Dementia prevention: shared questions for research and clinical management.
The emergence of advanced genetic technologies raises many challenges for dementia care and the conduct of related social, behavioural and clinical research. Genetic tests are already used to identify possible participants in dementia prevention trials. These tests are unlike any other in clinical medicine as they have the capacity to predict disease onset after intervals of many years with implications for other family members. Genetic counselling professionals support services in paediatrics, cancer diagnosis and some adult-onset diseases. Their capacity cannot meet the needs for pre- and post-test support of the many "at-risk" families living with late onset dementia. Most dementias are common, complex conditions in which multiple genetic and environmental factors play important and potentially modifiable roles. Large scale prevention studies are needed to test the effectiveness of interventions. Some economy of effort will be achieved by the preferential inclusion of "at-risk" families. Many such families are in contact with dementia care services and will be motivated to participate in prevention studies. However, practice standards and consensus-based guidelines do not yet exist. Support services are not available on a scale sufficient to prevent harm when risk is poorly communicated causing unnecessary psychological morbidity in unaffected family members. There is a pressing need for research to inform the development of study guidelines and to identify how services are strengthened to support these families during and after their participation in trials. Discourse analysis provides a useful method to collect and analyse data of this type and supports the conclusions of this review.


Eosinophils cocultured with endothelial cells have increased survival and functional properties.
Human peripheral blood eosinophils, cells often associated with allergic and parasitic diseases, were maintained in vitro for at least 14 days when they were cocultured with bovine endothelial cells and for at least 7 days when cultured with either bovine or human endothelial cell-derived conditioned medium. The cocultured eosinophils became hypodense and generated about three times as much leukotriene C4 upon activation with calcium ionophore and killed about three times as many antibody-coated larvae of Schistosoma mansoni as freshly isolated normodense eosinophils. That these cells can be maintained in vitro by coculture with endothelial cells, and the surprising finding that the cocultured eosinophils have biochemical, cytotoxic, and density properties similar to those of eosinophils in patients with allergic and other disorders, will facilitate investigation of the regulation and role of these cells in health and disease.


PDZ and LIM domain-encoding genes: molecular interactions and their role in development.
PDZ/LIM genes encode a group of proteins that play very important, but diverse, biological roles. They have been implicated in numerous vital processes, e.g., cytoskeleton organization, neuronal signaling, cell lineage specification, organ development, and oncogenesis. In mammals, there are ten genes that encode for both a PDZ domain, and one or several LIM domains: four genes of the ALP subfamily (ALP, Elfin, Mystique, and RIL), three of the Enigma subfamily (Enigma, Enigma Homolog, and ZASP), the two LIM kinases (LIMK1 and LIMK2), and the LIM only protein 7 (LMO7). Functionally, all PDZ and LIM domain proteins share an important trait, i.e., they can associate with and/or influence the actin cytoskeleton. We review here the PDZ and LIM domain-encoding genes and their different gene structures, their binding partners, and their role in development and disease. Emphasis is laid on the important questions: why the combination of a PDZ domain with one or more LIM domains is found in such a diverse group of proteins, and what role the PDZ/LIM module could have in signaling complex assembly and localization. Furthermore, the current knowledge on splice form specific expression and the function of these alternative transcripts during vertebrate development will be discussed, since another source of complexity for the PDZ and LIM domain-encoding proteins is introduced by alternative splicing, which often creates different domain combinations.


Photodoping of metal oxide nanocrystals for multi-charge accumulation and light-driven energy storage.
The growing demand for self-powered devices has led to the study of novel energy storage solutions that exploit green energies whilst ensuring self-sufficiency. In this context, doped metal oxide nanocrystals (MO NCs) are interesting nanosized candidates with the potential to unify solar energy conversion and storage into one set of materials. In this review, we aim to present recent and important developments of doped MO NCs for light-driven multi-charge accumulation (i.e., photodoping) and solar energy storage. We will discuss the general concept of photodoping, the spectroscopic and theoretical tools to determine the charging process, together with unresolved open questions. We conclude the review by highlighting possible device architectures based on doped MO NCs that are expected to considerably impact the field of energy storage by combining in a unique way the conversion and storage of solar power and opening the path towards competitive and novel light-driven energy storage solutions.


Comparison between preoperative biopsy and post-excision histology results in sarcoma: experience at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.
Tumour size, grade and subtype are the main prognostic factors in adult patients presenting with soft-tissue sarcoma. Planning for appropriate management, including the need for additional staging investigations and neoadjuvant therapy, is dependent on reliable preoperative histopathological results. To determine whether there is agreement between preoperative and post-excision histological findings in patients presenting with soft-tissue sarcoma, and whether the agreement is influenced by the subtypes of sarcomas. Records of adult patients who had soft-tissue sarcomas excised were reviewed. Kaposi's sarcoma and gastrointestinal stromal tumours were excluded. Data were retrieved from the Department of Anatomical Pathology of the National Health Laboratory Service and theatre records at Chris Hani Baragwanath Academic Hospital, and included patient demography, tumour sites and size, HIV status, biopsy types and post-excision histological findings. Records of 153 patients were found (median age 44 years). The majority of the sarcomas were >5 cm in diameter, deep seated and localised in extremities. The commonest subtype, irrespective of HIV status, was dermatofibrosarcoma protuberans. Fine-needle aspiration biopsy (FNAB) results were inaccurate in determining the malignant nature, grade and subtype of sarcoma. Rates of accurate tumour subtype classification following core needle and incision biopsies when compared with post-excision histological findings were 73.1% and 78.3%, respectively. FNAB should not be used in the primary evaluation of soft-tissue tumours. A report of spindle cells on the FNAB smear should be followed by core needle or incision biopsy. Incision biopsy is superior to core needle biopsy in the classification of sarcomas by subtype.


Does prophylactic anticoagulation reduce the risk of femoral tunneled dialysis catheter-related complications.
To determine the incidence and predictors of femoral tunneled dialysis catheter (TDC)-related complications and whether prophylactic anticoagulation is associated with reduced catheter-related deep vein thrombosis (CRT) or prolonged patency. A retrospective review of femoral TDCs inserted for maintenance hemodialysis in patients from two dialysis units that have used two different strategies to reduce thrombotic complications. One center routinely considered all femoral TDCs for prophylactic anticoagulation, whilst the other restricted anticoagulation to TDCs that had required repeated treatment with urokinase locks to maintain patency. Survival analyses were performed to establish complication rates, identify predictors of complications and assess the effect of prophylactic anticoagulation use. Of the 194 femoral TDCs identified, 178 (92%) were associated with at least one complication. Approximately three quarters did not provide adequate small solute clearance; one half were not in use by three months; one quarter had at least one catheter-related infection (2.3 per 1000 catheter days); and one in ten developed a CRT (1.1 per 1000 catheter days). Prophylactic anticoagulation was not associated with significant improvements in rates of catheter occlusion, CRT, catheter-related infection or dialysis adequacy. A previous ipsilateral femoral TDC was identified as a statistically significant predictor of a CRT (adjusted hazard ratio 3.7 [95% confidence interval 1.4-9.8]; P=.007). Femoral TDCs are associated with poor patency rates and high complication rates; reusing femoral veins for TDCs should be avoided where possible, and this study provides no evidence to support routine prophylactic anticoagulation in all patients with femoral TDCs.


The price of protein: combining evolutionary and economic analysis to understand excessive energy consumption.
Excessive weight gain appears, thermodynamically at least, straightforward: growing energy intake and/or falling energy expenditure create an energetic surplus, resulting in fat accumulation. The situation is, however, far more complex, with genetic, physiological, social, psychological and economic factors all implicated. Thus the causes of excessive weight gain remain difficult to disentangle. We combine two recent developments from different areas of nutrition research: the study of food prices in relation to energy content and the hypothesis that an evolved propensity to regulate protein intake more strongly than non-protein calories exerts powerful leverage on overall energy intake. We partition the energy content of a range of common supermarket foods, and show that increasing overall energy content only modestly raises the cost of foods, largely as a result of macronutrients having very different costs. Higher food prices are associated with higher protein content and lower carbohydrate content, whereas fat content was not significantly associated with food price. We show that the differential costs of energy from protein and carbohydrates may bias consumers towards diets high in carbohydrate energy, leading them to consume excessive energy to meet their dietary protein needs. We review evidence from physiology, evolution and economics that support our suggestion.


Specimen-specific nonlinear finite element modeling to predict vertebrae fracture loads after vertebroplasty.
Vertebral fracture load and stiffness from a metastatic vertebral defect model were predicted using nonlinear finite element models (FEM) and validated experimentally. The study objective was to develop and validate an FEM-based tool for predicting polymer-augmented lytic vertebral fracture load and stiffness and the influence of metastatic filling materials. Percutaneous vertebroplasty has the potential to reduce vertebral fracture risk affected with lytic metastases by providing mechanical stabilization. However, it has been shown that the mismatch in mechanical properties between poly(methyl-methacrylate) (PMMA) and bone induces secondary fractures and intervertebral disc degeneration. A biodegradable copolymer, poly(propylene fumarate-co-caprolactone) (P(PF-co-CL)), has been shown to possess the appropriate mechanical properties for bone defect repair. Simulated metastatic lytic defects were created in 40 cadaveric vertebral bodies, which were randomized into 4 groups: intact vertebral body (intact), simulated defect without treatment (negative), defect treated with P(PF-co-CL) (copolymer), and defect treated with PMMA (PMMA). Spines were imaged with quantitative computed tomography (QCT), and QCT/FEM-subject-specific, nonlinear models were created. Predicted fracture loads and stiffness were identified and compared with experimentally measured values using Pearson correlation analysis and paired t test. There was no significant difference between the measured and predicted fracture loads and stiffness for each group. Predicted fracture loads were larger for PMMA augmentation (3960 N [1371 N]) than that for the copolymer, negative and intact groups (3484 N [1497 N], 3237 N [1744 N], and 1747 N [702 N]). A similar trend was observed in the predicted stiffness. Moreover, predicted and experimental fracture loads were strongly correlated (R=0.78), whereas stiffness showed moderate correlation (R=0.39). QCT/FEM was successful for predicting fracture loads of metastatic, polymer-augmented vertebral bodies. Overall, we have demonstrated that QCT/FEM may be a useful tool for predicting in situ vertebral fracture load resulting from vertebroplasty. N/A.


