < 0.007, in all cases). These results suggest that evening-type subjects could display less capacity to face adversity and adapt positively, as well as less expectance of the occurrence of positive events compared to neither and morning-type individuals. In addition, these results provide new evidence that might improve our understanding about the relationships between circadian typology and psychological traits and disorders. Although future studies with longitudinal designs are needed, the obtained results emphasize that the evening-type could be a risk factor for the development of psychological problems and mental disorders, whereas the morning-type could be considered as a protective factor.


Physical risk factors for developing non-specific neck pain in office workers: a systematic review and meta-analysis.
Identifying risk factors associated with the development of work-related neck pain in office workers is necessary to facilitate the development of prevention strategies that aim to minimise this prevalent and costly health problem. The aim of this systematic review is to identify individual worker (e.g., lifestyle activity, muscular strength, and posture) and workplace (e.g., ergonomics and work environment) physical factors associated with the development of non-specific neck pain in office workers. Studies from 1980 to 2016 were identified by an electronic search of Pubmed, CINAHL, EMBASE, Psychlnfo and Proquest databases. Two authors independently screened search results, extracted data, and assessed risk of bias using the epidemiological appraisal instrument (EAI). A random effect model was used to estimate the risk of physical factors for neck pain. Twenty papers described the findings of ten prospective cohort studies and two randomized controlled trials. Low satisfaction with the workplace environment (pooled RR 1.28; CI 1.07-1.55), keyboard position close to the body [pooled RR 1.46; (CI 1.07-1.99)], low work task variation [RR 1.27; CI (1.08-1.50)] and self-perceived medium/high muscular tension (pooled RR 2.75/1.82; CI 1.60 /1.14-4.72/2.90) were found to be risk factors for the development of neck pain. This review found evidence for a few number of physical risk factors for the development of neck pain, however, there was also either limited or conflicting factors. Recommendations for future studies evaluating risk factors are reported and how these may contribute to the prevention of neck pain in office workers.


Gathering time-series data for evaluating behavior-change campaigns in developing countries: reactivity of diaries and interviews.
Gathering time-series data of behaviors and psychological variables is important to understand, guide, and evaluate behavior-change campaigns and other change processes. However, repeated measurement can affect the phenomena investigated, particularly frequent face-to-face interviews, which are often the only option in developing countries. This article presents three intervention control studies to investigate this issue. Daily diaries in Cuba did not affect behavior or attitudes for persons with intervention but reduced attitudes for persons without intervention. Reactivity of face-to-face interviews in Bolivia was negligible if applied weekly, but strong if applied twice per week. The article concludes with recommendations for gathering time-series data in developing countries.


Multisite Evaluation of APEX for Water Quality: I. Best Professional Judgment Parameterization.
The Agricultural Policy Environmental eXtender (APEX) model is capable of estimating edge-of-field water, nutrient, and sediment transport and is used to assess the environmental impacts of management practices. The current practice is to fully calibrate the model for each site simulation, a task that requires resources and data not always available. The objective of this study was to compare model performance for flow, sediment, and phosphorus transport under two parameterization schemes: a best professional judgment (BPJ) parameterization based on readily available data and a fully calibrated parameterization based on site-specific soil, weather, event flow, and water quality data. The analysis was conducted using 12 datasets at four locations representing poorly drained soils and row-crop production under different tillage systems. Model performance was based on the Nash-Sutcliffe efficiency (NSE), the coefficient of determination () and the regression slope between simulated and measured annualized loads across all site years. Although the BPJ model performance for flow was acceptable (NSE = 0.7) at the annual time step, calibration improved it (NSE = 0.9). Acceptable simulation of sediment and total phosphorus transport (NSE = 0.5 and 0.9, respectively) was obtained only after full calibration at each site. Given the unacceptable performance of the BPJ approach, uncalibrated use of APEX for planning or management purposes may be misleading. Model calibration with water quality data prior to using APEX for simulating sediment and total phosphorus loss is essential.


