Using Intervention Mapping to Develop an mHealth Intervention to Support Men Who Have Sex With Men Engaging in Chemsex (Budd): Development and Usability Study.
Chemsex refers to the intentional use of drugs before or during sex among men who have sex with men (MSM). Engaging in chemsex has been linked to significant negative impacts on physical, psychological, and social well-being. However, no evidence-based support tools have addressed either these harms or the care needs of MSM who engage in chemsex. The purpose of this paper was to describe the development of a mobile health intervention (named Budd) using the intervention mapping protocol (IMP). Budd aims to support and inform MSM who participate in chemsex, reduce the negative impacts associated with chemsex, and encourage more reasoned participation. The IMP consists of 6 steps to develop, implement, and evaluate evidence-based health interventions. A needs assessment was carried out between September 2, 2019, and March 31, 2020, by conducting a literature study and in-depth interviews. Change objectives were selected based on these findings, after which theory-based intervention methods were selected. The first version of the intervention was developed in December 2020 and pilot-tested between February 1, 2021, and April 30, 2021. Adjustments were made based on the findings from this study. A separate article will be dedicated to the effectiveness study, conducted between October 15, 2021, and February 24, 2022, and implementation of the intervention. The Budd app went live in April 2022. Budd aims to address individual factors and support chemsex participants in applying harm reduction measures when taking drugs (drug information, drug combination tool, and notebook), preparing for participation in a chemsex session (articles on chemsex, preparation tool, and event-specific checklist), planning sufficient time after a chemsex session to recover (planning tool), seeking support for their chemsex participation (overview of existing local health care and peer support services, reflection, personal statistics, and user testimonials), taking HIV medication or pre-exposure prophylaxis in a timely manner during a chemsex session (preparation tool), and contacting emergency services in case of an emergency and giving first aid to others (emergency information and personal buddy). The IMP proved to be a valuable tool in the planning and development of the Budd app. This study provides researchers and practitioners with valuable information that may help them to set up their own health interventions. RR1-10.2196/39678.


A call for action to the biomaterial community to tackle antimicrobial resistance.
The global surge of antimicrobial resistance (AMR) is a major concern for public health and proving to be a key challenge in modern disease treatment, requiring action plans at all levels. Microorganisms regularly and rapidly acquire resistance to antibiotic treatments and new drugs are continuously required. However, the inherent cost and risk to develop such molecules has resulted in a drying of the pipeline with very few compounds currently in development. Over the last two decades, efforts have been made to tackle the main sources of AMR. Nevertheless, these require the involvement of large governmental bodies, further increasing the complexity of the problem. As a group with a long innovation history, the biomaterials community is perfectly situated to push forward novel antimicrobial technologies to combat AMR. Although this involvement has been felt, it is necessary to ensure that the field offers a united front with special focus in areas that will facilitate the development and implementation of such systems. This paper reviews state of the art biomaterials strategies striving to limit AMR. Promising broad-spectrum antimicrobials and device modifications are showcased through two case studies for different applications, namely topical and implantables, demonstrating the potential for a highly efficacious physical and chemical approach. Finally, a critical review on barriers and limitations of these methods has been developed to provide a list of short and long-term focus areas in order to ensure the full potential of the biomaterials community is directed to helping tackle the AMR pandemic.


Alveolar Adenoma: A 20-Year Experience at a Western Balkan University Hospital and a Literature Review.
Alveolar adenoma is a rare benign lung tumor. We report 5 patients within a 20-year period diagnosed with this rare tumor and its clinical and histopathological features, in order to emphasize its significance in differential diagnosis of other lung tumors. Alveolar adenoma was more frequently diagnosed in female patients (80%). The patients ranged in age from 52 to 68. Eighty percent of the patients had symptoms like dyspnea, and shoulder or back pain. Three patients underwent a video-assisted thoracoscopic surgery, while 2 patients underwent a thoracotomy in order to remove the tumor. The tumor was localized within the right upper lobe, right lower lobe, and left lower lobe in 40%, 40%, and 20% of patients, respectively. The tumor size ranged from 14 to 30 mm. A frozen section finding of all 5 tumors reported that the lesion was benign. In all analyzed tumors, immunohistochemical analysis showed positive expression of TTF-1 and pankeratin in surface epithelial cells, and Vimentin positivity and TTF-1 and pankeratin negativity in round stromal cells. Alveolar adenoma should be carefully considered in the differential diagnosis of solitary pulmonary nodules. Complete surgical removal of the lesion is widely used in its primary management.


Radiomic analysis using contrast-enhanced CT: predict treatment response to pulsed low dose rate radiotherapy in gastric carcinoma with abdominal cavity metastasis.
To determine the feasibility of radiomic analysis for predicting the therapeutic response of gastric carcinoma (GC) with abdominal cavity metastasis (GCACM) to pulsed low dose rate radiotherapy (PLDRT) using contrast-enhanced computed tomography (CECT) images. Pretreatment CECT images of 43 GCACM patients were analyzed. Patients with complete response (CR) and partial response (PR) were considered responders, while stable disease (SD) and progressive disease (PD) as non-responders. A total of 1,117 image features were quantified from tumor region that segmented from arterial phase CT images. Intra-class correlation coefficient (ICC) and absolute correlation coefficient (ACC) were calculated for selecting influential feature subset. The capability of each influential feature on treatment response classification was assessed using Kruskal-Wallis test and receiver operating characteristic (ROC) analysis. Moreover, artificial neural network (ANN) and k-nearest neighbor (KNN) predictive models were constructed based on the training set (18 responders, 14 non-responders) and the testing set (6 responders, 5 non-responders) validated the reliability of the models. Comparison between the performances of the models was performed by using McNemar's test. The analyses showed that 6 features (1 first order-based, 1 texture-based, 1 LoG-based, and 3 wavelet-based) were significantly different between responders and non-responders (AUCs range from 0.686 to 0.728). Both two prediction models based on features extracted from CECT showed potential in predicting the treatment response with higher accuracies (ANN: 0.714, KNN: 0.749 for the training set; ANN: 0.816, KNN: 0.816 for the testing set). No statistical difference was observed between the performance of ANN and KNN (P=0.999). Pretreatment radiomic analysis using CECT can potentially provide important information regarding the therapeutic response to PLDRT for GCACM, improving risk stratification.


When self-direction meets conformity: Surfacing Schwartz's 10 basic human values in drug policy dialogue with lived/living experience participants.
Research on values is gaining in popularity within drug policy scholarship. To date, research has focused on analysing values within policy, through documentary analysis and interviews with key stakeholders. We extend this research enquiry to investigate the values that emerge from drug policy debate with those who have lived and/or living experience of using drugs. We used workshop data collected from the ESRC-funded Drug Policy Voices project as the basis for our analysis. Within the workshops, participants were given a range of drug policy scenarios to discuss. We selected three scenarios for this paper which discussed policies related to cannabis, heroin, and MDMA/ecstasy. We coded the workshop data using Schwartz's ten basic values, which is a framework that perceives values as the core 'motivators of action' that underpin choices, attitudes and behaviours. We found that the values of 'self-direction', 'security' and 'conformity' were prominent across this participant group, when discussing these policy topics. Yet the drug policy preferences discussed in the workshops revealed that it is the combinations of values that nuance preferences. Security combined with self-direction supports policies that enhance personal responsibility for change; self-direction combined with hedonism supports freedom to use drugs, whereas self-direction combined with conformity and achievement supports recovery policies; and conformity combined with tradition and power supports abstinence-based drug prevention. Schwartz's ten basic values provided a useful framework for surfacing values that underpin drug policy preferences. These exploratory findings demonstrate that identifying values within dialogue is a complex process and reinforces opposing values can explain policy preference differences. More importantly, policy preferences were underpinned by combinations of values including those that are apparently opposing in Schwartz's circumplex.


Heads or tails: how do chemically substituted fullerenes melt?
We address the question as to whether the melting of chemically substituted fullerenes is driven by the dynamics of the fullerene moiety (the head) or the substituted sub-unit (the tail). To this end, we have performed quasielastic neutron-scattering experiments and classical molecular-dynamics simulations as a function of temperature on the prototypical fullerene derivative phenyl-C61-butyric acid methyl ester. To enable a direct and quantitative comparison between experimental and simulation data, dynamic structure factors for the latter have been calculated from atomic trajectories and further convolved with the known instrument response. A detailed analysis of the energy- and momentum-transfer dependence of this observable in the quasielastic regime shows that melting is entirely driven by temperature-activated tail motions. We also provide quantitative estimates of the activation energy for this process as the material first enters a plastic-crystalline phase, followed by the emergence of a genuine liquid at higher temperatures.


The prevalence and characteristics associated with parent-infant bed-sharing in England.
To investigate the characteristics of parent-infant bed-sharing prevalence in England. Data on night-time sleeping practices from a two year, local, longitudinal study and a three-year, national, cross-sectional study were obtained. A total of 261 infants in North Tees were followed up at 1 and 3 months of age, as were 1095 infants aged 1 week to 1 year from five English health regions. Data from both studies found that almost half of all neonates bed-shared at some time with their parents (local = 47%, 95% CI 41 to 54; national = 46%, 95% CI 34 to 58), and on any one night in the first month over a quarter of parents slept with their baby (local = 27%, 95% CI 22 to 33; national = 30%, 95% CI 20 to 42). Bed-sharing was not related to younger mothers, single mothers, or larger families, and was not more common in the colder months, at weekends, or among the more socially deprived families; in fact bed-sharing was more common among the least deprived in the first months of life. Breast feeding was strongly associated with bed-sharing, both at birth and at 3 months. Bed-sharing prevalence was uniform with infant age from 3 to 12 months; on any one night over a fifth of parents (national = 21%, 95% CI 18 to 24) slept with their infants. Bed-sharing is a relatively common practice in England, not specific to class, but strongly related to breast feeding.


