Enhancing physical performance in elite junior tennis players with a caffeinated energy drink.
The aim of this study was to investigate the effectiveness of a caffeinated energy drink to enhance physical performance in elite junior tennis players. In 2 different sessions separated by 1 wk, 14 young (16 ± 1 y) elite-level tennis players ingested 3 mg caffeine per kg body mass in the form of an energy drink or the same drink without caffeine (placebo). After 60 min, participants performed a handgrip-strength test, a maximal-velocity serving test, and an 8 × 15-m sprint test and then played a simulated singles match (best of 3 sets). Instantaneous running speed during the matches was assessed using global positioning (GPS) devices. Furthermore, the matches were videotaped and notated afterward. In comparison with the placebo drink, the ingestion of the caffeinated energy drink increased handgrip force by ~4.2% ± 7.2% (P = .03) in both hands, the running pace at high intensity (46.7 ± 28.5 vs 63.3 ± 27.7 m/h, P = .02), and the number of sprints (12.1 ± 1.7 vs 13.2 ± 1.7, P = .05) during the simulated match. There was a tendency for increased maximal running velocity during the sprint test (22.3 ± 2.0 vs 22.9 ± 2.1 km/h, P = .07) and higher percentage of points won on service with the caffeinated energy drink (49.7% ± 9.8% vs 56.4% ± 10.0%, P = .07) in comparison with the placebo drink. The energy drink did not improve ball velocity during the serving test (42.6 ± 4.8 vs 42.7 ± 5.0 m/s, P = .49). The preexercise ingestion of caffeinated energy drinks was effective to enhance some aspects of physical performance of elite junior tennis players.


[Validation of the Diagnostic Interview for Genetic Studies (DIGS) in Colombia].
An interview tool, Diagnostic Interview for Genetic Studies (DIGS 3.0), was translated into Spanish for application in studies of psychiatric disorders in Colombia. Two Spanish translations of the original English version of DIGS were prepared and back-translated into English. A review committee verified the linguistic and cultural equivalence of the translations. The evaluator and test-retest reliability were assessed calculating Cohen's kappa for samples of 65 and 91 patients respectively. DIGS proved valid in both appearance and content. The confidence interval (C.I.) was excellent for schizophrenia (kappa = 0.81, C.I. 95% = 0.68-0.93), bipolar disorder (kappa = 0.87, C.I. 95% = 0.75-0.99), major depressive disorder (kappa = 0.86, C.I. 95% = 0.70-1.00), and for a normal diagnosis (kappa = 0.65, C.I. 95% = 0.41-0.89); it was good for other psychiatric diagnosis (kappa = 0.65, C.I. 95% = 0.41-0.89) and poor for schizoaffective disorder (kappa = 0.37, C.I. 95% = -0.02-0.76). Test-retest reliability was excellent for all diagnoses (kappa > 0.8), except for "other psychiatric diagnoses" (kappa = 0.64, C.I. 95% = 0.31-0.96). The Spanish translation of the DIGS was comprehensible, with face and content validity, and good test-retest and evaluator reliability. This translation will be a useful tool for genetic studies of psychiatric disorders in Latin America, particularly where schizophrenia and affective disorders are involved.


Lidocaine is a nocebo treatment for trigeminally mediated magnetic orientation in birds.
Even though previously described iron-containing structures in the upper beak of pigeons were almost certainly macrophages, not magnetosensitive neurons, behavioural and neurobiological evidence still supports the involvement of the ophthalmic branch of the trigeminal nerve (V1) in magnetoreception. In previous behavioural studies, inactivation of putative V1-associated magnetoreceptors involved either application of the surface anaesthetic lidocaine to the upper beak or sectioning of V1. Here, we compared the effects of lidocaine treatment, V1 ablations and sham ablations on magnetic field-driven neuronal activation in V1-recipient brain regions in European robins. V1 sectioning led to significantly fewer Egr-1-expressing neurons in the trigeminal brainstem than in the sham-ablated birds, whereas lidocaine treatment had no effect on neuronal activation. Furthermore, Prussian blue staining showed that nearly all iron-containing cells in the subepidermal layer of the upper beak are nucleated and are thus not part of the trigeminal nerve, and iron-containing cells appeared in highly variable numbers at inconsistent locations between individual robins and showed no systematic colocalization with a neuronal marker. Our data suggest that lidocaine treatment has been a nocebo to the birds and a placebo for the experimenters. Currently, the nature and location of any V1-associated magnetosensor remains elusive.


The dynamics of a metapopulation: changes in life-history traits in resident herring that co-occur with oceanic herring during spawning.
Different populations of Atlantic herring are regarded as forming a metapopulation, but we know little about the dynamics of the connectivity and degree of interbreeding between the populations. Based on data from three periods between 1962 and 2011, we identified the presence of two components of herring in a small semi-enclosed coastal marine ecosystem based on different somatic growth patterns and mean vertebrae sum (VS). The two components were interpreted as belonging to a resident herring population and the migratory, oceanic Norwegian spring spawning (NSS) herring population, and they co-occurred during spawning. In the 1960s, resident herring characterized by slow growth and low VS co-occurred with rapid growth, high VS oceanic NSS herring. Similar slow-growing resident and rapid-growing NSS herring were found in the 1970-80s, but both populations now had low VS suggesting similar origins. Finally, in the 2000s both populations showed rapid growth. The changes coincided with the NSS herring going from a state of high abundance and oceanic distribution to a collapse in the late 1960s that resulted in a coastal distribution closer to resident herring populations, before full recovery and resumption of the migratory, oceanic pattern in the 1990s. During all three periods, NSS herring were only present in the local system up to an age of about five years, but the synchronous spawning of the populations supports mixed spawning and interbreeding. During the investigation period both longevity, length at age (growth) and length-at-first maturity increased markedly for the resident herring, which then became more similar to the NSS herring. Genetic and/or cultural factors are believed to be the main causes of the observed changes in life history traits, although some effect of changes in environmental factors cannot be excluded. Our study suggests that relationships among populations in a metapopulation can be highly dynamic.


Nano-bio-chip sensor platform for examination of oral exfoliative cytology.
Oral cancer is a deadly and disfiguring disease that could greatly benefit from new diagnostic approaches enabling early detection. In this pilot study, we describe a nano-bio-chip (NBC) sensor technique for analysis of oral cancer biomarkers in exfoliative cytology specimens, targeting both biochemical and morphologic changes associated with early oral tumorigenesis. Here, oral lesions from 41 dental patients, along with normal epithelium from 11 healthy volunteers, were sampled using a noninvasive brush biopsy technique. Specimens were enriched, immunolabeled, and imaged in the NBC sensor according to previously established assays for the epidermal growth factor receptor (EGFR) biomarker and cytomorphometry. A total of 51 measurement parameters were extracted using custom image analysis macros, including EGFR labeling intensity, cell and nuclear size, and the nuclear-to-cytoplasmic ratio. Four key parameters were significantly elevated in both dysplastic and malignant lesions relative to healthy oral epithelium, including the nuclear area and diameter (P < 0.0001), the nuclear-to-cytoplasmic ratio (P < 0.0001), and EGFR biomarker expression (P < 0.03). Further examination using logistic regression and receiver operating characteristic curve analyses identified morphologic features as the best predictors of disease (area under the curve < or =0.93) individually, whereas a combination of all features further enhanced discrimination of oral cancer and precancerous conditions (area under the curve, 0.94) with high sensitivity and specificity. Further clinical trials are necessary to validate the regression model and evaluate other potential biomarkers, but this pilot study supports the NBC sensor technique as a promising new diagnostic tool for early detection of oral cancer, which could enhance patient care and survival.


Minimally invasive transforaminal lumbosacral interbody fusion.
In minimally invasive spinal fusion surgery, transforaminal lumbar (sacral) interbody fusion (TLIF) is one of the most common procedures that provides both anterior and posterior column support without retraction or violation to the neural structure. Direct and indirect decompression can be done through this single approach. Preoperative plain radiographs and MR scan should be carefully evaluated. This video demonstrates a standard approach for how to perform a minimally invasive transforaminal lumbosacral interbody fusion. The video can be found here: https://youtu.be/bhEeafKJ370 .


Comparison of Antibacterial Efficacy of Turmeric Extract, Morinda Citrifolia and 3% Sodium Hypochlorite on Enterococcus faecalis: An In-vitro Study.
Sodium hypochlorite (NaOCl), the most commonly used irrigant, has many potential properties like its unique ability to dissolve pulp tissue, excellent antimicrobial activity, but has a cytotoxic effect when injected into periapical tissues. It is also known to produce allergic reactions, foul smell and taste, and potential for corrosion. Facultative organisms such as Enterococcus faecalis and aerobes like Staphylococcus aureus are considered to be the most resistant species and one of the possible causes of root canal treatment failure. So there is a need to find an alternative to sodium hypochlorite to act against these resistant microorganisms. To evaluate and compare the antibacterial efficacy of morinda citrifolia and turmeric extract with 3% NaOCl as a root canal irrigant, against E. faecalis and S.aureus. The antimicrobial efficacy was assessed in vitro using agar well diffusion method. Agar plates were prepared using Brain-Heart Infusion (BHI) agar. Cultures of E.faecalis and S.aureus were grown in nutrient broth at 37°C. Plates were incubated for 24 hours at 37°C and microbial zones of inhibition were recorded. Statistical analysis was performed using ANOVA. NaOCl (3%) showed larger zones of inhibition than herbal irrigants against both the microorganisms. Among the herbal irrigants, morinda citrifolia showed larger zones of inhibition than turmeric hydro-alcoholic extract and turmeric water extract which was statistically significant (p<0.05). NaOCl (3%) showed maximum antibacterial activity against E. faecalis, followed by morinda citrifolia and turmeric extracts. Considering the potential for undesirable properties of NaOCl, use of herbal alternatives in endodontics might prove to be advantageous.