Depression and previous alcoholism in the elderly.
A prospective study of male in-patients over 55 years old who met Feighner criteria for non-bipolar depression was performed to determine if a previous history of alcoholism significantly influenced treatment or response to treatment. Among 58 subjects with complete follow-up information, the 16 who had a history of alcoholism had a presentation at index which differed from that of the non-alcoholics, and on follow-up they clearly had more chronic illness. This elderly sample with alcoholism resembles 'neurotic-reactive' depressives described in younger samples, and supports a past history of alcoholism as being a risk factor for chronicity of depression on follow-up in the elderly population.


Salmonella modulates metabolism during growth under conditions that induce expression of virulence genes.
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative pathogen that uses complex mechanisms to invade and proliferate within mammalian host cells. To investigate possible contributions of metabolic processes to virulence in S. Typhimurium grown under conditions known to induce expression of virulence genes, we used a metabolomics-driven systems biology approach coupled with genome-scale modeling. First, we identified distinct metabolite profiles associated with bacteria grown in either rich or virulence-inducing media and report the most comprehensive coverage of the S. Typhimurium metabolome to date. Second, we applied an omics-informed genome-scale modeling analysis of the functional consequences of adaptive alterations in S. Typhimurium metabolism during growth under our conditions. Modeling efforts highlighted a decreased cellular capability to both produce and utilize intracellular amino acids during stationary phase culture in virulence conditions, despite significant abundance increases for these molecules as observed by our metabolomics measurements. Furthermore, analyses of omics data in the context of the metabolic model indicated rewiring of the metabolic network to support pathways associated with virulence. For example, cellular concentrations of polyamines were perturbed, as well as the predicted capacity for secretion and uptake.


Framing Pictorial Cigarette Warning Labels to Motivate Young Smokers to Quit.
The Family Smoking Prevention and Tobacco Control Act requires new pictorial warnings for U.S. cigarette packs, but enactment has been delayed by tobacco industry lawsuits. Research can inform implementation of the pictorial warning requirement and identify ways to optimize their public health impact post-implementation. This study investigated the impact of warning label message framing on young smokers' motivation to quit, examining cessation self-efficacy, and perceived risks as moderators of message framing impact. Smokers ages 18-30 (n = 740) completed baseline measures and were randomized to view 4 images of cigarette packs with pictorial health warnings featuring gain- or loss-framed messages. Motivation to quit was assessed after participants viewed the pack images. Linear models accounting for repeated measures and adjusting for baseline covariates examined the impact of message framing and interactions with baseline self-efficacy to quit and perceived risks of smoking. Loss-framed warnings prompted significantly greater motivation to quit among smokers with high self-efficacy compared with smokers with low self-efficacy. Among smokers with low self-efficacy, gain-framed messages were superior to loss-framed messages. Gain-framed warnings generated significantly greater motivation to quit among smokers with high perceived risks compared with smokers with low perceived risks. Among smokers with high perceived risks, gain-framed messages were superior to loss-framed messages. A combination of pictorial warnings featuring risk-based (i.e., loss-framed) and efficacy-enhancing (i.e., gain-framed) information may promote better public health outcomes. Research is needed to investigate how strategically framed warning messages impact smokers' behaviors based on their pre-existing attitudes and beliefs in real-world settings.


The clinical correlates of neurological soft signs in chronic schizophrenia.
Among 16 chronic schizophrenic in-patients, all had at least one neurological soft sign (NSS), and 6 (40%) had definite neurodysfunction. NSS and TD scores were highly intercorrelated, and NSS were significantly correlated with neuroleptic drug exposure. NSS correlated positively with both positive and negative symptoms and cognitive impairment but not with cerebral ventricular size on CT. Patients with neurodysfunction had more positive and negative psychopathology, cognitive impairment and TD than those without. Cerebral ventricular sizes and family histories of schizophrenia were similar in both NSS groups. The presence of NSS may be a simple but important way of identifying a subgroup of schizophrenics with neurodevelopmental predisposing abnormalities, and vulnerability to TD.


Removal of oseltamivir (Tamiflu) and other selected pharmaceuticals from wastewater using a granular bioplastic formulation entrapping propagules of Phanerochaete chrysosporium.
The capacity of the ligninolytic fungus Phanerochaete chrysosporium to degrade a wide variety of environmentally persistent xenobiotics has been largely reported in the literature. Beside other factors, one barrier to a wider use of this bioremediation fungus is the availability of effective formulations that ensure easy preparation, handling and application. In this series of laboratory experiments, we evaluated the efficiency of a granular bioplastic formulation entrapping propagules of P. chrysosporium for removal of four selected pharmaceuticals from wastewater samples. Addition of inoculated granules to samples of the wastewater treatment plant of Bologna significantly increased the removal of the antiviral drug oseltamivir (Tamiflu), and the antibiotics, erythromycin, sulfamethoxazol, and ciprofloxacin. Similar effects were also observed in effluent water. Oseltamivir was the most persistent of the four active substances. After 30d of incubation, approximately two times more oseltamivir was removed in bioremediated wastewater than controls. The highest removal efficiency of the bioplastic formulation was observed with the antibiotic ciprofloxacin. Microbiological DNA-based analysis showed that the bioplastic matrix supported the growth of P. chrysosporium, thus facilitating its adaptation to unusual environment such as wastewater.


Determinants of influenza vaccination among the adult and older Italian population with chronic obstructive pulmonary disease: a secondary analysis of the multipurpose ISTAT survey on health and health care use.
We analyzed seasonal flu vaccination rates among the Italian population suffering from Chronic Obstructive Pulmonary Disease (COPD) in order to identify socio-demographic and clinical determinants for vaccination. We used data from the survey "Health and health care use in Italy", which interviewed 5,935 persons (age 15 - 102 years) suffering from COPD in the period 2004-2005. For each respondent, information on socioeconomic and health conditions, smoking status and patterns of health care utilization were retrieved. After bivariate analysis, we used two multilevel regression models to assess determinants of vaccination among the adult and the older Italian population. Overall 30.5% of adults (N=670) and 74.8% (N=2,796) of older people reported being vaccinated against seasonal flu. After controlling for potential confounders, older age increases the odds of vaccine uptake. Single marital status among the older people, smoking and not having contact with GPs in both age groups, are factors associated with non vaccination. Higher-educated elderly are less likely to be vaccinated, while coverage is higher among the wealthier adults. Vaccine coverage among adults with COPD in Italy remains low, especially among those with no comorbidities, and aged less than 44 years. It is only in older age that vaccination rates increase substantially. We found several risk factors for non vaccination, such as smoking, single marital status, and not having contacts with GPs, which should be considered in developing strategies to increase the coverage of influenza vaccine among people with COPD in Italy.


Identifying hospitals that may be at most financial risk from Medicaid disproportionate-share hospital payment cuts.
Medicaid disproportionate-share hospital (DSH) payments are expected to decline by $35.1 billion between fiscal years 2017 and 2024, a reduction brought about by the Affordable Care Act (ACA) and recent congressional action. DSH payments have long been a feature of the Medicaid program, intended to partially offset uncompensated care costs incurred by hospitals that treat uninsured and Medicaid populations. The DSH payment cuts were predicated on the expectation that the ACA's expansion of health insurance to millions of Americans would bring about a decline in many hospitals' uncompensated care costs. However, the decision of twenty-five states not to expand their Medicaid programs, combined with residual coverage gaps, may leave as many as thirty million people uninsured, and hospitals will bear the burden of their uncompensated care costs. We sought to identify the hospitals that may be the most financially vulnerable to reductions in Medicaid DSH payments. We found that of the 529 acute care hospitals that will be particularly affected by the cuts, 225 (42.5 percent) are in weak financial condition. Policy makers should recognize that decreases in revenue may affect these hospitals' ability to give vulnerable populations access to care.


Serum markers of bone metabolism show bone loss in hibernating bears.
Disuse osteopenia was studied in hibernating black bears (Ursus americanus) using serum markers of bone metabolism. Blood samples were collected from male and female, wild black bears during winter denning and active summer periods. Radioimmunoassays were done to determine serum concentrations of cortisol, the carboxy-terminal cross-linked telopeptide, and the carboxy-terminal propeptide of Type I procollagen, which are markers of bone resorption and formation, respectively. The bone resorption marker was significantly higher during winter hibernation than it was in the active summer months, but the bone formation marker was unchanged, suggesting an imbalance in bone remodeling and a net bone loss during disuse. Serum cortisol was significantly correlated with the bone resorption marker, but not with the bone formation marker. The bone formation marker was four- to fivefold higher in an adolescent and a 17-year-old bear early in the remobilization period compared with the later summer months. These findings raise the possibility that hibernating black bears may minimize bone loss during disuse by maintaining osteoblastic function and have a more efficient compensatory mechanism for recovering immobilization-induced bone loss than that of humans or other animals.


Apple Polyphenols Decrease Atherosclerosis and Hepatic Steatosis in ApoE-/- Mice through the ROS/MAPK/NF-κB Pathway.
In this study, we examined the effects of apple polyphenols (APs) on hyperlipidemia, atherosclerosis, hepatic steatosis and endothelial function and investigated the potential mechanisms. ApoE(-/-) mice were fed a western-type diet and orally treated with APs (100 mg/kg) or atorvastatin (10 mg/kg) for 12 weeks. Hyperlipidemia and atherosclerosis in the aortic sinuses and, and hepatic lipidosis were measured. The treatment with APs or atorvastatin induced a remarkable reduction in the atherosclerotic lesions and hepatic steatosis and decreased the levels of low-density lipoprotein, triglyceride, CCL-2 and VCAM-1 levels in the plasma. Conversely, the APs significantly increased the plasma levels of high-density lipoprotein (HDL) cholesterol and markedly up-regulated the glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) levels in liver tissues. Moreover, the APs treatment modulated lipid metabolism by up-regulating the transcription of associated hepatic genes including PPARα, while down-regulating the transcription of SCAP and its downstream genes associated with lipid synthesis in the liver. Histological assessment showed that the APs treatment also reduced the macrophage infiltration in the aortic root plaque and the inflammatory cells infiltrations to the liver tissues. Moreover, we confirmed that the APs treatment greatly reduced the ox-LDL-induced endothelial dysfunction and monocyte adhesion to rat aortic endothelial cells (RAECs). Mechanistically, the APs treatment suppressed the ROS/MAPK/NF-κB signaling pathway, and consequently, reduced CCL-2, ICAM-1 and VCAM-1 expression. Our results suggest that the APs are a beneficial nutritional supplement for the attenuation of atherosclerosis.


