Encapsulating peritoneal sclerosis: the state of affairs.
Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD) with a 50% mortality rate. EPS is characterized by progressive and excessive fibrotic thickening of the peritoneum, leading to encapsulation of the bowels and intestinal obstruction. At present, EPS cannot be detected with certainty during its early stages; however, a progressive loss of ultrafiltration capacity often precedes its development. Studies that attempted to elucidate the pathogenesis of EPS have shown that the duration of exposure to PD fluids is the most important risk factor for EPS, and that young age and possibly the effects of peritonitis are additional contributory factors. The pathophysiology of EPS is probably best described as a multiple-hit process with a central role for transforming growth factor β. A form of EPS that develops shortly after kidney transplantation has also been recognized as a distinct clinical entity, and may be a common form of EPS in countries with a high transplantation rate. Criteria have been developed to identify EPS by abdominal CT scan at the symptomatic stage, but further clinical research is needed to identify early EPS in asymptomatic patients, to clarify additional risk factors for EPS and to define optimal treatment strategies.


Phase-resolved mapping of the near-field vector and polarization state in nanoscale antenna gaps.
We demonstrate that the local near-field vector and polarization state on planar antenna structures and in nanoscale antenna gaps can be determined by scattering-type near-field optical microscopy (s-SNOM). The near-field vector is reconstructed from the amplitude and phase images of the in- and out-of-plane near-field components obtained by polarization-resolved interferometric detection. Experiments with a mid-infrared inverse bowtie antenna yield a vectorial near-field distribution with unprecedented resolution of about 10 nm and in excellent agreement with numerical simulations. Furthermore, we provide first direct experimental evidence that the nanoscale confined and strongly enhanced fields at the antenna gap are linearly polarized. s-SNOM vector-field mapping paves the way to a full near-field characterization of nanophotonic structures in the broad spectral range between visible and terahertz frequencies, which is essential for future development and quality control of metamaterials, optical sensors, and waveguides.


Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P(trend) = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P(trend) = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.


Karyotype and Mapping of Repetitive DNAs in the African Butterfly Fish Pantodon buchholzi, the Sole Species of the Family Pantodontidae.
The monophyletic order Osteoglossiformes represents one of the most ancestral groups of teleosts and has at least 1 representative in all continents of the southern hemisphere, with the exception of Antarctica. However, despite its phylogenetic and biogeographical importance, cytogenetic data in Osteoglossiformes are scarce. Here, karyotype and chromosomal characteristics of the lower Niger River population of the African butterfly fish Pantodon buchholzi, the sole species of the family Pantodontidae (Osteoglossiformes), were examined using conventional and molecular cytogenetic approaches. All specimens examined had 2n = 46 chromosomes, with a karyotype composed of 5 pairs of metacentric, 5 pairs of submetacentric, and 13 pairs of acrocentric chromosomes in both sexes. No morphologically differentiated sex chromosomes were identified. C-bands were located in the centromeric/pericentromeric region of all chromosomes and were associated with the single AgNOR site. FISH with ribosomal DNA probes revealed that both 5S and 18S rDNA were present in only 1 pair of chromosomes each, but did not colocalize. CMA3+ bands were observed near the telomeres in several chromosome pairs and also at the 18S rDNA sites. The mapping of di- and trinucleotide repeat motifs, Rex6 transposable element, and U2 snRNA showed a scattered distribution over most of the chromosomes, but for some microsatellites and the U2 snRNA also a preferential accumulation at telomeric regions. This study presents the first detailed cytogenetic analysis in the African butterfly fish by both conventional and molecular cytogenetic protocols. This is the first of a series of further cytogenetic and cytogenomic studies on osteoglossiforms, aiming to comprehensively examine the chromosomal evolution in this phylogenetically important fish order.


Blueberry peel extracts inhibit adipogenesis in 3T3-L1 cells and reduce high-fat diet-induced obesity.
This study examined the anti-obesity effect and mechanism of action of blueberry peel extracts (BPE) in 3T3-L1 cells and high-fat diet (HFD)-induced obese rats. The levels of lipid accumulation were measured, along with the changes in the expression of genes and proteins associated with adipocyte differentiation in 3T3-L1 cells. Evidenced by Oil-red O staining and triglyceride assay, BPE dose-dependently inhibited lipid accumulation at concentrations of 0, 50, and 200 µg/ml. BPE decreased the expression of the key adipocyte differentiation regulator C/EBPβ, as well as the C/EBPα and PPARγ genes, during the differentiation of preadipocytes into adipocytes. Moreover, BPE down-regulated adipocyte-specific genes such as aP2 and FAS compared with control adipocytes. The specific mechanism mediating the effects of BP revealed that insulin-stimulated phosphorylation of Akt was strongly decreased, and its downstream substrate, phospho-GSK3β, was downregulated by BPE treatment in 3T3-L1 cells. Together, these data indicated that BP exerted anti-adipogenic activity by inhibiting the expression of PPARγ and C/EBPβ and the Akt signaling pathway in 3T3-L1 adipocytes. Next, we investigated whether BP extracts attenuated HFD-induced obesity in rats. Oral administration of BPE reduced HFD-induced body weight gain significantly without affecting food intake. The epididymal or perirenal adipose tissue weights were lower in rats on an HFD plus BPE compared with the tissue weights of HFD-induced obese rats. Total cholesterol and triglyceride levels in the rats fed BPE were modestly reduced, and the HDL-cholesterol level was significantly increased in HFD plus BP-fed rats compared with those of HFD-fed rats. Taken together, these results demonstrated an inhibitory effect of BP on adipogenesis through the down-regulation of C/EBPβ, C/EBPα, and PPARγ and the reduction of the phospho-Akt adipogenic factor in 3T3-L1 cells. Moreover, BPE reduced body weight gain and inhibited fat accumulation in an HFD-induced animal model of obesity.


Rotavirus activates JNK and p38 signaling pathways in intestinal cells, leading to AP-1-driven transcriptional responses and enhanced virus replication.
Rotavirus infection is known to regulate transcriptional changes in many cellular genes. The transcription factors NF-kappaB and AP-1 are activated by rotavirus infection, but the upstream processes leading to these events are largely unidentified. We therefore studied the activation state during rotavirus infection of c-Jun NH2-terminal kinase (JNK) and p38, which are kinases known to activate AP-1. As assessed by Western blotting using phospho-specific antibodies, infection with rhesus rotavirus (RRV) or exposure to UV-psoralen-inactivated RRV (I-RRV) resulted in the activation of JNK in HT-29, Caco-2, and MA104 cells. Activation of p38 during RRV infection was observed in Caco-2 and MA104 cells but not in HT-29 cells, whereas exposure to I-RRV did not lead to p38 activation in these cell lines. Rotavirus strains SA11, CRW-8, Wa, and UK also activated JNK and p38. Consistent with the activation of JNK, a corresponding increase in the phosphorylation of the AP-1 component c-Jun was shown. The interleukin-8 (IL-8) and c-jun promoters contain AP-1 binding sequences, and these genes have been shown previously to be transcriptionally up-regulated during rotavirus infection. Using specific inhibitors of JNK (SP600125) and p38 (SB203580) and real-time PCR, we showed that maximal RRV-induced IL-8 and c-jun transcription required JNK and p38 activity. This highlights the importance of JNK and p38 in RRV-induced, AP-1-driven gene expression. Significantly, inhibition of p38 or JNK in Caco-2 cells reduced RRV growth but not viral structural antigen expression, demonstrating the potential importance of JNK and p38 activation for optimal rotavirus replication.


Controlled release of imatinib mesylate from PLGA microspheres inhibit craniopharyngioma mediated angiogenesis.
Poly(lactic-co-glycolic acid) microspheres loaded with imatinib mesylate has been developed as a new therapeutic strategy to prevent craniopharyngioma recurrence. Microspheres composed of different lactic/glycolic acid ratios, molecular weights and drug compositions were synthesized and loaded with imatinib mesylate by modified double-emulsion/solvent evaporation technique and subsequently characterized by particle-size distribution, scanning electron microscopy, encapsulation efficiency and in vitro drug release. Inhibitory potential of imatinib containing microspheres on tumor neovascularization was investigated on craniopharyngioma tumor samples by rat cornea angiogenesis assay. Results showed that microspheres in different LA:GA ratios [LA:GA 50:50 (G50), 75:25 (G25), 85:15 (G15)] considerably reduced neovascularization induced by recurrent tumor samples in an in vivo angiogenesis assay (P < 0.01). Our data indicate that local delivery of imatinib mesylate to the post-surgical tumoral cavity using biodegradable microspheres may be a promising biologically selective approach to prevent the recurrence of craniopharyngiomas, via inhibition of neovascularization.


Evolutionary divergence and salinity-mediated selection in halophilic archaea.
Halophilic (literally salt-loving) archaea are a highly evolved group of organisms that are uniquely able to survive in and exploit hypersaline environments. In this review, we examine the potential interplay between fluctuations in environmental salinity and the primary sequence and tertiary structure of halophilic proteins. The proteins of halophilic archaea are highly adapted and magnificently engineered to function in an intracellular milieu that is in ionic balance with an external environment containing between 2 and 5 M inorganic salt. To understand the nature of halophilic adaptation and to visualize this interplay, the sequences of genes encoding the L11, L1, L10, and L12 proteins of the large ribosome subunit and Mn/Fe superoxide dismutase proteins from three genera of halophilic archaea have been aligned and analyzed for the presence of synonymous and nonsynonymous nucleotide substitutions. Compared to homologous eubacterial genes, these halophilic genes exhibit an inordinately high proportion of nonsynonymous nucleotide substitutions that result in amino acid replacement in the encoded proteins. More than one-third of the replacements involve acidic amino acid residues. We suggest that fluctuations in environmental salinity provide the driving force for fixation of the excessive number of nonsynonymous substitutions. Tinkering with the number, location, and arrangement of acidic and other amino acid residues influences the fitness (i.e., hydrophobicity, surface hydration, and structural stability) of the halophilic protein. Tinkering is also evident at halophilic protein positions monomorphic or polymorphic for serine; more than one-third of these positions use both the TCN and the AGY serine codons, indicating that there have been multiple nonsynonymous substitutions at these positions. Our model suggests that fluctuating environmental salinity prevents optimization of fitness for many halophilic proteins and helps to explain the unusual evolutionary divergence of their encoding genes.


