Salient Region Detection via Integrating Diffusion-Based Compactness and Local Contrast.
Salient region detection is a challenging problem and an important topic in computer vision. It has a wide range of applications, such as object recognition and segmentation. Many approaches have been proposed to detect salient regions using different visual cues, such as compactness, uniqueness, and objectness. However, each visual cue-based method has its own limitations. After analyzing the advantages and limitations of different visual cues, we found that compactness and local contrast are complementary to each other. In addition, local contrast can very effectively recover incorrectly suppressed salient regions using compactness cues. Motivated by this, we propose a bottom-up salient region detection method that integrates compactness and local contrast cues. Furthermore, to produce a pixel-accurate saliency map that more uniformly covers the salient objects, we propagate the saliency information using a diffusion process. Our experimental results on four benchmark data sets demonstrate the effectiveness of the proposed method. Our method produces more accurate saliency maps with better precision-recall curve and higher F-Measure than other 19 state-of-the-arts approaches on ASD, CSSD, and ECSSD data sets.


Recent advances in hearing conservation programmes: A systematic review.
Current evidence from low- and middle-income (LAMI) countries, such as South Africa, indicates that occupational noise-induced hearing loss (ONIHL) continues to be a health and safety challenge for the mining industry. There is also evidence of hearing conservation programmes (HCPs) being implemented with limited success. The aim of this study was to explore and document current evidence reflecting recent advances in HCPs in order to identify gaps within the South African HCPs. A systematic literature review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Electronic databases including Sage, Science Direct, PubMed, Scopus MEDLINE, ProQuest and Google Scholar were searched for potential studies published in English between 2010 and 2019 reporting on recent advances in HCPs within the mining industry. The study findings revealed a number of important recent advances internationally, which require deliberation for possible implementation within the South African HCPs context. These advances have been presented under seven themes: (1) the use of metrics, (2) pharmacological interventions and hair cell regeneration, (3) artificial neural network, (4) audiology assessment measures, (5) noise monitoring advances, (6) conceptual approaches to HCPs and (7) buying quiet. The study findings raise important advances that may have significant implications for HCPs in LAMI countries where ONIHL remains a highly prevalent occupational health challenge. Establishing feasibility and efficacy of these advances in these contexts to ensure contextual relevance and responsiveness is one of the recommendations to facilitate the success of HCPs targets.


Plasmid-borne sulfonamide resistance determinants studied by restriction enzyme analysis.
The relationship between sulfonamide resistance genes carried on different plasmids was investigated by restriction enzyme analysis and DNA-DNA hybridization. The results showed that sulfonamide resistance mediated by different plasmids is determined by the production of at least two different types of drug-resistant dihydropteroate synthase. Plasmids pGS01, pGS02, and R22259, found in bacteria isolated from patients in Swedish hospitals, contained identical sulfonamide resistance genes, which were also identical to those of plasmids R1, R100, R6, and R388. These latter plasmids, which have been well studied in different laboratories, were originally from clinical isolates from different parts of the world. Two other clinically isolated plasmids, pGS04 and pGS05, were shown to contain sulfonamide resistance determinants of a completely different type.


Randomized Controlled Pilot Study of Antiretrovirals and a Behavioral Intervention for Persons With Acute HIV Infection: Opportunity for Interrupting Transmission.
Persons with acute HIV infection (AHI) have heightened transmission risk. We evaluated potential transmission reduction using behavioral and biomedical interventions in a randomized controlled pilot study in Malawi. Persons were randomized 1:2:2 to standard counseling (SC), 5-session behavioral intervention (BI), or behavioral intervention plus 12 weeks of antiretrovirals (ARVs; BIA). All were followed for 26-52 weeks and, regardless of arm, referred for treatment according to Malawi-ARV guidelines. Participants were asked to refer partners for testing. Among 46 persons (9 SC, 18 BI, 19 BIA), the average age was 28; 61% were male. The median viral load (VL) was 5.9 log copies/mL at enrollment. 67% (10/15) of BIA participants were suppressed (<1000 copies/mL) at week 12 vs 25% BI and 50% SC (P = .07). Although the mean number of reported condomless sexual acts in the past week decreased from baseline across all arms (1.5 vs 0.3 acts), 36% experienced incident sexually transmitted infection by 52 weeks (12% SC, 28% BI, 18% BIA). Forty-one percent (19/46) of participants referred partners (44% SC, 44% BI, 37% BIA); 15 of the partners were HIV-infected. Diagnosis of AHI facilitates behavioral and biomedical risk reduction strategies during a high-transmission period that begins years before people are typically identified and started on ARVs. Sexually transmitted infection incidence in this cohort suggests ongoing risk behaviors, reinforcing the importance of early intervention with ARVs to reduce transmission. Early diagnosis coupled with standard AHI counseling and early ARV referral quickly suppresses viremia, may effectively change behavior, and could have tremendous public health benefit in reducing onward transmission.


Primary prevention of childhood lead poisoning through community outreach.
The prevalence of childhood lead poisoning has substantially decreased in Milwaukee, Wisconsin over the past decade. Nevertheless, by the mid 1990s, 30% of children were still found to have elevated blood levels. To extend the reach of the Milwaukee Health Department (MHD) to previously underserved families in 1 inner city neighborhood with extremely old housing, the Sixteenth Street Community Health Center (SSCHC) implemented, in 1995, the Community Lead Outreach Project (CLOP). Going door-to-door, CLOP attempted to identify children 6 months to 6 years old with elevated blood lead levels (BLL), referring those > or = 20 micrograms/dL to MHD and enrolling those with BLLs 10-19 micrograms/dL in a program of prevention education and environmental clean-up with the specific aim of preventing BLLs increasing to 20 micrograms/dL and above. A team of community outreach workers led by a nurse-coordinator visited, over a 4-year period, families in their homes in 13 census tracts surrounding the SSCHC. During the home visits, capillary blood samples for BLLs were drawn, environmental assessments and scoring were conducted, lead poisoning prevention education provided and repair and cleaning of household lead hazards demonstrated. For control and comparison, BLL data for the entire city by ZIP Code and provider were obtained from the Milwaukee Health Department. Odds ratios for changes in the proportions of children screened > or = 10 micrograms/dL were calculated and compared for the years 1996 through 1999. The odds ratios of changes for various populations were compared for significant differences using tests of homogeneity. To control for age confounding, proportions of elevated BBLs for all groups and for all years were age-standardized, using the direct method. Over the entire study, 20.9% of the children screened had BLLs > or = 10 micrograms/dL and 3.0% were > or = 20 micrograms/dL. For 395 children with BLLs 10-19 micrograms/dL enrolled in the CLOP follow-up program, the mean BLL was 12.9 micrograms/dL. Mean levels at the first, second and third follow-up visits were 10.8, 10.3 and 9.8 micrograms/dL respectively, showing an overall decline of 3.1 micrograms/dL or 24%. At the first follow-up visit, 97% of the children tested were < 20 micrograms/dL while 76% were < 10 micrograms/dL. By the second follow-up visit, 100% were < 20 micrograms/dL. Initial environmental scores averaged 24.7, declining to 19.0 at first, 17.8 at second and 14.8 at third follow-up visits. For the entire CLOP population, the proportion of children testing > 10 micrograms/dL declined each year from 46.3% in 1996 to 22.5% in 1999. The geographic area in which CLOP operated recorded the highest screening penetration rate in the city: 61%. The odds ratio for CLOP clients to have elevated blood lead levels at the end of the study period, in contrast with the beginning, was 0.34 compared to 0.55 for the entire city and 0.75 for private physicians serving the same general population. Comparison of odds ratios showed the CLOP target population enjoyed a decrease in rate of elevated BLL 1.6 times that of the city-wide average, p-value = 0.016 and more than double that of the patients of area private providers. We conclude that the Sixteenth Street Community Health Center Childhood Lead Outreach Project has successfully accessed populations of children with high rates of lead poisoning who had escaped more traditional screening venues and effectively intervened to reduce their BLLs to < 10 micrograms/dL. Moreover, CLOP produced impressive and unanticipated primary prevention benefits in the community at large. The demonstrated ability of community outreach workers to access high-risk populations and reduce exposure to lead hazards suggests the potential of this strategy for extension to other geographic areas, to the patients of private physicians and to address other prevalent, urban health problems like asthma, injuries and violence.


Non-Adrenergic, Tamsulosin-Insensitive Smooth Muscle Contraction is Sufficient to Replace α1 -Adrenergic Tension in the Human Prostate.
Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia may be caused by prostate smooth muscle contraction. Although α1 -blockers may improve symptoms by prostate smooth muscle relaxation, their efficacy is limited. This may be explained by non-adrenergic mediators causing contraction in parallel to α1 -adrenoceptors. However, little is known about the relevance and cooperative actions of non-adrenergic mediators in the prostate. Prostate tissues were obtained from radical prostatectomy (n = 127 patients). Contractile responses were studied in an organ bath. Endothelin-1 and noradrenaline induced contractions of similar magnitude (116 ± 23 and 117 ± 18% of KCl-induced contractions). Endothelin-2- and -3-induced maximum contractions of 63 ± 8.6 and 71 ± 19% of KCl, while contractions by the thromboxane analog U46619 amounted up to 63 ± 9.4%. Dopamine-induced contractions averaged to 22 ± 4.5% of KCl, while maximum contractions by serotonin, histamine, and carbachol stayed below 10% of KCl-induced. While noradrenaline-induced contractions were inhibited by tamsulosin (300 nM), endothelin-1-, -2-, or -3-induced contraction were not. No additive effects were observed if endothelins and noradrenaline were applied consecutively to the same samples. If endothelin-1 was applied after U46619, resulting tension (172 ± 43% of KCl) significantly exceeded noradrenaline-induced contraction. Tensions following combined application of endothelin-2 or -3 with U46619 stayed below noradrenaline-induced contractions. Tension following combined application of all three endothelins with U46619 resembled maximum noradrenaline-induced tone. Contractions following concomitant confrontation of human prostate tissue with noradrenaline and endothelin-1 are not additive. Endothelin-1 is sufficient to induce a smooth muscle tone resembling that of noradrenaline. This may replace lacking α1 -adrenergic tone under therapy with α1 -blockers, explaining the limited efficacy of α1 -blockers in LUTS treatment. Contractions by thromboxane and endothelin-1 may be additive, and may exceed α1 -adrenergic tone. Prostate 77:697-707, 2017. © 2017 Wiley Periodicals, Inc.