The binuclear cluster of [FeFe] hydrogenase is formed with sulfur donated by cysteine of an [Fe(Cys)(CO)2(CN)] organometallic precursor.
The enzyme [FeFe]-hydrogenase (HydA1) contains a unique 6-iron cofactor, the H-cluster, that has unusual ligands to an Fe-Fe binuclear subcluster: CN-, CO, and an azadithiolate (adt) ligand that provides 2 S bridges between the 2 Fe atoms. In cells, the H-cluster is assembled by a collection of 3 maturases: HydE and HydF, whose roles aren't fully understood, and HydG, which has been shown to construct a [Fe(Cys)(CO)2(CN)] organometallic precursor to the binuclear cluster. Here, we report the in vitro assembly of the H-cluster in the absence of HydG, which is functionally replaced by adding a synthetic [Fe(Cys)(CO)2(CN)] carrier in the maturation reaction. The synthetic carrier and the HydG-generated analog exhibit similar infrared spectra. The carrier allows HydG-free maturation to HydA1, whose activity matches that of the native enzyme. Maturation with 13CN-containing carrier affords 13CN-labeled enzyme as verified by electron paramagnetic resonance (EPR)/electron nuclear double-resonance spectra. This synthetic surrogate approach complements existing biochemical strategies and greatly facilitates the understanding of pathways involved in the assembly of the H-cluster. As an immediate demonstration, we clarify that Cys is not the source of the carbon and nitrogen atoms in the adt ligand using pulse EPR to target the magnetic couplings introduced via a 13C3,15N-Cys-labeled synthetic carrier. Parallel mass-spectrometry experiments show that the Cys backbone is converted to pyruvate, consistent with a cysteine role in donating S in forming the adt bridge. This mechanistic scenario is confirmed via maturation with a seleno-Cys carrier to form HydA1-Se, where the incorporation of Se was characterized by extended X-ray absorption fine structure spectroscopy.


Inverted faces benefit from whole-face processing.
Upright faces are thought to engage holistic processing whereby local regions are integrated into a unified whole for the purposes of rapid, efficient analysis. In contrast, inverted faces are thought to recruit a slower, less-accurate serial analysis of local features. Aperture paradigms, whereby a target face is revealed by a dynamic viewing window that shifts over the stimulus image, offer a compelling test of this view. If upright faces are processed holistically, perceptual judgements ought to be substantially disrupted when stimuli are viewed through apertures. In contrast, aperture viewing should produce little or no decrement in perceptual decisions when judging inverted faces, as they are thought to be subjected to serial feature-based analysis. Here we present four experiments that elucidate the effects of aperture viewing on the perception of upright and inverted faces. In our first two experiments, we find evidence of disproportionate aperture effects for upright faces relative to inverted faces. However, these findings are qualified by the fact that observers found it harder to discriminate inverted faces presented in the 'baseline' whole-face condition. When observers' ability to discriminate faces in the whole-face condition was matched for difficulty (Experiments 3 and 4), we show that upright and inverted faces produce very similar aperture effects. These findings indicate that both upright and inverted faces benefit from whole-face processing and accord with other lines of evidence that faces engage qualitatively similar types of processing in both orientations.


Monte Carlo simulation of electron beams from an accelerator head using PENELOPE.
The Monte Carlo code PENELOPE has been used to simulate electron beams from a Siemens Mevatron KDS linac with nominal energies of 6, 12 and 18 MeV. Owing to its accuracy, which stems from that of the underlying physical interaction models, PENELOPE is suitable for simulating problems of interest to the medical physics community. It includes a geometry package that allows the definition of complex quadric geometries, such as those of irradiation instruments, in a straightforward manner. Dose distributions in water simulated with PENELOPE agree well with experimental measurements using a silicon detector and a monitoring ionization chamber. Insertion of a lead slab in the incident beam at the surface of the water phantom produces sharp variations in the dose distributions, which are correctly reproduced by the simulation code. Results from PENELOPE are also compared with those of equivalent simulations with the EGS4-based user codes BEAM and DOSXYZ. Angular and energy distributions of electrons and photons in the phase-space plane (at the downstream end of the applicator) obtained from both simulation codes are similar, although significant differences do appear in some cases. These differences, however, are shown to have a negligible effect on the calculated dose distributions. Various practical aspects of the simulations, such as the calculation of statistical uncertainties and the effect of the 'latent' variance in the phase-space file, are discussed in detail.


A review of nia as an exercise option for cancer survivors.
Nia is a fusion fitness program that blends elements from the dance arts, martial arts, and healing arts, creating a workout that is adaptable to all ages and fitness levels. As a nontraditional form of exercise, Nia integrates body, mind, and spirit as well as the five sensations of flexibility, agility, mobility, strength, and stability. Nia incorporates both cardiovascular and whole-body conditioning and is adaptable to those with a sedentary or active lifestyle, making it useful for the varying abilities of cancer survivors. Oncology nurses are in a key position to educate individuals with cancer on the benefits of exercise, such as improved physical functioning and quality of life, and decreased cancer-related fatigue. The purpose of this article is to familiarize oncology nurses with the potential benefits of Nia for cancer survivors.


B-Type Natriuretic Peptide at Admission Is a Predictor of All-Cause Mortality at One Year after the First Acute Episode of New-Onset Heart Failure with Preserved Ejection Fraction.
Background: Heart failure with preserved ejection fraction (HFpEF) has been assessed extensively, but few studies analysed the predictive value of the NT-proBNP in patients with de novo and acute HFpEF. We sought to identify NT-proBNP at admission as a predictor for all-cause mortality and rehospitalisation at 12 months in patients with new-onset HFpEF. Methods: We analysed 91 patients (73 ± 11 years, 68% females) admitted for de novo and acute HFpEF, using the Cox proportional hazard risk model. Results: An admission NT-proBNP level above the threshold of 2910 pg/mL identified increased all-cause mortality at 12 months (AUC = 0.72, sensitivity = 92%, specificity = 53%, p < 0.001). All-cause mortality adjusted for age, gender, medical history, and medication in the augmented NT-proBNP group was 16-fold higher (p = 0.018), but with no difference in rehospitalisation rates (p = 0.391). The predictors of increased NT-proBNP ≥ 2910 pg/mL were: age (p = 0.016), estimated glomerular filtration rate (p = 0.006), left atrial volume index (p = 0.001), history of atrial fibrillation (p = 0.006), and TAPSE (p = 0.009). Conclusions: NT-proBNP above 2910 pg/mL at admission for de novo and acute HFpEF predicted a 16-fold increased mortality at 12 months, whereas values less than 2910 pg/mL forecast a high likelihood of survival (99.3%) in the next 12 months, and should be considered as a useful prognostic tool, in addition to its utility in diagnosing heart failure.


Maternal Age at Delivery Is Associated with an Epigenetic Signature in Both Newborns and Adults.
Offspring of older mothers are at increased risk of adverse birth outcomes, childhood cancers, type 1 diabetes, and neurodevelopmental disorders. The underlying biologic mechanisms for most of these associations remain obscure. One possibility is that maternal aging may produce lasting changes in the epigenetic features of a child's DNA. To test this, we explored the association of mothers' age at pregnancy with methylation in her offspring, using blood samples from 890 Norwegian newborns and measuring DNA methylation at more than 450,000 CpG sites across the genome. We examined replication of a maternal-age finding in an independent group of 1062 Norwegian newborns, and then in 200 US middle-aged women. Older maternal age was significantly associated with reduced methylation at four adjacent CpGs near the 2nd exon of KLHL35 in newborns (p-values ranging from 3x10-6 to 8x10-7). These associations were replicated in the independent set of newborns, and replicated again in women 40 to 60 years after their birth. This study provides the first example of parental age permanently affecting the epigenetic profile of offspring. While the specific functions of the affected gene are unknown, this finding opens the possibility that a mother's age at pregnancy could affect her child's health through epigenetic mechanisms.


Opt-out HIV testing during antenatal care: experiences of pregnant women in rural Uganda.
Two years after the introduction of provider-initiated, opt-out HIV counselling and testing during antenatal care (ANC) in Uganda, HIV testing uptake is still low. This study was carried out to explore pregnant women's experiences of, and views on, the policies for opt-out, and couple HIV testing, and to understand how the policy implementation could be improved in order to increase access to prevention of mother-to-child-transmission (PMTCT) services. The study was conducted at three ANC health facilities at different levels of care in rural eastern Uganda. Data were collected through sit-in observations during ANC and 18 semi-structured interviews with pregnant women receiving ANC, and thereafter analysed using latent content analysis. Pregnant women who received ANC from facilities that provided HIV testing on-site perceived HIV testing as compulsory without actually fully realizing the benefits of HIV testing and PMTCT. No referral for HIV testing or information about testing was given at ANC facilities that lacked HIV testing on-site. A major challenge of couple HIV testing was that pregnant women were made responsible for recruiting their spouses for testing, a precarious dilemma for many women who tried to fulfil health workers' requests without having the power to do so. In order to increase uptake of PMTCT services, the pre-test counselling in groups that precedes the provider-initiated HIV testing should be adjusted to inform women about the benefits of PMTCT. Further, if testing is perceived as compulsory it could potentially deter some women from seeking ANC services. In order to increase HIV testing of male partners new strategies are needed, for example peer-sensitization and male clinics. Moreover, to achieve the desired outcomes of the PMTCT programme, monitoring and evaluation should be built into the programme.