Evidence of paternal nutrient provisioning to embryos in broad-nosed pipefish Syngnathus typhle.
In two experiments, radioactively labelled nutrients (either (3)H-labelled amino-acid mixture or (14)C-labelled glucose) were tube-fed to brooding male Syngnathus typhle. Both nutrients were taken up by the males and radioactivity generally increased in the brood pouch tissue with time. Furthermore, a low but significant increase of (3)H-labelled amino acids in embryos was found over the experimental interval (48 h), whereas in the (14)C-glucose experiment the radioactivity was taken up by the embryos but did not increase over the experimental time (320 min). Uptake of radioisotopes per embryo did not differ with embryo size. A higher uptake mg(-1) tissue of both (3)H-labelled amino acids and (14)C-labelled glucose was found in smaller embryos, possibly due to a higher relative metabolic rate or to a higher surface-area-to-volume ratio compared to larger embryos. Uptake in embryos was not influenced by male size, embryonic developmental advancement or position in the brood pouch. It is concluded that brooding males provide amino acids, and probably also glucose, to the developing embryos in the brood pouch.


Coadministration of puerarin (low dose) and zinc attenuates bone loss and suppresses bone marrow adiposity in ovariectomized rats.
Puerarin is a phytoestrogen that shows osteogenic effects. Meanwhile, zinc stimulates bone formation and inhibits bone resorption. The study aims to investigate the effects of coadministration of puerarin (low dose) and zinc on bone formation in ovariectomized rats. Co-administration or use alone of puerarin (low dose) and/or zinc were gavaged in OVX rats. The estrogen-like effects were detected by the uterus weight, the histologic observation and the IGF-1 protein expression. The osteogenic effects were determined by bone histomorphometric and mechanical parameters, osteogenic and adipogenic blood markers, and so on. The results showed that oral administration of puerarin (low dose) plus zinc didn't significantly increase uterus weight. The glandular epithelial of endometrium had no proliferation and no protein expression of IGF-1. Moreover, co-administration attenuated bone loss and biomechanical decrease more than single use of puerarin or zinc (p<0.05). Next, combined administration of puerarin and zinc promoted the serological level of osteocalcin, bone marrow stromal cell (BMSC) proliferation, and the expression of alkaline phosphatase (ALP), and suppressed the serological level of adiponectin and adiposity in bone marrow (BM). In conclusion, co-administrated puerarin (low dose) and zinc can partially reverse OVX-induced bone loss and suppress the adiposity of BM in rats, which shed light on the potential use of puerarin and zinc in the treatment of osteoporosis.


Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation.
ASK1 activates JNK and p38 mitogen-activated protein kinases and constitutes a pivotal signaling pathway in cytokine- and stress-induced apoptosis. However, little is known about the mechanism of how ASK1 executes apoptosis. Here we investigated the roles of caspases and mitochondria in ASK1-induced apoptosis. We found that benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk), a broad-spectrum caspase inhibitor, mostly inhibited ASK1-induced cell death, suggesting that caspases are required for ASK1-induced apoptosis. Overexpression of ASK1DeltaN, a constitutively active mutant of ASK1, induced cytochrome c release from mitochondria and activation of caspase-9 and caspase-3 but not of caspase-8-like proteases. Consistently, caspase-8-deficient (Casp8 (-/-)) cells were sensitive to ASK1-induced caspase-3 activation and apoptosis, suggesting that caspase-8 is dispensable for ASK1-induced apoptosis, whereas ASK1 failed to activate caspase-3 in caspase-9-dificient (Casp9 (-/-)) cells. Moreover, mitochondrial cytochrome c release, which was not inhibited by zVAD-fmk, preceded the onset of caspase-3 activation and cell death induced by ASK1. ASK1 thus appears to execute apoptosis mainly by the mitochondria-dependent caspase activation.


Separation of splenic red and white pulp occurs before birth in a LTalphabeta-independent manner.
For the formation of lymph nodes and Peyer's patches, lymphoid tissue inducer (LTi) cells are crucial in triggering stromal cells to recruit and retain hematopoietic cells. Although LTi cells have been observed in fetal spleen, not much is known about fetal spleen development and the role of LTi cells in this process. Here, we show that LTi cells collect in a periarteriolar manner in fetal spleen at the periphery of the white pulp anlagen. Expression of the homeostatic chemokines can be detected in stromal and endothelial cells, suggesting that LTi cells are attracted by these chemokines. As lymphotoxin (LT)alpha1beta2 can be detected on B cells but not LTi cells in neonatal spleen, starting at 4 days after birth, the earliest formation of the white pulp in fetal spleen occurs in a LTalpha1beta2-independent manner. The postnatal development of the splenic white pulp, involving the influx of T cells, depends on LTalpha1beta2 expressed by B cells.


Staggered-grid PSTD on local Fourier basis and its applications to surface tissue modeling.
We introduce a high performance parallelization to the PSTD solution of Maxwell equations by employing the fast Fourier transform on local Fourier basis. Meanwhile a reformatted derivative operator allows the adoption of a staggered-grid such as the Yee lattice in PSTD, which can overcome the numerical errors in a collocated-grid when spatial discontinuities are present. The accuracy and capability of our method are confirmed by two analytical models. In two applications to surface tissue optics, an ultra wide coherent backscattering cone from the surface layer is found, and the penetration depth of polarization gating identified. Our development prepares a tool for investigating the optical properties of surface tissue structures.


Why does the world need another rotavirus vaccine?
A "Meeting on Upstream Rotavirus Vaccines and Emerging Vaccine Producers" was held at the World Health Organization in Geneva, Switzerland on March 28-30, 2006. The purpose was to discuss, evaluate, and weigh the importance of additional rotavirus vaccine candidates following the successful international licensure of rotavirus vaccines by two major pharmaceutical companies (GlaxoSmithKline and Merck) that had been in development for many years. Both licensed vaccines are composed of live rotaviruses that are delivered orally as have been all candidate rotavirus vaccines evaluated in humans. Each is built on the experience gained with previous candidates whose development had either been discontinued or, in the case of the previously licensed rhesus rotavirus reassortant vaccine (Rotashield), was withdrawn by its manufacturer after the discovery of a rare association with intussusception. Although which alternative candidate vaccines should be supported for development and where this should be done are controversial topics, there was general agreement expressed at the Geneva meeting that further development of alternative candidates is a high priority. This development will help insure that the most safe, effective and economic vaccines are available to children in Third World nations where the vast majority of the >600,000 deaths due to rotavirus occur each year. This review is intended to provide the history and present status of rotavirus vaccines as well as a perspective on the future development of candidate vaccines as a means of promulgating plans suggested at the Geneva meeting.


An expanding universe of noncoding RNAs.
Noncoding RNAs (ncRNAs) have been found to have roles in a great variety of processes, including transcriptional regulation, chromosome replication, RNA processing and modification, messenger RNA stability and translation, and even protein degradation and translocation. Recent studies indicate that ncRNAs are far more abundant and important than initially imagined. These findings raise several fundamental questions: How many ncRNAs are encoded by a genome? Given the absence of a diagnostic open reading frame, how can these genes be identified? How can all the functions of ncRNAs be elucidated?


Summary of the International Multicenter Prospective Angioedema C1-inhibitor Trials 1 and 2 (IMPACT1 and 2).
Hereditary angioedema (HAE) is an autosomal dominant disease characterized by deficiency of C1 inhibitor (C1-INH) that commonly presents with recurrent swelling affecting different parts of the body. Supplementation with C1-INH is successfully used to treat HAE in selected countries, mostly in Europe. Berinert P (CSL Behring, Marburg, Germany), a human plasma-derived C1-INH, was studied in the International Multicenter Prospective Angioedema C1-inhibitor Trial 1 (IMPACT1) that was completed in 2007. It was the first safety and dose-finding study of C1-INH in patients with acute abdominal and facial angioedema. IMPACT2 was the extension of the first trial to study C1-INH efficacy and safety in multiple treatments of acute HAE attacks in various areas of the body. Berinert P has excellent potential to become a first-line therapy for treating patients with acute HAE attacks in the USA and other countries involved in the IMPACT trials. While final data from the IMPACT2 trial are not yet released, this article reviews currently available data from previous reports and abstract presentations.


Hepatitis C in men who have sex with men in London--a community survey.
For the last 10 years there has been an epidemic of hepatitis C virus (HCV) infection in men who have sex with men (MSM) in Europe, North America and Australia. The majority of those infected are also HIV-positive and it is unclear to what extent HIV-negative MSM are also at increased risk of infection with HCV. This study provides the first examination of the association between HIV and hepatitis C serostatus in a sample of MSM recruited in community settings. A total of 1121 participants completed a short questionnaire in 2008/2009 giving demographic and behavioural data, and donated a sample of oral fluid that was subsequently tested for antibodies to selected pathogens (HIV, syphilis and HCV). The seroprevalence of hepatitis C antibody was 2.1% [95% confidence interval (CI) 1.4-3.2%]. It was more common in those with HIV infection [7.7% (95% CI 4.2-12.9%) vs. 1.2% (95% CI 0.6-2.1%) in those without HIV infection; P < 0.001], those with a history of syphilis [12.2% (95% CI 4.6-24.8%) vs. 1.7% (95% CI 1.0-2.6%) in those without such a history; P < 0.001] and those who reported casual unprotected anal intercourse in the previous year [4.1% (95% CI 2.0-7.4%) vs. 1.2% (95% CI 0.5-2.2%) in those who did not report such intercourse; P = 0.01]. There was no relationship between hepatitis C antibody (anti-HCV) status and other demographic variables (age, ethnicity, employment status or education). The seroprevalence of anti-HCV in HIV-negative MSM (1.2%) was higher, but not significantly higher, than that in the general population (0.67%). The prevalence was significantly higher in those infected with HIV or with previous syphilis infection and in those reporting unprotected anal intercourse. Our findings support current British Association for Sexual Health and HIV guidelines recommending the provision of selective HCV testing in MSM according to individual risk profile.