Assessing cognition following petrol sniffing for Indigenous Australians.
Chronic petrol inhalation can be associated with significant cognitive impairment. While rehabilitation programs can rely on such skills to educate clients and achieve treatment outcomes, cognitive function is rarely assessed on admission. This is particularly true for Indigenous populations where standard assessments are not appropriate. This paper describes a process for assessing cognition in Indigenous Australians. Two studies investigate firstly the demographic factors impacting on cognition for healthy Indigenous Australians and secondly the utility of the assessment process for detecting petrol sniffing related cognitive impairments. Study One assessed a naturalistic sample of healthy Indigenous Australians from the Northern Territory (N = 206; mean age = 28.03) on computerised tests of psychomotor speed, visual attention, memory, learning, spatial awareness and executive functions. Multiple regression analyses determined the unique contributions of six factors (age, education, gender, familiarity with computers, regular long term cannabis use and locality) to the variance in performance for this group. Study Two examined group differences in cognitive performance on the same tests between healthy Indigenous Australians (N = 96) and Indigenous petrol sniffers (N = 50; both age restricted to < 26 years) while controlling those factors found to impact on performance from Study One. Age, computer familiarity, and education significantly contributed to the variance in performance measures. While controlling these factors, petrol abuse was associated with poorer performance on complex tasks of psychomotor, visual attention, memory, learning, spatial awareness and executive function. This assessment process is useful for detecting substance abuse related impairments in Indigenous Australians and when using this assessment process, age and computer familiarity in particular should be controlled for.


Genes, pathways, and animal models in primary open-angle glaucoma.
Glaucoma is an optic neuropathy characterized by loss of retinal ganglion cells (RGCs) and consequently visual field loss. It is a complex and heterogeneous disease in which both environmental and genetic factors play a role. With the advent of genome-wide association studies (GWASs), the number of loci associated with primary open-angle glaucoma (POAG) have increased greatly. There has also been major progress in understanding the genes determining the vertical cup-disc ratio (VCDR), disc area (DA), cup area (CA), intraocular pressure (IOP), and central corneal thickness (CCT). In this review, we will update and summarize the genetic loci associated so far with POAG, VCDR, DA, CA, IOP, and CCT. We will describe the pathways revealed and supported by genetic association studies, integrating current knowledge from human and experimental data. Finally, we will discuss approaches for functional genomics and clinical translation.


Antireflection coatings designed for two different infrared substrates.
It is shown that it is possible to design normal-incidence antireflection coatings that simultaneously reduce the reflectance of two different substrates. Although this is at the expense of some deterioration in performance when compared with that of conventional coatings, it can lead to significant time and cost savings in small thin-film production facilities. Numerical examples are presented for ZnS/ZnSe, Si/Ge, and ZnS/Ge substrate pairs. The experimental measurements on one such coating are in good agreement with the calculated performance.


Evaluation of glucose tolerance and intestinal luminal membrane glucose transporter function in horses with equine motor neuron disease.
To confirm whether the plasma glucose concentration curve obtained during oral glucose tolerance tests (OGTTs) in horses with equine motor neuron disease (EMND) is decreased, compared with that obtained in clinically normal horses, and determine whether that decrease is a result of defective glucose metabolism or intestinal glucose transport dysfunction. 8 horses with EMND and 44 matched control horses. Electromyography and OGTTs were performed in all 8 affected horses and 10 control horses. Intravenous GTTs (IVGTTs) were performed in 6 affected horses and another 11 control horses. The activity and levels of jejunal luminal membrane glucose transporter (Na+ / glucose cotransporter isoform 1 [SGLT1]) were measured in 2 affected horses and 23 control horses. In horses with EMND, generalized neuropathy was detected via quantitative electromyography; the mean increase in plasma glucose concentration during the OGTT was significantly decreased, compared with the value in control horses. During the IVGTT the mean increase in plasma glucose concentration was significantly lower than that of control horses. The activity and levels of SGLT1 in 2 affected horses were similar to those of control horses. Diagnosis of EMND was confirmed postmortem in all affected horses. Data suggest that the decreased plasma glucose curve obtained in horses with EMND during OGTTs (compared with control horses) is a result of overall enhanced glucose metabolism or abnormalities in the facilitated glucose transporters; definitive identification of the underlying mechanisms could aid in the development of appropriate treatments of EMND in horses.