Rociletinib in EGFR-mutated non-small-cell lung cancer.
Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51). Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).


A home sleep apnea screening device with time-domain signal processing and autonomous scoring capability.
Current solutions of sleep apnea diagnosis require the patient to undergo overnight studies at a specialized sleep laboratory. Due to such inconvenience and high cost, millions of sleep apnea patients remain undiagnosed and thus untreated. Based on a micro-electro-mechanical systems (MEMS) sensor and an effective apnea detection algorithm, we propose a low-cost single-channel apnea screening solution applicable in the comfort of patients' homes. A prototype device was designed and assembled including a MEMS sensor for measuring the patient's nasal air flows, and a time-domain signal processing IC for apnea detection and autonomous scoring. The IC chip was fabricated in standard 0.5- μm CMOS technology. The proposed device was tested for both respiratory rhythm detection and sleep apnea screening under clinical environment. Apnea-hypopnea indices (AHI) were scored to indicate severity of sleep apnea conditions. Test results suggest that the proposed device can be a valuable screening solution for the broader public with undiagnosed apnea conditions.


Biomechanical analysis of movement strategies in human forward trunk bending. II. Experimental study.
The large mass of the human upper trunk, its elevated position during erect stance, and the small area limited by the size of the feet, stress the importance of equilibrium control during trunk movements. The objective of the present study was to perform a biomechanical analysis of fast forward trunk movements in order to understand the coordination between movement and posture. The analysis is based on a comparison between experimentally observed bending and hypothetical "optimal bending" performed on an infinitely narrow support, as presented in a companion paper. The experimental data were obtained from 16 subjects who performed fast forward bending while standing on a wide platform or on a narrow beam. The analysis is performed by decomposition of the movement into three dynamically independent components, each representing a movement along one of the three eigenvectors of the motion equation. The eigenmovements are termed "hip", "ankle", and "knee" eigenmovements, according to the dominant joint. The experimentally observed movement is characterized mainly by the hip and ankle eigenmovements, whereas the knee eigenmovement is negligible. Similarly to the "optimal bending" the ankle eigenmovement starts earlier and lasts longer than the hip eigenmovement. An early forward acceleration of the center of gravity in the ankle eigenmovement is caused by anticipatory changes in the ankle joint torque. This clarifies the role of the early tibialis anterior burst and/or soleus inhibition usually observed in electromyographic recordings during forward bending. The results suggest that the hip and the ankle eigenmovements can be treated as independently controlled motion units aimed at functionally different behavioral goals: the bending per se and postural adjustment. It is proposed that the central nervous system has to control these motion units sequentially in order to perform the movement and maintain equilibrium. It is also suggested that the hip and ankle eigenmovements can be regarded as a biomechanical background for the hip and ankle strategies introduced by Horak and Nashner (1986) on the basis of electromyographic recordings and kinematic patterns in response to postural perturbations.


Enzymatic C5-cytosine methylation of DNA: mechanistic implications of new crystal structures for HhaL methyltransferase-DNA-AdoHcy complexes.
The refined crystal structures of HhaI methyltransferase complexed with cognate unmethylated or methylated DNA together with S-adenosyl-L-homocysteine, along with the previously-solved binary and covalent ternary structures, offer a detailed picture of the active site at individual stages throughout the reaction cycle. This picture supports and extends a proposed mechanism for C5-cytosine methylation that may be general for the whole family of C5-cytosine methyltransferases. The structures of the two new complexes have been refined to crystallographic R-factors of 0.189 and 0.178, respectively, at 2.7 A resolution. We observe that both unmethylated 2'-deoxycytidine and 5-methyl-2'-deoxycytidine flip out of the DNA helix and fit into the active site of the enzyme. The catalytic sulfur atom of Cys81 interacts strongly with C6. The C5 methyl group of the flipped 5-methyl-2'-deoxycytidine is bent approximately 50 degrees out of the plane of the cytosine ring and towards the sulfur atom of S-adenosyl-L-homocysteine. This unusual position is probably due to partial sp3 character at C5 and C6 and to steric effects of the conserved amino acid residues Pro80 and Cys81. Two water molecules are held near the hydrophobic edge (C5 and C6) of the flipped cytosine by two conserved amino acid residues (Gln82 and Asn304) and the phosphoryl oxygen atom of the phosphate group 3' to the flipped nucleotide, and one of them may serve as the general base for eliminating the proton from C5. Protonation of the cytosine N3 during the methylation reaction may involve Glu119, which itself might be protonated via a water-mediated interaction between the terminal carboxyl group of Glu119 and the amino group of the methionine moiety of S-adenosyl-L-methionine. The cofactor thus plays two key roles in the reaction.


Metformin and breast cancer stage at diagnosis: a population-based study.
The objective of the present study was to use a large, population-based cohort to examine the association between metformin and breast cancer stage at diagnosis while accounting for mammography differences. We used data from Ontario administrative health databases to identify women 68 years of age or older with diabetes and invasive breast cancer diagnosed from 1 January 2007 to 31 December 2012. Adjusted logistic regression models were used to compare breast cancer stage at diagnosis (stages i and ii vs. iii and iv) between the women exposed and not exposed to metformin. We also examined the association between metformin use and estrogen receptor status, tumour size, and lymph node status in the subset of women for whom those data were available. We identified 3125 women with diabetes and breast cancer; 1519 (48.6%) had been exposed to metformin before their cancer diagnosis. Median age at breast cancer diagnosis was 76 years (interquartile range: 72-82 years), and mean duration of diabetes was 8.8 ± 5.9 years. In multivariable analyses, metformin exposure was not associated with an earlier stage of breast cancer (odds ratio: 0.98; 95% confidence interval: 0.81 to 1.19). In secondary analyses, metformin exposure was not associated with estrogen receptor-positive breast cancer, tumours larger than 2 cm, or positive lymph nodes. This population-based study did not show an association between metformin use and breast cancer stage or tumour characteristics at diagnosis. Our study considered older women with long-standing diabetes, and therefore further studies in younger patients could be warranted.


Diabetes mellitus type 2 and other chronic non-communicable diseases in the central region, Saudi Arabia (Riyadh cohort 2): a decade of an epidemic.
Follow-up epidemiologic studies are needed to assess trends and patterns of disease spread. No follow-up epidemiologic study has been done in the Kingdom of Saudi Arabia to assess the current prevalence of major chronic, noncommunicable diseases, specifically in the urban region, where modifiable risk factors remain rampant. This study aims to fill this gap. A total of 9,149 adult Saudis ages seven to eighty years (5,357 males (58.6%) and 3,792 females (41.4%)) were randomly selected from the Riyadh Cohort Study for inclusion. Diagnosis of type 2 diabetes mellitus (DMT2) and obesity were based on the World Health Organization definitions. Diagnoses of hypertension and coronary artery disease (CAD) were based on the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and American Heart Association criteria, respectively. The overall crude prevalence of DMT2 was 23.1% (95% confidence interval (95% CI) 20.47 to 22.15). The age-adjusted prevalence of DMT2 was 31.6%. DMT2 prevalence was significantly higher in males, with an overall age-adjusted prevalence of 34.7% (95% CI 32.6 to 35.4), than in females, who had an overall age-adjusted prevalence of 28.6% (95% CI 26.7 to 29.3) (P < 0.001). The overall crude prevalence of obesity was 31.1% (95% CI 30.1 to 32.0). The age-adjusted prevalence of obesity was 40.0%. The prevalence of obesity was higher in females, with an overall prevalence of 36.5% (95% CI 35.1 to 37.83), than in males (25.1% (95% CI 23.7 to 26.3)) (P < 0.001). The age-adjusted prevalence of hypertension and CAD were 32.6% (95% CI 31.7 to 33.6) and 6.9% (95% CI 6.4 to 7.4), respectively. Comparisons of our findings with earlier data show that the prevalence of DMT2, hypertension and CAD in Riyadh, Saudi Arabia, has alarmingly worsened. Aggressive promotion of public awareness, continued screening and early intervention are pivotal to boosting a positive response.


Quantifying foot deformation using finite helical angle.
Foot intrinsic motion originates from the combination of numerous joint motions giving this segment a high adaptive ability. Existing foot kinematic models are mostly focused on analyzing small scale foot bone to bone motions which require both complex experimental methodology and complex interpretative work to assess the global foot functionality. This study proposes a method to assess the total foot deformation by calculating a helical angle from the relative motions of the rearfoot and the forefoot. This method required a limited number of retro-reflective markers placed on the foot and was tested for five different movements (walking, forefoot impact running, heel impact running, 90° cutting, and 180° U-turn) and 12 participants. Overtime intraclass correlation coefficients were calculated to quantify the helical angle pattern repeatability for each movement. Our results indicated that the method was suitable to identify the different motions as different amplitudes of helical angle were observed according to the flexibility required in each movement. Moreover, the results showed that the repeatability could be used to identify the mastering of each motion as this repeatability was high for well mastered movements. Together with existing methods, this new protocol could be applied to fully assess foot function in sport or clinical contexts.


Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers.
Limited guidance exists for selecting a laboratory method for diagnosing GH deficiency (GHD) when it occurs as a late effect of radiotherapy in childhood cancer survivors (CCSs). We searched Medline, Embase, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus for studies evaluating GHD that used IGF-1 or IGF-binding protein 3 (IGFBP-3) measurements compared with GH dynamic testing. We included 15 studies [IGF-1 (8 studies) and IGFBP-3 (7 studies)] enrolling 477 patients. Comparator tests varied widely. Overall, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy but were strongly correlated. The use of both tests simultaneously in the same cohort did not improve the diagnostic accuracy. Despite high variability in the testing protocols, dynamic tests remained the most accurate for appropriately identifying patients with GHD. The insulin tolerance test (ITT) appears to be the most accepted reference test when used alone or in combination with arginine; however, standardized testing strategies among practice groups are absent. GHRH and arginine stimulation performed almost similarly to the ITT; however, in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT. Insufficient data were available to assess the accuracy of serial GH testing (nocturnal or over 24 hours). The diagnostic accuracy of various dynamic tests for GHD in CCSs appears to follow the same patterns as those in non-CCSs. Interpreting GHRH stimulation is a challenge given the primarily hypothalamic dysfunction in CCSs. IGF-1 and IGFBP-3 perform poorly in this population.


