An international collaborative family-based whole genome quantitative trait linkage scan for myopic refractive error.
To investigate quantitative trait loci linked to refractive error, we performed a genome-wide quantitative trait linkage analysis using single nucleotide polymorphism markers and family data from five international sites. Genomic DNA samples from 254 families were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel IVb. Quantitative trait linkage analysis was performed on 225 Caucasian families and 4,656 markers after accounting for linkage disequilibrium and quality control exclusions. Two refractive quantitative phenotypes, sphere (SPH) and spherical equivalent (SE), were analyzed. The SOLAR program was used to estimate identity by descent probabilities and to conduct two-point and multipoint quantitative trait linkage analyses. We found 29 markers and 11 linkage regions reaching peak two-point and multipoint logarithms of the odds (LODs)>1.5. Four linkage regions revealed at least one LOD score greater than 2: chromosome 6q13-6q16.1 (LOD=1.96 for SPH, 2.18 for SE), chromosome 5q35.1-35.2 (LOD=2.05 for SPH, 1.80 for SE), chromosome 7q11.23-7q21.2 (LOD=1.19 for SPH, 2.03 for SE), and chromosome 3q29 (LOD=1.07 for SPH, 2.05 for SE). Among these, the chromosome 6 and chromosome 5 regions showed the most consistent results between SPH and SEM. Four linkage regions with multipoint scores above 1.5 are near or within the known myopia (MYP) loci of MYP3, MYP12, MYP14, and MYP16. Overall, we observed consistent linkage signals across the SPH and SEM phenotypes, although scores were generally higher for the SEM phenotype. Our quantitative trait linkage analyses of a large myopia family cohort provided additional evidence for several known MYP loci, and identified two additional potential loci at chromosome 6q13-16.1 and chromosome 5q35.1-35.2 for myopia. These results will benefit the efforts toward determining genes for myopic refractive error.


A study of [2 + 2] cycloaddition-retroelectrocyclization in water: observation of substrate-driven transient-nanoreactor-induced new reactivity.
Organic solvents limit [2 + 2] cycloaddition-retroelectrocyclization (CA-RE) in biological fields. We examined the formation of 1,1,4,4-tetracyanobuta-1,3-dienes (TCBDs) through CA-RE reactions and their unusual reactivity to produce N-heterocyclic compounds when the nature of the surfactant and the concentrations were varied in the aqueous phase. An environment in which transient self-assemblies (vesicles) were induced by the substrate and surfactant molecules initiated new reactivity through H2O addition on the TCBD, generating the enol form of the intermediate, which results in the formation of the 6,6-dicyano-heteropentafulvene (amidofulvene) compound, while lamellar sheets at higher concentrations favored TCBD generation. Interestingly, the amidofulvene underwent a clean transformation to 6-membered heterocycles that resemble cardiotonic drugs (milrinone, amrinone) via keto-enol tautomerism mediated by a polar aprotic solvent, opening up a new avenue for drug discovery. Unlike organic-solvent-mediated CA-RE reactions, the present nanoreactor-mediated approach enabled the selective production of TCBDs as well as new heterocycles using H2O as a green solvent. In addition to the widely explored organic electronics/materials, we believe that this study will help to overcome the long-standing limitation of CA-RE reaction applicability in biological fields.


Research training in psychiatric residency programs: a survey.
Although it seems reasonable to assume that the absence of research training may account for the fact that few psychiatrists involve themselves in research, there is at present little, if any, objective data regarding the extent of research training in psychiatric residency programs. Accordingly, an 11-item questionnaire designed to assess training opportunities and staff and resident interest in research was sent to 400 training facilities in general and child psychiatry. An 82% return rate was obtained. In general, findings suggest that while in many training centers research is viewed as unimportant and frequently given the lowest priority, most facilities appear to have ample personnel to provide adequate research training. While opportunities for research training may be "available" in most training programs for those students sufficiently motivated to seek them out, the low priority assigned to this aspect of training may deflect most residents from becoming involved in research. This is likely to leave the resident poorly equipped to engage in research activities after the completion of training. The implications of the findings for residency training are discussed.


Violations of implicit theories and the sense of prediction and control: implications for motivated person perception.
Beginning with the assumption that implicit theories of personality are crucial tools for understanding social behavior, the authors tested the hypothesis that perceivers would process person information that violated their predominant theory in a biased manner. Using an attentional probe paradigm (Experiment 1) and a recognition memory paradigm (Experiment 2), the authors presented entity theorists (who believe that human attributes are fixed) and incremental theorists (who believe that human attributes are malleable) with stereotype-relevant information about a target person that supported or violated their respective theory. Both groups of participants showed evidence of motivated, selective processing only with respect to theory-violating information. In Experiment 3, the authors found that after exposure to theory-violating information, participants felt greater anxiety and worked harder to reestablish their sense of prediction and control mastery. The authors discuss the epistemic functions of implicit theories of personality and the impact of violated assumptions.


First episode of self-harm in older age: a report from the 10-year prospective Manchester Self-Harm project.
Self-harm is closely related to completed suicide, especially in older age. As empirical research of self-harm in older age is scarce, with no studies confined to first-ever episodes in older age, we examined the clinical characteristics and the risk of repetition in first-ever self-harm in older age. The Manchester Self-Harm (MaSH) project, a prospective cohort study, gathered data from September 1, 1997, through August 31, 2007, for individuals presenting with self-harm at emergency departments of 3 large hospitals in North West England. The characteristics of older patients (aged ≥ 55 years) who presented with a first-ever episode of self-harm are described and compared to those of middle-aged patients (35-54 years) presenting with a first-ever episode of self-harm. Following each episode, the MaSH form, a standard assessment form developed for the MaSH project, was completed by a clinician. Potential risk factors for repetition were examined by Cox regression analyses. A total of 374 older patients and 1,937 middle-aged patients presented with a first-ever episode of self-harm. The circumstances at the time of self-harm suggested higher suicidal intent in older age. In comparison with middle-aged patients, the rate of repetition in older-aged patients was lower (15.4% versus 11.8%, respectively; hazard ratio for older age = 0.65; 95% CI, 0.45-0.93; P = .019), although repetition was more often fatal among the older group (3.3% versus 13.6%, respectively; P = .009). The most important predictor of repetition in older age, ie, physical health problems, had no predictive value in middle-aged patients, whereas psychiatric characteristics had little impact on the risk of repetition in old age. High suicidal intent and different predictors of repetition in first-ever self-harm in older age highlight the need for age-specific interventions beyond the scope of psychiatric care alone.


Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?
Glomerular deposition of monoclonal Ig has been exceptionally described as the cause of membranoproliferative glomerulonephritis, through activation of the complement alternative pathway (CAP). We retrospectively studied six adults with monoclonal gammopathy and glomerulonephritis (GN) characterized by isolated C3 deposits. All patients presented with hematuria, associated with chronic renal failure and proteinuria in five patients, three of whom had nephrotic syndrome. Five patients had monoclonal gammopathy of undetermined significance and one had smoldering myeloma. The serum monoclonal IgG (κ four of six, λ two of six) was associated with light chain (LC) proteinuria in five patients. Four patients had low serum C3 and/or factor B levels. C4, factor H (CFH), and I protein levels were normal in five of five patients; none had detectable C3NeF. IgG anti-CFH activity was positive in one case. No mutations in CFH, CFI, and MCP genes were identified in four of four patients. Deposits were intramembranous, subepithelial, and mesangial by electron microscopy, and stained positive for C3 (six of six), properdin, and CFH (two of two) but negative for Ig LC and heavy chains, C4, and C1q (6/6) by immunofluorescence. Five patients progressed to end-stage renal disease over a median period of 47 months, despite chemotherapy in four patients. In one patient, monoclonal λLC deposits were observed on a follow-up kidney biopsy after 4 years. GN with isolated glomerular C3 deposits might represent an unusual complication of plasma cell dyscrasia, related to complement activation through an autoantibody activity of the monoclonal Ig against a CAP regulator protein.


Effect of Electroacupuncture Combined with Guizhi Gegen Decoction on Cervical Vertigo and Its Influence on TCD of Vertebrobasilar Artery, Blood Rheology Indexes, and Quality of Life.
Cervical vertigo is a common clinical disease. In this study, we investigated the clinical efficacy of adding the treatment protocol of Gui Zhi Ge Gen Tang and electroacupuncture to the Western medical treatment in cervical vertigo. The results showed that the total effective rate of the study group was higher than that of the control group (P < 0.05). After treatment, the vertigo, headache, neck and shoulder pain, daily life and work, and psychological and social adjustment scores were higher in the study group than in the control group (P < 0.05). LVA, RVA, and VB were higher in the study group than in the control group after treatment (P < 0.05). The whole blood viscosity high cut, whole blood viscosity low cut, and plasma viscosity levels were lower in the study group than in the control group after treatment (P < 0.05). After treatment, PF, RF, RE, BP, GH, VT, SF, MH, and HT were higher in the study group than those before treatment (P < 0.05). The incidence of adverse reactions was not statistically significant in the study group compared with the control group (P > 0.05). This means that electroacupuncture combined with Gui Zhi Ge Gen Tang can effectively increase the blood flow velocity of the vertebrobasilar artery in patients with cervical vertigo and improve their blood rheology and quality of life with definite efficacy and high safety.


'One Health' infectious diseases surveillance in Tanzania: are we all on board the same flight?
Infectious diseases account for nearly 40% of the burden of human mortality and morbidity in low-income countries, of which 7% is attributable to zoonoses and 13% to recently emerging diseases from animals. One of the strategic approaches for effective surveillance, monitoring and control of infectious diseases compromising health in both humans and animals could be through a combination of multiple disciplines. The approach can be achieved through a joint effort from stakeholders comprising health professionals (medical and veterinary), social, economic, agricultural, environmental and other interested parties. With resource scarcity in terms of number of staff, skills and facility in low-income countries, participatory multi- sectoral and multidisciplinary approaches in limiting the burden of zoonotic diseases could be worthwhile. We review challenging issues that may limit the 'One Health' approach for infectious diseases surveillance in Tanzania with a focus on Health Policy and how best the human and animal health systems could be complemented or linked to suit the community in need for disease control under the theme's context.


Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study.
Determine incidence of posttraumatic seizure (PTS) following traumatic brain injury (TBI) among individuals with moderate-to-severe TBI requiring rehabilitation and surviving at least 5 years. Using the prospective TBI Model Systems National Database, we calculated PTS incidence during acute hospitalization, and at years 1, 2, and 5 postinjury in a continuously followed cohort enrolled from 1989 to 2000 (n = 795). Incidence rates were stratified by risk factors, and adjusted relative risk (RR) was calculated. Late PTS associations with immediate (<24 h), early (24 h-7 day), or late seizures (>7 day) versus no seizure prior to discharge from acute hospitalization was also examined. PTS incidence during acute hospitalization was highest immediately (<24 h) post-TBI (8.9%). New onset PTS incidence was greatest between discharge from inpatient rehabilitation and year 1 (9.2%). Late PTS cumulative incidence from injury to year 1 was 11.9%, and reached 20.5% by year 5. Immediate/early PTS RR (2.04) was increased for those undergoing surgical evacuation procedures. Late PTS RR was significantly greater for individuals who self-identified as a race other than black/white (year 1 RR = 2.22), and for black individuals (year 5 RR = 3.02) versus white individuals. Late PTS was greater for individuals with subarachnoid hemorrhage (year 1 RR = 2.06) and individuals age 23-32 (year 5 RR = 2.43) and 33-44 (year 5 RR = 3.02). Late PTS RR years 1 and 5 was significantly higher for those undergoing surgical evacuation procedures (RR: 3.05 and 2.72, respectively). In this prospective, longitudinal, observational study, PTS incidence was similar to that in studies published previously. Individuals with immediate/late seizures during acute hospitalization have increased late PTS risk. Race, intracranial pathologies, and neurosurgical procedures also influenced PTS RR. Further studies are needed to examine the impact of seizure prophylaxis in high-risk subgroups and to delineate contributors to race/age associations on long-term seizure outcomes.


Solution Combustion Synthesis of Porous MgO Nanostructures for Efficient Removal of Congo Red.
Porous MgO nanostructures were synthesized in large-scale by a simple solution combustion method using citric acid and glucose as the fuel. The resulting porous nanostructure powders were characterized by X-ray diffraction (XRD), scanning electronic microscopy (SEM), transmission electron microscopy (TEM), and N₂ adsorption-desorption isotherms. The SEM and TEM images demonstrated that the type of fuel used during the combustion synthesis strongly affects the morphology and structure. The use of glucose aggregated the structure with majority particle sizes in the range 3560 nm and a surface area of 40.55 m²g-1, while the use of citric acid results in a large network structure with smaller particle sizes (30-50 nm) and a larger surface area of 53.88 m²g-1. The two samples synthesized from glucose and citric acid exhibited excellent adsorption performance for Congo red with the maximum capacity reaching 1500.98 mg g-1 and 1638.08 mg g-1, respectively. These results indicate that the porous MgO synthesized by the solution combustion is a potential candidate for the removal of pollutant dye in water.


Who is HOT and who is LOT? Detailed characterization of prescription opioid-induced changes in behavior between 129P3/J and 129S1/SvlmJ mouse substrains.
Genetic factors are theorized to contribute to the substantial inter-individual variability in opioid abuse/addiction. To advance the behavioral genetics of prescription opioid abuse, our prior work identified the 129S1/SvlmJ (S1) and related 129P3/J (P3) mouse substrains, respectively, as low and high opioid-taking. Herein, we related our prior results to measures of sucrose reward/reinforcement, basal anxiety, opioid-induced place-conditioning, locomotor activity and Straub tail reaction, as well as behavioral and physiological signs of withdrawal. Substrains were also re-examined for higher-dose oxycodone and fentanyl intake under limited-access drinking procedures. S1 mice failed to acquire sucrose self-administration under various operant-conditioning procedures and exhibited lower sucrose intake in the home-cage. However, sucrose intake under limited-access procedures escalated in both substrains with repeated sucrose experience. S1 mice exhibited less spontaneous locomotor activity, as well as less opioid-induced locomotor activity and Straub tail reaction, than P3 mice and failed to exhibit an oxycodone-induced place-preference. The lack of conditioned behavior by S1 mice was unrelated to behavioral signs of withdrawal-induced negative affect or dependence severity, but might reflect high levels of basal anxiety-like behavior. Intriguingly, S1 and P3 mice initially exhibited equivalent oxycodone and fentanyl consumption in the home-cage; however opioid intake escalated only in P3 mice with repeated opioid experience. No sex differences were observed for any of our measures. These data provide additional evidence for robust differences in opioid addiction-related behaviors between P3 and S1 substrains and suggest that anxiety, learning, and/or motivational impairments might confound interpretation of operant- and place-conditioning studies employing the S1 substrain.


Performance of international prognostic indices in plasmablastic lymphoma: a comparative evaluation.
Plasmablastic lymphoma (PBL) is a rare and aggressive B-cell malignancy with a heterogenous clinical and prognostic spectrum, determined by multiple factors, including age, HIV- and MYC-status. While there exist several validated scoring systems for diffuse large B-cell lymphoma, which incorporate basic clinical features (age, lactate dehydrogenase, sites of (extranodal) involvement, stage and performance), none of these have been systematically assessed in PBL. We determined the (age-adjusted; aa)-International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI) in a comprehensive multi-center cohort (n = 78) of PBL patients. Further, all indices were comparatively investigated for model quality and concordance. Univariate analysis revealed significant prognostic capabilities for all indices, all of which identified a subgroup with favorable outcome. Discriminatory power between patients with less benign prognosis and especially refractory disease exhibited significant variability. Subsequently, stratified models for each risk score were compared employing corrected Akaike's information criterion (cAIC) and Harrel's concordance index (c-index). Here, the NCCN-IPI outperformed both IPI and R-IPI regarding c-index with ambiguous cAIC results, underlining its clinical utility and suggesting it for preferential use in clinical practice. Our current observations support the use of the IPI and its enhanced derivatives in PBL patients. There is, however, a distinct requirement for novel prognostic tools to better delineate subgroups at risk for early relapse or refractory disease as well as late relapse. A comprehensive molecular characterization of a clinically annotated cohort of PBL patients is therefore urgently warranted.


NIH conference: Primary biliary cirrhosis: a model autoimmune disease.
Primary biliary cirrhosis is characterized by chronic inflammation and necrosis of the intrahepatic bile ducts and by chronic cholestasis. The presence of autoantibodies in serum, the association of this disease with other autoimmune diseases, the histologic appearance of typical hepatic lesions, the presence of bile duct lesions that resemble those seen in chronic graft-versus-host disease, and the possible recurrence of a chronic cholestatic syndrome in patients having hepatic transplants indicate that immune mechanisms play a role in the syndrome's pathogenesis. Patients have diminished function of suppressor T cells that may be due to abnormal activation of suppressor T cells caused by interactions with autologous non-T cells. This nonspecific immunologic defect and other immune defects may cause the autoimmune manifestations of primary biliary cirrhosis. Treatments to arrest the disease's progress have included corticosteroids, azathioprine, cyclosporin, and D-penicillamine. These treatments, which affect immune functions, have not had a beneficial effect on the disease process. Better understanding of the pathogenesis of primary biliary cirrhosis is needed to develop specific immunotherapies.


Evaluation of EMLA cream for preventing pain during tattooing of rabbits: changes in physiological, behavioural and facial expression responses.
Ear tattooing is a routine procedure performed on laboratory, commercial and companion rabbits for the purpose of identification. Although this procedure is potentially painful, it is usually performed without the provision of analgesia, so compromising animal welfare. Furthermore, current means to assess pain in rabbits are poor and more reliable methods are required. The objectives of this study were to assess the physiological and behavioural effects of ear tattooing on rabbits, evaluate the analgesic efficacy of topical local anaesthetic cream application prior to this procedure, and to develop a scale to assess pain in rabbits based on changes in facial expression. In a crossover study, eight New Zealand White rabbits each underwent four different treatments of actual or sham ear tattooing, with and without prior application of a topical local anaesthetic (lidocaine/prilocaine). Changes in immediate behaviour, heart rate, arterial blood pressure, serum corticosterone concentrations, facial expression and home pen behaviours were assessed. Changes in facial expression were examined to develop the Rabbit Grimace Scale in order to assess acute pain. Tattooing without EMLA cream resulted in significantly greater struggling behaviour and vocalisation, greater facial expression scores of pain, higher peak heart rate, as well as higher systolic and mean arterial blood pressure compared to all other treatments. Physiological and behavioural changes following tattooing with EMLA cream were similar to those in animals receiving sham tattoos with or without EMLA cream. Behavioural changes 1 hour post-treatment were minimal with no pain behaviours identifiable in any group. Serum corticosterone responses did not differ between sham and tattoo treatments. Ear tattooing causes transient and potentially severe pain in rabbits, which is almost completely prevented by prior application of local anaesthetic cream. The Rabbit Grimace Scale developed appears to be a reliable and accurate way to assess acute pain in rabbits.


HIV-1 gp120 Promotes Lysosomal Exocytosis in Human Schwann Cells.
Human immunodeficiency virus type 1 (HIV-1) associated neuropathy is the most common neurological complication of HIV-1, with debilitating pain affecting the quality of life. HIV-1 gp120 plays an important role in the pathogenesis of HIV neuropathy via direct neurotoxic effects or indirect pro-inflammatory responses. Studies have shown that gp120-induced release of mediators from Schwann cells induce CCR5-dependent DRG neurotoxicity, however, CCR5 antagonists failed to improve pain in HIV- infected individuals. Thus, there is an urgent need for a better understanding of neuropathic pain pathogenesis and developing effective therapeutic strategies. Because lysosomal exocytosis in Schwann cells is an indispensable process for regulating myelination and demyelination, we determined the extent to which gp120 affected lysosomal exocytosis in human Schwann cells. We demonstrated that gp120 promoted the movement of lysosomes toward plasma membranes, induced lysosomal exocytosis, and increased the release of ATP into the extracellular media. Mechanistically, we demonstrated lysosome de-acidification, and activation of P2X4 and VNUT to underlie gp120-induced lysosome exocytosis. Functionally, we demonstrated that gp120-induced lysosome exocytosis and release of ATP from Schwann cells leads to increases in intracellular calcium and generation of cytosolic reactive oxygen species in DRG neurons. Our results suggest that gp120-induced lysosome exocytosis and release of ATP from Schwann cells and DRG neurons contribute to the pathogenesis of HIV-1 associated neuropathy.