Implementation and adoption of nationwide electronic health records in secondary care in England: final qualitative results from prospective national evaluation in "early adopter" hospitals.
To evaluate the implementation and adoption of the NHS detailed care records service in "early adopter" hospitals in England. Theoretically informed, longitudinal qualitative evaluation based on case studies. 12 "early adopter" NHS acute hospitals and specialist care settings studied over two and a half years. Data were collected through in depth interviews, observations, and relevant documents relating directly to case study sites and to wider national developments that were perceived to impact on the implementation strategy. Data were thematically analysed, initially within and then across cases. The dataset consisted of 431 semistructured interviews with key stakeholders, including hospital staff, developers, and governmental stakeholders; 590 hours of observations of strategic meetings and use of the software in context; 334 sets of notes from observations, researchers' field notes, and notes from national conferences; 809 NHS documents; and 58 regional and national documents. Implementation has proceeded more slowly, with a narrower scope and substantially less clinical functionality than was originally planned. The national strategy had considerable local consequences (summarised under five key themes), and wider national developments impacted heavily on implementation and adoption. More specifically, delays related to unrealistic expectations about the capabilities of systems; the time needed to build, configure, and customise the software; the work needed to ensure that systems were supporting provision of care; and the needs of end users for training and support. Other factors hampering progress included the changing milieu of NHS policy and priorities; repeatedly renegotiated national contracts; different stages of development of diverse NHS care records service systems; and a complex communication process between different stakeholders, along with contractual arrangements that largely excluded NHS providers. There was early evidence that deploying systems resulted in important learning within and between organisations and the development of relevant competencies within NHS hospitals. Implementation of the NHS Care Records Service in "early adopter" sites proved time consuming and challenging, with as yet limited discernible benefits for clinicians and no clear advantages for patients. Although our results might not be directly transferable to later adopting sites because the functionalities we evaluated were new and untried in the English context, they shed light on the processes involved in implementing major new systems. The move to increased local decision making that we advocated based on our interim analysis has been pursued and welcomed by the NHS, but it is important that policymakers do not lose sight of the overall goal of an integrated interoperable solution.


Endoscopic evaluation of bronchial morphology in rabbits.
To evaluate bronchial morphology endoscopically in rabbits and develop a valid nomenclature for the endobronchial branching pattern. 10 mature New Zealand White rabbits. Flexible bronchoscopy was performed in rabbits anesthetized with isoflurane via nasal mask. Airways were systematically evaluated from the larynx to the terminal branches accessible with a 2.5-mm-outer diameter flexible endoscope. Airway branching patterns were identified and assessed for variation among subjects. Airways of all rabbits were readily examined with the 2.5-mm flexible endoscope. Laryngeal structure and function were normal in each rabbit, and airway branching patterns in all rabbits evaluated were identical. At the carina, branching into left and right principal bronchi was evident. The left principal bronchus divided immediately into the left cranial and left caudal lobar bronchi. The left cranial lobe bronchus further divided into dorsal and ventral segmental bronchi. The left caudal lobe bronchus gave rise to branches originating dorsally, ventrally, and medially before continuing caudally. The right principal bronchus divided into the right cranial, right middle, and accessory lobar bronchi and continued distally as the right caudal lobar bronchus. The right cranial lobe bronchus also divided into dorsal and ventral segmental bronchi, and the right caudal lobe bronchus had branches that originated dorsally, ventrally, and medially. Definition of a standard nomenclature for airway branching in rabbits will allow precise localization of disease in clinical cases and accurate collection of airway samples in clinical and scientific evaluations.


Combined testosterone and vardenafil treatment for restoring erectile function in hypogonadal patients who failed to respond to testosterone therapy alone.
The role of testosterone in erectile dysfunction (ED) is increasingly recognized. It is suggested that assessment of testosterone deficiency in men with ED and symptoms of hypogonadism, prior to first-line treatment, may be a useful tool for improving therapy. In this prospective, observational, and longitudinal study, we investigated the effects of vardenafil treatment as adjunctive therapy to testosterone undecanoate in hypogonadal ED patients who failed to respond to testosterone treatment alone. One hundred twenty-nine testosterone deficient (serum total testosterone ≤ 3.4 ng/mL) patients aged 56 ± 3.9 years received intramuscular injections of long-acting parenteral testosterone undecanoate at 3-month intervals for 8 months mean follow-up. Scores on the International Index of Erectile Function Questionnaire-five items (IIEF-5) and partner survey scores were compared at baseline and posttreatment with testosterone therapy alone or in combination with vardenafil. Patient baseline demographics and concomitant disease were correlated with patients' IIEF-5 scores. Seventy one (58.2%) responded well to monotherapy within 3 months. Nonresponders had lower testosterone levels and higher rates of concomitant diseases and smoking. Thirty-four of the 51 nonresponders accepted the addition of 20 mg vardenafil on demand. Efficacy assessments were measured by the IIEF-erectile function domain (IIEF-EF, questions 1-5 plus 15, 30 points) and partner self-designed survey at baseline after 4-6 weeks and at study end point. Thirty out of 34 patients responded well to this combination. IIEF-EF Sexual Health Inventory for Men score improved from 12 to 24 (P < 0.0001), and partner survey showed significantly higher satisfaction (P < 0.001). These patients reported spontaneous or nocturnal and morning erections or tumescence. No changes in adverse effects were recorded. These data suggest that combination therapy of testosterone and vardenafil is safe and effective in treating hypogonadal ED patients who failed to respond to testosterone monotherapy.


Relationships between plasma fatty acid composition and coronary artery disease.
The Japan EPA Lipid Intervention Study (JELIS) was the first prospective randomized clinical trial to demonstrate prevention of coronary events by pure eicosapentaenoic acid (EPA). The aim of this study was to examine the relationships between various plasma fatty acid concentrations and the risk of coronary events in JELIS participants. In 15,534 participants, we calculated the hazard ratio for major coronary events (sudden cardiac death, fatal or nonfatal myocardial infarction, unstable angina pectoris, and angioplasty/stenting or coronary artery bypass grafting) relative to the on-treatment average level of plasma fatty acids with the Cox proportional hazard model. As a result of EPA intervention, the plasma EPA concentration increased, but the docosahexaenoic acid (DHA) concentration did not. The other fatty acids measured decreased slightly. The higher plasma level of EPA (hazard ratio=0.83, p=0.049, in all participants and hazard ratio=0.71, p=0.018, in the EPA intervention group), but not of DHA, was inversely associated with the risk of major coronary events. The associations between other fatty acids and the risk of major coronary events were not significant. In all JELIS participants, the risk of major coronary events was significantly decreased (20%) in the group with high (150 µg/mL or more) on-treatment plasma EPA concentration compared with that in the low (less than 87 µg/mL) group. The risk of coronary artery disease is influenced by variations in plasma fatty acid composition. Among n-3 polyunsaturated fatty acids, EPA and DHA exhibited differences in the correlation with the risk of major coronary events.


Absolute identification is relative: a reply to Brown, Marley, and Lacouture (2007).
N. Stewart, G. D. A. Brown, and N. Chater presented a relative judgment model (RJM) of absolute identification, in which the current stimulus is judged relative to the preceding stimulus. S. Brown, A. A. J. Marley, and Y. Lacouture found that the RJM does not predict their finding of increased accuracy after large stimulus jumps, except at the expense of other effects. In fact, the RJM does predict both the core effects and increased accuracy after large jumps (although it underestimates this effect) when better constrained parameters are estimated from the trial-by-trial raw data rather than from summary plots. Further, a modified RJM, in which the stimulus from two trials ago is sometimes used as a referent, provides a better fit.


Ricin toxicokinetics and its sensitive detection in mouse sera or feces using immuno-PCR.
Ricin (also called RCA-II or RCA(60)), one of the most potent toxins and documented bioweapons, is derived from castor beans of Ricinus communis. Several in vitro methods have been designed for ricin detection in complex food matrices in the event of intentional contamination. Recently, a novel Immuno-PCR (IPCR) assay was developed with a limit of detection of 10 fg/ml in a buffer matrix and about 10-1000-fold greater sensitivity than other methods in various food matrices. In order to devise a better diagnostic test for ricin, the IPCR assay was adapted for the detection of ricin in biological samples collected from mice after intoxication. The limit of detection in both mouse sera and feces was as low as 1 pg/ml. Using the mouse intravenous (iv) model for ricin intoxication, a biphasic half-life of ricin, with a rapid t(1/2)α of 4 min and a slower t(1/2)β of 86 min were observed. The molecular biodistribution time for ricin following oral ingestion was estimated using an antibody neutralization assay. Ricin was detected in the blood stream starting at approximately 6-7 h post- oral intoxication. Whole animal histopathological analysis was performed on mice treated orally or systemically with ricin. Severe lesions were observed in the pancreas, spleen and intestinal mesenteric lymph nodes, but no severe pathology in other major organs was observed. The determination of in vivo toxicokinetics and pathological effects of ricin following systemic and oral intoxication provide a better understanding of the etiology of intoxication and will help in the future design of more effective diagnostic and therapeutic methods.


Dietary fiber and risk of benign proliferative epithelial disorders of the breast.
Following a recent finding, from a case-control study in Adelaide, South Australia, of a reduced risk of breast cancer among women consuming diets rich in fiber, the fiber densities in the diets of 354 women with incident benign proliferative epithelial disorders of the breast (BPED) were compared with the fiber densities of the diets of 354 matched community controls and with those of 189 unmatched controls having breast conditions for which there was no evidence of BPED at biopsy. Fiber intakes were estimated by means of a self-administered quantitative food-frequency questionnaire, and the risk of BPED was estimated for each quintile of fiber density (grams of fiber/megaJoule of total energy intake) relative to an arbitrarily assigned risk of one for the lowest quintile. For women with the highest dietary fiber densities the estimated risk was 0.64 (95% CI 0.34, 1.19) when cases were compared with community controls, and 0.45 (95% CI 0.24, 0.82) when cases were compared with biopsy-negative controls. Similar trends in risk were observed for the intakes of other major fiber components, the association being stronger when the comparison was made with biopsy-negative as opposed to community controls. If these findings can be substantiated, they may open the way to dietary intervention strategies for reducing the incidence of breast cancer.


Color effects of uniform colloidal particles of different morphologies packed into films.
The experimentally determined chromaticities and reflectance spectra of films consisting of uniform ellipsoidal or spherical colloidal hematite particles are compared with calculated values and are found to be in good agreement. The theoretical treatment of the light-scattering problem involves the Mie theory for the spheres and the T-matrix method for the ellipsoids. The reflectance spectra for the pigment films are calculated through the use of the Kubelka-Munk analysis.


