Effect of epidermal growth factor on experimental colitis in the rat.
The effect of epidermal growth factor on the rate of healing was examined in a rat model of colitis. Ulceration and inflammation of the distal colon were induced by a single intracolonic administration of 0.25 ml of 30% ethanol containing 30 mg of trinitrobenzenesulfonic acid. Epidermal growth factor was delivered intracolonically via the rectum or s.c. for 7 days after induction of colitis. Repeated s.c. injections of epidermal growth factor (25 and 100 micrograms/kg/12 hr) or continuous s.c. delivery with Alzet osmotic pumps (50 and 200 micrograms/kg/24 hr) significantly reduced colonic ulceration and inflammation. Epidermal growth factor significantly reduced myeloperoxidase activity in colonic tissue and there was restitution of the glandular mucosa after epidermal growth factor treatment. In contrast, daily intracolonic treatment with epidermal growth factor (25, 100 and 200 micrograms/kg/24 hr) did not significantly reduce the colonic damage. However, intracolonic delivery of 5-aminosalicylic acid (100 and 200 mg/kg/24 hr) dose-dependently reduced the colonic damage as assessed macroscopically and histologically. We conclude that systemic and not intracolonic administration of epidermal growth factor can accelerate healing of colonic ulceration and is effective in reducing inflammation in this model of colitis.


Anesthetic neurotoxicity in the newborn and infant.
Every year, millions of children undergo anesthesia. Emerging evidence from experimental in-vitro and in-vivo models supports a role for neuropathologic injury and neurobehavioral deficits at older age after early exposure to various anesthetic regimens. Clinical studies have sought to identify a phenotype of developmental anesthesia neurotoxicity in humans, but the current evidence is limited to data from retrospective studies with their associated confounders. Experimental models have been used to further define the injury and to help identify potential mechanisms of this neurotoxicity. A recent clinical trial from an Australian birth cohort suggests a single anesthesia exposure as a neonate or infant may increase the risk for language and abstract reasoning deficits later in life, though residual data confounders may remain. Several ongoing clinical trials like Mayo Safety in Kids, Pediatric Anesthesia NeuroDevelopment Assessment, and General Anesthesia and Apoptosis Study will likely offer more clear answers in the future. In the interim, experimental models have described roles for neuroinflammation, mitochondrial damage from reactive oxygen species, and the presence of several neuronal morphology changes from anesthesia exposure. Additionally, several potential neuroprotective agents and strategies have been tested in the laboratory. Whether anesthesia-associated neurotoxicity affects the developing human brain and whether this leads to clinically measurable deficits remains unclear.


Structural and functional analysis of the human POT1-TPP1 telomeric complex.
POT1 and TPP1 are part of the shelterin complex and are essential for telomere length regulation and maintenance. Naturally occurring mutations of the telomeric POT1-TPP1 complex are implicated in familial glioma, melanoma and chronic lymphocytic leukaemia. Here we report the atomic structure of the interacting portion of the human telomeric POT1-TPP1 complex and suggest how several of these mutations contribute to malignant cancer. The POT1 C-terminus (POT1C) forms a bilobal structure consisting of an OB-fold and a holiday junction resolvase domain. TPP1 consists of several loops and helices involved in extensive interactions with POT1C. Biochemical data shows that several of the cancer-associated mutations, partially disrupt the POT1-TPP1 complex, which affects its ability to bind telomeric DNA efficiently. A defective POT1-TPP1 complex leads to longer and fragile telomeres, which in turn promotes genomic instability and cancer.


Stepwise solubilization-based antigen removal for xenogeneic scaffold generation in tissue engineering.
The ability of residual antigens on decellularized tissue to elicit the immune response upon implantation motivates development of a more rigorous antigen removal (AR) process for xenogeneic scaffold generation. Antigen removal strategies promoting solubilization of hydrophilic proteins (predominantly cytoplasmic) enhance the reduction of hydrophilic antigenicity in bovine pericardium (BP); however, the diversity of protein antigens within a tissue necessitates development of AR strategies capable of addressing a spectrum of protein antigen solubilities. In the present study, methods for promoting solubilization of lipophilic proteins (predominantly membrane) were investigated for their ability to reduce lipophilic antigenicity of BP when applied as a second AR step following our previously described hydrophilic AR method. Bovine pericardium following AR (BP-AR) was assessed for residual hydrophilic and lipophilic antigenicity, removal of known lipophilic xenoantigens, tensile properties, and extracellular matrix structure and composition. Facilitating hydrophile solubilization (using dithiothreitol and potassium chloride) followed by lipophile solubilization (using amidosulfobetaine-14 (ASB-14)), in a two-step sequential, differential AR strategy, significantly reduces residual hydrophilic and lipophilic antigenicity of BP-AR beyond that achieved with either one-step hydrophilic AR or decellularization using 1% (w/v) sodium dodecyl sulfate. Moreover, use of 1% (w/v) ASB-14 for lipophilic AR eliminates the two most critical known barriers to xenotransplantation (galactose-α(1,3)-galactose and major histocompatibility complex I)) from BP-AR without compromising the structure-function properties of the biomaterial. This study demonstrates the importance of a sequential, differential protein solubilization approach to reduce biomaterial antigenicity in the production of a xenogeneic scaffold for heart valve tissue engineering.


Acute Physiological and Chronic Health Evaluation II Score and its Correlation with Three Surgical Strategies for Management of Ileal Perforations.
Ileal perforation peritonitis is a common surgical emergency in the Indian subcontinent and in tropical countries. It is reported to constitute the fifth common cause of abdominal emergencies due to high incidence of enteric fever and tuberculosis in these management based on Acute Physiological and Chronic Health Evaluation II (APACHE II) score. The following study was conducted in the Department of General Surgery, Government Medical College, Patiala. A total of 57 patients were studied and divided in to Group I, II, and III. APACHE II score accessed and score between 10 and 19 were blindly randomized into three procedures primary closure, resection-anastomosis, and ileostomy. The outcome was compared. Ileal perforations were most commonly observed in the third and fourth decade of life with male dominance. APACHE II score was accessed and out of total 57 patients, 6 patients had APACHE II score of 0-9, 48 patients had APACHE II score of 10-19, and 3 patients had APACHE II score of ≥20. In APACHE II score 10-19, 15 patients underwent primary closure, 16 patients underwent resection-anastomosis, and 17 patients underwent ileostomy. Primary closure of perforation is advocated in patients with single, small perforation (<1 cm) with APACHE II score 10-19 irrespective of duration of perforation. Ileostomy is advocated in APACHE II score 10-19, where the terminal ileum is grossly inflamed with multiple perforations, large perforations (>1 cm), fecal peritonitis, matted bowel loops, intraoperative evidence of caseating lymph nodes, strictures, and an unhealthy gut due to edema.


Infection-related stillbirths.
Infection is an important cause of stillbirths worldwide: in low-income and middle-income countries, 50% of stillbirths or more are probably caused by infection. By contrast, in high-income countries only 10-25% of stillbirths are caused by infection. Syphilis, where prevalent, causes most infectious stillbirths, and is the infection most amenable to screening and treatment. Ascending bacterial infection is a common cause of stillbirths, but prevention has proven elusive. Many viral infections cause stillbirths but aside from vaccination for common childhood diseases, we do not have a clear prevention strategy. Malaria, because of its high prevalence and extensive placental damage, accounts for large numbers of stillbirths. Intermittent malarial prophylaxis and insecticide-treated bednets should decrease stillbirths. Many infections borne by animals and vectors cause stillbirths, and these types of infections occur frequently in low-income countries. Research that better defines the relation between these infections and stillbirths, and develops strategies to reduce associated adverse outcomes, should play an important part in reduction of stillbirths in low-income countries.


Macromolecular organization of saliva: identification of 'insoluble' MUC5B assemblies and non-mucin proteins in the gel phase.
Stimulated human submandibular/sublingual (HSMSL) and whole saliva were separated into sol and gel phases and mucins were isolated by density-gradient centrifugation in CsCl/4M guanidinium chloride. MUC5B and MUC7 were identified using anti-peptide antisera raised against sequences within the MUC5B and MUC7 apoproteins respectively. MUC7 was found mainly in the sol phase of both HSMSL and whole saliva, but some MUC7 was consistently present in the gel phase, suggesting that this mucin may interact with the salivary gel matrix. In HSMSL saliva, MUC5B was found in the gel phase; however, most of the material was 'insoluble' in guanidinium chloride and was only brought into solution by reduction. In whole saliva, the MUC5B mucin was present both in the sol and gel phases although some material was again 'insoluble'. Rate-zonal centrifugation of whole saliva showed that MUC5B mucins in the sol phase were smaller than those in the gel phase, suggesting differences in oligomerization and/or degradation. Antibodies against IgA, secretory component, lysozyme and lactoferrin were used to study the distribution of non-gel-forming proteins in the different phases of saliva. The majority of these proteins was found in the sol phase of both HSMSL and whole saliva. However, a significant fraction was present in the gel phase of whole saliva, suggesting a post-secretory interaction with the salivary gel matrix. A monoclonal antibody against a parotid salivary agglutinin was used to show that this protein is present mainly in the gel phase of both whole saliva and parotid secretion.


Assessment of Diet Quality and Adherence to Dietary Guidelines in Gastrointestinal Cancer Survivors: A Cross-Sectional Study.
Diet quality among short- and long-term gastrointestinal (GI) cancer survivors with different tumor sites was investigated compared to a reference population cohort. Diet quality of GI cancer survivors (n = 307) was compared to an age- and sex-matched reference population with no history of cancer (n = 3070). All were selected from Lifelines, a population-based cohort. GI cancers were defined as having a history of cancer of the bowel, esophagus, or stomach. Diet quality was assessed by a self-administrated food frequency questionnaire in terms of: (i) Lifelines Diet (LLD) scores, where higher scores indicate higher diet quality; (ii) the adherence to dietary guidelines, quantified by the percentage of meeting dietary recommendations, as given by Dutch dietary guidelines; and (iii) the mean daily intake of food components. All analyses were adjusted for lifestyle factors. Diet scores in GI cancer survivors were not different from the reference population (OR = 0.97, 95% CI: 0.73-1.23). Stratification for time since diagnosis and tumor site gave similar results. The intake of vegetables, unsweetened dairies, and nuts and legumes was almost 50% lower than the recommended amount, and the mean intake of unhealthy food components was at least one serving/day among GI cancer survivors, as well as in the reference population. In the long run, GI cancer survivors do not differ from the reference population in their diet quality. In conclusion, both groups can improve their diet quality.


