Social inequalities in osteoporosis and fracture among community-dwelling older men and women: findings from the Hertfordshire Cohort Study.
It is unknown whether osteoporosis is socially patterned. Using data from the Hertfordshire Cohort Study we found no consistent evidence for social inequalities in prevalent or incident fracture, bone mineral density or loss rates, or bone strength. Public health strategies for prevention of osteoporosis should focus on the whole population. Osteoporosis and osteoporotic fracture are major public health issues for society; the burden for the affected individual is also high. It is unclear whether osteoporosis and osteoporotic fracture are socially patterned. This study aims to analyse social inequalities in osteoporosis and osteoporotic fracture among the 3,225 community-dwelling men and women, aged 59-73 years, who participated in the Hertfordshire Cohort Study (HCS), UK. A panel of markers of bone health (fracture since 45 years of age; DXA bone mineral density and loss rate at the total femur; pQCT strength strain indices for the radius and tibia; and incident fracture) were analysed in relation to the social circumstances of the HCS participants (characterised at the individual level by: age left full time education; current social class; housing tenure and car availability). We found little strong or consistent evidence among men, or women, for social inequalities in prevalent or incident fracture, DXA bone mineral density, bone loss rates, or pQCT bone strength, with or without adjustment for age, anthropometry, lifestyle and clinical characteristics. Reduced car availability at baseline was associated with lower pQCT radius and tibia strength strain indices at follow-up among men only (p = 0.02 radius and p < 0.01 tibia unadjusted; p = 0.05 radius and p = 0.01 tibia, adjusted for age, anthropometry, lifestyle and clinical characteristics). Our results suggest that fracture and osteoporosis do not have a strong direct social gradient and that public health strategies for prevention and treatment of osteoporosis should continue to focus on the whole population.


High oligomycin concentrations augment 6-keto-PGF1 alpha production in ventricular cardiomyocytes.
Incubation of cultured ventricular cardiomyocytes with high oligomycin concentrations (100 micrograms/ml), either alone or combined with 2-deoxyglucose (20 mM), led to the rapid depletion of cellular ATP. Inositol (poly)phosphate production decreased, and 6-keto PGF1 alpha production was increased. In cells depleted of ATP, either by low oligomycin concentrations or by sodium azide, 6-keto PGF1 alpha was not appreciably increased. There was a 25% rise in the release of fatty acids from the sn-2 position in glycerophospholipids. We suggest that oligomycin at high concentrations causes the release of free arachidonic acid from phospholipids either by non-PIP2-specific PLC and DG lipase or by phospholipase D, phosphatidic acid phosphatase and DG lipase. The effect is unrelated to decreased cellular ATP content.


Three-dimensional virtual imaging of renal tumours: a new tool to improve the accuracy of nephrometry scores.
To apply the standard PADUA and RENAL nephrometry score variables to three-dimensional (3D) virtual models (VMs) produced from standard bi-dimensional imaging, thereby creating three-dimensional (3D)-based (PADUA and RENAL) nephrometry scores/categories for the reclassification of the surgical complexity of renal masses, and to compare the new 3D nephrometry score/category with the standard 2D-based nephrometry score/category, in order to evaluate their predictive role for postoperative complications. All patients with localized renal tumours scheduled for minimally invasive partial nephrectomy (PN) between September 2016 and September 2018 underwent 3D and 2D nephrometry score/category assessments preoperatively. After nephrometry score/category evaluation, all the patients underwent surgery. Chi-squared tests were used to evaluate the individual patients' grouping on the basis of the imaging tool (3D VMs and 2D imaging) used to assess the nephrometry score/category, while Cohen's κ coefficient was used to test the concordance between classifications. Receiver-operating characteristic curves were produced to evaluate the sensitivity and specificity of the 3D nephrometry score/category vs the 2D nephrometry score/category in predicting the occurrence of postoperative complications. A general linear model was used to perform multivariable analyses to identify predictors of overall and major postoperative complications. A total of 101 patients were included in the study. The evaluation of PADUA and RENAL nephrometry scores via 3D VMs showed a downgrading in comparison with the same scores evaluated with 2D imaging in 48.5% and 52.4% of the cases. Similar results were obtained for nephrometry categories (29.7% and 30.7% for PADUA risk and RENAL complexity categories, respectively). The 3D nephrometry score/category demonstrated better accuracy than the 2D nephrometry score/category in predicting overall and major postoperative complications (differences in areas under the curve for each nephrometry score/category were statistically significant comparing the 3D VMs with 2D imaging assessment). Multivariable analyses confirmed 3D PADUA/RENAL nephrometry category as the only independent predictors of overall (P = 0.007; P = 0.003) and major postoperative complications (P = 0.03; P = 0.003). In the present study, we showed that 3D VMs were more precise than 2D standard imaging in evaluating the surgical complexity of renal masses according to nephrometry score/category. This was attributable to a better perception of tumour depth and its relationships with intrarenal structures using the 3D VM, as confirmed by the higher accuracy of the 3D VM in predicting postoperative complications.


Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients.
Pneumocystis jirovecii is the only fungus of its kind to be pathogenic in humans. It is primarily responsible for pneumonia (PJP). The key to understanding immune defences has focused on T-cells, mainly because of the HIV infection epidemic. Patients presenting with PJP all have a CD4 count below 200/mm(3). The introduction of systematic primary prophylaxis and the use of new anti-retroviral drugs have significantly reduced the incidence of this disease in the HIV-infected population, mainly in developed countries. The increasingly frequent use of corticosteroids, chemotherapy, and other immunosuppressive drugs has led to an outbreak of PJP in patients not infected by HIV. These patients presenting with PJP have more rapid and severe symptoms, sometimes atypical, leading to delay the initiation of a specific anti-infective therapy, sometimes a cause of death. However, the contribution of new diagnostic tools and a better understanding of patients at risk should improve their survival.


Pediatric antidepressant medication errors in a national error reporting database.
To describe inpatient and outpatient pediatric antidepressant medication errors. We analyzed all error reports from the United States Pharmacopeia MEDMARX database, from 2003 to 2006, involving antidepressant medications and patients younger than 18 years. Of the 451 error reports identified, 95% reached the patient, 6.4% reached the patient and necessitated increased monitoring and/or treatment, and 77% involved medications being used off label. Thirty-three percent of errors cited administering as the macrolevel cause of the error, 30% cited dispensing, 28% cited transcribing, and 7.9% cited prescribing. The most commonly cited medications were sertraline (20%), bupropion (19%), fluoxetine (15%), and trazodone (11%). We found no statistically significant association between medication and reported patient harm; harmful errors involved significantly more administering errors (59% vs 32%, p = .023), errors occurring in inpatient care (93% vs 68%, p = .012) and extra doses of medication (31% vs 10%, p = .025) compared with nonharmful errors. Outpatient errors involved significantly more dispensing errors (p < .001) and more errors due to inaccurate or omitted transcription (p < .001), compared with inpatient errors. Family notification of medication errors was reported in only 12% of errors. Pediatric antidepressant errors often reach patients, frequently involve off-label use of medications, and occur with varying severity and type depending on location and type of medication prescribed. Education and research should be directed toward prompt medication error disclosure and targeted error reduction strategies for specific medication types and settings.


A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns.
Congenital diaphragmatic hernia (CDH) is a condition with a highly variable outcome. Some infants have a relatively mild disease process, whereas others have significant pulmonary hypoplasia and hypertension. Identifying high-risk infants postnatally may allow for targeted therapy. Data were obtained on 2202 infants from the Congenital Diaphragmatic Hernia Study Group database from January 2007 to October 2011. Using binary baseline predictors generated from birth weight, 5-minute Apgar score, congenital heart anomalies, and chromosome anomalies, as well as echocardiographic evidence of pulmonary hypertension, a clinical prediction rule was developed on a randomly selected subset of the data by using a backward selection algorithm. An integer-based clinical prediction rule was created. The performance of the model was validated by using the remaining data in terms of calibration and discrimination. The final model included the following predictors: very low birth weight, absent or low 5-minute Apgar score, presence of chromosomal or major cardiac anomaly, and suprasystemic pulmonary hypertension. This model discriminated between a population at high risk of death (∼50%) intermediate risk (∼20%), or low risk (<10%). The model performed well, with a C statistic of 0.806 in the derivation set and 0.769 in the validation set and good calibration (Hosmer-Lemeshow test, P = .2). A simple, generalizable scoring system was developed for CDH that can be calculated rapidly at the bedside. Using this model, intermediate- and high-risk infants could be selected for transfer to high-volume centers while infants at highest risk could be considered for advanced medical therapies.


3D/2D convertible projection-type integral imaging using concave half mirror array.
We propose a new method for implementing 3D/2D convertible feature in the projection-type integral imaging by using concave half mirror array. The concave half mirror array has the partially reflective characteristic to the incident light. And the reflected term is modulated by the concave mirror array structure, while the transmitted term is unaffected. With such unique characteristic, 3D/2D conversion or even the simultaneous display of 3D and 2D images is also possible. The prototype was fabricated by the aluminum coating and the polydimethylsiloxane molding process. We could experimentally verify the 3D/2D conversion and the display of 3D image on 2D background with the fabricated prototype.


Higher Cord Blood Levels of Fatty Acids in Pregnant Women With Type 1 Diabetes Mellitus.
Type 1 diabetes mellitus (T1DM) is associated with a disturbance of carbohydrate and lipid metabolism. To determine whether T1DM alters maternal and neonatal fatty acid (FA) levels. Observational study. Academic hospital. Sixty pregnant women (30 women with T1DM with good glycemic control and 30 healthy women) were included in the study. Maternal blood, umbilical vein, and artery blood samples were collected immediately upon delivery. Following lipid extraction, the FA profiles of the total FA pool of maternal serum and umbilical vein and artery serum were determined by gas chromatography. Total FA concentration in maternal serum did not differ between the study groups; it was significantly higher in umbilical vein serum of the T1DM group compared with that in the control group [median (interquartile range)]: T1DM 2126.2 (1446.4 to 3181.3) and control 1073.8 (657.5 to 2226.0; P < 0.001), and in umbilical artery vein serum: T1DM 1805.7 (1393.1 to 2125.0) and control 990.0 (643.3 to 1668.0; P < 0.001). Composition of FAs in umbilical vein serum showed significantly higher concentrations of saturated, monounsaturated, and polyunsaturated FAs (SFAs, MUFAs, and PUFAs, respectively) in the T1DM group than compared with those in the control group (P = 0.001). Furthermore, cord blood levels of leptin (P < 0.001), C-peptide (P < 0.001), and insulin resistance (P = 0.015) were higher in the T1DM group compared with controls. The neonates born to mothers with T1DM had higher concentrations of total FAs, SFAs and MUFAs, as well as PUFAs, compared with control newborns.


