Impact of electron acceptor on three-photon absorption cross-section of the fluorene derivatives.
Small three-photon absorption (3PA) cross-section values of present nonlinear organic molecules limit their practical applications. Although electron donors and electron acceptors have a great effect on 3PA cross-section, little is known about how the strength and situation of electron acceptors influence the 3PA cross-section value of a compound. The present work reports 3PA effects of two fluorene derivatives with symmetric D-π-π(A)-π-D archetype, which are named as 2,7-bis(4-methoxyphenylacetylene)-9-fluorenone (FATT) and 2,7-bis(4-methoxyphenylacetylene)-9-thoine-fluorene (TSATL). Large 3PA cross-section and ideal 3PA-induced optical limiting effects have been found in the two fluorene derivatives. The two molecules both have a different electron acceptor on the fluorene core, by which the 3PA cross-section value for FATT is enhanced by nearly 3-fold compared with that for TSATL. The mechanism of this significant enhancement in 3PA cross-section has been investigated by density functional theory (DFT) and configuration interaction singles (CIS) method with use of 6-311+G basis set in combination with conductor polarizable continuum model (CPCM). The theoretical results show that increase of electronegative character of the electron acceptor on the core is responsible for the increase of 3PA cross-section values of the two molecules.


The global meningitis genome partnership.
Genomic surveillance of bacterial meningitis pathogens is essential for effective disease control globally, enabling identification of emerging and expanding strains and consequent public health interventions. While there has been a rise in the use of whole genome sequencing, this has been driven predominately by a subset of countries with adequate capacity and resources. Global capacity to participate in surveillance needs to be expanded, particularly in low and middle-income countries with high disease burdens. In light of this, the WHO-led collaboration, Defeating Meningitis by 2030 Global Roadmap, has called for the establishment of a Global Meningitis Genome Partnership that links resources for: N. meningitidis (Nm), S. pneumoniae (Sp), H. influenzae (Hi) and S. agalactiae (Sa) to improve worldwide co-ordination of strain identification and tracking. Existing platforms containing relevant genomes include: PubMLST: Nm (31,622), Sp (15,132), Hi (1935), Sa (9026); The Wellcome Sanger Institute: Nm (13,711), Sp (> 24,000), Sa (6200), Hi (1738); and BMGAP: Nm (8785), Hi (2030). A steering group is being established to coordinate the initiative and encourage high-quality data curation. Next steps include: developing guidelines on open-access sharing of genomic data; defining a core set of metadata; and facilitating development of user-friendly interfaces that represent publicly available data.


Parental origin of diabetes-associated HLA types in sibling pairs with type I diabetes.
Genetic susceptibility to type I diabetes is partly determined by genes located in the human leukocyte antigen (HLA) region on chromosome 6. It has been claimed that the transmission of HLA-encoded susceptibility is influenced by parental sex. Fathers are reported to transmit HLA-DR4 haplotypes more frequently to their diabetic offspring than mothers. More recently, it has been suggested that the presence of HLA-DR4 in a mother may influence susceptibility in her offspring, even when it is not inherited. We have analyzed 172 multiplex diabetic pedigrees from the U.K. and find no evidence to support an important effect of parental sex on the inheritance of HLA-encoded susceptibility. Examination of a further 110 pedigrees from the U.S. supports this finding. These results have important implications for strategies involving genetic screening for type I diabetes.


Single-Electron Occupation in Quantum Dot Arrays at Selectable Plunger Gate Voltage.
The small footprint of semiconductor qubits is favorable for scalable quantum computing. However, their size also makes them sensitive to their local environment and variations in the gate structure. Currently, each device requires tailored gate voltages to confine a single charge per quantum dot, clearly challenging scalability. Here, we tune these gate voltages and equalize them solely through the temporary application of stress voltages. In a double quantum dot, we reach a stable (1,1) charge state at identical and predetermined plunger gate voltage and for various interdot couplings. Applying our findings, we tune a 2 × 2 quadruple quantum dot such that the (1,1,1,1) charge state is reached when all plunger gates are set to 1 V. The ability to define required gate voltages may relax requirements on control electronics and operations for spin qubit devices, providing means to advance quantum hardware.


A prospective study of coffee drinking and suicide in women.
Among the many reported central nervous system effects of long-term caffeine use is improvement in mood. To examine prospectively the relationship of coffee and caffeine intake to risk of death from suicide. We conducted a 10-year follow-up study (1980 to 1990) in an ongoing cohort of 86 626 US female registered nurses aged 34 to 59 years in 1980, who were free of diagnosed coronary heart disease, stroke, or cancer. Information on coffee and caffeine intake was collected by a semiquantitative food frequency questionnaire in 1980. Deaths from suicide were determined by physician review of death certificates. Fifty-six cases of suicide occurred during 832 704 person-years of observation. Compared with non-drinkers of coffee, the age-adjusted relative risk of suicide in women who consumed two to three cups per day was 0.34 (95% confidence interval [CI, 0.17 to 0.68) and 0.42 (95% CI, 0.21 to 0.86) in women who consumed four or more cups per day (P for linear trend=.002). These findings remained essentially unchanged after adjusting for a broad range of potential confounding factors, including smoking habit, alcohol intake, medication use (diazepam and phenothiazine), history of comorbid disease (hypertension, hypercholesterolemia, or diabetes), marital status, and self-reported stress. A strong inverse relationship was similarly found for caffeine intake from all sources and risk of suicide. The data suggest a strong inverse association between coffee intake and risk of suicide. Whether regular intake of coffee or caffeine has clinically significant effects on the maintenance of affect or the prevention of depression merits further investigation in clinical trials and population-based prospective studies.


Simplified quantitative assay system for measuring activities of drugs against intracellular Legionella pneumophila.
We developed a new simple assay for the quantitation of the activities of drugs against intracellular Legionella pneumophila. The cells of a murine macrophage-like cell line (J774.1 cells) allowed the intracellular growth and replication of the bacteria, which ultimately resulted in cell death. The infected J774.1 cell monolayers in 96-well microplates were first treated with antibiotics and were further cultured for 72 h. The number of viable J774.1 cells in each well was quantified by a colorimetric assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and an enzyme-linked immunosorbent assay reader. The number of growing bacteria in each well was also determined by counting the numbers of CFU on buffered charcoal yeast extract-alpha agar plates. Viable J774.1 cell counts, determined by the colorimetric assay, were inversely proportional to the number of intracellular replicating bacteria. The minimum extracellular concentrations (MIECs) of 24 antibiotics causing inhibition of intracellular growth of L. pneumophila were determined by the colorimetric assay system. The MIECs of beta-lactams and aminoglycosides were markedly higher than the MICs in buffered yeast extract-alpha broth. The MIECs of macrolides, fluoroquinolones, rifampin, and minocycline were similar to the respective MICs. According to their intracellular activities, clarithromycin and sparfloxacin were the most potent among the macrolides or fluoroquinolones tested in this study. Our results indicated that the MTT assay system allows comparative and quantitative evaluations of the intracellular activities of antibiotics and efficient processing of a large number of samples.


Masked hypertension in obesity: potential predictors and arterial damage.
Masked hypertension (MHT), defined as normal office blood pressure (BP) but high ambulatory BP, has been associated with increased cardiovascular risk. Although MHT has been associated with obesity, there is limited knowledge on the prevalence and covariates of MHT in obese cohorts. Office and ambulatory BP recordings and other cardiovascular risk factors were assessed in 323 obese participants included in the fat-associated cardiovascular dysfunction study (mean age 48.9±9.0 years, 55% women, mean BMI 32.3±4.4 kg/m). Office BP 130-139/85-89 mmHg was considered high-normal. Subclinical arterial damage was identified as carotid-femoral pulse wave velocity more than 10 m/s by applanation tonometry or carotid plaque by ultrasound (maximal intima-media thickness ≥1.5 mm). MHT was present in 17.1% of the population. Patients with MHT had a higher prevalence of metabolic syndrome, high-normal office BP, and were more often male compared with the normotensive (NT) individuals (all P<0.05), but were younger and had lower prevalence of diabetes and subclinical arterial damage than the sustained hypertensive group (all P<0.05). In multinomial logistic regression analysis, MHT was associated with the presence of metabolic syndrome and high-normal office BP compared with NT individuals, and lower pulse wave velocity and fewer carotid plaques than sustained hypertension (all P<0.05). In obese patients, MHT was associated with the presence of metabolic syndrome and high-normal office BP compared with NT individuals, but less subclinical arterial damage than sustained hypertensive patients.


Contextual control of audiovisual integration in low-level sensory cortices.
Potential sources of multisensory influences on low-level sensory cortices include direct projections from sensory cortices of different modalities, as well as more indirect feedback inputs from higher order multisensory cortical regions. These multiple architectures may be functionally complementary, but the exact roles and inter-relationships of the circuits are unknown. Using a fully balanced context manipulation, we tested the hypotheses that: (1) feedforward and lateral pathways subserve speed functions, such as detecting peripheral stimuli. Multisensory integration effects in this context are predicted in peripheral fields of low-level sensory cortices. (2) Slower feedback pathways underpin accuracy functions, such as object discrimination. Integration effects in this context are predicted in higher-order association cortices and central/foveal fields of low-level sensory cortex. We used functional magnetic resonance imaging to compare the effects of central versus peripheral stimulation on audiovisual integration, while varying speed and accuracy requirements for behavioral responses. We found that interactions of task demands and stimulus eccentricity in low-level sensory cortices are more complex than would be predicted by a simple dichotomy such as our hypothesized peripheral/speed and foveal/accuracy functions. Additionally, our findings point to individual differences in integration that may be related to skills and strategy. Overall, our findings suggest that instead of using fixed, specialized pathways, the exact circuits and mechanisms that are used for low-level multisensory integration are much more flexible and contingent upon both individual and contextual factors than previously assumed.