Using the Comprehensive Unit-based Safety Program model for sustained reduction in hospital infections.
Prompted by the high number of central line-associated bloodstream infections (CLABSIs), our institution joined the national On the CUSP: Stop BSI initiative. We not only report the significant impact that the Comprehensive Unit-based Safety Program (CUSP) had in reducing CLABSI, but also report catheter-associated urinary tract infections (CAUTIs) and ventilator-associated pneumonia (VAP) in 2 intensive care units (ICUs). At our community-based academic health care system, 2 ICUs implemented CUSP tools and developed local interventions to reduce CLABSI and other safety problems. We measured CLABSI, CAUTI, and VAP during baseline, the CUSP period, and a post-CUSP period. CLABSIs decreased from 3.9 per 1,000 catheter days at baseline to 1.2 during the CUSP period to 0.6 during the post-CUSP period (rate ratio, 0.16; 95% confidence interval [CI], 0.07-0.35). CAUTIs decreased from 2.4 per 1,000 patient days to 1.2 during the post-CUSP period (rate ratio, 0.4; 95% CI, 0.24-0.65). VAP rate decreased from 2.7 per 1,000 ventilator days to 1.6 during the CUSP and post-CUSP periods (rate ratio, 0.58; 95% CI, 0.30-1.10). Device utilization decreased significantly in both ICUs. Implementation of CUSP was associated with significant decreases in CLABSI, CAUTI, and VAP. The CUSP model, allowing for implementation of evidence-based practices and engagement of frontline staff, creates sustainable improvements that reach far beyond the initial targeted problem.


A novel phosphorescent iridium(iii) complex bearing a donor-acceptor-type o-carboranylated ligand for endocellular hypoxia imaging.
The structure-property relationship of carborane-embedded cationic iridium(iii) complexes was investigated in this work, especially with donor-acceptor-type ligands. Firstly, an efficient synthetic approach for the new donor-acceptor-type ligands (2 and 4) was developed. By using these ligands, novel iridium(iii) complexes II and IV were prepared. Complex IV shows about a 92 nm red-shift in solution (ΦP = 0.13 in ethanol), and the emission color has an obvious change from green to red when compared with the Model complex. In addition, the photophysical characteristics of complex IV are quite sensitive to the oxygen level in living cells, based on which endocellular hypoxia imaging of complex IV has been realized by the phosphorescence lifetime imaging microscopy (PLIM) technology. Besides the experimental studies, density functional theory (DFT) and time dependent DFT (TD-DFT) calculations have been successfully applied to investigate the excited-state electronic structures of carborane-modified iridium complexes.


Rotation of the polarization direction and reversal of helicity of ultrashort pulsed beams propagating in free space.
We unveil the origin of the recently revealed polarization-state changes of polarization-shaped few-cycle pulses induced by free-space beam propagation. Simple rules are formulated to show how the orientation and ellipticity of the instantaneous polarization ellipse of the source and propagated pulses relate to each other. We demonstrate our findings with examples that clearly display the relationships found and highlight their relevance. We show, for example, that pulses often used in high-harmonic generation or attosecond pulse production rotate as a whole during free-space beam propagation or upon focusing. A pulse that may reverse its ellipticity from right-handed to left-handed during propagation is also introduced. It is shown that these effects are independent of the beam size and/or focal length. We also present how these instantaneous polarization-state changes could be noticed in classical measurements of light polarization using polarizers, phase retarders, and time-integrating detectors.


PE_PGRS30 is required for the full virulence of Mycobacterium tuberculosis.
The role and function of PE_PGRS proteins of Mycobacterium tuberculosis (Mtb) remains elusive. In this study for the first time, Mtb isogenic mutants missing selected PE_PGRSs were used to investigate their role in the pathogenesis of tuberculosis (TB). We demonstrate that the MtbΔPE_PGRS30 mutant was impaired in its ability to colonize lung tissue and to cause tissue damage, specifically during the chronic steps of infection. Inactivation of PE_PGRS30 resulted in an attenuated phenotype in murine and human macrophages due to the inability of the Mtb mutant to inhibit phagosome-lysosome fusion. Using a series of functional deletion mutants of PE_PGRS30 to complement MtbΔPE_PGRS30, we show that the unique C-terminal domain of the protein is not required for the full virulence. Interestingly, when Mycobacterium smegmatis recombinant strain expressing PE_PGRS30 was used to infect macrophages or mice in vivo, we observed enhanced cytotoxicity and cell death, and this effect was dependent upon the PGRS domain of the protein.Taken together these results indicate that PE_PGRS30 is necessary for the full virulence of Mtb and sufficient to induce cell death in host cells by the otherwise non-pathogenic species M. smegmatis, clearly demonstrating that PE_PGRS30 is an Mtb virulence factor.


smFISH in chips: a microfluidic-based pipeline to quantify in situ gene expression in whole organisms.
Gene expression and genetic regulatory networks in multi-cellular organisms control complex physiological processes ranging from cellular differentiation to development to aging. Traditional methods to investigate gene expression relationships rely on using bulk, pooled-population assays (e.g. RNA-sequencing and RT-PCR) to compare gene expression levels in hypo- or hyper-morphic mutant animals (e.g. gain-of-function or knockout). This approach is limited, especially in complex gene networks, as these genetic mutations may affect the expressions of related genes in unforseen ways. In contrast, we developed a microfluidic-based pipeline to discover gene relationships in a single genetic background. The microfluidic device provides efficient reagent exchange and the ability to track individual animals. By automating a robust microfluidic reagent exchange strategy, we adapted and validated single molecule fluorescent in situ hybridization (smFISH) on-chip and combined this technology with live-imaging of fluorescent transcriptional reporters. Together, this multi-level information enabled us to quantify a gene expression relationship with single-animal resolution. While this microfluidic-based pipeline is optimized for live-imaging and smFISH C. elegans studies, the strategy is highly-adaptable to other biological models as well as combining other live and end-point biological assays, such as behavior-based toxicology screening and immunohistochemistry.


A dedicated vascular access clinic for children on haemodialysis: Two years' experience.
Arteriovenous fistula (AVF) formation for long-term haemodialysis in children is a niche discipline with little data for guidance. We developed a dedicated Vascular Access Clinic that is run jointly by a transplant surgeon, paediatric nephrologist, dialysis nurse and a clinical vascular scientist specialised in vascular sonography for the assessment and surveillance of AVFs. We report the experience and 2-year outcomes of this clinic. Twelve new AVFs were formed and 11 existing AVFs were followed up for 2 years. All children were assessed by clinical and ultrasound examination. During the study period 12 brachiocephalic, nine basilic vein transpositions and two radiocephalic AVFs were followed up. The median age (interquartile range) and weight of those children undergoing new AVF creation were 9.4 (interquartile 3-17) years and 26.9 (14-67) kg, respectively. Pre-operative ultrasound vascular mapping showed maximum median vein and artery diameters of 3.0 (2-5) and 2.7 (2.0-5.3) mm, respectively. Maturation scans 6 weeks after AVF formation showed a median flow of 1277 (432-2880) ml/min. Primary maturation rate was 83 % (10/12). Assisted maturation was 100 %, with two patients requiring a single angioplasty. For the 11 children with an existing AVF the maximum median vein diameter was 14.0 (8.0-26.0) mm, and the median flow rate was 1781 (800-2971) ml/min at a median of 153 weeks after AVF formation. Twenty-two AVFs were used successfully for dialysis, a median kt/V of 1.97 (1.8-2.9), and urea reduction ratio of 80.7 % (79.3-86 %) was observed. One child was transplanted before the AVF was used. A multidisciplinary vascular clinic incorporating ultrasound assessment is key to maintaining young children on chronic haemodialysis via an AVF.


Preventive mechanism of bioactive dietary foods on obesity-related inflammation and diseases.
Obesity is associated with low-grade chronic inflammation of adipose tissue, which leads to the development of metabolic disorders such as insulin resistance, type 2 diabetes, cardiovascular disease (CVD), and cancer. Obesity and a high calorie diet are associated with altered endocrine and metabolic functions of adipose tissue, contributing to systemic inflammation as a result of the release of pro-inflammatory cytokines/adipokines into the circulation and metabolic endotoxemia. Furthermore, the accumulation of proinflammatory macrophages within the visceral adipose tissue may also be a major cause of chronic inflammation of adipocytes. Thus, it is important to understand the factors that regulate the function of both adipocytes and macrophages to find attractive strategies against the burden of obesity-induced health problems. Although the vast range of activities of dietary bioactive compounds on obesity and inflammation have been widely investigated, the mechanisms underlying their beneficial effects on obesity-associated inflammatory response are still poorly understood. This review focuses on the molecular biology mechanism of obesity-induced inflammation and the reciprocal interactions between the major molecular mechanisms and a range of dietary bioactive compounds.


2.0 Å resolution crystal structure of human polκ reveals a new catalytic function of N-clasp in DNA replication.
Human polymerase kappa (polκ) is a distinct Y-family DNA polymerase with a unique N-terminal N-clasp domain. The N-clasp renders polκ's high efficiency and accuracy in DNA replication and lesion bypass. How N-clasp empowers polκ in replication remains unclear due to the disordering of N-clasp. Here, we present a 2.0-Å resolution crystal structure of a polκ ternary complex with DNA and an incoming nucleotide. The structure-function study reveals an ordered N-clasp domain that brings conserved and functionally important residues in contact with the replicating basepair in the active site and contributes to the nucleotidyl transfer reaction. Particularly, a fully ordered Lys25 from the N-clasp domain is in H-bonding with the α- and γ-phosphates of the incoming nucleotide. K25A mutation reduces the polymerase activity of polκ significantly. This lysine is structurally analogous to a conserved lysine in the A-family DNA polymerases in the closed form. In contrast, Lys25 in the previous structures of polκ does not have any contacts with the incoming nucleotide, resembling an open form of a DNA polymerase. Based on structural and functional similarity, we propose a local open/closed mechanism for polκ in DNA replication catalysis, which mimics the common mechanism for all DNA polymerases.