A canine model of mechanical thrombectomy in stroke.
To develop a preclinical model of stroke with a large vessel occlusion treated with mechanical thrombectomy. An ischemic stroke model was created in dogs by the introduction of an autologous clot into the middle cerebral artery (MCA). A microcatheter was navigated to the clot and a stent retriever thrombectomy was performed with the goal to achieve Thrombolysis in Cerebral Ischemia (TICI) 2b/3 reperfusion. Perfusion and diffusion MRI was acquired after clot placement and following thrombectomy to monitor the progression of restricted diffusion as well as changes in ischemia as a result of mechanical thrombectomy. Post-mortem histology was done to confirm MCA territory infarct volume. Initial MCA occlusion with TICI 0 flow was documented in all six hound-cross dogs entered into the study. TICI 2b/3 revascularization was achieved with one thrombectomy pass in four of six animals (67%). Intra-procedural events including clot autolysis leading to spontaneous revascularization (n=1) and unresolved vasospasm (n=1) accounted for thrombectomy failure. In one case, iatrogenic trauma during microcatheter navigation resulted in a direct arteriovenous fistula at the level of the cavernous carotid. Analysis of MRI indicated that a volume of tissue from the initial perfusion deficit was spared with reperfusion following thrombectomy, and there was also a volume of tissue that infarcted between MRI and ultimate recanalization. We describe a large animal stroke model in which mechanical thrombectomy can be performed. This model may facilitate, in a preclinical setting, optimization of complex multimodal stroke treatment paradigms for clinical translation.


Exercise, GLUT4, and skeletal muscle glucose uptake.
Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction. Here we discuss the current understanding of how exercise-induced muscle glucose uptake is regulated. We briefly discuss the role of glucose supply and metabolism and concentrate on GLUT4 translocation and the molecular signaling that sets this in motion during muscle contractions. Contraction-induced molecular signaling is complex and involves a variety of signaling molecules including AMPK, Ca(2+), and NOS in the proximal part of the signaling cascade as well as GTPases, Rab, and SNARE proteins and cytoskeletal components in the distal part. While acute regulation of muscle glucose uptake relies on GLUT4 translocation, glucose uptake also depends on muscle GLUT4 expression which is increased following exercise. AMPK and CaMKII are key signaling kinases that appear to regulate GLUT4 expression via the HDAC4/5-MEF2 axis and MEF2-GEF interactions resulting in nuclear export of HDAC4/5 in turn leading to histone hyperacetylation on the GLUT4 promoter and increased GLUT4 transcription. Exercise training is the most potent stimulus to increase skeletal muscle GLUT4 expression, an effect that may partly contribute to improved insulin action and glucose disposal and enhanced muscle glycogen storage following exercise training in health and disease.


A very unusual cause of dysphagia: mantle cell lymphoma.
Dysphagia is an alarm symptom requiring a prompt investigation. Different benign and malignant diseases may present such a symptom. We describe a case of a 79-year-old patient who complained of fluctuating dysphagia episodes following solid food ingestion in the previous 5 months with mild weight loss. No other gastrointestinal symptoms were present. The patient was referred by the General Practitioner for a videofluoroscopic swallow examination which revealed nodularity of mucosa surface in the oropharynx, esophagus, fundus, and gastric body. Upper endoscopy confirmed the feature, also showing a normal mucosa of the antrum and duodenum. The histological examination revealed a mantle cell lymphoma (MCL). A stage III, MCL involving the esophagus and proximal stomach was eventually diagnosed. Esophageal MCL localization is extremely rare, and this is the first report showing a clinical onset with dysphagia.


Septal-lateral annnular cinching perturbs basal left ventricular transmural strains.
Septal-lateral annular cinching ('SLAC') corrects both acute and chronic ischemic mitral regurgitation in animal experiments, which has led to the development of therapeutic surgical and interventional strategies incorporating this concept (e.g., Edwards GeoForm ring, Myocor Coapsys, Ample Medical PS3). Changes in left ventricular (LV) transmural cardiac and fiber-sheet strains after SLAC, however, remain unknown. Eight normal sheep hearts had two triads of transmural radiopaque bead columns inserted adjacent to (anterobasal) and remote from (midlateral equatorial) the mitral annulus. Under acute, open chest conditions, 4D bead coordinates were obtained using videofluoroscopy before and after SLAC. Transmural systolic strains were calculated from bead displacements relative to local circumferential, longitudinal, and radial cardiac axes. Transmural cardiac strains were transformed into fiber-sheet coordinates (X(f), X(s), X(n)) oriented along the fiber (f), sheet (s), and sheet-normal (n) axes using fiber (alpha) and sheet (beta) angle measurements. SLAC markedly reduced (approximately 60%) septal-lateral annular diameter at both end-diastole (ED) (2.5+/-0.3 to 1.0+/-0.3 cm, p=0.001) and end-systole (ES) (2.4+/-0.4 to 1.0+/-0.3 cm, p=0.001). In the LV wall remote from the mitral annulus, transmural systolic strains did not change. In the anterobasal region adjacent to the mitral annulus, ED wall thickness increased (p=0.01) and systolic wall thickening was less in the epicardial (0.28+/-0.12 vs 0.20+/-0.06, p=0.05) and midwall (0.36+/-0.24 vs 0.19+/-0.11, p=0.04) LV layers. This impaired wall thickening was due to decreased systolic sheet thickening (0.20+/-0.8 to 0.12+/-0.07, p=0.01) and sheet shear (-0.15+/-0.07 to -0.11+/-0.04, p=0.02) in the epicardium and sheet extension (0.21+/-0.11 to 0.10+/-0.04, p=0.03) in the midwall. Transmural systolic and remodeling strains in the lateral midwall (remote from the annulus) were unaffected. Although SLAC is an alluring concept to correct ischemic mitral regurgitation, these data suggest that extreme SLAC adversely effects systolic wall thickening adjacent to the mitral annulus by inhibiting systolic sheet thickening, sheet shear, and sheet extension. Such alterations in LV strains could result in unanticipated deleterious remodeling and warrant further investigation.


Parental Supervision and Alcohol Abuse Among Adolescent Girls.
Inadequate parent supervision during the early adolescent years forecasts a host of conduct problems, including illicit alcohol consumption. Early pubertal maturation may exacerbate problems, because girls alienated from same-age peers seek the company of older, more mature youth. The current study examines overtime associations between parent autonomy granting and adolescent alcohol abuse during a developmental period when alcohol consumption becomes increasingly normative, to determine if early maturing girls are at special risk for problems arising from a lack of parent supervision. At annual intervals for 4 consecutive years, a community sample of 957 Swedish girls completed surveys beginning in the first year of secondary school (approximate age: 13 years) describing rates of alcohol intoxication and perceptions of parent autonomy granting. Participants also reported age at menarche. Multiple-group parallel process growth curve models revealed that early pubertal maturation exacerbated the risk associated with premature autonomy granting: Alcohol intoxication rates increased 3 times faster for early maturing girls with the greatest autonomy than they did for early maturing girls with the least autonomy. Child-driven effects were also found such that higher initial levels of alcohol abuse predicted greater increases in autonomy granting as parent supervision over children engaged in illicit drinking waned. Early maturing girls are at elevated risk for physical and psychological adjustment difficulties. The etiology of escalating problems with alcohol can be traced, in part, to a relative absence of parent supervision during a time when peer interactions assume special significance.


Split Face Comparative Study of Microneedling with PRP Versus Microneedling with Vitamin C in Treating Atrophic Post Acne Scars.
Acne scars are largely preventable complications of acne. 95% of the scars occur over the face thus impacting the quality of life. Correction of scars is the priority for acne patients. Thirty patients with post acne atrophic facial scars attending the OPD during the period from April to October 2013 were offered four sittings of microneedling with PRP on one side and microneedling with vitamin C on other side of the face at an interval of 1 month. Twenty-seven out of the total 30 patients completed the treatment schedule. Two patients were lost to follow up and one dropped out of the study due to severe PIH. Mean age of the patients was 27.5 years. Out of 30 patients, 23 achieved reduction in scarring by one or two grades. Excellent response was seen in five (18.5%) patients with platelet-rich plasma (PRP) as compared to two (7%) patients who received treatment with vitamin C according to physician's assessment. As far as up gradation by 1 score is considered, i.e., good response, it was similar in both cases. Vitamin C did not prove to be as efficacious as PRP since 10 (37%) patients had poor response in vitamin C-treated area compared to only 6 (22.2%) patients who underwent PRP therapy, but vitamin C proved to be efficacious in dealing with post inflammatory hyper-pigmentation secondary to acne. Patients were more satisfied with PRP as compared to vitamin C. The results were evaluated and statistical analysis was done using SPSS 16.0.2. Overall results were better with microneedling and PRP. Vitamin C combined with microneedling also showed improvement with respect to firmness and smoothness of skin; as well as post inflammatory hyper-pigmentation. Microneedling combined with PRP proved to be good in treating boxcar and rolling scars but had limited efficacy in dealing with ice pick scars.


Coercive paternalism and back-door perfectionism.
In this response piece, I argue that the 'coercive paternalism' that Sarah Conly endorses in her book Against Autonomy veers towards a back-door perfectionism. Although Conly points out that coercive paternalism does not mandate the imposition of alien values upon us in the same way that perfectionism does, I argue that coercive paternalism might yet impose an alien weighting of our own values; this, I suggest, means that coercive paternalism remains perfectionist in spirit, if not in letter. I go on to concede to Conly that coercive paternalism might be warranted in preventing actions that threaten health and that are only carried out on the basis of cognitive error. However, I conclude by claiming that we must take great care about what we presume that people are consuming only on the basis of cognitive error. More specifically, I suggest that it is crucial that we avoid defining our terms in such a manner that it becomes impossible for agents to choose some action that poses a risk to their health without them being accused of making a cognitive error in weighing their values in that way.


Fibrinogen and coronary heart disease: test of causality by 'Mendelian randomization'.
Blood concentrations of fibrinogen have been associated with coronary heart disease risk in epidemiological studies, but it is uncertain whether this association is causal or reflects residual confounding by other risk factors. We investigated the relationship between the single nucleotide polymorphism at position -148 in the beta-fibrinogen gene promoter (beta - 148C/T), blood fibrinogen levels, and risk of myocardial infarction (MI) in sufficiently large numbers of coronary disease cases to reliably address this question. Genotyping and measurement of blood fibrinogen concentration were carried out in 4,685 cases of confirmed MI and 3,460 controls with no history of coronary disease. A meta-analysis of ISIS and 19 other studies of beta-fibrinogen genotypes involving a total of 12,220 coronary disease cases and 18,716 controls was conducted. Among the ISIS controls, mean plasma fibrinogen concentrations with the C/C, C/T and T/T genotypes were 3.34 (SE 0.015), 3.48 (0.022), and 3.60 (0.064) g/l, respectively, corresponding to an increase of 0.14 (0.024) g/l per T allele (trend P < 0.0001). In the case-control comparison, 0.14 g/l higher usual plasma fibrinogen concentration was associated with an age-adjusted and sex-adjusted risk ratio for MI of 1.17 [95% confidence interval (95% CI) 1.14-1.19; P < 0.0001]. But, after further adjustment for smoking, body mass index, and plasma apolipoprotein B/A(1) ratio, this risk ratio fell to 1.03 (95% CI 1.00-1.05; P = 0.05). Moreover, fibrinogen genotype was not significantly associated with MI incidence: risk ratio of 1.06 (95% CI 0.96-1.16) per higher-fibrinogen allele in ISIS alone and of 1.00 (95% CI 0.95-1.04) per allele in the meta-analysis. Genotypes that produce lifelong differences in fibrinogen concentrations do not materially influence coronary disease incidence. As these genotype-dependent differences in fibrinogen were allocated randomly at conception (Mendelian randomization), this association is not likely to be confounded by other factors. Consequently, these genetic results provide strong evidence that long-term differences in fibrinogen concentrations are not a major determinant of coronary disease risk.