Cannabinoid-Based Ocular Therapies and Formulations.
The interest in the pharmacological applications of cannabinoids is largely increasing in a wide range of medical areas. Recently, research on its potential role in eye conditions, many of which are chronic and/or disabling and in need of new alternative treatments, has intensified. However, due to cannabinoids' unfavorable physicochemical properties and adverse systemic effects, along with ocular biological barriers to local drug administration, drug delivery systems are needed. Hence, this review focused on the following: (i) identifying eye disease conditions potentially subject to treatment with cannabinoids and their pharmacological role, with emphasis on glaucoma, uveitis, diabetic retinopathy, keratitis and the prevention of Pseudomonas aeruginosa infections; (ii) reviewing the physicochemical properties of formulations that must be controlled and/or optimized for successful ocular administration; (iii) analyzing works evaluating cannabinoid-based formulations for ocular administration, with emphasis on results and limitations; and (iv) identifying alternative cannabinoid-based formulations that could potentially be useful for ocular administration strategies. Finally, an overview of the current advances and limitations in the field, the technological challenges to overcome and the prospective further developments, is provided.


Experimental reproduction of postweaning multisystemic wasting syndrome (PMWS) in pigs in Sweden and Denmark with a Swedish isolate of porcine circovirus type 2.
An experimental model using 3-day-old snatch-farrowed colostrum-deprived piglets co-infected with porcine circovirus type 2 (PCV2) and porcine parvovirus (PPV) is at present one of the best methods to study factors affecting development of postweaning multisystemic wasting syndrome (PMWS). A Swedish isolate of PCV2 (S-PCV2) retrieved in 1993 from a healthy pig has been used in this model to reproduce PMWS in pigs from Northern Ireland. This virus has been present in the Swedish pig population for at least a decade without causing any known PMWS disease problems, despite its potential pathogenicity. The reasons for this are unknown, but could be related to genetics, absence of triggers for PCV2 upregulation (infectious agent and/or management forms) within Swedish pig husbandry. In order to confirm the pathogenicity of S-PCV2, Swedish and Danish pigs were experimentally infected with this isolate according to the established model. Swedish pigs were also infected with a reference isolate of PCV2 (PCV2-1010) to compare the severity of disease caused by the two isolates in Swedish pigs. Both Danish and Swedish pigs developed PMWS after the experimental infection with S-PCV2. Antibodies to PCV2 developed later and reached lower levels in serum from pigs infected with S-PCV2 than in pigs inoculated with PCV2-1010. In general, pigs infected with S-PCV2 showed more severe clinical signs of disease than pigs infected with PCV2-1010, but pigs from all PCV2-inoculated groups displayed gross and histological lesions consistent with PMWS. All pigs inoculated with PPV, alone or in combination with PCV2, displayed interleukin-10 responses in serum while only pigs infected with PPV in combination with PCV2 showed interferon-alpha in serum on repeated occasions. Thus, the pathogenicity of S-PCV2 was confirmed and a role for cytokines in the etiology of PMWS was indicated.


Nutrient partitioning between reproductive and immune functions in animals.
The physiological processes that underlie the reproductive cycle impose considerable metabolisable protein (MP) demands on a female, especially during the periparturient period. When MP supply falls short of MP demand (i.e. MP becomes scarce), certain, if not all, bodily functions are expected to be penalised. It has been proposed that partitioning of scarce MP is prioritised to reproductive rather than to immune functions. In other words, at times of MP scarcity, the penalty on expression of immunity would be expected to be greater than that on reproduction. This hypothesis forms a nutritional basis for the occurrence of periparturient breakdown of immunity to parasites (BIP), which can be observed in many host-parasite systems. In the present review we explore this nutritional basis, using periparturient sheep infected with the abomasal nematode Teladorsagia circumcincta as an example, and attempt to quantify its occurrence. Evidence supporting the nutritional basis of periparturient BIP is reviewed, covering experiments in which nutrient supply (from both exogenous and endogenous sources) and/or nutrient demand were manipulated. Quantitatively, MP requirements for expression of immunity to T. circumcincta were estimated to be about 1 g/kg metabolic body weight (body weight 0.75) per d, approximately 5% of the maximum MP requirements of periparturient sheep. The major component of this requirement was assumed to be for replenishing irreversible plasma protein losses into the gastrointestinal tract. Although confirmation of this estimate is required, such estimates may be used to improve the known MP requirements of periparturient animals, enabling the extent and the consequences of periparturient BIP to be minimised.


Investigating the utility of intraoperative neurophysiological monitoring for anterior cervical discectomy and fusion: analysis of over 140,000 cases from the National (Nationwide) Inpatient Sample data set.
Intraoperative neurophysiological monitoring (IONM) is a useful adjunct in spine surgery, with proven benefit in scoliosis-correction surgery. However, its utility for anterior cervical discectomy and fusion (ACDF) is unclear, as there are few head-to-head comparisons of ACDF outcomes with and without the use of IONM. The authors sought to evaluate the impact of IONM on the safety and cost of ACDF. This was a retrospective analysis of data from the National (Nationwide) Inpatient Sample of the Healthcare Cost and Utilization Project from 2009 to 2013. Patients with a primary procedure code for ACDF were identified, and diagnosis codes were searched to identify cases with postoperative neurological complications. The authors performed univariate and multivariate logistic regression for postoperative neurological complications with use of IONM as the independent variable; additional covariates included age, sex, surgical indication, multilevel fusion, Charlson Comorbidity Index (CCI) score, and admission type. They also conducted propensity score matching in a 1:1 ratio (nearest neighbor) with the use of IONM as the treatment indicator and the aforementioned variables as covariates. In the propensity score-matched cohort, they compared neurological complications, length of stay (LOS), and hospital charges (in US dollars). A total of 141,007 ACDF operations were identified. IONM was used in 9540 cases (6.8%). No significant association was found between neurological complications and use of IONM on univariate analysis (OR 0.80, p = 0.39) or multivariate regression (OR 0.82, p = 0.45). By contrast, age ≥ 65 years, multilevel fusion, CCI score > 0, and a nonelective admission were associated with greater incidence of neurological complication. The propensity score-matched cohort consisted of 18,760 patients who underwent ACDF with (n = 9380) or without (n = 9380) IONM. Rates of neurological complication were comparable between IONM and non-IONM (0.17% vs 0.22%, p = 0.41) groups. IONM and non-IONM groups had a comparable proportion of patients with LOS ≥ 2 days (19% vs 18%, p = 0.15). The use of IONM was associated with an additional $6843 (p < 0.01) in hospital charges. The use of IONM was not associated with a reduced rate of neurological complications following ACDF. Limitations of the data source precluded a specific assessment of the effectiveness of IONM in preventing neurological complications in patients with more complex pathology (i.e., ossification of the posterior longitudinal ligament or cervical deformity).


Consummation of the legislative map of transplantation in Latin America: Law on Donation and Transplantation Nicaragua--the last piece of the puzzle.
Latin America started its transplant activity early-as soon as the first transplants in the world took place. Its member states have created their laws of donation and transplantation also. The first laws for transplants in the region were created in Brazil in 1963. Subsequently, all states approved its regulatory framework for transplants. Until 2012, Nicaragua was the only country in the region that did not have a transplants law. In October 2013, Nicaragua adopted the "Law on Donation and Transplantation of Organs, Tissues and Cells for Human Beings," which consummates the process that creates the legal framework for donation and transplantation in Latin America, a journey of 50 years' duration, from Brazil's law to Nicaragua's law. This achievement is the fundament for searching an exercise of transplantation in a ground of accessibility, equity, ethics, and transparency as part of comprehensive health care services in the region.


Atomic layer deposition in nanostructured photovoltaics: tuning optical, electronic and surface properties.
Nanostructured materials offer key advantages for third-generation photovoltaics, such as the ability to achieve high optical absorption together with enhanced charge carrier collection using low cost components. However, the extensive interfacial areas in nanostructured photovoltaic devices can cause high recombination rates and a high density of surface electronic states. In this feature article, we provide a brief review of some nanostructured photovoltaic technologies including dye-sensitized, quantum dot sensitized and colloidal quantum dot solar cells. We then introduce the technique of atomic layer deposition (ALD), which is a vapor phase deposition method using a sequence of self-limiting surface reaction steps to grow thin, uniform and conformal films. We discuss how ALD has established itself as a promising tool for addressing different aspects of nanostructured photovoltaics. Examples include the use of ALD to synthesize absorber materials for both quantum dot and plasmonic solar cells, to grow barrier layers for dye and quantum dot sensitized solar cells, and to infiltrate coatings into colloidal quantum dot solar cell to improve charge carrier mobilities as well as stability. We also provide an example of monolayer surface modification in which adsorbed ligand molecules on quantum dots are used to tune the band structure of colloidal quantum dot solar cells for improved charge collection. Finally, we comment on the present challenges and future outlook of the use of ALD for nanostructured photovoltaics.