Large-scale synthesis of fluorinated graphene by rapid thermal exfoliation of highly fluorinated graphite.
Weakly fluorinated graphene nanosheets were efficiently prepared via fast thermal exfoliation of highly fluorinated graphite. This scalable method consists of a fast temperature increase (around 10 °C s-1) of fluorinated HOPG performed under an argon atmosphere, without any post-treatment. The mechanism of exfoliation induced by the defluorination step, evolving volatile fluorocarbons, has been highlighted thanks to thermogravimetric analysis (TGA), high temperature X-ray diffraction (HTK-XRD), X-ray Photoelectron Spectrometry (XPS) studies on temperature, and Raman and infrared spectroscopy. The advantages of the described process are its high-yield for the preparation of fluorinated graphene nanosheets, its ease of implementation and scalability. Moreover, the fluorine content drastically decreases during such a process and graphene layers are slightly functionalized, i.e. conductive contrary to the precursor.


Global change, parasite transmission and disease control: lessons from ecology.
Parasitic infections are ubiquitous in wildlife, livestock and human populations, and healthy ecosystems are often parasite rich. Yet, their negative impacts can be extreme. Understanding how both anticipated and cryptic changes in a system might affect parasite transmission at an individual, local and global level is critical for sustainable control in humans and livestock. Here we highlight and synthesize evidence regarding potential effects of 'system changes' (both climatic and anthropogenic) on parasite transmission from wild host-parasite systems. Such information could inform more efficient and sustainable parasite control programmes in domestic animals or humans. Many examples from diverse terrestrial and aquatic natural systems show how abiotic and biotic factors affected by system changes can interact additively, multiplicatively or antagonistically to influence parasite transmission, including through altered habitat structure, biodiversity, host demographics and evolution. Despite this, few studies of managed systems explicitly consider these higher-order interactions, or the subsequent effects of parasite evolution, which can conceal or exaggerate measured impacts of control actions. We call for a more integrated approach to investigating transmission dynamics, which recognizes these complexities and makes use of new technologies for data capture and monitoring, and to support robust predictions of altered parasite dynamics in a rapidly changing world.This article is part of the themed issue 'Opening the black box: re-examining the ecology and evolution of parasite transmission'.


Imaging Aβ(1-42) fibril elongation reveals strongly polarised growth and growth incompetent states.
The major hallmark of Alzheimer's disease is the deposition of plaques of amyloid fibrils formed from amyloid-β (Aβ) peptides. Kinetic studies have contributed significantly towards a mechanistic understanding of amyloid fibril self-assembly, however dynamic features of the aggregation process cannot be captured using ensemble methods. Here we present an assay for imaging Aβ42 aggregation dynamics at the single fibril level, allowing for the quantitative extraction of concentration and temperature dependent kinetic parameters. From direct observation of elongation using TIRF and super-resolution optical microscopy, we find that Aβ42 fibril growth is strongly polarized, with fast and slow growing ends arising from different elongation rates, but also from a growth incompetent state, which dominates the process at the slow growing end. Our findings reveal the surprising complexity of the Aβ42 fibril elongation reaction at the microscopic level.


In vitro and in vivo studies using non-traditional bisphosphonates.
Non-traditional bisphosphonates, that is, bisphosphonates that do not inhibit osteoclast viability or function, were initially reported in the 1990s by Socrates Papapoulos' group. Originally designed to study the role of the R1 residue of aminobisphosphonates on bisphosphonate affinity for hydroxyapatite, these modified bisphosphonates retained similar affinity for mineralized bone as their parent compounds, but they lacked the potential to inhibit the mevalonate pathway or bone resorption. We found that, similar to classical bisphosphonates, these non-traditional compounds prevented osteoblast and osteocyte apoptosis in vitro through a pathway that requires the expression of the gap junction protein connexin 43, and the activation of the Src/MEK/ERK signaling pathway. Furthermore, one of those compounds named IG9402 (also known as amino-olpadronate or lidadronate), was able to inhibit osteoblast and osteocyte apoptosis, without affecting osteoclast number or bone resorption in vivo in a model of glucocorticoid-induced osteoporosis. IG9402 administration also ameliorated the decrease in bone mass and in bone mechanical properties induced by glucocorticoids. Similarly, IG9402 prevented apoptosis of osteoblastic cells in a model of immobilization due to hindlimb unloading. However, in this case, the bisphosphonate was not able to preserve the bone mass, and only partially prevented the decrease in bone mechanical properties induced by immobilization. The effect of IG9402 administration was also tested in a mouse model of masticatory hypofunction through the induction of masseter muscle atrophy by unilateral injection of botulinum toxin type A (BoNTA). IG9402 partially inhibited the loss of trabecular bone microstructure in the mandibular condyle, but not the decrease in masseter muscle mass induced by BoNTA administration. In summary, these non-traditional bisphosphonates that lack anti-resorptive activity but are able to preserve osteoblast and osteocyte viability could constitute useful tools to study the consequences of preventing apoptosis of osteoblastic cells in animal models. Furthermore, they could be used to treat conditions associated with reduced bone mass and increased bone fragility in which a reduction of bone remodeling is not desirable.


Health and Well-Being Metrics in Business: The Value of Integrated Reporting.
Health and well-being (HWB) are material to sustainable business performance. Yet, corporate reporting largely lacks the intentional inclusion of HWB metrics. This brief report presents an argument for inclusion of HWB metrics into existing standards for corporate reporting. A Core Scorecard and a Comprehensive Scorecard, designed by a team of subject matter experts, based on available evidence of effectiveness, and organized around the categories of Governance, Management, and Evidence of Success, may be integrated into corporate reporting efforts. Pursuit of corporate integrated reporting requires corporate governance and ethical leadership and values that ultimately align with environmental, social, and economic performance. Agreement on metrics that intentionally include HWB may allow for integrated reporting that has the potential to yield significant value for business and society alike.


Influence of coronary collateral vessels on myocardial infarct size in humans. Results of phase I thrombolysis in myocardial infarction (TIMI) trial. The TIMI Investigators.
The influence of coronary collateral vessels on infarct size in humans remains controversial, partly because no previous study has examined the impact of collaterals present at the onset of acute myocardial infarction on infarct size. The present study used the data base of the Thrombolysis in Myocardial Infarction (TIMI) Phase I trial to correlate the presence or absence of angiographically documented collaterals in the initial hours of myocardial infarct evolution with the size of the infarct as assessed by serial measurements of serum creatine kinase (CK). To avoid the confounding effects of reperfusion on enzymatic estimates of infarct size, this report is limited to those 125 patients who failed to recanalize at 90 minutes after administration of tissue plasminogen activator or streptokinase. Patients with angiographically documented collaterals (group A, n = 51) had significantly lower values of peak serum CK than patients without collaterals (group B, n = 74) (1,877 +/- 216 versus 2,661 +/- 212 IU/l, respectively [mean +/- SEM], p = 0.004). Similarly, CK-derived infarct size estimates were significantly lower in group A than in group B (20.6 +/- 2.5 versus 31.4 +/- 2.8 CK gram equivalents, p = 0.001). The infarct size observed in patients with collaterals was less for anterior infarctions as well as for infarctions of other locations; thus, the beneficial effects of collaterals were independent of the site of the infarct. In 65 of the 125 patients who failed to reperfuse, left ventricular ejection fraction (LVEF) was assessed by contrast ventriculography both at initial cardiac catheterization (before thrombolytic therapy) and at hospital discharge. Among the patients who had both studies, global LVEF tended to increase from pretreatment to hospital discharge in group A (from 50.6 +/- 1.8% to 53.4 +/- 1.8%, p = 0.10) but decreased in group B patients (from 50.3 +/- 1.8% to 47.8 +/- 1.7%, p = 0.02). At hospital discharge, global LVEF was greater in patients with coronary collaterals (53.5 +/- 1.7% versus 49.6 +/- 1.7%, p = 0.01). The results demonstrate that, in patients in whom thrombolytic therapy fails to induce reperfusion, the presence of coronary collateral vessels at the onset of myocardial infarction is associated with limitation of infarct size as assessed enzymatically and with improved ventricular function on discharge as assessed by LVEF.


Developmental Changes in Sleep Oscillations during Early Childhood.
Although quantitative analysis of the sleep electroencephalogram (EEG) has uncovered important aspects of brain activity during sleep in adolescents and adults, similar findings from preschool-age children remain scarce. This study utilized our time-frequency method to examine sleep oscillations as characteristic features of human sleep EEG. Data were collected from a longitudinal sample of young children (n = 8; 3 males) at ages 2, 3, and 5 years. Following sleep stage scoring, we detected and characterized oscillatory events across age and examined how their features corresponded to spectral changes in the sleep EEG. Results indicated a developmental decrease in the incidence of delta and theta oscillations. Spindle oscillations, however, were almost absent at 2 years but pronounced at 5 years. All oscillatory event changes were stronger during light sleep than slow-wave sleep. Large interindividual differences in sleep oscillations and their characteristics (e.g., "ultrafast" spindle-like oscillations, theta oscillation incidence/frequency) also existed. Changes in delta and spindle oscillations across early childhood may indicate early maturation of the thalamocortical system. Our analytic approach holds promise for revealing novel types of sleep oscillatory events that are specific to periods of rapid normal development across the lifespan and during other times of aberrant changes in neurobehavioral function.