First Report of the Root-Knot Nematode Meloidogyne ethiopica on Tomato in Slovenia.
The root-knot nematode Meloidogyne ethiopica Whitehead originally described from Tanzania is also distributed in South Africa, Zimbabwe, and Ethiopia (3). Although this species is a relatively unknown root-knot nematode, M. ethiopica parasitizes several economical important crops, such as tomato, cowpea, bean, cabbage, pepper, pumpkin, tobacco, lettuce, and soybean (4). This species can be morphologically confused with M. incognita (Kofoid & White), and therefore, is probably easily overlooked (1). Recently, characteristic esterase isozyme patterns were described for this species, which provide a more reliable identification (2). In October 2003, Lycopersicum esculentum cv. Belle plants with large root-galls were observed in a greenhouse at Dornberk, Slovenia, which were identified as an unknown root-knot nematode within the M. incognita group. Subsequent sampling revealed infestation of all tomato plants within this greenhouse with obvious aboveground symptoms of stunting and wilting. Additional morphological and isozyme studies identified this root-knot nematode as M. ethiopica. The identification was based on female, male, and second-stage juvenile morphology and malate dehydrogenase and esterase isozyme phenotypes from young egg-laying females isolated from 20 tomato plants and compared with a culture of M. ethiopica from Africa. To our knowledge, this is not only the first report of M. ethiopica in Slovenia, but also the first report of this species in Europe. References: (1) A. M. Golden. Fundam. Appl. Nematol. 15:189, 1992. (2) W. Mandefro and K. Dagne. Afr. J. Plant Prot. 10:39, 2000. (3) A. G. Whitehead. Trans. Zool. Soc. Lond. 31:263, 1968. (4) A. G. Whitehead. Nematologica 15:315, 1969.


Adherence to depression treatment in older adults: a narrative review.
Depression in older adults has been detected, diagnosed and treated more frequently in recent years. However, substantial gaps in effective treatment remain. Adherence to depression treatment can be viewed as the 'next frontier' in the treatment of late-life depression. Using the Theory of Reasoned Action, a model of health behaviours, this paper conceptualizes and reviews the current evidence for key patient-level factors associated with depression treatment adherence among older adults. We categorize these factors according to how their impact on adherence might be affected by specialized treatment approaches or interventions as: (i) modifiable; (ii) potentially modifiable; and (iii) non-modifiable. Based on current evidence, modifiable factors associated with depression treatment adherence include patient attitudes, beliefs and social norms. Patient attitudes include perceptions of the effectiveness of depression treatment, preferences for the type of depression treatment and concepts regarding the aetiology of depression (e.g. resistance to viewing depression as a medical illness). There is also evidence from the literature that spiritual and religious beliefs may be important determinants of adherence to depression care. Social norms such as the impact of caregiver agreement with treatment recommendations and stigma may also affect adherence to depression treatment. Other factors may be less modifiable per se, but they may have an impact on adherence that is potentially modifiable by specialized interventions. Based upon a review of the current literature, potentially modifiable factors associated with adherence to depression treatment include co-morbid anxiety, substance use, cognitive status, polypharmacy and medical co-morbidity, social support and the cost of treatment. Finally, non-modifiable factors include patient gender and race. Importantly, non-modifiable factors may interact with modifiable factors to affect health behavioural intent (e.g. race and spiritual beliefs). Thus, adherence to depression treatment in older adults is associated with multiple factors. Strategies to improve patient adherence need to be multidimensional, including consideration of age-related cognitive and co-morbidity factors, environmental and social factors, functional status and belief systems. Evidence-based interventions involving greater patient, caregiver, provider and public health education should be developed to decrease stigma, negative attitudes and other modifiable barriers to detection, diagnosis, treatment and adherence to depression treatment. These interventions should also be tailored to the individual as well as to the treatment setting. While important progress has been made in increasing detection of depression in older adults, greater focus now needs to be placed on treatment engagement and continuation of improvements in quality of life, reducing suffering and achieving better outcomes.


Responses of bovine chimaeras combining trypanosomosis resistant and susceptible genotypes to experimental infection with Trypanosoma congolense.
West African N'Dama cattle have developed a genetic capacity to survive, reproduce and remain productive under trypanosomosis risk. The cellular and molecular bases of this so-called trypanotolerance are not known, but the trait is manifested by the N'Dama's greater capacity to control parasitaemia and anaemia development during an infection. In order to examine the role of the haematopoietic system in trypanotolerance, we have exploited the tendency for the placentas of bovine twin embryos to fuse. Placental fusion in cattle results in bone marrow chimaerism in twins. By comparison with the N'Dama, cattle of the East African Boran breed are relatively susceptible. We evaluated the role of the haemopoietic system in trypanotolerance by comparing the performance of five Chimaeric Boran/N'Dama twin calves with that of singletons of the two breeds. Chimaeric Boran/N'Dama pairs of twins were produced in recipient Boran cows by embryo transfer, and the majority of haemopoietic cells in all twinned individuals were of Boran origin. Thus, N'Dama chimaeras differed from N'Dama singletons in that the bulk of their haemopoietic system was derived from their susceptible Boran twins, while Boran chimaeras differed little from Boran control animals. All cattle became parasitaemic and developed anaemia. The N'Dama chimaeras did not manage their anaemia and white blood cell counts effectively. However, they were able to limit parasitaemia development. These results suggest that trypanotolerance is the result of two mechanisms, one that improves parasite control and is independent of the genetic origin of the haemopoietic tissue, and another that is influenced by haemopoietic tissue genotype and which improves control over anaemia. The capacity to maintain growth during infection was similarly dependent on the genetic origin of the haemopoietic tissue.