Effect of melatonin on human nighttime endotoxaemia: randomized, double-blinded, cross-over study.
Endotoxaemia is widely used as an experimental model to study sepsis under controlled conditions. Nighttime endotoxaemia induces a more pronounced inflammatory stress response compared to daytime. Previously, we have shown that melatonin has antioxidative and anti-inflammatory effects in inflammatory response to daytime endotoxaemia. Herein, we examined the effect of melatonin in response to human nighttime endotoxaemia. Twelve healthy male volunteers were enrolled in a randomized, placebo-controlled, double-blinded cross-over trial. Subjects were induced by lipopolysaccharide (LPS) endotoxin 0.3 ng/kg body weight intravenously at 24:00. One hour prior to induction of endotoxaemia, an 8-h infusion of melatonin 100 mg or placebo was initiated. Blood samples were drawn before and 2, 4, 6 and 8 h after induction of endotoxaemia and plasma was tested for pro-inflammatory markers (tumor necrosis factor alpha, TNF-α, interleukin-1β, IL-1β, interleukin-1, IL-6, and YKL-40), anti-inflammatory markers (interleukin-1 receptor antagonist, IL-1Ra, interleukin-10, IL-10, soluble tumor necrosis factor receptors I and II, sTNF-RI and sTNF-RII), marker for oxidative damage (malondialdehyde (MDA)) and antioxidative enzyme (ascorbic acid (AA) and dehydroascorbic acid (DHA)). Compared to placebo, melatonin did not reduce plasma levels of any of pro- and anti-inflammatory markers and it also failed to influence levels of AA, DHA and MDA. Melatonin has no beneficial effect on inflammation and oxidative damage induced by nighttime endotoxaemia in contrast to daytime endotoxaemia.


The influence of risk factors on the onset and outcome of psychosis: What we learned from the GAP study.
The GAP multidisciplinary study carried out in South London, recruited 410 first episode of psychosis patients and 370 controls; the aim was to elucidate the multiple genetic and environmental factors influencing the onset and outcome of psychosis. The study demonstrated the risk increasing effect of adversity in childhood (especially parental loss, abuse, and bullying) on onset of psychosis especially positive symptoms. Adverse life events more proximal to onset, being from an ethnic minority, and cannabis use also played important roles; indeed, one quarter of new cases of psychosis could be attributed to use of high potency cannabis. The "jumping to conclusions" bias appeared to mediate the effect of lower IQ on vulnerability to psychosis. We confirmed that environmental factors operate on the background of polygenic risk, and that genetic and environment act together to push individuals over the threshold for manifesting the clinical disorder. The study demonstrated how biological pathways involved in the stress response (HPA axis and immune system) provide important mechanisms linking social risk factors to the development of psychotic symptoms. Further evidence implicating an immune/inflammatory component to psychosis came from our finding of complement dysregulation in FEP. Patients also showed an upregulation of the antimicrobial alpha-defensins, as well as differences in expression patterns of genes involved in NF-κB signaling and Cytokine Production. Being of African origin not only increased risk of onset but also of a more difficult course of illness. The malign effect of childhood adversity predicted a poorer outcome as did continued use of high potency cannabis.


The experience of a sore mouth and associated symptoms in patients with cancer receiving outpatient chemotherapy.
This study aimed to describe sore mouth (SM) severity and distress, associated symptoms, and consequences in cancer chemotherapy outpatients. Secondary analysis was used in this study. A total of 223 patients in 4 treatment centers participated in the study. Data from an intervention study using a computer-based telephone communication system to assess patients' daily symptom experience were analyzed to obtain highest, average, and lowest ratings of severity and distress for SM, fatigue, trouble sleeping, feeling down/blue, and feeling anxious. Consequence data included oral intake, time spent lying down, ability to work, and daily activity. Approximately 51% reported SM, with a mean highest, average, and lowest severity score of 3.1 in cycle 2 and 3.09 in cycle 3. Sore mouth severity was correlated with severity of fatigue, feeling down/blue, feeling anxious, and trouble sleeping. Sore mouth distress was correlated with the same symptoms. Sore mouth severity was correlated with the number of 8-oz glasses of liquid consumed, effect on daily activity, time spent lying down, but not with ability to work. Half of patients experienced SM, which was associated with several other symptoms and led to specific consequences. Understanding the complex symptom experience of patients with SM, including consequences, will assist nurses in developing more comprehensive clinical assessments and interventions. In addition, the association of multiple symptoms with SM will provide a foundation for further research investigation in oral mucositis.


CTL escape viral variants. I. Generation and molecular characterization.
Cytotoxic T lymphocytes (CTL) play a pivotal role in preventing persistent viral infections and aborting acute infections. H-2Db-restricted CTL optimally recognize a specific peptide of 9 to 11 amino acids (aa) derived from a viral protein and held in place (restricted) by a MHC class I glycoprotein on the surfaces of infected cells. Only three peptide sequences with the appropriate Db motif from lymphocytic choriomeningitis virus Armstrong strain (LCMV) are known to be presented to CTL by H-2Db molecules; they are from the glycoproteins (GP), residues 33-41 KAVYNFATC (GP1) and 276-286 SGVENPGGYCL (GP2), and the nucleoprotein (NP), 396-404 FQPQNGQFI. Incubation of virally infected H-2b cells with CTL clones that recognize only GP1, GP2, or NP leads to the selection of viral variants which upon infecting cells bearing H-2b molecules, escape recognition by CTL of the appropriate specificity. Nucleic acid sequencing showed a single mutation in GP1 (aa 38 F-->L), GP2 (aa 282 G-->D), or NP (aa 403 F-->L) in the variant viruses. When wild-type (wt) LCMV peptides and the three variant peptides (GP1, GP2, NP) were synthesized and subjected to a competitive inhibition binding assay, no differences in binding affinity for H-2Db were found between the wt and variant peptides. Uninfected cells coated with the wt peptide were recognized and lysed by the appropriate CTL clone or by in vivo-primed bulk CTL, but similar targets coated with the GP1, GP2, or NP variant peptides were not. This result, coupled with computer graphic analysis of these variant peptides with the recently solved three-dimensional structure for the Db MHC class I molecule, placed the side chain of the mutated residues on the outer surface of the MHC-peptide complex and accessible to the T cell receptor. Ala substitution at GP residue 38 or 282 or at NP 403 also abrogated CTL recognition and lysis. Inoculation of any one of the mutated viral variants into mice produced an effective CTL response to the other two nonmutated GP or NP peptides, suggesting that production of biologically relevant CTL escape virus variants in vivo requires selection of mutations in more than one and likely all the CTL epitopes, a low probability event.


Metabolically Distinct Pools of Phosphatidylcholine Are Involved in Trafficking of Fatty Acids out of and into the Chloroplast for Membrane Production.
The eukaryotic pathway of galactolipid synthesis involves fatty acid synthesis in the chloroplast, followed by assembly of phosphatidylcholine (PC) in the endoplasmic reticulum (ER), and then turnover of PC to provide a substrate for chloroplast galactolipid synthesis. However, the mechanisms and classes of lipids transported between the chloroplast and the ER are unclear. PC, PC-derived diacylglycerol, phosphatidic acid, and lyso-phosphatidylcholine (LPC) have all been implicated in ER-to-chloroplast lipid transfer. LPC transport requires lysophosphatidylcholine acyltransferase (LPCAT) activity at the chloroplast to form PC before conversion to galactolipids. However, LPCAT has also been implicated in the opposite chloroplast-to-ER trafficking of newly synthesized fatty acids through PC acyl editing. To understand the role of LPC and LPCAT in acyl trafficking we produced and analyzed the Arabidopsis (Arabidopsis thaliana) act1 lpcat1 lpcat2 triple mutant. LPCAT1 and LPCAT2 encode the major lysophospholipid acyltransferase activity of the chloroplast, and it is predominantly for incorporation of nascent fatty acids exported form the chloroplast into PC by acyl editing. In vivo acyl flux analysis revealed eukaryotic galactolipid synthesis is not impaired in act1 lpcat1 lpcat2 and uses a PC pool distinct from that of PC acyl editing. We present a model for the eukaryotic pathway with metabolically distinct pools of PC, suggesting an underlying spatial organization of PC metabolism as part of the ER-chloroplast metabolic interactions.


Somatic coding mutations in human induced pluripotent stem cells.
Defined transcription factors can induce epigenetic reprogramming of adult mammalian cells into induced pluripotent stem cells. Although DNA factors are integrated during some reprogramming methods, it is unknown whether the genome remains unchanged at the single nucleotide level. Here we show that 22 human induced pluripotent stem (hiPS) cell lines reprogrammed using five different methods each contained an average of five protein-coding point mutations in the regions sampled (an estimated six protein-coding point mutations per exome). The majority of these mutations were non-synonymous, nonsense or splice variants, and were enriched in genes mutated or having causative effects in cancers. At least half of these reprogramming-associated mutations pre-existed in fibroblast progenitors at low frequencies, whereas the rest occurred during or after reprogramming. Thus, hiPS cells acquire genetic modifications in addition to epigenetic modifications. Extensive genetic screening should become a standard procedure to ensure hiPS cell safety before clinical use.


Hand hygiene compliance and environmental contamination with gram-negative bacilli in a rural hospital in Madarounfa, Niger.
Healthcare-associated infections pose a major, yet often preventable risk to patient safety. Poor hand hygiene among healthcare personnel and unsanitary hospital environments may contribute to this risk in low-income settings. We aimed to describe hand hygiene behaviour and environmental contamination by season in a rural, sub-Saharan African hospital setting. We conducted a concurrent triangulation mixed-methods study combining three types of data at a hospital in Madarounfa, Niger. Hand hygiene observations among healthcare personnel during two seasons contributed quantitative data describing hand hygiene frequency and its variability in relation to seasonal changes in caseload. Semistructured interviews with healthcare personnel contributed qualitative data on knowledge, attitudes and barriers to hand hygiene. Biweekly environmental samples evaluated microbial contamination from October 2016 to December 2017. Triangulation identified convergences, complements and contradictions across results. Hand hygiene compliance, or the proportion of actions (handrubbing or handwashing) performed out of all actions required, was low (11% during non-peak and 36% during peak caseload seasons). Interviews with healthcare personnel suggesting good general knowledge of hand hygiene contradicted the low hand hygiene compliance. However, compliance by healthcare activity was convergent with poor knowledge of precise hand hygiene steps and the motivation to prevent personal acquisition of infection identified during interviews. Contamination of environmental samples with gram-negative bacilli was high (45%), with the highest rates of contamination observed during the peak caseload season. Low hand hygiene compliance coupled with high contamination rates of hospital environments may increase the risk of hospital-acquired infections in sub-Saharan African settings.


Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1.
We have isolated a novel liver-specific organic anion transporter, LST-1, that is expressed exclusively in the human, rat, and mouse liver. LST-1 is a new gene family located between the organic anion transporter family and prostaglandin transporter. LST-1 transports taurocholate (Km = 13.6 microM) in a sodium-independent manner. LST-1 also shows broad substrate specificity. It transports conjugated steroids (dehydroepiandrosterone sulfate, estradiol-17beta-glucuronide, and estrone-3-sulfate), eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, leukotriene E4), and thyroid hormones (thyroxine, Km = 3.0 microM and triiodothyronine, Km = 2.7 microM), reflecting hepatic multispecificity. LST-1 is probably the most important transporter in human liver for clearance of bile acids and organic anions because hepatic levels of another organic anion transporter, OATP, is very low. This is also the first report of the human molecule that transports thyroid hormones.


Reflection-mode optical injection locking.
A novel model including the interference effect of master laser reflection is established for reflection-mode optical injection locking. This model sheds insight on the physical origin of some rather distinct but unexplained modulation characteristics of optical injection-locked vertical-cavity surface-emitting lasers (VCSELs), including data pattern inversion in on-off keying modulation, a large RF gain at low frequency, and an anomalous DC-suppression under small signal modulation, in specific locking conditions. Excellent agreement is obtained between the simulation and experiment results.


Interaction between the genetic risk score and dietary protein intake on cardiometabolic traits in Southeast Asian.
Cardiometabolic diseases are complex traits which are influenced by several single nucleotide polymorphisms (SNPs). Thus, analysing the combined effects of multiple gene variants might provide a better understanding of disease risk than using a single gene variant approach. Furthermore, studies have found that the effect of SNPs on cardiometabolic traits can be influenced by lifestyle factors, highlighting the importance of analysing gene-lifestyle interactions. In the present study, we investigated the association of 15 gene variants with cardiometabolic traits and examined whether these associations were modified by lifestyle factors such as dietary intake and physical activity. The study included 110 Minangkabau women [aged 25-60 years and body mass index (BMI) 25.13 ± 4.2 kg/m2] from Padang, Indonesia. All participants underwent a physical examination followed by anthropometric, biochemical and dietary assessments and genetic tests. A genetic risk score (GRS) was developed based on 15 cardiometabolic disease-related SNPs. The effect of GRS on cardiometabolic traits was analysed using general linear models. GRS-lifestyle interactions on continuous outcomes were tested by including the interaction term (e.g. lifestyle factor*GRS) in the regression model. Models were adjusted for age, BMI and location (rural or urban), wherever appropriate. There was a significant association between GRS and BMI, where individuals carrying 6 or more risk alleles had higher BMI compared to those carrying 5 or less risk alleles (P = 0.018). Furthermore, there were significant interactions of GRS with protein intake on waist circumference (WC) and triglyceride concentrations (Pinteraction = 0.002 and 0.003, respectively). Among women who had a lower protein intake (13.51 ± 1.18% of the total daily energy intake), carriers of six or more risk alleles had significantly lower WC and triglyceride concentrations compared with carriers of five or less risk alleles (P = 0.0118 and 0.002, respectively). Our study confirmed the association of GRS with higher BMI and further showed a significant effect of the GRS on WC and triglyceride levels through the influence of a low-protein diet. These findings suggest that following a lower protein diet, particularly in genetically predisposed individuals, might be an effective approach for addressing cardiometabolic diseases among Southeast Asian women.


SU-E-T-305: Limitations of Using DICOM Data for BrachyVision Treatment Plan Evaluation.
To evaluate the accuracy of a real-time automated method of performing dosimetric quality assurance using Eclipse DICOM files for patients receiving HDR-brachytherapy and IMRT. GYN patients are treated with concurrent high-dose rate brachtherapy and IMRT. The dosimetric parameters were obtained through an in-house QA program developed using Matlab. The DICOM files containing DVH data for organsat-risk (OAR) were analyzed Dosimetric data for 7 patients (total 42 fractions) were collected for bladder, rectum and sigmoid. The accuracy of the dosimetric parameters was estimated by comparing the parameters obtained from the DICOM based QA program and those in BrachyVision. The maximal dose values (Dmax) for the OARs obtained using the DICOM-based program are significantly smaller than those valued reported in BrachyVision by 36.2%-48.3%. The mean dose has a deviation from 1% - 2.4%. The dose for the volume of 2cc (D2cc) has a difference up to 7.6% for structures with the volume larger than 200 cc. The average difference of D2cc is 0.5% for structures less than 200 cc. We found that Eclipse BrachyVision only exports DVH data down to a volume equivalent to 1% of the maximum volume for a given structure. Therefore, the reported maximal dose values obtained from DICOM RT dose file do not accurately reflect the maximum dose in a treatment plan. This will also slightly affect the mean dose calculation and D2cc when the structure volume is larger than 200cc. The automatic QA tool based on DICOM files provides a quick retrieval of dose to organs-at-risk and coverage of targets. However, maximal dose to structures is not accurate due to the truncationof the DVH information contained in DICOM files.


The influence of selection for protein stability on dN/dS estimations.
Understanding the relative contributions of various evolutionary processes-purifying selection, neutral drift, and adaptation-is fundamental to evolutionary biology. A common metric to distinguish these processes is the ratio of nonsynonymous to synonymous substitutions (i.e., dN/dS) interpreted from the neutral theory as a null model. However, from biophysical considerations, mutations have non-negligible effects on the biophysical properties of proteins such as folding stability. In this work, we investigated how stability affects the rate of protein evolution in phylogenetic trees by using simulations that combine explicit protein sequences with associated stability changes. We first simulated myoglobin evolution in phylogenetic trees with a biophysically realistic approach that accounts for 3D structural information and estimates of changes in stability upon mutation. We then compared evolutionary rates inferred directly from simulation to those estimated using maximum-likelihood (ML) methods. We found that the dN/dS estimated by ML methods (ωML) is highly predictive of the per gene dN/dS inferred from the simulated phylogenetic trees. This agreement is strong in the regime of high stability where protein evolution is neutral. At low folding stabilities and under mutation-selection balance, we observe deviations from neutrality (per gene dN/dS > 1 and dN/dS < 1). We showed that although per gene dN/dS is robust to these deviations, ML tests for positive selection detect statistically significant per site dN/dS > 1. Altogether, we show how protein biophysics affects the dN/dS estimations and its subsequent interpretation. These results are important for improving the current approaches for detecting positive selection.


An optimization study of the screw orientation on the interfacial strength of the anterior lumbar plate system using neurogenetic algorithms and experimental validation.
Anterior lumbar plate (ALP) systems have been widely used as an effective interbody fusion device for treating spinal cord compression. However, clinical complications, such as implant loosening and breakage, still occur. Past studies have investigated the effects of the screw orientation on the interfacial strength, but these studies were inconsistent. The purpose of this study was to identify an ALP system with excellent interfacial strength by varying the screw orientation. Three-dimensional finite element models of L4-L5 segments with an ALP system were first constructed. A neurogenetic algorithm, which combines artificial neural networks and genetic algorithms, was subsequently developed to discover the optimum plate design. Finally, biomechanical tests were conducted to validate the results of the finite element models and the engineering algorithm. The results indicated that the interfacial strength of the optimum plate design obtained using the neurogenetic algorithm was excellent compared with the other designs and that all of the locking screws should be inserted divergently. Both the numerical and experimental outcomes can provide clinical suggestions to surgeons and help them to understand the interfacial strength of ALP systems in terms of the screw orientation.


Heart failure risk prediction in the Multi-Ethnic Study of Atherosclerosis.
Heart failure (HF) is a leading cause of mortality especially in older populations. Early detection of high-risk individuals is imperative for primary prevention. The purpose of this study was to develop a HF risk model from a population without clinical cardiac disease. The Multi-Ethnic Study of Atherosclerosis is a multicentre observational cohort study following 6814 subjects (mean age 62±10 years; 47% men) who were free of clinical cardiovascular disease at baseline. Median follow-up was 4.7 years. HF events developed in 176 participants. Cox proportional hazards models and regression coefficients were used to determine independent risk factors and generate a 5-year risk score for incident HF. Bootstrapping with bias correction was used for internal validation. Independent predictors for HF (HR, p value) were age (1.30 (1.10 to 1.50) per 10 years), male gender (2.27 (1.53 to 3.36)), current smoking (1.97 (1.15 to 3.36)), body mass index (1.40 (1.10 to 1.80) per 5 kg/m(2)), systolic blood pressure (1.10 (1.00 to 1.10) per 10 mm Hg), heart rate (1.30) (1.10 to 1.40) per 10 bpm), diabetes (2.27 (1.48 to 3.47)), N-terminal pro-B-type natriuretic peptide (NT proBNP) (2.48 (2.16 to 2.84) per unit log increment) and left ventricular mass index (1.40 (1.30 to 1.40) per 10 g/m(2)). A parsimonious model based on age, gender, body mass index, smoking status, systolic blood pressure, heart rate, diabetes and NT proBNP natriuretic peptide predicted incident HF risk with a c-statistic of 0.87. A clinical algorithm based on risk factors readily available in the primary care setting can used to identify individuals with high likelihood of developing HF without pre-existing cardiac disease.


Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.