Feasibility of adapted aerobic cycle ergometry tasks to encourage paretic limb use after stroke: a case series.
Cardiorespiratory fitness, along with sensorimotor recovery, is important for optimal function after stroke. Development of exercises that simultaneously address aerobic training and increase paretic limb involvement may improve outcomes and maximize productivity of therapy sessions. This case series assessed the feasibility of and characterized the cardiorespiratory and sensorimotor demands of adapted aerobic cycle ergometer activities hypothesized to increase paretic limb use. Mechanically loaded and electromyographic (EMG) feedback pedaling were compared to traditional pedaling in three poststroke case studies and a healthy control group. Submaximal oxygen uptake (Vo2), heart rate, perceived rate of exertion (RPE), and EMG of four leg muscles were assessed. Mechanically loaded ergometry increased RPE and altered muscle activity in healthy participants, while participants with stroke did not consistently increase paretic limb activation. EMG feedback pedaling increased target limb activity in healthy participants and decreased nonparetic activity in stroke participants. This paper highlights the challenges involved in adapting training tasks for individuals who are not able to walk at training intensities. Further work is necessary to refine adapted tasks for optimal effectiveness, and consideration of additional methods that permit differential interlimb loading may have additional value.


EGCG and Polyphenon E attenuate inflammation-related mouse colon carcinogenesis induced by AOM plus DDS.
Chronic inflammation raises the risk of the development of colorectal cancer (CRC). Green tea catechins (GTCs), which possess anti-inflammatory properties, are known to be anti-carcinogenic in a variety of organ sites, including the colorectum. This study investigated whether (-)-epigallocatechin gallate (EGCG), a candidate chemopreventive agent and major biologically-active component of green tea, and Polyphenon E (Poly E), a mixture of GTCs, suppress inflammation-related colon carcinogenesis induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). Male ICR mice aged 5 weeks were given a single intraperitoneal injection of AOM (10 mg/kg body weight), followed by 2% (w/v) DSS in drinking water for 7 days to induce colitis-related colonic tumors. They also received drinking water containing EGCG (0.01 or 0.1%) or Poly E (0.01 or 0.1%) up to week 17. At week 17, treatment with EGCG or Poly E had significantly suppressed the multiplicity and volume of colonic neoplasms as compared to the AOM/DSS group, and had resulted in a lesser degree of malignancy. In addition, treatment with EGCG or Poly E decreased the protein and mRNA expression levels of Cyclooxygenase (COX)-2 and the mRNA expression of inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-12 and IL-18) in the colonic mucosa. Our findings provide evidence that tea catechins are beneficial to the suppression of cancer development in the inflamed colon.


Preference of DNA methyltransferases for CpG islands in mouse embryonic stem cells.
Many CpG islands have tissue-dependent and differentially methylated regions (T-DMRs) in normal cells and tissues. To elucidate how DNA methyltransferases (Dnmts) participate in methylation of the genomic components, we investigated the genome-wide DNA methylation pattern of the T-DMRs with Dnmt1-, Dnmt3a-, and/or Dnmt3b-deficient ES cells by restriction landmark genomic scanning (RLGS). Approximately 1300 spots were detected in wild-type ES cells. In Dnmt1(-/-) ES cells, additional 236 spots emerged, indicating that the corresponding loci are methylated by Dnmt1 in wild-type ES cells. Intriguingly, in Dnmt3a(-/-)Dnmt3b(-/-) ES cells, the same 236 spots also emerged, and no additional spots appeared differentially. Therefore, Dnmt1 and Dnmt3a/3b share targets in CpG islands. Cloning and virtual image RLGS revealed that 81% of the RLGS spots were associated with genes, and 62% of the loci were in CpG islands. By contrast to the previous reports that demethylation at repeated sequences was severe in Dnmt1(-/-) cells compared with Dnmt3a(-/-)Dnmt3b(-/-) cells, a complete loss of methylation was observed at RLGS loci in Dnmt3a(-/-)Dnmt3b(-/-) cells, whereas methylation levels only decreased to 16% to 48% in the Dnmt1(-/-) cells. We concluded that there are CpG islands with T-DMR as targets shared by Dnmt1 and Dnmt3a/3b and that each Dnmt has target preferences depending on the genomic components.


When to use one-dimensional, two-dimensional, and Shifted Transversal Design pooling in mycotoxin screening.
While complex sample pooling strategies have been developed for large-scale experiments with robotic liquid handling, many medium-scale experiments like mycotoxin screening by Enzyme-Linked Immunosorbent Assay (ELISA) are still conducted manually in 48- and 96-well plates. At this scale, the opportunity to save on reagent costs is offset by the increased costs of labor, materials, and risk-of-error caused by increasingly complex pooling strategies. This paper compares one-dimensional (1D), two-dimensional (2D), and Shifted Transversal Design (STD) pooling to study whether pooling affects assay accuracy and experimental cost and to provide guidance for when a human experimentalist might benefit from pooling. We approximated mycotoxin contamination in single corn kernels by fitting statistical distributions to experimental data (432 kernels for aflatoxin and 528 kernels for fumonisin) and used experimentally-validated Monte-Carlo simulation (10,000 iterations) to evaluate assay sensitivity, specificity, reagent cost, and pipetting cost. Based on the validated simulation results, assay sensitivity remains 100% for all four pooling strategies while specificity decreases as prevalence level rises. Reagent cost could be reduced by 70% and 80% in 48- and 96-well plates, with 1D and STD pooling being most reagent-saving respectively. Such a reagent-saving effect is only valid when prevalence level is < 21% for 48-well plates and < 13%-21% for 96-well plates. Pipetting cost will rise by 1.3-3.3 fold for 48-well plates and 1.2-4.3 fold for 96-well plates, with 1D pooling by row requiring the least pipetting. Thus, it is advisable to employ pooling when the expected prevalence level is below 21% and when the likely savings of up to 80% on reagent cost outweighs the increased materials and labor costs of up to 4 fold increases in pipetting.


MMSPix - A multimedia service (MMS) medical images weblog.
Smartphones with cameras have added a new dimension to augmenting medical image collections for education and teleconsultation. It allows healthcare personnel to instantly capture and send images through the multimedia messaging service (MMS) protocol. We developed a searchable archive, a mobile images Weblog of camera phone images for medical education. Registered users can view and comment on uploaded images. The archive is compartmentalized to allow sharing images with all viewers and by clinical specialty groups.


Extracellular chaperones and proteostasis.
There exists a family of currently untreatable, serious human diseases that arise from the inappropriate misfolding and aggregation of extracellular proteins. At present our understanding of mechanisms that operate to maintain proteostasis in extracellular body fluids is limited, but it has significantly advanced with the discovery of a small but growing family of constitutively secreted extracellular chaperones. The available evidence strongly suggests that these chaperones act as both sensors and disposal mediators of misfolded proteins in extracellular fluids, thereby normally protecting us from disease pathologies. It is critically important to further increase our understanding of the mechanisms that operate to effect extracellular proteostasis, as this is essential knowledge upon which to base the development of effective therapies for some of the world's most debilitating, costly, and intractable diseases.


Radiological Study on Sesamoid Bones of the Foot among Omani Subjects.
The prevalence and appearance of sesamoid bones in the foot vary considerably among different populations and ethnic groups. We sought to evaluate the prevalence and distribution patterns of foot sesamoid bones among Omani patients referred for radiological investigation. We conducted a retrospective study among patients who had been referred for foot X-ray from January to December 2018. We used the chi-square test to determine the gender and age influence on the prevalence of sesamoid bones, and the Spearman's correlation coefficient to assess the coincidence of specific distributions of sesamoid bones at the metatarsophalangeal (MTP) joints. A total of 774 foot radiographs composed of 442 right foot radiographs and 332 left foot radiographs were reviewed for the presence of sesamoid bones at MTP and interphalangeal (IP) joints of the foot. We observed a high prevalence rate of sesamoid bones at the fifth MTP joint (13.7%), and first IP of the great toe (9.9%). There were nine distinctive patterns of sesamoid bones. The coincidence of sesamoid bones at two or more MTP joints was 14.6%, with a high prevalence rate at first and fifth MTP joints (10.3%). Moreover, the prevalence rate of sesamoid bones increased with increasing age at the fifth MTP joint. The prevalence of sesamoid bones in the foot is considerably high in Omani subjects and needs further prospective studies. Meanwhile, our findings could be helpful for clinicians to consider ailments of sesamoid bones during differential diagnosis in Omani patients who present with foot pain and discomfort.


Sex and drugs and nuclear war: secular, developmental and type A influences upon adolescents' fears of the nuclear threat, AIDS and drug addiction.
Researchers are divided over the significance of teenagers' expressed fear of nuclear war. This study of 3556 secondary school pupils examined whether (1) fear of nuclear war remains a feature of adolescent concern during the current east-west détente; (2) the examination of responses in a large sample reveals age and sex differences in such expressed fears; (3) worry about 'real world' issues like nuclear war, AIDS and drug addiction relates more generally to Type A proneness in adolescents. The results suggest that fewer teenagers spontaneously raise fear of nuclear war than in previous "pre-Glasnost" research in Britain, that such concern is expressed differentially according to the child's age and sex and that secondary school pupils who express concern about nuclear war and AIDS are more likely to show significantly higher Type A identification.