Anticipatory attentional suppression of visual features indexed by oscillatory alpha-band power increases: a high-density electrical mapping study.
Retinotopically specific increases in alpha-band ( approximately 10 Hz) oscillatory power have been strongly implicated in the suppression of processing for irrelevant parts of the visual field during the deployment of visuospatial attention. Here, we asked whether this alpha suppression mechanism also plays a role in the nonspatial anticipatory biasing of feature-based attention. Visual word cues informed subjects what the task-relevant feature of an upcoming visual stimulus (S2) was, while high-density electroencephalographic recordings were acquired. We examined anticipatory oscillatory activity in the Cue-to-S2 interval ( approximately 2 s). Subjects were cued on a trial-by-trial basis to attend to either the color or direction of motion of an upcoming dot field array, and to respond when they detected that a subset of the dots differed from the majority along the target feature dimension. We used the features of color and motion, expressly because they have well known, spatially separated cortical processing areas, to distinguish shifts in alpha power over areas processing each feature. Alpha power from dorsal regions increased when motion was the irrelevant feature (i.e., color was cued), and alpha power from ventral regions increased when color was irrelevant. Thus, alpha-suppression mechanisms appear to operate during feature-based selection in much the same manner as has been shown for space-based attention.


Microvascular pressures measured by micropipettes in isolated edematous rabbit lungs.
To study the mechanical effects of lung edema on the pulmonary circulation, we determined the longitudinal distribution of vascular resistance in the arteries, veins, and microvessels, and the distribution of blood flow in isolated blood-perfused rabbit lungs with varying degrees of edema. Active vasomotor changes were eliminated by adding papaverine to the perfusate. In three groups of lungs with either minimal [group I, mean wet-to-dry weight ratio (W/D) = 5.3 +/- 0.6 (SD), n = 7], moderate (group II, W/D = 8.5 +/- 1.2, n = 10), or severe (group III, W/D = 9.9 +/- 1.6, n = 5) edema, we measured by direct micropuncture the pressure in subpleural arterioles and venules (20-60 micron diam) and in the interstitium surrounding these vessels. We also measured pulmonary arterial and left atrial pressures and lung blood flow, and in four additional experiments we used radio-labeled microspheres to determine the distribution of blood flow during mild and severe pulmonary edema. In lungs with little or no edema (group I) we found that 33% of total vascular pressure drop was in arteries, 60% was in microvessels, and 7% was in veins. Moderate edema (group II) had no effect on total vascular resistance or on the vascular pressure profile, but severe edema (group III) did increase vascular resistance without changing the longitudinal distribution of vascular resistance in the subpleural microcirculation. Perivascular interstitial pressure relative to pleural pressure increased from 1 cmH2O in group I to 2 in group II to 4 in group III lungs.(ABSTRACT TRUNCATED AT 250 WORDS)


E-learning in radiology: an Italian multicentre experience.
The aim of this study was to design, deliver and evaluate an e-learning teaching programme for post-graduate radiodiagnostics training that would involve various post-graduate schools throughout Italy. All of the Directors of Italian post-graduate schools of radiodiagnostics were sent an e-mail on 27 September 2010 informing them of our willingness to set up an e-learning project for the academic year 2010-2011 in the form of single-subject teaching seminars. The proposed subjects were the semeiotics of the various organs and apparatuses in the context of "Urgent/Emergency Pathology". After having received registrations, a calendar of lessons was planned to be held between 10 November 2010 and 12 October 2011. The validity of the project was tested by means of a multiple-choice questionnaire covering the technical and didactic quality of the entire project, to be completed by the students. Fifty-one percent of the universities in Italy participated in the project: Trieste, Udine, Verona, Milan-Bicocca, Novara, Varese, Genoa, Sassari, Rome Campus, the Catholic University of Rome, Chieti, Foggia, Catania, Modena, Florence, Palermo, Bologna, Pavia, Parma and Ferrara. The lessons were attended by a total of 10,261 post-graduate medical students, for an average of 513.1 students per lesson. Seventy percent of the students judged the didactic content "excellent", 25% "good", and 5% "satisfactory"; none said it was unsatisfactory. In terms of visual quality (particularly the details of the radiological images proposed in the form of slides and/or video clips), 73% judged it "excellent", 20% "good", 6% "satisfactory", and 1% "poor". The audio quality was judged "excellent" by 71%, "good" by 22%, "satisfactory" by 6% and "poor" by 1%. In relation to judgement of audio and video quality, it has to be underlined that this was greatly affected by the hardware/software configuration and the band speed and technology of the Internet connection. Technological evolution is overcoming all barriers, and technology is also having a positive impact on the approach to teaching. Our multicentre teaching experience merits the following considerations: the quality of the teaching product was certified by the students' judgements of its didactic content and the quality of reception; the economic cost of the teaching had a minimal impact on the post-graduate schools (€ 18 per lesson). In terms of breaking down national barriers, it is to be hoped that the coordination and integration of diagnostic imaging e-learning projects, with the participation of post-graduate schools in different European countries, can be developed not only in a spirit of "cultural sharing" and the exchange of teaching experiences.


Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro.
Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were conducted to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib. The abilities of iniparib, olaparib, and veliparib to (i) selectively induce apoptosis or inhibit colony formation in HR-deficient cell lines, (ii) selectively sensitize HR-proficient cells to topoisomerase I poisons, and (iii) inhibit formation of poly(ADP-ribose) polymer (pADPr) in intact cells were compared. Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons camptothecin and topotecan. Finally, olaparib and veliparib inhibited formation of pADPr in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit pADPr formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine, or paclitaxel. While iniparib kills normal and neoplastic cells at high (>40 μmol/L) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.


The electrochemical and spectroelectrochemical properties of metal free and metallophthalocyanines containing triazole/piperazine units.
The synthesis and characterization of novel peripherally tetra [1,2,4]-triazole substituted metal-free phthalocyanine and its metal complexes (Zn(II), Ni(II), Pb(II), Cu(II) and Fe(II)) and the investigation of electrochemical and spectroelectrochemical properties of metal-free, Zn(II), Pb(II), Fe(II) phthalocyanines were performed for the first time in this study. Electrochemical characterizations of the complexes were performed with voltammetric and in situ spectroelectrochemical measurements. Voltammetric responses of the complexes supported the proposed structures, since complexes bearing redox inactive Pc ring metal centers just gave Pc based electron transfer reactions, while iron phthalocyanine went to metal based electron transfer reaction in addition to the Pc based ones. Electron withdrawing nature of [1,2,4]-triazole substituents shifted the redox processes toward the positive potentials. All complexes were electropolymerized during the oxidation reactions in dichloromethane (DCM) solvent. Types of the metal center of the complexes altered the electropolymerization reactions of the complexes. Spectra and colors of the electrogenerated redox species of the complexes were also determined with in situ spectroelectrochemical and in situ electrocolorimetric measurements.


Environmental Factors Affecting Pupation Decision in the Horned Flour Beetle Gnatocerus cornutus.
Social environments often affect the development of organisms. In Tenebrionidae beetles, larval development can be arrested at the final instar stage in the presence of conspecific larvae. This developmental plasticity is considered to be an anti-cannibalistic strategy but the critical environmental determinants and actual effects remain to be elucidated. In this study, we examined the effects of the heterospecific environment, conspecific sexual environment (i.e., presence of conspecific male or female), and abiotic physical stimulation on the pupation decision of the sexually dimorphic horned-flour beetle Gnatocerus cornutus. Additionally, actual anti-cannibalistic or antipredatory effects of developmental arrest were evaluated by analyzing stage-dependent vulnerabilities. When G. cornutus larvae were maintained with a G. cornutus larva, a G. cornutus adult, or T. castaneum adult, the developmental period up to the prepupal stage was significantly elongated, suggesting that the cue is not species-specific. Sexual environment did not affect the timing of pupation in G. cornutus; however, we found that abiotic tactile stimulations by glass beads could repress pupation. We also discovered that prepupal and pupal stages were more vulnerable to cannibalism and predation than the larval stage. These data suggest that G. cornutus larvae use non-species specific tactile stimulation as a decision cue for pupation and it has broader defensive effects against heterospecific predation as well as conspecific cannibalism.


VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics.
Insulin resistance and lower muscle quality (strength divided by mass) are hallmarks of type 2 diabetes (T2D). Here, we explore whether alterations in muscle stem cells (myoblasts) from individuals with T2D contribute to these phenotypes. We identify VPS39 as an important regulator of myoblast differentiation and muscle glucose uptake, and VPS39 is downregulated in myoblasts and myotubes from individuals with T2D. We discover a pathway connecting VPS39-deficiency in human myoblasts to impaired autophagy, abnormal epigenetic reprogramming, dysregulation of myogenic regulators, and perturbed differentiation. VPS39 knockdown in human myoblasts has profound effects on autophagic flux, insulin signaling, epigenetic enzymes, DNA methylation and expression of myogenic regulators, and gene sets related to the cell cycle, muscle structure and apoptosis. These data mimic what is observed in myoblasts from individuals with T2D. Furthermore, the muscle of Vps39+/- mice display reduced glucose uptake and altered expression of genes regulating autophagy, epigenetic programming, and myogenesis. Overall, VPS39-deficiency contributes to impaired muscle differentiation and reduced glucose uptake. VPS39 thereby offers a therapeutic target for T2D.