Substantia nigra echogenicity is normal in non-extrapyramidal cerebral disorders but increased in Parkinson's disease.
Transcranial sonography (TCS) revealed substantia nigra (SN) hyperechogenicity in idiopathic Parkinson's disease (IPD). To further evaluate specificity of this finding, we examined 30 IPD patients and 30 age-matched subjects with non-extrapyramidal cerebral disorders (NED). All IPD patients showed a SN hyperechogenicity, in 17 it was bilateral and in 13 unilateral. 7 NED patients had a SN hyperechogenicity, in all it was unilateral, confirming previous results in healthy subjects. Bilateral SN hyperechogenicity indicates IPD and normal SN echogenicity indicates NED. In 30% of patients TCS does not distinguish between IPD and NED. Data further support the assumption that bilateral SN hyperechogenicity is specific for IPD.


Use of leisure time by cardiac patients.
There has been increasing evidence that psychological stress is a risk factor in the development of heart disease. How an individual copes with stress will determine its impact on his or her health. The literature proposes that the effects of stress can be minimized, reduced, or reversed by factors such as goal-directed activity, physical exercise, relaxation, or emotionally supportive relationships. An exploratory study was conducted to compare activity patterns and leisure concepts between matched groups of cardiac and noncardiac subjects. The data indicate trends in the differences between these two groups in activity patterns and in the variety of activities that characterized their leisure time. The results suggest areas for occupational therapy intervention in the treatment of cardiac patients.


Postnatal development and behavior effects of in-utero exposure of rats to radiofrequency waves emitted from conventional WiFi devices.
The present work investigated the effects of prenatal exposure to radiofrequency waves of conventional WiFi devices on postnatal development and behavior of rat offspring. Ten Wistar albino pregnant rats were randomly assigned to two groups (n=5). The experimental group was exposed to a 2.45GHz WiFi signal for 2h a day throughout gestation period. Control females were subjected to the same conditions as treated group without applying WiFi radiations. After delivery, the offspring was tested for physical and neurodevelopment during its 17 postnatal days (PND), then for anxiety (PND 28) and motricity (PND 40-43), as well as for cerebral oxidative stress response and cholinesterase activity in brain and serum (PND 28 and 43). Our main results showed that the in-utero WiFi exposure impaired offspring neurodevelopment during the first seventeen postnatal days without altering emotional and motor behavior at adult age. Besides, prenatal WiFi exposure induced cerebral oxidative stress imbalance (increase in malondialdehyde level (MDA) and hydrogen peroxide (H2O2) levels and decrease in catalase (CAT) and superoxide dismutase (SOD) activities) at 28 but not 43days old, also the exposure affected acethylcolinesterase activity at both cerebral and seric levels. Thus, the current study revealed that maternal exposure to WiFi radiofrequencies led to various adverse neurological effects in the offspring by affecting neurodevelopment, cerebral stress equilibrium and cholinesterase activity.


Biochemical properties and subcellular distribution of the BI and rbA isoforms of alpha 1A subunits of brain calcium channels.
Biochemical properties and subcellular distribution of the class A calcium channel alpha 1 subunits (alpha 1A) from rat and rabbit brain were examined using site-directed anti-peptide antibodies specific for rat rbA (anti-CNA3) and for rabbit BI (anti-NBI-1 and anti-NBI-2) isoforms of alpha 1A. In immunoblotting experiments, anti-CNA3 specifically identifies multiple alpha 1A polypeptides with apparent molecular masses of 210, 190, and 160 kD, and anti-NBI-1 and anti-NBI-2 specifically recognize 190-kD alpha 1A polypeptides in rat brain membrane. In rabbit brain, anti-NBI-1 or anti-NBI-2 specifically detect alpha 1A polypeptides with apparent molecular masses of 220, 200, and 190 kD, while anti-CNA3 specifically recognizes 190-kD alpha 1A polypeptides. These polypeptides evidently represent multiple isoforms of alpha 1A present in both rat and rabbit brain. Anti-CNA3 specifically immunoprecipitates high affinity receptor sites for omega-conotoxin MVIIC (Kd approximately 100 pM), whereas anti-NBI-2 immunoprecipitates two distinct affinity receptor sites for omega-conotoxin MVIIC (Kd approximately 100 pM and approximately 1 microM). Coimmunoprecipitation experiments indicate that alpha 1A subunits recognized by anti-CNA3 and anti-NBI-2 are associated with syntaxin in a stable, SDS-resistant complex and with synaptotagmin. Immunofluorescence studies reveal that calcium channels recognized by anti-NBI-2 are localized predominantly in dendrites and nerve terminals forming synapses on them, while calcium channels recognized by anti-CNA3 are localized more prominently in cell bodies and in nerve terminals. The mossy fiber terminals in hippocampus and the terminals of climbing and parallel fibers in cerebellum are differentially stained by these isoform-specific antibodies. These results indicate that both rbA and BI isoforms of alpha 1A are expressed in rat and rabbit brain and form calcium channels having alpha 1A subunits with distinct molecular mass, pharmacology, and subcellular localization.


Structural role of the tyrosine residues of cytochrome c.
The tertiary structures of horse, tuna, Neurospora crassa, horse [Hse65,Leu67]- and horse [Hse65,Leu74]-cytochromes c were studied with high-resolution 1H n.m.r. spectroscopy. The amino acid sequences of these proteins differ at position 46, which is occupied by phenylalanine in the horse proteins but by tyrosine in the remaining two, and at positions 67, 74 and 97, which are all occupied by tyrosine residues in horse and tuna cytochrome c but in the other proteins are substituted by phenylalanine or leucine, though there is only one such substitution per protein. The various aromatic-amino-acid substitutions do not seriously affect the protein structure.


Selective isolation of live/dead cells using contactless dielectrophoresis (cDEP).
Contactless dielectrophoresis (cDEP) is a recently developed method of cell manipulation in which the electrodes are physically isolated from the sample. Here we present two microfluidic devices capable of selectively isolating live human leukemia cells from dead cells utilizing their electrical signatures. The effect of different voltages and frequencies on the gradient of the electric field and device performance was investigated numerically and validated experimentally. With these prototype devices we were able to achieve greater than 95% removal efficiency at 0.2-0.5 mm s(-1) with 100% selectivity between live and dead cells. In conjunction with enrichment, cDEP could be integrated with other technologies to yield fully automated lab-on-a-chip systems capable of sensing, sorting, and identifying rare cells.


Evaluation of fecal calprotectin as a marker of gastrointestinal inflammation in rosacea: A case-control study.
A higher incidence of gastrointestinal diseases has been well established in patients with rosacea. However, no screening tool has been introduced for gastrointestinal disease development in rosacea. Fecal calprotectin (FC) is a calcium-binding protein, mainly derived from polymorpho-nuclear cells, such as neutrophils. It has been established as a marker of gastrointestinal inflammation. The aim of the present study was to evaluate FC levels in patients with rosacea without any gastrointestinal diseases. A prospective, case-control study was planned to investigate the relationship between rosacea and gastrointestinal involvement by evaluating FC levels and the Gastrointestinal Symptom Rating Scale (GSRS). A total of 47 patients with rosacea and 39 healthy control subjects were included in the study. The FC levels were statistically significantly higher in rosacea group than in the control group (65.96 ± 58.86 ng/mL vs 31.99 ± 20.12 ng/mL, P = .026, respectively). A statistically significant difference was also observed in GSRS values between the patient and the control groups (30.26 ± 12.48 vs 22.62 ± 7.64, P = .001, respectively). A positive correlation was noted between FC levels and the values of GSRS in the study group (r: 0.354; P = .001) and in the rosacea group (r = 0.392, P = .006). The measurement of FC may be useful in the early detection of gastrointestinal system diseases that may accompany rosacea and may provide a pathway to develop treatment strategies targeting both skin and intestinal mucosa.


Bidirectional Encoder Representations from Transformers-like large language models in patient safety and pharmacovigilance: A comprehensive assessment of causal inference implications.
Causality assessment is vital in patient safety and pharmacovigilance (PSPV) for safety signal detection, adverse reaction management, and regulatory submission. Large language models (LLMs), especially those designed with transformer architecture, are revolutionizing various fields, including PSPV. While attempts to utilize Bidirectional Encoder Representations from Transformers (BERT)-like LLMs for causal inference in PSPV are underway, a detailed evaluation of "fit-for-purpose" BERT-like model selection to enhance causal inference performance within PSPV applications remains absent. This study conducts an in-depth exploration of BERT-like LLMs, including generic pre-trained BERT LLMs, domain-specific pre-trained LLMs, and domain-specific pre-trained LLMs with safety knowledge-specific fine-tuning, for causal inference in PSPV. Our investigation centers around (1) the influence of data complexity and model architecture, (2) the correlation between the BERT size and its impact, and (3) the role of domain-specific training and fine-tuning on three publicly accessible PSPV data sets. The findings suggest that (1) BERT-like LLMs deliver consistent predictive power across varied data complexity levels, (2) the predictive performance and causal inference results do not directly correspond to the BERT-like model size, and (3) domain-specific pre-trained LLMs, with or without safety knowledge-specific fine-tuning, surpass generic pre-trained BERT models in causal inference. The findings are valuable to guide the future application of LLMs in a broad range of application.


Adverse effects of cystoscopy and its impact on patients' quality of life and sexual performance.
Cystoscopy, the principal means of diagnosis and surveillance of bladder tumors, is invasive and associated with unpleasant side effects. To determine the early complications of rigid cystoscopy and the impact on patients' quality of life and sexual performance. One hundred consecutive patients undergoing diagnostic rigid cystoscopy filled in questionnaires that included anxiety and pain levels (0-5 visual analogue scale), adverse events, Short-Form Health Survey, International Prostate Symptom Score, and functional sexual performance. Questionnaires were administered before, immediately after, and 1, 2 days, 2 and 4 weeks following cystoscopy. The pre-cystoscopy anxiety level was 2.01. The average pain during the examination was 1.41. SF-36 score was not affected by cystoscopy. The subjective impact on patients' quality of life was 0.51. The mean IPSS increased following cystoscopy (6.75 vs. 5.43, P = 0.001) and returned to baseline 2 weeks later. A decline in libido was reported by 55.6% (25/45) and 50% (3/6) of the sexually active men and women, respectively. Cystoscopy was associated with a decreased Erectile Dysfunction Intensity Score, from 15.6 to 9.26 during the first 2 weeks (P = 0.04). The overall complication rate was 15% and included urethrorrhagia and dysuria, None of the patients had fever or urinary retention and none was hospitalized. The complication rate was higher in patients with benign prostatic hyperplasia (24% vs. 9.7%, P = 0.001). Rigid cystoscopy is well tolerated by most patients and has only a minor impact on quality of life. However, cystoscopy transiently impairs sexual performance and libido. The early complications are mild and correlate with a diagnosis of BPH.