Building learning catchments for integrated catchment managing: designing learning systems based on experiences in the UK and South Africa.
We examine challenges and opportunities for developing 'learning systems' for integrated catchment managing (ICMg) drawing on our experiences in two contexts: UK and South Africa (SA). Our research question is: what is it that we would have to experience to claim that a catchment was a learning catchment? We suggest that any valid answer to this question will arise in social relations in context-determined ways. From this perspective ICMg is an emergent 'performance' of stakeholders engaged in mutual action, or social learning (SL), in which understandings and practices are transformed in situation improving ways. These questions are relevant given recent reviews suggesting that implementation of the European Water Framework Directive (WFD) is not nurturing adaptive management. Our European and SA experiences demonstrate that it is possible to invest in social learning as a governance mechanism for water managing, but key constraints exist. Our SA work based on (i) appreciating the situation, especially the history, and (ii) contextual appreciation and design of learning systems (as a result of (i)) is described in response to these constraints. We conclude that more attention on developing an effective praxis for ICMg is required.


Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth.
Hepatocellular carcinoma (HCC) is characterized by a propensity for multifocality, growth by local spread, and dysregulation of multiple signaling pathways. These features may be determined by the tumoral microenvironment. The potential of tumor cells to modulate HCC growth and behavior by secreted proteins has been extensively studied. In contrast, the potential for genetic modulation is poorly understood. We investigated the role and involvement of tumor-derived nanovesicles capable of altering gene expression and characterized their ability to modulate cell signaling and biological effects in other cells. We show that HCC cells can produce nanovesicles and exosomes that differ in both RNA and protein content from their cells of origin. These can be taken up and internalized by other cells and can transmit a functional transgene. The microRNA (miRNA) content of these exosomes was examined, and a subset highly enriched within exosomes was identified. A combinatorial approach to identify potential targets identified transforming growth factor β activated kinase-1 (TAK1) as the most likely candidate pathway that could be modulated by these miRNAs. Loss of TAK1 has been implicated in hepatocarcinogenesis and is a biologically plausible target for intercellular modulation. We show that HCC cell-derived exosomes can modulate TAK1 expression and associated signaling and enhance transformed cell growth in recipient cells. Exosome-mediated miRNA transfer is an important mechanism of intercellular communication in HCC cells. These observations identify a unique intercellular mechanism that could potentially contribute to local spread, intrahepatic metastases, or multifocal growth in HCC.


Identification and characterization of an Aspergillus fumigatus "supermater" pair.
The mating efficiency of 50 Aspergillus fumigatus isolates from both clinical and environmental sources was analyzed. Forty isolates completed the sexual cycle in 4 weeks with variable levels of fertility designated high, medium, or low. Two opposite-mating-type strains exhibiting the highest fertility, AFB62 (MAT1-1), isolated from a case of invasive aspergillosis, and AFIR928 (MAT1-2), isolated from the environment, were chosen as the supermater pair. Single cleistothecia obtained from a cross of the two strains harbored a minimum of 1 × 10(4) ascospores. The viability of ascospores increased with the age of the fruiting body, 17% at 4 weeks and reaching 95% at 20 weeks. AFB62 and AFIR928 were equally virulent in two different murine models, despite differences in their sources. High recombination frequencies were observed when the closely linked genes alb1 (AFUA_2G17600) and abr2 (AFUA_2G17530) were used as genetic markers. Comparative genome hybridization analyses revealed that only 86 genes (ca. 0.86% of the genome) are significantly diverged between AFB62 and AFIR928. The high fertility in a relatively short period, combined with a high degree of virulence and a high recombination frequency, demonstrates that the mating pair AFB62 and AFIR928 provides an excellent tool for genetic studies of A. fumigatus. Aspergillus fumigatus is a heterothallic fungal pathogen that causes life-threatening infections in immunocompromised hosts. Although heterothallism facilitates genetic study via recombinational analysis, previous work showed that a 6-month incubation period is required for the completion of sexual reproduction in this species. Such a long incubation period impedes progress in genetic research. To discover a highly fertile (supermater) pair that can complete the sexual cycle in a considerably shorter period, we screened 50 strains collected from various geographic regions for mating efficiency. We identified a highly virulent pair of supermaters that can be an invaluable tool for genetic study.


Fecal microbiota transplantation for gastrointestinal diseases.
Fecal microbiota transplantation (FMT) is a treatment to restore the normal microbial composition of the gut by introducing fecal microbiota obtained from a healthy donor into a diseased individual. There has been a growing interest in the use of FMT as a treatment of various diseases including Clostridium difficile infection (CDI), inflammatory bowel disease, and irritable bowel syndrome. Despite the increasing application of FMT, there are no standard protocols. Many aspects of FMT procedures vary regarding donor selection, preparation of fecal materials, recipient preparation, and route of administration. FMT is most successful in treating recurrent CDI. A randomized controlled trial reported a success rate of approximaetly 90%. Ulcerative colitis (UC) is a potentially good indication for FMT, although limited evidence is available on the use of FMT for the treatment of UC. Only several small case series have been reported, and the results in terms of efficacy are inconsistent. FMT can also be used to treat diseases other than gastrointestinal disorders in which the gut microbiota is disturbed, e.g., cardiovascular diseases, autoimmune diseases, and metabolic disorders. There remain many unanswered questions with regard to FMT, and more research is required in this field.


Role of hydrogen sulfide in early blood-brain barrier disruption following transient focal cerebral ischemia.
We determined the role of endogenous hydrogen sulfide (H2S) in cerebral vasodilation/hyperemia and early BBB disruption following ischemic stroke. A cranial window was prepared over the left frontal, parietal and temporal cortex in mice. Transient focal cerebral Ischemia was induced by directly ligating the middle cerebral artery (MCA) for two hours. Regional vascular response and cerebral blood flow (CBF) during ischemia and reperfusion were measured in real time. Early BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. Topical treatment with DL-propargylglycine (PAG, an inhibitor for cystathionine γ-lyase (CSE)) and aspartate (ASP, inhibitor for cysteine aminotransferase/3-mercaptopyruvate sulfurtransferase (CAT/3-MST)), but not O-(Carboxymethyl)hydroxylamine hemihydrochloride (CHH, an inhibitor for cystathionine β-synthase (CBS)), abolished postischemic cerebral vasodilation/hyperemia and prevented EB and Na-F extravasation. CSE knockout (CSE-/-) reduced postischemic cerebral vasodilation/hyperemia but only inhibited Na-F extravasation. An upregulated CBS was found in cerebral cortex of CSE-/- mice. Topical treatment with CHH didn't further alter postischemic cerebral vasodilation/hyperemia, but prevented EB extravasation in CSE-/- mice. In addition, L-cysteine-induced hydrogen sulfide (H2S) production similarly increased in ischemic side cerebral cortex of control and CSE-/- mice. Our findings suggest that endogenous production of H2S by CSE and CAT/3-MST during reperfusion may be involved in postischemic cerebral vasodilation/hyperemia and play an important role in early BBB disruption following transient focal cerebral ischemia.


Neuro-cognitive impairment following acquired central nervous system infections in childhood: a systematic review.
The morbid consequences of central nervous system (CNS) infections are often overlooked in the face of high mortality rates. However, neurological impairments not only affect the child's development and future prospects but also place an economic and social burden on communities and countries that often have few resources to deal with such problems. We conducted a systematic review to investigate the occurrence and pattern of persisting neurological impairment after common CNS infections. A comprehensive search of MEDLINE, EMBASE and PsycINFO databases, supplemented by hand-searches of key journals, resulted in forty-six eligible studies, five of which gave information on the spectrum of developmental domains. Despite the lack of comprehensive, methodologically-sound studies, the results show that postinfectious neurological impairment persists, most commonly in cognition and motor functions. Deficits include more subtle problems, which can be difficult to detect on gross neurological assessment but may still be deleterious to the child's social and educational functioning. Higher morbidity for similar mortality in acute bacterial meningitis compared with cerebral malaria in the epidemiological data may suggest future research directions for clinical research to devise more effective interventions.


Carbon nanotube actuators
Electromechanical actuators based on sheets of single-walled carbon nanotubes were shown to generate higher stresses than natural muscle and higher strains than high-modulus ferroelectrics. Like natural muscles, the macroscopic actuators are assemblies of billions of individual nanoscale actuators. The actuation mechanism (quantum chemical-based expansion due to electrochemical double-layer charging) does not require ion intercalation, which limits the life and rate of faradaic conducting polymer actuators. Unlike conventional ferroelectric actuators, low operating voltages of a few volts generate large actuator strains. Predictions based on measurements suggest that actuators using optimized nanotube sheets may eventually provide substantially higher work densities per cycle than any previously known technology.


Stabilized lasers and precision measurements.
This article traces the development of stabilized lasers from the Massachusetts Institute of Technology passive-stabilization experiments of the early 1960's up through the current epoch of highly stabilized helium-neon and carbon dioxide and continuous wave dye lasers. The utility, present performance, and limitations of stabilized lasers as standards of length or frequency for precision measurements are discussed. Examples considered of laser applications to physical measurements of outstanding scientific interest include determination of the speed of light, redefinition of the meter, resolution of the photon recoil-induced spectral doubling, use of optical "Ramsey" interference fringes from ultrahigh-resolution spectroscopy, and two improved tests of special relativity.


The effects of intraperitoneal chemotherapeutic agents on adhesion formation.
Intra-abdominal adhesions are a major complication of healing. Furthermore these adhesions may cause morbidity and sometimes mortality for patients, and also are a financial burden to the health system. Cecum abrasion was performed in all rats and solutions containing saline to group 1, 5-fluorouracil to group 2, cisplatin to group 3, paclitaxel to the group 4, and mitomycin-C were administered into the abdomen of the groups, respectively. The intra-abdominal adhesions were scored after the macroscopic evaluation. Among the chemotherapeutic drugs, paclitaxel significantly increases occurring of intra-abdominal adhesions in comparison with the control group and the other drugs according to the evaluation of scoring and statistical studies. It is suggested to use the drugs which have a proven anti-adhesion feature or barriers to the patients who are going to be applied intraperitoneal chemotherapy with paclitaxel.