Predicting factors of postoperative complications in appendectomies.
to evaluate the main risk factors for postoperative complications in patients undergoing appendectomy for acute appendicitis. we retrospectively analyzed 1241 patients undergoing open or laparoscopic appendectomy. Patients were allocated to four groups: Group 1, without postoperative complications, and Groups 2, 3, and 4, with postoperative complications defined according to their severity, following Clavien-Dindo classification (I, II, and ≥III, respectively). patients aged ≥38.5 years had more severe complications (p<0.0001). Patients in Group 1, without postoperative complications, had, for the most part, a laparoscopic approach. Groups 2, 3, and 4 underwent, predominantly, to an open surgery (p<0.0001). In cases of acute appendicitis, the odds ratio (OR) for complications was 3.09, 3.04, and 12.41 for Groups 2, 3, and 4, respectively (p<0.0001). Anesthetic risk, duration of the procedure, and length of hospital stay were related to a higher risk and severity of complications. the main predicting factors of postoperative complications in patients operated for acute appendicitis were: age ≥38.5 years, conventional or open surgical access, complicated appendicitis, ASA≥2, and surgical time >77 minutes.


STRategies to manage Emergency ambulance Telephone Callers with sustained High needs: an Evaluation using linked Data (STRETCHED) - a study protocol.
UK ambulance services have identified a concern with high users of the 999 service and have set up 'frequent callers' services, ranging from within-service management to cross-sectoral multidisciplinary case management approaches. There is little evidence about how to address the needs of this patient group. To evaluate effectiveness, safety and efficiency of case management approaches to the care of people who frequently call the emergency ambulance service, and gain an understanding of barriers and facilitators to implementation. (1) Develop an understanding of predicted mechanisms of change to underpin evaluation. (2) Describe epidemiology of sustained high users of 999 services. (3) Evaluate case management approaches to the care of people who call the 999 ambulance service frequently in terms of: (i) Further emergency contacts (999, emergency department, emergency admissions to hospital) (ii) Effects on other services (iii) Adverse events (deaths, injuries, serious medical emergencies and police arrests) (iv) Costs of intervention and care (v) Patient experience of care. (4) Identify challenges and opportunities associated with using case management models, including features associated with success, and develop theories about how case management works in this population. We will conduct a multisite mixed-methods evaluation of case management for people who use ambulance services frequently by using anonymised linked routine data outcomes in a 'natural experiment' cohort design, in four regional ambulance services. We will conduct interviews and focus groups with service users, commissioners and emergency and non-acute care providers. The planned start and end dates of the study are 1 April 2019 and 1 September 2022, respectively ETHICS AND DISSEMINATION: The study received approval from the UK Health Research Authority (Confidentiality Advisory Group reference number: 19/CAG/0195; research ethics committee reference number: 19/WA/0216).We will collate feedback from our Lived Experience Advisory Panel, the Frequent Caller National Network and Research Management Group for targeted dissemination activities.


Biological mediators for periodontal regeneration.
A review of the literature on the use of growth-regulatory molecules in the oral cavity permits a model in which to consider approaches to oral tissue engineering. These concepts apply to periodontal regeneration and to regeneration of alveolar bone. In either case, the formation of tissues is complex but proceeds in a deliberate and orderly sequence. In these sequence of events resulting in either bone or cementum formation, periodontal ligament and bone can be stimulated at various points. Different signals can apparently be used to stimulate tissue formation including mitogenic signals and differentiation factors. Additionally, both hard and soft tissue stimulatory molecules appear to be permissive. Classic receptor-mediated peptides or extracellular matrix molecules for soft and hard tissues appear to allow stimulation of tissue formation cascades. Importantly, it also appears that the stimulatory event is transitory (that is, short-lived) and leads itself to a sequence of cellular events. These cellular events in turn stimulate a number of subsequent events (such as chemotaxis, proliferation, differentiation or angiogenesis), which lead to further progression of tissue formation. While a solid scientific rationale exists for the use of a variety of growth and attachment factors in regeneration of oral tissues, only a small number are being pursued clinically. Many therapeutic regimens have failed in preclinical testing or have resulted in limited regenerative capacity. The mitogenic polypeptides that stimulate soft tissue growth (such as platelet-derived growth factor) and both hard and soft tissue growth (such as transforming growth factor-beta) appear to have not led to successful enough outcomes to facilitate further work towards regulatory approval. The demonstrated ability of bone morphogenetic proteins to generate substantial quantities of bone suggest many applications in the oral cavity where this is the only tissue desired. Another therapeutic candidate is enamel matrix derivative, a set of matrix proteins. Enamel matrix derivative appears to stimulate first acellular cementum formation, which may allow for functional periodontal ligament formation. It will be of interest in the future to determine whether the protein matrix contains classic mitogenic or differentiation factors as well as the amelogenins. It is also evident that the bone morphogenetic proteins permit periodontal ligament formation. The conditions for stimulating predictable periodontal ligament tissues with bone morphogenetic proteins however are not known. It is clear that the bone morphogenetic proteins are excellent molecules for stimulating oral bone formation. The results of all these studies will determine the future therapeutic potential for these growth molecules such that they may be used to optimally stimulate and direct specific points along tissue formation cascades.


Amylosin from Bacillus amyloliquefaciens, a K+ and Na+ channel-forming toxic peptide containing a polyene structure.
Bacillus amyloliquefaciens strains isolated from the indoor environment of moisture-damaged buildings produce a 1197 Da toxin, named amylosin. Nuclear magnetic resonance (NMR) data showed that amylosin contains a chromophoric polyene structure and the amino acids leucine/isoleucine, proline, aspartic acid/asparagine, glutamic acid/glutamine and tyrosine. A quantitation method for amylosin was developed using commercially available amphotericin B as a reference compound and a known concentration of amylosin determined by NMR with the electronic reference to access in vivo concentration (ERETIC) method. Purified amylosin inhibited motility of boar sperm cells at an exposure concentration of 135 nM and hyperpolarized their cell membrane and depolarized their mitochondria at exposure to concentration of 33-67 nM for 10 min. In a 3-d exposure time only 27 nM of amylosin was needed to provoke the same toxicity functions. Amylosin was cytotoxic to feline lung cells at concentrations of <170 nM. Purified amylosin provoked adenosine 5'-triphosphate (ATP)-independent cation influx into isolated rat liver mitochondria (RLM), inducing swelling of the mitochondria at concentrations of 200 nM K(+) or >250 nM Na(+) medium. In the K(+)- or Na(+)-containing medium, amylosin uncoupled RLM, causing oxidation of pyridine nucleotides (PN), loss of the mitochondrial membrane potential, and suppressed ATP synthesis. Purified amylosin produced cation channels in black-lipid membranes (BLMs) with a selectivity K(+)>Na(+) at a concentration of 26 nM, i.e. the same concentration at which amylosin was toxic to boar sperm cells. The amylosin cation channels were cholesterol- and ATP-independent and more effective with K(+) than with Na(+). We propose that the toxicity of amylosin may be due its ionophoric properties, representing the first K(+)/Na(+) channel-forming substance reported from B. amyloliquefaciens.


5-HTTLPR status moderates the effect of early adolescent substance use on risky sexual behavior.
A longitudinal, prospective design was used to investigate a moderation effect in the association between early adolescent substance use and risky sexual behavior 2 years later. A genetic vulnerability factor, a variable nucleotide repeat polymorphism (VNTR) in the promoter region of the serotonin transporter gene SLC6A4, known as 5-HTTLPR, was hypothesized to moderate the link between substance use at age 14 and risky sexual behavior at age 16. This VNTR has been associated with risk-taking behavior. African American youths in rural Georgia (N = 185) provided 2 waves of data on their substance use and sexual behavior. Genetic data were obtained via saliva samples. Substance use and sexual risk behavior were assessed using youth self-report items developed for this investigation. Multiple regression analyses indicated that the presence of 1 or 2 copies of the short allele of the VNTR interacted with substance use to predict sexual behavior. Substance use had little effect on sexual behavior for youths without the short allele; this effect was greatly increased for youths with the short allele. Genetic vulnerability affected the implications of early onset substance use for later sexual behavior.


Phosphodiesterase 5 Inhibitor for Pediatric Pulmonary Arterial Hypertension: A Cost-Utility Analysis.
Despite the growing evidence of efficacy, scarce information exists regarding the cost of tadalafil to improve the functional classes of pediatric patients with pulmonary arterial hypertension. This study aims to determine the cost-utility of tadalafil compared sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. A Markov model was developed to compare expected costs, outcomes, and quality-adjusted life-years of sildenafil and tadalafil in pediatric patients with pulmonary arterial hypertension. The model was analyzed probabilistically, and a value of information analysis was conducted to inform the value of conducting further research to reduce current uncertainties in the evidence base. Cost-effectiveness was evaluated at a willingness-to-pay value of US $5180. The mean incremental cost of tadalafil versus sildenafil is US $15 270. The 95% credible interval for the incremental cost ranges from US $28 033.65 to US $5940.86. The mean incremental benefit of tadalafil versus sildenafil is 1.00 quality-adjusted life-years (QALY). The 95% credible interval for the incremental benefit ranges from 1.88 to 0.31 QALY. The expected incremental cost per QALY is estimated at US $15 286. There is a probability less than 1% that tadalafil is more cost-effective than sildenafil at a threshold of US $5180 per QALY. Form the value of information analysis, the theoretical upper bound on the value of further research was US $9.298 for Colombia. Our economic evaluation shows that tadalafil is not cost-effective regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines.