Hospital production cost of transcranial direct current stimulation (tDCS) in the treatment of depression.
Due to its ease of use, tolerance, and cost of acquisition, transcranial direct current stimulation (tDCS) could constitute a credible therapeutic option for non-resistant depression in primary care, when combined with drug management. This indication has yet to receive official recognition in France. The objective of this study is to evaluate the production cost of tDCS for the treatment of depression in hospitals, under realistic conditions. The methodology adopted is based on cost accounting and was validated by a multidisciplinary working group. It includes equipment, staff, and structural costs to obtain the most realistic estimate possible. We first estimated the cost of producing a tDCS session, based on our annual activity objective, and then estimated the cost of a 15-session treatment program. This was followed up with a sensitivity analysis applying appropriate parameters. The hospital production cost of a tDCS depression treatment program for a single patient was estimated at €1555.60 euros: €99 in equipment costs, €1076.95 in staff costs, and €379.65 in structural costs. This cost analysis should make it possible to draw up pricing proposals in compliance with regulations and health policy choices and to develop health-economic studies. This would ultimately lead to official recognition of tDCS treatment for depression in France and pave the way for studying various scenarios of coverage by the French national health insurance system.


Validating measures of psychological flexibility in a population with acquired brain injury.
This study presents preliminary validation data on both the Acceptance and Action Questionnaire-Acquired Brain Injury (AAQ-ABI) and the Acceptance and Action Questionnaire-II (AAQ-II). Data from 150 participants with ABI was subject to exploratory factor analysis on the AAQ-ABI (15 items). A subset of 75 participants with ABI completed a larger battery of measures to test construct validity for the AAQ-ABI and to undertake a confirmatory factor analysis (CFA) on the AAQ-II (7 items). Three meaningful factors were identified on the AAQ-ABI: Reactive Avoidance, Denial, and Active Acceptance. Reactive Avoidance demonstrated good internal and test-retest consistency (α = .89) and correlated in expected directions with other related measures including the AAQ-II. CFA of the AAQ-II did not provide a good fit but did have similar correlations with measures of psychological distress as found in prior non-ABI samples. The results suggest both measures can be used with individuals following an ABI but they index different facets of psychological flexibility. The AAQ-ABI appears to measure psychological flexibility about the thoughts and feelings relating to the brain injury itself while the AAQ-II measures psychological flexibility around general psychological distress. Future research could explore the additional 2 factors of the AAQ-ABI and use these measures in outcome studies that promote psychological flexibility in individuals with an ABI.


Pathologic Examination of Pancreatic Specimens Resected for Treated Pancreatic Ductal Adenocarcinoma: Recommendations From the Pancreatobiliary Pathology Society.
Currently, there are no internationally accepted consensus guidelines for pathologic evaluation of posttherapy pancreatectomy specimens. The Neoadjuvant Therapy Working Group of Pancreatobiliary Pathology Society was formed in 2018 to review grossing protocols, literature, and major issues and to develop recommendations for pathologic evaluation of posttherapy pancreatectomy specimens. The working group generated the following recommendations: (1) Systematic and standardized grossing and sampling protocols should be adopted for pancreatectomy specimens for treated pancreatic ductal adenocarcinoma (PDAC). (2) Consecutive mapping sections along the largest gross tumor dimension are recommended to validate tumor size by histology as required by the College of American Pathologists (CAP) cancer protocol. (3) Tumor size of treated PDACs should be measured microscopically as the largest dimension of tumor outer limits that is bound by viable tumor cells, including intervening stroma. (4) The MD Anderson grading system for tumor response has a better correlation with prognosis and better interobserver concordance among pathologists than does the CAP system. (5) A case should not be classified as a complete response unless the entire pancreas, peripancreatic tissues, ampulla of Vater, common bile duct, and duodenum adjacent to the pancreas are submitted for microscopic examination. (6) Future studies on tumor response of lymph node metastases, molecular and/or immunohistochemical markers, as well as application of artificial intelligence in grading tumor response of treated PDAC are needed. In summary, systematic, standardized pathologic evaluation, accurate tumor size measurement, and reproducible tumor response grading to neoadjuvant therapy are needed for optimal patient care. The criteria and discussions provided here may provide guidance towards these goals.