3D-ultrasound guided radiation therapy in the post-prostatectomy setting.
Daily transabdominal ultrasound-directed localization has proven valuable in correcting for setup error and organ motion in the treatment of prostate cancer with three-dimensional conformal radiation therapy (3DCRT). The present study sought to determine whether this transabdominal ultrasound technology could also be reliably applied in the post-operative adjuvant or salvage setting to improve the reproducibility of coverage of the intended volumes and to enhance conformal avoidance of adjacent normal structures. Sixteen consecutive patients who received external beam radiotherapy underwent daily localization using an optically guided 3D-ultrasound target localization system (SonArray, Zmed, Inc., Ashland, MA). Six of the above patients were treated in a post-prostatectomy setting, either adjuvantly or for salvage, while the remaining 10 with intact prostates were treated definitively. Because the bladder neck generally approximates the postoperative prostatic fossa, it was used during ultrasound localization as the primary reference structure for the post-prostatectomy patients. For patients treated definitively, the prostate was the primary reference structure. Daily shifts were recorded and port films were taken weekly immediately after ultrasound-based repositioning. By comparing port films taken after ultrasound localization, which evaluates for both set-up error and internal shift, with the original digitally reconstructed radiographs (DRRs), which represents a zero clinical set-up error situation, the degree of variability in organ position was determined. The average absolute, ultrasound-based shifts from the clinical set-up position in the anterior/posterior, lateral, and cranial/caudal directions for the post-prostatectomy patients were 5 +/- 4 mm SD, 3 +/- 3 mm SD, and 3 +/- 4 mm SD over the entire course of treatment, respectively. The average vector length shift was 8 +/- 4 mm SD. For patients treated with an intact prostate, the analogous average absolute shifts in the anterior/posterior, lateral, and cranial/caudal directions were 4 +/- 3 mm SD, 4 +/- 3 mm SD, and 4 +/- 3 mm SD over the entire course of treatment. The average vector length shift was 7 +/- 4 mm SD. Vector length shifts representing interfraction internal motion were estimated by comparing post-ultrasound port films with DRRs. These were 5 +/- 3 mm SD and 4 +/- 4mm SD for post-prostatectomy and intact prostate patients, respectively. These ultrasound-based displacements were not statistically different in patients with an intact prostate versus patients post-prostatectomy (p > 0.1). In conclusion, daily transabdominal 3D-ultrasound localization proved to be a clinically feasible method of correcting for set-up and internal motion displacements. The bladder neck, which serves as an adequate localization reference structure for the prostatic fossa, could be readily ultrasound imaged and repositioned as necessary. Daily internal motion errors that would have occurred if only pre-treatment port films were used were similar in magnitude to those observed for the patients with intact prostates and were of sufficient magnitude to support the use of daily pre-treatment ultrasound localization in the post-prostatectomy setting.


Optical lens compression via transformation optics.
Transformation optics is widely associated with the design of unconventional electromagnetic devices, such as electromagnetic cloaks or concentrators. However, a wide range of conventional optical devices with potentially advantageous properties can be designed by the transformation optical approach. For example, a coordinate transformation can be introduced that compresses a region of space, resulting in an overall decrease in the thickness of an optical instrument such as a lens. The optical properties of a transformed lens, such as Fresnel reflection or aberration profile, are equivalent to those of the original lens, while the transformed lens and the bounding transformation optical material are thinner than the original lens. This approach to flattening the profile of a lens represents an advantage over the use of a higher dielectric material because it does not introduce greater Fresnel reflections or require a redesign of the basic optic. Though transformation optical media are generally anisotropic, with both electric and magnetic response, it is possible to arrive at a dielectric-only transformation optical distribution for a lens interacting with transverse-magnetic (TM) polarized light. The dielectric-only distribution can be implemented using broad-band, low-loss metamaterials. Lens designs for both a full transformation and a dielectric-only implementation are discussed and confirmed via finite-element simulations.


The antimutagenic effect of a truncated epsilon subunit of DNA polymerase III in Escherichia coli cells irradiated with UV light.
It has previously been suggested that inhibition of the proofreading 3'-5' exonuclease activity of DNA polymerase may play an important role in generation of UV-induced mutations in Escherichia coli. Our previous work showing that overproduction of epsilon, the proofreading subunit of DNA polymerase III, counteracts the SOS mutagenic response of E. coli seemed to be consistent with this hypothesis. To explore further the nature of the antimutagenic effect of epsilon we constructed plasmid pMK17, which encodes only two of the three highly conserved segments of epsilon--ExoI and ExoII; the third segment, ExoIII, which is essential for 3'-5' exonuclease activity, is deleted. We show that at 40 degrees C, overproduction of the truncated epsilon subunit significantly delays production of M13 phage, suggesting that the protein retains its capacity to bind to DNA. On the other hand, the presence of pMK17 in a trpE65 strain growing at 40 degrees C causes a 10-fold decrease in the frequency of UV-induced Trp+ mutations. This antimutagenic effect of the truncated epsilon is effectively relieved by excess UmuD,C proteins. We also show that the presence of plasmid pIP21, which contains the dnaQ49 allele encoding an epsilon subunit that is defective in proofreading activity, almost completely prevents generation of UV-induced mutations in the trpE65 strain. We propose that the DNA binding ability of free epsilon, rather than its 3'-5' exonuclease activity, affects processing of premutagenic UV-induced lesions, possibly by interfering with the interaction between the UmuC-UmuD'-RecA complex and Pol III holoenzyme. This interaction is probably a necessary condition for translesion synthesis.


Comparison of three-implant-supported fixed dentures and two-implant-retained overdentures in the edentulous mandible: a pilot study of treatment efficacy and patient satisfaction.
The mandibular two-implant overdenture has been shown to be a highly successful treatment. However, overdenture patients who desire a fixed prosthesis may not be satisfied with a removable overdenture. This prospective study sought to compare prosthetic outcomes, patient satisfaction, and survival rates of implants between two-implant-supported overdentures (IODs) and three-implant-supported fixed dentures (ISFDs). Twenty completely edentulous patients were randomly and equally assigned to two groups. New conventional complete dentures were made, and the mandibular denture was used as a surgical guide during implant placement. Implants were placed in one stage, followed by a mandibular denture soft reline (provisional loading). Ball attachments were inserted at 8 weeks, and ISFDs were delivered at 16 weeks. IODs were connected to the attachments at 8 weeks, using each patients's existing denture. The definitive ISFDs were fabricated using computer-aided design/computer-assisted manufacture milled titanium frameworks and acrylic resin base and teeth. Patient satisfaction and panoramic radiographs were investigated at 6 and 12 months. Both treatments had significant and positive effects on patient satisfaction and quality of life. None of the 50 implants placed had failed at 12 months of follow-up; therefore, the implant survival rate was 100%. Prosthetic complications were generally rare and easily manageable. Both the treatment modalities-the ISFD supported by three implants and the IOD supported by two implants-significantly and similarly improved patient satisfaction and oral health-related quality of life, and prosthetic complications were relatively rare for both treatments. Three implants can be used to support a mandibular fixed prosthesis; however, a longer observation period is needed to validate this treatment modality.


Environmental lead levels in a coastal city of India: the lead burden continues.
Urbanization, rapid industrialization, increased vehicular traffic, and consequent increase in the use of petroleum fuels in India are constantly emitting lead along with other pollutants into the environment. Apart from atmospheric lead, this element is the most widely used in everyday life. Although infants and children are the most susceptible to the effects of lead, adults are also affected to varying degrees and it had ranked as one of the most serious environmental threats to human health. Hence, we must understand the benefits of preventing lead exposure as it reduces treatment costs, increases productivity in industry, and also reduces infant mortality. These are good enough reasons for a nation wide program to prevent lead poisoning. In the view of elevated blood lead levels (BLL) in majority of the school children in the city of Mangalore, we aimed to identify the potential sources of lead in the environment which would have probably caused the elevated BLL. More than 600 readings were taken throughout the city of Mangalore using X-ray fluorimeter. Our results showed that there were elevated levels of lead in the environment surrounding the battery repair shops, battery recyclers, automotive workshops, and tyre retreaders, but interestingly, the soil around the petrol bunks did not show elevated levels of lead. Among the paints, the yellow paint showed high levels of lead. Similar surveys would be useful elsewhere in India and in other developing countries in order to identify the potential sources of lead and to prevent lead poisoning.


Bitter melon extract impairs prostate cancer cell-cycle progression and delays prostatic intraepithelial neoplasia in TRAMP model.
Prostate cancer remains the second leading cause of cancer deaths among American men. Earlier diagnosis increases survival rate in patients. However, treatments for advanced disease are limited to hormone ablation techniques and palliative care. Thus, new methods of treatment and prevention are necessary for inhibiting disease progression to a hormone refractory state. One of the approaches to control prostate cancer is prevention through diet, which inhibits one or more neoplastic events and reduces the cancer risk. For centuries, Ayurveda has recommended the use of bitter melon (Momordica charantia) as a functional food to prevent and treat human health related issues. In this study, we have initially used human prostate cancer cells, PC3 and LNCaP, as an in vitro model to assess the efficacy of bitter melon extract (BME) as an anticancer agent. We observed that prostate cancer cells treated with BME accumulate during the S phase of the cell cycle and modulate cyclin D1, cyclin E, and p21 expression. Treatment of prostate cancer cells with BME enhanced Bax expression and induced PARP cleavage. Oral gavage of BME, as a dietary compound, delayed the progression to high-grade prostatic intraepithelial neoplasia in TRAMP (transgenic adenocarcinoma of mouse prostate) mice (31%). Prostate tissue from BME-fed mice displayed approximately 51% reduction of proliferating cell nuclear antigen expression. Together, our results suggest for the first time that oral administration of BME inhibits prostate cancer progression in TRAMP mice by interfering cell-cycle progression and proliferation.