The Role of CD8+ T-Cells and their Cytokines in the Pathogenesis of Psoriasis.
The important role of CD8+ T-cells in the pathogenesis of psoriasis is well-determined. However, besides type 1 cytokines that were formerly known, it was recently found that these cells secrete type 17 and type 22 cytokines. The majority of IL-17A+CD8+ T-cells in the blood belong to a subset of innate T-cells named mucosa-associated invariant T-cells (MAIT). However, the majority of IL-17A+CD8+ T-cells in psoriatic epidermis are conventional T-cells and are up-regulated in psoriasis. In contrast to Th17 cells that secrete only IL-17, Tc17 cells secrete IFN-ϒ, TNF-α, CCL20, IL-22, and granzyme B as well. The key cytokine is IL-17A, which promotes keratinocyte hyperproliferation and stimulates them to produce other proinflammatory cytokines. These activities initiate and propagate the inflammation and architectural changes in the skin that clinically manifest as psoriatic lesions. However, a relatively novel cell subtype named Tc22 has been discovered in psoriasis that could secrete IL-22 in the absence of IL-17 and IFN-gamma. IL-22 stimulates proliferation and de-differentiation of keratinocytes, subsequently leading to epidermal acanthosis. As the understanding of the pathogenesis of psoriasis increases, the new selective therapies may offer an optimal balance between increased clinical benefit and reduced risk of side-effects.


Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis.
Animal models of psychosis propose that abnormal hippocampal activity drives increased subcortical dopamine function, which is thought to contribute to aberrant salience processing and psychotic symptoms. These effects appear to be mediated through connections between the hippocampus, ventral striatum/pallidum and the midbrain. The aim of the present study was to examine the activity and connectivity in this pathway in people at ultra high risk (UHR) for psychosis. Functional magnetic resonance imaging was used to compare neural responses in a hippocampal-basal ganglia-midbrain network during reward, novelty and aversion processing between 29 UHR subjects and 32 healthy controls. We then investigated whether effective connectivity within this network is perturbed in UHR subjects, using dynamic causal modelling (DCM). Finally, we examined the relationship between alterations in activation and connectivity in the UHR subjects and the severity of their psychotic symptoms. During reward anticipation, UHR subjects showed greater activation than controls in the ventral pallidum bilaterally. There were no differences in activation during novelty or aversion processing. DCM revealed that reward-induced modulation of connectivity from the ventral striatum/pallidum to the midbrain was greater in UHR subjects than controls, and that in UHR subjects, the strength of connectivity in this pathway was correlated with the severity of their abnormal beliefs. In conclusion, ventral striatal/pallidal function is altered in people at UHR for psychosis and this is related to the level of their psychotic symptoms.


[Alcohol and drug interactions].
Alcohol metabolism occurs mainly in the liver, where in abstainers the alcoholdehydrogenase (ADH) pathway plays the major role. After chronic alcohol consumption, the microsomal ethanol-oxidizing system (MEOS), involving the ethanol-inducible cytochrome P450 2E1, increases in importance with a four- to ten-fold increase in the contribution to alcohol metabolism. Because of the fact that this enzyme system catalyses not only the metabolism of ethanol but also activates a great number of drugs, it is a very common site of alcohol-drug interactions. Clinically relevant interactions will be discussed. Only a small amount of alcohol is metabolized outside the liver, mainly in the stomach by gastric ADH, which leads to the so-called first-pass metabolism of ethanol. Its significance in alcohol metabolism is reviewed. The only way to prevent severe alcohol-drug interactions is to make medical doctors as well as their patients more aware of these possible secondary effects.


Tubulin is phosphorylated at tyrosine by pp60c-src in nerve growth cone membranes.
We show here that tubulin is the major in vivo substrate of the tyrosine-specific protein kinase pp60c-src in nerve growth cone membranes. Phosphotyrosine antibodies were used to demonstrate phosphotyrosyl residues in a subpopulation of alpha- and beta-tubulin that was highly enriched in a subcellular fraction of growth cone membranes from fetal rat brain. The presence of phosphotyrosine-modified isoforms of alpha- and beta-tubulin in vivo was confirmed by 32p labeling of rat cortical neurons in culture. Tubulin in growth cone membranes was phosphorylated at tyrosine in endogenous membrane phosphorylation reactions (0.068 mol phosphotyrosine/mol alpha-tubulin and 0.045 mol phosphotyrosine/mol beta-tubulin), and phosphorylation was specifically inhibited by antibodies directed against pp60c-src, which is localized in the growth cone membranes. pp60c-src was capable of directly phosphorylating tubulin as shown in immune complex kinase assays with purified brain tubulin. Phosphopeptide mapping revealed a limited number of sites of tyrosine phosphorylation in alpha- and beta-tubulin, with similar phosphopeptides observed in vivo and in vitro. These results reveal a novel posttranslational modification of tubulin that could regulate microtubule dynamics at the growth cone.


Analytical propagation of errors in dynamic SPECT: estimators, degrading factors, bias and noise.
Dynamic SPECT is a relatively new technique that may potentially benefit many imaging applications. Though similar to dynamic PET, the accuracy and precision of dynamic SPECT parameter estimates are degraded by factors that differ from those encountered in PET. In this work we formulate a methodology for analytically studying the propagation of errors from dynamic projection data to kinetic parameter estimates. This methodology is used to study the relationships between reconstruction estimators, image degrading factors, bias and statistical noise for the application of dynamic cardiac imaging with 99mTc-teboroxime. Dynamic data were simulated for a torso phantom, and the effects of attenuation, detector response and scatter were successively included to produce several data sets. The data were reconstructed to obtain both weighted and unweighted least squares solutions, and the kinetic rate parameters for a two-compartment model were estimated. The expected values and standard deviations describing the statistical distribution of parameters that would be estimated from noisy data were calculated analytically. The results of this analysis present several interesting implications for dynamic SPECT. Statistically weighted estimators performed only marginally better than unweighted ones, implying that more computationally efficient unweighted estimators may be appropriate. This also suggests that it may be beneficial to focus future research efforts upon regularization methods with beneficial bias-variance trade-offs. Other aspects of the study describe the fundamental limits of the bias variance trade-off regarding physical degrading factors and their compensation. The results characterize the effects of attenuation, detector response and scatter, and they are intended to guide future research into dynamic SPECT reconstruction and compensation methods.


Anesthesia for the mentally retarded patient.
In summary, their are a great many causes of mental retardation, each of which must be investigated carefully prior to induction of anesthesia. There are a few basic points to be remembered, no matter what the disease: (1) establish how much the patient understands and whether or not the patient can communicate, (2) establish whatever rapport is possible and use that both preoperatively and postoperatively in place of medication if possible, (3) avoid early extubation, and (4) be prepared for fairly long-term ventilation if the child cannot cooperate. The choice of anesthetic agents and preoperative and postoperative medications, their route of administration, and amount will be dictated by the disease entity, its severity, and the scope of the contemplated surgery.


Hemophagocytic Lymphohistiocytosis in Adults: Associated Diagnoses and Outcomes, a Ten-Year Experience at a Single Institution.
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive systemic inflammation which causes tissue damage due to abnormal immune system activation and has a high fatality rate even with treatment. HLH continues to be a difficult diagnosis to make because of lack of awareness and its overlap with other illnesses. This disorder is well defined in pediatric patients under the age of 18, but there is also a paucity of data in the adult population. The goals of this study were to describe associated disorders, clinical course and outcomes, and to determine if additional clinical criteria can be used to help with the diagnosis of HLH in adult patients. Patients' electronic medical records from 2007 to 2017 (who were ≥ 18 years old at the time of the search) were screened by ICD 9 and ICD 10 codes which contain the diagnosis of HLH or hemophagocytic syndrome, infection-associated. We identified 41 adult cases of HLH that were treated at our medical center over the course of 10 years and assessed these patients using both the historical and newly proposed diagnostic criteria. We also identified underlying diagnoses related to the development of HLH and fatality rates. Median age at diagnosis was 55 years old (18 - 87 years old) and 22 were male. Twenty-two had an infection, 16 with malignancy, seven had an autoimmune disorder and one with Sweet syndrome. Fifteen patients were treated with steroids alone, 18 with steroids and chemotherapy, three with steroids and antiviral agents, and two with chemotherapy alone. Sixteen (39%) died and 25 (60%) survived discharge. Seven patients died after discharge. Median survival of all patients was 1,095 days. Our data show that HLH is primarily associated with infections and malignancies. Newly proposed diagnostic criteria are not as specific, but can be helpful in making the diagnosis of HLH. We also showed that the fatality rate at our institution was lower than currently published rates of adult HLH.


The impact of iodine deficiency exposure on thyroid nodule cytology and pathology - A single institute, case-control study.
The association between follicular carcinoma and iodine deficiency (ID) is based on epidemiological studies and their inherent biases. The aim of the study was to assess the impact of long-term ID exposure on thyroid nodule cytology and final pathology in a distinct group of patients within a single institution. Ethiopian origin patients were compared to an aged-matched group of non-Ethiopian patients. Demographics, risk factors, clinical presentation, cytology and pathology were collected and compared. Final outcomes were cytology and pathology distribution. A total of 489 (246 Ethiopian, 243 control) nodules of 461 patients (230 and 231 respectively) were included. Ethiopian patients had lower rates of thyroid cancer risk factors (p=0.05). Cytology analysis demonstrated significant group differences (p=0.03), as Ethiopian patients had higher rates of benign cytology (85% vs. 75.7%, respectively). Pathology analysis demonstrated a significantly lower malignancy rate among Ethiopian patients (39.2% (20/51) vs. 63.3% (31/49), p=0.027, respectively). The Ethiopian group had a significant higher rate of follicular carcinoma compared to the control group (25% [5/20] vs. 3.2% [1/31], p=0.034, respectively) and lower rates of papillary thyroid carcinoma (25% [5/20] vs. 61.3% [19/31], p=0.017, respectively). The association between ID and FC exists years following immigration and exposure to a better iodine diet, implying that differentiation may be affected in earlier stages and levels of exposure.