Mechanical thrombolysis in acute ischemic stroke with endovascular photoacoustic recanalization.
We present the results of endovascular photoacoustic recanalization (EPAR) treatment for acute ischemic stroke from the Safety and Performance Study at 6 centers in Europe and North America. The objectives of mechanical thrombolysis are rapid vessel recanalization and minimal use of chemical thrombolysis. This study was a prospective, nonrandomized study. The National Institutes of Health Stroke Scale (NIHSS) score and the modified Rankin Scale (mRS) score were recorded before treatment. The presence of recanalization was assessed by angiography. To measure outcome, follow-up examinations were performed at 24 hours, 7 days, and 30 days after stroke onset. Thirty-four patients (median NIHSS 19) were enrolled. Ten patients had internal carotid artery occlusion, 12 patients had middle cerebral artery occlusion, 11 patients had vertebrobasilar occlusion, and 1 patient had posterior cerebral artery occlusion. The overall recanalization rate was 41.1% (14/34). Complete EPAR treatment was possible in 18 patients (median NIHSS 18), with vessel recanalization in 11 patients (61.1%) after EPAR. The average lasing time was 9.65 minutes. Incomplete EPAR treatment (16/34, median NIHSS 19) was defined as intention to treat with EPAR and that the EPAR microcatheter entered the patient. Additional treatment with intraarterial application of rTPA occurred in 13 patients. An adverse event associated with use of the device occurred in 1 patient. Symptomatic hemorrhages occurred in 2 patients (5.9%). The mortality rate was 38.2%. This study demonstrates the safety and technical feasibility of EPAR. This new technique may provide another treatment option in the therapeutic armamentarium for patients with acute ischemic stroke.


Matrix association of early- and late-replicating chromatin studied by single-cell electrophoresis.
CHO-K1 cells were synchronized at the G(1)/S border by mitotic shake-off and aphidicolin incubation. Pulse-labeling with tritium was done at 30 min, 2 or 5 h into the S-phase, with chase incubations for different times in non-radioactive medium. The cells were subjected to neutral microelectrophoresis to extend the DNA into "comets," after which the label was visualized through autoradiography. At zero chase time, all label was positioned in the head. The displacement of label into the tails increased with time, reaching a maximum at about 5 h after the pulse. A lag phase of 2-3 h was observed for the early-labeled cells before the displacement started. Also, more label was released after overnight serum starvation, but this was reversed through a 3-h incubation at normal growth conditions. It was found that late-replicating chromatin is organized in larger domains than early-replicating chromatin, and DNA polymerase seems to be an important organizer. Early-replicating chromatin has other important attachments to the nuclear matrix, dependent on metabolic activity.


Liquid-Infused Structured Titanium Surfaces: Antiadhesive Mechanism to Repel Streptococcus oralis Biofilms.
To combat implant-associated infections, there is a need for novel materials which effectively inhibit bacterial biofilm formation. In the present study, the antiadhesive properties of titanium surface functionalization based on the "slippery liquid-infused porous surfaces" (SLIPS) principle were demonstrated and the underlying mechanism was analyzed. The immobilized liquid layer was stable over 13 days of continuous flow in an oral flow chamber system. With increasing flow rates, the surface exhibited a significant reduction in attached biofilm of both the oral initial colonizer Streptococcus oralis and an oral multispecies biofilm composed of S. oralis, Actinomyces naeslundii, Veillonella dispar, and Porphyromonas gingivalis. Using single cell force spectroscopy, reduced S. oralis adhesion forces on the lubricant layer could be measured. Gene expression patterns in biofilms on SLIPS, on control surfaces, and expression patterns of planktonic cultures were also compared. For this purpose, the genome of S. oralis strain ATCC 9811 was sequenced using PacBio Sequel technology. Even though biofilm cells showed clear changes in gene expression compared to planktonic cells, no differences could be detected between bacteria on SLIPS and on control surfaces. Therefore, it can be concluded that the ability of liquid-infused titanium to repel S. oralis biofilms is mainly due to weakened bacterial adhesion to the underlying liquid interface.


Regeneration of the mammalian inner ear sensory epithelium.
This review will focus on 'self-repair' of the mammalian inner ear sensory epithelium, including recruiting the in-situ proliferation and differentiation of endogenous cells at the damaged site and the autologous transplantation Self-repair refers to a favorable structural and functional outcome of damaged inner ear sensory epithelium. Our advanced ability of manipulating the fate of inner ear sensory cells makes in-situ proliferation a possible candidate of hearing restoration. A practical alternative of the unavoidable immune rejection is to introduce autologous cells. Ependymal cells, induced pluripotent stem cells, and olfactory neuroepithelial cells have been recognized as promising sources, which will spur ongoing efforts to evaluate these new cell sources for cell replacement therapy. Further exploration of the innate advantages of in-situ proliferation and use of novel cell sources for autologous transplantation may serve as rehearsals for clinical trials in the near future.


Investigation of the acceptance of a handbook for safe driving at an older age.
The objective of this research is the investigation of older drivers' attitudes towards a handbook for safe driving at an older age. The handbook was developed with the purpose of increasing elderly drivers' awareness of their driving abilities and providing information about the effects of ageing on driving and about safe driving practices and compensation strategies. A survey was carried out in which 64 active drivers between 65 and 74 years of age participated. Participants regard the handbook for safe driving as useful, interesting, providing knowledge and relevant information. More than half of them reported that they had become more aware of changes in their driving after reading it. Binary logistic analysis was conducted to identify individual driver characteristics that might predict acceptance of the handbook by active older drivers in terms of reported increased awareness and intended repeated use. The findings of the research indicate a positive attitude of elderly active drivers towards the handbook, implying acceptance by its users. The characteristics of the drivers' who reported increased awareness after reading have been identified.


Scavenger receptors clear the air.
Inhaled environmental oxidants, such as ozone and particulates, have been variably linked to epithelial injury, inflammation, and perturbations in lung development, growth, and function. Reactions between ozone and lung surface lipids likely account for exposure-related pathophysiologic sequelae. In this issue of the JCI, Dahl et al. document a previously unrecognized pulmonary defense against inhaled oxidants in mice: macrophage scavenger receptors (SRs) bind proinflammatory oxidized lipids, thereby decreasing pulmonary inflammation (see the related article beginning on page 757). The study adds to our knowledge of diverse lung oxidative processes and identifies a potential regulatory mechanism governing pulmonary inflammation. Further investigations to elucidate more precise mechanisms and to determine the influence of SRs on airway epithelial injury, repair, and remodeling are warranted.


Exchange-transfusion with pyridoxalated polymerized hemoglobin: effects on liver PO2.
To examine the efficacy of modified stroma-free hemoglobin in maintaining liver PO2, rats were exchange-transfused to hematocrit 10% using pyridoxalated polymerized hemoglobin (plp-polyHb, 10-12 g/dl) prepared from crystalline Hb. Following hemodilution, plasma Hb was 7.4 g/dl, and rats were normotensive. Mean liver PO2 was 3.4 vs 23.3 mm Hg in sham-exchanged controls. Other rats, hemodiluted similarly with 6% albumin or hydroxyethylstarch, were hypotensive and died. At 24 hours plasma Hb was 2.0 g/dl, indicating an intravascular half-life of approximately 16 hours. Hepatic PO2 was 12.4 vs 26.8 mm Hg in nonhemodiluted controls. Data provided by clearance of low-dose indocyanine green suggested reduced plasma volume and depressed liver blood flow. Scattered foci of midzonal hypoxic damage were observed in liver lobules. The basis for hypoxic injury is considered to be due in part to the acute restriction of oxygen supply induced by exchange-transfusion with plp-polyHb. The rate of loss of intravascular hemoglobin and diminished plasma volume could have contributed to oxygen insufficiency as well. Endotoxin present in the plp-polyHb was not a factor.


How Do Newly Diagnosed Chronic Health Conditions Affect Older Workers' Vitality and Worries About Functional Ability?
With increasing retirement ages, older workers are working longer while being newly diagnosed with chronic health conditions (CHCs). Our knowledge on how newly diagnosed CHCs influence older workers' vitality and worries is limited. We examine how four newly diagnosed CHCs affect older workers' vitality and worries about physical and mental functional ability. We used data from a Dutch pension panel survey. A sample of 1,894 older workers (60-62 years) was analyzed using conditional change OLS regression models. Having CHCs decreased vitality and increased worries. This effect was worse for older workers newly diagnosed with CHCs. Being newly diagnosed with physically disabling conditions increased worries about physical functioning, while being newly diagnosed with mentally disabling conditions increased worries about mental functioning. These findings aid the identification of vulnerable groups of older workers, thereby informing interventions that could improve quality of life, while promoting healthy aging at work.


Enhancement of basolateral amygdaloid neuronal dendritic arborization following Bacopa monniera extract treatment in adult rats.
In the ancient Indian system of medicine, Ayurveda, Bacopa monniera is classified as Medhya rasayana, which includes medicinal plants that rejuvenate intellect and memory. Here, we investigated the effect of a standardized extract of Bacopa monniera on the dendritic morphology of neurons in the basolateral amygdala, a region that is concerned with learning and memory. The present study was conducted on 2½-month-old Wistar rats. The rats were divided into 2-, 4- and 6-week treatment groups. Rats in each of these groups were further divided into 20 mg/kg, 40 mg/kg and 80 mg/kg dose groups (n = 8 for each dose). After the treatment period, treated rats and age-matched control rats were subjected to spatial learning (T-maze) and passive avoidance tests. Subsequently, these rats were killed by decapitation, the brains were removed, and the amygdaloid neurons were impregnated with silver nitrate (Golgi staining). Basolateral amygdaloid neurons were traced using camera lucida, and dendritic branching points (a measure of dendritic arborization) and dendritic intersections (a measure of dendritic length) were quantified. These data were compared with the data from the age-matched control rats. The results showed an improvement in spatial learning performance and enhanced memory retention in rats treated with Bacopa monniera extract. Furthermore, a significant increase in dendritic length and the number of dendritic branching points was observed along the length of the dendrites of the basolateral amygdaloid neurons of rats treated with 40 mg/kg and 80 mg/kg of Bacopa monniera (BM) for longer periods of time (i.e., 4 and 6 weeks). We conclude that constituents present in Bacopa monniera extract have neuronal dendritic growth-stimulating properties.