Prevalence of mood disorders and service use among US mothers by race and ethnicity: results from the National Survey of American Life.
To describe the rates of mood disorders, the social and demographic correlates of mood disorders, and mental health services utilization among African American, Caribbean black, and non-Hispanic white mothers. Study data were collected between February 2001 and June 2003 as part of the National Survey of American Life: Coping With Stress in the 21st Century. National household probability samples of African Americans and Caribbean blacks were surveyed using a slightly modified World Mental Health version of the World Health Organization Composite International Diagnostic Interview. Participants included 2,019 African American, 799 Caribbean black, and 400 non-Hispanic white mothers 18 years and older (N = 3,218). The main outcomes measured were lifetime and 12-month diagnoses of DSM-IV mood disorders (major depressive episode, dysthymic disorder, bipolar I and II disorders) and mental health services utilization. The lifetime prevalence estimate of mood disorders is higher for white mothers (21.67%) than for African American mothers (16.77%) and Caribbean black mothers (16.42%); however, 12-month mood disorder estimates are similar across groups. African American mothers have higher 12-month prevalence estimates of bipolar disorder (2.48%) than white mothers (0.59%) and Caribbean black mothers (1.16%). African American mothers with higher education levels and white mothers who became parents as teenagers are more likely to have a lifetime mood disorder. Less than half (45.8%) of black mothers with a past 12-month mood disorder diagnosis utilized mental health services. Among black mothers with a 12-month diagnosis of bipolar disorder, Caribbean blacks utilized mental health services at higher rates than African Americans. Demographic correlates for mood disorders varied by race and ethnicity. The findings illustrated underutilization of treatment by black mothers, especially African American mothers with bipolar disorder.


Definition of transcriptional promoters in the human beta globin locus control region.
Our previous studies on the human beta globin gene cluster revealed the presence of intergenic transcripts throughout the locus, and demonstrated that transcription of the locus control region (LCR) initiates within an ERV9 endogenous retroviral long-terminal repeat (LTR) upstream of DNase I hypersensitive site 5. We show, using a combination of assays, that there are additional sites of transcription initiation within the LCR at hypersensitive sites 2 and 3. We have defined sites of transcription initiation, which occurs at discrete positions in a direction towards the globin genes. In addition, we show that mutation of specific transcription factor binding sites within HS2 leads to a reduction in transcription levels from within this site. We propose that these initiation events within the LCR can account for the observed orientation dependence of LCR function, and contribute to the open chromatin configuration of the beta globin locus. In addition, transcription from within the LCR hypersensitive sites could compensate for the absence of the ERV9 LTR in many transgenic mice lines, which nevertheless regulate their globin clusters correctly.


Post-embryonic root organogenesis in cereals: branching out from model plants.
The root architecture of higher plants is amazingly diverse. In this review, we compare the lateral root developmental programme in cereals and Arabidopsis thaliana. In cereals, cells in the endodermis are recruited to form the new root cap and overlying cortical cells divide to facilitate the emergence of the lateral root primordium. The TIR1/ABF2 auxin receptors and the AUX/IAA, ARF, and LBD transcriptional regulatory proteins are conserved in cereals and Arabidopsis. Several elements of this regulatory network are common to lateral and crown roots in cereals. Also, the ground meristem from which crown roots differentiate shows similarities with the root pericycle. Studies in cereals promise to give complementary insights into the mechanisms regulating the development of post-embryonic roots in plants.


Designing a balanced scorecard for a tertiary care hospital in Pakistan: a modified Delphi group exercise.
Balanced Scorecards (BSC) are being implemented in high income health settings linking organizational strategies with performance data. At this private university hospital in Pakistan an elaborate information system exists. This study aimed to make best use of available data for better performance management. Applying the modified Delphi technique an expert panel of clinicians and hospital managers reduced a long list of indicators to a manageable size. Indicators from existing documents were evaluated for their importance, scientific soundness, appropriateness to hospital's strategic plan, feasibility and modifiability. Panel members individually rated each indicator on a scale of 1-9 for the above criteria. Median scores were assigned. Of an initial set of 50 indicators, 20 were finally selected to be assigned to the four BSC quadrants. These were financial (n = 4), customer or patient (n = 4), internal business or quality of care (n = 7) and innovation/learning or employee perspectives (n = 5). A need for stringent definitions, international benchmarking and standardized measurement methods was identified. BSC compels individual clinicians and managers to jointly work towards improving performance. This scorecard is now ready to be implemented by this hospital as a performance management tool for monitoring indicators, addressing measurement issues and enabling comparisons with hospitals in other settings.


Factors influencing the selection of surgical specialty among Pakistani medical graduates.
The delineation between selection of surgery and non-surgery residency programmes could provide a pragmatic view of the influences on medical graduates' careers. This would also help coordinators and educators of residency programmes in surgery to further understand the dynamics of specialty selection. To identify the different factors that influence the graduates to select surgical specialties in Pakistan. A cross-sectional survey was conducted in 4 teaching hospitals of Karachi between July 1999 and January 2001. A total of 455 residents in 1-5 years of residency programmes were contacted. Three hundred and forty-one residents consented to the interview. Residents who were registered both with the College of Physicians and Surgeons of Pakistan (CPSP) and the Post Graduate Medical Education (PGME) office of the selected hospitals were included in this study. STATISTICAL METHOD USED: Logistic regression analysis. Final multivariate analysis identified 4 factors that remained significantly associated with the selection of surgical specialty: deriving gratification from direct patient care (adjusted odds ratio [aOR] = 5.79; 95% confidence interval [CI]: 1.24, 26.99), procedure-based medical practice (aOR = 2.85; 95% CI: 1.23, 6.61), nature of clinical problems (aOR = 3.39; 95% CI: 1.47, 7.84), and lack of consideration of stress during professional work (aOR = 2.27, 95%CI: 1.25, 4.13). Direct patient care is perceived to be an integral part of surgery residency and immediate patient outcome is a positive influence in selecting surgical specialty. The inclination towards surgery appeared to be determined by the type of procedures and technical skills involved in its practice. The nature of clinical problems is an important determinant of the choice of specialty. Stress was not perceived to be an important influencing factor for those who decided to select surgical specialties.


Early social deprivation negatively affects social skill acquisition in chimpanzees (Pan troglodytes).
In a highly social species like chimpanzees, the process by which individuals become attuned to their social environment may be of vital importance to their chances of survival. Typically, this socialization process, defined by all acquisition experiences and fine-tuning efforts of social interaction patterns during ontogeny, occurs in large part through parental investment. In this study, we investigated whether maternal presence enhances the socialization process in chimpanzees by comparing the social interactions of orphaned and mother-reared individuals at the Chimfunshi Wildlife Orphanage Trust in Zambia. As response variables, we selected social interactions during which an elaborate level of fine-tuning is assumed to be necessary for sustaining the interaction and preventing escalation: social play. Comparing orphaned (n = 8) to sex- and age-matched mother-reared juvenile chimpanzees (n = 9), we hypothesized that the orphaned juveniles would play less frequently than the mother-reared and would be less equipped for fine-tuning social play (which we assayed by rates of aggression) because of the lack of a safe and facilitating social environment provided by the mother. First, contrary to our hypothesis, results showed that the orphaned juveniles engaged in social play more frequently than the mother-reared juveniles, although for significantly shorter amounts of time. Second, in support of our hypothesis, results showed that social play of the orphaned juveniles more often resulted in aggression than social play of the mother-reared juveniles. In conjunction, these results may indicate that, just like in humans, chimpanzee mothers provide their offspring with adequate social skills that might be of pivotal importance for future challenges like successful group-living and securing competitive fitness advantages.


Effects of Greek legume plant extracts on xanthine oxidase, catalase and superoxide dismutase activities.
Legumes are considered to have beneficial health implications, which have been attributed to their phytochemical content. Polyphenols are considered the most important phytochemical compounds extensively studied for their antioxidant properties. The aim of the present study was to examine the effects of potent antioxidant legume plant extracts on xanthine oxidase (XO), catalase (CAT) and superoxide dismutase (SOD) activities. XO exerts a dual role, as it is the major contributor of free radicals during exercise while it generates uric acid, the most potent antioxidant molecule in plasma. CAT and SOD are two of the main enzymes of the antioxidant defence of tissues. We demonstrate that the majority of the extracts inhibited XO activity, but they had no effect on CAT inhibition and SOD induction when used at low concentrations. These results imply that the tested extracts may be considered as possible source of novel XO inhibitors. However, we have shown that allopurinol administration, a known XO inhibitor, before exercise reduces performance and induces oxidative stress in rats. Considering the fact that the extracts examined had an inhibitory effect on XO activity, possibly posing a restriction in their characterization as antioxidants, phytochemical antioxidant administration before exercise should probably be reconsidered.


Entangled symplectic wavelet transformation.
The symplectic wavelet transformation proposed in Opt. Lett. 31, 3432 (2006), which is related to the optical Fresnel transform in the quantum optics version, is developed into an entangled symplectic wavelet transformation (ESWT) after pointing out the contrast between the single-mode Fresnel operator and the entangled Fresnel operator. The ESWT possesses well-behaved properties and corresponds to the entangled Fresnel transform [Phys. Lett. A334, 132 (2005)].


Minimum Detectable Measurement Difference for Health-Related Quality of Life Measures Varies With Age and Disability in Adult Spinal Deformity: Implications for Calculating Minimal Clinically Important Difference.
Retrospective cohort. To investigate the minimum detectable measurement difference (MDMD) in the Scoliosis Research Society-22r (SRS-22r) outcomes instrument in adult spinal deformity (ASD) and to evaluate the effect of baseline data on measurable difference. The minimum clinically important difference (MCID) is the smallest, clinically relevant change observed and has been proposed for the SRS-22r instrument in ASD as 0.4. The MCID must be greater than the MDMD to be useful. The MDMD for the SRS-22r has not been calculated, nor have the effect of patient baseline values on MDMD. A prospective observation cohort was queried for patients treated both operatively and nonoperatively for ASD. Patients with baseline and 1-year, 2-year follow-up SRS-22r data were included in the analysis. The MDMD was calculated using classical test theory and item-response theory methods. Effect size and standardized response means were calculated. The effect of baseline data values was evaluated for MDMD. A total 839 Patients were eligible for cohort inclusion with 428 (51%) eligible for analysis with complete data. MDMD for Pain (0.6) and Self-Image (0.5) were greater than 0.4. MDMD varied with age (highest for the youngest patients) and with disability (highest for SF-36 Physical Component Summary <28.6). MDMD was less than 0.4 for Activity (0.3), Mental Health (0.3), and Total Score (0.2). Gender and mental health did not affect MDMD for the SRS-22r instrument. An MCID of 0.4 for the SRS-22r total score and domain scores may not be an appropriate value as the calculated MDMD is greater than 0.4 for both the Pain and Self-Image subscores. The MDMD for the SRS-22r instrument varied with age and baseline disability, making the assessment of clinically significant change more difficult using this tool. The MCID must be considered in the setting of the MDMD for instruments used to assess outcomes in ASD. 3.