Novel acetylcholinesterase target site for malaria mosquito control.
Current anticholinesterase pesticides were developed during World War II and are toxic to mammals because they target a catalytic serine residue of acetylcholinesterases (AChEs) in insects and in mammals. A sequence analysis of AChEs from 73 species and a three-dimensional model of a malaria-carrying mosquito (Anopheles gambiae) AChE (AgAChE) reported here show that C286 and R339 of AgAChE are conserved at the opening of the active site of AChEs in 17 invertebrate and four insect species, respectively. Both residues are absent in the active site of AChEs of human, monkey, dog, cat, cattle, rabbit, rat, and mouse. The 17 invertebrates include house mosquito, Japanese encephalitis mosquito, African malaria mosquito, German cockroach, Florida lancelet, rice leaf beetle, African bollworm, beet armyworm, codling moth, diamondback moth, domestic silkworm, honey bee, oat or wheat aphid, the greenbug, melon or cotton aphid, green peach aphid, and English grain aphid. The four insects are house mosquito, Japanese encephalitis mosquito, African malaria mosquito, and German cockroach. The discovery of the two invertebrate-specific residues enables the development of effective and safer pesticides that target the residues present only in mosquito AChEs rather than the ubiquitous serine residue, thus potentially offering an effective control of mosquito-borne malaria. Anti-AgAChE pesticides can be designed to interact with R339 and subsequently covalently bond to C286. Such pesticides would be toxic to mosquitoes but not to mammals.


The development of the Melbourne low-vision ADL index: a measure of vision disability.
To develop a new test of activities of daily living (ADLs) appropriate for the low-vision population: the Melbourne Low-Vision ADL Index (MLVAI). The MLVAI was designed as a desk-based clinical assessment, comprising 18 observed items on complex ADLs in part (a) and 9 questions on broad self-care ADLs in part (b). Each item was rated on a five-level descriptive scale from 0 to 4, based on independence, speed, and accuracy of performance. It was designed to be administered under standardized conditions with regard to the instructions, illumination, and working distances. The validity and reliability of the new MLVAI was determined for 122 subjects who were representative of the general low-vision population, in a cross-sectional study. Two items were found to be redundant and were eliminated from the test. Thus, the final test comprised 25 items, with 100 being the highest possible score. Cronbach's alpha indicated an internal reliability of 0.96, and an intraclass correlation coefficient indicated an overall reliability of 0.95. The SE of measurement was 4.5. According to Spearman's correlation coefficient, the test-retest reliability was 0.94 (P < 0.001), and the interpractitioner reliability for five different pairs of practitioners was 0.90 or higher (P < 0.001). With regard to validity, there was a moderately high correlation with vision impairment (r = -0.68, P < 0.001). Using Rasch analysis, content validity was also demonstrated by good separation indexes (4.70 and 9.88) and high reliability scores (0.96 and 0.99) for the person and items parameters, respectively. Separate calculation of indexes and reliability scores for parts (a) and (b) indicated high content validity and reliability of each part. However, the separation indexes and reliability scores were higher for part (a) than for part (b). The correlation coefficient for part (a) and part (b) was 0.68. The MLVAI is a highly valid and reliable standardized test of ADL performance for the general low-vision population. It may be used to assess patients with low vision and has the potential to be used as a measure of low-vision rehabilitation outcomes.


Regression dilution of systolic and diastolic blood pressure in patients with established cerebrovascular disease.
Blood pressure (BP) is a major risk factor for stroke and cardiovascular events. To quantify its effect, it is necessary to correct for regression dilution bias (RDB). RDB has been estimated from repeated measurements of BP in population-based studies, but there are no data in patients with established vascular disease. We analyzed repeat measurements of BP from three large studies of patients with cerebrovascular disease: UK-TIA trial (n=2098), Dutch TIA trial (n=2953), and the European Carotid Surgery Trial (n=2646). The regression dilution ratio (RDR) was estimated by parametric and nonparametric methods at follow-up intervals ranging from 4 months to 6 years. After an interval of only 4-5 months, nonparametric RDRs of 0.56, 0.40, and 0.45 for systolic BP and 0.45, 0.33, and 0.31 for diastolic BP were observed in the three studies, respectively. These values are much smaller than those reported in population-based studies, indicating greater within-person variability in BP. RDRs from population-based studies cannot necessarily be applied to cohorts with established vascular disease.


The Protective Effect of Exercise in Neurodegenerative Diseases: The Potential Role of Extracellular Vesicles.
Physical activity has systemic effects on the body, affecting almost every organ. It is important not only for general health and wellbeing, but also in the prevention of diseases. The mechanisms behind the therapeutic effects of physical activity are not completely understood; however, studies indicate these benefits are not confined to simply managing energy balance and body weight. They also include systemic factors which are released into the circulation during exercise and which appear to underlie the myriad of benefits exercise can elicit. It was shown that along with a number of classical cytokines, active tissues also engage in inter-tissue communication via extracellular vesicles (EVs), specifically exosomes and other small EVs, which are able to deliver biomolecules to cells and alter their metabolism. Thus, EVs may play a role in the acute and systemic adaptations that take place during and after physical activity, and may be therapeutically useful in the treatment of a range of diseases, including metabolic disorders such as type 2 diabetes and obesity; and the focus of this review, neurological disorders such as Alzheimer's disease.


A linguistic analysis of grooming strategies of online child sex offenders: Implications for our understanding of predatory sexual behavior in an increasingly computer-mediated world.
There is a large body of evidence to suggest that child sex offenders engage in grooming to facilitate victimization. It has been speculated that this step-by-step grooming process is also used by offenders who access their underage victims online; however, little research has been done to examine whether there are unique aspects of computer-mediated communication that impact the traditional face-to-face grooming process. This study considered the similarities and differences in the grooming process in online environments by analyzing the language used by online offenders when communicating with their victims. The transcripts of 44 convicted online offenders were analyzed to assess a proposed theory of the online grooming process (O'Connell, 2003). Using a stage-based approach, computerized text analysis examined the types of language used in each stage of the offender-victim interaction. The transcripts also were content analyzed to examine the frequency of specific techniques known to be employed by both face-to-face and online offenders, such as flattery. Results reveal that while some evidence of the strategies used by offenders throughout the grooming process are present in online environments, the order and timing of these stages appear to be different. The types (and potential underlying pattern) of strategies used in online grooming support the development of a revised model for grooming in online environments.


Detection of Epileptic Seizure Using Pretrained Deep Convolutional Neural Network and Transfer Learning.
The diagnosis of epilepsy takes a certain process, depending entirely on the attending physician. However, the human factor may cause erroneous diagnosis in the analysis of the EEG signal. In the past 2 decades, many advanced signal processing and machine learning methods have been developed for the detection of epileptic seizures. However, many of these methods require large data sets and complex operations. In this study, an end-to-end machine learning model is presented for detection of epileptic seizure using the pretrained deep two-dimensional convolutional neural network (CNN) and the concept of transfer learning. The EEG signal is converted directly into visual data with a spectrogram and used directly as input data. The authors analyzed the results of the training of the proposed pretrained AlexNet CNN model. Both binary and ternary classifications were performed without any extra procedure such as feature extraction. By performing data set creation from short-term spectrogram graphic images, the authors were able to achieve 100% accuracy for binary classification for epileptic seizure detection and 100% for ternary classification. The proposed automatic identification and classification model can help in the early diagnosis of epilepsy, thus providing the opportunity for effective early treatment.


Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study.
This prospective longitudinal 15-year multifollow-up research studied whether unmedicated patients with schizophrenia can function as well as schizophrenia patients on antipsychotic medications. If so, can differences in premorbid characteristics and personality factors account for this? One hundred and forty-five patients, including 64 with schizophrenia, were evaluated on premorbid variables, assessed prospectively at index hospitalization, and then followed up 5 times over 15 years. At each follow-up, patients were compared on symptoms and global outcome. A larger percent of schizophrenia patients not on antipsychotics showed periods of recovery and better global functioning (p < .001). The longitudinal data identify a subgroup of schizophrenia patients who do not immediately relapse while off antipsychotics and experience intervals of recovery. Their more favorable outcome is associated with internal characteristics of the patients, including better premorbid developmental achievements, favorable personality and attitudinal approaches, less vulnerability, greater resilience, and favorable prognostic factors. The current longitudinal data suggest not all schizophrenia patients need to use antipsychotic medications continuously throughout their lives.


West Nile virus blood transfusion-related infection despite nucleic acid testing.
A case of West Nile virus (WNV) encephalitis associated with transfusion of blood that did not react when tested for WNV by minipool (MP) nucleic acid testing (NAT) is described. A Nebraska man developed clinical encephalitis 13 days after surgery and transfusion of 26 blood components. Antibody testing confirmed WNV infection. An investigation was initiated to determine the source of this infection. The patient's family members were interviewed to identify risk factors for WNV infection. Residual samples were retested for WNV RNA using transcription-mediated amplification (TMA) assay and two polymerase chain reaction (PCR) assays. Blood donors' follow-up serum samples were collected. All samples were tested for WNV-specific immunoglobulin M antibodies. The patient's family denied recent mosquito exposure. The 20 blood components collected after July 2003 did not react when tested for WNV in a six-member MP-NAT at the time of donation. Retrospective individual testing identified one sample as WNV-reactive by the TMA assay and one of the PCR assays. Seroconversion was demonstrated in the donor associated with this sample. WNV RNA detection by individual donation NAT demonstrates viremic blood escaping MP-NAT and supports transfusion-related WNV transmission. MP-NAT may not detect all WNV-infected blood donors, allowing WNV transmission to continue at low levels. WNV NAT assays might vary in sensitivity and pooling donations could further impact test performance. Understanding MP NAT limitations can improve strategies to maintain safety of the blood supply in the United States.


Characterization of the 2016-2017 Dermatology Standardized Letter of Recommendation.
Objective: We aimed to analyze the reformatted standard letter of recommendation (SLOR) for dermatology residents to examine trends in grading and content based on the positions of the letter writers, their backgrounds, and their relationship with the applicant, as well as to evaluate the SLOR's ability to discriminate applicants. Design: This was a retrospective characterization study of dermatology SLORs from the 2016-17 application cycle. Setting: We examined SLORs received by The Ohio State University, the University of Oklahoma, and Hofstra University Northwell Health dermatology residency programs. Participants: We included dermatology residency applicants and their letter writers from the 2016-17 application cycle. Results: A total of 141 SLORs were analyzed from 115 applicants. SLORs demonstrated grade inflation from letter writers of all backgrounds. Ratings for research potential and inquisitive nature were significantly lower than ratings for other categories. Letter writers with limited clinical and research contact graded applicants significantly lower than did writers who had more extensive contact. Word boxes were underutilized. Conclusion: The dermatology SLOR is useful in differentiating applicants, and ratings correlate with the relationships that letter writers have with their applicants. Residency programs should be aware of these findings when evaluating letters of recommendation for applicants.