Mechanism of injury predicts patient mortality and impairment after blunt trauma.
Different mechanisms of injury (MOI), such as motor vehicle crashes, falls, or pedestrians struck by motor vehicle impart varying degrees of force and energy transfer that may impact outcomes. This study analyzed the independent relationship between MOI and mortality and functional outcomes following blunt trauma among adults. Retrospective review of blunt trauma patients 15 y and older in the National Trauma Data Bank from 2001 to 2005. Primary outcome measures were mortality and presence of functional deficit in speech, walking, or feeding at discharge. MOI categories, identified by ICD-9 E codes, were motor vehicle crash, pedestrian struck by motor vehicle, motorcycle crash, falls at same level and from any height, and bicycle crash. A multiple regression analysis was performed adjusting for patient demographics and injury severity variables with motor vehicle crash as the reference mechanism group. Over the period studied, 515,464 patients met inclusion criteria. Mean Injury Severity Score (16.9), mortality rate (11%), and extremity injury (20%) were highest among pedestrians struck by motor vehicle, and head injury (16%) highest for motorcyclists. Overall, 52% had impaired ambulation, 16% impaired feeding, and 10% impaired speech. Adjusted odds of death, impaired walking, and impaired speaking were highest for pedestrians struck by motor vehicle, and impaired feeding highest for motorcyclists. After adjusting for confounders, MOI was found to independently predict mortality and functional impairment at hospital discharge. Current injury assessment models could be greatly enhanced by including MOI, and we propose routine adjustment for injury mechanism in trauma outcomes research.


Role of 17β-estradiol and testosterone in apoptosis.
17β-Estradiol (E2) and Testosterone (T) exert actions in most animal tissues, in addition to the reproductive system. Thus, both sex steroid hormones affect growth and different cell functions in several organs. Accordingly, the nuclear estrogen (ER) and androgen (AR) receptors are ubiquitously expressed. Moreover, ER and AR may have non-classical intracellular localizations, e.g. plasma membrane, mitochondria and endoplasmic reticulum, raising additional complexity to the functional roles of E2 and T. In addition to the modulation of gene transcription by direct interaction with their cognate nuclear receptors, the steroids can rapidly activate signaling pathways by a non-genomic mechanism mediated by receptors identical to or different from known steroid receptors. Among various functions, E2 and T can regulate apoptosis through those pathways. In mitochondria, the presence of ER and AR and actions of estrogen and androgen have been shown, in keeping with the organelle being a control point of apoptosis. The most recurrent action for each steroid hormone is the protection of mitochondria against different insults, resulting in antiapoptosis. This review summarizes the molecular basis of the modulation of programmed cell death by E2 and T in several tissues.


Impact of lithium on radioactive iodine therapy for hyperthyroidism.
Radioactive Iodine (RAI) is a common therapy for hyperthyroidism. However hyperthyroidism recurs or persists in 15-18% of patients after RAI. Studies report variable percentage of failure after RAI therapy depending on several variables including I(131). Lithium enhances efficacy of treatment by increasing RAI retention in the thyroid. To evaluate the efficacy of Lithium to RAI therapy in terms of cure, reduction of mean thyroid volume, and its safety. A prospective comparative study. Forty hyperthyroid patients were assigned to two groups, RAI alone and RAI plus lithium and followed for 1 year. Lithium was given in a dose of 900 mg/day in three divided doses for 6 days starting on the day of RAI therapy. Total T3, total T4, and thyroid-stimulating hormone (TSH) were done at baseline, 2,4,6,9, and 12 months. Ultrasound of thyroid was done at baseline and at the end of 1 year. Monitoring was done for side effects of lithium and RAI therapy. Cure rate and time to cure were assessed by Chi-square test. Mean change in thyroid volume was compared by student's t-test. P < 0.05 was considered significant. RAI combined with lithium had a trend towards better cure rate (90%) compared to RAI alone (70%) (P 0.11). Mean time taken to cure was 4.69 months in RAI plus lithium and 7.12 months in RAI alone (P 0.001). Mean change in thyroid volume was similar in both the groups (P = 0.75). There were no side effects of Lithium or RAI. RAI therapy combined with lithium showed a trend towards higher cure rate, safe and time to cure was less than RAI alone. Hence RAI combined with lithium is a better option in the management of hyperthyroidism than RAI alone.


The efficacy and safety of closure of brachial access using the AngioSeal closure device: experience with 161 interventions in diabetic patients with critical limb ischemia.
This study retrospectively evaluated the efficacy and safety of the 6F Angio-Seal (St. Jude Medical, St. Paul, Minn) as a closure device for transbrachial artery access for endovascular procedures in diabetic patients with critical limb ischemia. From January 2005 and September 2007, 1887 diabetic patients underwent interventional procedures in the lower limbs at a two diabetic foot centers. Patients presented with rest pain (16%), ulcers (80%), or gangrene (4%). Systemic anticoagulation with sodium heparin (70 IU/kg) was obtained for all patients at the beginning of the endovascular treatment. A total of 249 brachial arteries (238 patients) were evaluated for possible Angio-Seal use after endovascular recanalization of the leg. Color Doppler ultrasound imaging of the artery was obtained before revascularization only in patients with previous Angio-Seal placement in the brachial artery. No further imaging studies were done in the remaining brachial arteries where the Angio-Seal was deployed at the operator's discretion. Impairment or disappearance of the radial pulse or onsets of hand ischemia or hand pain, or impairment of hand function during or at the end of the endovascular revascularization were all regarded as contraindications to Angio-Seal usage. Evidence of a highly calcified plaque of the brachial artery access site at the time of vessel puncture was regarded as an absolute contraindication to the Angio-Seal use. Patients were seen before discharge, at 1, 3, and 8 weeks after the procedure, and at 3-month intervals thereafter. Complications included hemorrhage, pseudoaneurysm, infection, and vessel occlusion. A total of 1947 Angio-Seal collagen plugs were deployed in 1709 diabetic patients (90.5%). The Angio-Seal was used for brachial artery closure in 159 patients (8.4%) in 161 procedures (159 in the left, 2 in the right brachial artery). In 79 patients (4.2%) in 88 procedures (87 in the left and 1 in the right brachial artery), the device was deemed contraindicated due to small vessel size in 73 patients (92.4%) or presence of calcium at the access site in five patients (6.3%). One patient (1.3%) refused the collagen plug closure after revascularization. The non-Angio-Seal group was evaluated for comparison. The success rate for achieving hemostasis in the Angio-Seal group was 96.9%. Five major complications (3.1%) at 30 days consisted of two puncture site hematomas >4 cm, two brachial artery occlusions, and one brachial artery pseudoaneurysm, with three patients requiring open surgery. Minor complications (7.50%) were three puncture site hematomas < 4 cm, three oozing of blood from the access site, and six patients had mild pain in the cubital fossa. No further complications were recorded in the 14-month follow-up (range 1-25 months) of a total of 140 patients. This retrospective study shows that the 6F Angio-Seal is a valuable and safe vascular closure device for transbrachial access in diabetic patients undergoing interventional procedures for critical limb ischemia.


Applying Classic Social Psychology Principles to Improve Healthcare Teams.
This article was migrated. The article was marked as recommended. Modern healthcare involves teams composed of educators, learners, healthcare providers, patients, patients' significant others and families, healthcare administrators, and information sources. Principles of social psychology are relevant to interactions among team members when learning and performing professional duties; communicating to build trust, commitment, and teamwork; and collaborating among members of the healthcare team. This paper briefly discusses several classic principles of social psychology and how they apply to healthcare teams and medical education. Understanding and applying these principles will help healthcare providers optimize performance and interactions with colleagues, learners, and patients. It is important to incorporate study and practice of these principles into medical education and professional development.


Genital dysplasia in women infected with human immunodeficiency virus.
Women infected with human immunodeficiency virus (HIV) are at increased risk for the development of dysplastic genital lesions. Traditionally, markers of immunosuppression were predictive of the development of dysplasia. Recent advances in antiretroviral medications allow restoration of a once-depressed CD4+ cell count and suppression of HIV replication. In this new era, additional predictive markers of genital dysplasia are needed for management of women infected with with HIV. To find predictive markers of genital dysplasia in women infected with HIV. Observational study of a consecutive sample of 200 women infected with HIV from an urban university clinic. Measurements of histopathology, CD4+ count, CD4+ nadir, HIV viral load, human papillomavirus (HPV), and usage of highly active antiretroviral therapy (HAART) were evaluated for an association with genital dysplasia. There was a trend toward a protective effect against any genital dysplasia when HAART had been prescribed [relative risk = 0.77, 95% confidence interval (CI) 0.56, 1.06] and HAART therapy resulted in an immune response (relative risk, 0.61; 95% CI, 36, 1.02). High-risk HPV DNA was a strong predictor of dysplasia (P =.0003). A lower CD4+ count nadir was strongly associated with genital dysplasia (P =.0003). A history of greater immunosuppression, as measured by the nadir of a patient's CD4+ count, is the strongest predictor of genital dysplasia in women infected with HIV.


Intraoperative radiotherapy in patients with recurrent head and neck cancer.
Patients with head and neck cancer who have a relapse of the disease above the clavicles can sometimes be salvaged by additional surgery. However, if all gross tumor cannot be removed during surgery or if the resection margins are unsatisfactory, the likelihood of salvage is remote, especially when postoperative radiotherapy is not feasible due to previous radiotherapy. Between 1979 and 1983, we employed intraoperative brachytherapy for 21 such patients. Sixteen patients had a recurrence after previous surgery and radiotherapy, and 5 after radical radiotherapy. All gross tumor could not be removed in 15 patients, whereas satisfactory margins could not be obtained in 6. In 11 patients, we delivered radiotherapy by a temporary implant of iridium-192 (median dose 4,800 rads in 6 days). In 10 patients, radiotherapy was delivered by a permanent implant of iodine-125 (median activity 13 mCi). Three patients (14 percent) had a relapse within the surgical field, whereas six others (28 percent) had a relapse elsewhere or had development of metastases. Complications developed in four patients (19 percent) and were fatal in one patient. The actuarial disease-free survival rate at 2 years was 55 percent, whereas the rate of local disease control was 81 percent. Our experience suggests that intraoperative brachytherapy can salvage certain high-risk patients with head and neck cancer.