Clinical features of avian vacuolar myelinopathy in American coots.
To characterize clinical features of avian vacuolar myelinopathy (AVM) in American coots. Case-control study. 26 AVM-affected American coots and 12 unaffected coots. Complete physical, neurologic, hematologic, and plasma biochemical evaluations were performed. Affected coots received supportive care. All coots died or were euthanatized, and AVM status was confirmed via histopathologic findings. 3 severely affected coots were euthanatized immediately after examination. Seventeen affected coots were found dead within 7 days of admission, but 5 affected coots survived > 21 days and had signs of clinical recovery. Abnormal physical examination findings appeared to be related to general debilitation. Ataxia (88%), decreased withdrawal reflexes (88%), proprioceptive deficits (81%), decreased vent responses (69%), beak or tongue weakness (42%), and head tremors (31%), as well as absent pupillary light responses (46%), anisocoria (15%), apparent blindness (4%), nystagmus (4%), and strabismus (4%) were detected. Few gross abnormalities were detected at necropsy, but histologically, all AVM-affected coots had severe vacuolation of white matter of the brain. None of the control coots had vacuolation. Although there was considerable variability in form and severity of clinical neurologic abnormalities, clinical signs common in AVM-affected birds were identified. Clinical recovery of some AVM-affected coots can occur when supportive care is administered. Until the etiology is identified, caution should be exercised when rehabilitating and releasing coots thought to be affected by AVM.


Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.
The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 x 10(-7)), PDXK (vitamin B6/dopamine metabolism, p = 3.27 x 10(-6)), SRGAP3 (axon guidance, p = 5.65 x 10(-6)), and TRAPPC4 (vesicle transport, p = 5.81 x 10(-6)). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 x 10(-7) (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44). We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.


Liver transplantation in hepatitis C. A Spanish multi-centre experience.
The purpose of this retrospective survey was to determine the prevalence and outcome of hepatitis C virus (HCV) infection in cirrhotic patients undergoing liver transplantation (OLT) in Spain in 1992. Post-OLT HCV infection was defined by anti-HCV (second-generation ELISA) and/or PCR. Patients were divided into groups A (HCV-positive pre-OLT: n = 124, 46%) and B (HCV-negative pre-OLT: n = 145, 54%). HCV infection was more prevalent in patients originally diagnosed as having non-A non-B cirrhosis (97%) and cryptogenic cirrhosis (79%) than in patients with cholestatic or metabolic diseases. Group A patients were older (53.3+/-7.9 versus 47.6+/-9.7; P< 0.05) and had a higher prevalence of hepatocellular carcinoma (22% versus 4%, P< 0.05). Post-OLT HCV infection was 99% in group A versus 4% in group B (P< 0.05). Histological hepatitis developed in 39% (66% in group A versus 14% in group B, P< 0.05) with similar follow-up. Chronic rejection occurred in 6% (3% in group A versus 8.5% in group B, P= 0.07). Retransplantation rate (overall 8%) and two-year patient survival did not differ between groups (79% versus 72%). Graft survival was higher in group A (74% versus 65% at 2 years, P= 0.04). HCV-cirrhosis represented the most frequent indication for OLT in Spain in 1992. While HCV recurrence was universal, de novo acquisition was rare. HCV accounted for most post-OLT hepatitis (87%), but was not associated with chronic rejection, nor with a higher retransplantation rate. Patient survival was not different in HCV patients compared to a control group after a follow-up of 2-3 years. Therefore, at present, HCV-cirrhosis is an acceptable indication for OLT.


On professional power and conflict of interest: state licensing boards on trial.
Licensing of the health professions is an issue of public policy which has been under fire for years. Economists argue that licensing stifles competition and increases health care costs. Manpower specialists contend that statutory scopes of practice create arbitrary barriers to both geographic and career mobility, and contribute to the reduced utilization of newer, emergent categories of health personnel. This paper addresses a subject that is often overlooked in the literature on licensing: the inherent conflict-of-interest in professional licensing boards, where the predominant voice on the boards is that of the regulated profession and, more directly, of practitioners who have a vested interested interest in their own policy making. A number of seminal court decisions are examined that address this issue and a new model for licensing boards is proposed. While this model would do away with the present structure of the boards, it would not sacrifice the critical role of technical information that only the licensed professions can provide.


Oligomers of Heat-Shock Proteins: Structures That Don't Imply Function.
Most proteins must remain soluble in the cytosol in order to perform their biological functions. To protect against undesired protein aggregation, living cells maintain a population of molecular chaperones that ensure the solubility of the proteome. Here we report simulations of a lattice model of interacting proteins to understand how low concentrations of passive molecular chaperones, such as small heat-shock proteins, suppress thermodynamic instabilities in protein solutions. Given fixed concentrations of chaperones and client proteins, the solubility of the proteome can be increased by tuning the chaperone-client binding strength. Surprisingly, we find that the binding strength that optimizes solubility while preventing irreversible chaperone binding also promotes the formation of weakly bound chaperone oligomers, although the presence of these oligomers does not significantly affect the thermodynamic stability of the solution. Such oligomers are commonly observed in experiments on small heat-shock proteins, but their connection to the biological function of these chaperones has remained unclear. Our simulations suggest that this clustering may not have any essential biological function, but rather emerges as a natural side-effect of optimizing the thermodynamic stability of the proteome.


The potential for respiratory droplet-transmissible A/H5N1 influenza virus to evolve in a mammalian host.
Avian A/H5N1 influenza viruses pose a pandemic threat. As few as five amino acid substitutions, or four with reassortment, might be sufficient for mammal-to-mammal transmission through respiratory droplets. From surveillance data, we found that two of these substitutions are common in A/H5N1 viruses, and thus, some viruses might require only three additional substitutions to become transmissible via respiratory droplets between mammals. We used a mathematical model of within-host virus evolution to study factors that could increase and decrease the probability of the remaining substitutions evolving after the virus has infected a mammalian host. These factors, combined with the presence of some of these substitutions in circulating strains, make a virus evolving in nature a potentially serious threat. These results highlight critical areas in which more data are needed for assessing, and potentially averting, this threat.


Prenatal and Newborn Immunoglobulin Levels from Mother-Child Pairs and Risk of Autism Spectrum Disorders.
An etiological role for immune factors operating during early brain development in children with autism spectrum disorders (ASD) has not yet been established. A major obstacle has been the lack of early biologic specimens that can be linked to later diagnosis. In a prior study, we found lower risk of ASD associated with higher levels of maternally-derived total IgG and Toxoplasmosis gondii (Toxo) IgG in newborn blood spot specimens from children later diagnosed with ASD compared to population controls. We obtained maternal mid-gestational serum specimens and newborn screening blood spots from the California Genetics Disease Screening Program (GDSP) for linked mother-baby pairs for 84 children with ASD and 49 children with developmental delay but not ASD (DD) identified from California Department of Developmental Services records and for 159 population controls sampled from birth certificates.Immunoglobulin levels in maternal and newborn specimens were measured by solid phase immunoassays and analyzed in logistic regression models for total IgG, total IgM, and Toxo IgG, and, for maternal specimens only, Toxo IgM. Correlations between maternal and newborn ranked values were evaluated. In both maternal and newborn specimens, we found significantly lower risk of ASD associated with higher levels of Toxo IgG. In addition, point estimates for all comparisons were < 1.0 suggesting an overall pattern of lower immunoglobulin levels associated with higher ASD risk but most did not reach statistical significance. We did not find differences in maternal or newborn specimens comparing children with DD to controls. These results are consistent with evidence from our prior study and other published reports indicating that immune factors during early neurodevelopment may be etiologically relevant to ASD. Lowered immunoglobulin levels may represent suboptimal function of the maternal immune system or reduced maternal exposure to common infectious agents. Patterns seen in these selected immunoglobulins may provide clues to mechanisms of early abnormalities in neurodevelopment contributing to ASD. We recommend further study of immunoglobulin profiles in larger samples of linked mother-baby pairs to evaluate possible etiologic relevance.


Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia.
A strong candidate gene for schizophrenia and major mental disorders, disrupted-in-schizophrenia 1 (DISC1) was first described in a large Scottish family in which a balanced chromosomal translocation segregates with schizophrenia and other psychiatric illnesses. The translocation mutation may result in loss of DISC1 function via haploinsufficiency or dominant-negative effects of a predicted mutant DISC1 truncated protein product. DISC1 has been implicated in neurodevelopment, including maturation of the cerebral cortex. To evaluate the neuronal and behavioral effects of mutant DISC1, the Tet-off system under the regulation of the CAMKII promoter was used to generate transgenic mice with inducible expression of mutant human DISC1 (hDISC1) limited to forebrain regions, including cerebral cortex, hippocampus and striatum. Expression of mutant hDISC1 was not associated with gross neurodevelopmental abnormalities, but led to a mild enlargement of the lateral ventricles and attenuation of neurite outgrowth in primary cortical neurons. These morphological changes were associated with decreased protein levels of endogenous mouse DISC1, LIS1 and SNAP-25. Compared to their sex-matched littermate controls, mutant hDISC1 transgenic male mice exhibited spontaneous hyperactivity in the open field and alterations in social interaction, and transgenic female mice showed deficient spatial memory. The results show that the neuronal and behavioral effects of mutant hDISC1 are consistent with a dominant-negative mechanism, and are similar to some features of schizophrenia. The present mouse model may facilitate the study of aspects of the pathogenesis of schizophrenia.