A major effect QTL determined by multiple genes in epileptic EL mice.
The EL mouse strain provides a polygenic model for epilepsy. Previous mapping experiments between EL and nonepileptic ABP mice identified, and a congenic strain confirmed, a quantitative trait locus (QTL), El2, which lowered the threshold to seizures induced by gentle rhythmic tossing. To narrow the map interval further we used a nested strategy to analyze a series of recombinants derived from the congenic strain. The recombinant strains revealed a complex pattern of inheritance, with at least two independent regions of Chromosome 2 necessary for rhythmic tossing seizures and additional regions associated with unusual gender effects. Similar results obtained using a completely independent paradigm, pentylenetetrazole-induced tonic-clonic seizures, exclude the possibility that the genetic complexity was a unique property of the testing assay. Thus, although conventional QTL mapping efforts detected and appeared to confirm a trait locus with effects large enough for fine-structure mapping, subsequent dissection revealed multiple loci. Although at least one of these loci was mapped to a 1-cM interval, its individual effect is small, perhaps approaching the practical limits for further study. Our results in the EL mouse may be prophetic for similar assaults on other polygenic, composite neurological behaviors which vary among inbred strains, begging the consideration of alternative strategies toward gene identification in these models.


Melanoma cultures show different susceptibility towards E1A-, E1B-19 kDa- and fiber-modified replication-competent adenoviruses.
Replicating adenovirus (Ad) vectors with tumour tissue specificity hold great promise for treatment of cancer. We have recently constructed a conditionally replicating Ad5 AdDeltaEP-TETP inducing tumour regression in a xenograft mouse model. For further improvement of this vector, we introduced four genetic modifications and analysed the viral cytotoxicity in a large panel of melanoma cell lines and patient-derived melanoma cells. (1) The antiapoptotic gene E1B-19 kDa (Delta19 mutant) was deleted increasing the cytolytic activity in 18 of 21 melanoma cells. (2) Introduction of the E1A 122-129 deletion (Delta24 mutant), suggested to attenuate viral replication in cell cycle-arrested cells, did not abrogate this activity and increased the cytolytic activity in two of 21 melanoma cells. (3) We inserted an RGD sequence into the fiber to extend viral tropism to alphav integrin-expressing cells, and (4) swapped the fiber with the Ad35 fiber (F35) enhancing the tropism to malignant melanoma cells expressing CD46. The RGD-fiber modification strongly increased cytolysis in all of the 11 CAR-low melanoma cells. The F35 fiber-chimeric vector boosted the cytotoxicity in nine of 11 cells. Our results show that rational engineering additively enhances the cytolytic potential of Ad vectors, a prerequisite for the development of patient-customized viral therapies.


First aid and harm minimization for victims of road trauma: a population study.
This project examined the use of first aid by bystanders at road traffic crashes (RTC) and was undertaken in the context of increasing average ambulance response times to RTC throughout Australia and the potential impact of early first aid intervention on the mortality and morbidity associated with RTC. The aim of this project was to acquire knowledge about the prevalence of first aid training; the incidence of being a bystander and of providing first aid; the range of first aid skills being utilized; the motivation to intervene; and, the perceived impact of first aid training. An Internet-based survey was distributed to a potential population of 12,500 road users and a total of 773 responded. Descriptive and comparative statistical analysis of quantitative data and thematic analysis of qualitative data were completed. Seventy-seven percent (77%) of participants had first aid training at some stage in their lives; 28% held a current first aid certificate; 11% had provided first aid at RTC; 75.3% who had provided first aid were travelling in a vehicle. Having first aid training increased the likelihood of intervention and of owning a first aid kit or pocket mask. First aid training, even if it is not current, is an enabler for providing first aid at RTCs. The first aid skills most commonly used were changing posture, opening an airway, and providing comfort and reassurance. Key concerns for first aiders included a feeling of a lack of follow-up, and lack of an opportunity to debrief. Strategies to increase first aid training, to improve information and support, and to increase the knowledge of first aider's are discussed.


Chitosan: a propitious biopolymer for drug delivery.
Scientists have always been interested in the use of natural polymers for drug delivery. Chitosan, being a natural cationic polysaccharide has received a great deal of attention in the past few years. It is obtained by deacetylation of chitin and is regarded as the second most ubiquitous polymer subsequent to cellulose on earth. Unlike other natural polymers, the cationic charge possessed by chitosan is accountable for imparting interesting physical and chemical properties. Chitosan has been widely exploited for its mucoadhesive character, permeation enhancing properties and controlled release of drugs. Moreover it's non-toxic, biocompatible and biodegradable properties make it a good candidate for novel drug delivery system. This review provides an insight on various chitosan based formulations for drug delivery. Some of the current applications of chitosan in areas like ophthalmic, nasal, buccal, sublingual, gastro-retentive, pulmonary, transdermal, colon-specific and vaginal drug delivery have been discussed. In addition, active targeting of drugs to tumor cells using chitosan has been described. Lastly a brief section covering the safety aspects of chitosan has also been reviewed.


Phylogenetic and experimental characterization of an acyl-ACP thioesterase family reveals significant diversity in enzymatic specificity and activity.
Acyl-acyl carrier protein thioesterases (acyl-ACP TEs) catalyze the hydrolysis of the thioester bond that links the acyl chain to the sulfhydryl group of the phosphopantetheine prosthetic group of ACP. This reaction terminates acyl chain elongation of fatty acid biosynthesis, and in plant seeds it is the biochemical determinant of the fatty acid compositions of storage lipids. To explore acyl-ACP TE diversity and to identify novel acyl ACP-TEs, 31 acyl-ACP TEs from wide-ranging phylogenetic sources were characterized to ascertain their in vivo activities and substrate specificities. These acyl-ACP TEs were chosen by two different approaches: 1) 24 TEs were selected from public databases on the basis of phylogenetic analysis and fatty acid profile knowledge of their source organisms; and 2) seven TEs were molecularly cloned from oil palm (Elaeis guineensis), coconut (Cocos nucifera) and Cuphea viscosissima, organisms that produce medium-chain and short-chain fatty acids in their seeds. The in vivo substrate specificities of the acyl-ACP TEs were determined in E. coli. Based on their specificities, these enzymes were clustered into three classes: 1) Class I acyl-ACP TEs act primarily on 14- and 16-carbon acyl-ACP substrates; 2) Class II acyl-ACP TEs have broad substrate specificities, with major activities toward 8- and 14-carbon acyl-ACP substrates; and 3) Class III acyl-ACP TEs act predominantly on 8-carbon acyl-ACPs. Several novel acyl-ACP TEs act on short-chain and unsaturated acyl-ACP or 3-ketoacyl-ACP substrates, indicating the diversity of enzymatic specificity in this enzyme family. These acyl-ACP TEs can potentially be used to diversify the fatty acid biosynthesis pathway to produce novel fatty acids.


Hemopericardium and cardiac tamponade associated with dabigatran use.
To describe 2 cases of hemopericardium following treatment with dabigatran. A 70-year-old male with a history of dabigatran use presented with cough, fatigue, and bloody stools. The patient had a large hyperdense pericardial effusion caused by accumulation of bloody fluid, leading to hypotension and shock. Approximately 1000 mL of hemorrhagic fluid was drained from the pericardial space. A 77-year-old female was admitted for treatment of pneumonia and atrial fibrillation. Dabigatran was initiated and, after 6 doses, the patient developed abdominal pain, respiratory distress, and shock. She was diagnosed with pericardial effusion leading to cardiac tamponade. Pericardiocentesis and thoracentesis procedures removed a cumulative total of 2000 mL of bloody fluid. Dabigatran is an oral direct thrombin inhibitor approved for the reduction of stroke and systemic embolism risk in patients with nonvalvular atrial fibrillation. In December 2011, the Food and Drug Administration released a statement describing serious bleeding events associated with dabigatran use. According to the Naranjo scale, the cases presented here had probable associations between hemopericardium and dabigatran. While there is no known literature supporting this relationship, there are documented cases of warfarin-induced hemopericardium. These case reports highlight the potential for dabigatran to cause hemopericardium and cardiac tamponade. Additional reports may better elucidate (or characterize) the risk of dabigatran-induced hemopericardium and cardiac tamponade.


Frustrated binding of biopolymer crosslinkers.
Transiently crosslinked actin filament networks allow cells to combine elastic rigidity with the ability to deform viscoelastically. Theoretical models of semiflexible polymer networks predict that the crosslinker unbinding rate governs the timescale beyond which viscoelastic flow occurs. However a direct comparison between network and crosslinker dynamics is lacking. Here we measure the network's stress relaxation timescale using rheology and the lifetime of bound crosslinkers using fluorescence recovery after photobleaching (FRAP). Intriguingly, we observe that the crosslinker unbinding rate measured by FRAP is more than an order of magnitude slower than the rate measured by rheology. We rationalize this difference with a three-state model where crosslinkers are bound to either 0, 1 or 2 filaments, which allows us to extract crosslinker transition rates that are otherwise difficult to access. We find that the unbinding rate of singly bound crosslinkers is nearly two orders of magnitude slower than for doubly bound ones. We attribute the increased unbinding rate of doubly bound crosslinkers to the high stiffness of biopolymers, which frustrates crosslinker binding.