Disorder-Induced Broadband Near-Infrared Persistent and Photostimulated Luminescence in Mg2SnO4:Cr3.
Materials with near-infrared (NIR) persistent luminescence (PersL) and NIR-to-NIR photostimulated luminescence (PSL) properties are attractive platforms for photonic energy harvesting and release. In this work, we develop Mg2SnO4:Cr as a broadband NIR PersL and NIR-to-NIR PSL material (luminescence maxima at ∼800 nm) and reveal the origin of the PersL and PSL properties. The material has an inverse spinel structure with the Mg2+ and Sn4+ disorder at the Wyckoff 16d site based on the Rietveld refinement. Cr K-edge X-ray absorption near-edge structure (XANES) spectra uncover that the doped Cr ions have a +3 valence state and occupy the disordered (Mg,Sn) site with octahedral coordination. The disorder results in multiple Cr3+ centers, and the broadband luminescence originates from the 4T2(4F) → 4A2 transition of Cr3+ at sites with intermediate crystal field strength. The distribution of trap depths is continuous according to the analysis of thermoluminescence (TL) spectra using the initial rising method, which relates to the random distribution of Mg2+ and Sn4+ at the second coordination sphere of the Cr3+ centers rather than the oxygen-related defects. Stimulating the material with a NIR laser, the NIR PersL gets significantly enhanced due to a PSL process. The broadband PersL and PSL are detectable beyond 100 h and have good tissue penetrability and therefore the developed Mg2SnO4:Cr3+ has potential in applications of optical information storage/reading and autofluorescence-free bioimaging. Finally, three crystal and electronic structure factors are proposed for screening new Cr3+-activated PersL and PSL materials.


Higher adalimumab serum levels do not increase the risk of adverse events in patients with inflammatory bowel disease.
Background: The relationship between serum adalimumab concentrations and adverse events in patients with inflammatory bowel disease (IBD) is unknown. We aimed to determine whether patients with IBD using adalimumab are at increased risk of adverse events if they have higher adalimumab serum levels compared to those with lower adalimumab levels. Methods: This was a retrospective study of 191 IBD patients with at least one serum adalimumab level measurement available. The cohort was divided using a cutoff level of 10 mcg/mL. The primary outcome was the rate of overall adverse events between the two groups. Secondary outcomes included rate of infections, dermatologic reactions, injection-site reactions and other adverse events in both groups. Rates of discontinuation of adalimumab due to adverse events were evaluated. Multivariate logistic regression analysis was performed to evaluate the relationship between adalimumab levels and adverse events. Results: A total of 41 adverse events were reported in 191 patients in the overall cohort. Among 86 patients with higher adalimumab levels, 22 adverse events were reported, vs. 19 adverse events among 105 patients with lower adalimumab levels (25.6% vs. 18.1%, p = .21). Analysis according to adalimumab level tertiles also did not show significant differences in the rates of adverse events. A multivariate forward selection model also did not find higher odds of an adverse event in IBD patients with higher adalimumab levels compared to lower levels (OR 1.54, 95% CI 0.77-3.08). Conclusions: There does not appear to be a relationship between adalimumab exposure and risk of adverse events in IBD patients.


A Genome-Wide Association Study To Understand the Effect of Fusarium verticillioides Infection on Seedlings of a Maize Diversity Panel.
Fusarium verticillioides, which causes ear, kernel and stem rots, has been reported as the most prevalent species on maize worldwide. Kernel infection by F. verticillioides results in reduced seed yield and quality as well as fumonisin contamination, and may affect seedling traits like germination rate, entire plant seedling length and weight. Maize resistance to Fusarium is a quantitative and complex trait controlled by numerous genes with small effects. In the present work, a Genome Wide Association Study (GWAS) of traits related to Fusarium seedling rot was carried out in 230 lines of a maize association population using 226,446 SNP markers. Phenotypes were scored on artificially infected kernels applying the rolled towel assay screening method and three traits related to disease response were measured in inoculated and not-inoculated seedlings: plant seedling length (PL), plant seedling weight (PW) and germination rate (GERM). Overall, GWAS resulted in 42 SNPs significantly associated with the examined traits. Two and eleven SNPs were associated with PL in inoculated and not-inoculated samples, respectively. Additionally, six and one SNPs were associated with PW and GERM traits in not-inoculated kernels, and further nine and thirteen SNPs were associated to the same traits in inoculated kernels. Five genes containing the significant SNPs or physically closed to them were proposed for Fusarium resistance, and 18 out of 25 genes containing or adjacent to significant SNPs identified by GWAS in the current research co-localized within QTL regions previously reported for resistance to Fusarium seed rot, Fusarium ear rot and fumonisin accumulation. Furthermore, linkage disequilibrium analysis revealed an additional gene not directly observed by GWAS analysis. These findings could aid to better understand the complex interaction between maize and F. verticillioides.


"ECT should never stop": Exploring the experiences and recommendations of ECT clinical directors and anesthetists about ECT during the COVID-19 pandemic.
Electroconvulsive therapy (ECT) is an effective treatment option for severe, treatment-resistant, and life-threating psychiatric illness. The COVID-19 pandemic has significantly disrupted ECT services. Services across North America, Europe, and Australia have reported decreased ECT delivery, and changes in the ways ECT is delivered. This study aimed to identify the impacts of COVID-19 on ECT services globally by exploring clinicians' experiences about ECT during the pandemic, and their recommendations for reducing the negative impacts of the pandemic. Data were collected using an electronic, cross-sectional survey, which included elicitation of free-text responses. The survey was open from March to November 2021. Clinical directors in ECT services, their delegates, and anesthetists were invited to participate. This paper reports the qualitative analysis of responses provided. Fifty-two participants provided qualitative response/s; 74.5% were clinical directors or their delegates, and 25.5% were anesthetists. Greater than one-third of participants were from Australia/New Zealand, and there was also representation from North America, Europe, and the UK. Participants' responses were detailed, averaging 43 words. Three themes were identified: (1) Service provision, about the importance of ECT services continuing during the pandemic, (2) Preparedness, through guidelines and environmental design, and (3) Personal protection, about strategies to increase staff safety. This is the first multi-site, international study to document the experiences and recommendations of ECT clinical directors and anesthetists about the effect of COVID-19 on ECT practice. The findings inform evidence-based practice, and ensure people with major psychiatric illnesses continue to receive ECT during the pandemic.


Functional alteration in frontolimbic systems relevant to moral judgment in cocaine-dependent subjects.
Cocaine addiction is characterized by persistent decision-making deficits, which are linked to structural and functional abnormalities in frontolimbic systems. Moral judgment is as a special instance of decision making, in which both cognitive and emotional signals must be adequately integrated to decide how to resolve moral dilemmas. Here, we employed a moral dilemmas functional magnetic resonance imaging (fMRI) task to explore possible alterations of frontolimbic systems in cocaine-dependent subjects. We also explored if these alterations relate to more basic deficits in functional connectivity within these systems during spontaneous resting-state activation. Ten cocaine-dependent subjects and 14 non-drug-using controls participated in the study. Cocaine-dependent subjects were carefully selected to discard potentially confounding co-morbidities, and they underwent a uniform supervised abstinence period of 10 days. Both groups were scanned, and fMRI maps were generated to identify (1) brain response to moral dilemmas; and (2) the strength of functional connectivity within frontolimbic systems during resting-state. During the moral dilemmas task, cocaine-dependent subjects showed reduced activation involving frontolimbic structures as the anterior cingulate cortex (ACC), left insula and brain stem. Connectivity analyses showed that cocaine users had less resting-state functional connectivity between ACC, thalamus, insula and brain stem. These results demonstrate that cocaine-dependent subjects have functional alterations in the frontolimbic systems that support moral judgment and social decision making.


Magnetic resonance: new approaches to imaging of the musculoskeletal system.
Recent technical advances in magnetic resonance imaging are reviewed. Purpose designed musculoskeletal magnetic resonance (MR) systems are now available. A great deal of pulse sequence development has been carried out with ultrashort TE (UTE) imaging, blood oxygenation level detection (BOLD) studies, diffusion weighted and other sequences. Image processing and measurement techniques have improved. In hyaline articular cartilage the deep layer can now be identified. Contrast agents are now being used to study the reduction in proteoglycans in cartilage. Enhancement is seen in tendons, ligaments and menisci and can be used to study perfusion. Signal is detected from cortical bone and periosteum and this can be used to monitor perfusion in serial studies. Muscle metabolism can also be studied. Contrast transport into intervertebral discs can be observed as well as effects attributable to iron deposition.


Activation of NF-kappaB/Rel occurs early during neoplastic transformation of mammary cells.
NF-kappaB/Rel is a family of transcription factors which are expressed in all cells; however, in most non-B cells, they are sequestered in the cytoplasm in inactive complexes with specific inhibitory proteins, termed IkappaBs. We have recently shown that NF-kappaB/Rel factors are aberrantly activated in human breast cancer and rodent mammary tumors, and function to promote tumor cell survival and proliferation. Here, we have examined the time-course of induction of NF-kappaB/Rel factors upon carcinogen treatment of female Sprague-Dawley (S-D) rats in vivo and in human mammary epithelial cells (HMECs) in culture. We observed that NF-kappaB/Rel activation is an early event, occurring prior to malignant transformation. In S-D rats, increased NF-kappaB/Rel binding was detected in nuclear extracts of mammary glands from 40% of animals 3 weeks post-treatment with 15 mg/kg 7,12-dimethylbenz[a]anthracene (DMBA); this is prior to formation of tumors which normally begin to be detected after 7-9 weeks. In non-tumorigenic MCF-10F cells, in vitro malignant transformation upon treatment with either DMBA or benzo[a]pyrene (B[a]P) resulted in a 4- to 12-fold increase in activity of classical NF-kappaB (p65/p50). NF-kappaB induction was corrrelated with a decrease in the stability of the NF-kappaB-specific inhibitory protein IkappaB-alpha. Ectopic expression of the transactivating p65 subunit of NF-kappaB in MCF-10F cells induced the c-myc oncogene promoter, which is driven by two NF-kappaB elements, and endogenous c-Myc levels. Furthermore, reduction mammoplasty-derived HMECs, immortalized following B[a]P exposure, showed dysregulated induction of classical NF-kappaB prior to malignant transformation. Together these findings suggest that activation of NF-kappaB plays an early, critical role in the carcinogen-driven transformation of mammary glands.