CT scan for suspected acute abdominal process: impact of combinations of IV, oral, and rectal contrast.
BACKGROUND There are limited data available on the ability of computed tomography (CT) to accurately diagnose abdominopelvic pathology in acutely ill inpatients suspected of having an acute abdominal process. The purpose of this study was to evaluate the diagnostic accuracy of abdominal/pelvic CT with varying use of contrast agents in hospitalized patients. METHODS A retrospective review of all hospital inpatients (3/1/07-5/31/07) who underwent urgent or emergent abdominal/pelvic CT with any combination of contrast, intravenous (IV), oral, rectal, or unenhanced for a suspected acute abdominal process was performed. Data collected included demographics, combination of contrast used, CT diagnosis, time from CT scan to subsequent intervention, intervention type, and actual diagnosis of the acute abdominal process. Accuracy of CT was compared between enhanced and unenhanced imaging using Fisher's exact test. RESULTS A total of 661 patients were identified. Use of IV contrast alone was found in 54.2% of CT scans and was correct in 92.5% of cases. IV and oral contrast was used in 22.2% of CT scans and was 94.6% correct. Unenhanced imaging was performed in 16.2% and was correct in 92.5%. Oral contrast alone was used in 7.0% and was 93.5% correct. There was no significant difference in the ability to correctly diagnose a suspected acute abdominal process when enhanced CT imaging was compared to unenhanced (p > 0.05). CONCLUSIONS CT contrast administration in critically ill hospitalized patients is not necessary to accurately diagnose an acute abdominal process. Eliminating the use of contrast may improve patient comfort, decrease patient risk, and minimize financial cost.


Periungual verrucae. Diagnosis and treatment.
In order to diagnose periungual verrucae the practitioner must be able to rely on clinical judgment and choose the best treatment for the patient. This article provides multiple treatment options with advantages and disadvantages to aid the decision-making process.


Degradation and loss of matrix proteins from developing enamel.
The pattern and timing of the breakdown and loss of matrix proteins were studied in developing rat incisor enamel using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), fluorography, radioautography, and in vitro incubations of proteins isolated from freshly dissected, crushed pieces of enamel. For biochemical studies, the technique of Robinson et al. (1974, 1977, 1983) was used to transect the enamel organ and enamel into a series of strips at 1 mm intervals along the length of the tooth. The proteins in each strip were extracted and either quantified by Lowry analysis or applied to 12% slab (enamel) or 5-15% continuous gradient (enamel organ) SDS-polyacrylamide gels and separated by electrophoresis. The biochemical studies indicated that the amount of protein contained within an enamel strip increased gradually by volume across the secretory stage, reached a peak early during the maturation stage, and then declined rapidly thereafter. The distribution of enamel proteins on SDS-polyacrylamide gels changed markedly throughout this period. These changes included increases and decreases in the intensity of staining of proteins at certain molecular weights (e.g., 18 kDa) and the appearance and disappearance of some proteins not seen clearly near the start of the secretory stage of amelogenesis (e.g., 32 and 10 kDa). Labeling studies with 35S-methionine suggested that the "stacked" arrangement of proteins typical of forming enamel (secretory stage) actually represented a very dynamic association of proteins, with new ones being added at the top of the stack and then breaking down with time to become those seen at lower molecular weights. Across the secretory stage, new proteins were always added to the top of the stack, but during early maturation this activity slowed dramatically, allowing the breakdown of aging proteins to be visualized more clearly. Radioautographic studies with 3H-methionine indicated that the breakdown of newly secreted proteins also was correlated with a movement of label from the site of secretion into deeper, previously unlabeled, areas of forming enamel. In vitro studies revealed that the rate and degree of breakdown of enamel proteins varied markedly, depending on the stage of amelogenesis from which the proteins were extracted. Secretory stage enamel proteins showed slow in vitro degradation with accumulation of proteins near 18 kDa. Early maturation stage enamel proteins showed more rapid breakdown with little accumulation of proteins near 18 kDa, whereas late maturation stage enamel proteins showed complete degradation by 2 days of incubation in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)


Do clinical variables predict pathologic radiographs in the first episode of wheezing?
To determine if clinical variables assessed in relation to Albuterol aerosol treatments accurately identify children with pathologic radiographs during their initial episode of bronchospasm. A prospective convenience sample of children with a first episode of wheezing. Data collected included demographics, baseline and post-treatment clinical score and physical examination, number of aerosols, requirement for supplemental oxygen, and disposition. Chest radiographs were obtained and interpreted, and patients were divided into 2 groups based on a pathologic versus nonpathologic radiograph interpretation. Chi2 testing was performed for categoric variables, and the student t test was performed for continuous variables. A discriminant analysis was used to develop a model. Pathologic radiographs were identified in 61 patients (9%). Between groups, a significant difference was noted for pretreatment oxygen saturation only. Clinical score, respiratory rate, and presence of rales both pretreatment and posttreatment were not significantly different between groups. The discriminant analysis correctly predicted 90% of nonpathologic radiographs but only 15% of pathologic radiographs. Clinical variables, either isolated or as components of a model, could not identify all children with pathologic radiographs.


Contributions of primary coordination ligands and importance of outer sphere interactions in UFsc, a de novo designed protein with high affinity for metal ions.
Metalloproteins constitute nearly half of all proteins and catalyze some of the most complex chemical reactions. Recently, we reported a design of 4G-UFsc (Uno Ferro single chain), a single chain four-helical bundle with extraordinarily high (30 pM) affinity for zinc. We evaluated the contribution of different side chains to binding of Co(II), Ni(II), Zn(II) and Mn(II) using systematic mutagenesis of the amino acids that constitute the primary metal coordination and outer spheres. The binding affinity of proteins for metals was then measured using isothermal titration calorimetry. Our results show that both primary metal coordination environment and side chains in the outer sphere of UFsc are highly sensitive to even slight changes and can be adapted to binding different 3d metals, including hard-to-tightly bind metal ions such as Mn(II). The studies on the origins of tight metal binding will guide future metalloprotein design efforts.


[School Food in Brazil and the United States: an integrative review].
This paper is an integrative review of the literature that sought to identify the factors that influence the adhesion and acceptance of school food among Brazilian and American students, and to show the main differences between the programs of these two countries. the following databases were consulted: Latin American and Caribbean Health Sciences (Lilacs); Pubmed; Scientific Electronic Library Online (Scielo); and Science Direct. Data were collected between July and August 2015, using the following key words in Portuguese and English: "adherence to school food" (adesão à alimentação escolar), "accepting of school feeding" (aceitação à alimentação escolar) and the "National School Lunch Program" ("Programa Nacional de Alimentação Escolar"). The search resulted in 7 Brazilian articles and 7 Americans articles published between 2004 and 2014, besides the current laws of each program, selected in the electronic sites of agencies responsible for administrating them. After descriptive and comparative analysis, the results revealed that adherence and acceptance are low in both programs, and they are influenced by socioeconomic factors, competitive foods present in the school environment and students' food preferences.


Reporting cumulative proportion of subjects with an adverse event based on data from multiple studies.
Experience has shown us that when data are pooled from multiple studies to create an integrated summary, an analysis based on naïvely-pooled data is vulnerable to the mischief of Simpson's Paradox. Using the proportions of patients with a target adverse event (AE) as an example, we demonstrate the Paradox's effect on both the comparison and the estimation of the proportions. While meta analytic approaches have been recommended and increasingly used for comparing safety data between treatments, reporting proportions of subjects experiencing a target AE based on data from multiple studies has received little attention. In this paper, we suggest two possible approaches to report these cumulative proportions. In addition, we urge that regulatory guidelines on reporting such proportions be established so that risks can be communicated in a scientifically defensible and balanced manner.


Doxorubicin induces apoptosis by activation of caspase-3 in cultured cardiomyocytes in vitro and rat cardiac ventricles in vivo.
Doxorubicin (DOX) is widely used to treat patients suffering from cancer, but the usage for patients is limited because of the dose-dependent cardiotoxicity. We hypothesized that DOX induces apoptosis through caspase activation in cardiomyocytes, and we examined this hypothesis using both rat primary cultured cardiomyocytes and rat hearts from an animal model. Cardiomyocytes were treated with DOX for 24 h. The activity of caspase-3 was significantly increased by DOX treatment. In rats with DOX injected intravenously once a week for 5 weeks, left ventricular fractional shortening evaluated by echocardiography was significantly decreased at age 14 weeks, 2 weeks after the end of DOX-administration. At 16 weeks of age, endothelin-1 mRNA and atrial natriuretic peptide mRNA were also significantly increased, likewise, and TUNEL positive cells were significantly increased in the ventricles of DOX-treated rats. The activity of caspase-3 in the ventricles was also significantly increased compared to that of untreated rats at 16 weeks. However, the activity of caspase-8 and the expression level of Fas-ligand mRNA were comparable with those of the untreated rats. In conclusion, DOX induces apoptosis through the activation of caspase-3, suggesting that apoptosis has an important role in the progression of cardiomyopathy due to DOX.


Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient.
Human breast tumors often exist in an acidic and hypoxic microenvironment, which can promote resistance to radiation and chemotherapies. A tumor-selective pH gradient arises in these tumors which favors uptake and retention of drugs like camptothecin that are weak acids. We evaluated the effect of alkyl substitutions at the 7 position in seven CPTs with varying groups at the 10 position on modulation by acidic extracellular pH in three human breast cancer cell lines. Growth inhibition was assessed by propidium iodide staining of nucleic acids in human breast cancer cells cultured at either extracellular pH 6.8 or 7.4 that were (1) hormone-sensitive (MCF-7/wt), (2) hormone insensitive (MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc). Over 10-fold pH modulation was observed in 7-halomethyl analogs of methylenedioxy-CPT and in 7-alkyl analogs of 10-amino-CPT. Of 39 analogs tested, the overall pattern of activity across breast tumor cell lines was similar with some notable exceptions. For example, 7-propyl-10-amino-CPT was modulated 16- to 20-fold by acidic extracellular pH in the MCF-7 cell lines, but only 6-fold in MDA-MB-231 cells. One mechanism that can contribute to pH modulation is enhanced cellular drug uptake and retention. In MCF-7/wt cells, uptake of 10-amino-CPT increased 4-fold, while retention increased over 10-fold at acidic extracellular pH. In addition, gene expression analysis of MCF-7/wt cells indicated that expression of a number of genes changed under acidic culture conditions, including down-regulation of the CPT efflux protein pump breast cancer resistance protein (BCRP). Interestingly, expression of topoisomerase I, the molecular target of CPT, was not affected by acidic growth conditions. These results highlight the importance of maintaining key features of tumor physiology in cell culture models used to study cancer biology and to discover and develop new anticancer drugs. While several substitutions at the 7 and 10 positions enhance potency, 7-halomethyl and 10-amino CPT analogs show selective activity at the acidic pH common to the microenvironment of most solid tumors.


Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function.
The human immunodeficiency virus rev gene product regulates the expression of viral structural genes. It was recently shown that Rev regulates the export of viral structural mRNAs from the nucleus to the cytoplasm. Analysis of Rev subcellular localization reveals marked accumulation in the nucleolus, suggesting a role for the nucleolus in this export process. We report here the identification of amino acid residues critical to the nucleolar localization of Rev. Consistent with this finding, a Rev/beta-galactosidase fusion protein, harboring this region of Rev, localized entirely within the nucleolus. Of most significance, mutations that eliminated nucleolar localization markedly diminished Rev function, even though accumulation in the nucleoplasm was retained. These findings support a model whereby Rev-induced export of human immunodeficiency virus structural mRNAs from the nucleus to the cytoplasm is likely to involve nucleolar events.


Is there a role for small molecule metabolite biomarkers in the development of a diagnostic test for endometriosis?
Endometriosis is a disease defined by the presence of benign lesions of endometrial-like glands and stroma outside the endometrial cavity. Affecting an estimated 11.4% of Australian women, symptoms include chronic pelvic pain, dysmenorrhea and infertility. The current gold standard of diagnosis requires an expensive and invasive laparoscopic surgery, resulting in delayed time to treatment. The identification of a non-invasive endometriosis biomarker - a measurable factor correlating with disease presence or activity - has therefore become a priority in endometriosis research, although no biomarker has yet been validated. As small molecule metabolites and lipids have emerged as a potential focus, this review with systematic approach, aims to summarize studies examining metabolomic biomarkers of endometriosis in order to guide future research. EMBASE, PubMed and Web of Science were searched using keywords: lipidomics OR metabolomics OR metabolome AND diagnostic tests OR biomarkers AND endometriosis, and only studies written in English from August 2000 to August 2020 were included. Twenty-nine studies met inclusion and exclusion criteria and were included. These studies identified potential biomarkers in serum, ectopic tissue, eutopic endometrium, peritoneal fluid, follicular fluid, urine, cervical swabs and endometrial fluid. Glycerophospholipids were identified as potential biomarkers in all specimens, except urine and cervical swab specimens. However, no individual molecule or metabolite combination has reached clinical diagnostic utility. Further research using large study populations with robust patient phenotype and specimen characterisation is required if we are to make progress in identifying and validating a non-invasive diagnostic test for endometriosis.


Predictors of surgical outcomes following anterior transposition of ulnar nerve for cubital tunnel syndrome: a systematic review.
Although cubital tunnel syndrome is the second most common nerve entrapment neuropathy, few studies explore potential predictor(s) of surgical outcomes. The purpose of this systematic review was to determine which factors affect the postoperative outcome for patients who undertake anterior transposition of the ulnar nerve. We included all studies reporting predictor(s) of clinical, electrophysiological study, or functional outcome after any anterior transposition of the ulnar nerve. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and CINAHL from 1980 to April 2011 and reference lists of articles. Two reviewers performed study selection, assessment of methodological quality, and data extraction independently of each other. We assessed 26 studies including 2 randomized controlled trials, 10 cohort studies, and 14 case series. Overall, the methodological quality of the studies ranged from low to moderate. Six aspects of prognosis were sufficiently studied for a narrative evidence synthesis on age, duration of symptom, severity of operative status, preoperative electrodiagnostic testing results, type of surgery, and work compensation status. Evidence was conflicting across studies in terms of both the direction and intensity of the impact of these 6 potential predictors on surgical outcomes. Because of conflicting results, we were unable to conclude which predictor(s) affect surgical outcomes after anterior transposition of the ulnar nerve. Surgeons who are aware of only a limited number of prognostic studies and their limited scope of evidence may not appreciate the extent of the inconsistency about whether factors commonly viewed as prognostic actually have a noteworthy impact on outcomes achieved. Such factors may be identified in the future with higher-quality studies, because limitations in the current research undoubtedly contribute to the controversies observed.


Angiopathic serum factor in perinephritic hypertensive dogs.
To investigate the role of circulating humoral substances in the pathogenesis of increased vascular wall water and sodium concentration in experimental hypertension, rabbit aortic media explants were cultured in tissue culture medium supplemented (10-20%) with serum obtained from the same dogs (n = 7): 1) before the induction of hypertension; 2) after wrapping one kidney in silk (two-kidney perinephritic hypertension, 2-KPHT); and 3) after contralateral nephrectomy (1-KPHT). Cultures also were run with serum of sham-wrapped and then unilaterally nephrectomized normotensive dogs (n = 4). After 3 weeks of culture, the explants were harvested, and their water, sodium and potassium concentration was measured. Compared to the composition of explants cultured in prehypertensive serum, the water concentration of explants cultured in 1-KPHT and the sodium concentration of explants cultured in 2-KPHT and 1-KPHT serum were increased (p < 0.05). The water and electrolyte content of explants cultured in sera of sham-operated normotensive control dogs was the same regardless of the type of serum used, pre- or post-sham surgery or post-nephrectomy. The effects of serum from hypertensive dogs were not explained by variations in serum creatinine, sodium and potassium levels or in plasma renin activities. The experiments provide evidence for the role of serum factor(s) in the pathogenesis of abnormal vascular wall water and sodium concentration in experimental hypertension.


Amino acid sequence of the trypsin-generated C3d fragment from human complement factor C3.
Human C3d (try-C3d), prepared from trypsin-digested C3, was fragmented by cleavage with CNBr. Eight peptides were defined and separated by h.p.l.c. on reversed-phase columns. By automatic Edman degradation the complete sequences of five peptides and partial sequences of three peptides were determined. To obtain overlapping peptides the latter three fragments were digested with trypsin, chymotrypsin or Staphylococcus aureus V8 proteinase, after which the fragments were separated on reversed-phase columns. Two of the CNBr-cleavage peptides were completely sequenced, and 70% of the sequence of the remaining CNBr-cleavage peptide was determined. The non-sequenced part represents a very hydrophobic segment of try-C3d. The sequence data obtained represent 90% of the primary structure of try-C3d. Alignment of the CNBr-cleavage fragments was made easier by comparison with the cDNA sequence of mouse pro-C3 [Wetsel, Lundwall, Davidson, Gibson, Tack & Fey (1984) J. Biol. Chem. 259, 13857-13862]. Comparison of try-C3d with the equivalent part of human C4B revealed an extensive sequence homology in the N-terminal half of the molecules.


[Peripheral circulatory changes in patients in the acute period of transmural myocardial infarct].
Altogether 107 patients with transmural myocardial infarction were investigated by determination over time the volumetric blood flow rate in the forearm using a plethysmograph with mercury-rubber gages and A-V oxyhemoglobin difference. With relation to a degree of expression of acute heart failure all the patients were divided into 4 groups. Considerable volumetric peripheral blood flow rate changes were noted in the acute phase of transmural myocardial infarction. A degree of a decrease in the rate well correlated with expression of clinical signs of heart failure. Indices of A-V oxyhemoglobin difference also showed correlation with expression of acute heart failure growing with its increase. The combined determination of these indices, probably reflecting 2 tendencies (blood flow decrease and centralization), is of certain prognostic value.


Adult adjustment disorder: a review of its current diagnostic status.
Adjustment disorder is a diagnosis that is commonly used, particularly in primary care and general medical settings. However, there has been relatively little research done on this disorder. In this article, the author reviews the information that is available on the epidemiology, clinical features, validity, measurement, and treatment of adjustment disorder. She first reviews the historical development of the diagnosis from transient situational personality disorder in DSM-I to its current definition in DSM-IV. The author also considers similarities and differences in how adjustment disorder is defined in the DSM and ICD systems. The clinical features of the disorder that distinguish it from disorders such as major depressive disorder, generalized anxiety disorder, posttraumatic stress disorder, and acute stress disorder are described. The author highlights a number of the common controversies concerning adjustment disorder, especially criticisms that the diagnostic criteria are often poorly applied and that the disorder itself involves the medicalizing of problems of living. Evidence in support of the validity of the adjustment disorder diagnosis is reviewed and the author concludes that the findings support the content and predictive validity of the diagnosis. The author then discusses the epidemiology of adjustment disorders, their comorbidity with other conditions, including personality disorders, substance abuse, and suicidal behavior, and their treatment and outcome. The article concludes with a discussion of the special problems involved in evaluating for and measuring adjustment disorder.


A competency-based medical student curriculum: taking the medication history in older adults.
Older adults are the largest consumers of prescription medications. Taking multiple medications, which interact with medical, psychological, and socioeconomic factors, increases a person's risk of nonadherence and adverse events. A curriculum was developed to train medical students to identify these risks and make recommendations for improving medication safety. The curriculum, consisting of a self-study computer tutorial, a small-group simulated-patient (SP) experience, and an online competency assessment, was implemented in the students' second year of training. Groups (N = 28) of five to seven students interviewed the SP and were assessed on their ability to identify medication concerns (N = 18) and make recommendations (N = 18) on improving medication safety. On average, student groups identified 16.1 concerns and made 15.4 recommendations. On the competency assessment several months later, students were given a case scenario and again asked to identify concerns (N = 7) and make recommendations (N = 7). Students (N = 176) were required to achieve a preset performance standard on the assessment. A high percentage (97.2%) of students achieved the standard (a score of 8/14) on their first attempt; the remainder achieved the standard on their second attempt. Student evaluations indicated high levels of satisfaction with the curriculum. The learning objectives, competency assessment, and instructional activities were closely aligned. Instructional activities provided students with an opportunity to practice the competency in a nonthreatening environment. The SP session materials are available through MedEdPORTAL and can readily be incorporated by other institutions into existing curricula.