A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial).
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy. This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients<30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks. This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis. ISRCTN10065623.


Regulation of lipogenesis. Stimulation of fatty acid synthesis in vivo and in vitro in the liver of the newly hatched chick.
1. A single glucose meal stimulated the incorporation of acetate into fatty acids in liver slices. If the glucose was added in vitro, it had no effect. Fructose and glycerol in vitro markedly stimulated fatty acid synthesis from acetate. Fructose and glycerol probably by-passed a rate-controlling reaction between glucose and triose phosphate. This reaction may have been stimulated by glucose administered in vivo. 2. The stimulation of fatty acid synthesis caused by fructose did not require the synthesis of enzyme, thus indicating that fatty acid-synthesizing enzymes were present in a latent form in the livers from unfed chicks.


Successful endoscopic resection of an unusually enlarged and pedunculated type I gastric carcinoid tumour.
Three distinct gastric carcinoid (GC) tumour types have been described based on differing biological behaviour and prognoses. Type I GC tumours account for the vast majority (70%-80%), are associated with chronic atrophic gastritis and have a low metastatic potential. Type II carcinoid tumours are the least common (5%-10%), are related to Zollinger-Ellison syndrome and occur in relation to multiple neoplasia type I. Sporadic type III tumours (15%-25%) are the most aggressive type, are unrelated to gastrin over secretion and carry the worst prognosis. In this case report, we present a patient with longstanding gastroesophageal reflux disease (GERD) who presented with epigastric abdominal pain and tarry stools and was found to have a large gastric polyp on endoscopy. Despite current literature recommending surgical resection for larger GC tumours, endoscopic resection was successfully used to excise the tumour with pathology demonstrating complete resection with negative margins.


Long-term results after standard endovascular aneurysm repair with the Endurant and Excluder stent grafts.
Many endografts are currently available for standard endovascular repair of infrarenal abdominal aortic aneurysms. Comparison of long-term outcomes between devices might aid in this decision process, but comparative data are scarce. The purpose of this study was to report long-term clinical outcomes of two commercially available endoprosthesis, the Endurant (Medtronic Vascular, Inc, Minneapolis, Minn) and the Excluder (W. L. Gore & Associates, Flagstaff, Ariz) stent grafts. Patients undergoing standard endovascular repair from July 2004 to December 2011 in a single institution with the Endurant or the Low-Porosity Excluder endografts were eligible. Only patients treated for intact degenerative abdominal infrarenal aneurysms were included. All measurements were performed on center-lumen line reconstructions obtained on dedicated software. The primary end point was primary clinical success, defined as clinical success without the need for an additional or secondary surgical or endovascular procedure. Neck-related events (a composite of type IA endoleak, neck-related secondary intervention, or migration of >5 mm), neck morphology changes, renal function, and overall survival were secondary end points. The study included 277 patients (156 Endurants; 121 Excluders). The median follow-up was 5.8 years (range, 0.1-12.4 years) and did not differ between groups (P = .18). Patients treated with the Endurant stent graft had wider (neck diameter of >28 mm, 27.3% vs 1.7% [P < .001]; neck diameter of 27 mm, [interquartile range (IQR), 24-29 mm] for Endurant and 24 mm [IQR, 22-25 mm] for Excluder; P < .001) and more angulated necks (β-angle of >60°, 26.7% vs 12.5%; P = .004). Oversizing was greater in the Endurant group (16% [IQR, 12%-22%] vs 13% [IQR, 8%-17%], respectively; P < .001). Patients were treated outside device instructions for use regarding proximal neck: 16.7% in the Endurant and 17.3% in the Excluder group (P = .720). The 7-year primary clinical success was 54.7% for the Endurant and 58.1% for the Excluder groups (P = .53). Freedom from neck-related events at 7 years was 76.7% for the Endurant and 78.8% for Excluder group (P = .94). The Endurant stent graft (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.3-5.8; P = .009) was an independent predictor of significant renal function decline. Neck dilatation was greater in Endurant-implanted patients (13% [95% CI, 2%-22%] vs 4% [95% CI, 0%-10%]; P < .001). Overall survival at 7 years was 61.4% in the Endurant and 50.3% (n = 50; standard error, 0.047) in the Excluder group (P = .39). This study reveals that durable and sustainable results can be obtained with either of these late generation devices. This finding suggests that careful planning and a tailored device selection taking into account the patient's anatomy are more relevant determinants than the graft model itself to obtain clinical success. The Endurant endoprosthesis seems to be associated with a higher rate of neck dilatation and faster decrease in the estimated glomerular filtration rate, but further studies with longer follow-up are necessary to determine the clinical relevance of these findings.


The Aegean Sea oil spill on the Galician Coast (NW Spain). III:The assessment of long-term sublethal effects on mussels.
Several biomarkers of exposure to organic pollutants, namely the cytochrome P450 system, glutathione S-transferases, superoxide dismutase, DT-diaphorase and lipid peroxidation, were measured on mussels collected in five locations along the Galician Coast (NW Spain), 6, 9 and 12 months after the Aegean Sea oil spill. Among the studied biomarkers, a significant induction of the cytochrome P450 content and lipid peroxidation, determined as tissue concentration of malondialdehyde equivalents, was detected in mussels collected near the wreck point 6 months after the spillage. Thereafter, no significant differences between reference and polluted sites were detected. Nevertheless, the data suggest the existence of oxidative stress in mussel populations during the September-December samplings. A significant elevation of superoxide dismutase activity was detected in September-9 months after the accident-and this elevation was particularly evident in those stations located closest to the wreck point. Lipid peroxidation increased throughout the year and despite the existence of a strong seasonal effect, the whole data set was correlated with total PAH body burden (R= 0.56).


An intranasal lentiviral booster reinforces the waning mRNA vaccine-induced SARS-CoV-2 immunity that it targets to lung mucosa.
As the coronavirus disease 2019 (COVID-19) pandemic continues and new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern emerge, the adaptive immunity initially induced by the first-generation COVID-19 vaccines starts waning and needs to be strengthened and broadened in specificity. Vaccination by the nasal route induces mucosal, humoral, and cellular immunity at the entry point of SARS-CoV-2 into the host organism and has been shown to be the most effective for reducing viral transmission. The lentiviral vaccination vector (LV) is particularly suitable for this route of immunization owing to its non-cytopathic, non-replicative, and scarcely inflammatory properties. Here, to set up an optimized cross-protective intranasal booster against COVID-19, we generated an LV encoding stabilized spike of SARS-CoV-2 Beta variant (LV::SBeta-2P). mRNA vaccine-primed and -boosted mice, with waning primary humoral immunity at 4 months after vaccination, were boosted intranasally with LV::SBeta-2P. A strong boost effect was detected on cross-sero-neutralizing activity and systemic T cell immunity. In addition, mucosal anti-spike IgG and IgA, lung-resident B cells, and effector memory and resident T cells were efficiently induced, correlating with complete pulmonary protection against the SARS-CoV-2 Delta variant, demonstrating the suitability of the LV::SBeta-2P vaccine candidate as an intranasal booster against COVID-19. LV::SBeta-2P vaccination was also fully protective against Omicron infection of the lungs and central nervous system, in the highly susceptible B6.K18-hACE2IP-THV transgenic mice.


What is the nutritional status of children of obese mothers in South Africa?
To evaluate the anthropometric status of children of obese (body mass index [BMI] ≥30 kg/m2) mothers who participated during the 2005 National Food Consumption Study. The survey population consisted of children 1-9 y of age and their mothers 16 to 35 y of age living in the same households (n = 1532). A national sample of households was drawn, representative of all nine provinces and urban and rural areas. Trained fieldworkers measured the heights and weights of participants at their homes. The prevalence of obesity was high in the mothers (27.9%), particularly in the 26- to 35-y-old (older) group (32.3%) and in urban areas (29.1%). Children of older mothers had a significantly (P < 0.05) higher mean height-for-age Z-score (-0.91) than those of younger mothers (16 to 25 y old, -1.06). Mean weight-for-age and weight-for-height Z-scores were significantly higher in children of obese women compared with those of non-obese women (BMI <30 kg/m2, P < 0.001). Furthermore, obese mothers had significantly more overweight children than non-obese mothers (P < 0.0001). Eighty-four percent of overweight children also had mothers with a BMI ≥25 kg/m2 and 52% had mothers with a BMI ≥30 kg/m2(∗ indicates statistical significance of confidence interval). Stunted mothers had a 1.5 times higher risk of being overweight (BMI ≥25 kg/m2, odds ratio 1.45, confidence interval 1.06-2.01). Overall, children of obese mothers had significantly higher mean Z-scores than those of mothers who were non-obese. Overweight and obese women were significantly less likely to have stunted or underweight children, whereas underweight women and stunted women were significantly more likely to have underweight and stunted children, respectively.


Utility of MRI in diagnosis and treatment of acute focal bacterial nephritis with abscess formation in a paediatric patient.
Contrast-enhanced CT is the gold standard for the diagnosis of acute focal bacterial nephritis (AFBN). However, owing to radiation exposure and the possibility of contrast agent-induced side effects, contrast-enhanced CT is not always recommended for children. A paediatric patient presenting with a 1-week history of fever was admitted to our hospital. After a urine culture detected Escherichia coli, antimicrobials were administered; however, the fever had not resolved by the third day of hospitalisation. Renal diffusion-weighted MRI was performed and showed multiple wedge-shaped areas of high signal intensity in the right kidney. Additionally, the same site showed an area of low signal intensity in the apparent diffusion coefficient, and a diagnosis of AFBN with abscess was made. A chronic-phase technetium-99m-labelled dimercaptosuccinic acid renal scintigraphy was performed, but there was no renal scarring. MRI may be a more suitable tool for diagnosing AFBN given no radiation exposure.