Highly regioselective nickel-catalyzed cross-coupling of N-tosylaziridines and alkylzinc reagents.
Herein, we report the first ligand-controlled, nickel-catalyzed cross-coupling of aliphatic N-tosylaziridines with aliphatic organozinc reagents. The reaction protocol displays complete regioselectivity for reaction at the less hindered C-N bond, and the products are furnished in good to excellent yield for a broad selection of substrates. Moreover, we have developed an air-stable nickel(II) chloride/ligand precatalyst that can be handled and stored outside a glovebox. In addition to increasing the activity of this catalyst system, this also greatly improves the practicality of this reaction, as the use of the very air-sensitive Ni(cod)2 is avoided. Finally, mechanistic investigations, including deuterium-labeling studies, show that the reaction proceeds with overall inversion of configuration at the terminal position of the aziridine by way of aziridine ring opening by Ni (inversion), transmetalation (retention), and reductive elimination (retention).


Evaluation of evidence for pharmacokinetics-pharmacodynamics-based dose optimization of antimicrobials for treating Gram-negative infections in neonates.
Neonates present a special subgroup of population in whom optimization of antimicrobial dosing can be particularly challenging. Gram-negative infections are common in neonates, and inpatient treatment along with critical care is needed for the management of these infections. Dosing recommendations are often extrapolated from evidence generated in older patient populations. This systematic review was done to identify the knowledge gaps in the pharmacokinetics-pharmacodynamics (PK-PD)-based optimized dosing schedule for parenteral antimicrobials for Gram-negative neonatal infections. Relevant research questions were identified. An extensive electronic and manual search methodology was used. Potentially eligible articles were screened for eligibility. The relevant data were extracted independently in a pre-specified data extraction form. Pooling of data was planned. Of the 340 records screened, 24 studies were included for data extraction and incorporation in the review [carbapenems - imipenem and meropenem (n=7); aminoglycosides - amikacin and gentamicin (n=9); piperacillin-tazobactam (n=2); quinolones (n=2); third- and fourth-generation cephalosporins (n=4) and colistin nil]. For each of the drug categories, the information for all the questions that the review sought to answer was incomplete. There was a wide variability in the covariates assessed, and pooling of results could not be undertaken. There is a wide knowledge gap for determining the doses of antimicrobials used for Gram-negative infections in neonates. A different profile of newborns in the developing countries could affect the disposition of antimicrobials for Gram negative infections, necessitating the generation of PK-PD data of antimicrobials in neonates from developing countries. Further, guidelines for treatment of neonatal conditions may incorporate the evidence-based PK-PD-guided dosing regimens.


Integrated system for temperature-controlled fast protein liquid chromatography. III. Continuous downstream processing of monoclonal antibodies.
Three different applications of travelling heating zone reactor (THZR) chromatography for the downstream processing of monoclonal antibodies (mAbs) are described. mAb containing feedstocks were applied to a fixed bed of the thermoresponsive rProtein A matrix, Byzen Pro™, contained in a bespoke column (held at 15 °C) fitted with a travelling heating (42 °C) device encircling a narrow section of the column. For the demonstration of continuous concentration, uninterrupted loading of 1.0 g/L mAb in a pH 8 binding buffer was synchronized with 5 repeated movements of the heating zone along the column's full length at a velocity of 0.1 mm/s. Elution of mAbs was induced solely by the travelling heating zone's action, each full movement generating a sharp concentrated elution peak accompanied by a small transient mAb concentration-dependent dip in conductivity. Quasi-steady-state operation occurred from the third elution onwards, delivering a mean mAb concentration of 4.9 g/L and process yield >93%. Quasi-continuous separation of the target mAb (1.41 g/L) from bovine serum albumin, BSA (1.0 g/L), was achieved by cyclically alternating the feeding of the mAb + BSA feedstock, with that of the binding buffer alone; supply of the latter was timed to coincide with movement of the heating zone. Accurate coordination of the heating zone's travel and switching from feed to buffer permitted quasi-steady-state collection (elutions 3-6) of sharp peaks of mAb in high purity (98.7%) and yield (88.7%) in 4.5-fold concentrated form, with BSA exiting in the flow through fractions between successive mAb elution peaks. Fully automated THZR-mediated quasi-continuous buffer exchange of 1.34 g/L mAb from a phosphate buffer pH 8 into a HEPES buffer pH 8 of slightly lower conductivity was performed over a 19 h period by carefully timed switching from one feed solution to the other and back again, whilst synchronising movement of the heating zone with feeding of the exchange buffer. Quasi-steady-state operation (elutions 2-9) resulted in an average eluted mAb yield of 94.5% and concentration of 4.8 g/L. Triggering movement of the heating zone slightly ahead of the switch from mAb feed to exchange buffer permitted the positioning of mAb elution peaks in 9 mL volume segments with the lowest recorded conductivity. Measurements of buffer exchange performance conducted with two 'protein-free' systems demonstrated that compared to tangential flow filtration in diafiltration mode, which represents the 'state-of-the-art' technology for buffer exchange, the THZR chromatography based approach affords a >60% saving in minimum volume of exchange buffer required to remove 99.9% of the original buffer. Combined far and near UV circular dichroism, intrinsic fluorescence and thermal melting experiments showed that, unlike conventional Protein A/G affinity chromatography, the conditions for THZR Protein A chromatography respect maintenance of a favourable structural profile for mAbs.


MET17 and hydrogen sulfide formation in Saccharomyces cerevisiae.
Commercial isolates of Saccharomyces cerevisiae differ in the production of hydrogen sulfide (H(2)S) during fermentation, which has been attributed to variation in the ability to incorporate reduced sulfur into organic compounds. We transformed two commercial strains (UCD522 and UCD713) with a plasmid overexpressing the MET17 gene, which encodes the bifunctional O-acetylserine/O-acetylhomoserine sulfhydrylase (OAS/OAH SHLase), to test the hypothesis that the level of activity of this enzyme limits reduced sulfur incorporation, leading to H(2)S release. Overexpression of MET17 resulted in a 10- to 70-fold increase in OAS/OAH SHLase activity in UCD522 but had no impact on the level of H(2)S produced. In contrast, OAS/OAH SHLase activity was not as highly expressed in transformants of UCD713 (0.5- to 10-fold) but resulted in greatly reduced H(2)S formation. Overexpression of OAS/OAH SHLase activity was greater in UCD713 when grown under low-nitrogen conditions, but the impact on reduction of H(2)S was greater under high-nitrogen conditions. Thus, there was not a good correlation between the level of enzyme activity and H(2)S production. We measured cellular levels of cysteine to determine the impact of overexpression of OAS/OAH SHLase activity on sulfur incorporation. While Met17p activity was not correlated with increased cysteine production, conditions that led to elevated cytoplasmic levels of cysteine also reduced H(2)S formation. Our data do not support the simple hypothesis that variation in OAS/OAH SHLase activity is correlated with H(2)S production and release.


Expanding horizons of tandem repeats in biology and medicine: Why 'genomic dark matter' matters.
Approximately half of the human genome includes repetitive sequences, and these DNA sequences (as well as their transcribed repetitive RNA and translated amino-acid repeat sequences) are known as the repeatome. Within this repeatome there are a couple of million tandem repeats, dispersed throughout the genome. These tandem repeats have been estimated to constitute ∼8% of the entire human genome. These tandem repeats can be located throughout exons, introns and intergenic regions, thus potentially affecting the structure and function of tandemly repetitive DNA, RNA and protein sequences. Over more than three decades, more than 60 monogenic human disorders have been found to be caused by tandem-repeat mutations. These monogenic tandem-repeat disorders include Huntington's disease, a variety of ataxias, amyotrophic lateral sclerosis and frontotemporal dementia, as well as many other neurodegenerative diseases. Furthermore, tandem-repeat disorders can include fragile X syndrome, related fragile X disorders, as well as other neurological and psychiatric disorders. However, these monogenic tandem-repeat disorders, which were discovered via their dominant or recessive modes of inheritance, may represent the 'tip of the iceberg' with respect to tandem-repeat contributions to human disorders. A previous proposal that tandem repeats may contribute to the 'missing heritability' of various common polygenic human disorders has recently been supported by a variety of new evidence. This includes genome-wide studies that associate tandem-repeat mutations with autism, schizophrenia, Parkinson's disease and various types of cancers. In this article, I will discuss how tandem-repeat mutations and polymorphisms could contribute to a wide range of common disorders, along with some of the many major challenges of tandem-repeat biology and medicine. Finally, I will discuss the potential of tandem repeats to be therapeutically targeted, so as to prevent and treat an expanding range of human disorders.


Studies on drug-human serum albumin binding: the current state of the matter.
Human serum albumin (HSA) is the major plasma protein with vital functions acting as depot and career for many endogenous (fatty acids, bilirubin, etc.) and exogenous substances (drugs, nutrients, etc.) in the blood. Binding to HSA controls the free, active concentration of the drug and may affect considerably the overall pharmacodynamic and pharmacokinetic profile. Studies on drug - protein binding are important from both theoretical and practical point of view as they allow better understanding of the processes underlying drug disposition and elimination and the effect of several pathological states or co-administered drugs on drug delivery and efficacy. The present review focuses on the current state of drug - HSA binding studies. The major functions and consequences of drug - protein binding are described. The X-ray structure of HSA is discussed focusing on the location and the architecture of the primary drug and fatty acids binding sites. Some of the most commonly used methods for drug - HSA binding assay are presented together with examples for their application. The most extensive studied topics in the area are discussed including quantitative characterization of drug - HSA complexation, identification of the binding sites, stereoselectivity of drug - HSA interactions, and thermodynamic characterization of the binding process. A short section is devoted to in silico prediction of drug - HSA binding as an important step in drug design and development.