Intra-luminal thermometry: is tissue type assignment a necessity for thermal analysis?
Tissue type assignment, i.e. differentiation tumour from normal tissue, is a normal procedure for interstitial thermometry. In our department, thermometry in patients with a tumour in the lower pelvis is usually restricted to the intra-luminal tracks. It is unknown whether discrimination between normal and tumour tissue is relevant for deep regional hyperthermia thermal dosimetry using only intra-luminal tumour contact and tumour adjacent thermometry. This study has analysed the acquired temperature data in order to answer this question. Seventy-five patients with locally advanced cervical carcinoma were selected randomly. Patients were treated with a two or three modality combination, i.e. radiotherapy +hyperthermia or radiotherapy + hyperthermia + chemotherapy from October 1997 to September 2003. The first 100 hyperthermia treatments fulfilling the only selection criterion: no displacement of the thermometry catheter along the insertion length during the treatment, were included in the study, resulting in 43 patients with one-to-five treatments/patient (median 2). Using RHyThM (Rotterdam Hyperthermia Thermal Modulator), for each single treatment tissue type, was defined on the basis of information given by a CT scan in radiotherapy position. A step change in the slope of the profile of the first temperature map was identified to verify the insertion length of the catheter. The average T50 (median temperature) in bladder tumour indicative, vagina tumour contact and rectum tumour indicative was 40.9 +/- 0.9 degrees C, 39.7 +/- 0.9 degrees C and 40.6 +/- 0.8 degrees C, respectively. The average normal tissue T50 in bladder, vagina and rectum was 40.8 +/- 0.9 degrees C, 40.1 +/- 0.9 degrees C and 40.7 +/- 0.8 degrees C, respectively. The differences between bladder tumour indicative T50 and bladder normal tissue T50 and also between vagina tumour contact T50 and vagina normal tissue T50 were significant ( p = 0.0001). No statistical difference was found between rectum tumour indicative t50 and rectum normal tissue T50. At present the cause of the temperature difference is not known. However, as the difference between tumour (indicative/contact) and normal tissue is very small and considering also the inaccuracy in the tissue type assignment it can be stated that this study does not provide sufficient evidence to conclude that the statistical difference has clinical relevance. Therefore, it was concluded that at this time there is no need to differentiate between normal and tumour tissue in intra-luminal thermometry.


Absent virtues: the poacher becomes gamekeeper.
Since its inception, bioethics' principled stance has been to argue against paternalism and elitism, and for an inclusive ethical perspective. But at least in North America, the growth of bioethics as a special area of applied ethics has created conflicts within the field itself. Those who, a generation earlier, argued against paternalism and for both professional and public accountability in medical decision making are now part of the decision making process. Too often, it is argued in this paper, their allegiance is to the employer, or to a view of medicine that is institutionally based. As a result, it is suggested by this review, medical ethicists have adopted the perspective that, in the early 1970s, they most criticised. The answer, it is argued here, is to revisit a lexicographical ordering of responsibility in bioethics, one that recognises professionals as individuals with responsibilities, as citizens with a public posture, and finally, as professionals involved in the process of medical decision making.


Five polymorphisms of the apolipoprotein B gene in healthy Bulgarians.
Five APOB polymorphisms (I/D in the promoter region, XbaI [codon 24881, MspI [codon 3611], EcoRI [codon 41541, and 3' VNTRs) were studied in a population sample of 147 healthy normolipemic Bulgarians. For all biallelic loci, the observed genotype distributions do not deviate from Hardy-Weinberg equilibrium. In Bulgaria the insertion allele and the MspI+ allele of APOB presented the highest allelic frequencies (0.793 +/- 0.024 and 0.959 +/- 0.012, respectively) among the European population groups studied so far. The allele frequencies of the other two biallelic polymorphisms (XbaI and EcoRI) found in the Bulgarian population are similar to those previously described in other Caucasian populations. Analysis of the 3' VNTR polymorphism revealed 11 different alleles. Like studies in other Caucasian populations, this study found bimodal allele-size distribution and a high level of heterozygosity. The frequency of allele *31 (0.162 +/- 0.022) among Bulgarians is higher than that of any other European population group studied so far. Genetic distances between Bulgarians and each of six populations from southeastern Europe for which 3' VNTR allele frequencies are available showed an increase in the order: Albanians<Greeks<Slovaks<Croatians<Serbians<Hungarians. The major differences in the allele-size distributions are in the frequencies of alleles *31, *39, and *47.


Validation of International Classification of Diseases Codes for the Epidemiologic Study of Dermatomyositis.
To assess the validity of using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 710.3 to identify adult patients with dermatomyositis in outpatient and inpatient settings. Electronic medical records of adult patients with ICD-9 code 710.3 between January 2001 and November 2014 (n = 511) were examined. Physician diagnosis, clinical findings, and diagnostic testing results were recorded. A dermatomyositis rating scale was assigned based on classic cutaneous findings and at least 2 additional clinical and diagnostic findings from the Bohan criteria. Sensitivity and positive predictive values (PPVs) were determined. Sensitivity analyses were performed to evaluate the accuracy of multiple ICD-9 codes in the outpatient setting, as well as primary and secondary inpatient codes. The sensitivity and PPV for multiple 710.3 ICD-9 codes in the outpatient setting were 0.89 and 0.35, respectively. The PPV for primary and secondary 710.3 inpatient codes was 0.95 and as high as 0.8. However, the sensitivity of ICD-9 code 710.3 was poor in the inpatient setting (primary 0.23 and secondary 0.26). The most common reason for failure to meet appropriate dermatomyositis criteria was miscoding as diabetes mellitus (32%), followed by diagnosis at an outside institution (19%), dermatomyositis as a rule-out diagnosis (10%), cutaneous dermatomyositis (8%), and juvenile dermatomyositis (6%). One or more occurrences of ICD-9 code 710.3 is insufficient to support the diagnosis of dermatomyositis in the outpatient setting. However, ICD-9 710.3 codes appear to be valid in the inpatient setting.


[Study on quantitative model for suspended sediment concentration in Taihu Lake].
The complicated compositions of Case II waters result in the complex properties of spectral curves. The present paper analyzed the in situ measurements data of spectral curves, and further realized the relationships between the properties of spectral curves and suspended sediment concentration. The study found that the max peak of spectral curves was moving to the direction of shortwavelength as increasing suspended sediment concentration, namely the blue shift of wavelength; the area enclosed by spectral curve and coordinate axis in the range of sensitive bands had preferably linear relationship with the suspended sediment concentration (curve area model); the trapezoidal area model which was an approximation of curve area model could also excellently reflect those relationships, and be greatly suitable for multi-spectral satellite imagery retrieval such as LandSat/TM, MODIS and so on. The inversion results of trapezoidal area model for LandSat/TM imagery on October 27, 2003 in Taihu Lake showed that the suspended sediment concentration ranged from 30 to 80 mg x L(-1), the distribution pattern was higher in the west, south and central lake and lower in the east lake; compared with the in situ measurements in the regions, and the relative error of retrieval model was 6.035%.


de Quervain's thyroiditis: surgical experience.
To review a 35-year experience with management of de Quervain's thyroiditis (dQT), an uncommon inflammatory process of the thyroid gland that is usually treated medically and seldom necessitates surgical intervention. A retrospective review was performed of medical records of patients with dQT treated surgically at a single institution between 1966 and 2000. The study group consisted of 11 women and 6 men (mean age, 50 years; range, 23 to 66). All pathology specimens were reviewed. Of the 17 study patients, 14 had surgical treatment before 1980. Typical symptoms of dQT, including pain and tenderness of the thyroid gland, occurred in eight patients, and two had dysphagia from an enlarged thyroid gland. Seven patients were asymptomatic. The indications for operation were a clinically indeterminate thyroid nodule (N = 14), dysphagia (N = 2), and hyperthyroidism with nodular goiter (N = 1). Fine-needle aspiration biopsy (FNAB) was performed in only two patients; biopsy findings were suspicious for a malignant lesion in one patient, and nondiagnostic in the other patient. Thyroid function tests (N = 14) revealed that 12 patients were euthyroid and 2 had hyperthyroidism. Surgical treatment consisted of unilateral lobectomy in 4 patients, near-total thyroidectomy in 12, and total thyroidectomy in 1. Temporary vocal cord palsy and temporary hypocalcemia occurred in one patient each. Fourteen patients (mean follow-up, 204 months) required long-term thyroid replacement therapy. No patient required further thyroid surgical intervention or had further thyroid disease. Although surgical intervention is not the primary treatment for dQT, when resection is performed it can be done safely and with low associated morbidity. In the modern era, with routine use of FNAB, fewer patients with this rare entity will require surgical exploration. Patients with atypical features and ones with euthyroidism are more likely candidates than others for surgical intervention.


Recombination gives a new insight in the effective population size and the history of the old world human populations.
The information left by recombination in our genomes can be used to make inferences on our recent evolutionary history. Specifically, the number of past recombination events in a population sample is a function of its effective population size (Ne). We have applied a method, Identifying Recombination in Sequences (IRiS), to detect specific past recombination events in 30 Old World populations to infer their Ne. We have found that sub-Saharan African populations have an Ne that is approximately four times greater than those of non-African populations and that outside of Africa, South Asian populations had the largest Ne. We also observe that the patterns of recombinational diversity of these populations correlate with distance out of Africa if that distance is measured along a path crossing South Arabia. No such correlation is found through a Sinai route, suggesting that anatomically modern humans first left Africa through the Bab-el-Mandeb strait rather than through present Egypt.