Characterization of the pace-maker current kinetics in calf Purkinje fibres.
Kinetics of the cardiac pace-maker current (if) were studied using high K+, low Na+ solutions under conditions where the current time course could be dissected from other components. Activation of if during relatively large negative pulses is S-shaped, and is approximated by an exponential function of time to the third power. Less-pronounced S-shaped activation occurs at potentials close to the middle of the activation curve (near -70/-80 mV). Here, allowing for the presence of a very slow component, the power required to fit the current activation approaches 1. The comparison between current activation and deactivation at the same potentials shows that although deactivation can be approximated by a single exponential, the two processes have a quite different time dependence, and this difference depends on the membrane potential. This behaviour is not compatible with Hodgkin-Huxley kinetics. While near the half-activation range the current decays with an apparently single exponential time course, at more positive potentials the current deactivation becomes sigmoidal. At least the third power of an exponential is required to fit its time course at potentials positive to about -40 mV. These data imply that both open and closed states correspond to several distinct channel configurations. The 'delay' in the current onset during a hyperpolarization is decreased by applying large, short hyperpolarizations before activation. Suitable pre-pulse durations and/or amplitudes can reduce the subsequent current activation to a single exponential. Records with and without a pre-pulse do not always superimpose. After the activation 'delay' has been removed by a suitable hyperpolarization preceding an activating pulse, the time course of its recovery can be studied by applying depolarizations of given amplitude and variable duration. The time course of the delay recovery does not seem to be linked to the time course of current deactivation recorded at the same voltage. Reduction of the activation 'delay' by conditioning pre-hyperpolarizations does not affect current decay during a subsequent depolarizing pulse. The current decay appears to depend only on the current amplitude reached before a deactivating pulse is applied. This, and the evidence in the preceding paragraph, suggest that the delay recovery and the current deactivation are independent processes. A reaction scheme is proposed, which has been developed on the basis of the experimentally determined kinetic properties of if. The channel model is composed of five gating subunits of three different types, not all independent in their movements.(ABSTRACT TRUNCATED AT 400 WORDS)


A comparative study of pomegranate Sb@C yolk-shell microspheres as Li and Na-ion battery anodes.
Alloy-based nanostructure anodes have the privilege of alleviating the challenges of large volume expansion and improving the cycling stability and rate performance for high energy lithium- and sodium-ion batteries (LIBs and SIBs). Yet, they face the dilemma of worsening the parasitic reactions at the electrode-electrolyte interface and low packing density for the fabrication of practical electrodes. Here, pomegranate Sb@C yolk-shell microspheres were developed as a high-performance anode for LIBs and SIBs with controlled interfacial properties and enhanced packing density. Although the same yolk-shell nanostructure (primary particle size, porosity) and three-dimensional architecture alleviated the volume change induced stress and swelling in both batteries, the SIBs show 99% capacity retention over 200 cycles, much better than the 78% capacity retention of the LIBs. The comparative electrochemical study and X-ray photoelectron spectroscopy characterization revealed that the different SEIs, besides the distinct phase transition mechanism, played a critical role in the divergent cycling performance.


The pneumococcal cell envelope stress-sensing system LiaFSR is activated by murein hydrolases and lipid II-interacting antibiotics.
In the Firmicutes, two-component regulatory systems of the LiaSR type sense and orchestrate the response to various agents that perturb cell envelope functions, in particular lipid II cycle inhibitors. In the current study, we found that the corresponding system in Streptococcus pneumoniae displays similar properties but, in addition, responds to cell envelope stress elicited by murein hydrolases. During competence for genetic transformation, pneumococci attack and lyse noncompetent siblings present in the same environment. This phenomenon, termed fratricide, increases the efficiency of horizontal gene transfer in vitro and is believed to stimulate gene exchange also under natural conditions. Lysis of noncompetent target cells is mediated by the putative murein hydrolase CbpD, the key effector of the fratricide mechanism, and the autolysins LytA and LytC. To avoid succumbing to their own lysins, competent attacker cells must possess a protective mechanism rendering them immune. The most important component of this mechanism is ComM, an integral membrane protein of unknown function that is expressed only in competent cells. Here, we show that a second layer of self-protection is provided by the pneumococcal LiaFSR system, which senses the damage inflicted to the cell wall by CbpD, LytA, and LytC. Two members of the LiaFSR regulon, spr0810 and PcpC (spr0351), were shown to contribute to the LiaFSR-coordinated protection against fratricide-induced self-lysis.


Ultrasound versus microwave as green processes for extraction of rosmarinic, carnosic and ursolic acids from rosemary.
Ultrasound and microwave as green processes are investigated in this study, focusing on the extraction selectivity towards antioxidant extraction from rosemary leaves. Due to its richness in valuable compounds such as rosmarinic, carnosic and ursolic acids, rosemary is a reference matrix for extraction study. In this work, six alternative processes are compared: ultrasound (bath, reactor and probe), microwave (reflux under microwave, microwave under nitrogen pressure and microwave under vapor pressure). The main result of this study is that selective extraction can be achieved according to extraction techniques and therefore to the extraction process.


Acute toxicity of pesticides to the tropical freshwater shrimp Caridina laevis.
To determine the potential risk of pesticides frequently used in Indonesia, a new toxicity test was developed using the indigenous freshwater shrimp Caridina laevis, which is representative of tropical ecosystems. The test species could easily be maintained in the laboratory. Acute toxicity tests with different insecticides, fungicides, and herbicides assessing adult survival after 24 and 96 h of static exposure showed low control mortality (<10%) and good reproducibility for diazinon. Juvenile C. laevis appeared approximately two to three times more sensitive to diazinon than adult ones. Compared to other species of freshwater crustacean commonly used in standard aquatic toxicity tests, C. laevis showed similar sensitivity for diazinon and lambda cyhalothrin, much greater sensitivity for endosulfan and paraquat and much lower sensitivity for carbofuran. It may be concluded that the acute toxicity test using C. laevis may be a suitable alternative for determining the potential risk of chemicals under tropical conditions.


Treatment of Nonreplantable Total Thumb Amputation at the CMC Level Using Index Finger Pollicization.
Pollicization of the index finger is a rarely performed reconstructive option for patients with total thumb amputations with nonsalvageable carpometacarpal (CMC) joint and thenar muscles. Successful pollicization can provide basic grasp and pinch to help patients carry out activities of daily living. We present a retrospective review of 4 patients who underwent index finger pollicization for traumatic total thumb amputations. A retrospective review of 4 cases of pollicization using an injured index finger for traumatic thumb amputation was performed. Patients available for follow-up were contacted for functional assessment. Outcomes including range of motion (ROM), grip strength, key pinch, 2-point discrimination, and Disabilities of the Arm, Shoulder, and Hand score were obtained. Functional thenar muscle and the CMC joint were absent in all cases. Injury mechanism was firework in 2 patients and crush in 2 patients. The time from injury to pollicization ranged from 8 days to 17 months. Follow-up time ranged from 10 weeks to 3 years. Three patients regularly used the pollicized thumb in activities of daily living such as writing. Tip pinch and lateral pinch along with grip strength were weak in all cases; the best recorded pinch strength was 24% and grip strength was 25% compared with the contralateral hand. The ROM of the pollicized thumb was limited. Index finger pollicization following total thumb amputation can be a viable last-resort option for patients. The pollicized digit acts as a sensate post and avoids further morbidity from the traumatized extremity.


The role of angiotensin converting enzyme genotype in coronary artery ectasia.
Coronary artery ectasia (CAE) is characterised by irregular, diffuse, saccular, or fusiform dilatation of the coronary arteries. Although the underlying mechanisms are not fully understood, CAE is considered to be an original form of vascular remodelling in response to atherosclerosis. However, it is not clear why some patients develop CAE while most do not. Experimental data suggest that activation of the renin angiotensin system may lead to an increased inflammatory response in the vessel wall or to an activation of matrix metalloproteinases. In addition, an insertion/deletion (ID) polymorphism of angiotensin converting enzyme (ACE) has been associated with coronary vascular tone and the development of aneurysms. Accordingly, we hypothesised that the gene polymorphism of ACE may be a potential factor influencing the genesis of CAE. We retrospectively evaluated 112 patients who underwent coronary angiography. ACE ID genotype was determined in two groups of patients. Group 1 consisted of 56 patients who were found to have CAE. Group 2 consisted of 56 patients with significant coronary artery disease (CAD) (> 50% stenosis in any of the major epicardial coronary arteries or their branches) but without any evidence of coronary ectasia. Polymerase Chain Reaction (PCR) was used to detect ACE genotype. The ratio of DD genotype was found to be greater in group 1 than group in 2 (39% versus 18%, respectively, P < 0.05). When assessed according to the presence of the I allele, it was greater was greater in group 2 than in group 1 (82.1% versus 60.7%, respectively, P < 0.05). The results indicate that an ACE DD genotype may be a risk factor for CAE.


Development of one-step isothermal methods to detect RNAs using hairpin-loop signal converters and proximity proteolysis reaction.
Ribonucleic acids (RNAs) provide valuable information for biological systems and act as important indicators of disease states. RNAs are diverse in size and structure, and various strategies have been proposed for the detection of nucleic acids; however, developing them into point-of-care (POC) tests has been challenging as most of them consist of complex time-consuming steps. Here, we propose a strategy to assay RNAs using a hairpin-loop (HP) converter and proximity proteolysis reaction (PPR). Interaction between the loop part of HP and its target exposes a single strand of nucleotides, which acts as the template for PPR. A pair of protease and zymogen-conjugated nucleic acids associates with the adjacent regions of the template, resulting in an enhanced proteolysis reaction between protease and zymogen. The activated zymogen then generates a color signal through the hydrolysis of a chromogenic substrate. The combination of HP converter and PPR allowed the same pair of protease- and zymogen-nucleic acids to be used for different RNAs. Guidelines were provided for designing HP converters based on computational analyses and experimental characterizations. This strategy using an HP converter and PPR has been successfully applied to develop simple isothermal methods for the detection of various RNAs, including several microRNAs and KRAS mRNA, in the picomolar range in 1 h. The simplicity of designing HP converters and the beneficial properties of PPR as POC tests would enable the development of novel methods to detect RNAs under low-resource conditions.