Fisheries conservation on the high seas: linking conservation physiology and fisheries ecology for the management of large pelagic fishes.
Populations of tunas, billfishes and pelagic sharks are fished at or over capacity in many regions of the world. They are captured by directed commercial and recreational fisheries (the latter of which often promote catch and release) or as incidental catch or bycatch in commercial fisheries. Population assessments of pelagic fishes typically incorporate catch-per-unit-effort time-series data from commercial and recreational fisheries; however, there have been notable changes in target species, areas fished and depth-specific gear deployments over the years that may have affected catchability. Some regional fisheries management organizations take into account the effects of time- and area-specific changes in the behaviours of fish and fishers, as well as fishing gear, to standardize catch-per-unit-effort indices and refine population estimates. However, estimates of changes in stock size over time may be very sensitive to underlying assumptions of the effects of oceanographic conditions and prey distribution on the horizontal and vertical movement patterns and distribution of pelagic fishes. Effective management and successful conservation of pelagic fishes requires a mechanistic understanding of their physiological and behavioural responses to environmental variability, potential for interaction with commercial and recreational fishing gear, and the capture process. The interdisciplinary field of conservation physiology can provide insights into pelagic fish demography and ecology (including environmental relationships and interspecific interactions) by uniting the complementary expertise and skills of fish physiologists and fisheries scientists. The iterative testing by one discipline of hypotheses generated by the other can span the fundamental-applied science continuum, leading to the development of robust insights supporting informed management. The resulting species-specific understanding of physiological abilities and tolerances can help to improve stock assessments, develop effective bycatch-reduction strategies, predict rates of post-release mortality, and forecast the population effects of environmental change. In this synthesis, we review several examples of these interdisciplinary collaborations that currently benefit pelagic fisheries management.


Diel metabolomics analysis of a hot spring chlorophototrophic microbial mat leads to new hypotheses of community member metabolisms.
Dynamic environmental factors such as light, nutrients, salt, and temperature continuously affect chlorophototrophic microbial mats, requiring adaptive and acclimative responses to stabilize composition and function. Quantitative metabolomics analysis can provide insights into metabolite dynamics for understanding community response to such changing environmental conditions. In this study, we quantified volatile organic acids, polar metabolites (amino acids, glycolytic and citric acid cycle intermediates, nucleobases, nucleosides, and sugars), wax esters, and polyhydroxyalkanoates, resulting in the identification of 104 metabolites and related molecules in thermal chlorophototrophic microbial mat cores collected over a diel cycle in Mushroom Spring, Yellowstone National Park. A limited number of predominant taxa inhabit this community and their functional potentials have been previously identified through metagenomic and metatranscriptomic analyses and in situ metabolisms, and metabolic interactions among these taxa have been hypothesized. Our metabolomics results confirmed the diel cycling of photorespiration (e.g., glycolate) and fermentation (e.g., acetate, propionate, and lactate) products, the carbon storage polymers polyhydroxyalkanoates, and dissolved gasses (e.g., H2 and CO2) in the waters overlying the mat, which were hypothesized to occur in major mat chlorophototrophic community members. In addition, we have formulated the following new hypotheses: (1) the morning hours are a time of biosynthesis of amino acids, DNA, and RNA; (2) photo-inhibited cells may also produce lactate via fermentation as an alternate metabolism; (3) glycolate and lactate are exchanged among Synechococcus and Roseiflexus spp.; and (4) fluctuations in many metabolite pools (e.g., wax esters) at different times of day result from species found at different depths within the mat responding to temporal differences in their niches.


A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma.
Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge, with limited effective treatment options available after stem cell transplantation. In a multicenter phase 2 study, the efficacy of lenalidomide in rel/ref cHL patients was evaluated at a dose of 25 mg/d on days 1-21 of a 28-day cycle. Patients remained on lenalidomide until disease progression or an unacceptable adverse event (AE) occurred. Thirty-eight cHL patients were enrolled with a median of 4 (range, 2-9) prior therapies; 87% had undergone prior stem cell transplantation and 55% of patients did not respond to their last prior therapy. Of 36 evaluable patients, responses were 1 complete remission (CR), 6 partial remissions (PRs), and 5 patients with stable disease (SD) for ≥ 6 months resulting in an International Working Committee (IWC) objective overall response rate (ORR) of 19% and a cytostatic ORR of 33%. Decreased chemokine (CCL17 and CCL22) plasma levels at 2 weeks were associated with a subsequent response. The treatment was well tolerated, and the most common grade 3/4 AEs were neutropenia (47%), anemia (29%), and thrombocytopenia (18%). Four patients discontinued lenalidomide because of rash, elevated transaminases/bilirubin, and cytopenias. We provide preliminary evidence of lenalidomide's activity in patients with rel/ref cHL, and therefore exploration of lenalidomide in combination with other active agents is warranted. This trial is registered at www.ClinicalTrials.gov as NCT00540007.