Transforming growth factor beta promotes complexes between Smad proteins and the CCCTC-binding factor on the H19 imprinting control region chromatin.
Whether signal transduction pathways regulate epigenetic states in response to environmental cues remains poorly understood. We demonstrate here that Smad3, signaling downstream of transforming growth factor beta, interacts with the zinc finger domain of CCCTC-binding factor (CTCF), a nuclear protein known to act as "the master weaver of the genome." This interaction occurs via the Mad homology 1 domain of Smad3. Although Smad2 and Smad4 fail to interact, an alternatively spliced form of Smad2 lacking exon 3 interacts with CTCF. CTCF does not perturb well established transforming growth factor beta gene responses. However, Smads and CTCF co-localize to the H19 imprinting control region (ICR), which emerges as an insulator in cis and regulator of transcription and replication in trans via direct CTCF binding to the ICR. Smad recruitment to the ICR requires intact CTCF binding to this locus. Smad2/3 binding to the ICR requires Smad4, which potentially provides stability to the complex. Because the CTCF-Smad complex is not essential for the chromatin insulator function of the H19 ICR, we propose that it can play a role in chromatin cross-talk organized by the H19 ICR.


Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies.
A major public health issue is to determine whether long-term benzodiazepine use may induce cognitive deficits persisting after withdrawal. The aim of the present review was to examine findings from prospective studies carried out in general population samples exploring whether exposure to benzodiazepines is associated with an increased risk of incident cognitive decline. Using a MEDLINE search and a hand-search of related references in selected papers, we retrieved original studies published in peer-reviewed journals that explored in general population samples the association between benzodiazepine exposure and change in cognitive performance between baseline and follow-up assessment. Six papers met the inclusion criteria. Two studies reported a lower risk of cognitive decline in former or ever users, two found no association whatever the category of user, and three found an increased risk of cognitive decline in benzodiazepine users. The discrepant findings obtained by studies examining the link between benzodiazepine exposure and risk of cognitive decline may be due to methodological differences, especially regarding the definitions of exposure and cognitive outcome. As a large proportion of subjects are exposed to benzodiazepines, a small increase in the risk of cognitive decline may have marked deleterious consequences for the health of the general population. This issue needs to be explored further by pharmaco-epidemiological studies.


Persistent human cytomegalovirus infection induces drug resistance and alteration of programmed cell death in human neuroblastoma cells.
Infection with human cytomegalovirus (HCMV) is a common and generally asymptomatic affection in childhood. Its role in neuroblastoma (NB) patients has not yet been elucidated. As evidence grows that HCMV interacts with apoptotic signaling due to the interaction of HCMV gene products with cellular proteins of apoptotic pathways, we used human NB cell line UKF-NB-2 persistently infected with HCMV strain AD169 to study the effects of long-term HCMV infection on programmed cell death of neuroectodermal tumor cells. The cells designated UKF-NB-2AD169 continued to produce infectious virus in successive subcultures over a period of more than 1 year. Up to 20% of cells expressed viral genes or produced infectious virus after initiation of infection. UKF-NB-2AD169 cells were significantly less sensitive to the cytotoxic agents cisplatinum and etoposide than parental (noninfected) UKF-NB-2 cells. These effects were associated with decreased ability of UKF-NB-2AD169 cells to undergo apoptosis and continuous viral replication. UKF-NB-2AD169 cells showed increased levels of antiapoptosis Bcl-2 protein (up to 12-fold), whereas expression of p53 and c-myc was not changed. Treatment of UKF-NB-2AD169 cells with ganciclovir, abolishing virus production, reestablished sensitivity to chemotherapy, lowered Bcl-2 expression, and facilitated inducibility of apoptosis to the level of the parental cell line. The results demonstrate that persistent HCMV infection confers resistance to cytotoxic agents on neuroectodermal tumor cells and protects from apoptosis, probably due to increased levels of Bcl-2 protein. Hence, it is conceivable that HCMV infection before or during tumorigenesis may contribute in some NB patients to failure of therapy.


Boundary issues and multiple relationships in genetic counseling supervision: supervisor, non-supervisor, and student perspectives.
Boundary issues and multiple relationships potentially affect all supervision interactions. Boundary crossings are departures from the strictest professional role and may or may not benefit supervisees. Boundary violations are outside common practice and may place supervisees at significant risk. Multiple relationships occur when supervisors concurrently or consecutively hold two or more roles with supervisees. Studies in other fields indicate supervisors and supervisees may be uncertain about professional conduct regarding these issues. In this study, genetic counselor supervisors (n = 126), non-supervisors (n = 72), and genetic counseling students (n = 129) completed an anonymous survey investigating four major questions: 1) Are various boundary issues and multiple relationships perceived as differentially appropriate? 2) Do supervisor, non-supervisor, and student perceptions differ? 3) What challenging situations have respondents experienced? and 4) What management strategies did they use? There was general agreement among groups in their appropriateness ratings of 56 hypothetical supervisor behaviors, although supervisor ratings tended to reflect stricter boundaries regarding the appropriateness of interactions than student ratings. A majority rated unavoidable boundary crossings and supervisor multiple relationships involving an academic relationship as most appropriate, and romantic/sexual multiple relationships and/or boundary violations as least appropriate. Analysis of respondents' actual challenging situations revealed many involved boundary violations, placed students at risk of harm, and often resulted in student compliance.


1-Octanol/Water Partition Coefficients of n-Alkanes from Molecular Simulations of Absolute Solvation Free Energies.
The 1-octanol/water partition coefficient is an important thermodynamic variable usually employed to understand and quantify the partitioning of solutes between aqueous and organic phases. It finds widespread use in many empirical correlations to evaluate the environmental fate of pollutants as well as in the design of pharmaceuticals. The experimental evaluation of 1-octanol/water partition coefficients is an expensive and time-consuming procedure, and thus, theoretical estimation methods are needed, particularly when a physical sample of the solute may not yet be available, such as in pharmaceutical screening. 1-Octanol/water partition coefficients can be obtained from Gibbs free energies of solvation of the solute in both the aqueous and the octanol phases. The accurate evaluation of free energy differences remains today a challenging problem in computational chemistry. In order to study the absolute solvation Gibbs free energies in 1-octanol, a solvent that can mimic many properties of important biological systems, free energy calculations for n-alkanes in the range C1-C8 were performed using molecular simulation techniques, following the thermodynamic integration approach. In the first part of this paper, we test different force fields by evaluating their performance in reproducing pure 1-octanol properties. It is concluded that all-atom force fields can provide good accuracy but at the cost of a higher computational time compared to that of the united-atom force fields. Recent versions of united-atom force fields, such as Gromos and TraPPE, provide satisfactory results and are, thus, useful alternatives to the more expensive all-atom models. In the second part of the paper, the Gibbs free energy of solvation in 1-octanol is calculated for several n-alkanes using three force fields to describe the solutes, namely Gromos, TraPPE, and OPLS-AA. Generally, the results obtained are in excellent agreement with the available experimental data and are of similar accuracy to commonly used QSPR models. Moreover, we have estimated the Gibbs free energy of hydration for the different compounds with the three force fields, reaching average deviations from experimental data of less than 0.2 kcal/mol for the case of the Gromos force field. Finally, we systematically compare different strategies to obtain the 1-octanol/water partition coefficient from the simulations. It is shown that a fully predictive method combining the Gromos force field in the aqueous phase and the OPLS-AA/TraPPE force field for the organic phase can give excellent predictions for n-alkanes up to C8 with an absolute average deviation of 0.1 log P units to the experimental data.


Environmental and demographic determinants of avian influenza viruses in waterfowl across the contiguous United States.
Outbreaks of avian influenza in North American poultry have been linked to wild waterfowl. A first step towards understanding where and when avian influenza viruses might emerge from North American waterfowl is to identify environmental and demographic determinants of infection in their populations. Laboratory studies indicate water temperature as one determinant of environmental viral persistence and we explored this hypothesis at the landscape scale. We also hypothesized that the interval apparent prevalence in ducks within a local watershed during the overwintering season would influence infection probabilities during the following breeding season within the same local watershed. Using avian influenza virus surveillance data collected from 19,965 wild waterfowl across the contiguous United States between October 2006 and September 2009 We fit Logistic regression models relating the infection status of individual birds sampled on their breeding grounds to demographic characteristics, temperature, and interval apparent prevalence during the preceding overwintering season at the local watershed scale. We found strong support for sex, age, and species differences in the probability an individual duck tested positive for avian influenza virus. In addition, we found that for every seven days the local minimum temperature fell below zero, the chance an individual would test positive for avian influenza virus increased by 5.9 percent. We also found a twelve percent increase in the chance an individual would test positive during the breeding season for every ten percent increase in the interval apparent prevalence during the prior overwintering season. These results suggest that viral deposition in water and sub-freezing temperatures during the overwintering season may act as determinants of individual level infection risk during the subsequent breeding season. Our findings have implications for future surveillance activities in waterfowl and domestic poultry populations. Further study is needed to identify how these drivers might interact with other host-specific infection determinants, such as species phylogeny, immunological status, and behavioral characteristics.


Three-phase equilibria in density-functional theory: Interfacial tensions.
A mean-field density-functional model for three-phase equilibria in fluids (or other soft condensed matter) with two spatially varying densities is analyzed analytically and numerically. The interfacial tension between any two out of three thermodynamically coexisting phases is found to be captured by a surprisingly simple analytic expression that has a geometric interpretation in the space of the two densities. The analytic expression is based on arguments involving symmetries and invariances. It is supported by numerical computations of high precision, and it agrees with earlier conjectures obtained for special cases in the same model. An application is presented to three-phase equilibria in the vicinity of a tricritical point. Using the interfacial tension expression and employing the field variables compatible with tricritical point scaling, the expected mean-field critical exponent is derived for the vanishing of the critical interfacial tension as a function of the deviation of the noncritical interfacial tension from its limiting value, upon approach to a critical endpoint in the phase diagram. The analytic results are again confirmed by numerical computations of high precision.


Episodic ataxia type-1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel.
Episodic ataxia type-1 is a rare human neurological syndrome which occurs during childhood and persists through the whole life of affected patients. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene hKv1.1 of different affected families. V408A and E325D mutations are located in the cytoplasmic putative pore region of hKv1.1 channels and profoundly alter their gating properties. V408A channels showed increased kinetic rates of activation, deactivation and C-type inactivation. Expression of E325D channels in Xenopus oocytes led to an approximately 13-fold current amplitude reduction and to a 52.4 mV positive shift in the voltage dependence of activation. Moreover, the E325D mutation altered the kinetics of activation, deactivation, C-type inactivation and channel open probability. Heteromeric channels composed of two wild-type and two mutated subunits, linked as dimers, showed gating properties intermediate between channels formed from four normal or four mutated subunits. The results demonstrate that the highly conserved residues Val408 and Glu325 play a pivotal role in several gating processes of a human potassium channel, and suggest a pathogenetic mechanism by which the impairment of the delayed-rectifier function of affected neurons is related to the type and number of mutated subunits which make up the hKv1.1 channels.