Herbs-partitioned moxibustion alleviates aberrant intestinal epithelial cell apoptosis by upregulating A20 expression in a mouse model of Crohn's disease.
A20 inhibits intestinal epithelial cell apoptosis in Crohn's disease, and herbs-partitioned moxibustion (HPM) has been demonstrated to be an effective treatment for Crohn's disease. However, the mechanism by which HPM reduces intestinal epithelial cell apoptosis in Crohn's disease has not been thoroughly elucidated to date. To elucidate whether HPM exerts its effects by upregulating A20 to affect intestinal epithelial cell apoptosis in a Crohn's disease mouse model. In this study, mice with A20 deletion in intestinal epithelial cells (A20IEC-KO) were utilized to establish a Crohn's disease mouse model with 2,4,6-trinitrobenzene sulfonic acid (TNBS) administration, as well as wild-type mice. Mice were randomly divided into normal control (NC), model control (MC), mesalazine (MESA), and HPM groups. The morphology of the colonic mucosa was observed by hematoxylin-eosin staining, and serum endotoxin and apoptosis of epithelial cells were evaluated by enzyme-linked immunosorbent assay and terminal dUTP nick-end labeling assay accordingly. The protein expression levels of A20 and tumor necrosis factor receptor 1 (TNFR1)-related signaling molecules were evaluated by Western blot, and co-expression of A20 and TNFR1-associated death domain (TRADD) and co-expression of A20 and receptor-interacting protein 1 (RIP1) were observed by double immunofluorescence staining. The intestinal epithelial barrier was noted to have an improvement in the HPM group of wild-type (WT) mice compared with that in A20IEC-KO mice. Compared with A20 IEC-KO HPM mice, serum endotoxin levels and apoptosis percentages were decreased (P < 0.01), A20 expression levels were increased (P < 0.01), and expression of TNFR1, TRADDD, and RIP1 was decreased in the HPM group of WT mice (P TNFR1 < 0.05, P TRADD < 0.01, P RIP1 < 0.01). Both of the co-expression of A20/TRADD and A20/RIP1 showed a predominantly yellow fluorescence in the HPM group of WT mice, while a predominantly red fluorescence was noted in the HPM group of A20IEC-KO mice. Our findings suggest that HPM in treating Crohn's disease functions possibly via upregulation of the A20 expression level, resulting in downregulation of TNFR1, TRADD, and RIP1 to alleviate increased cell apoptosis in the intestinal epithelial barrier in Crohn's disease.


Perceptually Guided Photo Retargeting.
We propose perceptually guided photo retargeting, which shrinks a photo by simulating a human's process of sequentially perceiving visually/semantically important regions in a photo. In particular, we first project the local features (graphlets in this paper) onto a semantic space, wherein visual cues such as global spatial layout and rough geometric context are exploited. Thereafter, a sparsity-constrained learning algorithm is derived to select semantically representative graphlets of a photo, and the selecting process can be interpreted by a path which simulates how a human actively perceives semantics in a photo. Furthermore, we learn the prior distribution of such active graphlet paths (AGPs) from training photos that are marked as esthetically pleasing by multiple users. The learned priors enforce the corresponding AGP of a retargeted photo to be maximally similar to those from the training photos. On top of the retargeting model, we further design an online learning scheme to incrementally update the model with new photos that are esthetically pleasing. The online update module makes the algorithm less dependent on the number and contents of the initial training data. Experimental results show that: 1) the proposed AGP is over 90% consistent with human gaze shifting path, as verified by the eye-tracking data, and 2) the retargeting algorithm outperforms its competitors significantly, as AGP is more indicative of photo esthetics than conventional saliency maps.


Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study.
We examined the risk of cervical neoplasia (dysplasia or cancer) in women with ulcerative colitis (UC) or Crohn's disease (CD). We also calculated the reverse, the risk for diagnosis with cervical neoplasia before development of inflammatory bowel disease (IBD). We established a national cohort of women diagnosed with UC (n = 18,691) or CD (n = 8717) between 1979 and 2011 and a control cohort of individually matched women from the general population (controls, n = 1,508,334). Incidence rate ratios (IRRs) of screening activity and diagnosis of cervical neoplasia in women with IBD were assessed by Cox proportional hazards regression analysis. Odds ratios (ORs) of cervical neoplasia before diagnosis of IBD were calculated by using conditional logistic regression. Women with CD underwent cervical cancer screening as often as women in the general population (IRR, 0.99; 95% confidence interval [CI], 0.96-1.02), whereas screening frequency was slightly increased in women with UC (IRR, 1.06; 95% CI, 1.04-1.08). A total of 561 patients with UC were diagnosed with dysplasia during a median follow-up time of 7.8 years, and 28 patients with UC developed cervical cancer, compared with 1918 controls. A total of 407 patients with CD were diagnosed with dysplasia during a median follow-up time of 8.3 years, and 26 patients with CD developed cervical cancer, compared with 940 controls. Patients with UC had increased risk of low-grade (IRR, 1.15; 95% CI, 1.00-1.32) and high-grade (IRR, 1.12; 95% CI, 1.01-1.25) squamous intraepithelial lesions (SILs), whereas patients with CD had increased risks of low-grade SIL (IRR, 1.26; 95% CI, 1.07-1.48), high-grade SIL (IRR, 1.28; 95% CI, 1.13-1.45), and cervical cancer compared with controls (IRR, 1.53; 95% CI, 1.04-2.27). ORs for cervical cancer were also increased 1-9 years before diagnosis of UC, compared with women without UC (OR, 2.78; 95% CI, 2.12-3.64) or CD (OR, 1.85; 95% CI, 1.08-3.15). In a population-based nationwide cohort study, we found a 2-way association between IBD, notably CD, and neoplastic lesions of the uterine cervix. This observation is not explained by differences in screening activity.


Stereological Evidence of Non-Selective Hippocampal Neurodegeneration, IGF-1 Depletion, and Behavioral Deficit following Short Term Bilateral Adrenalectomy in Wistar Rats.
The development of animal models to study cell death in the brain is a delicate task. One of the models, that was discovered in the late eighties, is the induction of neurodegeneration through glucocorticoid withdrawal by adrenalectomy in albino rats. Such a model is one of the few noninvasive models for studying neurodegeneration. In the present study, using stereological technique and ultrastructural examination, we aimed to investigate the impact of short-term adrenalectomy (2 weeks) on different hippocampal neuronal populations in Wistar rats. In addition, the underlying mechanism(s) of degeneration in these neurons were investigated by measuring the levels of insulin-like growth factor-1 (IGF-1) and β-nerve growth factor (β-NGF). Moreover, we examined whether the biochemical and histological changes in the hippocampus, after short-term adrenalectomy, have an impact on the cognitive behavior of Wistar rats. Stereological counting in the hippocampus revealed significant neuronal deaths in the dentate gyrus and CA4/CA3, but not in the CA2 and CA1 areas, 7 and 14 days post adrenalectomy. The ultrastructural examinations revealed degenerated and degenerating neurons in the dentate, as well as CA4, and CA3 areas, over the course of 3, 7 and 14 days. The levels of IGF-1 were significantly decreased in the hippocampus of ADX rats 24 h post adrenalectomy, and lasted over the course of two weeks. However, β-NGF was not affected in rats. Using a passive avoidance task, we found a cognitive deficit in the ADX compared to the SHAM operated rats over time (3, 7, and 14 days). In conclusion, both granule and pyramidal cells were degenerated in the hippocampus following short-term adrenalectomy. The early depletion of IGF-1 might play a role in hippocampal neuronal degeneration. Consequently, the loss of the hippocampal neurons after adrenalectomy leads to cognitive deficits.


Exploring the high-resolution mapping of gender-disaggregated development indicators.
Improved understanding of geographical variation and inequity in health status, wealth and access to resources within countries is increasingly being recognized as central to meeting development goals. Development and health indicators assessed at national or subnational scale can often conceal important inequities, with the rural poor often least well represented. The ability to target limited resources is fundamental, especially in an international context where funding for health and development comes under pressure. This has recently prompted the exploration of the potential of spatial interpolation methods based on geolocated clusters from national household survey data for the high-resolution mapping of features such as population age structures, vaccination coverage and access to sanitation. It remains unclear, however, how predictable these different factors are across different settings, variables and between demographic groups. Here we test the accuracy of spatial interpolation methods in producing gender-disaggregated high-resolution maps of the rates of literacy, stunting and the use of modern contraceptive methods from a combination of geolocated demographic and health surveys cluster data and geospatial covariates. Bayesian geostatistical and machine learning modelling methods were tested across four low-income countries and varying gridded environmental and socio-economic covariate datasets to build 1×1 km spatial resolution maps with uncertainty estimates. Results show the potential of the approach in producing high-resolution maps of key gender-disaggregated socio-economic indicators, with explained variance through cross-validation being as high as 74-75% for female literacy in Nigeria and Kenya, and in the 50-70% range for many other variables. However, substantial variations by both country and variable were seen, with many variables showing poor mapping accuracies in the range of 2-30% explained variance using both geostatistical and machine learning approaches. The analyses offer a robust basis for the construction of timely maps with levels of detail that support geographically stratified decision-making and the monitoring of progress towards development goals. However, the great variability in results between countries and variables highlights the challenges in applying these interpolation methods universally across multiple countries, and the importance of validation and quantifying uncertainty if this is undertaken.