Injection of air bubbles during flushing of angiocatheters: an in vitro trial of conventional hardware and techniques.
Injected air bubbles are a well-accepted cause of stroke during cerebral angiography. We used an in vitro model to determine the frequency of occurrence of air emboli during catheter flushing using conventional hardware and techniques. Two experimental models were used in this study. The first incorporated an in-line bubble trap. Ten members of our angiography section flushed this system in their usual fashion and then with two modifications of the hardware. The trap was inspected after each trial of seven injections and any visible bubble was measured with calipers. The second model used a peristaltic pump along with a transcranial Doppler device to look at the relative number of bubble events with modifications of the flush solution or technique. The closed-flush set in common usage in our department caused an increase in the number of visible bubbles in the trap as compared with an open basin. Degassing the solution and delaying injection decreased the number of bubble events noted in model 2. Bubble emboli are commonplace during flushing of angiography catheters when using conventional techniques and equipment.


A comparison of symptoms experienced following minor head injury and acute neck strain (whiplash injury).
The symptoms reported by patients who have experienced minor head or minor neck injury are compared. Symptoms were identified using a questionnaire-based out-patients interview. Rank order correlation analyses were carried out on data obtained at 2 and 6-12 weeks post-injury. Data on 24 head-injured and 29 neck-injured patients are presented. There was a significant rank order correlation at both assessments but neck injured patients reported more phobia (fear of travelling in car) and depression, and head-injured more dizziness. It is likely that neck-injury contributes to the symptomatology experienced after minor head injury, and vice-versa.


Timing of surgery in Crohn's disease: a key issue in the management.
The timing of the decision for operation in Crohn's disease is based on an evaluation of the several factors such as the failure of medical treatment, complications due to the Crohn's disease or to the pharmacological therapy, development of dysplasia or cancer and growth retardation. A complete evaluation of these factors should result in operation timed to the patient's best advantage, achieving maximal relief of symptoms with improvement of quality of life. Given the complexity and heterogeneity of the disease and the different options for treatment, is difficult to systematize when the optimal moment for the surgery is arrived. A very important factor in the management of Crohn's disease is the multidisciplinary approach and the patient preference should be a significant factor in determining the choice of therapy. The surgery should be considered such another option in the sequential treatment of Crohn's disease. We have analyzed the factors that are involved in the decision taking of the surgical treatment regarding to the experience and the published literature. When did the medical therapy fail? when is the appropriate moment to operate on the patient? Or which complications of Crohn's disease need surgery? These are some of the questions we will try to answer.


Pharmacokinetics of propofol in children.
The pharmacokinetics of propofol were studied in 12 healthy Chinese children, aged 4-12 yr, undergoing circumcision under inhalation anaesthesia. All patients received a single i.v. bolus dose of propofol 2.5 mg kg-1 and blood concentrations of propofol over the subsequent 24 h were measured using high pressure liquid chromatography with fluorimetric detection. Data were consistent with a three-compartment model with a mean (SEM) elimination half-life of 209 (29) min and total body clearance of 40.4 (3.6) ml min-1 kg-1. The mean (SEM) apparent volume of distribution at steady state was 5.0 (2.7) litre kg-1 and volume of the central compartment was 0.6 (0.1) litre kg-1. The mean (SEM) ratio of k12:k21 was 1.4 (0.2), suggesting that, after injection of a single bolus dose in children, propofol is distributed rapidly to the shallow compartment. The mean ratio of k31:k10 suggests that lipophilicity constrains return of the drug to the central compartment.


The stability and equivalence reliability of the functional independence measure for children (WeeFIM).
The reliability of the Functional Independence Measure for Children (WeeFIM) was examined in 37 non-disabled children and 30 children with disabilities, from 12 to 76 months of age. The WeeFIM is derived from the Functional Independence Measure (FIM) and includes 18 items involving six functional subscales. Stability was assessed by administering the WeeFIM instrument to each child's caregiver on two occasions separated by 7 to 14 days. Intraclass correlation co-efficients (ICCs) for individual items ranged from 0.90 to 0.99. The ICC for the six WeeFIM subscales ranged from 0.94 for social cognition to 0.99 for transfers and locomotion. The ICC value for total WeeFIM test-retest reliability was 0.98 for children with disabilities and 0.99 for children without disabilities. Equivalence reliability was examined by comparing ratings obtained when using personal assessment with ratings collected during a telephone interview. No statistically significant differences were found for individual items, subscale scores or total WeeFIM values.


The HEDGEHOG-GLI1 pathway is important for fibroproliferative properties in keloids and as a candidate therapeutic target.
Keloids are benign fibroproliferative skin tumors caused by aberrant wound healing that can negatively impact patient quality of life. The lack of animal models has limited research on pathogenesis or developing effective treatments, and the etiology of keloids remains unknown. Here, we found that the characteristics of stem-like cells from keloid lesions and the surrounding dermis differ from those of normal skin. Furthermore, the HEDGEHOG (HH) signal and its downstream transcription factor GLI1 were upregulated in keloid patient-derived stem-like cells. Inhibition of the HH-GLI1 pathway reduced the expression of genes involved in keloids and fibrosis-inducing cytokines, including osteopontin. Moreover, the HH signal inhibitor vismodegib reduced keloid reconstituted tumor size and keloid-related gene expression in nude mice and the collagen bundle and expression of cytokines characteristic for keloids in ex vivo culture of keloid tissues. These results implicate the HH-GLI1 pathway in keloid pathogenesis and suggest therapeutic targets of keloids.


Purification and Structural Characterization of Sulfated Polysaccharide from Sargassum myriocystum and its Efficacy in Scavenging Free Radicals.
Sulfated polysaccharides from marine algae are one of the commercially beneficial compounds with a range of pharmaceutical and biomedical applications. They are testified to be effective against free radicals and related health complications. This study aims to determine the antioxidant potential of the sulfated polysaccharide from Sargassum myriocystum, followed by its purification and structural characterization. Amount of extract obtained was 5% from 10 g of plant material. The carbohydrate and sulfate content were found to be 31 and 0.34 mg/10 g of plant material, respectively. Total sulfated polysaccharide extract showed a good radical scavenging activity at lower concentrations. The active principle from the total sulfated polysaccharide was fractionated in anion exchange and gel filtration columns followed by structural characterization using Fourier transform infrared and nuclear magnetic resonance spectroscopy. Fraction 12 closely matched with the Fourier transform infrared and nuclear magnetic resonance spectra of fucoidan. Based on the results obtained, we conclude that sulfated polysaccharide from Sargassum myriocystum is identified as Fucoidan with potential radical scavenging activity compared to butylated hydroxyl toluene.


Interaction of right and left carotid sinus baroreflexes in the dog.
Carotid sinus reflex interactions were studied in 10 dogs anesthetized with pentobarbital sodium. The right and left carotid sinus regions were isolated and perfused at controlled pressures. Pressure in the right and left carotid sinuses were independently varied, and the resulting steady-state reflex changes in arterial pressure, heart rate, respiratory frequency, tidal volume, and total ventilation were measured. Reflex changes when carotid sinus pressure was changed on one side were strongly influenced by pressure in the contralateral carotid sinus (P less than 0.05). Right carotid sinus gain was found to be 0.628 +/- 0.058 at a left carotid sinus pressure of 50 mmHg and 0.148 +/- 0.027 when left carotid sinus pressure was 200 mmHg. Similar results were found for left carotid sinus gain. Suppression was also found for heart rate, respiratory rate, tidal volume, and total ventilation. The hypothesis that rapid resetting of one carotid sinus baroreflex might influence responses from the other side was also tested. Although ipsilateral resetting was consistently observed, no contralateral component of the resetting was detected. An additional inhibitory summation between the right and left carotid sinuses was found such that simultaneous excitation of both receptors resulted in a smaller reflex response than did the sum of individual responses. Sympathetic denervation of the carotid sinus region had no effect.


Separating the environmental and genetic factors that may be causes of bovine spongiform encephalopathy.
The initial cause of the bovine spongiform encephalopathy (BSE) epidemic is generally accepted to have been the feeding of infected animal protein to cattle. The proportion of animals affected in any year in a particular herd has generally been low. This suggests either considerable variation in the extent of challenge of the individual animals or variation in their susceptibility to challenge or both. There is known to be genetic variation in susceptibility in other spongiform encephalopathies, such as scrapie in sheep. However, earlier indications that there may be associations between the incidence of BSE in cattle and polymorphisms and mutations in the PrP gene have not been confirmed (Hunter et al. 1994). Here, we attempt to model the likely extent of challenge of the individual animals in five Holstein Friesian pedigree herds and also the distribution of incubation times to the date of clinical onset. By studying the incidence of the disease in related animals we first found that single locus genetic models fitted the data much better than a non-genetic model. This was the first statistical evidence found of genetic variation in susceptibility to BSE. A check on the model in which individual animals were randomly allocated to 'parents' showed that the result was due to the lack of allowance in the non-genetic model for those animals insufficiently challenged or, for non-genetic reasons, resistant to their level of challenge. Thus there is still no evidence, molecular or statistical, for genetic variation in susceptibility. The importance of checking the attribution of genetic effects in complex models by the random allocation of progeny to parents is clear.


siRNA-mediated downregulation of MMP-9 and uPAR in combination with radiation induces G2/M cell-cycle arrest in Medulloblastoma.
Our previous work and that of other investigators strongly suggest a relationship between the upregulation of metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator receptor (uPAR) in tumor angiogenesis and metastasis. In this study, we evaluated the role of MMP-9 and uPAR in medulloblastoma cancer cell resistance to ionizing irradiation (IR) and tested the antitumor efficacy of siRNA (short interfering RNA) against MMP-9 [plasmid siRNA vector for MMP-9 (pM)] and uPAR [plasmid vector for uPAR (pU)] either alone or in combination [plasmid siRNA vector for both uPAR and MMP-9 (pUM)]. Cell proliferation (BrdU assay), apoptosis (in situ TUNEL for DNA fragmentation), and cell-cycle (FACS) analyses were carried out to determine the effect of siRNA either alone or in combination with IR on G2/M cell-cycle arrest in medulloblastoma cells. IR upregulated MMP-9 and uPAR expression in medulloblastoma cells; pM, pU, and pUM in combination with IR effectively reduced both MMP-9 and uPAR expression, thereby leading to increased radiosensitivity of medulloblastoma cells. siRNA treatments (pM, pU, and pUM) also promoted IR-induced apoptosis and enhanced IR-induced G2/M arrest during cell-cycle progression. While IR induces G2/M cell-cycle arrest through inhibition of the pCdc2- and cyclin B-regulated signaling pathways involving p53, p21/WAF1, and Chk2 gene expression, siRNA (pM, pU, and pUM) alone or in combination with IR induced G2/M arrest mediated through inhibition of the pCdc2- and cyclin B1-regulated signaling pathways involving Chk1 and Cdc25A gene expression. Taken together, our data suggest that downregulation of MMP-9 and uPAR induces Chk1-mediated G2/M cell-cycle arrest, whereas the disruption caused by IR alone is dependent on p53- and Chk2-mediated G2/M cell-cycle arrest.