Lipid replacement therapy: a nutraceutical approach for reducing cancer-associated fatigue and the adverse effects of cancer therapy while restoring mitochondrial function.
Cancer-associated fatigue is one of the most common symptoms in all forms and stages of cancer, yet scant attention is usually given to patients who have symptomatic complaints of fatigue. Cancer-associated fatigue is also associated with cellular oxidative stress, and during cancer therapy, excess drug-induced oxidative stress can limit therapeutic effectiveness and cause a number of side effects, including fatigue, nausea, vomiting, and more serious adverse effects. Cancer-associated fatigue and the chronic adverse effects of cancer therapy can be reduced by lipid replacement therapy using membrane lipids along with antioxidants and enzymatic cofactors, such as coenzyme Q(10), given as food supplements. Administering these nutraceutical supplements can reduce oxidative membrane damage and restore mitochondrial and other cellular functions. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefits of lipid replacement therapy in reducing fatigue and restoring mitochondrial electron transport function.


Ascorbic acid has superior ex vivo antiproliferative, cell death-inducing and immunomodulatory effects over IFN-α in HTLV-1-associated myelopathy.
Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP. Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes. In comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.


Ambient carbon monoxide and daily mortality in three Chinese cities: the China Air Pollution and Health Effects Study (CAPES).
Ambient carbon monoxide (CO) is an air pollutant primarily generated by traffic. CO has been associated with increased mortality and morbidity in developed countries, but few studies have been conducted in Asian developing countries. In the China Air Pollution and Health Effects Study (CAPES), the short-term associations between ambient CO and daily mortality were examined in three Chinese cities: Shanghai, Anshan and Taiyuan. Poisson regression models incorporating natural spline smoothing functions were used to adjust for long-term and seasonal trend of mortality, as well as other time-varying covariates. Effect estimates were obtained for each city and then for the cities combined. In both individual-city and combined analysis, significant associations of CO with both total non-accidental and cardiovascular mortality were observed. In the combined analysis, a 1 mg/m(3) increase of 2-day moving average concentrations of CO corresponded to 2.89% (95%CI: 1.68, 4.11) and 4.17% (95%CI: 2.66, 5.68) increase of total and cardiovascular mortality, respectively. CO was not significantly associated with respiratory mortality. Sensitivity analyses showed that our findings were generally insensitive to alternative model specifications. In conclusion, ambient CO was associated with increased risk of daily mortality in these three cities. Our findings suggest that the role of exposure to CO and other traffic-related air pollutants should be further investigated in China.


Photodarkening in Tb(3+)-doped phosphosilicate and germanosilicate optical fibers.
The presence of Tb(3+) is found to sensitize greatly phosphosilicate and germanosilicate optical fibers to photodarkening when they are exposed to 488-nm light. The darkening is a three-photon process and may involve the photoionization of Tb(3+) to Tb(4+). This sensitivity raises the possibility of side writing refractive-index gratings into silica-based optical fibers with 488-nm light.


Overexpression in yeast, photocycle, and in vitro structural change of an avian putative magnetoreceptor cryptochrome4.
Cryptochromes (CRYs) have been found in a wide variety of living organisms and can function as blue light photoreceptors, circadian clock molecules, or magnetoreceptors. Non-mammalian vertebrates have CRY4 in addition to the CRY1 and CRY2 circadian clock components. Though the function of CRY4 is not well understood, chicken CRY4 (cCRY4) may be a magnetoreceptor because of its high level of expression in the retina and light-dependent structural changes in retinal homogenates. To further characterize the photosensitive nature of cCRY4, we developed an expression system using budding yeast and purified cCRY4 at yields of submilligrams of protein per liter with binding of the flavin adenine dinucleotide (FAD) chromophore. Recombinant cCRY4 dissociated from anti-cCRY4 C1 mAb, which recognizes the C-terminal region of cCRY4, in a light-dependent manner and showed a light-dependent change in its trypsin digestion pattern, suggesting that cCRY4 changes its conformation with light irradiation in the absence of other retinal factors. Combinatorial analyses with UV-visible spectroscopy and immunoprecipitation revealed that there is chromophore reduction in the cCRY4 photocycle and formation of a flavosemiquinone radical intermediate that is likely accompanied by a conformational change in the carboxyl-terminal region. Thus, cCRY4 seems to be an intrinsically photosensitive and photoswitchable molecule and may exemplify a vertebrate model of cryptochrome with possible function as a photosensor and/or magnetoreceptor.


Fertilizer demand and potential supply through nutrient recovery from organic waste digestate in California.
Diversion of organic waste from landfills offers an opportunity to recover valuable nutrients such as nitrogen and phosphorus that are typically discarded. Although prior research has explored the potential for buildout of anaerobic digestion (AD) infrastructure to treat organic waste and generate energy, a better understanding is needed of the nutrient recovery potential from the solid and liquid byproducts (digestate) resulting from AD of these waste streams. We quantified the system-wide mass of nutrients that can potentially be recovered in California by integrating current and potential future AD facilities with existing nutrient recovery technologies. Based on a profitable build-out scenario for AD, the potential for nitrogen and phosphorus recovery by mass was greatest from municipal sewage sludge. The nutrient recovery (% total mass) was determined for three different end products for the combined organic waste streams: liquid fertilizer [38% of the total recovered nitrogen (TN)], struvite [50% TN, 66% total phosphorous (TP)], and compost (12% TN, 34% TP). Based on the profitable build-out scenario of AD facilities in California, the recovered nutrients would offset an estimated 11% of TN and 29% of TP of in-state synthetic fertilizer demand, whereas a scenario in which all technically recoverable biomass is collected and treated could offset 44% of TN and 97% of TP demand.


Generating Ampicillin-Level Antimicrobial Peptides with Activity-Aware Generative Adversarial Networks.
Antimicrobial peptides are a potential solution to the threat of multidrug-resistant bacterial pathogens. Recently, deep generative models including generative adversarial networks (GANs) have been shown to be capable of designing new antimicrobial peptides. Intuitively, a GAN controls the probability distribution of generated sequences to cover active peptides as much as possible. This paper presents a peptide-specialized model called PepGAN that takes the balance between covering active peptides and dodging nonactive peptides. As a result, PepGAN has superior statistical fidelity with respect to physicochemical descriptors including charge, hydrophobicity, and weight. Top six peptides were synthesized, and one of them was confirmed to be highly antimicrobial. The minimum inhibitory concentration was 3.1 μg/mL, indicating that the peptide is twice as strong as ampicillin.


Vascular anomalies: what a radiologist needs to know.
Most haemangiomas and vascular malformations are identified according to clinical criteria. A good knowledge of the classification and clinical characteristics of the vascular anomalies is necessary when managing these patients. However, some cases are challenging either because of an atypical presentation (e.g., soft-tissue mass with normal overlying skin) or because of classification difficulties. Doppler US and MRI are the two main imaging modalities that allow classification of the vascular anomalies and are useful in those clinically uncertain cases to establish the correct diagnosis. This aids the choice of the most appropriate treatment and to inform the parents of the prognosis. High-resolution grey-scale and Doppler US allow excellent visualization of most superficial masses. Doppler US is the easiest way to assess the haemodynamics of a vascular lesion and to clarify a doubtful diagnosis between a haemangioma and vascular malformation. MRI is the best technique for evaluating the extent of the lesions and their relationship to adjacent structures. While newly developed drugs from angiogenesis research labs are awaited, radiologists have an important role in the treatment of haemangiomas and vascular malformations. Intervention remains crucial in cases of alarming haemangiomas and venous malformations (VM), lymphatic malformations (LM) and arteriovenous malformations (AVM). A multidisciplinary team, including paediatricians, haematologists, surgeons and radiologists, must manage the problem cases both in terms of diagnostic work-up and therapeutic options. This paper will briefly discuss the imaging findings and treatment of vascular anomalies.


Peripheral Blood Examination Findings in SARS-CoV-2 Infection.
Peripheral blood abnormalities in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been fully elucidated. We report qualitative and quantitative peripheral blood findings in coronavirus disease 2019 (COVID-19) patients and compare them with a control group. We reviewed electronic medical records, complete blood counts, peripheral blood smears, and flow cytometry data in 12 patients with SARS-CoV-2. These were compared with 10 control patients with symptoms suspicious for SARS-CoV-2 but who tested negative. No significant differences were noted in blood counts, except that absolute lymphopenia was present frequently in the control group (P < .05). Acquired Pelger-Huët anomaly (APHA) was noted in all COVID-19 cases, in most cases affecting over 5% of granulocytes. This contrasted with APHA in only 50% of control cases, affecting fewer than 5% of granulocytes in all cases (P < .05). Monolobate neutrophils were exclusive to COVID-19 cases. COVID-19 patients had greater frequency of plasmacytoid lymphocytes (P < .05). Flow cytometry data revealed absolute CD3+ T-cell count reduction in 6 of 7 patients; all of them required mechanical ventilation. Lymphopenia was infrequent in our COVID-19 cohort; however, flow cytometric analysis revealed absolute T-cell count reduction in most cases. COVID-19 cases had significant APHA with monolobate neutrophils and plasmacytoid lymphocytes as compared to controls.


Continuous sorting of heterogeneous-sized embryoid bodies.
This paper presents a microfluidic device for sorting embryoid bodies (EBs) with large dynamic size ranges up to 300 microm. The proposed separation scheme utilizes appropriately spaced pillars within a microchannel to alter the fluid flow pathway, thus allowing particles of defined sizes to be diverted towards specific flow paths. We test the device functionality by separating polystyrene beads 90, 175 and 275 microm in diameter, demonstrating separation efficiencies approaching 100%. We then demonstrate for the first time on-chip separation of mouse EBs, which were separated into three size groups. The ability to extract specific size ranges of EBs will greatly facilitate their subsequent differentiation studies.