Endotoxin and cancer.
Exposure to endotoxin, a component of gram-negative bacterial cell walls, is widespread in many industrial settings and in the ambient environment. Heavy-exposure environments include livestock farms, cotton textile facilities, and saw mills. In this article, we review epidemiologic, clinical trial, and experimental studies pertinent to the hypothesis that endotoxin prevents cancer. Since the 1970s, epidemiologic studies of cotton textile and other endotoxin-exposed occupational groups have consistently demonstrated reduced lung cancer risks. Experimental animal toxicology research and some limited therapeutic trials in cancer patients offer additional support for an anticarcinogenic potential. The underlying biological mechanisms of anticarcinogenesis are not entirely understood but are thought to involve the recruitment and activation of immune cells and proinflammatory mediators (e.g., tumor necrosis factor α and interleukin-1 and -6). In view of the current state of knowledge, it would be premature to recommend endotoxin as a cancer-chemopreventive agent. However, further epidemiologic and experimental investigations that can clarify further dose-effect and exposure-timing relations could have substantial public health and basic biomedical benefits.


Fabrication of Scaffold-Based 3D Magnetic Nanowires for Domain Wall Applications.
Three-dimensional magnetic nanostructures hold great potential to revolutionize information technologies and to enable the study of novel physical phenomena. In this work, we describe a hybrid nanofabrication process combining bottom-up 3D nano-printing and top-down thin film deposition, which leads to the fabrication of complex magnetic nanostructures suitable for the study of new 3D magnetic effects. First, a non-magnetic 3D scaffold is nano-printed using Focused Electron Beam Induced Deposition; then a thin film magnetic material is thermally evaporated onto the scaffold, leading to a functional 3D magnetic nanostructure. Scaffold geometries are extended beyond recently developed single-segment geometries by introducing a dual-pitch patterning strategy. Additionally, by tilting the substrate during growth, low-angle segments can be patterned, circumventing a major limitation of this nano-printing process; this is demonstrated by the fabrication of 'staircase' nanostructures with segments parallel to the substrate. The suitability of nano-printed scaffolds to support thermally evaporated thin films is discussed, outlining the importance of including supporting pillars to prevent deformation during the evaporation process. Employing this set of methods, a set of nanostructures tailored to precisely match a dark-field magneto-optical magnetometer have been fabricated and characterized. This work demonstrates the versatility of this hybrid technique and the interesting magnetic properties of the nanostructures produced, opening a promising route for the development of new 3D devices for applications and fundamental studies.


Plane wave analysis of coherent holographic image reconstruction by phase transfer (CHIRPT).
Fluorescent imaging plays a critical role in a myriad of scientific endeavors, particularly in the biological sciences. Three-dimensional imaging of fluorescent intensity often requires serial data acquisition, that is, voxel-by-voxel collection of fluorescent light emitted throughout the specimen with a nonimaging single-element detector. While nonimaging fluorescence detection offers some measure of scattering robustness, the rate at which dynamic specimens can be imaged is severely limited. Other fluorescent imaging techniques utilize imaging detection to enhance collection rates. A notable example is light-sheet fluorescence microscopy, also known as selective-plane illumination microscopy, which illuminates a large region within the specimen and collects emitted fluorescent light at an angle either perpendicular or oblique to the illumination light sheet. Unfortunately, scattering of the emitted fluorescent light can cause blurring of the collected images in highly turbid biological media. We recently introduced an imaging technique called coherent holographic image reconstruction by phase transfer (CHIRPT) that combines light-sheet-like illumination with nonimaging fluorescent light detection. By combining the speed of light-sheet illumination with the scattering robustness of nonimaging detection, CHIRPT is poised to have a dramatic impact on biological imaging, particularly for in vivo preparations. Here we present the mathematical formalism for CHIRPT imaging under spatially coherent illumination and present experimental data that verifies the theoretical model.


metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data.
The detection of differentially methylated regions (DMRs) is a necessary prerequisite for characterizing different epigenetic states. We present a novel program, metilene, to identify DMRs within whole-genome and targeted data with unrivaled specificity and sensitivity. A binary segmentation algorithm combined with a two-dimensional statistical test allows the detection of DMRs in large methylation experiments with multiple groups of samples in minutes rather than days using off-the-shelf hardware. metilene outperforms other state-of-the-art tools for low coverage data and can estimate missing data. Hence, metilene is a versatile tool to study the effect of epigenetic modifications in differentiation/development, tumorigenesis, and systems biology on a global, genome-wide level. Whether in the framework of international consortia with dozens of samples per group, or even without biological replicates, it produces highly significant and reliable results.


Retinopathy of Type 1 Diabetes in Arab Countries: Systematic Review and Meta-Analysis.
To conduct a systematic review and meta-analysis of retinopathy prevalence in patients with type 1 diabetes (T1D) in 22 Arab countries. We systematically searched 4 different literature databases (PubMed, Science Direct, Web of Science and Embase), from the date of inception until December 2017, to collect all the information about patients with T1D who developed retinopathy complications; for statistical analysis, we used MetaXL to evaluate the pooled prevalence estimate and the subgroup prevalence estimates employing double arcsine transformation and inverse variance heterogeneity models. Our search strategy returned 475 studies, of which 39 met our inclusion criteria; of those, 16 were eligible for meta-analysis that were captured only in 15 Arab countries, through 45 years (1969-2014). The number of retinopathy patients was 396 out of 1,931 patients with T1D. The prevalence of retinopathy was 19% (95% CI 10-28%). Substantial heterogeneity was observed (Q 240.78, p < 0.0001, I2 93.77%, 95% CI 91.35-95.52%); however, no single study considerably affected the overall pooled prevalence estimate. Almost one fifth of T1D patients in 15 Arab countries have diabetic retinopathy, therefore it is important to improve the care of patients with T1D and in Arab countries to avoid the development of such a devastating complication.


Function of conserved histidine-243 in phosphatase activity of EnvZ, the sensor for porin osmoregulation in Escherichia coli.
EnvZ and OmpR are the sensor and response regulator proteins of a two-component system that controls the porin regulon of Escherichia coli in response to osmolarity. Three enzymatic activities are associated with EnvZ: autokinase, OmpR kinase, and OmpR-phosphate (OmpR-P) phosphatase. Conserved histidine-243 is critical for both autokinase and OmpR kinase activities. To investigate its involvement in OmpR-P phosphatase activity, histidine-243 was mutated to several other amino acids and the phosphatase activity of mutated EnvZ was measured both in vivo and in vitro. In agreement with previous reports, we found that certain substitutions abolished the phosphatase activity of EnvZ. However, a significant level of phosphatase activity remained when histidine-243 was replaced with certain amino acids, such as tyrosine. In addition, the phosphatase activity of a previously identified kinase- phosphatase+ mutant was not abolished by the replacement of histidine-243 with asparagine. These data indicated that although conserved histidine-243 is important for the phosphatase activity, a histidine-243-P intermediate is not required. Our data are consistent with a previous model that proposes a common transition state with histidine-243 (EnvZ) in close contact with aspartate-55 (OmpR) for both OmpR phosphorylation and dephosphorylation. Phosphotransfer occurs from histidine-243-P to aspartate-55 during phosphorylation, but water replaces the phosphorylated histidine side chain leading to hydrolysis during dephosphorylation.


Molecular cloning and characterization of an aquaporin cDNA from salivary, lacrimal, and respiratory tissues.
The Aquaporin family of water channels plays a fundamental role in transmembrane water movements in numerous plant and animal tissues. Since the molecular pathway by which water is secreted by salivary glands is unknown, a cDNA was isolated from rat submandibular gland by homology cloning. Similar to other Aquaporins, the salivary cDNA encodes a 265-residue polypeptide with six putative transmembrane domains separated by five connecting loops (A-E); the NH2- and COOH-terminal halves of the polypeptide are sequence-related, and each contains the motif Asn-Pro-Ala. A mercurial-inhibition site is present in extracellular loop E, and cytoplasmic loop D contains a cAMP-protein kinase phosphorylation consensus. In vitro translation yielded a 27-kDa polypeptide, and expression of the cRNA in Xenopus oocytes conferred a 20-fold increase in osmotic water permeability (Pf) which was reversibly inhibited by 1 mM HgCl2. Northern analysis demonstrated a 1.6-kilobase mRNA in submandibular, parotid, and sublingual salivary glands, lacrimal gland, eye, trachea, and lung. In situ hybridization revealed a strong hybridization over the corneal epithelium in eye and over the secretory lobules in salivary glands. These studies have identified a new mammalian member of the Aquaporin water channel family (gene symbol AQP5) which is implicated in the generation of saliva, tears, and pulmonary secretions.


Lack of circadian rhythm of plasma concentrations of vasoactive intestinal peptide in patients with orthotopic heart transplants.
To study the circadian pattern of plasma concentrations of vasoactive intestinal peptide (VIP) in patients with orthotopic heart transplants. Circulating VIP is known to have neural and immunological sources. 13 patients with orthotopic heart transplants were studied 12-53 months (mean 31.8 months) after operation. All were haemodynamically compensated and had no histological evidence of rejection. They were being treated with cyclosporin, azathioprine, and prednisone. Ten healthy individuals were studied as controls. Circulating VIP was assayed six times within a 24h period. Time qualified data were analysed by ANOVA and the cosinor method. Student's t test for unpaired data and Bingham's test for cosinor-derived parameters were used for statistical comparisons. Plasma concentrations of VIP were lower in the patients with orthotopic heart transplants than in the controls (p < 0.001). ANOVA and the cosinor method respectively showed a statistically significant within-day variability and circadian rhythm in the controls but not in the patients with heart transplants. The low plasma concentrations of VIP in the patients with heart transplants could be the result of the lack of contribution by the cardiac VIPergic fibres, a reduction of VIP release by the pharmacologically suppressed immune system, the inhibitory effects of cyclosporin on neural function and humoral secretions, and the effects of negative feedback on VIP release of high concentrations of atrial natriuretic peptide. The lack of the circadian rhythm suggests a structural disorder, which should be further investigated.