Enhancing screening, brief intervention, and referral to treatment among socioeconomically disadvantaged patients: study protocol for a knowledge exchange intervention involving patients and physicians.
Screening, Brief Intervention, and Referral for Treatment (SBIRT) is an effective approach for managing alcohol and other drug misuse in primary care; however, uptake into routine care has been limited. Uptake of SBIRT by healthcare providers may be particularly problematic for disadvantaged populations exhibiting alcohol and other drug problems, and requires creative approaches to enhance patient engagement. This knowledge translation project developed and evaluated a group of patient and health care provider resources designed to enhance the capacity of health care providers to use SBIRT and improve patient engagement with health care. A nonrandomized, two-group, pre-post, quasi-experimental intervention design was used, with baseline, 6-, and 12-month follow-ups. Low income patients using alcohol and other drugs and who sought care in family medicine and emergency medicine settings in Edmonton, Canada, along with physicians providing care in these settings, were recruited. Patients and physicians were allocated to the intervention or control condition by geographic location of care. Intervention patients received a health care navigation booklet developed by inner city community members and also had access to an experienced community member for consultation on health service navigation. Intervention physicians had access to online educational modules, accompanying presentations, point of care resources, addiction medicine champions, and orientations to the inner city. Resource development was informed by a literature review, needs assessment, and iterative consultation with an advisory board and other content experts. Participants completed baseline and follow-up questionnaires (6 months for patients, 6 and 12 months for physicians) and administrative health service data were also retrieved for consenting patients. Control participants were provided access to all resources after follow-up data collection was completed. The primary outcome measure was patient satisfaction with care; secondary outcome measures included alcohol and drug use, health care and addiction treatment use, uptake of SBIRT strategies, and physician attitudes about addiction. Effective knowledge translation requires careful consideration of the intended knowledge recipient's context and needs. Knowledge translation in disadvantaged settings may be optimized by using a community-based participatory approach to resource development that takes into account relevant patient engagement issues. Northern Alberta Clinical Trials and Research Centre #30094.


Lung cancer risks from plutonium: an updated analysis of data from the Mayak worker cohort.
Workers at the Mayak nuclear facility in the Russian Federation offer a unique opportunity to evaluate health risks from exposure to inhaled plutonium. Risks of mortality from lung cancer, the most serious carcinogenic effect of plutonium, were evaluated in 14,621 Mayak workers who were hired in the period from 1948-1982, followed for at least 5 years, and either monitored for plutonium or never worked with plutonium. Over the follow-up period from 1953-2008, there were 486 deaths from lung cancer, 446 of them in men. In analyses that were adjusted for external radiation dose and smoking, the plutonium excess relative risk (ERR) per Gy declined with attained age and was higher for females than for males. The ERR per Gy for males at age 60 was 7.4 (95% CI: 5.0-11) while that for females was 24 (95% CI: 11-56). When analyses were restricted to plutonium doses <0.2 Gy, the ERR per Gy for males at age 60 was similar: 7.0 (95% CI: 2.5-13). Of the 486 lung cancer deaths, 105 (22%) were attributed to plutonium exposure and 29 (6%) to external exposure. Analyses of the 12,708 workers with information on smoking indicated that the relationship of plutonium exposure and smoking was likely sub-multiplicative (P = 0.011) and strongly indicated that it was super-additive (P < 0.001). Although extensive efforts have been made to improve plutonium dose estimates in this cohort, they are nevertheless subject to large uncertainties. Large bioassay measurement errors alone are likely to have resulted in serious underestimation of risks, whereas other sources of uncertainty may have biased results in ways that are difficult to predict.


Fundamental Cardiovascular Research: Returns on Societal Investment: A Scientific Statement From the American Heart Association.
Recent decades have witnessed robust successes in conquering the acutely lethal manifestations of heart and vascular diseases. Many patients who previously would have died now survive. Lifesaving successes like these provide a tremendous and easily recognized benefit to individuals and society. Although cardiovascular mortality has declined, the devastating impact of chronic heart disease and comorbidities on quality of life and healthcare resources continues unabated. Future strides, extending those made in recent decades, will require continued research into mechanisms underlying disease prevention, pathogenesis, progression, and therapeutic intervention. However, severe financial constraints currently jeopardize these efforts. To chart a path for the future, this report analyzes the challenges and opportunities we face in continuing the battle against cardiovascular disease and highlights the return on societal investment afforded by fundamental cardiovascular research.


Cannabis and Cannabinoids for Chronic Pain.
The purpose of this study was to provide the most up-to-date scientific evidence of the potential analgesic effects, or lack thereof, of the marijuana plant (cannabis) or cannabinoids, and of safety or tolerability of their long-term use. We found that inhaled (smoked or vaporized) cannabis is consistently effective in reducing chronic non-cancer pain. Oral cannabinoids seem to improve some aspects of chronic pain (sleep and general quality of life), or cancer chronic pain, but they do not seem effective in acute postoperative pain, abdominal chronic pain, or rheumatoid pain. The available literature shows that inhaled cannabis seems to be more tolerable and predictable than oral cannabinoids. Cannabis or cannabinoids are not universally effective for pain. Continued research on cannabis constituents and improving bioavailability for oral cannabinoids is needed. Other aspects of pain management in patients using cannabis require further open discussion: concomitant opioid use, medical vs. recreational cannabis, abuse potential, etc.


Novel tenascin variants with a distinctive pattern of expression in the avian embryo.
Previous studies have shown that several forms of the glycoprotein tenascin are present in the embryonic extracellular matrix. These forms are the result of alternative splicing, which generates tenascin variants with different numbers of fibronectin type III repeats. We have used degenerate primers and PCR to isolate a novel tenascin exon from an avian genomic library. Genomic clones contained a sequence encoding a fibronectin type III repeat that corresponds to repeat 'C' from the variable domain of human tenascin. To demonstrate that tenascin containing repeat 'C' is actually synthesized by avian cells, a monospecific antiserum was raised against a repeat 'C' fusion protein. This antiserum recognized a novel high-molecular-weight variant on immunoblots of tenascin isolated from chicken embryo fibroblast-conditioned medium, and stained tendons on frozen sections of chicken embryos. A cDNA probe specific for mRNA encoding repeat 'C' was used for in situ hybridization. This probe hybridized in a subset of the embryonic tissues labelled with a universal tenascin probe, including tendons, ligaments and mesenchyme at sites of epithelial-mesenchymal interactions. Finally, we provide evidence that additional fibronectin type III repeats, one corresponding to a recently discovered human repeat as well as one entirely novel sequence, also exists in chicken tenascin mRNA. These data indicate that tenascin is present in the embryonic matrix in a multitude of forms and that these forms have distinctive distributions that may reflect more than one function for tenascin in development.


Unrelated donor or autologous marrow transplantation for treatment of acute leukemia.
High-dose chemoradiotherapy followed by marrow transplantation from an HLA-matched sibling donor is curative for patients with acute leukemia. Autologous marrow transplantation has been used with success for some patients without such a sibling. Alternatively, the option of performing a transplant from an HLA-matched unrelated donor has been made possible by the recent development of large registries of HLA-typed volunteers. The purpose of this study was to compare the outcomes for patients with advanced leukemia treated by unrelated or autologous marrow transplantation. Forty-three patients with acute myeloid or lymphoid leukemia were transplanted from a closely HLA-matched unrelated donor. Results were compared with those of a disease-, disease-stage-, and age-matched cohort of 77 patients treated with autologous marrow transplantation at the same institution during the same period. Myeloid reconstitution with peripheral granulocyte counts greater than 10(9)/L was achieved in 93% of unrelated recipients and 70% of autologous recipients at a median of 24 and 36 days after transplantation, respectively (P = .0001). The cumulative proportions of patients discharged alive (79% v 77%) and times from transplant to first hospital discharge (35 v 34 days) were not different between unrelated and autologous recipients (P = .65). For patients transplanted in complete remission, relapse occurred after transplantation in 27% of the unrelated and in 55% of the autologous recipients (P = .08). For patients transplanted in relapse, the corresponding posttransplant relapse rates were 48% and 63%, respectively (P = .72). Forty percent of unrelated recipients and 28% of autologous recipients died in remission. Leukemia-free survivals were 33% for unrelated and 25% for autologous recipients transplanted in remission (P = .45), and 12% for unrelated and 5% for autologous recipients transplanted in relapse (P = .75). Unrelated donor transplants appear no less effective than autologous transplants to achieve long-term survival and may be more effective in eradicating leukemia in patients who have failed conventional chemotherapy. Further studies are warranted to assess the relative effectiveness of unrelated and autologous transplantation performed earlier in the course of the disease.


Molecular dynamics study of tryptophylglycine: a dipeptide nanotube with confined water.
To investigate the mechanism of structural changes of a peptide nanotube and water confined inside the channel, the helical peptide tryptophylglycine monohydrate (WG.H2O) was studied by molecular dynamics (MD) simulations using the three-dimension parallel MD program ddgmq (software package) and a consistent force field. Simulations were performed on both the water-containing system and a model system without water molecules. The details of the structural behavior with temperature are investigated for the entire simulated temperature range. Phase transitions were obtained at 115, 245, 270, 310, and 385 K, due to the contributions of both the peptide and the confined water subsystems. The crystalline, amorphous, liquidlike, liquid, and superheated phases of water were observed in the temperature ranges 40-115, 115-245, 245-310, 310-385, and >385 K, respectively. At 300 K, the diffusion constant of the confined water is 0.46 x 10-5 cm2 s-1, a value comparable to that of other peptide nanotubes. The empty peptide system melts at 440 K. Mechanisms of the negative thermal expansion (NTE) along the tube axis were investigated for different temperature ranges. The contraction of the crystalline water (or amorphous water) draws also the tube walls in and leads to NTE below 245 K. The other NTEs appear to be connected to the collapse of the ice network or the solid peptide network between 245 K and room temperature or from 310 to 440 K, respectively.


Molecular diagnosis of malaria by photo-induced electron transfer fluorogenic primers: PET-PCR.
There is a critical need for developing new malaria diagnostic tools that are sensitive, cost effective and capable of performing large scale diagnosis. The real-time PCR methods are particularly robust for large scale screening and they can be used in malaria control and elimination programs. We have designed novel self-quenching photo-induced electron transfer (PET) fluorogenic primers for the detection of P. falciparum and the Plasmodium genus by real-time PCR. A total of 119 samples consisting of different malaria species and mixed infections were used to test the utility of the novel PET-PCR primers in the diagnosis of clinical samples. The sensitivity and specificity were calculated using a nested PCR as the gold standard and the novel primer sets demonstrated 100% sensitivity and specificity. The limits of detection for P. falciparum was shown to be 3.2 parasites/µl using both Plasmodium genus and P. falciparum-specific primers and 5.8 parasites/µl for P. ovale, 3.5 parasites/µl for P. malariae and 5 parasites/µl for P. vivax using the genus specific primer set. Moreover, the reaction can be duplexed to detect both Plasmodium spp. and P. falciparum in a single reaction. The PET-PCR assay does not require internal probes or intercalating dyes which makes it convenient to use and less expensive than other real-time PCR diagnostic formats. Further validation of this technique in the field will help to assess its utility for large scale screening in malaria control and elimination programs.