Bone cement with a modified polyphosphate network structure stimulates hard tissue regeneration.
In this study, a calcium polyphosphate cement (CpPC) consisting of basic components was investigated to assess its potential for hard tissue regeneration. The added basic components for improving the structural stability, which controlled the setting time, where the setting reaction resulted in the formation of amorphous structure with a re-constructed polyphosphate. Moreover, the characteristics were controlled by the composition, which determined the polyphosphate structure. CpPC exhibited outstanding dissolution rate compared with the common biodegradable cement, brushite cement (2.5 times). Despite high amounts of dissolution products, no significant cytotoxicity ensued. Induction of calcification in MG-63 cells treated with CpPC, the level of calcification increased with increasing CpPC dissolution rate. Induced calcification was observed also in CpPC-treated ST2 cells, in contrast with MG-63 and ST2 treated with brushite cement, for which no calcification was observed. In vivo tests using a rat calvarial defect model showed that resorbed CpPC resulted in favorable host responses and promoted bone formation. Additionally, there was a significant increase in defect closure, and new bone formation progressed from CpPC mid-sites as well as defect margins. From these results, CpPC exhibits significant potential as biodegradable bone substitute for bone regeneration.


Bilateral Decompressive Craniectomy in Malignant Cerebral Venous Thrombosis.
Despite the extremely favourable prognosis of patients with cerebral venous thrombosis (CVT), death occurs in 10-15% of patients. In severe cases of malignant CVT with supratentorial haemorrhagic lesions, cerebral oedema and brain herniation, decompressive surgery may be the only life-saving treatment. We present the case of a puerperal young woman with progressive headache, seizures and decreased alertness. Thrombosis of the entire superior sagittal sinus with bifrontal venous infarcts and midline shift was confirmed by magnetic resonance imaging with venography sequencing. Despite medical treatment with anticoagulation, progressive neurological deterioration was observed, so bilateral, frontal decompressive craniectomy was performed. At the 6-month follow-up, we observed partial functional recovery with a modified Rankin score of 3. Bilateral decompressive craniectomy may be a life-saving therapeutic option when medical therapy fails and there are clinical and radiological features of progression in both cerebral hemispheres. Malignant cerebral venous thrombosis presents with diffuse haemorrhagic lesions or cerebral oedema associated with brain herniation and rapid clinical deterioration.Decompressive surgery may be the only life-saving treatment in severe cases.Early and adequate intervention based on the characteristics of the lesions allowed preservation of life and improvement in long-term functionality.


SARS: systematic review of treatment effects.
The SARS outbreak of 2002-2003 presented clinicians with a new, life-threatening disease for which they had no experience in treating and no research on the effectiveness of treatment options. The World Health Organization (WHO) expert panel on SARS treatment requested a systematic review and comprehensive summary of treatments used for SARS-infected patients in order to guide future treatment and identify priorities for research. In response to the WHO request we conducted a systematic review of the published literature on ribavirin, corticosteroids, lopinavir and ritonavir (LPV/r), type I interferon (IFN), intravenous immunoglobulin (IVIG), and SARS convalescent plasma from both in vitro studies and in SARS patients. We also searched for clinical trial evidence of treatment for acute respiratory distress syndrome. Sources of data were the literature databases MEDLINE, EMBASE, BIOSIS, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to February 2005. Data from publications were extracted and evidence within studies was classified using predefined criteria. In total, 54 SARS treatment studies, 15 in vitro studies, and three acute respiratory distress syndrome studies met our inclusion criteria. Within in vitro studies, ribavirin, lopinavir, and type I IFN showed inhibition of SARS-CoV in tissue culture. In SARS-infected patient reports on ribavirin, 26 studies were classified as inconclusive, and four showed possible harm. Seven studies of convalescent plasma or IVIG, three of IFN type I, and two of LPV/r were inconclusive. In 29 studies of steroid use, 25 were inconclusive and four were classified as causing possible harm. Despite an extensive literature reporting on SARS treatments, it was not possible to determine whether treatments benefited patients during the SARS outbreak. Some may have been harmful. Clinical trials should be designed to validate a standard protocol for dosage and timing, and to accrue data in real time during future outbreaks to monitor specific adverse effects and help inform treatment.


Significant gender difference in serum levels of fibroblast growth factor 21 in Danish children and adolescents.
Fibroblast Growth Factor 21 (FGF21) is a novel metabolic factor with effect on glucose and lipid metabolism, and shown to be elevated in diseases related to metabolic syndrome. Due to the increasing frequency of metabolic syndrome in the pediatric population, and as FGF21 studies in children are limited, we investigated baseline serum levels of FGF21 in healthy children during an oral glucose tolerance test. A total of 179 children and adolescents from the COPENHAGEN Puberty Study were included. An OGTT with glucose and insulin measurements, a dual energy X-ray absorptiometry (DXA) scan and a clinical examination including pubertal staging were done on all subjects. Serum levels of FGF21, adiponectin, and leptin were determined by immunoassays at baseline. The girls had significantly higher levels of FGF21 compared with boys (155 pg/mL vs. 105 pg/mL, P = 0.04). 38 children (21%) had levels below detection limit of assay. Baseline levels of FGF21 showed positive correlation with triglycerides, but no significant correlations were found between FGF21-concentration and body mass index (BMI), DXA-derived fat percentage, LDL- HDL- and non-HDL cholesterol, leptin or adiponectin levels, respectively. Neither was any correlation found between baseline FGF21-levels and the dynamic changes in glucose and insulin levels during the OGTT. FGF21 is independent of adiposity in children, and the significant metabolic effect seems to be limited to pathological conditions associated with insulin resistance. The higher levels of triglycerides in the girls may explain the significantly higher levels of FGF21 in girls compared with boys. The COPENHAGEN Puberty Study was registered in ClinicalTrials.gov (identifier NCT01411527), and approved by the local ethics committee (reference no. KF 01 282214 and KF 11 2006-2033).


Electoral concerns reduce restrictive measures during the COVID-19 pandemic.
The outbreak of COVID-19 has called for swift action by governments, often involving the adoption of restrictive measures such as lockdowns. In this context, leaders have faced a trade-off between imposing stringent measures to limit the contagion, and minimizing the short-run costs on their national economy, which could impact their electoral prospects. Leveraging on both the timing of elections and the constitutional term limits faced by leaders in presidential systems, we document how incumbents who can run for re-election implement less stringent restrictions when the election is closer in time. The effect is driven by measures more likely to have a negative economic impact. This shows how electoral concerns help explain the observed differences in the response to the onset of the COVID-19 epidemic across different countries.


A case of argyria: multiple forms of silver ingestion in a patient with comorbid schizoaffective disorder.
Argyria is a rare cutaneous manifestation of silver deposits in the skin, characterized by a grayish blue discoloration, particularly in sun-exposed areas. We report the case of a patient with a history of schizoaffective disorder and type 2 diabetes mellitus who presented with argyria of the face and neck. The patient had a history of ingesting colloidal silver proteins (CSPs) for approximately 10 years as a self-prescribed remedy for his medical conditions. Colloidal silver protein has gained popularity among patients who seek alternative medical therapies. Argyria is the most predominant manifestation of silver toxicity. It is unclear if our patient began taking CSP because of his schizoaffective disorder or if silver toxicity may have induced somatic delusions; however, it is important for physicians to have a thorough understanding of alternative therapies on the market. We present a detailed background on silver ingestion and its systemic effects.


Persistent infectivity of a disease-associated herpesvirus in green turtles after exposure to seawater.
Herpesviruses are associated with several diseases of marine turtles including lung-eye-trachea disease (LETD) and gray patch disease (GPD) of green turtles (Chelonia mydas) and fibropapillomatosis (FP) of green, loggerhead (Caretta caretta), and olive ridley turtles (Lepidochelys olivacea). The stability of chelonian herpesviruses in the marine environment, which may influence transmission, has not been previously studied. In these experiments, LETD-associated herpesvirus (LETV) was used as a model chelonian herpesvirus to test viral infectivity after exposure to seawater. The LETV virus preparations grown in terrapene heart (TH-1) cells were dialyzed for 24 to 120 hr against aerated artificial or natural seawater or Hank's balanced salt solution (HBBS). Fresh TH-1 cells were inoculated with dialyzed LETV, and on day 10 post-infection cells were scored for cytopathic effect. Virus samples dialyzed up to 120 hr were positive for the herpesvirus DNA polymerase gene by polymerase chain reaction. Electron microscopy revealed intact LETV nucleocapsids after exposure of LETV to artificial seawater or HBSS for 24 hr at 23 C. LETV preparations remained infectious as long as 120 hr in natural and artificial seawater at 23 C. Similar results were obtained with a second culturable chelonian herpesvirus, HV2245. LETV infectivity could not be detected after 48 hr exposure to artificial seawater at 30 C. Since LETV and HV2245 remain infectious for extended periods of time in the marine environment, it is possible that FP-associated and GPD-associated herpesviruses also may be stable. These findings are significant both for researchers studying the epidemiological association of herpesviruses with diseases of marine turtles and for individuals who handle turtles in marine turtle conservation efforts.