Immunohistochemical Characterization of a Large Cohort of Triple Negative Breast Cancer.
Introduction. Triple negative breast carcinomas are characterized by a lack of hormone receptor and HER2 expression and inconsistent expression of breast-specific immunohistochemical markers. The expression of many site-specific markers in these tumors is largely unknown. The objective of the study was to examine the expression of widely used immunohistochemical markers on a large cohort of triple negative breast cancer. Methods. Sections from tissue microarrays were stained with 47 markers using routine protocols. Most markers were scored using a modified Allred method. ATRX, BAP1, SMAD4, e-cadherin, and beta-catenin were scored as retained or lost. Mammaglobin was considered positive if there was at least moderate intensity staining in any tumor cells. P16 was scored as overexpressed or not overexpressed; p53 was scored as wildtype, overexpressed, null, or cytoplasmic. Results. The cohort consisted of 639 tumors including 601 primary and 32 metastases. Overall, 96% expressed GATA3, mammaglobin, and/or SOX10 while 97% of no special type tumors expressed this panel. Carcinoma of apocrine differentiation demonstrated an AR positive, SOX10 negative, K5 negative/focal immunophenotype. PAX8 (SP348), WT1, Napsin A, and TTF1 (8G7G3/1) were never or rarely expressed while CA9, CDX2, NKX3.1, SATB2 (SATBA410), synaptophysin, and vimentin were variably expressed. Conclusions. Almost all TNBC express at least 1 of the 3 IHC markers: GATA3, mammaglobin, and/or SOX10. Carcinoma of apocrine differentiation is characterized by an AR positive, SOX10 negative, K5 negative or focal immunophenotype. Cautious interpretation of so-called site-specific markers, with knowledge of antibody clones, is required in excluding the diagnosis of triple negative breast cancer.


Methylation profiles of endometrioid and serous endometrial cancers.
Promoter methylation is a gene- and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous endometrial cancers (uterine papillary serous carcinoma, UPSC) exhibit different clinical, histological and molecular genetic characteristics, we hypothesized that these differences may be reflected in epigenetic phenomena as well. Identification of a panel of methylation biomarkers could be helpful in a correct histological classification of these two subtypes, which solely on the basis of morphology is not always easy. Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of different tumour suppressor genes in EEC and UPSC. Methylation results were correlated with histology and survival. The median cumulative methylation index of all genes was significantly higher in EEC (124) than in UPSC (93) (P<0.001). Promoter methylation of CDH13 and MLH1 was more frequently present in EEC, while CDKN2B and TP73 were more frequently methylated in UPSC. Almost 90% of EEC and 70% of UPSC could be predicted by CDH13 and TP73. In EEC, methylation of MLH1 was associated with a shorter disease-free survival (DFS; P<0.0001) and overall survival (OS; P=0.005). In a multivariate model, MLH1 methylation emerged as an additional prognostic factor to stage for DFS (P=0.002). In conclusion, promoter methylation is more common in EEC than UPSC. A panel of methylation biomarkers could be useful to distinguish between the two histological subtypes of endometrial cancer. Furthermore, methylation of MLH1 may have prognostic value in EEC.


The fallibility of memory in judicial processes: lessons from the past and their modern consequences.
The capability of adult and child witnesses to accurately recollect events from the past and provide reliable testimony has been hotly debated for more than 100 years. Prominent legal cases of the 1980s and 1990s sparked lengthy debates and important research questions surrounding the fallibility and general reliability of memory. But what lessons have we learned, some 35 years later, about the role of memory in the judicial system? In this review, we focus on what we now know about the consequences of the fallibility of memory for legal proceedings. We present a brief historical overview of false memories that focuses on three critical forensic areas that changed memory research: children as eyewitnesses, historic sexual abuse and eyewitness (mis)identification. We revisit some of the prominent trials of the 1980s and 1990s to not only consider the role false memories have played in judicial decisions, but also to see how this has helped us understand memory today. Finally, we consider the way in which the research on memory (true and false) has been successfully integrated into some courtroom procedures.


European perspectives on the public health risks posed by farmed game mammals.
As consumers have become aware of the health risks associated with the high levels of saturated fats present in conventional red meats, an interest in new domesticants has developed. Meat from these species represents the only sector of the European red meat industry which is currently experiencing growth. The production of meat from grazing animals other than cattle and sheep is not subsidised within the European Union (EU), so that despite the fact that game farming for meat exists in all the Member States, much of the farmed game meat consumed within Europe is imported from the rapidly developing deer farming industry in New Zealand. Less severely regulated industries world-wide also export a great variety of wild game into Europe, but health controls and labelling do not permit the consumer to discriminate between wild and farmed produce, or even between species or countries of origin. This paper describes the scale of game farming within Europe, and the quantities of game imported. The author reviews the diverse production systems in different regions of Europe and the various harvesting systems, including the present measures enforced for veterinary public health reasons, and considers the threats posed by the zoonoses known to affect game mammals and the public health risks posed by contamination. An explanation is given of the differences between the production and processing of farmed and wild game.


Frequency of hallway ambulation by hospitalized older adults on medical units of an academic hospital.
Lack of activity during hospitalization may contribute to functional decline. The purpose of this study was to determine the frequency of hallway walking by older adults hospitalized for medical illness. The study was an observational time-sampled study, which was conducted in the hallways of 3 medical units of a 485-bed academic health care center. Each unit was observed weekdays for eight 3-hour intervals covering 8 AM to 8 PM. Before each observation, nursing staff were questioned about walking abilities of patients aged <or=55 years. During observation, frequency and minutes of patients' hallway ambulation were recorded. Of 118 patients considered by nurses as able to walk in the hallways, 18.6% walked once, 5.1% twice, 3.4% more than twice, and 72.9% did not walk at all per 3-hour period. The median minutes for ambulation was 5.5. Frequency of ambulation was as low for patients independent in walking as for those dependent (28% vs 26%, P=.507). Of the 32 patients who walked in the hallways, most did so alone (46.8%, n=15) or with therapy staff (41%, n=13); few walked with nursing staff (9.4%, n=3) or family (18.8%, n=6). In this setting, hallway walking was very low for hospitalized older patients. If this trend of limited walking is found to be prevalent across other settings, then both independent and dependent patients will require additional interventions to improve ambulation during hospitalization.


The actin cytoskeleton regulates LFA-1 ligand binding through avidity rather than affinity changes.
To elucidate the role of the cytoskeleton regulating avidity or affinity changes in the leukocyte adhesion receptor lymphocyte function-associated antigen-1 (LFA-1) (alpha(L)beta(2)), we generated mutant cytoplasmic LFA-1 receptors and expressed these into the erythroleukemic cell line K562. We determined whether intercellular adhesion molecule-1 (ICAM-1)-mediated adhesion of LFA-1, lacking parts of its cytoplasmic tails, is regulated through receptor diffusion/clustering and/or by altered ligand binding affinity. All cytoplasmic deletion mutants that lack the complete beta(2) cytoplasmic tail and/or the conserved KVGFFKR sequence in the alpha(L) cytoplasmic tail were constitutively active and expressed high levels of the activation epitopes NKI-L16 and M24. Surprisingly, whereas these mutants showed a clustered cell surface distribution of LFA-1, the ligand-binding affinity as measured by titration of soluble ligand ICAM-1 remained unaltered. The notion that redistribution of LFA-1 does not alter ligand-binding affinity is further supported by the finding that disruption of the cytoskeleton by cytochalasin D did not alter the binding affinity nor adhesion to ICAM-1 of these mutants. Most cytoplasmic deletion mutants that spontaneously bound ICAM-1 were not capable to spread on ICAM-1, demonstrating that on these mutants LFA-1 is not coupled to the actin cytoskeleton. From these data we conclude that LFA-1-mediated cell adhesion to ICAM-1 is predominantly regulated by receptor clustering and that affinity alterations do not necessarily coincide with strong ICAM-1 binding.


[Pancreas transplantation--a review].
According to the International Pancreas Transplant Registry, more than 1,000 pancreas transplantations are now performed annually. When performed simultaneously with a kidney transplant, pancreas transplantation is a generally accepted treatment for type 1 diabetic patients with end stage renal disease, and the pancreas graft survival in this setting is equivalent to that of the kidney graft. The reported results of solitary pancreatic transplantation in non-uraemic diabetic patients have been less favourable due to a high rejection rate in combination with difficulties in rejection diagnosis and treatment. However, the introduction of new immunosuppressive drugs over the last few years has drastically improved the survival of solitary pancreatic grafts and allows for a rising enthusiasm. The majority of the 122 transplantations performed in Oslo so far were simultaneous kidney and pancreas transplantations. Duct occluded segmental grafts were used until 1988 when the pancreatico-duodenal technique with bladder drainage was introduced. In March 1998 we changed to enteric drainage of the exocrine pancreas due to a high percentage of lower urinary tract problems and bicarbonate loss associated with the bladder drainage technique. The positive impact of a functioning pancreas transplant on the recipient's quality of life is well recognised, whereas long-term beneficial effects on the secondary complications of diabetes are not well documented. A short overview of various aspects of pancreas transplantation is given, including experience with the 122 transplantations performed at the National Hospital, Oslo, Norway.


The impact of hospital volume on liver resection: A systematic review and Bayesian network meta-analysis.
This study aims to compare the outcomes of high-volume, medium-volume, and low-volume hospitals performing hepatic resections using a network meta-analysis. A literature search until June 2023 was conducted across major databases to identify studies comparing outcomes in high-volume, medium-volume, and low-volume hospitals for liver resection. Bayesian network meta-analysis was conducted, and surface under cumulative ranking area values, odds ratio, and mean difference with 95% credible intervals were reported for postoperative mortality, failure-to-rescue, morbidity, length of stay, and hospital costs. Twenty studies comprising 248,707 patients undergoing liver resection were included. For the primary mortality outcome, overall and subgroup analyses were performed: group I: high-volume = 5 to 20 resections/year; group II: high-volume = 21 to 49 resections/year; group III: high-volume ≥50 resections/year. Results demonstrated a significant association between hospital volume and mortality (overall-high-volume versus medium-volume: odds ratio 0.66, 95% credible interval 0.49-0.87; high-volume versus low-volume: odds ratio 0.52, 95% credible interval 0.41-0.65; group I-high-volume versus low-volume: odds ratio 0.34, 95% credible interval 0.22-0.50; medium-volume versus low-volume: odds ratio 0.56, 95% credible interval 0.33-0.92; group II-high-volume versus low-volume: odds ratio 0.67, 95% credible interval 0.45-0.91), as well as length of stay (high-volume versus low-volume: mean difference -1.24, 95% credible interval -2.07 to -0.41), favoring high-volume hospitals. No significant difference was observed in failure-to-rescue, morbidity, or hospital costs across the 3 groups. This study supports a positive relationship between hospital volume and surgical outcomes in liver resection. Patients from high-volume hospitals experience superior outcomes in terms of lower postoperative mortality and shorter lengths of stay than medium-volume and low-volume hospitals.