Ischemic stroke associated with adenoviral infection in a 4-year-old boy.
We present a case of childhood arterial ischemic stroke associated with proven adenoviral upper respiratory tract infection in a previously healthy 4-year-old boy. Adenoviral meningitis and encephalitis have been reported repeatedly, thus confirming the neuroinvasive capability of these viruses. However, an association between adenoviral infection and arterial ischemic stroke has not been described thus far. HIV and varicella zoster virus are the only microorganisms that have been consistently associated with arterial ischemic stroke in the absence of acute central nervous system infection. In HIV-infected individuals ischemic stroke can be caused by vasculitis and hypercoagulability. Granulomatous arteritis of the vessel wall causes post-varicella cerebral infarction and ischemic stroke after herpes zoster ophthalmicus. We suggest that in our patient a post-varicella cerebral infarction-like mechanism of adenoviral spread to the affected artery wall occurred through the ophthalmic branch of the trigeminal nerve. Adenoviruses are neuroinvasive and inflamed conjunctiva might have permitted introduction of the virus into ophthalmic nerve tissue. In consequence, the stenotic lesion of the artery might have been induced by the presence of adenovirus and the subsequent inflammatory reaction. We recommend a prompt quest for adenoviral infection in all previously healthy children with fever and clinical presentation compatible with ischemic stroke, because timely diagnosis and treatment could improve the outcome and hasten neurological recovery.


The training induced increase in whole-body peak fat oxidation rate may be attenuated with aging.
An attenuated ability to appropriately oxidize fat (metabolic inflexibility) has been associated with the development of obesity and type 2 diabetes. Previous studies have found that regular exercise training increases the body's ability to oxidize fat during exercise, but also shown that fat oxidation at the same relative and absolute exercise intensity is lower in old compared with young adults. Based on these studies we investigated the effect of training status on the whole-body peak fat oxidation rate (PFO) during exercise in young and middle-aged trained and untrained men. We hypothesized that aging was associated with decreased PFO, but regular exercise training could counteract this decline. 36 healthy non-overweight young and middle-aged men were recruited into a four groups: young (27 [24-30] yrs, (Mean [95% CI])) untrained (⩒O2peak: 47 [44-49] ml/min/kg), young (28 [26-30] yrs) trained (⩒O2peak: 64 [62-67] ml/min/kg), middle-aged (55 [53-57] yrs) untrained (⩒O2peak: 37 [32-42] ml/min/kg) and middle-aged (54 [51-57] yrs) trained (⩒O2peak: 55 [51-58] ml/min/kg). PFO was measured by indirect calorimetry while subjects performed a validated incremental exercise protocol on a cycle ergometer. Whole-body peak fat oxidation rate was higher in the young trained compared to young untrained subjects (0.70 [0.65-0.75] vs.0.45 [0.36-0.54] g/min, post-hoc: p < 0.001); however, this training effect was attenuated in middle-aged trained and untrained subjects (0.44 [0.38-0.50] vs. 0.41 [0.35-0.47] g/min, post-hoc: p = 0.83, respectively). In summary, these findings suggest that the training induced effects on whole-body fat oxidation found in young men may be attenuated in middle-aged men.


Getting back to life after stroke: co-designing a peer-led coaching intervention to enable stroke survivors to rebuild a meaningful life after stroke.
Purpose: Rebuilding one's life after stroke is a key priority persistently identified by patients yet professionally led interventions have little impact. This co-design study constructs and tests a novel peer-led coaching intervention to improve post-stroke leisure and general social participation.Methods: This study followed the principles of co-design by actively engaging and harnessing the knowledge of stroke survivors in order to develop and test a peer-lead coaching intervention. Phase 1 assessed function, mood, and involvement in leisure and social activities 6 months following stroke (n = 79). Phase 2 involved semi-structured, in-depth interviews with 18 stroke survivors, and 10 family carers to explore experiences related to social and leisure participation. Phase 3 tested the co-designed peer-led coaching intervention. Data collected also included co-design feedback sessions and a training workshop with selected peer coaches and in addition, interviews with stroke survivors and their peer coaches at two time-points: following the training program (n = 5) and delivery of the intervention (n = 2).Results: A peer-coaching intervention was successfully co-designed and tested combining the use of lay knowledge sociocognitive and self-regulatory theories with principles of transformational leadership theory. Both peers and stroke survivors reported having benefited at a personal level.Conclusions: This study reports on an innovative community-based and peer-led intervention and its results have generated new evidence on how stroke survivors engage with and respond to peer coaching support. It further provides a theoretical platform for designing and implementing peer interventions. Hence, these results have the potential to inform the development of future peer coaching intervention not only for stroke rehabilitation but also for a wide range of chronic conditions.Implications for rehabilitationThe results of this co-design study, if replicated and extended, provide a theoretical framework to guide rehabilitation professionals about the optimal timing of peer-coaching interventions and contextual factors that need to be taken into account.Applying transformational leadership theory principles to the training of peers may prove useful at the time of the implementation of a coaching intervention.Peer-led coaching interventions, which are community-based and tailored to stroke survivors at the time of discharge, may help support re-engagement in social and leisure activities.