Antarctic emerald rockcod have the capacity to compensate for warming when uncoupled from CO2 -acidification.
Increases in atmospheric CO2 levels and associated ocean changes are expected to have dramatic impacts on marine ecosystems. Although the Southern Ocean is experiencing some of the fastest rates of change, few studies have explored how Antarctic fishes may be affected by co-occurring ocean changes, and even fewer have examined early life stages. To date, no studies have characterized potential trade-offs in physiology and behavior in response to projected multiple climate change stressors (ocean acidification and warming) on Antarctic fishes. We exposed juvenile emerald rockcod Trematomus bernacchii to three PCO2 treatments (~450, ~850, and ~1,200 μatm PCO2 ) at two temperatures (-1 or 2°C). After 2, 7, 14, and 28 days, metrics of physiological performance including cardiorespiratory function (heart rate [fH ] and ventilation rate [fV ]), metabolic rate (M˙O2), and cellular enzyme activity were measured. Behavioral responses, including scototaxis, activity, exploration, and escape response were assessed after 7 and 14 days. Elevated PCO2 independently had little impact on either physiology or behavior in juvenile rockcod, whereas warming resulted in significant changes across acclimation time. After 14 days, fH , fV and M˙O2 significantly increased with warming, but not with elevated PCO2 . Increased physiological costs were accompanied by behavioral alterations including increased dark zone preference up to 14%, reduced activity by 12%, as well as reduced escape time suggesting potential trade-offs in energetics. After 28 days, juvenile rockcod demonstrated a degree of temperature compensation as fV , M˙O2, and cellular metabolism significantly decreased following the peak at 14 days; however, temperature compensation was only evident in the absence of elevated PCO2 . Sustained increases in fV and M˙O2 after 28 days exposure to elevated PCO2 indicate additive (fV ) and synergistic (M˙O2) interactions occurred in combination with warming. Stressor-induced energetic trade-offs in physiology and behavior may be an important mechanism leading to vulnerability of Antarctic fishes to future ocean change.


Upper limb position control in fibromyalgia.
Motor problems are reported by patients with fibromyalgia (FM). However, the mechanisms leading to alterations in motor performance are not well understood. In this study, upper limb position control during sustained isometric contractions was investigated in patients with FM and in healthy controls (HCs). Fifteen female FM patients and 13 HCs were asked to keep a constant upper limb position during sustained elbow flexion and shoulder abduction, respectively. Subjects received real-time visual feedback on limb position and both tasks were performed unloaded and while supporting loads (1, 2, and 3 kg). Accelerations of the dominant upper limb were recorded, with variance (SD of mean position) and power spectrum analysis used to characterize limb position control. Normalized power of the acceleration signal was extracted for three frequency bands: 1-3 Hz, 4-7 Hz, and 8-12 Hz. Variance increased with load in both tasks (P < 0.001) but did not differ significantly between patients and HCs (P > 0.17). Power spectrum analysis showed that the FM patients had a higher proportion of normalized power in the 1-3 Hz band, and a lower proportion of normalized power in the 8-12 Hz band compared to HCs (P < 0.05). The results were consistent for all load conditions and for both elbow flexion and shoulder abduction. FM patients exhibit an altered neuromuscular strategy for upper limb position control compared to HCs. The predominance of low-frequency limb oscillations among FM patients may indicate a sensory deficit.


Association between frequency domain heart rate variability and unplanned readmission to hospital in geriatric patients.
An accurate prediction of unplanned readmission (UR) after discharge from hospital can facilitate physician's decision making processes for providing better quality of care in geriatric patients. The objective of this study was to explore the association of cardiac autonomic functions as measured by frequency domain heart rate variability (HRV) and 14-day UR in geriatric patients. Patients admitted to the geriatric ward of a regional hospital in Chiayi county in Taiwan were followed prospectively from July 2006 to June 2007. Those with invasive tubes and those who were heavy smokers, heavy alcohol drinkers, on medications that might influence HRV, or previously admitted to the hospital within 30 days were excluded. Cardiac autonomic functions were evaluated by frequency domain indices of HRV. Multiple logistic regression was used to assess the association between UR and HRV indices adjusted for age and length of hospitalization. A total of 78 patients met the inclusion criteria and 15 of them were readmitted within 14 days after discharge. The risk of UR was significantly higher in patients with lower levels of total power (OR = 1.39; 95% CI = 1.04-2.00), low frequency power (LF) (OR = 1.22; 95% CI = 1.03-1.49), high frequency power (HF) (OR = 1.27; 95% CI = 1.02-1.64), and lower ratios of low frequency power to high frequency power (LF/HF ratio) (OR = 1.96; 95% CI = 1.07-3.84). This is the first study to evaluate the association between frequency domain heart rate variability and the risk of UR in geriatric patients. Frequency domain heart rate variability indices measured on admission were significantly associated with increased risk of UR in geriatric patients. Additional studies are required to confirm the value and feasibility of using HRV indices on admission as a non-invasive tool to assist the prediction of UR in geriatric patients.


Improved sensing characteristics of methane over ZnO nano sheets upon implanting defects and foreign atoms substitution.
Thanks to the growing interests of metal oxide sensors in environmental and industrial uses, this study presents the sensing mechanism of methane gas (CH4) on recently synthesized two-dimensional form of ZnO, ZnO nano sheets (ZnO-NS). The adsorption energy of CH4 on pristine ZnO-NS, calculated by means of van der Waals corrected first-principles calculations, is found to be insufficient restricting its application as an efficient nano sensor. However, the creation of (O/Zn) vacancies and the substitution of foreign dopants into ZnO-NS considerably intensify the binding energy of CH4. Through a comprehensive energetic analysis, it is observed that among all the substituents, boron (B), sulphur (S) and gallium (Ga) improves the binding of CH4 to 2.75, 6.1 and 7.5 times respectively than its values on pristine ZnO-NS. In addition to the CH4 binding energies falling ideally between physisorption and chemisorption range, a prominent variation in the electronic properties before and after CH4 exposure indicates the promise of substituted Zn-NS as a useful nano sensors.


Prognostic value of pre-procedural left ventricular strain for clinical events after transcatheter aortic valve implantation.
Transcatheter aortic valve implantation (TAVI) is an alternative therapy for surgically high-risk patients with severe aortic stenosis (AS). Although TAVI improves survival of patients with severe AS, the mechanism of this effect remains to be clarified. We investigated the effects of TAVI on left ventricular (LV) function and identified the predictive parameters for cardiac events after TAVI. We studied 128 patients with severe symptomatic AS who underwent TAVI. Echocardiographic assessments were performed before and after TAVI. In addition to the conventional echocardiographic parameters such as LV ejection fraction (LVEF) and LV mass index (LVMI), the LV global longitudinal strain (GLS) and early diastolic peak strain rate (SR_E) using two-dimensional speckle tracking echocardiography were also evaluated. All patients were assessed for clinical events including major adverse cardiac events and stroke according to Valve Academic Research Consortium-2 criteria. GLS, early diastolic peak velocity (e'), aortic regurgitation (AR) severity, and SR_E were significantly improved after TAVI. Thirteen patients had an event during the observational period of 591 days (median). Patients with events had higher LVMI, more severe AR, and worse GLS compared to those without events. Furthermore, receiver-operating curve analysis revealed that GLS was the strongest predictor for clinical events (p = 0.009; area under the curve, 0.73). Preoperative LV geometric deformation and dysfunction, as a consequence of the cumulative burden of pressure overload, improved after TAVI and could predict cardiac events after TAVI.


Retinoblastoma protein disrupts interactions required for RNA polymerase III transcription.
The retinoblastoma protein (RB) has been shown to suppress RNA polymerase (Pol) III transcription in vivo (R. J. White, D. Trouche, K. Martin, S. P. Jackson, and T. Kouzarides, Nature 382:88-90, 1996). This regulation involves interaction with TFIIIB, a multisubunit factor that is required for the expression of all Pol III templates (C. G. C. Larminie, C. A. Cairns, R. Mital, K. Martin, T. Kouzarides, S. P. Jackson, and R. J. White, EMBO J. 16:2061-2071, 1997; W.-M. Chu, Z. Wang, R. G. Roeder, and C. W. Schmid, J. Biol. Chem. 272:14755-14761, 1997). However, it has not been established why RB binding to TFIIIB results in transcriptional repression. For several Pol II-transcribed genes, RB has been shown to inhibit expression by recruiting histone deacetylases, which are thought to decrease promoter accessibility. We present evidence that histone deacetylases exert a negative effect on Pol III activity in vivo. However, RB remains able to regulate Pol III transcription in the presence of the histone deacetylase inhibitor trichostatin A. Instead, RB represses by disrupting interactions between TFIIIB and other components of the basal Pol III transcription apparatus. Recruitment of TFIIIB to most class III genes requires its binding to TFIIIC2, but this can be blocked by RB. In addition, RB disrupts the interaction between TFIIIB and Pol III that is essential for transcription. The ability of RB to inhibit these key interactions can explain its action as a potent repressor of class III gene expression.


Recruitment of black women with type 2 diabetes into a self-management intervention trial.
The purpose of this study was to evaluate the relationship of recruitment methods to enrollment status in Black women with type 2 diabetes screened for entry into a randomized clinical trial (RCT). Using a cross-sectional study design with convenience sampling procedures, data were collected on recruitment methods to which the women responded (N=236). Results demonstrated that the RCT had a moderate overall recruitment rate of 46% and achieved only 84% of its projected accrual goal (N=109). Chi-square analysis demonstrated that enrollment outcomes varied significantly according to recruitment methods (P=.05). Recruitment methods such as community health fairs (77.8%), private practice referrals (75.0%), participant referrals (61.5%), community clinic referrals (44.6%), community advertising and marketing (40.9%), and chart review (40.4%) demonstrated variable enrollment yields. Results confirm previous findings that indicate that Black Americans may be successfully recruited into research studies at moderate rates when traditional recruitment methods are enhanced and integrated with more culturally sensitive methods. Lessons learned are considered.


Potential of anti-inflammatory agents for treatment of atherosclerosis.
Chronic inflammation is a central pathogenic mechanism of atherosclerosis induction and progression. Vascular inflammation is associated with accelerated onset of late atherosclerosis complications. Atherosclerosis-related inflammation is mediated by a complex cocktail of pro-inflammatory cytokines, chemokines, bioactive lipids, and adhesion molecules, and blocking the key pro-atherogenic inflammatory mechanisms can be beneficial for treatment of atherosclerosis. Therapeutic agents that specifically target some of the atherosclerosis-related inflammatory mechanisms have been evaluated in preclinical and clinical studies. The most promising anti-inflammatory compounds for treatment of atherosclerosis include non-specific anti-inflammatory drugs, phospholipase inhibitors, blockers of major inflammatory cytokines, leukotrienes, adhesion molecules, and pro-inflammatory signaling pathways, such as CCL2-CCR2 axis or p38 MAPK pathway. Ongoing studies attempt evaluating therapeutic utility of these anti-inflammatory drugs for treatment of atherosclerosis. The obtained results are important for our understanding of atherosclerosis-related inflammatory mechanisms and for designing randomized controlled studies assessing the effect of specific anti-inflammatory strategies on cardiovascular outcomes.


Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis.
Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.


The complex nature of informal care in home-based heart failure management.
This paper is a report of a study to examine the complexities of informal caregiving for people with chronic heart failure. Little is known of the activities involved and underlying informal care. Heart failure is a common and burdensome condition in which carers play an important management role. Semi-structured interviews were carried out with 30 informal carers nominated by patients with mild-to-moderate heart failure (24 spouses, four children, one sibling and one neighbour). Interviews examined knowledge of heart failure, its effects, reported management practices and concerns, decision making and support. The data were collected in 2001. The management of heart failure was a shared and ongoing responsibility between the carer and patient. Carers' clinical knowledge of the condition and management was often limited, but they developed extensive knowledge of its personal effects on the patient. Invisible care activities included monitoring signs of symptom exacerbation and energy boundaries against perceived current and future demands and priorities. Visible care activities included medication management, dressing, bathing and help-seeking. Carers responded to patients' capacities, and adopted philosophies that sought to foster independence while facilitating as normal a life for the patient as was possible and safe. Interventions for informal carers around effective chronic heart failure management should address both visible and invisible informal caring. Future research is needed to develop interventions with carers to improve quality of care, reduce costs and improve patient quality of life. More research is needed to explore the complexities of lay caregiving and to explore the invisible dimensions of informal care further.


Optical encryption system with a binary key code.
A double-random-phase optical encryption system that uses a binary key code is proposed. The key code is generated as a binary computer-generated hologram. The binary key code can be displayed on a binary spatial light modulator (SLM) such as a ferroelectric liquid-crystal display. The use of a binary SLM enables us to renew the key at high speed. A joint transform correlator based on a photorefractive crystal in the Fourier domain is used to perform shift-invariant encryption and decryption. Computer simulations of the effects of using a binary encoded key code instead of a complex amplitude key code are shown. Preliminary optical experimental results are presented to demonstrate the effectiveness of the proposed system.


A Multidimensional Approach to Post-concussion Symptoms in Mild Traumatic Brain Injury.
Mild traumatic brain injury (mTBI) presents a substantial burden to patients, families, and health care systems. Whereas, recovery can be expected in the majority of patients, a subset continues to report persisting somatic, cognitive, emotional, and/or behavioral problems, generally referred to as post-concussion syndrome (PCS). However, this term has been the subject of debate since the mechanisms underlying post-concussion symptoms and the role of pre- and post-injury-related factors are still poorly understood. We review current evidence and controversies concerning the use of the terms post-concussion symptoms vs. syndrome, its diagnosis, etiology, prevalence, assessment, and treatment in both adults and children. Prevalence rates of post-concussion symptoms vary between 11 and 82%, depending on diagnostic criteria, population and timing of assessment. Post-concussion symptoms are dependent on complex interactions between somatic, psychological, and social factors. Progress in understanding has been hampered by inconsistent classification and variable assessment procedures. There are substantial limitations in research to date, resulting in gaps in our understanding, leading to uncertainty regarding epidemiology, etiology, prognosis, and treatment. Future directions including the identification of potential mechanisms, new imaging techniques, comprehensive, multidisciplinary assessment and treatment options are discussed. Treatment of post-concussion symptoms is highly variable, and primarily directed at symptom relief, rather than at modifying the underlying pathology. Longitudinal studies applying standardized assessment strategies, diagnoses, and evidence-based interventions are required in adult and pediatric mTBI populations to optimize recovery and reduce the substantial socio-economic burden of post-concussion symptoms.


Considerations for target oxygen saturation in COVID-19 patients: are we under-shooting?
The current target oxygen saturation range for patients with COVID-19 recommended by the National Institutes of Health is 92-96%. This article critically examines the evidence guiding current target oxygen saturation recommendation for COVID-19 patients, and raises important concerns in the extrapolation of data from the two studies stated to be guiding the recommendation. Next, it examines the influence of hypoxia on upregulation of ACE2 (target receptor for SARS-CoV-2 entry) expression, with supporting transcriptomic analysis of a publicly available gene expression profile dataset of human renal proximal tubular epithelial cells cultured in normoxic or hypoxic conditions. Finally, it discusses potential implications of specific clinical observations and considerations in COVID-19 patients on target oxygen saturation, such as diffuse systemic endothelitis and microthrombi playing an important pathogenic role in the wide range of systemic manifestations, exacerbation of hypoxic pulmonary vasoconstriction in the setting of pulmonary vascular endothelitis/microthrombi, the phenomenon of "silent hypoxemia" with some patients presenting to the hospital with severe hypoxemia disproportional to symptoms, and overburdened health systems and public health resources in many parts of the world with adverse implications on outpatient monitoring and early institution of oxygen supplementation. The above factors and analyses, put together, call for an urgent exploration and re-evaluation of target oxygen saturation in COVID-19 patients, both in the inpatient and outpatient settings. Until data from such trials become available, where possible, it may be prudent to target an oxygen saturation at least at the upper end of the recommended 92-96% range in COVID-19 patients both in the inpatient and outpatient settings (in patients that are normoxemic at pre-COVID baseline). Home pulse oximetry, tele-monitoring, and earlier institution of oxygen supplementation for hypoxemic COVID-19 outpatients could be beneficial, where public health resources allow for their implementation.


Melipona mondury produces a geopropolis with antioxidant, antibacterial and antiproliferative activities.
Geopropolis is a special type of propolis produced by stingless bees. Several pharmacological properties have been described for different types of geopropolis, but there have been no previous studies of the geopropolis from Melipona mondury. In this study, we investigated the antioxidant, antibacterial, and antiproliferative activities of M. mondury geopropolis, and determined its chemical profile. The antioxidant activity was determined using in vitro ABTS·+, ·DPPH, and β-carotene/linoleic acid co-oxidation methods. The antibacterial activity was determined using a microdilution method with Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin-resistant S. aureus. The antiproliferative effect was determined in tumor cell lines using the Alamar Blue assay. The chemical profile was obtained using UHPLC-MS and UHPLC-MS/MS. The butanolic fraction had the highest concentration of phenolic compounds and more potent antioxidant properties in all assays. This fraction also had bacteriostatic and bactericidal effects against all bacterial strains at low concentrations, especially S. aureus. The hexane fraction had the highest antiproliferative potential, with IC50 values ranging from 24.2 to 46.6 µg/mL in HL-60 (human promyelocytic leukemia cell) and K562 (human chronic myelocytic leukemia cell), respectively. Preliminary chemical analysis indicates the presence of terpenes and gallic acid in the geopropolis. Our results indicate the therapeutic potential of geopropolis from M. mondury against inflammatory, oxidative, infectious, and neoplastic diseases.


Sequence variation within botulinum neurotoxin serotypes impacts antibody binding and neutralization.
The botulinum neurotoxins (BoNTs) are category A biothreat agents which have been the focus of intensive efforts to develop vaccines and antibody-based prophylaxis and treatment. Such approaches must take into account the extensive BoNT sequence variability; the seven BoNT serotypes differ by up to 70% at the amino acid level. Here, we have analyzed 49 complete published sequences of BoNTs and show that all toxins also exhibit variability within serotypes ranging between 2.6 and 31.6%. To determine the impact of such sequence differences on immune recognition, we studied the binding and neutralization capacity of six BoNT serotype A (BoNT/A) monoclonal antibodies (MAbs) to BoNT/A1 and BoNT/A2, which differ by 10% at the amino acid level. While all six MAbs bound BoNT/A1 with high affinity, three of the six MAbs showed a marked reduction in binding affinity of 500- to more than 1,000-fold to BoNT/A2 toxin. Binding results predicted in vivo toxin neutralization; MAbs or MAb combinations that potently neutralized A1 toxin but did not bind A2 toxin had minimal neutralizing capacity for A2 toxin. This was most striking for a combination of three binding domain MAbs which together neutralized >40,000 mouse 50% lethal doses (LD(50)s) of A1 toxin but less than 500 LD(50)s of A2 toxin. Combining three MAbs which bound both A1 and A2 toxins potently neutralized both toxins. We conclude that sequence variability exists within all toxin serotypes, and this impacts monoclonal antibody binding and neutralization. Such subtype sequence variability must be accounted for when generating and evaluating diagnostic and therapeutic antibodies.


The influence of fish consumption on serum n-3 polyunsaturated fatty acid (PUFA) concentrations in women of childbearing age: a randomised controlled trial (the iFish Study).
Long-chain polyunsaturated fatty acids (LCPUFA) can be synthesised endogenously from linoleic acid (LA) and α-linolenic acid (ALA) in a pathway involving the fatty acid desaturase (FADS) genes. Endogenous synthesis is inefficient; therefore, dietary intake of preformed LCPUFA from their richest source of fish is preferred. This study investigated the effect of fish consumption on PUFA concentrations in women of childbearing age while stratifying by FADS genotype. The influence of fish consumption on lipid profile, and markers of inflammation and oxidative stress was also examined. Healthy women (n = 49) provided a buccal swab which was analysed for FADS2 genotype (rs3834458; T/deletion). Participants were stratified according to genotype and randomised to an intervention group to receive either no fish (n = 18), 1 portion (n = 14) or 2 portions (n = 17) (140 g per portion) of fish per week for a period of 8 weeks. Serum PUFA was analysed at baseline and post-intervention. Lipid profile, and markers of inflammation and oxidative stress were also analysed. Participants consuming 2 portions of fish per week had significantly higher concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and total n-3 PUFA, and a lower n-6:n-3 ratio compared to those in the no fish or 1 portion per week group (all p < 0.05). Fish consumption did not have a significant effect on biomarkers of oxidative stress, inflammation and lipid profile in the current study. Consumption of 2 portions of fish per week has beneficial effects on biological n-3 PUFA concentrations in women of childbearing age; however, no effects on oxidative stress, inflammation or lipid profile were observed. This trial was registered at www.clinicaltrials.gov (NCT03765580), registered December 2018.