Alcohol consumption and outcome in stable outpatients with peripheral artery disease.
The influence of alcohol consumption on outcome in patients with peripheral artery disease (PAD) has not been thoroughly studied. Factores de Riesgo y ENfermedad Arterial (FRENA) is an ongoing, multicenter, observational registry of consecutive stable outpatients with arterial disease. We compared the mortality rate and the incidence of subsequent ischemic events in patients with PAD, according to their alcohol habits. As of August 2010, 1073 patients with PAD were recruited, of whom 863 (80%) had intermittent claudication (Fontaine stage II), 102 (9.5%) had rest pain (Fontaine stage III), and 108 (10%) had ischemic skin lesions (Fontaine stage IV). In all, 422 patients (39%) consumed alcohol during the study period. Over a mean follow-up of 13 months, 150 patients (14%) developed subsequent ischemic events (myocardial infarction 28, stroke 30, disabling claudication/critical limb ischemia 100), and 70 patients (6.5%) died. The incidence of subsequent events was the same in both subgroups: 11.8 events per 100 patient-years (rate ratio: 1.00; 95% confidence interval [CI], 0.72-1.41), but the mortality rate was significantly lower in alcohol consumers than in non-consumers: 2.78 vs 6.58 deaths per 100 patient-years (rate ratio: 0.42; 95% CI, 0.23-0.74; P = .002). This better outcome was consistently found in patients with Fontaine stages II and III or IV, and persisted after multivariate adjustment (relative risk: 0.49; 95% CI, 0.28-0.88). In patients with PAD, moderate alcohol consumption was associated with lower cardiovascular mortality and overall mortality than abstention. These patients should be informed that low to moderate alcohol consumption may not be harmful to their health.


c-Src links a RANK/αvβ3 integrin complex to the osteoclast cytoskeleton.
RANK ligand (RANKL), by mechanisms unknown, directly activates osteoclasts to resorb bone. Because c-Src is key to organizing the cell's cytoskeleton, we asked if the tyrosine kinase also mediates RANKL-stimulated osteoclast activity. RANKL induces c-Src to associate with RANK(369-373) in an αvβ3-dependent manner. Furthermore, RANK(369-373) is the only one of six putative TRAF binding motifs sufficient to generate actin rings and activate the same cytoskeleton-organizing proteins as the integrin. While c-Src organizes the cell's cytoskeleton in response to the cytokine, it does not participate in RANKL-stimulated osteoclast formation. Attesting to their collaboration, αvβ3 and activated RANK coprecipitate, but only in the presence of c-Src. c-Src binds activated RANK via its Src homology 2 (SH2) domain and αvβ3 via its SH3 domain, suggesting the kinase links the two receptors. Supporting this hypothesis, deletion or inactivating point mutation of either the c-Src SH2 or SH3 domain obviates the RANK/αvβ3 association. Thus, activated RANK prompts two distinct signaling pathways; one promotes osteoclast formation, and the other, in collaboration with c-Src-mediated linkage to αvβ3, organizes the cell's cytoskeleton.


Imaging characteristics of primary laryngeal lymphoma.
The larynx is a rare site for primary NHL. Fewer than 100 cases have been reported in the literature, with the largest imaging review involving only 4 patients. We describe the findings of laryngeal lymphoma on CT, PET, and MR imaging and identify features that may distinguish laryngeal lymphoma from the far more common laryngeal squamous cell carcinoma. Multi-institutional retrospective chart review revealed 20 patients with histopathologically proved laryngeal lymphoma. Pretreatment CT, PET, and MR images were reviewed by a head and neck radiologist, focusing on extent of tumor, cervical lymph node involvement, and enhancement patterns. Patients ranged from 30 to 90 years of age with a mean of 63 years at the time of initial diagnosis and a 2:1 female predominance. The average tumor size was 37 +/- 19 mm. In all patients, laryngeal lymphoma involved the supraglottis but also extended into the glottis (65%) and hypopharynx (60%). The subglottis was less frequently involved (35%). Laryngeal cartilage invasion and cervical lymphadenopathy were each seen in 20% of patients. Lymphoma was consistently FDG-avid (100%) and usually enhanced uniformly with iodinated contrast (73%). Necrosis and calcification were not seen in any cases. Although laryngeal lymphoma is rare, particular imaging features suggest this diagnosis. A large uniformly enhancing supraglottic tumor without central necrosis and without cervical lymphadenopathy is a characteristic finding of lymphoma. Similar to squamous cell carcinoma, lymphoma may extend into the subglottis, pharynx, and laryngeal cartilages.


Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay.
Predicting the clinical course of breast cancer is often difficult because it is a diverse disease comprised of many biological subtypes. Gene expression profiling by microarray analysis has identified breast cancer signatures that are important for prognosis and treatment. In the current article, we use microarray analysis and a real-time quantitative reverse-transcription (qRT)-PCR assay to risk-stratify breast cancers based on biological 'intrinsic' subtypes and proliferation. Gene sets were selected from microarray data to assess proliferation and to classify breast cancers into four different molecular subtypes, designated Luminal, Normal-like, HER2+/ER-, and Basal-like. One-hundred and twenty-three breast samples (117 invasive carcinomas, one fibroadenoma and five normal tissues) and three breast cancer cell lines were prospectively analyzed using a microarray (Agilent) and a qRT-PCR assay comprised of 53 genes. Biological subtypes were assigned from the microarray and qRT-PCR data by hierarchical clustering. A proliferation signature was used as a single meta-gene (log2 average of 14 genes) to predict outcome within the context of estrogen receptor status and biological 'intrinsic' subtype. We found that the qRT-PCR assay could determine the intrinsic subtype (93% concordance with microarray-based assignments) and that the intrinsic subtypes were predictive of outcome. The proliferation meta-gene provided additional prognostic information for patients with the Luminal subtype (P = 0.0012), and for patients with estrogen receptor-positive tumors (P = 3.4 x 10-6). High proliferation in the Luminal subtype conferred a 19-fold relative risk of relapse (confidence interval = 95%) compared with Luminal tumors with low proliferation. A real-time qRT-PCR assay can recapitulate microarray classifications of breast cancer and can risk-stratify patients using the intrinsic subtype and proliferation. The proliferation meta-gene offers an objective and quantitative measurement for grade and adds significant prognostic information to the biological subtypes.


The penny pusher: a cellular model of lens growth.
The mechanisms that regulate the number of cells in the lens and, therefore, its size and shape are unknown. We examined the dynamic relationship between proliferative behavior in the epithelial layer and macroscopic lens growth. The distribution of S-phase cells across the epithelium was visualized by confocal microscopy and cell populations were determined from orthographic projections of the lens surface. The number of S-phase cells in the mouse lens epithelium fell exponentially, to an asymptotic value of approximately 200 cells by 6 months. Mitosis became increasingly restricted to a 300-μm-wide swath of equatorial epithelium, the germinative zone (GZ), within which two peaks in labeling index were detected. Postnatally, the cell population increased to approximately 50,000 cells at 4 weeks of age. Thereafter, the number of cells declined, despite continued growth in lens dimensions. This apparently paradoxical observation was explained by a time-dependent increase in the surface area of cells at all locations. The cell biological measurements were incorporated into a physical model, the Penny Pusher. In this simple model, cells were considered to be of a single type, the proliferative behavior of which depended solely on latitude. Simulations using the Penny Pusher predicted the emergence of cell clones and were in good agreement with data obtained from earlier lineage-tracing studies. The Penny Pusher, a simple stochastic model, offers a useful conceptual framework for the investigation of lens growth mechanisms and provides a plausible alternative to growth models that postulate the existence of lens stem cells.


Effects of Structured Supervised Exercise Training or Motivational Counseling on Pregnant Women's Physical Activity Level: FitMum - Randomized Controlled Trial.
Physical activity (PA) during pregnancy is an effective and safe way to improve maternal health in uncomplicated pregnancies. However, compliance with PA recommendations remains low among pregnant women. The purpose of this study was to evaluate the effects of offering structured supervised exercise training (EXE) or motivational counseling on PA (MOT) during pregnancy on moderate-to-vigorous intensity physical activity (MVPA) level. Additionally, complementary measures of PA using the Pregnancy Physical Activity Questionnaire (PPAQ) and gold standard doubly labeled water (DLW) technique were investigated. The hypotheses were that both EXE and MOT would increase MVPA in pregnancy compared with standard care (CON) and that EXE would be more effective than MOT. In addition, the association between MVPA and the number of sessions attended was explored. A randomized controlled trial included 220 healthy, inactive pregnant women with a median gestational age of 12.9 (IQR 9.4-13.9) weeks. A total of 219 women were randomized to CON (45/219), EXE (87/219), or MOT (87/219). The primary outcome was MVPA (minutes per week) from randomization to the 29th gestational week obtained by a wrist-worn commercial activity tracker (Vivosport, Garmin International). PA was measured by the activity tracker throughout pregnancy, PPAQ, and DLW. The primary outcome analysis was performed as an analysis of covariance model adjusting for baseline PA. The average MVPA (minutes per week) from randomization to the 29th gestational week was 33 (95% CI 18 to 47) in CON, 50 (95% CI 39 to 60) in EXE, and 40 (95% CI 30 to 51) in MOT. When adjusted for baseline MVPA, participants in EXE performed 20 (95% CI 4 to 36) minutes per week more MVPA than participants in CON (P=.02). MOT was not more effective than CON; EXE and MOT also did not differ. MVPA was positively associated with the number of exercise sessions attended in EXE from randomization to delivery (P=.04). Attendance was higher for online (due to COVID-19 restrictions) compared with physical exercise training (P=.03). Adverse events and serious adverse events did not differ between groups. Offering EXE was more effective than CON to increase MVPA among pregnant women, whereas offering MOT was not. MVPA in the intervention groups did not reach the recommended level in pregnancy. Changing the intervention to online due to COVID-19 restrictions did not affect MVPA level but increased exercise participation. ClinicalTrials.gov NCT03679130; https://clinicaltrials.gov/ct2/show/NCT03679130. RR2-10.1136/bmjopen-2020-043671.