Characteristics of second harmonic generation of Lamb waves in nonlinear elastic plates.
This paper investigates the characteristics of the second harmonic generation of Lamb waves in a plate with quadratic nonlinearity. Analytical asymptotic solutions to Lamb waves are first obtained through the use of a perturbation method. Then, based on a careful analysis of these asymptotic solutions, it is shown that the cross-modal generation of a symmetric second harmonic mode by an antisymmetric primary mode is possible. These solutions also demonstrate that modes showing internal resonance-nonzero power flux to the second harmonic mode, plus phase velocity matching-are most useful for measurements. In addition, when using finite wave packets, which is the case in most experimental measurements, group velocity matching is required for a cumulative increase in the second harmonic amplitude with propagation distance. Finally, five mode types (which are independent of material properties) that satisfy all three requirements for this cumulative increase in second harmonic amplitude-nonzero power flux, plus phase and group velocity matching-are identified. These results are important for the development of an experimental procedure to measure material nonlinearity with Lamb waves.


The Association of Coloproctology of Great Britain and Ireland consensus guidelines in surgery for inflammatory bowel disease.
There is a requirement of an expansive and up to date review of surgical management of inflammatory bowel disease (IBD) that can dovetail with the medical guidelines produced by the British Society of Gastroenterology. Surgeons who are members of the ACPGBI with a recognised interest in IBD were invited to contribute various sections of the guidelines. They were directed to produce a procedure based document using literature searches that were systematic, comprehensible, transparent and reproducible. Levels of evidence were graded. An editorial board was convened to ensure consistency of style, presentation and quality. Each author was asked to provide a set of recommendations which were evidence based and unambiguous. These recommendations were submitted to the whole guideline group and scored. They were then refined and submitted to a second vote. Only those that achieved >80% consensus at level 5 (strongly agree) or level 4 (agree) after 2 votes were included in the guidelines. All aspects of surgical care for IBD have been included along with 157 recommendations for management. These guidelines provide an up to date and evidence based summary of the current surgical knowledge in the management of IBD and will serve as a useful practical text for clinicians performing this type of surgery.


Decreased UV sensitivity, mismatch repair activity and abnormal cell cycle checkpoints in skin cancer cell lines derived from UVB-irradiated XPA-deficient mice.
Xeroderma pigmentosum group A gene (XPA)-deficient mice are defective in nucleotide excision repair (NER) and are therefore highly sensitive to ultraviolet (UV)-induced skin carcinogenesis. We established cell lines from skin cancers of UVB-irradiated XPA-deficient mice to investigate the phenotypic changes occurring during skin carcinogenesis. As anticipated, the skin cancer cell lines were devoid of NER activity but were less sensitive to killing by UV-irradiation than the XPA(-/-) fibroblast cell line. The lines were also more resistant to 6-thioguanine (6-TG) than XPA(-/-) and XPA(+/+) fibroblasts, which was suggestive of a mismatch repair (MMR) defect. Indeed, in vitro mismatch binding and MMR activity were impaired in several of these cell lines. Moreover, these cell lines displayed cell cycle checkpoint derangements following UV-irradiation and 6-TG exposure. The above findings suggest that MMR downregulation may help cells escape killing by UVB, as was seen previously for methylating agents and cisplatin, and thus that MMR deficient clones are selected for during the tumorigenic transformation of XPA(-/-) cells.