Hepatitis B Virus X Protein Stabilizes Cyclin D1 and Increases Cyclin D1 Nuclear Accumulation through ERK-Mediated Inactivation of GSK-3β.
The Hepatitis B virus X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). It has been suggested that the transcriptional activation of cyclin D1 by HBx is implicated in the development of HCC. However, numerous studies have shown that overexpression of cyclin D1 alone is not sufficient to drive oncogenic transformation. Herein, we investigated whether HBx can stabilize cyclin D1 and induce cyclin D1 protein nuclear accumulation, and thereby accelerate hepatocarcinogenesis. The effects of HBx on cyclin D1 stabilization were assessed in cell-based transfection, Western blot, immunoprecipitation, immunocytofluorescence staining, and flow-cytometric assays. The results demonstrated that ectopic expression of HBx in HCC cells could extend the half-life of cyclin D1 protein from 40-60 minutes to 80-110 minutes. HBx stabilized cyclin D1 primarily in the S phase of the cell cycle, in a manner dependent on the inactivation of GSK-3β, which was mediated by ERK activation. HBx also prompted the nuclear accumulation of cyclin D1, and cotransfection of the constitutively active mutant of GSK-3β along with HBx could reverse the nuclear accumulation and subsequent cell proliferation induced by HBx. Further, a positive correlation between HBx and nuclear cyclin D1 level was established in HCC specimens detected by an immunohistochemical assay. Taken together, our results indicated that HBx could stabilize and increase cyclin D1 nuclear accumulation through ERK-mediated inactivation of GSK-3β. This HBx-induced cyclin D1 upregulation might play an important role in HCC development and progression.


Intestinal inflammation targets cancer-inducing activity of the microbiota.
Inflammation alters host physiology to promote cancer, as seen in colitis-associated colorectal cancer (CRC). Here, we identify the intestinal microbiota as a target of inflammation that affects the progression of CRC. High-throughput sequencing revealed that inflammation modifies gut microbial composition in colitis-susceptible interleukin-10-deficient (Il10(-/-)) mice. Monocolonization with the commensal Escherichia coli NC101 promoted invasive carcinoma in azoxymethane (AOM)-treated Il10(-/-) mice. Deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 decreased tumor multiplicity and invasion in AOM/Il10(-/-) mice, without altering intestinal inflammation. Mucosa-associated pks(+) E. coli were found in a significantly high percentage of inflammatory bowel disease and CRC patients. This suggests that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities.


Estimates of mass and angular momentum in the oort cloud.
Estimates can be made of unseen mass (in the form of cometary nuclei) at the heliocentric distances between 3 x 10(3) and 2 x 10(4) astronomical units(AU) under the assumptions (i) that the Oort cloud is a rarefied halo surrounding the core (dense, inner cometary cloud) and (ii) that the mass and albedo of comet Halley is typical for comets both in the core and the Oort cloud populations. The mass appears to be approximately 0.03 solar masses, with angular momentum of the order of 10(52) to 10(53) g-cm(2)/s. This mass is of the order of the total mass of the planetary system before the loss of volatiles. This leads to an estimate of a mass M(o) approximately 100 M( plus sign in circle) (where M( plus sign in circle) is the mass of Earth) concentrated in the Oort cloud (r > 2 x 10(4) AU) with an angular momentum that may exceed the present angular momentum of the whole planetary system by one order of magnitude. The present angular momentum of the Oort cloud appears to be of the same order as the total angular momentum of the planetary system before the loss of volatiles.


Evaluation and treatment of lower urinary tract symptoms in older men.
The 6th International Consultation on New Developments in Prostate Cancer and Prostate Diseases met from June 24-28, 2005 in Paris, France to review new developments in benign prostatic disease. A series of committees were asked to produce recommendations on the evaluation and treatment of lower urinary tract symptoms in older men. Each committee was asked to base recommendations on a thorough assessment of the available literature according to the International Consultation on Incontinence level of evidence and grading system adapted from the Oxford system. The Consultation endorsed the appropriate use of the current terminology lower urinary tract symptoms/benign prostatic hyperplasia/benign prostate enlargement and benign prostatic obstruction, and recommended that terms such as "clinical benign prostatic hyperplasia" or "the benign prostatic hyperplasia patient" be abandoned, and asked the authorities to endorse the new nomenclature. The diagnostic evaluation describes recommended and optional tests, and in general places the focus on the impact (bother) of lower urinary tract symptoms on the individual patient when determining investigation and treatment. The importance of symptom assessment, impact on quality of life, physical examination and urinalysis is emphasized. The frequency volume chart is recommended when nocturia is a bothersome symptom to exclude nocturnal polyuria. The recommendations are summarized in 2 algorithms, 1 for basic management and 1 for specialized management of persistent bothersome lower urinary tract symptoms. The use of urodynamics and transrectal ultrasound should be limited to situations in which the results are likely to benefit the patient such as in selection for surgery. It is emphasized that imaging and endoscopy of the urinary tract have specific indications such as dipstick hematuria. Treatment should be holistic, and may include conservative measures, lifestyle interventions and behavioral modifications as well as medication and surgery. Only treatments with a strong evidence base for their clinical effectiveness should be used.


Vaccinia virus: a model system for actin-membrane interactions.
Our understanding of the interactions between the actin cytoskeleton and cellular membranes at the molecular level is rudimentary. One system that offers an opportunity to examine these interactions in greater detail is provided by vaccinia virus, which induces the nucleation of actin tails from the outer membrane surrounding the virion. To further understand the mechanism of their formation and how they generate motility, we have examined the structure of these actin tails in detail. Actin filaments in vaccinia tails are organized so they splay out at up to 45 degrees from the centre of the tail and are up to 0.74 micron in length, which is considerably longer than those reported in the Listeria system. Actin filaments show unidirectional polarity with their barbed filament ends pointing towards the surface of the virus particle. Rhodamine-actin incorporation experiments show that the first stage of tail assembly involves a polarized recruitment of G-actin, and not pre-formed actin filaments, to the membrane surrounding the virion. Incorporation of actin into the tail only occurs by nucleation from the viral surface, suggesting filament ends in the tail are blocked against further actin addition. As virus particles fuse with the plasma membrane during the extention of projections, actin nucleation sites previously in the viral membrane become localized to the plasma membrane, where they are able to nucleate actin polymerization in a manner analogous to the leading edge of motile cells.


Novel housing designs for nanofiltration and ultrafiltration gravity-driven recycled membrane-based systems.
Ultra-low pressure gravity-driven membrane (GDM) systems have the potential to be significantly less costly and complex than conventional membranes for water treatment applications. To build upon this inherent advantage, this study assesses the reuse of recycled membranes in GDM systems for producing drinking water. Two reverse osmosis spiral-wound modules were recycled into nanofiltration (NF)-like and ultrafiltration (UF)-like membranes via controlled exposure to free chlorine. To operate the recycled membranes, two housing devices, based on a simple fitting and an advanced end-caps design, were developed. The recycled membrane systems were tested under a range of conditions (submerged vs. external system configuration and continuous vs. intermittent filtration mode). Synthetic river water feed solutions were used in the tests where performance, fouling, and clogging were measured. NF-like recycled membranes resulted in poor salt rejection and low permeability (~1.7 L m-2 h-1 bar-1), but also in high rejection (>81%) of dissolved organic carbon. UF-like recycled membranes maintained their capacity to reject biopolymers (BP) (>74%) and featured up to 18-fold higher permeate rate than NF-like recycled membranes. The optimized operating conditions were found when the recycled membranes were housed in the end-caps device and operated intermittently (relaxation time plus forward flushing). Flushing reduced the fouling accumulation inside the membrane (only 12% and 40% of BP accumulation was observed in the NF-like and UF-like, respectively). However, the end-caps-based device was estimated to be more expensive during the economic analysis. To address this techno-economic trade-off, a decision-making tree was developed to select the appropriate configuration based upon the implementation context. Overall, this study concludes that these designs can serve as robust, low-cost (water production cost <1 USD ct. yr. L-1), and light-weight GDM alternatives. This study is beneficial for developing compact GDM systems based on recycled spiral-wound membranes for both rural areas and emergency response.


p54(nrb)/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A.
Dysregulation of lipid metabolism is common in breast cancer. However, the underlying mechanisms remain elusive and the contribution of aberrant lipid metabolism to the malignant phenotypes of breast cancer is poorly understood. Here, we show that the nuclear protein p54(nrb)/Nono is highly expressed in breast cancer tissues as compared with the adjacent normal tissues in human patients. To determine the functions of p54(nrb) in breast cancer, we performed a biochemical screen and identified SREBP-1a, a master activator for genes involved in lipid biosynthesis, as a novel interacting protein of p54(nrb). In human breast cancer tissues, the levels of p54(nrb) and SREBP-1a proteins were positively correlated with each other. Our biochemical analyses showed that the conserved Y267 residue of p54(nrb) was required for its binding to the nuclear form of SREBP-1a. Interestingly, p54(nrb) binding to nuclear SREBP-1a caused an increase of nuclear SREBP-1a protein stability. As a result, p54(nrb) stimulates SREBP-1-meidated transcription of lipogenic genes and lipid production in breast cancer cells. Moreover, both p54(nrb) and SREBP-1a were required for breast cancer cell growth in vitro, and p54(nrb) binding to nuclear SREBP-1a was also critical for breast tumor development in vivo. Together, we conclude that p54(nrb) is a novel regulator of SREBP-1a in the nucleus, and our data suggest that p54(nrb) regulation of SREBP-1a supports the increased cellular demand of lipids for breast cancer growth. Thus, the SREBP pathway may represent a novel target for treating breast cancer.


Tequila, a neurotrypsin ortholog, regulates long-term memory formation in Drosophila.
Mutations in the human neurotrypsin gene are associated with autosomal recessive mental retardation. To further understand the pathophysiological consequences of the lack of this serine protease, we studied Tequila (Teq), the Drosophila neurotrypsin ortholog, using associative memory as a behavioral readout. We found that teq inactivation resulted in a long-term memory (LTM)-specific defect. After LTM conditioning of wild-type flies, teq expression transiently increased in the mushroom bodies. Moreover, specific inhibition of teq expression in adult mushroom bodies resulted in a reversible LTM defect. Hence, the Teq pathway is essential for information processing in Drosophila.