Falls incidence, risk factors, and consequences in Chinese older people: a systematic review.
Falls incidence in Chinese older people has been reported to be approximately half that of Caucasian populations. It is possible that the falls risk factor profile may differ significantly between Caucasian and Chinese populations, and a better understanding of this reported difference in incidence and associated risk factors may influence potential approaches to future intervention. A systematic literature review was conducted using the EMBase, Medline, Chinese Electronic Periodical Services, and WanFangdata databases to collate and evaluate the studies that have addressed the incidence and risk factors for falls in Chinese older people. Twenty-one studies conducted in China, Hong Kong, Macao, Singapore, and Taiwan met the inclusion criteria. Fall rates ranged between 14.7% and 34% per annum (median 18%). In the four prospective studies, injuries were reported by 60% to 75% of those reporting falls, with fractures constituting 6% to 8% of all injuries. One hundred thirty-two variables were identified as fall risk factors, with commonly reported factors being female sex, older age, use of multiple medications, gait instability, fear of falling, and decline in activities of daily living. The findings reveal a consistently lower incidence of self-reported falls in Chinese older people than in Caucasian older people, although the types and prevalence of risk factors were not dissimilar from those found in studies of Caucasian older people. A greater understanding of the health, behavioral, and lifestyle factors that influence fall rates in Chinese populations is required for elucidating fall prevention strategies in Chinese and non-Chinese older people.


A prenatally recognizable malformation syndrome associated with a recurrent post-zygotic chromosome rearrangement der(Y)t(Y;1)(q12:q21).
Several cases of mos 46,X,der(Y)t(Y;1)(q12;q21)/46,XY with multiple anomalies have been reported. I report on an additional case of a male fetus with a mosaic male karyotype mos 46,X,der(Y)t(Y;1)(q12;q21)[31]/46,XY[21] and multiple anomalies that included "teardrop"-shaped head with a triangular face, a short-nasal bridge with upturned nose, microretrognathia, microtia, kyphoscoliosis, oligodactyly, syndactyly, joint contractures, CNS malformation, omphalocele, diaphragmatic hernia, cardiac anomaly, and urogenital malformation. The findings together suggest a recurrent and recognizable syndrome and argue for using tissues such as skin or cartilage or amniotic fluid, instead of cord blood, for postmortem karyotyping in order to avoid missing mosaicism as a potential cause of multiple congenital anomalies.


Hyperparasites influence population structure of the chestnut blight pathogen, Cryphonectria parasitica.
Vegetative compatibility (VC) is commonly used to characterize structure and diversity in fungal populations. In the chestnut blight fungus, Cryphonectria parasitica, high VC diversity is hypothesized to be responsible for the failure of hyperparasitic mycoviruses to spread through pathogen populations in North America. To test this hypothesis, we assessed VC diversity at three recovering sites in Michigan where mycoviruses had invaded and compared them with four epidemic population sites where mycoviruses were absent. VC diversity was assessed for samples collected in 1996 and 2009, which allowed us to determine how C. parasitica populations changed with time. Twelve VC types were found in 1996 while 29 were found in 2009; 75% of types overlapped between the sample dates. Sites where mycoviruses were present had unique VC structures with the exception of the recovering population site at County Line where the main VC group was also detected at two epidemic sites. With one exception, epidemic sites contained more VC groups and displayed higher population level diversity than recovering sites. Mating-type analyses of blight populations revealed that two of three recovering populations were significantly skewed for MAT2 suggesting asexual reproduction, while epidemic sites with a long history of blight infection had ratios near 50:50 suggesting sexual reproduction. We propose that selection in the largely asexual C. parasitica populations at two recovering sites favors the most-fit fungal genotype by mycovirus combination and results in reduced diversity relative to the sexually reproducing pathogen populations at epidemic sites.


[Effect of memantine on membrane properties and postsynaptic potentials in neurons of Aplysia californica].
The effect of 1,3-dimethyl-5-aminoadamantane (DMAA, D-145, memantine, Memantine) in the concentration range of 10(-6) to 10(-3) mol/l was investigated on membrane properties and synaptic transmission by the current or voltage clamp method on neurons in the visceral ganglion of Aplysia california. In the lower range (concentrations 10(-6) to 10(-5) mol/l) the substance increases the speed of voltage changes during the course of the action potential, increases spontaneous synaptic activity, and induces a slight membrane depolarization. With increasing concentration the effects reverse in that slope of action potential is slowed and synaptic transmission delayed or blocked. At the RC-R15 synapse, isolated from its interneuron, 10(-5) mol/l DMAA evokes spontaneously and regularly firing EPSPs; 10(-3) mol/l blocks both, spontaneous activity, and its responsiveness to electrical stimulation.


Pseudomonas aeruginosa in adults with chronic obstructive pulmonary disease.
Pseudomonas aeruginosa is isolated in sputum cultures from adults with chronic obstructive pulmonary disease (COPD) but the significance of the organism in this clinical setting is not well known. The purpose of this review is to critically review the literature in an effort to understand the role of P. aeruginosa in the course and pathogenesis of COPD. When examined longitudinally, two distinct patterns of carriage of P. aeruginosa are observed in adults with COPD: short-term colonization followed by clearance and long-term persistence. Acquisition of P. aeruginosa is associated with the occurrence of an exacerbation, indicating that the organism causes exacerbations. Exacerbations caused by P. aeruginosa are more likely to be seen in patients with more advanced COPD, those who have received recent antibiotic therapy and those who require mechanical ventilation for an exacerbation. A subset of adults with COPD becomes chronically colonized with P. aeruginosa, but whether such patients benefit from antimicrobial therapy is not yet known. P. aeruginosa has several different manifestations in the setting of COPD. The organism is a colonizer that is cleared quickly, causes acute exacerbations and also may cause chronic infection in a subset of adults with COPD.


Recurrent Barrett's esophagus and adenocarcinoma after esophagectomy.
Esophagectomy is considered the gold standard for the treatment of high-grade dysplasia in Barrett's esophagus (BE) and for noninvasive adenocarcinoma (ACA) of the distal esophagus. If all of the metaplastic epithelium is removed, the patient is considered "cured". Despite this, BE has been reported in patients who have previously undergone esophagectomy. It is often debated whether this is "new" BE or the result of an esophagectomy that did not include a sufficiently proximal margin. Our aim was to determine if BE recurred in esophagectomy patients where the entire segment of BE had been removed. Records were searched for patients who had undergone esophagectomy for cure at our institution. Records were reviewed for surgical, endoscopic, and histopathologic findings. The patients in whom we have endoscopic follow-up are the subjects of this report. Since 1995, 45 patients have undergone esophagectomy for cure for Barrett's dysplasia or localized ACA. Thirty-six of these 45 patients underwent endoscopy after surgery including 8/45 patients (18%) with recurrent Barrett's metaplasia or neoplasia after curative resection. Recurrent Barrett's esophagus or adenocarcinoma after esophagectomy was common in our patients who underwent at least one endoscopy after surgery. This appears to represent the development of metachronous disease after complete resection of esophageal disease. Half of these patients have required subsequent treatment thus far, either repeat surgery or photodynamic therapy. These results support the use of endoscopic surveillance in patients who have undergone "curative" esophagectomy for Barrett's dysplasia or localized cancer.


Health behaviors of older Chinese adults living in New York City.
The dramatic increase in the number of older immigrants living in the U.S. presents new challenges to policy makers concerned with promoting healthy aging. To date, however, strikingly little is known regarding the health and health trajectories of older immigrants. This paper examines the prevalence and predictors of important health behaviors associated with chronic disease prevention, including current smoking status, physical activity, alcohol use, and body mass index (BMI). We analyzed data from the 2003 New York City Chinese Health Survey (NYC CHS), the largest probability-based sample of Chinese immigrants residing in two distinct communities. In-person interviews were conducted with 517 representative men and women aged 55-75. Logistic regression modeling was used to test the influence of demographic, socioeconomic status, acculturation, and health characteristics on selected health behaviors. Results revealed that having more education and better physical health status were associated with greater participation in physical activity. Gender-specific analyses indicated that the effect of selected predictors varied between the sexes. For example, among older Chinese women, acculturation was negatively associated with alcohol use. This study provides some of the first evidence on health behaviors of one of the fastest growing older immigrant groups in the U.S. Study results add to the emerging literature on the complex nature of immigrant health trajectories, and demonstrate that contrary to prior research, living a greater proportion of time in the U.S. can be associated with selected positive health behaviors. Further longitudinal studies are needed to help inform policy initiatives to encourage healthy aging among diverse older immigrant groups.