Nitric oxide synthases and cardiovascular diseases: insights from genetically modified mice.
Nitric oxide (NO) is produced in almost all tissues and organs, exerting a variety of biological actions under both physiological and pathological conditions. NO is synthesized by 3 distinct NO synthase (NOS) isoforms (neuronal, inducible, and endothelial NOS), all of which are expressed in the human cardiovascular system. The regulatory roles of NOSs in cardiovascular diseases have been described in pharmacological studies with selective and non-selective NOS inhibitors. However, the specificity of the NOS inhibitors continues to be an issue of debate. To overcome this issue, genetically engineered animals have been used. All types of NOS gene-deficient (knockout: KO) animals, including singly, doubly, and triply NOS-KO mice, and various types of NOS gene-transgenic (TG) animals, including conditional and non-conditional TG mice bearing endothelium-specific or cardiomyocyte-specific overexpression of each NOS gene, have thus far been developed. The roles of individual NOS isoforms, as well as the entire NOS system, in the cardiovascular system have been extensively investigated in those mice, and the results provide pivotal insights into the pathophysiology of NOSs in human cardiovascular diseases. Based on studies with murine NOS genetic models, this review summarizes the latest knowledge of NOSs and cardiovascular diseases.


A comparison of the effects of three GM corn varieties on mammalian health.
We present for the first time a comparative analysis of blood and organ system data from trials with rats fed three main commercialized genetically modified (GM) maize (NK 603, MON 810, MON 863), which are present in food and feed in the world. NK 603 has been modified to be tolerant to the broad spectrum herbicide Roundup and thus contains residues of this formulation. MON 810 and MON 863 are engineered to synthesize two different Bt toxins used as insecticides. Approximately 60 different biochemical parameters were classified per organ and measured in serum and urine after 5 and 14 weeks of feeding. GM maize-fed rats were compared first to their respective isogenic or parental non-GM equivalent control groups. This was followed by comparison to six reference groups, which had consumed various other non-GM maize varieties. We applied nonparametric methods, including multiple pairwise comparisons with a False Discovery Rate approach. Principal Component Analysis allowed the investigation of scattering of different factors (sex, weeks of feeding, diet, dose and group). Our analysis clearly reveals for the 3 GMOs new side effects linked with GM maize consumption, which were sex- and often dose-dependent. Effects were mostly associated with the kidney and liver, the dietary detoxifying organs, although different between the 3 GMOs. Other effects were also noticed in the heart, adrenal glands, spleen and haematopoietic system. We conclude that these data highlight signs of hepatorenal toxicity, possibly due to the new pesticides specific to each GM corn. In addition, unintended direct or indirect metabolic consequences of the genetic modification cannot be excluded.


Development of a cervical cancer prevention text-messaging program for women living with HIV.
Cervical cancer screening and human papillomavirus (HPV) vaccination are critical for those immunocompromised due to human immunodeficiency virus (HIV). Health education programs, including text messaging, can effectively improve knowledge of cervical cancer and recommended screening. This paper describes the data-driven development of a 4-week text-messaging intervention to improve HPV and cervical cancer knowledge among women living with HIV (WLH). This study reports data from surveys (n = 81; January 2020 to September 2021) and focus group discussions (FGDs, n = 39; April-June 2020) conducted among WLH in the DC area. While most WLH revealed that their usual sources of health information were through in-person group sessions, they pointed out that these were impractical options due to the coronavirus 2019 pandemic. They noted that a text-messaging intervention was feasible and acceptable. FGD participants' responses structured around the Protection Motivation Theory constructs informed the text-messaging library, covering topics such as (I) understanding of cervical cancer and HPV, (II) cervical cancer prevention and (III) HPV self-sampling. The utilization of low-cost and easily accessible health education interventions, such as mobile-based text messaging, can effectively increase knowledge and awareness of cervical cancer in populations that have been historically difficult to access and during times when health services are disrupted such as during a global pandemic or public health emergency.


Immune reactivity to dengue and Aedes albopictus mosquitoes in the population from Macao, China, before dengue occurrence.
A serological survey was conducted in Macao, China, in 753 individuals, with the objective of looking for antibodies to the mosquito, Aedes albopictus (Skuse 1894) (Diptera: Culicidae), and to dengue, before the occurrence of any autochthonous dengue cases. Blood samples were collected at several public health services, a questionnaire was answered, and enzyme-linked immunosorbant assay (ELISA) and Western blot techniques were performed with extracts of mosquito head and thorax (HT). Anti-Aedes albopictus IgG antibodies were present in titres 1:10(2)-1:10(3) in 9%, and in titres 1:10(4)-1:10(5) in 42% of the sera tested. This reactivity was more frequent (59%) in the population which had resided only in Macao in the 2 years previous to the survey, as opposed to those that had also resided in other areas (50%). From the 230 reactive sera selected for immunoblot, 48 (21%) reacted with a wide range of proteins from above 224 kDa to 21 kDa, with different patterns according to individual sera. Proteins in the intervals 35.3-28.7 kDa and 28.7-21.1 kDa were labelled by the greatest number of sera, 15 and 19 respectively. The presence of anti-Aedes albopictus antibodies presented a statistical relation to skin reaction to mosquito bites, but immunoblot patterns did not. Anti-dengue IgG antibodies were found in 48% of the subjects, with a higher proportion in people who had resided out of Macao, or who were nationals from dengue-endemic neighboring countries. Anti-dengue reactivity was in agreement with anti-mosquito reactivity in half of the population. It would be interesting to see if this proportion has changed since dengue became endemic in Macao in 2001.


Redundant role of the Syk protein tyrosine kinase in mouse NK cell differentiation.
Syk and ZAP-70 subserve nonredundant functions in B and T lymphopoiesis. In the absence of Syk, B cell development is blocked, while T cell development is arrested in the absence of ZAP-70. The receptors and the signaling molecules required for differentiation of NK cells are poorly characterized. Here we investigate the role of the Syk protein tyrosine kinase in NK cell differentiation. Hemopoietic chimeras were generated by reconstituting alymphoid (B-, T-, NK-) recombinase-activating gene-2 x common cytokine receptor gamma-chain double-mutant mice with Syk-/- fetal liver cells. The phenotypically mature Syk-/- NK cells that developed in this context were fully competent in natural cytotoxicity and in calibrating functional inhibitory receptors for MHC molecules. Syk-deficient NK cells demonstrated reduced levels of Ab-dependent cellular cytotoxicity. Nevertheless, Syk-/- NK cells could signal through NK1. 1 and 2B4 activating receptors and expressed ZAP-70 protein. We conclude that the Syk protein tyrosine kinase is not essential for murine NK cell development, and that compensatory signaling pathways (including those mediated through ZAP-70) may sustain most NK cell functions in the absence of Syk.


Electrochemistry and catalytic properties for dioxygen reduction using ferrocene-substituted cobalt porphyrins.
Cobalt porphyrins having 0-4 meso-substituted ferrocenyl groups were synthesized and examined as to their electrochemical properties in N,N'-dimethylformamide (DMF) containing 0.1 M tetra-n-butylammonium perchlorate as a supporting electrolyte. The examined compounds are represented as (Fc)n(CH3Ph)(4-n)PorCo, where Por is a dianion of the substituted porphyrin, Fc and CH3Ph represent ferrocenyl and/or p-CH3C6H4 groups linked at the four meso-positions of the macrocycle, and n varies from 0 to 4. Each porphyrin undergoes two reversible one-electron reductions and two to six one-electron oxidations in DMF, with the exact number depending upon the number of Fc groups on the compound. The first electron addition is metal-centered to generate a Co(I) porphyrin. The second is porphyrin ring-centered and leads to formation of a Co(I) π-anion radical. The first oxidation of each Co(II) porphyrin is metal-centered to generate a Co(III) derivative under the given solution conditions. Each ferrocenyl substituent can also be oxidized by one electron, and this occurs at more positive potentials. Each compound was investigated as a catalyst for the electoreduction of dioxygen when adsorbed on a graphite electrode in 1.0 M HClO4. The number of electrons transferred (n) during the catalytic reduction was 2.0 for the three ferrocenyl substituted compounds, consistent with only H2O2 being produced as a product of the reaction. Most monomeric cobalt porphyrins exhibit n values between 2.6 and 3.1 under the same solution conditions, giving a mixture of H2O and H2O2 as a reduction product, although some monomeric porphyrins can give an n value of 4.0. Our results in the current study indicate that appending ferrocene groups directly to the meso positions of a porphyrin macrocycle will increase the selectivity of the oxygen reduction, resulting in formation of only H2O2 as a reaction product. This selectivity of the electrocatalytic oxygen reduction reaction is explained on the basis of steric hindrance by the ferrocene substituents which prevent dimerization.


Melatonin protects against oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the mouse nigrostriatum.
We tested the hypothesis that melatonin acts as a powerful hydroxyl radical (*OH) scavenger in vivo in the brain, and interferes with oxidative stress caused by the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We investigated the effect of melatonin on in vitro *OH production employing a Fenton-like reaction in test tubes, and ex vivo *OH generation in isolated mitochondria induced by 1-methyl-4-phenyl pyridinium (MPP+), as well as on in vivo *OH formation in the mouse striatum following systemic administration of MPTP. We also measured reduced glutathione (GSH) levels, and superoxide dismutase (SOD) activity in the nucleus caudatus putamen (NCP) and substantia nigra (SN), 7 days following MPTP and/or melatonin administration. Melatonin caused a significant and dose-dependent inhibition of the production of *OH in the in vitro, ex vivo and in vivo experimental conditions. Melatonin caused no changes in monoamine oxidase-B activity, in vitro in mitochondrial P2 fractions or in vivo following systemic administration. MPTP treatment in mice caused a significant depletion of GSH, and increased the specific activity of SOD both in SN and NCP on the seventh day. MPTP-induced GSH depletion was dose-dependently blocked in SN and NCP by melatonin. Higher doses of melatonin exhibited a synergistic effect on MPTP-induced increase in the SOD activity in the SN. These results suggest that while GSH inhibition is a direct consequence of *OH generation following neurotoxin administration, the increase in SOD activity is a compensatory mechanism for removing superoxide radicals generated as the result of MPTP. Our results not only point to the potency of melatonin in blocking the primary insults caused by MPTP, but also provide evidence for triggering secondary neuroprotective mechanisms, suggesting its use as a therapeutic agent in neurodegenerative disorders, such as Parkinson's disease.