Homologous cpn60 genes in Rhizobium leguminosarum are not functionally equivalent.
Many bacteria possess 2 or more genes for the chaperonin GroEL and the cochaperonin GroES. In particular, rhizobial species often have multiple groEL and groES genes, with a high degree of amino-acid similarity, in their genomes. The Rhizobium leguminosarum strain A34 has 3 complete groE operons, which we have named cpn.1, cpn.2 and cpn.3. Previously we have shown the cpn. 1 operon to be essential for growth, but the two other cpn operons to be dispensable. Here, we have investigated the extent to which loss of the essential GroEL homologue Cpn60.1 can be compensated for by expression of the other two GroEL homologues (Cnp60.2 and Cpn60.3). Cpn60.2 could not be overexpressed to high levels in R. leguminosarum, and was unable to replace Cpn60.1. A strain that overexpressed Cpn60.3 grew in the absence of Cpn60.1, but the complemented strain displayed a temperature-sensitive phenotype. Cpn60.1 and Cpn60.3, when coexpressed in Escherichia coli, preferentially selfassembled rather than forming mixed heteroligomers. We conclude that, despite their high amino acid similarity, the GroEL homologues of R. leguminosarum are not functionally equivalent in vivo.


Discovery of breast cancers within 1 year of a normal screening mammogram: how are they found?
We sought to determine how breast cancers that occur within 1 year after a normal mammogram are discovered. Using population-based mammography registry data from 2000-2002, we identified 143 women with interval breast cancers and 481 women with screen-detected breast cancers. We surveyed women's primary care clinicians to assess how the interval breast cancers were found and factors associated with their discovery. Women with interval cancers were twice as likely to have a personal history of breast cancer (30.1%) as women with screen-detected cancers (13.6%). Among women with interval cancers, one half of the invasive tumors (49.5%) were discovered when women initiated a health care visit because of a breast concern, and 16.8% were discovered when a clinician found an area of concern while conducting a routine clinical breast examination. Having a lump and both a personal and a family history of breast cancer was the most common reason why women initiated a health care visit (44%) (P <.01). Women with interval cancers are most likely to initiate a visit to a primary care clinician when they have 2 or more breast concerns. These concerns are most likely to include having a lump and a personal and/or family history of breast cancer. Women at highest risk for breast cancer may need closer surveillance by their primary care clinicians and may benefit from a strong educational message to come for a visit as soon as they find a lump.


Deferoxamine inhibition of malaria is independent of host iron status.
The mechanism whereby deferoxamine (DF) inhibits the growth of malaria parasites was studied in rats infected with Plasmodium berghei. Peak parasitemia was 32.6% (day 14) in untreated controls and 0.15% (day 7) in rats receiving 0.33 mg/g in 8 hourly DF injections, subcutaneously. DF inhibition of parasite growth was achieved without any reduction in transferrin saturation or hemoglobin synthesis and with only a partial (56%) depletion of hepatic iron stores. Dietary iron depletion resulted in anemia (hematocrit 25 vs. 46%), microcytosis (MCV 54 vs. 60 fl), and reduced transferrin saturation (17 vs. 96%) without any effect on infection (peak parasitemia 30 vs. 36%). Similarly, parenteral iron loading with ferric citrate over 10 d (75 mg iron/kg) failed to aggravate infection. In a search for evidence of direct interaction between DF and parasitized erythrocytes, gel filtration and ultrafiltration was performed on hemolysates obtained from in vivo 59Fe-labeled parasitized erythrocytes. This showed that 1.1-1.9% of the intracellular radioiron was located in a chelatable, labile iron pool. Incubation of intact cells with 0-500 microM DF resulted in a proportional increase in intracellular iron chelation, and the chelation of all available labile intracellular iron was completed within 6 h. These observations indicate that the severity of P. berghei infection in rats and its in vivo suppression by DF are independent of host iron status and suggest that DF inhibition of malaria involves intracellular chelation of a labile iron pool in parasitized erythrocytes.


Tumor-suppressive role of Kruppel-like factor 4 (KLF-4) in colorectal cancer.
Kruppel-like factors (KLFs) are a group of transcriptional regulators that have recently been identified to exhibit tumor-suppressive function against various gastrointestinal cancers. The present study aims to investigate the expression patterns and prognostic value of KLF-4 in colorectal cancers (CRCs). KLF-4 levels in CRC tissues were examined via immunohistochemistry analysis, real-time quantitative polymerase chain reaction, and western blotting. The chi-square test was performed to evaluate the correlation between KLF-4 expression and the clinicopathological characteristics. Kaplan-Meier analysis was performed to assess the prognostic value of KLF-4 in CRC patients. In addition, we evaluated the effect of KLF-4 knockdown on the proliferation of CRC HT-29 cells. Our results showed significant downregulation of KLF-4 in 31 CRC samples, collected from CRC patients showing more malignant characteristics such as lymphatic metastasis, low tumor cell differentiation, and tumor recurrence. CRC patients in the low KLF-4 group were found to have reduced overall survival and decreased disease-free survival time. Moreover, HT-29 cells transfected with siRNA-KLF-4 showed increased proliferation compared to those transfected with control siRNA. In summary, lower KLF-4 expression was correlated with malignant CRC status and poor prognosis in CRC patients. Moreover, KLF-4 suppression promoted the proliferation of CRC cells in vitro. These results provide novel insights into the tumor suppressive role of KLF-4 in CRC.


Multiple stages of information processing are modulated during acute bouts of exercise.
Acute bouts of aerobic physical exercise can modulate subsequent cognitive task performance and oscillatory brain activity measured with electroencephalography (EEG). Here, we investigated the sequencing of these modulations of perceptual and cognitive processes using scalp recorded EEG acquired during exercise. Twelve participants viewed pseudo-random sequences of frequent non-target stimuli (cars), infrequent distractors (obliquely oriented faces) and infrequent targets that required a simple detection response (obliquely oriented faces, where the angle was different than the infrequent distractors). The sequences were presented while seated on a stationary bike under three conditions during which scalp recorded EEG was also acquired: rest, low-intensity exercise, and high-intensity exercise. Behavioral target detection was faster during high-intensity exercise compared to both rest and low-intensity exercise. An event-related potential (ERP) analysis of the EEG data revealed that the mean amplitude of the visual P1 component evoked by frequent non-targets measured at parietal-occipital electrodes was larger during low-intensity exercise compared to rest. The P1 component evoked by infrequent targets also peaked earlier during low-intensity exercise compared to rest and high-intensity exercise. The P3a ERP component evoked by infrequent distractors measured at parietal electrodes peaked significantly earlier during both low- and high-intensity exercise when compared to rest. The modulation of the visual P1 and the later P3a components is consistent with the conclusion that exercise modulates multiple stages of neural information processing, ranging from early stage sensory processing (P1) to post-perceptual target categorization (P3a).


High-voltage electron microscopy and conventional transmission electron microscopy of the interface zone between bone and endosteal dental implants.
The interface between mandibular bone and endosteal dental implants was examined with an in vivo dog model. Undecalcified mandibular implant samples were observed with both conventional transmission electron microscopy and high-voltage transmission electron microscopy (HVEM). Results demonstrated the variable nature of the interfacial support tissues. Mineralized bone was often found within 50 nm of the implant surface, separated from that surface only by an electron dense deposit. Osteocytes were observed close to the interface encased within lacunae extending numerous cellular processes through canaliculi. An osteoblast was also observed directly at the interface within a developing lacuna. Other interfacial areas exhibited a finely fibrillar and more electron lucent morphology. Furthermore, other areas were shown to be composed of wider zones of extracellular products containing collagen fibrils, ground substance, and calcified inclusions. Because bone is an actively growing and remodeling tissue, these different morphological zones around the entire area of the implants would appear to confirm the dynamic tissue response to endosteal dental implants. Further, HVEM stereology was shown to be an exciting research tool to investigate this tissue response.


Craniula: A cranial window technique for prolonged imaging of brain surface vasculature with simultaneous adjacent intracerebral injection.
Imaging of the brain surface vasculature following inflammatory insults is critical to study structural and functional changes in the living brain under normal and pathological conditions. Although there have been published reports relating to the changes that occur in the blood brain barrier (BBB) during the inflammatory process, the ability to visualize and track such changes in vivo and over time has proven to be problematic. Different techniques have been used to achieve visualization of pial vessels, but the approach has limits, which can jeopardize the well-being of the animals. Development of the cranial window technique provided a major advance in the acquisition of live images of the brain vasculature and its response to different insults and treatments. We describe in detail a protocol for delivery of a localized inflammatory insult to the mouse brain via a craniula (cranial window and adjacent cannula) and subsequent imaging of the mouse brain vasculature by intravital microscopy and two-photon laser scanning microscopy. The surgical implantation of the craniula can be completed in 30-45 min and images can be acquired immediately and for several months thereafter. The technique is minimally invasive and permits serial injections directly to the brain, thereby allowing longitudinal imaging studies. The craniula technique permits the study of structural and functional changes of the BBB following inflammatory insult and as such has wide application to neuroscience research.


A new class of IMP dehydrogenase with a role in self-resistance of mycophenolic acid producing fungi.
Many secondary metabolites produced by filamentous fungi have potent biological activities, to which the producer organism must be resistant. An example of pharmaceutical interest is mycophenolic acid (MPA), an immunosuppressant molecule produced by several Penicillium species. The target of MPA is inosine-5'-monophosphate dehydrogenase (IMPDH), which catalyses the rate limiting step in the synthesis of guanine nucleotides. The recent discovery of the MPA biosynthetic gene cluster from Penicillium brevicompactum revealed an extra copy of the IMPDH-encoding gene (mpaF) embedded within the cluster. This finding suggests that the key component of MPA self resistance is likely based on the IMPDH encoded by mpaF. In accordance with our hypothesis, heterologous expression of mpaF dramatically increased MPA resistance in a model fungus, Aspergillus nidulans, which does not produce MPA. The growth of an A. nidulans strain expressing mpaF was only marginally affected by MPA at concentrations as high as 200 μg/ml. To further substantiate the role of mpaF in MPA resistance, we searched for mpaF orthologs in six MPA producer/non-producer strains from Penicillium subgenus Penicillium. All six strains were found to hold two copies of IMPDH. A cladistic analysis based on the corresponding cDNA sequences revealed a novel group constituting mpaF homologs. Interestingly, a conserved tyrosine residue in the original class of IMPDHs is replaced by a phenylalanine residue in the new IMPDH class. We identified a novel variant of the IMPDH-encoding gene in six different strains from Penicillium subgenus Penicillium. The novel IMPDH variant from MPA producer P. brevicompactum was shown to confer a high degree of MPA resistance when expressed in a non-producer fungus. Our study provides a basis for understanding the molecular mechanism of MPA resistance and has relevance for biotechnological and pharmaceutical applications.