Purification, characterization and immunological properties of the capsular polysaccharide of Pasteurella haemolytica serotype T15: its identity with the K62 (K2ab) capsular polysaccharide of Escherichia coli and the capsular polysaccharide of Neisseria meningitidis serogroup H.
Capsular polysaccharide from two strains of Pasteurella haemolytica serotype T15 was purified and characterized by chemical analysis and NMR spectroscopy. The polymer, a teichoic acid, proved to be very similar in structure to the capsular polysaccharide of P. haemolytica serotype T4 and identical to the previously described K62 (K2ab) capsular polysaccharide of Escherichia coli, and the capsular polysaccharide of Neisseria meningitidis serotype H, i.e. ----(2-glycerol-3)----(phosphate)----(4-alpha-D-galactopyranose -1)---- with partial O-acetylation on the galactose residues. Electron microscopy with Protein A-gold labelled antisera showed that the polysaccharide was peripherally located on the surface of all three organisms. Chemical removal of O-acetyl groups from the polysaccharide yielded a structure identical to that previously described for E. coli K2 (K2a). Both O-acetylated and de-O-acetylated P. haemolytica T15 polymers, when absorbed on to sheep erythrocytes in passive haemagglutination assays, yielded identical antibody titres with sera raised against P. haemolytica T15, E. coli K2 or N. meningitidis H whole cells. De-O-acetylation of the Pasteurella polysaccharide influenced its precipitability with immune sera, but this could not be related to the absence of O-acetyl groups because the non-acetylated E. coli K2 polymer readily precipitated with a line of 'identity' with the acetylated P. haemolytica T15 polymer.


The Role of Emerging Risk Factors in Cardiovascular Outcomes.
This review discusses the recent evidence for a selection of blood-based emerging risk factors, with particular reference to their relation with coronary heart disease and stroke. For lipid-related emerging risk factors, recent findings indicate that increasing high-density lipoprotein cholesterol is unlikely to reduce cardiovascular risk, whereas reducing triglyceride-rich lipoproteins and lipoprotein(a) may be beneficial. For inflammatory and hemostatic biomarkers, genetic studies suggest that IL-6 (a pro-inflammatory cytokine) and several coagulation factors are causal for cardiovascular disease, but such studies do not support a causal role for C-reactive protein and fibrinogen. Patients with chronic kidney disease are at high cardiovascular risk with some of this risk not mediated by blood pressure. Randomized evidence (trials or Mendelian) suggests homocysteine and uric acid are unlikely to be key causal mediators of chronic kidney disease-associated risk and sufficiently large trials of interventions which modify mineral bone disease biomarkers are unavailable. Despite not being causally related to cardiovascular disease, there is some evidence that cardiac biomarkers (e.g. troponin) may usefully improve cardiovascular risk scores. Many blood-based factors are strongly associated with cardiovascular risk. Evidence is accumulating, mainly from genetic studies and clinical trials, on which of these associations are causal. Non-causal risk factors may still have value, however, when added to cardiovascular risk scores. Although much of the burden of vascular disease can be explained by 'classic' risk factors (e.g. smoking and blood pressure), studies of blood-based emerging factors have contributed importantly to our understanding of pathophysiological mechanisms of vascular disease, and new targets for potential therapies have been identified.


Massive load of functional effector CD4+ and CD8+ T cells against cytomegalovirus in very old subjects.
A progressive, systemic, and low-grade proinflammatory status is one of the major characteristics of immunosenescence. Emerging data suggest a possible contribution of CMV, known to chronically infect a large proportion of humans, lifelong from newborns to centenarians. To test this hypothesis, we evaluated functional T cell responses to two CMV immunogenic proteins, pp65 and IE-1, in 65 chronically infected subjects aged 25-100 years. PBMC were stimulated with mixtures of peptides spanning the entire sequence of both proteins, and Ag specificity and magnitude of intracellular IFN-gamma- and TNF-alpha-positive cells were then analyzed within both CD4+ and CD8+ T cells. Results indicate that pp65 and, to a lesser extent, IE-1 constitute major Ags against which aged people target functionally efficient T cell effector responses with massive production of Th1 cytokines and exhibition of CD107a degranulation marker. As a result, the production of IFN-gamma induced in T cells by both Ags was seven to eight times greater in very old than in young subjects. The comparative analysis of pp65-specific responses in these very long-term carriers revealed a reciprocal relationship between CD4+ and CD8+ producing IFN-gamma in the same individuals. These results indicate that CMV represents an important pathogen responsible for a strong immune activation in human aging. Such a remarkable burden of effector CD4+ and CD8+ T cells may be necessary to protect the elderly from CMV endogenous reactivation, but can turn detrimental by giving a substantial contribution to the proinflammatory status that accompanies the main age-related diseases.


Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL2003.
The influence of thiopurine methyltransferase (TPMT) genotype on treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia trial ALL2003, a trial in which treatment intensity was adjusted based on minimal residual disease (MRD). TPMT genotype was measured in 2387 patients (76% of trial entrants): 2190 were homozygous wild-type, 189 were heterozygous for low activity TPMT alleles (166 TPMT*1/*3A, 19 TPMT*1/*3C, 3 TPMT*1/*2 and 1 TPMT*1/*9) and 8 were TPMT deficient. In contrast to the preceding trial ALL97, there was no difference in event-free survival (EFS) between the TPMT genotypes. The 5-year EFS for heterozygous TPMT*1/*3A patients was the same in both trials (88%), but for the homozygous wild-type TPMT*1/*1 patients, EFS improved from 80% in ALL97% to 88% in ALL2003. Importantly, the unexplained worse outcome for heterozygous TPMT*1/*3C patients observed in ALL97 (5-year EFS 53%) was not seen in ALL2003 (5-year EFS 94%). In a multivariate Cox regression analysis the only significant factor affecting EFS was MRD status (hazard ratio for high-risk MRD patients 4·22, 95% confidence interval 2·97-5·99, P < 0·0001). In conclusion, refinements in risk stratification and treatment have reduced the influence of TPMT genotype on treatment outcome in a contemporary protocol.


Computed tomography study of pineal calcification in schizophrenia.
Computed tomography studies concerning pineal calcification (PC) in schizophrenia have been conducted mainly by one author who correlated this calcification with several aspects of the illness. On the basis of these findings the aim of the present study was to analyze size and incidence of pineal gland calcification by CT in schizophrenics and healthy controls, and to verify the relationship between pineal calcification and age, and the possible correlation with psychopathologic variables. Pineal calcification was measured on CT scans of 87 schizophrenics and 46 controls divided into seven age subgroups of five years each. No significant differences in PC incidence and mean size between patients and controls were observed as far as the entire group was considered. PC size correlated with age both in schizophrenics and controls. We found a higher incidence of PC in schizophrenics in the age subgroup of 21-25 years, and a negative correlation with positive symptoms of schizophrenia in the overall group. These findings could suggest a premature calcific process in schizophrenics and a probable association with 'non-paranoid' aspects of the illness. Nevertheless the potential role of this process possibly related to some aspects of the altered neurodevelopment in schizophrenia is still unclear.


Largely reduced OAR doses, and planning and delivery times for challenging robotic SBRT cases, obtained with a novel optimizer.
Recently, VOLO™ was introduced as a new optimizer for CyberKnife® planning. In this study, we investigated possibilities to improve treatment plans for MLC-based prostate SBRT with enhanced peripheral zone dose while sparing the urethra, and central lung tumors, compared to existing Sequential Optimization (SO). The primary focus was on reducing OAR doses. For 25 prostate and 25 lung patients treated with SO plans, replanning with VOLO™ was performed with the same planning constraints. For equal PTV coverage, almost all OAR plan parameters were improved with VOLO™. For prostate patients, mean rectum and bladder doses were reduced by 34.2% (P < 0.001) and 23.5% (P < 0.001), with reductions in D0.03cc of 3.9%, 11.0% and 3.1% for rectum, mucosa and bladder (all P ≤ 0.01). Urethra D5% and D10% were 3.8% and 3.0% lower (P ≤ 0.002). For lung patients, esophagus, main bronchus, trachea, and spinal cord D0.03cc was reduced by 18.9%, 11.1%, 16.1%, and 13.2%, respectively (all P ≤ 0.01). Apart from the dosimetric advantages of VOLO™ planning, average reductions in MU, numbers of beams and nodes for prostate/lung were 48.7/32.8%, 26.5/7.9% and 13.4/7.9%, respectively (P ≤ 0.003). VOLO™ also resulted in reduced delivery times with mean/max reductions of: 27/43% (prostate) and 15/41% (lung), P < 0.001. Planning times reduced from 6 h to 1.1 h and from 3 h to 1.7 h for prostate and lung, respectively. The new VOLO™ planning was highly superior to SO planning in terms of dosimetric plan quality, and planning and delivery times.


In Operando X-Ray Nanodiffraction Reveals Electrically Induced Bending and Lattice Contraction in a Single Nanowire Device.
Hard X-ray diffraction (XRD) using a nanofocused beam is used to measure both lattice contraction and bending in a single nanowire device under electric bias. The shape of the nanowire is reconstructed in 3D with sub-nanometer precision. As the bias voltage is gradually increased, nonreversible structural changes in the contact regions are observed, correlated with degradation of the electrical conductance.


Rapid trifluoromethylation and perfluoroalkylation of five-membered heterocycles by photoredox catalysis in continuous flow.
Trifluoromethylated and perfluoroalkylated heterocycles are important building blocks for the synthesis of numerous pharmaceutical products, agrochemicals and are widely applied in material sciences. To date, trifluoromethylated and perfluoroalkylated hetero-aromatic systems can be prepared utilizing visible light photoredox catalysis methodologies in batch. While several limitations are associated with these batch protocols, the application of microflow technology could greatly enhance and intensify these reactions. A simple and straightforward photocatalytic trifluoromethylation and perfluoroalkylation method has been developed in continuous microflow, using commercially available photocatalysts and microflow components. A selection of five-membered hetero-aromatics were successfully trifluoromethylated (12 examples) and perfluoroalkylated (5 examples) within several minutes (8-20 min).