Fronto-insula network activity explains emotional dysfunctions in juvenile myoclonic epilepsy: combined evidence from pupillometry and fMRI.
Emotional instability, difficulties in social adjustment, and disinhibited behavior are the most common symptoms of the psychiatric comorbidities in juvenile myoclonic epilepsy (JME). This psychopathology has been associated with dysfunctions of mesial-frontal brain circuits. The present work is a first direct test of this link and adapted a paradigm for probing frontal circuits during empathy for pain. Neural and psychophysiological parameters of pain empathy were assessed by combining functional magnetic resonance imaging (fMRI) with simultaneous pupillometry in 15 JME patients and 15 matched healthy controls. In JME patients, we observed reduced neural activation of the anterior cingulate cortex (ACC), the anterior insula (AI), and the ventrolateral prefrontal cortex (VLPFC). This modulation was paralleled by reduced pupil dilation during empathy for pain in patients. At the same time, pupil dilation was positively related to neural activity of the ACC, AI, and VLPFC. In JME patients, the ACC additionally showed reduced functional connectivity with the primary and secondary somatosensory cortex, areas fundamentally implicated in processing the somatic cause of another's pain. Our results provide first evidence that alterations of mesial-frontal circuits directly affect psychosocial functioning in JME patients and draw a link of pupil dynamics with brain activity during emotional processing. The findings of reduced pain empathy related activation of the ACC and AI and aberrant functional integration of the ACC with somatosensory cortex areas provide further evidence for this network's role in social behavior and helps explaining the JME psychopathology and patients' difficulties in social adjustment.


Circulating beta chemokine and MMP 9 as markers of oxidative injury in extremely low birth weight infants.
Matrix metalloproteinases (MMPs) and chemokines seem to be induced by hyperoxia in preclinical studies. We hypothesized that O2 exposure immediately after birth is associated with altered blood spot MMP 9 and beta chemokine concentrations. The following analytes were measured on blood spots on d 1 and 3 of life, using luminex technology in 1059 infants (birth weights <1000 g) in the NICHD Neonatal Research Network: MMP 9, monocyte chemoattractant protein 1 (MCP 1), macrophage inflammatory proteins (1alpha and beta), and regulated upon activation, normal t cell expressed and secreted (RANTES). Infants administered O2 continually from 6 to 24 h of life (n = 729), when compared with those with <6 h exposure (n = 330), had significantly lower mean birth weight and higher rate of respiratory distress syndrome (p < 0.002). On d 3, MCP 1 was higher and RANTES lower among infants with early prolonged O2 exposure. After adjusting for covariates, prolonged early O2 exposure retained a statistically significant association with higher MCP 1 on d 3 (p = 0.003). The consistent association between O2 exposure and MCP 1 among extremely preterm infants suggests that further investigation of its role in oxidative injury is warranted.


The effects of pulmonary rehabilitation in the national emphysema treatment trial.
Pulmonary rehabilitation is an established treatment in patients with chronic lung disease but is not widely utilized. Most trials have been conducted in single centers. The National Emphysema Treatment Trial (NETT) provided an opportunity to evaluate pulmonary rehabilitation in a large cohort of patients who were treated in centers throughout the United States. Prospective observational study of cohort prior to randomization in a multicenter clinical trial. University-based clinical centers and community-based satellite pulmonary rehabilitation programs. A total of 1,218 patients with severe emphysema underwent pulmonary rehabilitation before and after randomization to lung volume reduction surgery (LVRS) or continued medical management. Rehabilitation was conducted at 17 NETT centers supplemented by 539 satellite centers. Lung function, exercise tolerance, dyspnea, and quality of life were evaluated at regular intervals. Significant (p < 0.001) improvements were observed consistently in exercise (cycle ergometry, 3.1 W; 6-min walk test distance, 76 feet), dyspnea (University of California, San Diego Shortness of Breath Questionnaire score, -3.2; Borg breathlessness score: breathing cycle, -0.8; 6-min walk, -0.5) and quality of life (St. George Respiratory Questionnaire score, -3.5; Quality of Well-Being Scale score, +0.035; Medical Outcomes Study 36-item short form score: physical health summary, +1.3; mental health summary, + 2.0). Patients who had not undergone prior rehabilitation improved more than those who had. In multivariate models, only prior rehabilitation status predicted changes after rehabilitation. In 20% of patients, exercise level changed sufficiently after rehabilitation to alter the NETT subgroup predictive of outcome. Overall, changes after rehabilitation did not predict differential mortality or improvement in exercise (primary outcomes) by treatment group. The NETT experience demonstrates the effectiveness of pulmonary rehabilitation in patients with severe emphysema who were treated in a national cross-section of programs. Pulmonary rehabilitation plays an important role in preparing and selecting patients for surgical interventions such as LVRS.