Anabolic ornithine carbamolytransferase of Pseudomonas. The bases of its functional specialization.
The anabolic ornithine carbamoyltransferase of Pseudomonas appears to be extremely specialized. Unlike the other carbamoyltransferases studied, this enzyme catalyzes the phosphorolytic cleavage of citrulline with a very poor efficiency. The main goal of this paper is to understand what, in the catalytic process, causes this directed functional specialization. On the basis of kinetic data and thermodynamic properties of the reaction, it appears that the reaction mechanism is the same as for ornithine carbamoyltransferases from other sources, that is, of the sequential ordered type, where carbamoylphosphate is the first substrate to be bound and phosphate the last product to be released. In addition to this, and here lies the difference with other ornithine carbamoyltransferases, the anabolic transferase of Pseudomonas forms a binary dead-end complex with citrulline, leading to inefficient binding of phosphate and citrulline to the enzyme. Therefore the phosphorolytic cleavage of citrulline is equally inefficient. It should be mentioned that the affinity of the enzyme for citrulline at its catalytic site is low as compared to other transferases.


Medial-grade calcium sulfate hemihydrate (surgiplaster) in healing of a human extraction socket--histologic observation at 3 months: a case report.
Following tooth extraction, wound healing is characterized by remodeling and resorption of the alveolar bone at the extraction site. This produces reduction in ridge volume. Medical-grade calcium sulfate hemihydrate (MGCSH) has been proposed as a graft material for extraction sockets to minimize the reduction in ridge volume. The aim of this study was to investigate the influence of MGCSH on the histopathologic pattern of intrasocket regenerated bone and to evaluate histologically the healed MGCSH-grafted extraction socket site at 3 months postextraction. MGCSH was grafted in a fresh human extraction socket, and at 3 months a cylindric tissue specimen, 2.5 mm in diameter, was trephined from the previously grafted site and an implant was placed. Non-decalcified specimens were sectioned at a horizontal plane and stained for histologic and histomorphometric evaluation. The mean trabecular area was 58.6% +/- 9.2% in the coronal sections, 58.1% +/- 6.2% in the middle sections, and 58.3% +/- 7.8% in the apical sections. The differences in mean trabecular area between sections were not statistically significant. It is significant that the MGCSH underwent complete resorption and replacement by newly formed bone because the most important negative attribute of other graft materials is the resorption time. Moreover, calcium sulfate shows great potential for guided bone regeneration in surgical sites. MGCSH seems to be an acceptable graft material for extraction socket bone regeneration because it is completely resorbable and allows new trabecular bone arrangement in a limited 3-month period.


Endothelial cells are critical regulators of iron transport in a model of the human blood-brain barrier.
Iron delivery to the brain is essential for multiple neurological processes such as myelination, neurotransmitter synthesis, and energy production. Loss of brain iron homeostasis is a significant factor in multiple neurological disorders. Understanding the mechanism by which the transport of iron across the blood-brain barrier (BBB) is regulated is crucial to address the impact of iron deficiency on brain development and excessive accumulation of iron in neurodegenerative diseases. Using induced pluripotent stem cell (iPSC)-derived brain endothelial cells (huECs) as a human BBB model, we demonstrate the ability of transferrin, hepcidin, and DMT1 to impact iron transport and release. Our model reveals a new function for H-ferritin to transport iron across the BBB by binding to the T-cell immunoglobulin and mucin receptor 1. We show that huECs secrete both transferrin and H-ferritin, which can serve as iron sources for the brain. Based on our data, brain iron status can exert control of iron transport across the endothelial cells that constitute the BBB. These data address a number of pertinent questions such as how brain iron uptake is regulated at the regional level, the source of iron delivery to the brain, and the clinical strategies for attempting to treat brain iron deficiency.


Statins and brain dysfunction: a hypothesis to reduce the burden of cognitive impairment in patients who are critically ill.
Delirium is a frequent form of acute brain dysfunction in patients who are critically ill and is associated with poor clinical outcomes, including a critical illness brain injury that may last for months to years. Despite widespread recognition of significant adverse outcomes, pharmacologic approaches to prevent or treat delirium during critical illness remain unproven. We hypothesize that commonly prescribed statin medications may prevent and treat delirium by targeting molecular pathways of inflammation (peripheral and central) and microglial activation that are central to the pathogenesis of delirium. Systemic inflammation, a principal mechanism of injury, for example, in sepsis, acute respiratory distress syndrome, and other critical illnesses, can cause neuronal apoptosis, blood-brain barrier injury, brain ischemia, and microglial activation. We hypothesize that the known pleiotropic effects of statins, which attenuate such neuroinflammation, may redirect microglial activation and promote an antiinflammatory phenotype, thereby offering the potential to reduce the public health burden of delirium and its associated long-term cognitive injury.


Stimulation of generation of inositol phosphates by carbamoylcholine and its inhibition by phorbol esters and iodide in dog thyroid cells.
The action of carbamoylcholine (Cchol), NaF and other agonists on the generation of inositol phosphates (IPs) was studied in dog thyroid slices prelabelled with myo-[2-3H]inositol. The stimulation by Cchol (0.1 microM-0.1 mM) of IPs accumulation through activation of a muscarinic receptor [Graff, Mockel, Laurent, Erneux & Dumont (1987) FEBS Lett. 210, 204-210] was pertussis- and cholera-toxin insensitive. Ins(1,4,5)P3, Ins(1,3,4)P3 and InsP4 were generated. NaF (5-20 mM) also increased IPs generation (Graff et al., 1987); this effect was potentiated by AlCl3 (10 microM) and unaffected by pertussis toxin. Although phorbol dibutyrate (5 microM) abolished the cholinergic stimulation of IPs generation (Graff et al., 1987), it did not affect the fluoride-induced response. Cchol and NaF did not require extracellular Ca2+ to exert their effect, and neither KCl-induced membrane depolarization nor ionophore A23187 (10 microM) had any influence on basal IPs levels, or on cholinergic stimulation. However, more stringent Ca2+ depletion with EGTA (0.1 or 1 mM) decreased basal IPs levels as well as the amplitude of the stimulation by Cchol without abolishing it. Dibutyryl cyclic AMP, forskolin, cholera toxin and prostaglandin E1 had no effect on basal IPs levels and did not decrease the response to Cchol. Iodide (4 or 40 microM) also strongly decreased the cholinergic action on IPs, this inhibition being relieved by methimazole (1 mM). Our data suggest that Cchol activates a phospholipase C hydrolysing PtdIns(4,5)P2 in the dog thyroid cell in a cyclic AMP-independent manner. This activation requires no extracellular Ca2+ and depends on a GTP-binding protein insensitive to both cholera toxin and requires no extracellular Ca2+ and depends on a GTP-binding protein insensitive to both cholera toxin and pertussis toxin. The data are consistent with a rapid metabolism of Ins(1,4,5)P3 to Ins(1,3,4)P3 via the Ins(1,4,5)P3 3-kinase pathway, followed by dephosphorylation by a 5-phosphomonoesterase. Indeed, a Ca2+-sensitive InsP3 3-kinase activity was demonstrated in tissue homogenate. Stimulation of protein kinase C and an organified form of iodine inhibit the Cchol-induced IPs generation. The negative feedback of activated protein kinase C could be exerted at the level of the receptor or of the receptor-G-protein interaction.


Early influences on the tempo of puberty.
Fetal growth retardation appears to be associated with an increased risk of premature adrenarche, early puberty, polycystic ovary syndrome and associated fertility problems. In a rat model of intrauterine growth retardation, based on ligation of the uterine arteries, the onset of puberty was delayed in female pups, with anovulation during the first cycle. The ovaries showed a lower number of follicles. The onset of puberty was also delayed in male pups. Testosterone production was lower in these growth-retarded rats compared with controls. The relationship between birth weight and the onset of puberty and pubertal progression in different cohorts of healthy children has been examined. In girls, no differences were observed in timing and progression of puberty, including age of menarche, between groups of different birth weights. In boys, a relatively delayed onset of puberty was observed in those with low birth weight, with a normally timed progression. In children with low birth weight, particularly boys, higher dehydroepiandrosterone levels were found compared with children with a normal birth weight, indicating an overactive adrenal gland in children with low birth weight. These data indicate that impaired fetal growth may have long-lasting effects on pubertal development. The fact that results of human studies on the relationship between fetal growth and the onset of puberty are often controversial may be explained by the heterogeneity of children born small for gestational age with respect to the intrauterine insult that they experience. From rat studies, it is clear that a serious intrauterine insult associated with growth failure can lead to dysregulation of puberty and gonadal function.


The innate immune response to lower respiratory tract E. Coli infection and the role of the CCL2-CCR2 axis in neonatal mice.
Neonates have greater morbidity/mortality from lower respiratory tract infections (LRTI) compared to older children. Lack of conditioning of the pulmonary immune system due to limited environmental exposures and/or infectious challenges likely contributes to the increase susceptibility in the neonate. In this study, we sought to gain insights into the nature and dynamics of the neonatal pulmonary immune response to LRTI using a murine model. Wildtype (WT) and Ccr2-/- C57BL/6 neonatal and juvenile mice received E. coli or PBS by direct pharyngeal aspiration. Flow cytometry was used to measure immune cell dynamics and identify cytokine-producing cells. Real-time PCR and ELISA were used to measure cytokine/chemokine expression. Innate immune cell recruitment in response to E. coli-induced LRTI was delayed in the neonatal lung compared to juvenile lung. Lung clearance of bacteria was also significantly delayed in the neonate. Ccr2-/- neonates, which lack an intact CCL2-CCR2 axis, had higher mortality after E. coli challenged than Ccr2+/+ neonates. A greater percentage of CD8+ T cells and monocytes from WT neonates challenged with E. coli produced TNF compared to controls. The pulmonary immune response to E. coli-induced LRTI differed significantly between neonatal and juvenile mice. Neonates were more susceptible to increasing doses of E. coli and exhibited greater mortality than juveniles. In the absence of an intact CCL2-CCR2 axis, susceptibility to LRTI-induced mortality was further increased in neonatal mice. Taken together these findings underscore the importance of age-related differences in the innate immune response to LRTI during early stages of postnatal life.