Using aircraft location data to estimate current economic activity.
Aviation is a key sector of the economy, contributing at least 3% to gross domestic product (GDP) in the UK and the US. Currently, airline performance statistics are published with a three month delay. However, aircraft now broadcast their location in real-time using the Automated Dependent Surveillance Broadcast system (ADS-B). In this paper, we analyse a global dataset of flights since July 2016. We first show that it is possible to accurately estimate airline flight volumes using ADS-B data, which is available immediately. Next, we demonstrate that real-time knowledge of flight volumes can be a leading indicator for aviation's direct contribution to GDP in both the UK and the US. Using ADS-B data could therefore help move us towards real-time estimates of GDP, which would equip policymakers with the information to respond to shocks more quickly.


Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor.
A member of the inwardly rectifying potassium channel family was cloned here. The channel, called BIR (Kir6.2), was expressed in large amounts in rat pancreatic islets and glucose-responsive insulin-secreting cell lines. Coexpression with the sulfonylurea receptor SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to adenosine triphosphate (ATP) (IKATP) and was inhibited by sulfonylureas and activated by diazoxide. The data indicate that these pancreatic beta cell potassium channels are a complex composed of at least two subunits--BIR, a member of the inward rectifier potassium channel family, and SUR, a member of the ATP-binding cassette superfamily. Gene mapping data show that these two potassium channel subunit genes are clustered on human chromosome 11 at position 11p15.1.


Evaluation of video tape and a simulator for instruction of basic surgical skills.
Twenty first-year veterinary students with no prior participatory experience in surgery were randomly paired and assigned into two study groups. Ten students (group V) viewed a hemostatic technique video tape until they thought they could competently perform and assist in performing a hand-tied ligature on a blood vessel in a live animal. Ten students (group VS) wer also given a simulator for technique practice. Paired students were video recorded and blindly evaluated on their ability to perform and assist proper ligation of a bleeding vessel. Inexpensive hemostasis models were very helpful for teaching students essential surgeon and assistant skills involved in hand-tied ligature placement. Students who practiced with simulators performed significantly better as surgeon and assistant, and in total psychomotor skill evaluation, then students watching the video only. Students using simulators performed ligation with significantly more accuracy and tended to be more expeditious at this task. Further training is needed for students to acquire skills necessary for efficient bleeding vessel exposure and isolation.


Every Newborn: progress, priorities, and potential beyond survival.
In this Series paper, we review trends since the 2005 Lancet Series on Neonatal Survival to inform acceleration of progress for newborn health post-2015. On the basis of multicountry analyses and multi-stakeholder consultations, we propose national targets for 2035 of no more than 10 stillbirths per 1000 total births, and no more than 10 neonatal deaths per 1000 livebirths, compatible with the under-5 mortality targets of no more than 20 per 1000 livebirths. We also give targets for 2030. Reduction of neonatal mortality has been slower than that for maternal and child (1-59 months) mortality, slowest in the highest burden countries, especially in Africa, and reduction is even slower for stillbirth rates. Birth is the time of highest risk, when more than 40% of maternal deaths (total about 290,000) and stillbirths or neonatal deaths (5·5 million) occur every year. These deaths happen rapidly, needing a rapid response by health-care workers. The 2·9 million annual neonatal deaths worldwide are attributable to three main causes: infections (0·6 million), intrapartum conditions (0·7 million), and preterm birth complications (1·0 million). Boys have a higher biological risk of neonatal death, but girls often have a higher social risk. Small size at birth--due to preterm birth or small-for-gestational-age (SGA), or both--is the biggest risk factor for more than 80% of neonatal deaths and increases risk of post-neonatal mortality, growth failure, and adult-onset non-communicable diseases. South Asia has the highest SGA rates and sub-Saharan Africa has the highest preterm birth rates. Babies who are term SGA low birthweight (10·4 million in these regions) are at risk of stunting and adult-onset metabolic conditions. 15 million preterm births, especially of those younger than 32 weeks' gestation, are at the highest risk of neonatal death, with ongoing post-neonatal mortality risk, and important risk of long-term neurodevelopmental impairment, stunting, and non-communicable conditions. 4 million neonates annually have other life-threatening or disabling conditions including intrapartum-related brain injury, severe bacterial infections, or pathological jaundice. Half of the world's newborn babies do not get a birth certificate, and most neonatal deaths and almost all stillbirths have no death certificate. To count deaths is crucial to change them. Failure to improve birth outcomes by 2035 will result in an estimated 116 million deaths, 99 million survivors with disability or lost development potential, and millions of adults at increased risk of non-communicable diseases after low birthweight. In the post-2015 era, improvements in child survival, development, and human capital depend on ensuring a healthy start for every newborn baby--the citizens and workforce of the future.


Hypnosis during pregnancy, childbirth, and the postnatal period for preventing postnatal depression.
The morbidity caused by postnatal depression is enormous. Several psychological or psychosocial interventions have appeared to be effective for treating the disorder although they have not shown a clear benefit in preventing the development of PND. As yet however, the effectiveness of hypnosis has not been evaluated in relation to this. To assess the effect of hypnosis for preventing postnatal depression compared with usual antenatal, intranatal, or postnatal care. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2011). Randomised controlled trials comparing hypnosis with usual antenatal, intranatal, or postnatal care, where the primary or secondary objective is to assess whether there is a reduced risk of developing postnatal depression. Two review authors independently assessed trials for inclusion and assessed the one included study for risk of bias. The included study did not contribute any data for analysis. There was one included study (involving 63 women). However, as it did not include the outcomes of interest, no data were available for analysis for this review. There was no evidence available from randomised controlled trials to assess the effectiveness of hypnosis during pregnancy, childbirth, and the postnatal period for preventing postnatal depression. Evidence from randomised controlled trials is needed to evaluate the use and effects of hypnosis during the perinatal period to prevent postnatal depression. Two trials are currently underway which may provide further information in the future.


Distribution of the excitatory amino acid receptor subunits GluR2(4) in monkey hippocampus and colocalization with subunits GluR5-7 and NMDAR1.
Ionotropic excitatory amino acid (EAA) receptors are divided pharmacologically into three categories termed NMDA, AMPA/kainate, and high affinity kainate receptors. Each of these receptor subtypes is composed of a specific subset of subunits termed GluR1-4 (AMPA/kainate), GluR5-7, KA1-2 (high affinity kainate), and NMDAR1, 2 A-D (NMDA). Although colocalization of NMDA and non-NMDA receptors has been previously demonstrated electrophysiologically in rat, comprehensive analyses of subunit specific colocalization patterns have not been possible until the advent of appropriate antibodies. The present study investigates such immunocytochemical colocalization of several EAA receptor subunits within individual cells as well as dendritic spines in the monkey hippocampus. Double-label immunohistochemical experiments using antibodies which are specific for GluR2(4), GluR5-7, and NMDAR1 demonstrated that virtually all projection neurons in each subfield of the hippocampus contain subunits from the AMPA/kainate, kainate, and NMDA receptor families. In addition, confocal microscopy has demonstrated that individual spines may contain subunits representative of multiple EAA receptor families. Furthermore, detailed regional, cellular, and ultrastructural distribution patterns of the EAA receptor subunits GluR2 and GluR4 in monkey hippocampus are presented based on the use of a monoclonal antibody (mAb), 3A11, which was generated against the putative extracellular N-terminal domain of GluR2. Since this antibody recognizes only GluR2 in Western blots, and GluR2 as well as GluR4 in fixed transiently transfected cells, it has been designated anti-GluR2(4). Immunocytochemical labeling with mAb 3A11 revealed pyramidal cell somata and dendrites in each field of the hippocampus, as well as granule cells and polymorphic hilar cells in the dentate gyrus. Small cells with the morphologic characteristics of astroglia were also immunolabeled for GluR2(4) within the alveus and fimbria. Immunoreactivity at the ultrastructural level was localized to postsynaptic densities on dendritic spines and shafts and within the somatodendritic cytoplasm in all major hippocampal regions, as well as in a subset of dentate granule cell axons within the mossy fiber projection.


Overexpression of hemopexin in the diabetic eye: a new pathogenic candidate for diabetic macular edema.
Hemopexin is a well-recognized permeability factor in the kidney, but its potential role in blood-retinal barrier (BRB) breakdown has not been explored. The main aims of this study were as follows: 1) to determine hemopexin expression in the retina and its content in the vitreous fluid from diabetic patients with diabetic macular edema (DME) and nondiabetic patients, 2) to evaluate the effect of hemopexin on BRB permeability, and 3) to determine whether dexamethasone prevents an eventual hemopexin-induced hyperpermeability. Biological material included 1) retinas from 10 diabetic donors with nonproliferative retinopathy and from 10 nondiabetic donors and 2) vitreous fluid from 14 patients with DME and 14 nondiabetic patients. Hemopexin and hemopexin receptor mRNA levels were measured by quantitative RT-PCR and hemopexin concentrations by ELISA. The effect of hemopexin on permeability in culture was evaluated in human retinal pigment epithelial (ARPE)-19 cells and bovine retinal endothelial cells. The experiments were repeated in the presence of hemopexin-neutralizing antibodies and dexamethasone. A higher expression of hemopexin was detected in the retinal pigment epithelium (RPE) from diabetic patients in comparison with nondiabetic control subjects. Intravitreal hemopexin concentration was higher in patients with DME than in nondiabetic subjects. Hemopexin significantly increased permeability in ARPE-19 cells, which was prevented by both hemopexin-neutralizing antibodies and dexamethasone. Hemopexin is overexpressed in the RPE of diabetic patients with DME and induces the breakdown of RPE cells in vitro. Dexamethasone was able to prevent hemopexin-induced hyperpermeability. Our results suggest that hemopexin can be considered a new pathogenic candidate for DME.