Association between altitude and depression in Peru: An 8-year pooled analysis of population-based surveys.
In high altitude regions, people experience biological, inflammatory and brain structure changes that increase the risk of depressive symptoms. The aim of this study was to determine the association between altitude and depressive symptoms in the Peruvian population, adjusting by demographic, socioeconomic and exposure to health risk factors. We performed a cross-sectional analytical study of data collected annually by the Demographic and Family Health Survey during the period 2013-2020. The presence of depressive symptoms during the last 14 days prior to the survey were measured using scores obtained from the Patient Health Questionnaire-9 (PHQ-9). A generalized linear model (GLM) of gamma family and log link function was used to report the crude and adjusted β coefficients. A quantile regression model was performed as a sensitivity analysis. Data from a total of 215,409 participants were included. After adjusting for demographic, socioeconomic and health risk exposures, the GLM showed that an increase in every 100 m of altitude of residence was positively and significantly associated with the depressive symptoms score (β=0•01 [95% confidence interval: 0•01-0•01]). The length of residence in high altitude areas of the population included cannot be established, requiring future research to determine if the results of the present study are similar in native people or permanent residents of high altitude regions. Altitude was positively associated with depressive symptom scores. Our results will allow the development of mental health interventions based on factors that increase the likelihood of depressive symptoms in high-altitudes.


Integrating microRNA and messenger RNA expression profiles in a rat model of deep vein thrombosis.
Deep vein thrombosis (DVT) is a disease involving multiple genes and systems. MicroRNAs (miRNAs) represent a class of non-coding small RNAs that post-transcriptionally suppress their target genes. The expression patterns of miRNA and messenger RNA (mRNA) in DVT remain poorly characterized. The aim of the present study was to evaluate miRNA and mRNA expression profiles in a stasis-induced DVT rat model. Male SD rats were randomly divided into three groups as follows: DVT, sham and control. The inferior vena cava (IVC) of rats was ligated to construct stasis-induced DVT models. Rats were sacrificed three days after ligation, and morphological changes in the vein tissues were observed by hematoxylin and eosin and Masson staining. The miRNA and mRNA expression profiles were evaluated by microarrays, followed by bioinformatics analysis. The microarray analysis identified 22 miRNAs and 487 mRNAs that were significantly differentially expressed between the experimental and control groups, and between the experimental and sham groups, but not between the control and sham groups (P≤0.05; ≥2.0‑fold change). By subsequent bioinformatics analysis, a 19 miRNA-98 mRNAs network was constructed in the stasis-induced DVT rat model. Notably, the majority of these miRNAs and mRNAs are reported to be expressed by endothelial cells (ECs) and are associated with the function of ECs. The results provide evidence indicating that the regulatory association of miRNA and mRNA points to key roles played by ECs in thrombosis. These findings advance our understanding of the molecular regulatory mechanisms underlying the pathophysiology of DVT.


Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents.
The goal of this work was to define the contributions of intrinsic and synaptic mechanisms toward spontaneous network-wide bursting activity, observed in dissociated rat hippocampal cell cultures. This network behavior is typically characterized by short-duration bursts, separated by order of magnitude longer interburst intervals. We hypothesize that while short-timescale synaptic processes modulate spectro-temporal intraburst properties and network-wide burst propagation, much longer timescales of intrinsic membrane properties such as persistent sodium (Nap) currents govern burst onset during interburst intervals. To test this, we used synaptic receptor antagonists picrotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (CPP) to selectively block GABAA, AMPA, and NMDA receptors and riluzole to selectively block Nap channels. We systematically compared intracellular activity (recorded with patch clamp) and network activity (recorded with multielectrode arrays) in eight different synaptic connectivity conditions: GABAA + NMDA + AMPA, NMDA + AMPA, GABAA + AMPA, GABAA + NMDA, AMPA, NMDA, GABAA, and all receptors blocked. Furthermore, we used mixed-effects modeling to quantify the aforementioned independent and interactive synaptic receptor contributions toward spectro-temporal burst properties including intraburst spike rate, burst activity index, burst duration, power in the local field potential, network connectivity, and transmission delays. We found that blocking intrinsic Nap currents completely abolished bursting activity, demonstrating their critical role in burst onset within the network. On the other hand, blocking different combinations of synaptic receptors revealed that spectro-temporal burst properties are uniquely associated with synaptic functionality and that excitatory connectivity is necessary for the presence of network-wide bursting. In addition to confirming the critical contribution of direct excitatory effects, mixed-effects modeling also revealed distinct combined (nonlinear) contributions of excitatory and inhibitory synaptic activity to network bursting properties.


Demonstration of Coherent Terahertz Transition Radiation from Relativistic Laser-Solid Interactions.
Coherent transition radiation in the terahertz (THz) region with energies of sub-mJ/pulse has been demonstrated by relativistic laser-driven electron beams crossing the solid-vacuum boundary. Targets including mass-limited foils and layered metal-plastic targets are used to verify the radiation mechanism and characterize the radiation properties. Observations of THz emissions as a function of target parameters agree well with the formation-zone and diffraction model of transition radiation. Particle-in-cell simulations also well reproduce the observed characteristics of THz emissions. The present THz transition radiation enables not only a potential tabletop brilliant THz source, but also a novel noninvasive diagnostic for fast electron generation and transport in laser-plasma interactions.


Upright magnetic resonance imaging of the lumbar spine: Back pain and radiculopathy.
Lumbar back pain and radiculopathy are common diagnoses. Unfortunately, conventional magnetic resonance imaging (MRI) findings and clinical symptoms do not necessarily correlate in the lumbar spine. With upright imaging, disc pathologies or foraminal stenosis may become more salient, leading to improvements in diagnosis. Seventeen adults (10 asymptomatic and 7 symptomatic volunteers) provided their informed consent and participated in the study. A 0.6T upright MRI scan was performed on each adult in the seated position. Parameters were obtained from the L2/3 level to the L5/S1 level including those pertaining to the foramen [cross-sectional area (CSA), height, mid-disc width, width, thickness of ligamentum flavum], disc (bulge, height, width), vertebral body (height and width), and alignment (lordosis angle, wedge angle, lumbosacral angle). Each parameter was compared based on the spinal level and volunteer group using two-factor analysis of variance (ANOVA). Bonferroni post hoc analysis was used to assess the differences between individual spinal levels. Mid-disc width accounted for 56% of maximum foramen width in symptomatic volunteers and over 63% in asymptomatic volunteers. Disc bulge was 48% greater in symptomatic volunteers compared to asymptomatic volunteers. CSA was generally smaller in symptomatic volunteers compared to asymptomatic volunteers, particularly at the L4-L5 and L5-S1 spinal levels. Thickness of ligamentum flavum (TLF) generally increased from the cranial to caudal spinal levels where the L4-L5 and L5-S1 spinal levels were significantly thicker than the L1-L2 spinal level. The data implied that upright MRI could be a useful diagnostic option, as it can delineate pertinent differences between symptomatic volunteers and asymptomatic volunteers, especially with respect to foraminal geometry.


Aging research using the common marmoset: Focus on aging interventions.
Traditional animal models have been used to make seminal discoveries in biomedical research including a better understanding of the biology of the aging process. However, translation of these findings from laboratory to clinical populations has likely been hindered due to fundamental biological and physiological differences between common laboratory animals and humans. Non-human primates (NHP) may serve as an effective bridge towards translation, and short-lived NHP like the common marmoset offer many advantages as models for aging research. Here, we address these advantages and discuss what is currently understood about the changes in physiology and pathology that occur with age in the marmoset. In addition, we discuss how aging research might best utilize this model resource, and outline an ongoing study to address whether pharmaceutical intervention can slow aging in the marmoset. With this manuscript, we clarify how common marmosets might assist researchers in geroscience as a potential model for pre-clinical translation.


Exposure to Environmental Tobacco Smoke and Prevalence of Atopic Dermatitis among Adolescents in Kuwait.
This study aimed to (i) assess the prevalence of exposure to environmental tobacco smoke (ETS) at homes, (ii) assess the prevalence of atopic dermatitis and (iii) evaluate the association between ETS exposure and atopic dermatitis status among adolescents. During October 2015, a cross-sectional study design was implemented using a self-administered, modified version of the ISAAC (International Study of Asthma and Allergies in Childhood) questionnaire among students enrolled in nine high schools of one of the six governorates of Kuwait. Prevalence of ETS exposure at home (1 or more smokers at home vs. none) and atopic dermatitis were computed. A multivariable log-binomial regression model was used to evaluate the adjusted association between ETS exposure and atopic dermatitis. Of 800 invited students, 746 (93.3%) participated, of whom 74.8% were Kuwaiti and 50.1% were female with a mean (SD) age of 16.8 (0.68) years. Prevalence of ETS exposure at home was 54%. Prevalence of atopic dermatitis was 14.9%. A final multivariable log-binomial regression model showed that compared with the adolescents free from atopic dermatitis, adolescents with atopic dermatitis were significantly more likely to have had ETS exposure at home (adjusted prevalence ratio = 1.49; 95% CI: 1.03-2.14; p = 0.034) or tended to be female (adjusted prevalence ratio = 1.42; 95% CI: 0.99-2.03; p = 0.054). A high prevalence of ETS exposure at home among adolescents was recorded. ETS exposure and female gender were significantly associated with atopic dermatitis status. Intervention fostering voluntary adoption of a smoke-free home rule may help protect the adolescents against ETS exposure and alleviate the menace of associated morbidity.