Cardiovascular effects of KM-13, a new, orally effective, cardiotonic sympathomimetic amine.
Dobutamine's chemical structure was modified to make it orally effective, while its pharmacological profile was preserved. Testing on anesthetized dogs showed that replacement of the para hydroxyl group with carboxyamide at the phenyl end of the molecule increased inotropic potency threefold, but it introduced pressor activity that spoiled the inotropic selective profile of dobutamine. However, shifting carboxyamide to the meta position avoided pressor activity and further enhanced inotropic potency to nine times that of dobutamine. When administered orally to conscious dogs, this compound, KM-13 (5 mg/kg), produced a sustained increase in left ventricular dP/dt with only immediate changes in heart rate; 10 mg/kg dobutamine was without cardiovascular effects. The (-) isomer of KM-13 contained twice the inotropic activity of the (+) isomer; in contrast, the (-) isomer had no effect on diastolic blood pressure, while the (+) isomer lowered blood pressure. The inotropic and chronotropic effects of dobutamine and KM-13 are both largely due to beta-adrenergic stimulation as shown by propranolol blockade. In contrast to dobutamine, KM-13 is an agent that is active by either oral or buccal administration and has greater inotropic potency.


Selection against pathogenic mtDNA mutations in a stem cell population leads to the loss of the 3243A-->G mutation in blood.
The mutation 3243A-->G is the most common heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutation in humans, but it is not understood why the proportion of this mutation decreases in blood during life. Changing levels of mtDNA heteroplasmy are fundamentally related to the pathophysiology of the mitochondrial disease and correlate with clinical progression. To understand this process, we simulated the segregation of mtDNA in hematopoietic stem cells and leukocyte precursors. Our observations show that the percentage of mutant mtDNA in blood decreases exponentially over time. This is consistent with the existence of a selective process acting at the stem cell level and explains why the level of mutant mtDNA in blood is almost invariably lower than in nondividing (postmitotic) tissues such as skeletal muscle. By using this approach, we derived a formula from human data to correct for the change in heteroplasmy over time. A comparison of age-corrected blood heteroplasmy levels with skeletal muscle, an embryologically distinct postmitotic tissue, provides independent confirmation of the model. These findings indicate that selection against pathogenic mtDNA mutations occurs in a stem cell population.


Cutaneous granulomatous vasculitis after herpes zoster infection showing polyarteritis nodosa-like features.
Various cutaneous lesions have been described after herpes zoster infection, such as lymphomas, pseudolymphoma and granulomatous conditions (granuloma annulare, tuberculoid granuloma, sarcoidosis). However, granulomatous vasculitis is an extremely rare sequel. We now describe a case of superficial granulomatous vasculitis with deep 'polyarteritis nodosa (PAN)-like' arteritis that developed after herpes zoster infection. Polymerase chain reaction did not detect genome of the herpes virus. We suggest that this condition could be an immune response to viral proteins.


Evolutionary versatility of eukaryotic protein domains revealed by their bigram networks.
Protein domains are globular structures of independently folded polypeptides that exert catalytic or binding activities. Their sequences are recognized as evolutionary units that, through genome recombination, constitute protein repertoires of linkage patterns. Via mutations, domains acquire modified functions that contribute to the fitness of cells and organisms. Recent studies have addressed the evolutionary selection that may have shaped the functions of individual domains and the emergence of particular domain combinations, which led to new cellular functions in multi-cellular animals. This study focuses on modeling domain linkage globally and investigates evolutionary implications that may be revealed by novel computational analysis. A survey of 77 completely sequenced eukaryotic genomes implies a potential hierarchical and modular organization of biological functions in most living organisms. Domains in a genome or multiple genomes are modeled as a network of hetero-duplex covalent linkages, termed bigrams. A novel computational technique is introduced to decompose such networks, whereby the notion of domain "networking versatility" is derived and measured. The most and least "versatile" domains (termed "core domains" and "peripheral domains" respectively) are examined both computationally via sequence conservation measures and experimentally using selected domains. Our study suggests that such a versatility measure extracted from the bigram networks correlates with the adaptivity of domains during evolution, where the network core domains are highly adaptive, significantly contrasting the network peripheral domains. Domain recombination has played a major part in the evolution of eukaryotes attributing to genome complexity. From a system point of view, as the results of selection and constant refinement, networks of domain linkage are structured in a hierarchical modular fashion. Domains with high degree of networking versatility appear to be evolutionary adaptive, potentially through functional innovations. Domain bigram networks are informative as a model of biological functions. The networking versatility indices extracted from such networks for individual domains reflect the strength of evolutionary selection that the domains have experienced.


[New approach to evaluating mutagenicity by cytogenetic techniques].
A two-population model that satisfactorily describes the emergence of multiaberrant cells during spontaneous mutagenesis is proposed. The model is based on the conception of existence of two cell populations. In the first basic part, the cells are distributed by the Poisson law. In the second rather small part, those are distributed in a geometric fashion. It is suggested that such distributions result from mutations in reparation and replication genes. These mutations determine higher incidence of chromosomal aberrations distributed by the geometrical law.


Transgenic expression of human connexin32 in myelinating Schwann cells prevents demyelination in connexin32-null mice.
Mutations in Gap Junction beta1 (GJB1), the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We investigated the possibility that the expression of mutant Cx32 in other cells besides myelinating Schwann cells contributes to the development of demyelination. Human Cx32 was expressed in transgenic mice using a rat myelin protein zero (Mpz) promoter, which is exclusively expressed by myelinating Schwann cells. Male mice expressing the human transgene were crossed with female Gjb1/cx32-null mice; the resulting male offspring were all cx32-null (on the X chromosome), and one-half were transgene positive. In these transgenic mice, all of the Cx32 was derived from the expression of the transgene and was found in the sciatic nerve but not in the spinal cord or the liver. Furthermore, the Cx32 protein was properly localized (within incisures and paranodes) in myelinating Schwann cells. Finally, the expression of human Cx32 protein "rescued" the phenotype of cx32-null mice, because the transgenic mice have significantly fewer demyelinated or remyelinated axons than their nontransgenic littermates. These results indicate that the loss of Schwann-cell-autonomous expression of Cx32 is sufficient to account for demyelination in CMT1X.


Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells.
MCL-1 (BCL-2 family anti-apoptotic protein) is responsible for melanoma's resistance to therapy. Cancer initiating cells also contribute to resistance and relapse from treatments. Here we examined the effects of the MCL-1 inhibitor SC-2001 in killing non melanoma-initiating-cells (bulk of melanoma), and melanoma-initiating-cells (MICs). By itself, SC-2001 significantly kills melanoma cells under monolayer conditions in vitro and in a conventional mouse xenograft model. However, even at high doses (10μM), SC-2001 does not effectively eliminate MICs. In contrast, the combination of SC-2001 with ABT-737 (a BCL-2/BCL-XL/BCL-W inhibitor) significantly decreases ALDH+ cells, disrupts primary spheres, and inhibits the self-renewability of MICs. These results were observed in multiple melanomas, including short term cultures of relapsed tumors from current treatments, independent of the mutation status of BRAF or NRAS. Using a low-cell-number mouse xenograft model, we examined the effects of these treatments on the tumor initiating ability of MIC-enriched cultures. The combination therapy reduces tumor formation significantly compared to either drug alone. Mechanistic studies using shRNA and the CRISPR-Cas9 technology demonstrated that the upregulation of pro-apoptotic proteins NOXA and BIM contribute to the combination-induced cell death. These results indicate that the MCL-1 inhibitor SC-2001 combined with ABT-737 is a promising treatment strategy for targeting melanoma.


Endoscopic treatment of vesicoureteric reflux with dextranomer/hyaluronic acid copolymer (Deflux): Single-surgeon experience with 48 ureters.
VUR is a common urologic problem in children. Cystoscopic injection of bulking agents (most commonly Deflux) has gained popularity as the first line treatment in the west. However, primarily due to cost factors, it has not gained much popularity in our country. We present our initial experience with cystoscopic Deflux injection for VUR. We reviewed our 3-yr experience with the use of Dx/HA (Deflux) for correction of VUR in children and adolescents. All children were evaluated with Ultrasound, MCUG and DMSA renal cortical scan. The indications for surgical correction of VUR included breakthrough infections while on antibiotic prophylaxis, persistent high-grade VUR beyond 3 yrs of age, and presence of significant renal damage on DMSA at diagnosis (in those children presenting with UTI). All children underwent cystoscopic Deflux injection using the standard technique of subureteral injection (0.4-1 ml per ureter). All children received antibiotic prophylaxis for 3-6 months after the injection. USG was done at 1 month and MCUG at 3-6 months after the injection. 33 patients (48 ureters) underwent cystoscopic Deflux injection for correction of VUR. Mean age was 4.5 yrs (1-17 yrs); there were 12 boys and 21 girls. Thirteen children had antenatally diagnosed HDN, while 20 children presented with febrile UTI. All children had primary VUR except one child with persistent VUR 4 yrs after PUV fulguration. The VUR was grade 1-2 in 8, grade 3-4 in 37, and grade 5 in 3 ureters. Every child had at least one ureter with dilating reflux (grades 3,4 or 5). When present, low grade VUR (grade 1or 2) was always on the contralateral side. Only one child received a 2(nd) injection after 6 months. Follow-up MCUG was done in 28 children (41 ureters). Complete reflux resolution was achieved in 27 ureters (65%), and the reflux was downgraded in 2 (5%). There were no complications of Deflux injection. Endoscopic correction of VUR in children is a safe and effective minimally invasive treatment for VUR. It stops or downgrades VUR in 70% of ureters. At present, we recommend it as a first-line treatment for grades 1-4 VUR requiring surgical management. Cost is the major factor limiting its use in our country.