Potentials, challenges and future of chimeric antigen receptor T-cell therapy in non-Hodgkin lymphomas.
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Disease progression or relapse following frontline chemoimmunotherapy, largely in the form of standard R-CHOP, occurs in 30-40% patients. Relapsed/refractory (R/R) DLBCL represents a major unmet medical need. In particular, patients with primary refractory disease or those whose lymphoma relapses after autologous stem cell transplantation have historically had poor outcomes.Material and methods: Chimeric antigen receptor T-cell (CART) therapy is a promising novel treatment with curative potential in this setting. CART is based on ex vivo genetic modification of autologous T-cells to express chimeric receptors targeting antigens highly expressed in tumors such as CD19 in DLBCL. After lymphocyte-depleting therapy, patients are infused with CARTs that expand in vivo and target CD19-positive lymphoma cells.Results: In initial phase I-II trials, investigators have demonstrated complete responses in 40-50% of patients with R/R DLBCL, resulting in durable remission approaching 3 years of follow-up in most of these patients without further treatment. The logistics of delivery are complex as cell products require timely long-distance transfer between hospitals and production facilities. The unique toxicity profile of CARTs, including the risk of fatal immunological and neurologic events, also requires specific hospital wide management approaches and education. The substantial direct and indirect costs of CART will limit access even in countries with well resourced health care systems.Conclusions: While only two products are commercially available at present, further approvals in coming years appear likely. Future directions include CARTs with reactivity to tumor antigens other than CD19 and products targeting multiple tumor antigens to overcome resistance. The availability of CART has altered the current treatment algorithm for R/R DLBCL, and indications will likely expand to earlier lines of therapy and other hematologic malignancies.


Divergent selection for residual feed intake affects the transcriptomic and proteomic profiles of pig skeletal muscle.
Improving feed efficiency is a relevant strategy to reduce feed cost and environmental waste in livestock production. Selection experiments on residual feed intake (RFI), a measure of feed efficiency, previously indicated that low RFI was associated with lower feed intake, similar growth rate, and greater lean meat content compared with high RFI. To gain insights into the molecular mechanisms underlying these differences, 24 Large White females from 2 lines divergently selected for RFI were examined. Pigs from a low-RFI ("efficient") and high-RFI ("inefficient") line were individually fed ad libitum from 67 d of age (27 kg BW) to slaughter at 115 kg BW (n = 8 per group). Additional pigs of the high-RFI line were feed restricted to the daily feed intake of the ad libitum low-RFI pigs (n = 8) to investigate the impact of selection independently of feed intake. Global gene and protein expression profiles were assessed in the LM collected at slaughter. The analyses involved a porcine commercial microarray and 2-dimensional gel electrophoresis. About 1,000 probes were differentially expressed (P < 0.01) between RFI lines. Only 10% of those probes were also affected by feed restriction. Gene functional classification indicated a greater expression of genes involved in protein synthesis and a lower expression of genes associated with mitochondrial energy metabolism in the low-RFI pigs compared with the high-RFI pigs. At the protein level, 11 unique identified proteins exhibited a differential abundance (P < 0.05) between RFI lines. Differentially expressed proteins were generally not significantly affected by feed restriction. Mitochondrial oxidative proteins such as aconitase hydratase, ATP synthase subunit α, and creatine kinase S-type had a lower abundance in the low-RFI pigs, whereas fructose-biphosphate aldolase A and glyceraldehyde-3-phosphate dehydrogenase, 2 proteins involved in glycolysis, had a greater abundance in those pigs compared with high-RFI pigs. Antioxidant proteins such as superoxide dismutase and glutathione peroxidase 3 at the mRNA level and peroxiredoxin-6 at the protein level were also less expressed in LM of the most efficient pigs, likely related to lower oxidative molecule production. Collectively, both the transcriptomic and proteomic approaches revealed a lower oxidative metabolism in muscle of the low-RFI pigs and all these modifications were largely independent of differences in feed intake.


'Modelling a Secure-Base' for Women with Complex Needs: Attachment-Based Interventions Used by Perinatal and Infant Mental Health Clinicians.
Infant well-being is intrinsically linked to maternal physical and emotional well-being. Internationally health services have implemented policies to identify women at risk of mental health problems and developed effective care pathways. The aim of this paper is to describe how perinatal and infant mental health clinicians perceive their role and the attachment-based interventions they use in their work. The study comes from a larger mixed methods study, which examined two specialist perinatal and infant mental health services in New South Wales (Australia). Two hundred and forty-four medical records were reviewed, and six perinatal and infant mental health clinicians participated in in-depth semi-structured interviews. Data were analysed by content and thematic analysis. One overarching theme, modelling a secure base and three supporting themes, enhancing reflective capacity, enhancing emotional regulation and enhancing empathy emerged from the analysis. These findings demonstrate how perinatal and infant mental health clinicians use attachment theory to inform practice by modelling "holding" and being a secure-base for women. They also provide a clearer understanding of perinatal mental health practice and can be used to inform educational programs for multidisciplinary mental health professionals particularly those working with women and infants.


YM155 reverses cisplatin resistance in head and neck cancer by decreasing cytoplasmic survivin levels.
Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of head and neck squamous cell carcinoma (HNSCC). However, acquisition of cisplatin resistance is common in patients with HNSCC, and it often leads to local and distant failure. In this study, we showed that survivin expression is significantly upregulated in HNSCC primary tumors and cell lines. In addition, survivin levels were significantly higher in human papilloma virus-negative patients that normally respond poorly to cisplatin treatment. Survivin expression was further increased in cisplatin-resistant cells (CAL27-CisR) as compared with its parent cells (CAL27). Therefore, we hypothesized that targeting of survivin in HNSCC could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of cisplatin. We used both in vitro and in vivo models to test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with cisplatin. YM155 significantly decreased survivin levels and cell proliferation in a dose-dependent manner. In addition, YM155 pretreatment significantly reversed cisplatin resistance in cancer cells. Interestingly, YM155 treatment altered the dynamic localization of survivin in cells by inducing a rapid reduction in cytoplasmic survivin, which plays a critical role in its antiapoptotic function. In a severe combined immunodeficient mouse xenograft model, YM155 significantly enhanced the antitumor and antiangiogenic effects of cisplatin, with no added systemic toxicity. Taken together, our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of the chemotherapy in HNSCC.


Delivering post-abortion care through a community-based reproductive health volunteer programme in Pakistan.
This qualitative study was conducted in May-June 2010 with women using post-abortion care (PAC) services provided by the Marie Stopes Society in Pakistan during the six month period preceding the study, more than 70% of whom had been referred to the clinics by reproductive health volunteers (RHVs). The aim of the study was to establish the socio-demographic profile of clients, determine their preferred method of treatment, explore their perceptions of the barriers to accessing post-abortion services and to understand the challenges faced by RHVs. The sample women were selected from six randomly selected districts of Sindh and Punjab. Eight focus group discussions were conducted with PAC clients and fifteen in-depth interviews with RHVs. In addition, a quantitative exit interview questionnaire was administered to 76 clients. Medical, rather than surgical, treatment for incomplete and unsafe abortions was preferred because it was perceived to 'cause less pain', was 'easy to employ' and 'having fewer complications'. Household economics influence women's decision-making on seeking post-abortion care. Other restraining factors include objection by husbands and in-laws, restrictions on female mobility, the views of religious clerics and a lack of transport. The involvement of all stakeholders could secure social approval and acceptance of the provision of safe post-abortion care services in Pakistan, and improve the quality of family planning services to the women who want to space their pregnancies.


[Infections and diseases after travelling].
With intensifying international travel numbers of travel associated infections and diseases will increase. Systematic studies on infections and diseases with regard to the travel destination in tropical and subtropical areas are scarce in Germany. Data regarding travel destination, reason, type and duration of travel, symptoms, clinical findings, laboratory results as well as diagnoses of 2024 patients (male 1010, mean age 35 years; female 1014, mean age 33 years) presenting at the outpatient clinic of the Institute of Tropical Medicine Berlin after returning from travel to tropical or subtropical areas were assessed. The most frequent reasons for consultation were diarrhea (33 %), fever (17 %) and skin affections (14 %). A definitive diagnosis was established in 31 % (635). Significant differences were found for prevalences of infectious diseases with regard to travel destinations. 1.5 % of the travellers had contracted malaria. Only 34% of the returnees from malaria-endemic areas had taken chemoprophylaxis; in case of travel to Africa and Asia, chemoprophyplaxis corresponded to international standards in only 48 % and 23%, respectively. Giardia lamblia was the most frequently detected intestinal pathogen. Blastocystis hominis was found to be significantly associated with diarrhea. Most of the travel-associated infections are self-limited. In case of fever, malaria and potentially hemorrhagic fever should be excluded and be followed by a stepwise investigation on the cause of fever. In case of diarrhea, parasitologic investigations should be performed by an experienced laboratory and fresh stool samples should be used. Intensive co-operation will be necessary between physician, pharmacists and others active in the field of travel medicine in order to address the shortcomings in chemoprophylaxis for malaria. An increasing need for expertise in tropical and travel medicine, especially among private physicians is expected.