Stem cell transplantation and MBL replacement therapy.
Mannose-binding lectin (or mannan-binding lectin, MBL) may have an influence on susceptibility to infection in patients given chemotherapy to induce remission or as conditioning before stem cell transplantation. The most surprising finding reported from an inconsistent literature was the observation that mbl-2 gene mutations in donors could influence the risk of serious infections in recipients of allogeneic stem cell transplants. This could be explained if leukocytes in the stem cell preparations (or their derivatives) were able to synthesize and secrete MBL, but the available evidence seems to exclude that possibility. An alternative mechanism could involve MBL binding to autologous cells and inducing immunological maturation of those cells. MBL can certainly bind to various cell types via surface glycoconjugates and the possible significance of this for MBL replacement therapy will be discussed.


Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer.
Pregnancy-associated plasma protein-A (PAPP-A) and its homolog PAPP-A2 are enzymes that modulate the availability and mitogenic activity of insulin-like growth factor-I (IGF-I). PAPP-A has been implicated in numerous cancers but reports on PAPP-A2 in malignancy are non-existent. In a prospective observational study of 689 patients under suspicion of lung cancer, we examined levels of PAPP-A and PAPP-A2 and their relationship with mortality. Serum PAPP-A and PAPP-A2 concentrations were determined in pre-diagnostic blood samples using ELISA, and immunohistochemical staining of PAPP-A and PAPP-A2 was performed in malignant tissue from five operable patients. A total of 144 patients were diagnosed with lung cancer, whereas the diagnosis was rejected in 545 subjects, who served as a control group. PAPP-A2 concentrations were higher in patients with lung cancer [median (IQR): 0.33 (0.21-0.56) ng/mL] than in controls [0.27 (0.17-0.39) ng/mL], p < 0.001, whereas PAPP-A levels did not differ. Presence of PAPP-A and PAPP-A2 were confirmed in tumor specimens, and staining occurred in a heterogeneous pattern. Patients were observed for a median (range) of 7 (6; 8) years, during which 114 patients (79.2%) died. Patient mortality differed according to PAPP-A2 tertile (p < 0.001). PAPP-A2 was associated with mortality with an unadjusted hazard ratio (95% CI) per doubling in protein concentration of 1.30 (1.12; 1.53), p = 0.001. In a multivariable model adjusted for age, sex, and BMI, PAPP-A2 remained predictive of the endpoint with a hazard ratio per doubling in protein concentration of 1.25 (1.05; 1.48), p = 0.013. Collectively, PAPP-A2, but not PAPP-A, is elevated in patients with lung cancer and associated with mortality. This novel role of PAPP-A2 in cancer warrants further functional studies as well as validation in external cohorts.


A clinically feasible multiplex proteomic immunoassay as a novel functional diagnostic for pancreatic ductal adenocarcinoma.
To date, targeted therapy for pancreatic ductal adenocarcinoma (PDAC) remains largely unsuccessful in the clinic. Current genomics-based technologies are unable to reflect the quantitative, dynamic signaling changes in the tumor, and require larger tumor samples that are difficult to obtain in PDAC patients. Therefore, a highly sensitive functional tool that can reliably and comprehensively inform intra-tumoral signaling events is direly needed to guide treatment decision. We tested the utility of a highly sensitive proteomics-based functional diagnostic platform, Collaborative Enzyme Enhanced Reactive-immunoassay (CEERTM), on fine-needle aspiration (FNA) samples obtained from 102 patients with radiographically-evident pancreatic tumors. Two FNA passes were collected from each patient, hybridized to customized chips coated with an array of capture antibodies, and detected using two enzyme-conjugated antibodies which emit quantifiable signals. We demonstrate that this technique is highly sensitive in detecting total and phosphorylated forms of multiple signaling molecules in FNA specimens, with reasonable correlation of marker intensities between two different FNA passes. Notably, signals of several markers were significantly higher in PDAC compared to non-cancerous samples. In PDAC samples, we found high total c-Met signal to be associated with poor survival, and confirmed this finding using an independent PDAC tissue microarray.


Diabetic and non-diabetic human cornea and tear γ-glutamyl transpeptidase activity.
Diabetes-related eye disease is due in part to oxidative stress. Gamma-glutamyl transpeptidase (GGT) is a γ-glutamyl cycle enzyme that protects against oxidative stress via glutathione recapture. This study investigates corneal and Schirmer tears GGT activity in diabetic and non-diabetic adults aged 50 to 83 years old. GGT activity was determined by colorimetric assay on 50 corneas from 14 diabetic (without keratopathy) and 20 non-diabetic donors and on Schirmer type 1 test strips (no anesthesia) of 14 diabetic and 14 non-diabetic subjects. Type 1 (T1) diabetic cornea GGT activity was 40% lower than Type 2 (T2) diabetic cornea GGT activity (P = 0.04), but GGT activity was similar for corneas (without keratopathy) from diabetic and non-diabetic donors (P ≥ 0.44 for all). The number of endothelial cells/unit of GGT activity in diabetic corneas was 22% higher (P = 0.1) than in non-diabetic corneas. GGT activity per Schirmer strip and GGT activity per mm of tears were 36% and 50% higher (P ≤ 0.008 for all) for non-diabetic (tear volume dependent) than diabetic donors (tear volume independent), respectively. GGT activity per mm was 50% lower in T1 than T2 diabetics (P = 0.02). Higher tear GGT activity in non-diabetic than diabetic females (P ≤ 0.05) was due to higher GGT activity in the African American females. GGT activity was less in T1 than T2 diabetics, but comparable to non-diabetic corneas. Schirmer tear GGT activity in diabetic eyes was tear volume independent, less in T1 than T2, lower than in tear volume dependent, non-diabetic female eyes. Low cornea and tear GGT activity suggests loss of antioxidant potential and supports ocular antioxidant therapy for diabetic patients.


Cerebral blood flow and oxygenation during venoarterial and venovenous extracorporeal membrane oxygenation in the newborn lamb.
Concern exists that extracorporeal membrane oxygenation (ECMO) may decrease cerebral blood flow (CBF), impair cerebral autoregulation, and thereby increase the risk of neurologic injury. This study was undertaken in newborn lambs to compare the effects of initiation of venoarterial and venovenous ECMO on CBF and cerebral oxygen delivery as measured by laser-Doppler flowmetry. This study also evaluates the effects of carotid artery and jugular vein ligation on CBF. CBF, arterial blood pressure, sagittal sinus pressure, heart rate, cardiac output, arterial blood gases, and hemoglobin saturation were measured. After anesthesia, instrumentation, and a 1-2 hr stabilization period, values were recorded during a 30-min control period, and the carotid artery or jugular vein was cannulated. The animals were then studied during venoarterial or venovenous ECMO for 1 hr. Carotid ligation resulted in a transient decrease in right cortex CBF that resolved within 60 secs. Next, during a 60-min period of venoarterial ECMO (flow rate of 100 mL.min(-1).kg(-1), n = 11), cerebral resistance to flow increased, CBF decreased 25%, and cerebral oxygen delivery decreased by 30%. Native cardiac output and Paco(2) remained constant. Pulsatility in the lingual artery, representing the pulsatility of arterial flow to the brain, decreased throughout venoarterial ECMO. In contrast, in those lambs receiving ECMO in the venovenous mode (n = 7), resistance to flow, CBF, cerebral oxygen delivery, and pulsatility did not change. There was no sustained decrease in CBF after ligation of either the carotid artery or jugular vein. Venoarterial but not venovenous ECMO induced decreases of CBF that could not be attributed to changes in blood gases or blood pressure but that may relate to diminished pulsatility in cerebral resistance vessels or to differences in levels of circulating vasoactive compounds.


An analysis of patient complaints in an observation unit.
All complaints relating to patients treated in a 20 bed observation unit of a large teaching hospital over a 26-month period are reviewed. From May 1994 to July 1996, 11,042 patients were admitted to the observation unit. During this period there were 28 patient complaints. These complaints consisted of staff attitude/behavior (42.9%), discharge processes (25%), environmental concerns (17.9%), difficulties with diagnostic investigations (10.7%), and miscellaneous issues (3.6%). The type and frequency of complaints were similar to those received in other areas of the hospital, although the profile of complaints was different to those commonly experienced in the emergency department. Observation units are frequently considered to be an extension of the emergency department. Patient complaints received in relation to care received in an observation unit are similar in nature to those recorded in inpatient units as opposed to those received in emergency departments.


Pheochromocytoma producing multiple vasoactive peptides.
Pheochromocytomas may produce several vasoactive peptides. We studied a 39-year-old man who presented with paroxysmal flushing and abdominal pain with normal blood pressure. Laboratory and radiologic studies established the diagnosis of right adrenal pheochromocytoma, and histologic and ultrastructural examination showed the tumor to be a typical pheochromocytoma. Tissue culture yielded large quantities of norepinephrine and epinephrine. However, immunohistochemical studies, tissue assays, and in vitro cultures documented production of several peptides, including calcitonin gene-related peptide and vasoactive intestinal polypeptide in tumor cells. The patient has been asymptomatic after tumor resection. Production of multiple peptides by this tumor may account for the flushing and lack of hypertension, despite elevated catecholamine levels in this patient.


Fate and effects of Composition B in multispecies marine exposures.
The vast majority of investigations into the bioavailability and toxicity of explosives to receptors in aquatic environments has focused on deriving toxicity metrics for discrete chemical exposures to single species using pure compounds at relatively high concentrations. This study assessed the environmental fate and potential for biological effects of a common military formulation, Composition B, under more realistic exposure scenarios (e.g., those that more closely simulate a breached artillery round or residual exposure following a low-order detonation). We used a novel approach incorporating multiple species and toxicity endpoints in sediment exposures over a 34-d exposure period. Composition B fragments exposed at the sediment surface rapidly released 2,4,6-trinitrotolune (TNT) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) to the overlying water column. In comparison, burial of fragments resulted in dramatically reduced exposure, bioconcentration, and toxicity. The addition of a conservative flow rate to the aquaria also reduced water and tissue concentrations by factors of two to three. Although the exposure system likely represented a worst-case scenario relative to most conditions found in coastal and estuarine environments, overlying water concentrations generally did not approach known toxicity thresholds, while porewater concentrations were sufficiently elevated above toxicity thresholds immediately adjacent to the fragments, limiting hazardous exposure only to very localized scales. Bioconcentration correlated closely with observed toxicity and was either not detectable (buried), or low (exposed), as is expected based on the low hydrophobicities of TNT and RDX.