Defined genetic events associated with the spontaneous in vitro transformation of ElA/Ras-expressing human IMR90 fibroblasts.
In contrast to rodent cells, normal human fibroblasts are generally resistant to neoplastic transformation in vitro. Here, we report the derivation and characterization of a spontaneously transformed cell line from normal human IMR90 fibroblasts transduced with E1A and Ras oncogenes. Unlike the parental, non-tumorigenic E1A/Ras-expressing IMR90 cells, these spontaneously transformed cells displayed aberrant growth potential in vitro and were capable of tumorigenesis in vivo. In contrast to the parental E1A/Ras-expressing cells, both the spontaneously transformed cells and cells derived from resultant tumors displayed specific t(7q;8q) and t(5q;17) structural chromosomal changes. Chromosome 8q contains c-Myc, which is capable of activating the telomerase catalytic subunit hTERT. Notably, upregulation of c-Myc, hTERT and telomerase activity were detected only in the tumorigenic cells. Transduction of Myc siRNA into the tumorigenic cells led to a concomitant downregulation of hTERT. Furthermore, transduction of Myc or hTERT into the non-tumorigenic E1A/Ras-expressing IMR90 cells was able to confer tumorigenesis on these cells. These studies suggest that the t(7;8) translocation may result in Myc overexpression and its subsequent activation of hTERT, which may contribute to the tumorigenicity of the IMR90 cells. Furthermore, this report describes additional successful neoplastic transformation of human IMR90 fibroblasts by defined genetic elements. The spontaneously transformed cells we have derived provide a valuable model system for the study of neoplastic transformation.


Nutritional prevention of cognitive decline and dementia.
Cognitive impairment results from a complex interplay of many factors. The most important independent predictor of cognitive decline is age but other contributing factors include demographic, genetic, socio-economic, and environmental parameters, including nutrition. The number of persons with cognitive decline and dementia will increase in the next decades in parallel with aging of the world population. Effective pharmaceutical treatments for age-related cognitive decline are lacking, emphasizing the importance of prevention strategies. There is extensive evidence supporting a relationship between diet and cognitive functions. Thus, nutritional approaches to prevent or slow cognitive decline could have a remarkable public health impact. Several dietary components and supplements have been examined in relation to their association with the development of cognitive decline. A number of studies have examined the role of dietary patterns on late-life cognition, with accumulating evidence that combinations of foods and nutrients may act synergistically to provide stronger benefit than those conferred by individual dietary components. Higher adherence to the Mediterranean dietary pattern has been associated with decreased cognitive decline and incident AD. Another dietary pattern with neuroprotective actions is the Dietary Approach to Stop Hypertension (DASH). The combination of these two dietary patterns has been associated with slower rates of cognitive decline and significant reduction in incident AD. This review evaluates the evidence for the effects of some dietary components, supplements, and dietary patterns as neuroprotective, with potential to delay cognitive decline and the onset of dementia.


Hepatocellular carcinoma amongst Aboriginal and Torres Strait Islander peoples of Australia.
Liver disease and hepatocellular carcinoma (HCC) are important contributors to the mortality gap between Indigenous and non-Indigenous Australians. However, there is a lack of population based high quality data assessing the differences in HCC epidemiology and outcomes according to Indigenous status. The aim of this study was therefore to perform a large epidemiological study of HCC investigating differences between Indigenous and non-Indigenous Australians with HCC. Study design was a retrospective cohort study. Data linkage methodology was used to link data from cancer registries with hospital separation summaries across three Australian jurisdictions during 2000-2017. Cumulative survival (Kaplan-Meier) and the differences in survival (Multivariable Cox-regression) by Indigenous status were assessed. A total of 229 Indigenous and 3587 non-Indigenous HCC cases were included in the analyses. Significant epidemiological differences identified for Indigenous HCC cases included younger age at onset, higher proportion of females, higher rurality, lower socioeconomic status, and higher comorbidity burden (all p < 0.001). The distribution of cofactors was also significantly different for Indigenous Australians including higher prevalence of alcohol misuse, hepatitis B, and diabetes and more frequent presence of multiple HCC cofactors (all p < 0.001). Indigenous Australians received curative HCC therapies less frequently (6.6% vs. 14.5%, p < 0.001) and had poorer 5-year survival (10.0% vs. 17.3%, p < 0.001; unadjusted hazard ratio (HR) =1.42 96%CI 1.21-1.65) compared to non-Indigenous Australians. The strength of the association between indigenous status and survival was weaker and statistically non-significant after adjusting for rurality, comorbidity burden and lack of curative therapy (adjusted-HR=1.20 95%CI 0.97-1.47). Such data provide a call to action to help design and implement health literacy, liver management and HCC surveillance programs for Indigenous people to help close the liver cancer mortality gap.


Evidence for histidine in the active site of papain.
Papain was irreversibly inhibited by 1,3-dibromoacetone, a reagent designed to react first with the active-site cysteine residue and subsequently with a second nucleophile. The molecular weight of the inhibited enzyme was indistinguishable from that of papain itself, and no evidence of dimeric or oligomeric species was found. The optical-rotatory-dispersion curves of chloroacetone-inhibited papain and 1,3-dibromoacetone-inhibited papain were essentially similar. Amino acid analysis of the 1,3-dibromo[2-(14)C]acetone-inhibited enzyme and the performic acid-oxidized material clearly showed that a cysteine and histidine residue had been alkylated through the thiol and N-1 of the imidazole group respectively. These groups must therefore be within 5å of each other in the tertiary structure of papain. Possible mechanistic implications are briefly discussed.


Diffractive optics applied to free-space optical interconnects.
The optimum design of free-space optical interconnection systems utilizing diffractive optics is determined from a practical engineering standpoint for systems ranging from space invariant to fully space variant. System volume is calculated in terms of parameters such as the f-number of the diffractive lens, the wavelength of light, and also the total number, size, and separation of the optical sources and detectors. Performance issues such as interconnection complexity, diffraction efficiency, and signal-tonoise ratio are discussed. Diffractive optics fabricated by electron-beam direct-write techniques are used to provide experimental results for both shuffle-exchange and twin-butterfly free-space optical interconnects.


Analysis of proteins secreted by mouse embryos developing in vivo and in vitro.
Proteins secreted by mouse blastocysts developing in vitro were compared to these from blastocysts developing in utero to determine if a simple medium supporting blastocyst development also supports secreted protein expression. In-vivo embryos were collected on days 3, 4, or 5 of pregnancy and incubated in 35S-methionine to produce conditioned medium containing released, labeled proteins. Embryos for culture were collected on day 3 and after 48 or 72 h labeled conditioned medium was produced. Labeled proteins were separated by two-dimensional electrophoresis and compared using a digital image analysis system. Day 3 embryos did not release proteins in detectable amounts, although synthesis of intracellular proteins was substantial. Day-4 and -5 blastocysts released proteins in increasing amount and complexity, consistent with previous results. When day-3 embryos were cultured in medium containing 4 mg/ml BSA for 48 h, secreted protein patterns were similar but not identical to those of day-5 uterine blastocysts. Although most of the proteins produced by uterine blastocysts were secreted by cultured embryos, differences were found in the relative quantities of certain proteins. Neither crystallized BSA nor polyvinyl alcohol at 4 mg/ml supported development of protein secretion as well as the crude fraction-V BSA. Blastocysts restricted to the oviduct also exhibited quantitative differences in protein secretion patterns compared to uterine blastocysts. Thus, although blastocyst development and the expression of many secreted proteins are supported outside the uterus, the full pattern of secretion characteristic of the peri-implantation embryo may be dependent on specific uterine influences.


Home-based voluntary HIV counselling and testing found highly acceptable and to reduce inequalities.
Low uptake of voluntary HIV counselling and testing (VCT) in sub-Saharan Africa is raising acceptability concerns which might be associated with ways by which it is offered. We investigated the acceptability of home-based delivery of counselling and HIV testing in urban and rural populations in Zambia where VCT has been offered mostly from local clinics. A population-based HIV survey was conducted in selected communities in 2003 (n = 5035). All participants stating willingness to be HIV tested were offered VCT at home and all counselling was conducted in the participants' homes. In the urban area post-test counselling and giving of results were done the following day whereas in rural areas this could take 1-3 weeks. Of those who indicated willingness to be HIV tested, 76.1% (95%CI 74.9-77.2) were counselled and received the test result. Overall, there was an increase in the proportion ever HIV tested from 18% before provision of home-based VCT to 38% after. The highest increase was in rural areas; among young rural men aged 15-24 years up from 14% to 42% vs. for urban men from 17% to 37%. Test rates by educational attainment changed from being positively associated to be evenly distributed after home-based VCT. A high uptake was achieved by delivering HIV counselling and testing at home. The highest uptakes were seen in rural areas, in young people and groups with low educational attainment, resulting in substantial reductions in existing inequalities in accessing VCT services.


Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations.
Identification and characterization of the genetic variants underlying type 2 diabetes susceptibility can provide important understanding of the etiology and pathogenesis of type 2 diabetes. We previously identified strong evidence of linkage for type 2 diabetes on chromosome 22 among 3,383 Hypertension Genetic Epidemiology Network (HyperGEN) participants from 1,124 families. The checkpoint 2 (CHEK2) gene, an important mediator of cellular responses to DNA damage, is located 0.22 Mb from this linkage peak. In this study, we tested the hypothesis that the CHEK2 gene contains one or more polymorphic variants that are associated with type 2 diabetes in HyperGEN individuals. In addition, we replicated our findings in two other Family Blood Pressure Program (FBPP) populations and in the population-based Atherosclerosis Risk in Communities (ARIC) study. We genotyped 1,584 African-American and 1,531 white HyperGEN participants, 1,843 African-American and 1,569 white GENOA participants, 871 African-American and 1,009 white GenNet participants, and 4,266 African-American and 11,478 white ARIC participants for four single nucleotide polymorphisms (SNPs) in CHEK2. Using additive models, we evaluated the association of CHEK2 SNPs with type 2 diabetes in participants within each study population stratified by race, and in a meta-analysis, adjusting for age, age(2), sex, sex-by-age interaction, study center, and relatedness. One CHEK2 variant, rs4035540, was associated with an increased risk of type 2 diabetes in HyperGEN participants, two replication samples, and in the meta-analysis. These results may suggest a new pathway in the pathogenesis of type 2 diabetes that involves pancreatic beta-cell damage and apoptosis.