Lifestyle and cancer: effect of parental divorce.
According to previous studies, divorced individuals have increased risks of cancers related to alcohol and tobacco consumption and sexual habits, but the increases are balanced with decreased risks of many common cancers. In the present study, cancer risks were analyzed for 0-70-year-old offspring of divorced parents, on the basis the Swedish Family-Cancer Database with cancer data from the years 1958 to 2002. We calculated standardized incidence ratios for cancer among offspring of divorced parents (19,000 cancer patients) and compared them with offspring of stably married parents (121,000 cancer patients). Standardized incidence ratios were adjusted for many factors, including socio-economic status. Offspring of divorced parents were divided into groups depending on whether their mothers, fathers or both had had children with different partners. Offspring of divorced parents had an increased risk of upper aerodigestive tract, esophageal, anal, pancreatic, lung and cervical cancers. Decreased risks were noted for Hodgkin's disease and bone cancer. For Hodgkin's disease, the data suggest protective effects through early exposure to childhood pathogens but for bone cancer mechanisms remain to be established. The overall cancer risk for offspring of divorced parents was at or above unity. The results show that offspring of divorced parents have increased cancer risks at tobacco-related, alcohol-related and sex-related sites, in analogy to their parent, but they lack decreased risks at common sites, experienced by their parents. Divorce is becoming increasingly common in many countries and any deviant cancer patterns among offspring of divorced parents will have an impact on the population risk.


HPV DNA frequency and subset analysis in human breast cancer patients' normal and tumoral tissue samples.
Viruses are known to be associated with human malignancies, e.g., Epstein-Barr virus, human papillomavirus (HPV) and human T-cell leukemia virus type I. We conducted a prospective study to define the role of HPV in breast cancer. The malignant and normal breast tissue samples of 50 consecutive breast cancer patients were obtained postoperatively. DNA extracted from all tissues was amplified with the polymerase chain reaction using HPV primers. HPV 11, 16, 18, 33 subtypes were searched in HPV-DNA positive samples. Thirty-seven samples (74%) of tumoral breast tissue expressed HPV-DNA, 16 normal breast tissue samples (32%) were positive as well. There was a significant difference in HPV-DNA positivity between normal and tumoral breast tissue samples. HPV 18 was detected in 20 of the HPV-DNA positive tumoral tissue (54.4%) and in 9 of the HPV-DNA positive normal tissue (56.3%). HPV-33 also was detected in 35 (94.6 %) of the HPV-DNA positive tumoral tissue and in 14 (87.5 %) of the HPV-DNA positive normal tissue samples. HPV DNA was significantly associated with breast tumor tissue compared to normal breast tissue. Additional studies looking at HPV and HPV subtypes are needed to clarify the etiological role of the HPV in breast cancer.


Hypometabolic homeostasis in overwintering aquatic amphibians.
Many amphibians encounter conditions each winter when their body temperature is so low that normal activities are suspended and the animals enter into a state of torpor. In ice-covered ponds or lakes, oxygen levels may also become limiting, thereby forcing animals to endure prolonged periods of severe hypoxia or anoxia. Certain frogs (e.g. Rana temporaria) can dramatically suppress their metabolism in anoxia but are not as tolerant as other facultative vertebrate anaerobes (e.g. turtle, goldfish) of prolonged periods of complete O2 lack. Many overwintering amphibians do, however, tolerate prolonged bouts of severe hypoxia, relying exclusively on cutaneous gas exchange. Rana temporaria overwintering for 2 months in hypoxic water (PO2 approximately 25 mmHg) at 3 degrees C progressively reduce their blood PCO2 to levels characteristic of water-breathing fish. The result is that blood pH rises and presumably facilitates transcutaneous O2 transfer by increasing Hb O2-affinity. Even after months of severe hypoxia, there is no substantial build-up of lactate as the animals continue to rely on cutaneous gas exchange to satisfy the requirements of a suppressed aerobic metabolism. Our recent experiments have shown that the skeletal muscle of frogs oxyconforms in vitro to the amount of O2 available. The cellular basis for the oxyconformation of skeletal muscle is unknown, but the hypothesis driving our continuing experiments theories that metabolic suppression at a cellular level is synonymous with suppressed ion leak across cellular membranes.


Chiropractic biophysics lateral cervical film analysis reliability.
To determine the degree to which the geometric line drawings used in Chiropractic Biophysics Technique (CBP) on lateral cervical radiographs are reliable. A blind, delayed repeated measures design was used. Three examiners were presented radiographs in random order. All identifying marks were removed prior to each examiner's individual marking and measurement. Each examiner was blinded as to how the previous examiners marked and measured the radiographs. Primary care private chiropractic clinic. Sixty-five subject films were provided from the patient records of a primary care private chiropractic clinic. The 65 radiographs qualified for inclusion in the study based on two criteria: C1 through C7 had to be clearly visible, and there had to be no identifying artifacts. Anterior head translation in millimeters, atlas plane to horizontal, Ruth Jackson's cervical stress lines, and five relative rotation angles for C2-C3, C3-C4, C4-C5, C5-C6, C6-C7. Inter- and intrareliability of the three examiners were statistically analyzed. Intraexaminer for a) C1 to horizontal reliability was .98-.99 with confidence intervals of .96-.99, b) absolute rotation angle from C2 to C7 reliability was .82-.95 with confidence intervals of .80-.99, c) anterior head translation [+Sz] reliability was .86-.99, with confidence intervals of .74-.99, d) relative rotation angle reliability ranges were (C2-C3) .99, and (C3-C4) .98-.99, (C4-C5) .88-.99, (C5-C6) .80-.99, and (C6-C7) .94-.98. Interexaminer reliabilities across examiners ranged from a) Winer:.89-.99 and b) Bartko: .72-.96. The reliabilities for intra- and interexaminer were all greater than .70, indicating that these measurements in CBP technique would be considered accurate enough to provide measurements for future clinical studies. The data indicated that the C6-C7 relative rotation angle was the least reliable measurement. This might be due to the very small angles found at this level.


Malpractice: future shock of the 1980s.
Once the therapeutic relationship is established, a client acquires certain rights and the social worker certain duties. If these duties are breached due to negligence, and the client is damaged in any way, the social worker may be financially liable, and this may lead to the cause of action called malpractice.


Modification of antigen expression in human and hamster pancreatic cancer cell lines induced by sodium butyrate.
The effects of sodium butyrate (NaB) on the growth, morphology, and expression of blood group A, Lewis(a), and CA 19-9 antigen in the hamster pancreatic cancer cell lines, PC-1 (well differentiated) and PC-1.0 (poorly differentiated), and of blood group A, DU-PAN-2, and CA 19-9 antigens in four human pancreatic cancer cell lines, HPAF and CD11 (well differentiated) and CD18 and PANC-1 (poorly differentiated), were examined. NaB inhibited the growth of all cell lines and induced cell enlargement, an increase in secretory material, microfilaments, and pseudopodia. NaB stimulated the production of blood group A antigen in PC-1.0 cells dose dependently, but no change in the expression of this antigen was observed in the human cell lines. However, NaB treatment increased the presence of cells positive for CA 19-9 in PANC-1 but not in the remaining cell lines, none of which reacted with the anti-CA 19-9 antibody before or after NaB treatment. Untreated PANC-1 cells did not produce either blood group A or DU-PAN-2 antigen, but expressed these antigens after NaB treatment in a dose-dependent manner. The results suggest that NaB stimulates the differentiation of the hamster and human pancreatic cancer cell lines and increases or induces the expression of some tumor-associated antigens.


The comprehensive electrophysiological study of curcuminoids on delayed-rectifier K+ currents in insulin-secreting cells.
Curcumin (CUR) has been demonstrated to induce insulin release from pancreatic β-cells; however, how curcuminoids (including demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)) exert any possible effects on membrane ion currents inherently in insulin-secreting cells remains largely unclear. The effects of CUR and other structurally similar curcuminoids on ion currents in rat insulin-secreting (INS-1) insulinoma cells were therefore investigated in this study. The effects of these compounds on ionic currents and membrane potential were studied by patch-clamp technique. CUR suppressed the amplitude of delayed-rectifier K+ current (IK(DR)) in a time-, state- and concentration-dependent manner in these cells and the inhibition was not reversed by diazoxide, nicorandil or chlorotoxin. The value of dissociation constant for CUR-induced suppression of IK(DR) in INS-1 cells was 1.26μM. Despite the inability of CUR to alter the activation rate of IK(DR), it accelerated current inactivation elicited by membrane depolarization. Increasing CUR concentrations shifted the inactivation curve of IK(DR) to hyperpolarized potential and slowed the recovery of IK(DR) inactivation. CUR, DMC, and BDMC all exerted depressant actions on IK(DR) amplitude to a similar magnitude, although DMC and BDMC did not increase current inactivation clearly. CUR slightly suppressed the peak amplitude of voltage-gated Na+ current. CUR, DMC and BDMC depolarized the resting potential and increased firing frequency of action potentials. The CUR-mediated decrease of IK(DR) and the increase of current inactivation also occurred in βTC-6 INS-1 cells. Taken these results together, these effects may be one of the possible mechanisms contributing their insulin-releasing effect.


Depleted uranium contamination by inhalation exposure and its detection after approximately 20 years: implications for human health assessment.
Inhaled depleted uranium (DU) aerosols are recognised as a distinct human health hazard and DU has been suggested to be responsible in part for illness in both military and civilian populations that may have been exposed. This study aimed to develop and use a testing procedure capable of detecting an individual's historic milligram-quantity aerosol exposure to DU up to 20 years after the event. This method was applied to individuals associated with or living proximal to a DU munitions plant in Colonie New York that were likely to have had a significant DU aerosol inhalation exposure, in order to improve DU-exposure screening reliability and gain insight into the residence time of DU in humans. We show using sensitive mass spectrometric techniques that when exposure to aerosol has been unambiguous and in sufficient quantity, urinary excretion of DU can be detected more than 20 years after primary DU inhalation contamination ceased, even when DU constitutes only approximately 1% of the total excreted uranium. It seems reasonable to conclude that a chronically DU-exposed population exists within the contamination 'footprint' of the munitions plant in Colonie, New York. The method allows even a modest DU exposure to be identified where other less sensitive methods would have failed entirely. This should allow better assessment of historical exposure incidence than currently exists.


Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer.
Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes. Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls. Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p ≤ 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79-0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43-0.88). There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes. These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality.


Diffuse hair loss: its triggers and management.
Diffuse hair loss can affect both sexes at any age. Anything that interrupts the normal hair cycle can trigger diffuse hair loss. Triggers include a wide variety of physiologic or emotional stresses, nutritional deficiencies, and endocrine imbalances. Loss of telogen-phase hairs is the most common. Hair loss during the anagen phase is usually caused by chemotherapy or radiation therapy. Finding the cause, or trigger, of the hair loss requires a thorough history and examination and will enable appropriate treatment. Patient education is key in the management of diffuse hair loss.


Cognitive representations of disability behaviours in people with mobility limitations: consistency with theoretical constructs.
Disability is conceptualized as behaviour by psychological theory and as a result of bodily impairment by medical models. However, how people with disabilities conceptualize those disabilities is unclear. The purpose of this study was to examine disability representations in people with mobility disabilities. Thirteen people with mobility disabilities completed personal repertory grids (using the method of triads) applied to activities used to measure disabilities. Ten judges with expertise in health psychology then examined the correspondence between the elicited disability constructs and psychological and medical models of disability. Participants with mobility disabilities generated 73 personal constructs of disability. These constructs were judged consistent with the content of two psychological models, namely the theory of planned behaviour and social cognitive theory and with the main medical model of disability, the International Classification of Functioning Disability and Health. Individuals with activity limitations conceptualize activities in a manner that is compatible with both psychological and medical models. This ensures adequate communication in contexts where the medical model is relevant, e.g., clinical contexts, as well as in everyday conversation about activities and behaviours. Finally, integrated models of disability may be of value for theory driven interdisciplinary approaches to disability and rehabilitation.


Poor functional status immediately after discharge from an intensive care unit.
To evaluate the functional status of patients within the first week of discharge from an intensive care unit (ICU), and to identify predictors and explanatory factors of functional status. A prospective, observational, cohort study was conducted with consecutive ICU patients who had stayed in a mixed, closed-format, university-level ICU for longer than 48 h. Between 3 and 7 days of discharge from the ICU, functional status (as primary outcome), walking ability, muscle strength, and sensory and cognitive functioning were assessed in 69 survivors. The overall functional status was poor (median Barthel Index 6). In their ability to perform basic activities of daily living, 67% percent were severely dependent, 15% were moderately dependent, and 9% were slightly dependent on other people. Independent walking was impossible for 73% of participants, grip strength was reduced for 50%, and 30% had cognitive impairments. Duration of ventilation was associated with functional status after ICU discharge. Reduced grip strength and walking ability were identified as explanatory factors for poorer functional status shortly after discharge from the ICU. In the first week after discharge from the ICU, the majority of the patients had substantial functional disabilities in activities of daily living. These disabilities were more severe in patients who experienced ventilation for a longer period of time. There is a need for prospective studies focusing on functional recovery to support informed decision-making concerning the care of critically ill patients after ICU discharge.


Enzyme immunoassay for anti-treponemal IgG: screening or confirmatory test?
To review the performance of the Venereal Diseases Research Laboratory (VDRL) test and the Treponema pallidum haemagglutination assay (TPHA) as a combined screen for syphilis to provide a baseline for assessing screening by anti-treponemal IGG EIA. Between 1980 and 1987 all serum samples were screened by both VDRL and TPHA tests. The FTA-ABS test was also used in suspected early primary syphilis, or when one of the other tests was positive. A positive result in a screening test was confirmed by quantitative testing. From 1988 all specimens were screened with an enzyme immunoassay (Captia Syph G) as a single screening test. Of the 44 primary, 47 secondary, and 38 early latent cases of syphilis, the VDRL and TPHA detected 32 (73%) and 31 (71%) of the primary cases; the combination detected 37 (84%). All 85 cases of cases of secondary and early latent infection were reactive in the TPHA test, whereas the VDRL was reactive in only 68 (80%). EIA had a reported sensitivity of 82% for primary infection. EIA can be used as a single screening test for detecting early syphilis because its results are comparable with those of the combined VDRL and TPHA tests. The conventional VDRL test should not be used as a single screening test.


Augmentation of the nasal floor with Surgicel in primary lip repair: a prospective study showing no efficacy.
The symmetry of the alar base and the nasal floor is very important in achieving a satisfactory result in primary lip and nasal reconstruction during cleft lip repair. The skeletal base of the nasal pyramid is usually hypoplastic even in incomplete clefts. A periosteal pocket filled with Surgicel can facilitate blood clot formation and can theoretically stimulate bone formation, thereby improving the asymmetry of the bone base. To test this hypothesis, a prospective study was performed in 64 primary lip repairs by comparing the effect of subperiosteal nasal floor augmentation with Surgicel. From February 1989 to June 1993, 64 patients with incomplete cleft lips (excluding occult cleft lip and complete clefts with Simonart's band) were operated by the same surgeon. The patients were divided randomly into two groups. One group had subperiosteal nasal floor augmentation with Surgicel and the other group did not. The lip repair was a rotation-advancement cheiloplasty with primary closed rhinoplasty of the tip and ala. In the first group, a subperiosteal pocket was created under the cleft alar base and the nasal floor. The pocket was filled with Surgicel up the point where the level of the alar base and the nasal floor was symmetrical with the noncleft side. The control group underwent a similar procedure, less the creation of the subperiosteal pocket and the use of Surgicel. All patients were followed for at least 3 years and their photographs were used to compare and analyze the results of their nasal correction. Critical attention was paid to the symmetry of their nasal floor and alar base. The results were evaluated by at least two plastic surgeons for consistency. The data indicate that the control group showed a higher number of subjects with asymmetry (10 of 32) compared with the study group (8 of 32). However, there was no statistical significance to the findings. Two patients in the study group who received Surgicel developed hypertrophic lip scars. This study, although unable to determine statistically the contributory affect of Surgicel in primary nasal reconstruction, does show a possible benefit from the use of osteogenic materials in the primary management of the deficient nasal floor. Hypertrophic scars developed by 2 patients in the study group may point to a possible soft-tissue reaction to the use of Surgicel in primary lip and nasal repair.


Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.
To evaluate the efficacy of open-label, highly purified cannabidiol (CBD, Epidiolex®) in treating refractory epilepsy relative to the concomitant use of clobazam (CLB) as well as the clinical implications of changes in CLB and norclobazam (nCLB) levels. Data were examined retrospectively, in patients who either used CBD with concomitant CLB or without concomitant CLB after two months of treatment with CBD and at the point of best seizure control within the first year of treatment with CBD. Responder rates (percentage of subjects with a 50 % or greater reduction in weekly seizures from their baseline) and mean reduction in weekly seizure frequency were calculated and compared between those who concomitantly used CLB and those who did not. The relationship between the change in CLB and nCLB levels and change in mean weekly seizure frequency was also investigated within the group of subjects using concomitant CLB and CBD. We analyzed data from 47 subjects between the ages of 2.5-51 years. There was no significant difference between the concomitant CLB (n = 32) and no concomitant CLB (n = 15) groups in terms of demographics (age (p = 0.4344), race (p = 1.0000), sex (p = 0.7507)) or most epilepsy characteristics (underlying condition (all p > 0.05), mean baseline seizure frequency (p = 0.6483)). There was only one significant difference between groups regarding seizure types (more subjects with epileptic spasms in concomitant CLB group (p = 0.0413)). Concomitant AED usage was not significantly different in the two groups (all p > 0.05). Mean reduction in weekly seizure frequency was greater at the best point of seizure control within the first year than at two months of treatment with CBD, regardless of concomitant CLB usage (all p > 0.05). There was no significant difference in reduction of mean weekly seizure frequency between those who took concomitant CLB and those who did not at either time point (all p > 0.05). There was a significantly greater responder rate for subjects taking CBD and CLB than those taking CBD without CLB only at the point of best seizure control within the first year of CBD treatment (p = 0.0240). There was no strong, significant correlation between change in nCLB or CLB levels and change in seizure frequency at either time point (all |p|<0.22). With or without concomitant CLB, CBD can be effective in reducing seizure frequency. Changes in nCLB and CLB levels do not have a clinically significant correlation with changes in weekly seizure frequency for those taking CBD with CLB.


Molecular profile and clinical variables in BRCA1-positive breast cancers. A population-based study.
To evaluate the clinical features of breast cancer patients with genetic susceptibility to this disease and to investigate the contribution of BRCA1 germline mutations to the phenotype of these tumors. We reviewed the clinical and pathological records of 102 women with suspected inherited susceptibility to breast cancer consecutively seen at the Genetic Oncology Service of Parma, Italy. Sixty-two patients with a high probability of harboring a germline, cancer-predisposing mutation were tested for BRCA1 mutations. Exon 11 was screened using the protein truncation test and detected mutations were confirmed by direct sequencing (DS). All other exons were analyzed by DS. Among the 62 patients with a completed mutation analysis, 48 (77.4%) had wild-type BRCA1, six (9.6%) had variants of unclear significance, eight (13%) had deleterious mutations. BRCA1-associated breast cancers (BABC) were significantly less likely to be diagnosed at stage I than breast cancers in women without mutations (12.5% vs 51%; P = 0.045), more likely to have a high proliferation rate (100% vs 24%, P < 0.001), and more likely to be histological grade 3 (100% vs 14%, P < 0.001), estrogen and progesterone receptor negative (87.5% vs 13%, P < 0.001; 75% vs 23%, P = 0.004), and p53 positive (87.5% vs 30%, P = 0.023). All tumors with BRCA1 mutations were HER-2/neu negative compared with 57% of the non-BRCA1 tumors (P = 0.04). There were no significant differences between BABC and non-BABC in 20-year relapse-free survival, 20-year event-free survival, and 20-year overall survival. In this population-based study, BABC seems to present with adverse molecular features when compared with non-BABC, although the prognosis appears to be similar.