Fine needle biopsy of double or multiple primary carcinomas of the lung.
Any pulmonary mass discovered after obvious successful surgery for bronchogenic carcinoma has to be suspected of potentially being a second primary cancer of the lung. "Recurrent" carcinoma in a bronchial stump may not be a continuation of the original tumor, but a new primary. Early recognition is important for patient management, therapy and prognosis, since curative resection of the second primary may still be feasible. Fine needle biopsy may be helpful in obtaining an early cytological and histological diagnosis and be decisive for specific treatment with improved prospects of cure. Fourty-eight patients, who underwent thoracotomy for a synchronous or successive mass in a patient with successfully removed bronchogenic carcinoma diagnosed by fine needle biopsy, showed a second primary carcinoma of the lung in 18 cases, while 30 cases showed evidence of metastatic disease.


The Capsicum terpenoid biosynthetic module is affected by spider-mite herbivory.
In response to herbivory, Capsicum annuum leaves adapt their specialized metabolome that may protect the plant against herbivore feeding either directly or indirectly through volatile metabolites acting as cues for natural enemies of the herbivore. The volatile blend of spider-mite infested leaves differs from non-challenged leaves predominantly by a higher contribution of mono- and sesquiterpenes. In addition to these terpenoids released into the headspace, the terpenoid composition of the leaves alters upon herbivory. All this suggests an important role for terpenoids and their biosynthetic machinery in the defence against herbivory. Here, we show that the C. annuum genome contains a terpene synthase (TPS) gene family of 103 putative members of which structural analysis revealed that 27 encode functional enzymes. Transcriptome analysis showed that several TPS loci were differentially expressed upon herbivory in leaves of two C. annuum genotypes, that differ in susceptibility towards spider mites. The relative expression of upstream biosynthetic genes from the mevalonate and the methylerythritol phosphate pathway also altered upon herbivory, revealing a shift in the metabolic flux through the terpene biosynthetic module. The expression of multiple genes potentially acting downstream of the TPSs, including cytochrome P450 monooxygenases, UDP-glucosyl transferases, and transcription factors strongly correlated with the herbivory-induced TPS genes. A selection of herbivory-induced TPS genes was functionally characterized through heterologous expression and the products that these enzymes catalysed matched with the volatile and non-volatile terpenoids induced in response to herbivory.


Estrogenic activities of Fatty acids and a sterol isolated from royal jelly.
We have previously reported that royal jelly (RJ) from honeybees (Apis mellifera) has weak estrogenic activity mediated by interaction with estrogen receptors that leads to changes in gene expression and cell proliferation. In this study, we isolated four compounds from RJ that exhibit estrogenic activity as evaluated by a ligand-binding assay for the estrogen receptor (ER) beta. These compounds were identified as 10-hydroxy-trans-2-decenoic acid, 10-hydroxydecanoic acid, trans-2-decenoic acid and 24-methylenecholesterol. All these compounds inhibited binding of 17beta-estradiol to ERbeta, although more weakly than diethylstilbestrol or phytoestrogens. However, these compounds had little or no effect on the binding of 17beta-estradiol to ERalpha. Expression assays suggested that these compounds activated ER, as evidenced by enhanced transcription of a reporter gene containing an estrogen-responsive element. Treatment of MCF-7 cells with these compounds enhanced their proliferation, but concomitant treatment with tamoxifen blocked this effect. Exposure of immature rats to these compounds by subcutaneous injection induced mild hypertrophy of the luminal epithelium of the uterus, but was not associated with an increase in uterine weight. These findings provide evidence that these compounds contribute to the estrogenic effect of RJ.


Pif1 Helicase Mediates Remodeling of Protein-Nucleic Acid Complexes by Promoting Dissociation of Sub1 from G-Quadruplex DNA and Cdc13 from G-Rich Single-Stranded DNA.
Pif1 is a molecular motor enzyme that is conserved from yeast to mammals. It translocates on ssDNA with a directional bias (5' → 3') and unwinds duplexes using the energy obtained from ATP hydrolysis. Pif1 is involved in dsDNA break repair, resolution of G-quadruplex (G4) structures, negative regulation of telomeres, and Okazaki fragment maturation. An important property of this helicase is to exert force and disrupt protein-DNA complexes, which may otherwise serve as barriers to various cellular pathways. Previously, Pif1 was reported to displace streptavidin from biotinylated DNA, Rap1 from telomeric DNA, and telomerase from DNA ends. Here, we have investigated the ability of S. cerevisiae Pif1 helicase to disrupt protein barriers from G4 and telomeric sites. Yeast chromatin-associated transcription coactivator Sub1 was characterized as a G4 binding protein. We found evidence for a physical interaction between Pif1 helicase and Sub1 protein. Here, we demonstrate that Pif1 is capable of catalyzing the disruption of Sub1-bound G4 structures in an ATP-dependent manner. We also investigated Pif1-mediated removal of yeast telomere-capping protein Cdc13 from DNA ends. Cdc13 exhibits a high-affinity interaction with an 11-mer derived from the yeast telomere sequence. Our results show that Pif1 uses its translocase activity to enhance the dissociation of this telomere-specific protein from its binding site. The rate of dissociation increased with an increase in the helicase loading site length. Additionally, we examined the biochemical mechanism for Pif1-catalyzed protein displacement by mutating the sequence of the telomeric 11-mer on the 5'-end and the 3'-end. The results support a model whereby Pif1 disrupts Cdc13 from the ssDNA in steps.


Polychromatic nonlinear surface modes generated by supercontinuum light.
We study propagation of polychromatic light near the edge of a nonlinear waveguide array. We describe simultaneous spatial and spectral beam reshaping associated with power and wavelength-dependent tunneling between the waveguides. We present experimental verifications of the effects predicted theoretically including the first observation of supercontinuum nonlinear surface modes.


Understanding the human condition: experimental strategies in mammalian genetics.
Mice have become the mammalian model of choice for the application of genetics in biomedical research due to the evolutionary conservation of physiological systems and their attendant pathologies among all mammals as well as the exceptional power of genetic research technologies in the species. Beginning from aberrant phenotypes, a large number of mouse mutants and natural polymorphisms have been cloned, providing much information about the molecular basis of physiological processes. Additionally, the variable expression of these mutations in different inbred strain backgrounds has demonstrated the importance of modifier genes, which are also susceptible to cloning. Research efforts are keeping pace with these developments. In the area of gene discovery, large, government-funded mutagenesis programs now exist, and as a matter of great practical importance, recent evidence suggests that the same genes may be involved in the natural polymorphisms affecting disease in mice and humans. In parallel, dramatic advances are also being made in our ability to measure physiological processes in mice, and the advent of expression profiling promises revolutionary advances in understanding phenotype at the molecular level. Gene-driven approaches have relied on engineering the mouse genome, including adding, subtracting, and replacing genes and, most recently, the ability to control gene activity reversibly. Together, these multiple advances in our technical abilities have created extraordinary opportunities for future discovery.


Highly sensitive immunoassay for the diagnosis of acute myocardial infarction using silica spheres encapsulating a quantum dot layer.
Commercial ELISA kits for substance P (SubP), which are helpful for the clinical diagnosis of acute myocardial infarction, are limited in efficacy because of low sensitivity. A highly sensitive immunoassay was developed using silica spheres encapsulating a quantum dot-layer (SQS) and labeling antibodies, on a Parylene A-modified plate. The high sensitivity was possible by taking advantage of the enhanced photoluminescence of the SQS and dense immobilization of SubP on a Parylene A-modified plate. Glutaraldehyde was used for cross-linking of SQS to the anti-SubP antibody and SubP to the Parylene A coating. The SQS-linked immunosorbent assay (SQSLISA) was optimized and validated. The dynamic range for the assay was 1-10000 pg/mL with a linear correlation factor of 0.9992 when the competitive SQSLISA was employed. The intra- and interday accuracies were 93-100% and 87-122%, respectively. The reproducibility was lower than 11%. The developed method was applied to clinical samples collected from healthy controls (n = 30) and acute myocardial infarction (n = 16) and it displayed a high correlation with the commercial ELISA kit, with a limit of detection that was 30-fold lower. Clinical sample analysis confirmed that SubP is a promising diagnostic marker for acute myocardial infarction. The SQSLISA is expected to be a practical and useful assay tool.


Venovenous Extracorporeal Membrane Oxygenation for Postoperative Acute Respiratory Distress Syndrome.
Extracorporeal membrane oxygenation (ECMO) has recently attracted interest as a treatment for severe acute respiratory distress syndrome (ARDS). However, the outcomes of this procedure in post-surgical settings have not yet been characterized. In this study, we evaluated the outcomes of ECMO in patients with severe postoperative ARDS. From January 2007 to December 2012, a total of 69 patients (aged 58.3±11.5 years, 23 females) who underwent venovenous ECMO to treat severe postoperative ARDS were reviewed. Of these patients, 22 (31.9%) had undergone cardiothoracic surgery, 32 (46.4%) had undergone liver transplantation, and 15 (21.7%) had undergone other procedures. Thirty-four patients (49.3%) were successfully weaned from ECMO, while the other 35 patients (50.7%) died on ECMO support. Among the 34 patients who were successfully weaned from ECMO, 21 patients (30.4%) eventually died before discharge from the hospital, resulting in 13 hospital survivors (18.8%). Multivariable analysis showed that the duration of pre-ECMO ventilation was a significant independent predictor of death (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.29 to 3.90; p=0.004), whereas the concomitant use of continuous venovenous hemodialysis (CVVHD) was associated with improved survival (OR, 0.55; 95% CI, 0.31 to 0.97; p=0.038). Although the overall survival rate of patients treated with ECMO for postoperative ARDS was unfavorable, ECMO offered an invaluable opportunity for survival to patients who would not have been expected to survive using conventional therapy. CVVHD may be beneficial in improving the outcomes of such patients, whereas a prolonged duration of pre-ECMO ventilator support was associated with poor survival.