Implementing paediatric early warning scores systems in the Netherlands: future implications.
Paediatric Early Warning Scores (PEWS) are increasingly being used for early identification and management of clinical deterioration in paediatric patients. A PEWS system includes scores, cut-off points and appropriate early intervention. In 2011, The Dutch Ministry of Health advised hospitals to implement a PEWS system in order to improve patient safety in paediatric wards. The objective of this study was to examine the results of implementation of PEWS systems and to gain insight into the attitudes of professionals towards using a PEWS system in Dutch non-university hospitals. Quantitative data were gathered at start, midway and at the end of the implementation period through retrospective patient record review (n = 554). Semi-structured interviews with professionals (n = 8) were used to gain insight in the implementation process and experiences. The interviews were transcribed and analysed using an inductive approach. Looking at PEWS systems of the five participating hospitals, different parameters and policies were found. While all hospitals included heart rate and respiratory rate, other variables differed among hospitals. At baseline, none of the hospitals used a PEWS system. After 1 year, PEWS were recorded in 69.2% of the patient records and elevated PEWS resulted in appropriate action in 49.1%. Three themes emerged from the interviews: 1) while the importance of using a PEWS system was acknowledged, professionals voiced some doubts about the effectiveness and validity of their PEWS system 2) registering PEWS required little extra effort and was facilitated by PEWS being integrated into the electronic patient record 3) Without a national PEWS system or guidelines, hospitals found it difficult to identify a suitable PEWS system for their setting. Existing systems were not always considered applicable in a non-university setting. After 1 year, hospitals showed improvements in the use of their PEWS system, although some were decidedly more successful than others. Doubts among staff about validity, effectiveness and communication with other hospitals during transfer to higher level care hospital might hinder sustainable implementation. For these purposes the development of a national PEWS system is recommended, consisting of a "core set" of PEWS, cut-off points and associated early intervention.


Effect of comorbid conditions on adherence to colorectal cancer screening.
Potential barriers to colorectal cancer (CRC) screening include preexisting medical conditions (comorbidities), physician recommendation, psychosocial factors, and screening preparedness. This study's purpose was to investigate the impact of comorbid conditions on CRC screening among African Americans. A stage-matched randomized clinical trial was performed. Asymptomatic African Americans over age 50, with a primary care physician, and eligible for CRC screening were recruited at The Mount Sinai Hospital from 2005 to 2008. One hundred sixty-one patients were assessed for referral for, and completion of, CRC screening, comorbid conditions, "readiness to change," and number of physician visits within the observation period. Data was compared to a pretrial index to predict the likely effect of comorbid conditions on CRC screening. One hundred fifty-nine patients completed the study; 108 (68.9%) were referred for and 34 (21.2%) completed CRC screening. No demographic characteristics were associated with CRC screening completion. CRC screening referrals were similar for all patients, regardless of comorbidities or clinical visits. Comorbidities rated as having extreme influence on CRC screening showed a trend toward lower screening rates. There was a significant increase in screening rates among participants in advanced stages of readiness at enrollment. These data suggest that while comorbidities did not predict colonoscopy completion, they may play a role in concert with other factors. This is the only study to assess the effect of screening colonoscopy in an African American primary care setting. We must continue to explore interventions to narrow the disparate gap in screening and mortality rates.


NHE8 Deficiency Promotes Colitis-Associated Cancer in Mice via Expansion of Lgr5-Expressing Cells.
Lgr5 overexpression has been detected in colorectal cancers (CRCs), including some cases of colitis-associated CRCs. In colitis-associated CRCs, chronic inflammation is a contributing factor in carcinogenesis. We recently reported that intestinal Na+/H+ exchanger isoform 8 (NHE8) plays an important role in intestinal mucosal protection and that loss of NHE8 expression results in an ulcerative colitis-like condition. Therefore, we hypothesized that NHE8 may be involved in the development of intestinal tumors. We assessed NHE8 expression in human CRCs by immunohistochemistry and studied tumor burden in NHE8 knockout (KO) mice using an azoxymethane/dextran sodium sulfate colon cancer model. We also evaluated cell proliferation in HT29NHE8KO cells and assessed tumor growth in NOD scid gamma (NSG) mice xenografted with HT29NHE8KO cells. To verify if a relationship exists between Lgr5 and NHE8 expression, we analyzed Lgr5 expression in NHE8KO mice by polymerase chain reaction and in situ hybridization. Lgr5 expression and cell proliferation in the absence of NHE8 were confirmed in colonic organoid cultures. The expression of β-catenin and c-Myc also were analyzed to evaluate Wnt/β-catenin activation. NHE8 was undetectable in human CRC tissues. Although only 9% of NHE8 wild-type mice showed tumorigenesis in the azoxymethane/dextran sodium sulfate colon cancer model, almost 10 times more NHE8KO mice (89%) developed tumors. In the absence of NHE8, a higher colony formation unit was discovered in HT29NHE8KO cells. In NSG mice, larger tumors developed at the site where HT29NHE8KO cells were injected compared with HT29NHE8 wild type cells. Furthermore, NHE8 deficiency resulted in increased Lgr5 expression in the colon, in HT29-derived tumors, and in colonoids. The absence of NHE8 also increased Wnt/β-catenin activation. NHE8 might be an intrinsic factor that regulates Wnt/β-catenin in the intestine.


Fall Risk Screening and Assessment for People Living With Dementia: A Scoping Review.
Falls are the leading cause of injury and hospitalization for older adults in Canada and the second leading cause of unintentional injury deaths worldwide. For people living with dementia (PLWD), falls have an even greater impact, but the standard testing methods for fall risk screening and assessment are often not practical for this population. The purpose of this scoping review is to identify and summarize recent research, practice guidelines and gray literature which have considered fall risk screening and assessment for PLWD. Database search results revealed a dearth in the literature that can support researchers and healthcare providers when considering which option/s are the most suitable for PLWD. Further primary studies into the validity of using the various tests with PLWD are needed if researchers and healthcare providers are to be empowered via the literature and clinical practice guidelines to provide the best possible fall risk care for PLWD.


Asthma exacerbation associated with glucosamine-chondroitin supplement.
Although dietary supplements are in widespread use, and some have been endorsed by the medical community and complementary and alternative practitioners, not much is known about their potential side effects or drug interactions. A case of asthma exacerbated by the use of a glucosamine-chondroitin supplement for osteoarthritis pain is described. The literature was searched from 1980 to 2002 using the terms "glucosamine," "chondroitin sulfate," "alternative medicine," and "dietary supplements," combined with "asthma." The biological link between both chondroitin and glucosamine and secretions from the respiratory tree of persons with asthma lends biologic plausibility to the hypothesis that the patient's asthmatic episode was related to the dietary substance. Physicians would be wise to question their patients about use of dietary supplements as self-medication and consider the possibility of such supplements causing exacerbations of underlying conditions.


Nucleotide ligands protect the inter-domain regions of the multifunctional polypeptide CAD against limited proteolysis, and also stabilize the thermolabile part-reactions of the carbamoyl-phosphate synthase II domains within the CAD polypeptide.
Improved methodologies are described which allow the measurement of the part-reactions, with glutamine or ammonia as nitrogen donor, of mammalian carbamoyl-phosphate synthase II (EC 126.96.36.199) through the incorporation of [14C]bicarbonate into either carbamoyl phosphate or carbamoylaspartate. The enzyme is part of the multifunctional polypeptide (CAD) which also comprises the pyrimidine-biosynthetic enzymes aspartate transcarbamoylase (EC 220.127.116.11) and dihydro-orotase (EC 184.108.40.206). The conformational stability of the carbamoyl-phosphate synthase was investigated through the inactivation of the part-reactions which occurred during incubation at 37 degrees C. The domain involved in the removal of the amide N from glutamine was more thermolabile than the ammonia-dependent synthase moiety. The former activity was stabilized in the presence of sodium aspartate or MgATP, whereas the latter was stabilized by MgATP and MgUTP. Binding of MgUTP and MgATP to CAD restricted the initial proteolysis by trypsin and elastase of one or both regions linking the carbamoyl-phosphate synthase domain to the other major domains. A model is described to account for both aspects of nucleotide binding to CAD; these stabilizing effects may be important in the cell, where similar concentrations of nucleotides are found.


IP-10/CXCL10 attracts regulatory T cells: Implication for pancreatic cancer.
Pancreatic stellate cells (PSCs) are key components of pancreatic ductal adenocarcinoma (PDAC). We recently demonstrated that IP-10/CXCL10 is highly expressed by PSCs in the presence of pancreatic cancer cells (PCCs) and its expression correlates with infiltration by regulatory T cells (Tregs) and poor survival. Thus, stromal cells in pancreatic cancer can promote immunosuppression and tumor progression, through the expression of IP-10.


Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens.
Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries, which GH dosage to use and which age to start puberty induction are issues of debate. This study shows final height (FH) in 60 girls with Turner syndrome treated in a randomized dose-response trial, combining GH treatment with low dose estrogens at a relatively young age. Girls were randomly assigned to group A (4 IU/m(2).d; approximately 0.045 mg/kg/d), group B (first year, 4 IU/m(2).d; thereafter 6 IU/m(2).d), or group C (first year, 4 IU/m(2).d; second year, 6 IU/m(2).d; thereafter, 8 IU/m(2).d). After a minimum of 4 yr of GH treatment, at a mean age of 12.7 +/- 0.7 yr, low dose micronized 17beta-estradiol was given orally. After a mean duration of GH treatment of 8.6 +/- 1.9 yr, FH was reached at a mean age of 15.8 +/- 0.9 yr. FH, expressed in centimeters or SD score, was 157.6 +/- 6.5 or -1.6 +/- 1.0 in group A, 162.9 +/- 6.1 or -0.7 +/- 1.0 in group B, and 163.6 +/- 6.0 or -0.6 +/- 1.0 in group C. The difference in FH in centimeters, corrected for height SD score and age at start of treatment, was significant between groups A and B [regression coefficient, 4.1; 95% confidence interval (CI), 1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3, 7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI, -1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD score, more than -2). After starting estrogen treatment, the decrease in height velocity (HV) changed significantly to a stable HV, without affecting bone maturation (change in bone age/change in chronological age). The following variables contributed significantly to predicting FH SD score: GH dose, height SD score (ref. normal girls), chronological age at start of treatment, and HV in the first year of GH treatment. GH treatment was well tolerated. In conclusion, GH treatment leads to a normalization of FH in most girls, even when puberty is induced at a normal pubertal age. The optimal GH dosage depends on height and age at the start of treatment and first year HV.


Fungi isolated from flue-cured tobacco inoculated in the field with storage fungi.
Flue-cured tobacco inoculated in the field with A. amstelodami, A. flavus, A. ochraceus, A. repens, A. ruber, and a species of Penicillium was rarely invaded by these fungi. Regardless of inoculum, the predominant fungi reisolated from green tissue were species of Alternaria and Cladosporium. After curing, A. repens, A. niger, and species of Alternaria and a species of Penicillium were the most commonly isolated fungi. The fungus used as inoculum was not the predominant fungus reisolated from green or cured tissue. Conditions during handling and storage prior to marketing probably determine when storage fungi become associated with the leaf and which species becomes predominant.


Multi-ethnic genome-wide association analyses of white blood cell and platelet traits in the Population Architecture using Genomics and Epidemiology (PAGE) study.
Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations. Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.


Lower limits for non-radiative recombination loss in organic donor/acceptor complexes.
Understanding the factors controlling radiative and non-radiative transition rates for charge transfer states in organic systems is important for applications ranging from organic photovoltaics (OPV) to lasers and LEDs. We explore the role of charge-transfer (CT) energetics, lifetimes, and photovoltaic properties in the limit of very slow non-radiative rates by using a model donor/acceptor system with photoluminescence dominated by thermally activated delayed fluorescence (TADF). This blend exhibits an extremely high photoluminescence quantum efficiency (PLQY = ∼22%) and comparatively long PL lifetime, while simultaneously yielding appreciable amounts of free charge generation (photocurrent external quantum efficiency EQE of 24%). In solar cells, this blend exhibits non-radiative voltage losses of only ∼0.1 V, among the lowest reported for an organic system. Notably, we find that the non-radiative decay rate, knr, is on the order of 105 s-1, approximately 4-5 orders of magnitude slower than typical OPV blends, thereby confirming that high radiative efficiency and low non-radiative voltage losses are achievable by reducing knr. Furthermore, despite the high radiative efficiency and already comparatively slow knr, we find that knr is nevertheless much faster than predicted by Marcus-Levich-Jortner two-state theory and we conclude that CT-local exciton (LE) hybridization is present. Our findings highlight that it is crucial to evaluate how radiative and non-radiative rates of the LE states individually influence the PLQY of charge-transfer states, rather than solely focusing on the PLQY of the LE. This conclusion will guide material selection in achieving low non-radiative voltage loss in organic solar cells and high luminescence efficiency in organic LEDs.


Dialysis prescription and kinetics in acute renal failure.
The recognition that both morbidity and mortality are inversely related to delivered hemodialysis (HD) dose in end-stage renal disease (ESRD) patients has substantially changed clinical practices in the United States. A number of quantification techniques, which differ greatly in complexity and sophistication, are now used in ESRD patients. Investigators recently have attempted to extrapolate some of these ESRD quantification methods to the acute renal failure (ARF) setting. This review focuses on these recent attempts. Both patient-related and renal replacement therapy (RRT)-related differences in ESRD and ARF are discussed. In addition, the potential pitfalls of extrapolating certain ESRD quantification methods to RRT in ARF are discussed. Prescription considerations for both intermittent HD (IHD) and continuous RRT (CRRT) are presented. Finally, recent data suggesting survival in critically ill ARF patients is directly correlated with delivered therapy dose are reviewed. The optimal technique for RRT quantification in ARF remains to be determined.


Racial and Ethnic Differences in Anthropometric Measures as Risk Factors for Diabetes.
The study objective was to examine the impact of race/ethnicity on associations between anthropometric measures and diabetes risk. A total of 136,112 postmenopausal women aged 50-79 years participating in the Women's Health Initiative without baseline cancer or diabetes were followed for 14.6 years. BMI, waist circumference (WC), and waist-to-hip ratio (WHR) were measured in all participants, and a subset of 9,695 had assessment of whole-body fat mass, whole-body percent fat, trunk fat mass, and leg fat mass by DXA. Incident diabetes was assessed via self-report. Multivariate Cox proportional hazards regression models were used to assess associations between anthropometrics and diabetes incidence. During follow-up, 18,706 cases of incident diabetes were identified. BMI, WC, and WHR were all positively associated with diabetes risk in each racial and ethnic group. WC had the strongest association with risk of diabetes across all racial and ethnic groups. Compared with non-Hispanic whites, associations with WC were weaker in black women (P < 0.0001) and stronger in Asian women (P < 0.0001). Among women with DXA determinations, black women had a weaker association with whole-body fat (P = 0.02) but a stronger association with trunk-to-leg fat ratio (P = 0.03) compared with white women. In postmenopausal women across all racial/ethnic groups, WC was a better predictor of diabetes risk, especially for Asian women. Better anthropometric measures that reflect trunk-to-leg fat ratio may improve diabetes risk assessment for black women.


Lateral preferences and their assessment in school-aged children.
A behaviour-based lateral preference instrument (the Lateral Preferences Questionnaire; LPQ; Van Strien, 1992, 2001) was administered to a large sample of school-aged children. The aims of the present study were twofold: (i) to evaluate the factor structure and the psychometric properties of the LPQ, and (ii) to evaluate the effects of age, gender, and mean level of parental education on lateral preferences and lateral consistency. Two factor models had an excellent fit with the data. In the first model the LPQ items were considered to be indicators of four different lateral preference factors (the hand, foot, eye, and ear preference factors). In the second model the LPQ items were considered to be indicators of four lateral preference factors, which were in turn expected to load on a single underlying general lateral preference factor. The psychometric properties of the derived hand and eye preference scales of the LPQ were good to excellent, and the psychometric properties of the foot and ear preference scales were acceptable. Lateral preferences and lateral consistency were not affected by age, gender, or mean level of parental education.


Ultrasound of the median arcuate ligament syndrome: a new approach to diagnosis.
The currently accepted pathophysiological concept behind median arcuate ligament syndrome (MALS) is vascular compromise by atypically positioned median arcuate ligament. Despite many articles on MALS, only sparse data on the outcome in general and the rather poor outcome after intervention have been reported and this makes at least questionable the current concepts of the underlying disease. A total of 364 patients with suspected celiac trunk pathology underwent a standardized ultrasound assessment procedure: suspected diagnostic features for MALS such as typically elevated peak flow velocities (PV) in the celiac trunk or atypical celiac trunk deflection-angles (DA) were defined in patients and in 20 matched volunteers. All the 6 retrospectively clearly diagnosed MALS-patients as well as 40% (8/20) of volunteers presented a DA of over 50°. MALS-patients presented a mean inspiratory PV of 172cm/s (+/- 40.9 cm/s), a mean expiratory PV of 425cm/s (+/-130.1 cm/s) with a PV-amplitude of 249.1% (+/-68.9%). Volunteers presented a mean inspiratory PV of 126.9cm/s (+/-42 cm/s), a mean expiratory PV of 209.9cm/s (+/-80.1 cm/s) with a PV-amplitude of 169.4% (+/-54.3%). The combination of a maximum expiratory PV of over 350 cm/s and a DA higher than 50° seems to be a most reliable indicator for MALS in this small series of patients. Based on these data we propose that functional ultrasound should be the first line in screening for MALS. However, a clear pathophysiological definition of MALS remains still obscure.


Hallmarks of Skin Aging: Update.
Aging is defined as impaired physiological integrity, decreased function, increased susceptibility to external risk factors and various diseases. Skin, the largest organ in our body, may become more vulnerable to insult as time goes by and behave as aged skin. Here, we systemically reviewed three categories including seven hallmarks of skin aging. These hallmarks including genomic instability and telomere attrition, epigenetic alterations and loss of proteostasis, deregulated nutrient-sensing, mitochondrial damage and dysfunction, cellular senescence, stem cell exhaustion/dysregulation, and altered intercellular communication. These seven hallmarks can generally be divided into three categories including (i) causes of damages as primary hallmarks in skin aging; (ii) responses to damage as antagonistic hallmarks in skin aging; and (iii) culprits of the phenotype as integrative hallmarks in skin aging.


CNS drug design: balancing physicochemical properties for optimal brain exposure.
The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.


EB virus in the owl monkey (Aotus trivirgatus).
Owl monkeys (Aotus trivirgatus) were inoculated with EB (Epstein-Barr) virus-containing material or virion-free control material. One out of three animals given the virus died after 14 weeks with a reticuloproliferative disease compatible with malignant lymphoma. A cell line was established from an abnormal lymph node of the diseased monkey and was found by electronmicroscopy to carry a herpesvirus identified as EB virus by two types of immunofluorescence test, by its biological behavior and by nucleic acid hybridization studies. None of the inoculated animals developed heterophile antibodies, and only the diseased animal had an antibody response to EB virus. The findings were discussed in relation to a possible oncogenic capacity of EB virus in vivo.