Recombination in hepatitis C virus genotype 1 evaluated by phylogenetic and population-genetic methods.
Although hepatitis C virus (HCV) is a major cause of viral hepatitis and hepatocellular carcinoma, many aspects of its evolution remain poorly understood. Relevant to its evolution and the development of antiviral drug resistance is the role of recombination in HCV, which has not been resolved using phylogenetic tests. In line with previous studies, we found no strong support for a role of recombination in the dominant subtypes 1A and 1B using phylogenetic approaches. In contrast, signatures of gene conversion were abundant if a population recombination model, which takes into account diversity within and between groups, was used (9676 gene conversion signatures between the genomes of subtypes 1A and 1B and 170 between the NS5A regions of subtypes 1A and 1B and the minor subtypes 1c-1g). The gene conversion signatures coincided with a striking lack of diagnostically informative sites between subtypes and a large number of shared mutations between complete subtype 1A and 1B genomes (0.76 and 62.2 % of nucleotide sites, respectively). Maximum-likelihood trees revealed significant topological incongruence among conserved PFAM domains and genome regions targeted by diagnostic assays, which underpins a major role for recombination. The same results were obtained with smaller numbers of genomes and with only synonymous sites. Topological concordance increased only marginally if larger genome regions were compared. The level of recombination in HCV subtype 1, which is probably significantly higher than can currently be measured, also illustrates the complexity of designing diagnostic assays based on the unusual patterns of genomic diversity of HCV.


The added value of percentage of free to total prostate-specific antigen, PCA3, and a kallikrein panel to the ERSPC risk calculator for prostate cancer in prescreened men.
Prostate-specific antigen (PSA) testing has limited accuracy for the early detection of prostate cancer (PCa). To assess the value added by percentage of free to total PSA (%fPSA), prostate cancer antigen 3 (PCA3), and a kallikrein panel (4k-panel) to the European Randomised Study of Screening for Prostate Cancer (ERSPC) multivariable prediction models: risk calculator (RC) 4, including transrectal ultrasound, and RC 4 plus digital rectal examination (4+DRE) for prescreened men. Participants were invited for rescreening between October 2007 and February 2009 within the Dutch part of the ERSPC study. Biopsies were taken in men with a PSA level ≥3.0 ng/ml or a PCA3 score ≥10. Additional analyses of the 4k-panel were done on serum samples. Outcome was defined as PCa detectable by sextant biopsy. Receiver operating characteristic curve and decision curve analyses were performed to compare the predictive capabilities of %fPSA, PCA3, 4k-panel, the ERSPC RCs, and their combinations in logistic regression models. PCa was detected in 119 of 708 men. The %fPSA did not perform better univariately or added to the RCs compared with the RCs alone. In 202 men with an elevated PSA, the 4k-panel discriminated better than PCA3 when modelled univariately (area under the curve [AUC]: 0.78 vs. 0.62; p=0.01). The multivariable models with PCA3 or the 4k-panel were equivalent (AUC: 0.80 for RC 4+DRE). In the total population, PCA3 discriminated better than the 4k-panel (univariate AUC: 0.63 vs. 0.56; p=0.05). There was no statistically significant difference between the multivariable model with PCA3 (AUC: 0.73) versus the model with the 4k-panel (AUC: 0.71; p=0.18). The multivariable model with PCA3 performed better than the reference model (0.73 vs. 0.70; p=0.02). Decision curves confirmed these patterns, although numbers were small. Both PCA3 and, to a lesser extent, a 4k-panel have added value to the DRE-based ERSPC RC in detecting PCa in prescreened men. We studied the added value of novel biomarkers to previously developed risk prediction models for prostate cancer. We found that inclusion of these biomarkers resulted in an increase in predictive ability.


Bioelectrical impedance phase angle in clinical practice: implications for prognosis in stage IIIB and IV non-small cell lung cancer.
A frequent manifestation of advanced lung cancer is malnutrition, timely identification and treatment of which can lead to improved patient outcomes. Bioelectrical impedance analysis (BIA) is an easy-to-use and non-invasive technique to evaluate changes in body composition and nutritional status. We investigated the prognostic role of BIA-derived phase angle in advanced non-small cell lung cancer (NSCLC). A case series of 165 stages IIIB and IV NSCLC patients treated at our center. The Kaplan Meier method was used to calculate survival. Cox proportional hazard models were constructed to evaluate the prognostic effect of phase angle, independent of stage at diagnosis and prior treatment history. 93 were males and 72 females. 61 had stage IIIB disease at diagnosis while 104 had stage IV. The median phase angle was 5.3 degrees (range = 2.9 - 8). Patients with phase angle <or= 5.3 had a median survival of 7.6 months (95% CI: 4.7 to 9.5; n = 81), while those with > 5.3 had 12.4 months (95% CI: 10.5 to 18.7; n = 84); (p = 0.02). After adjusting for age, stage at diagnosis and prior treatment history we found that every one degree increase in phase angle was associated with a relative risk of 0.79 (95% CI: 0.64 to 0.97, P = 0.02). We found BIA-derived phase angle to be an independent prognostic indicator in patients with stage IIIB and IV NSCLC. Nutritional interventions targeted at improving phase angle could potentially lead to an improved survival in patients with advanced NSCLC.


Intraoperative radiation therapy (IORT) in pancreatic cancer.
Despite the important improvements made in the fields of surgery, chemotherapy and radiation therapy, pancreatic cancer remains one of the most lethal malignancies. Improved outcomes with novel chemotherapy regimes led again to increased attention on the role of localized radiotherapy, since local tumor progression causes significant morbidity and mortality in patients. Even after resection local failure rates are as high as 50-80%. The immediate proximity to critical structures (bone marrow, spinal cord, kidneys, liver, and intestine) limits the dose of radiation that can be administered to the tumor bed with conventional external beam radiation therapy (EBRT). The intraoperative radiotherapy (IORT) appears to be an ideal therapeutic strategy for this disease, having the advantage of enabling the delivery of high doses of radiation to areas that are at risk for microscopic disease, saving critical organs and reducing the possibility of inducing radiotoxicity. This technique allows a theoretical increase in the radiation therapeutic index to tumor compared to the adjacent organs at risk (OAR). The aim of this review is to update and comment on IORT in the multidisciplinary management of pancreatic cancer.


Interventions to prevent softball related injuries: a review of the literature.
To examine the published evidence on interventions to prevent softball related injuries among adults, and to encourage more epidemiologic research as a foundation for future softball injury prevention efforts. The authors reviewed literature identified from six electronic databases for studies on softball related injuries. The search was limited to studies written in the English language, published between 1970 and 2002, and involving adult populations. Research was excluded that evaluated baseball ("hard ball") related injuries or was aimed at injury treatment. Identified studies were categorized by study design. Intervention/prevention papers were evaluated further and described in detail. The search strategy identified 39 studies specifically related to softball. Most studies were case reports/case series (n=13) or descriptive studies (n=11); only four were analytic or intervention/prevention studies. Studies collected data in a variety of ways, often without denominator data to permit calculation of injury rates. Studies also did not differentiate between slow or fast pitch softball activities and most did not mention the type of softball that was used. Surprisingly few studies exist on interventions to reduce injuries during softball, one of the most popular recreational sports in the US. Of the existing literature, much attention has been on sliding related injuries, which comprise only a segment of softball injuries. Basic epidemiologic studies describing the nature, severity, and risk factors for softball injuries in a variety of populations are needed, followed by additional intervention evaluation studies aimed at modifiable risk factors.


Poynting vector and orbital angular momentum density of superpositions of Bessel beams.
We study theoretically the orbital angular momentum (OAM) density in arbitrary scalar optical fields, and outline a simple approach using only a spatial light modulator to measure this density. We demonstrate the theory in the laboratory by creating superpositions of non-diffracting Bessel beams with digital holograms, and find that the OAM distribution in the superposition field matches the predicted values. Knowledge of the OAM distribution has relevance in optical trapping and tweezing, and quantum information processing.


N-type organic electrochemical transistors with stability in water.
Organic electrochemical transistors (OECTs) are receiving significant attention due to their ability to efficiently transduce biological signals. A major limitation of this technology is that only p-type materials have been reported, which precludes the development of complementary circuits, and limits sensor technologies. Here, we report the first ever n-type OECT, with relatively balanced ambipolar charge transport characteristics based on a polymer that supports both hole and electron transport along its backbone when doped through an aqueous electrolyte and in the presence of oxygen. This new semiconducting polymer is designed specifically to facilitate ion transport and promote electrochemical doping. Stability measurements in water show no degradation when tested for 2 h under continuous cycling. This demonstration opens the possibility to develop complementary circuits based on OECTs and to improve the sophistication of bioelectronic devices.


Inflammatory biomarkers and depression.
Antidepressants, predominantly serotonin- and/or noradrenaline reuptake inhibiting drugs have several shortcomings. The exact pathophysiological mechanisms leading to serotonergic-, noradrenergic- or dopaminergic dysfunction are still unclear. An inflammatory mechanism has been postulated and will be discussed here including possible therapeutic advantages of cyclooxygenase-2 (COX-2) inhibitors. Differences in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan-kynurenine metabolism resulting in an increased tryptophan and serotonin degradation and probably in an increased production of quinolinic acid might play a key role in major depression (MD). These differences are associated with an imbalance in the glutamatergic neurotransmission, which may contribute to an overweight of N-methyl-D: -aspartate agonism in MD. The immunological imbalance results in an increased prostaglandin E₂ production and probably also in an increased COX-2 expression. Although there is strong evidence for the view that the interactions of the immune system, IDO, the serotonergic system and the glutamatergic neurotransmission play a key role in MD, several gaps, e.g. the roles of genetics, disease course, sex, different psychopathological states, etc., have to be bridged by intense further research. There were already hints that anti-inflammatory therapy might have beneficial effects in MD. COX-2 inhibitors, however, have been tested in animal models and in preliminary clinical studies showing favourable effects compared to placebo in MD. The effects of COX-2 inhibition in the CNS as well as the different components of the inflammatory system, the kynurenine-metabolism and the glutamatergic neurotransmission, however, still need careful further scientific evaluation including clinical studies in bigger samples of patients.