Vitamin D receptor gene polymorphism is associated with metastatic breast cancer.
The vitamin D receptor (VDR) has been detected in breast tumor cells. We tested the hypothesis that VDR gene polymorphism might influence the outcome of women affected by breast cancer. A total of 88 breast cancer patients were recruited: 50 women were affected by newly diagnosed breast cancer whereas 38 women suffered from relapsing disease. The individual genetic pattern for VDR was evaluated by DNA extraction followed by PCR amplification of the VDR gene, and digestion with the restriction enzyme BsmI. In 167 healthy women, participating in the osteoporosis prevention trial and being used as a control, we detected 121 Bb heterozygotes (72%), 26 homozygotes for the bb alleles (16%), and 20 homozygotes for the BB alleles (12%). In the newly diagnosed breast cancer group the occurrence of Bb patients was 58% (29/50); bb patients represented 22% (11/50), and BB cases were 20% (10/50). The VDR frequency distribution in the control and primary disease patient groups was not statistically different. In the metastatic cancer group, the prevalence of the bb genotype (14/38; 37%) was double the percentage of control subjects, whereas the percentage of BB women with metastases was half the control group (2/38; 5%). Women who were homozygous bb appeared to have almost a four times higher risk of developing metastases than BB women. Whatever the molecular mechanisms underlying the VDR effects in cancer cells, we believe that the VDR gene polymorphism may represent an important determinant in the evaluation of women affected by breast cancer and might help design targeted therapy.


Danish men's experiences of cardiovascular screening and their views on preventive cardiovascular medication: A qualitative explorative nurse study.
This study explored Danish men's experience of participating in a screening program for cardiovascular disease (CVD) and their perceptions of preventive medication for CVD before and after participation in the screening program. An exploratory phenomenological-hermeneutical study. Fifteen men from a cardiovascular screening program for men aged 65-74 years participated. Semi-structured interviews were conducted before screening and one year later (2015-2017). The interviews were transcribed verbatim and analysed using Kvale and Brinkmann's approach to data analysis. Two main themes were identified: (i) seeking confirmation and control of health: familiarity with CVD; understanding the screening program; confirmation of health; perception of preventive medication, and (ii) sense of own health and prevention: experiences with the screening program; accept or denial of diagnosis and preventive medication. A minority of the men understood the nature of the diseases for which they were being examined. The invitation for screening and the outcome of the examinations must be communicated more skilfully. The health providers need to engage early in treatment after the screening and provide an individualised plan that addresses patients concerns and knowledge based on their needs.


Stress Sensitivity and Psychotic Experiences in 39 Low- and Middle-Income Countries.
Stress has a central role in most theories of psychosis etiology, but the relation between stress and psychosis has rarely been examined in large population-level data sets, particularly in low- and middle-income countries. We used data from 39 countries in the World Health Survey (n = 176 934) to test the hypothesis that stress sensitivity would be associated with psychotic experiences, using logistic regression analyses. Respondents in low-income countries reported higher stress sensitivity (P < .001) and prevalence of psychotic experiences (P < .001), compared to individuals in middle-income countries. Greater stress sensitivity was associated with increased odds for psychotic experiences, even when adjusted for co-occurring anxiety and depressive symptoms: adjusted odds ratio (95% CI) = 1.17 (1.15-1.19) per unit increase in stress sensitivity (range 2-10). This association was consistent and significant across nearly every country studied, and translated into a difference in psychotic experience prevalence ranging from 6.4% among those with the lowest levels of stress sensitivity up to 22.2% among those with the highest levels. These findings highlight the generalizability of the association between psychosis and stress sensitivity in the largest and most globally representative community-level sample to date, and support the targeting of stress sensitivity as a potential component of individual- and population-level interventions for psychosis.


Topical formulations containing Pimenta pseudocaryophyllus extract: In vitro antioxidant activity and in vivo efficacy against UV-B-induced oxidative stress.
Pimenta pseudocaryophyllus is a Brazilian native plant that presents high concentrations of flavonoids and other polyphenolic compounds. Herein, we evaluated: (1) the chemical properties of P. pseudocaryophyllus ethanolic extract (PPE), (2) the in vitro antioxidant activity (AA) of PPE and of two different topical formulations (F1 and F2) containing PPE, (3) physico-chemical and functional stability, (4) in vitro release of PPE, and (5) in vivo capacity of formulations to prevent UV-B irradiation-induced skin damage. Results show that the polyphenol and flavonoid contents in PPE were 199.33 and 28.32 mg/g, respectively, and HPLC results show the presence of eugenol, tannic acid, and rutin. Evaluation of the in vitro AA of PPE demonstrated a dose-dependent effect and an IC50 of 4.75 μg/mL in 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 3.0 μg/mL in 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. The ferric-reducing antioxidant power (FRAP assay) was 0.046 μmol/L trolox equivalent/μg/mL of extract. Among the AA, only the capacity to scavenge DPPH radical of PPE was maintained in F1 and F2. In addition, both formulations satisfactorily released the extract. The evaluation of the functional stability of F1 and F2 did not demonstrate loss of activity by storage at room temperature and at 4°C/6 months. In irradiated mice, treatment with F1 and F2 added with PPE significantly increased the capacity to scavenge ABTS radical and the FRAP of skin compared to vehicle-treated mice. In conclusion, the present results suggest that formulations containing PPE may be a topical source of antioxidant compounds to decrease oxidative damages of the skin.


Neuronal connexin36 association with zonula occludens-1 protein (ZO-1) in mouse brain and interaction with the first PDZ domain of ZO-1.
Among the 20 members in the connexin family of gap junction proteins, only connexin36 (Cx36) is firmly established to be expressed in neurons and to form electrical synapses at widely distributed interneuronal gap junctions in mammalian brain. Several connexins have recently been reported to interact with the PDZ domain-containing protein zonula occludens-1 (ZO-1), which was originally considered to be associated only with tight junctions, but has recently been reported to associate with other structures including gap junctions in various cell types. Based on the presence of sequence corresponding to a putative PDZ binding motif in Cx36, we investigated anatomical relationships and molecular association of Cx36 with ZO-1. By immunofluorescence, punctate Cx36/ZO-1 colocalization was observed throughout the central nervous system of wild-type mice, whereas labelling for Cx36 was absent in Cx36 knockout mice, confirming the specificity of the anti-Cx36 antibodies employed. By freeze-fracture replica immunogold labelling, Cx36 and ZO-1 in brain were found colocalized within individual ultrastructurally identified gap junction plaques, although some plaques contained only Cx36 whereas others contained only ZO-1. Cx36 from mouse brain and Cx36-transfected HeLa cells was found to coimmunoprecipitate with ZO-1. Unlike other connexins that bind the second of the three PDZ domains in ZO-1, glutathione S-transferase-PDZ pull-down and mutational analyses indicated Cx36 interaction with the first PDZ domain of ZO-1, which required at most the presence of the four c-terminus amino acids of Cx36. These results demonstrating a Cx36/ZO-1 association suggest a regulatory and/or scaffolding role of ZO-1 at gap junctions that form electrical synapses between neurons in mammalian brain.


Ventricular size and shape by two-dimensional echocardiography.
The evaluation of cardiac size and shape has been aided by the recent development of high resolution real-time two-dimensional echocardiography, which permits dynamic cross-sectional evaluation of all or a large portion of the left ventricle throughout the cardiac cycle. This review addresses itself to the determination of left ventricular size and shape by two-dimensional echocardiography. A method is described for accurate volume determination in the intact, isolated, ejecting canine heart. By combining the two-dimensional echocardiogram with knowledge of transducer position and orientation with respect to the heart, it is possible to reconstruct a three-dimensional representation of a chamber and thereby measure volume without reliance on major geometric assumptions. Because of the unique ability of two-dimensional echocardiography to produce a cross-sectional image of the beating heart in a large number of planes, it is suitable for the determination of cardiac shape and architecture. The recognition of early regional cardiac dilatation in acute myocardial infarction is described. Changes in ventricular shape brought about by the dynamic alterations lend themselves well to two-dimensional echocardiographic study. The pivotal nature of the interventricular septum renders it susceptible to changes in the functional state of both ventricles. That the interventricular septum may mediate ventricular interaction acutely is suggested by the acute effects of right ventricular loading in man using the Mueller maneuver. Leftward septal displacement and flattening of the septum during the early maximal Mueller maneuver is evidenced by a substantial increase in the radius of curvature of the septal segment, without a change in the left ventricular free wall. This septal flattening occurs in diastole and persists during systole. Diastolic events thus appear to influence systolic shape. Changed septal shape may be an important mechanism of, and evidence for, ventricular interdependence in normal man.


Clinical technical performance of dental therapists in Alaska.
The Alaska Dental Health Aide Therapist program has matured to the point that therapists have been in practice for up to four years. A case-study evaluation of the program included assessments of the clinical technical performance of five of these therapists practicing in clinics in small Alaskan villages and towns. The results indicate that therapists are performing at an acceptable level, with short-term restorative outcomes comparable with those of dentists treating the same populations. Therapists' performance when operating within their scope of practice suggested no reason for continued close scrutiny. Further evaluations of therapists should shift their principal focus from clinical technical performance of therapists to effectiveness of the therapist program in improving the targeted population's oral health. Therapists are capable of providing acceptable restorative treatment under indirect supervision.


A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters.
The aim of this study was to collect and describe all published reports of local tissue injury or extravasation from vasopressor administration via either peripheral intravenous (IV) or central venous catheter. A systematic search of Medline, Embase, and Cochrane databases was performed from inception through January 2014 for reports of adults who received vasopressor intravenously via peripheral IV or central venous catheter for a therapeutic purpose. We included primary studies or case reports of vasopressor administration that resulted in local tissue injury or extravasation of vasopressor solution. Eighty-five articles with 270 patients met all inclusion criteria. A total of 325 separate local tissue injury and extravasation events were identified, with 318 events resulting from peripheral vasopressor administration and 7 events resulting from central administration. There were 204 local tissue injury events from peripheral administration of vasopressors, with an average duration of infusion of 55.9 hours (±68.1), median time of 24 hours, and range of 0.08 to 528 hours. In most of these events (174/204, 85.3%), the infusion site was located distal to the antecubital or popliteal fossae. Published data on tissue injury or extravasation from vasopressor administration via peripheral IVs are derived mainly from case reports. Further study is warranted to clarify the safety of vasopressor administration via peripheral IVs.