Monochromatic breast computed tomography with synchrotron radiation: phase-contrast and phase-retrieved image comparison and full-volume reconstruction.
A program devoted to performing the first in vivo synchrotron radiation (SR) breast computed tomography (BCT) is ongoing at the Elettra facility. Using the high spatial coherence of SR, phase-contrast (PhC) imaging techniques can be used. The latest high-resolution BCT acquisitions of breast specimens, obtained with the propagation-based PhC approach, are herein presented as part of the SYRMA-3D collaboration effort toward the clinical exam. Images are acquired with a 60 - μ m pixel dead-time-free single-photon-counting CdTe detector. The samples are imaged at 32 and 38 keV in a continuous rotating mode, delivering 5 to 20 mGy of mean glandular dose. Contrast-to-noise ratio (CNR) and spatial resolution performances are evaluated for both PhC and phase-retrieved images, showing that by applying the phase-retrieval algorithm a five-time CNR increase can be obtained with a minor loss in spatial resolution across soft tissue interfaces. It is shown that, despite having a poorer CNR, PhC images can provide a sharper visualization of microcalcifications, thus being complementary to phase-retrieved images. Furthermore, the first full-volume scan of a mastectomy sample ( 9 × 9 × 3 cm 3 ) is reported. This investigation into surgical specimens indicates that SR BCT in terms of CNR, spatial resolution, scan duration, and scan volume is feasible.


Effect of dual substrate environment on the formation of intracellular storage biopolymers.
We investigated the effect of a starch/acetate mixture on the formation of intracellular storage biopolymers compared with system behaviour where these compounds served as a single organic substrate. Three laboratory-scale sequencing batch reactors (SBRs) were operated at steady state with a sludge age of 8 days, one fed with acetate, another with starch and the third with a starch/acetate mixture. The SBR operation involved six cycles per day and continuous feeding during each cycle. Both acetate and starch generated storage biopolymers under continuous feeding. A poly-hydroxybutyrate (PHB) or glycogen pool was formed depending on the selected single substrate. In addition, around 18% of the acetate fed within each cycle was converted to PHB, while the remaining 82% was directly utilized for microbial growth. A higher glycogen formation of 44% was observed for starch. Substrate storage as PHB and glycogen continued with the feeding of the acetate/starch mixture. This observation, supported by microbiological analyses, indicated that the acclimated biomass in the corresponding SBR system sustained microbial fractions capable of performing metabolic functions associated with the formation of the two storage biopolymers. PHB accumulation was reduced as acetate could be more readily used for direct microbial growth in the presence of starch.


Marked reduction of radiation-induced micronuclei in human blood lymphocytes pretreated with melatonin.
Human peripheral blood lymphocytes which were pretreated in vitro with melatonin, an endogenously synthesized pineal hormone, for 20 min at 37 +/- 1 degree C exhibited a significant and concentration-dependent reduction in the frequency of gamma-radiation-induced micronuclei compared with irradiated cells which did not receive the pretreatment. The extent of the reduction observed with 2.0 mM melatonin was similar to that found in lymphocytes pretreated for 20 min with 1.0 M dimethylsulfoxide, a known free radical scavenger. These observations indicate that melatonin may have an active role in protection of humans against genetic damage due to endogenously produced free radicals, and also may be of use in reducing damage due to exposure to physical and chemical mutagens and carcinogens which generate free radicals.


Is chronic fatigue the symptom of venous insufficiency associated with multiple sclerosis? A longitudinal pilot study.
Chronic fatigue (CF) severely affects patients with multiple sclerosis (MS), but its pathogenesis remains elusive and the effectiveness of available treatments is modest. We aimed to evaluate the effect on CF of the balloon dilatation of stenosing lesions affecting the main extracranial veins configuring the chronic cerebrospinal venous insufficiency (CCSVI), a condition strongly associated with MS. Thirty-one MS consecutive patients (16 males, age 46.2+/-9.4 years) with associated CCSVI and CF underwent the endovascular procedure. Fatigue was assessed using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) at baseline (T0) and one (T1), six (T6) and twelve (T12) months after the procedure. In ambulatory patients (N.=28), mobility was evaluated using the 6-min walking test at T0 and T1. and MFIS scores significantly improved from preoperative values, and the positive trend was maintained at one year (FSS: T0=5.1+/-1.0 to T12=3.5+/-1.8, P<0.001; MFIS-total score: T0=34.9+/-14.8 to T12=22.5+/-13.7, P<0.001; MFIS-Physical subscale: T0=21.2+/-8.0 to T12=13.5+/-9.7 P<0.001; MFIS-Cognitive subscale: T0=9.2+/-9.5 to T12=6.0+/-6.3, P=0.03; MFIS-Psychosocial subscale: T0=4.5+/-2.1 to T12=2.5+/-2.1, P<0.001). Six-min walking distance (6MWD) at T1 improved significantly (332+/-190m to 378+/-200m, P=0.0002). In addition, an inverted correlation between 6MWD and MFIS-physical subscale variations was found in the subgroup of patients (N.=8) with no lower limb motor impairment (r=-0.74, P=0.035). The reestablishment of cerebral venous return dramatically reduced CF perception in a group of MS patients with associated CCSVI, suggesting that CF is likely the symptom of CCSVI.


Nuclear translocation of anamorsin during drug-induced dopaminergic neurodegeneration in culture and in rat brain.
Anamorsin, also called cytokine-induced apoptosis inhibitor 1 (CIAPIN1), was recently identified to confer resistance to apoptosis induced by growth factor deprivation and to be indispensible for hematopoiesis. Recently, it was demonstrated that anamorsin is also widely distributed in both fetal and adult tissues. In this study, we evaluated the tissue distribution of anamorsin in the central nervous system (CNS) during development. In situ hybridization and immunoblot analyses revealed that anamorsin mRNA and protein were both highly and widely expressed in various regions of the CNS, including the cerebral cortex, hippocampus, midbrain, cerebellum, medulla, and spinal cord. Based on these findings, we examined its cellular localization during drug-induced neurodegeneration in MN9D dopaminergic cells. Both immunocytochemical localization and immunoblot analyses indicated that cytosolic anamorsin was translocated into the nucleus in a time-dependent manner following treatment with a reactive oxygen species (ROS)-inducing drug, 6-hydroxydopamine (6-OHDA). Treatment of cells with the apoptosis-inducing reagent, staurosporine, did not appear to cause translocation of anamorsin into the nucleus. When cells were treated with the nuclear export inhibitor, Leptomycin B, alone or with 6-OHDA, nuclear anamorsin levels increased, indicating that nuclear influx and efflux of anamorsin are regulated by 6-OHDA treatment. In rat brain injected with 6-OHDA, nuclear translocation of anamorsin was identified in certain tyrosine hydroxylase (TH)-positive neurons as well as TH-negative cells. Furthermore, treatment of MN9D cells with hydrogen peroxide or ROS-inducing trace metals caused nuclear translocation of anamorsin. Taken together, our data indicate that nuclear translocation of anamorsin is a ROS-dependent event and may participate in the regulation of transcription of critical molecules during dopaminergic neurodegeneration.


Telomere extension by telomerase and ALT generates variant repeats by mechanistically distinct processes.
Telomeres are terminal repetitive DNA sequences on chromosomes, and are considered to comprise almost exclusively hexameric TTAGGG repeats. We have evaluated telomere sequence content in human cells using whole-genome sequencing followed by telomere read extraction in a panel of mortal cell strains and immortal cell lines. We identified a wide range of telomere variant repeats in human cells, and found evidence that variant repeats are generated by mechanistically distinct processes during telomerase- and ALT-mediated telomere lengthening. Telomerase-mediated telomere extension resulted in biased repeat synthesis of variant repeats that differed from the canonical sequence at positions 1 and 3, but not at positions 2, 4, 5 or 6. This indicates that telomerase is most likely an error-prone reverse transcriptase that misincorporates nucleotides at specific positions on the telomerase RNA template. In contrast, cell lines that use the ALT pathway contained a large range of variant repeats that varied greatly between lines. This is consistent with variant repeats spreading from proximal telomeric regions throughout telomeres in a stochastic manner by recombination-mediated templating of DNA synthesis. The presence of unexpectedly large numbers of variant repeats in cells utilizing either telomere maintenance mechanism suggests a conserved role for variant sequences at human telomeres.


Comparative analysis of sodium coupled vitamin C transporter 2 in human osteoarthritis grade 1 and grade 3 tissues.
Nutrient levels are known to influence the development of osteoarthritis (OA), presumably by modulating levels of matrix biosynthesis and degradation. These processes may be affected by ascorbic acid (AA), an antioxidant which acts as a cofactor for numerous biochemical reactions and is essential for post-translational modifications of collagen. In this study we examined the expression of SVCT2, the only known Sodium coupled vitamin C transporter isoform present in articular cartilage, in human articular cartilage explants derived from both normal and osteoarthritis articular cartilage. OA1 and OA3 human articular cartilage was carefully dissected and macroscopically graded for degeneration via the Collins scale. The tissue samples were histologically examined by Hematoxylin and Eosin and Safranin O and Fast Green staining. SVCT2 expression analysis was performed at mRNA level by quantitative real time PCR and at a protein level by immunohistochemistry. Our quantitative real time PCR showed marked variation in the expression of SVCT2 in human osteoarthritic articular cartilage. SVCT2 expression was significantly down-regulated (p = 0.0001) in the Collins grade 3 (OA3) compared to Collins grade 1 (OA1) tissue. Furthermore, slides stained with fluorescent antibodies to SVCT2 demonstrated greatly reduced fluorescence for the SVCT2 transporter on the chondrocyte plasma membrane in the osteoarthritic tissue samples. These findings demonstrate that the expression of SVCT2 transporter is significantly altered in human osteoarthritic tissues (OA3). The modulation of this transporter could therefore potentially influence the prevention, management and treatment of osteoarthritis.