Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study.
Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7-17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15-50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22-163.90 and 1.60-83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01-90.99 and 1.00-524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84-33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08-0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according to risk-stratification is necessary to improve overall outcomes.


Reproductive health services and the law and ethics of conscientious objection.
Reproductive health services address contraception, sterilization and abortion, and new technologies such as gamete selection and manipulation, in vitro fertilization and surrogate motherhood. Artificial fertility control and medically assisted reproduction are opposed by conservative religions and philosophies, whose adherents may object to participation. Physicians' conscientious objection to non-lifesaving interventions in pregnancy have long been accepted. Nurses' claims are less recognized, allowing nonparticipation in abortions but not refusal of patient preparation and aftercare. Objections of others in health-related activities, such as serving meals to abortion patients and typing abortion referral letters, have been disallowed. Pharmacists may claim refusal rights over fulfilling prescriptions for emergency (post-coital) contraceptives and drugs for medical (i.e. non-surgical) abortion. This paper addresses limits to conscientious objection to participation in reproductive health services, and conditions to which rights of objection may be subject. Individuals have human rights to freedom of religious conscience, but institutions, as artificial legal persons, may not claim this right.


Modification of estrone at the 6, 16, and 17 positions: novel potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.
The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyze the interconversion between the oxidized and reduced forms of androgens and estrogens at the 17 position. The 17beta-HSD type 1 enzyme (17beta-HSD1) catalyzes the reduction of estrone to estradiol and is expressed in malignant breast cells. Inhibitors of this enzyme thus have potential as treatments for hormone dependent breast cancer. Here we report the syntheses and biological evaluation of novel inhibitors based on the estrone or estradiol template. These have been investigated by modification at the 6, 16 or 17 positions or combinations of these in order to gain information about structure-activity relationships by probing different areas in the enzyme active site. Activity data have been incorporated into a QSAR with predictive power, and the X-ray crystal structures of compounds 15 and 16c have been determined. Compound 15 has an IC50 of 320 nM for 17beta-HSD1 and is selective for 17beta-HSD1 over 17beta-HSD2. Three libraries of amides are also reported that led to the identification of inhibitors 19e and 20a, which have IC50 values of 510 and 380 nM respectively, and 20 h which, having an IC50 value of 37 nM, is the most potent inhibitor of 17beta-HSD1 reported to date. These amides are also selective for 17beta-HSD1 over 17beta-HSD2.


Comparison of aortic dissection in Chinese patients with and without Marfan syndrome.
Aortic dissection is a life-threatening cardiovascular disease with high mortality. Little is known about comparisons of the clinical characteristics or the factors that influence the long-term prognosis of Chinese patients with aortic dissection with and without Marfan syndrome (MFS). The authors studied the data of 246 patients with aortic dissection. The patients were hospitalised for aortic abnormalities from 2004 to 2008 in Fuwai Hospital. Medical charts were reviewed to obtain clinical data using a standardised data collection sheet. Of the 246 patients with acute aortic dissection, 56 had MFS. Compared with the non-MFS patients, those with MFS were considerably younger (mean ± SD age 35.27 ± 11.11 vs 54.11 ± 11.96 years, p<0.001) and had pre-existing hypertension much less commonly (5.4% vs 80.0%, p<0.001). The patients with MFS presented with a wider ascending aorta diameter (63.60 ± 9.00 vs 38.55 ± 9.44 mm, p<0.001) and a lower body mass index (20.14 ± 2.00 vs 25.62 ± 3.41, p<0.001) than the non-MFS patients. Overall, 91.1% of the MFS patients underwent surgical treatment, whereas 55.78% of the non-MFS patients accepted medical treatment. However, mortality in the two groups did not differ significantly (6 vs 17, p=0.527). Multivariate analysis showed that the aortic diameter (OR=1.072) was a risk factor and surgical treatment (OR=0.006) was a protective factor for the survival of MFS patients with aortic dissection. With increased diastolic blood pressure, mortality decreased in non-MFS patients with aortic dissection (OR=0.905). These clinical results could be useful for rapid assessment of the treatment and prognosis of patients with aortic dissection.


Transforming Clinical Documentation in EHRs for 2020: Recommendations from University of Minnesota's Big Data Conference Working Group.
In 2014, a group of diverse informatics leaders from practice, academia, and the software industry formed to address how best to transform electronic documentation to provide knowledge at the point of care and to deliver value to front line nurses and nurse leaders. This presentation reports the recommendations from this Working Group geared towards a 2020 framework. The recommendations propose redesign to optimize nurses' documentation efficiency while contributing to knowledge generation and attaining a balance that ensures the capture of nursing's impact on safety, quality, yet minimizes "death by data entry."


Influences of APOA5 variants on plasma triglyceride levels in Uyghur population.
Single nucleotide polymorphisms (SNPs) in apolipoprotein A5 (APOA5) gene are associated with triglyceride (TG) levels. However, the minor allele frequencies and linkage disequilibriums (LDs) of the SNPs in addition to their effects on TG levels vary greatly between Caucasians and East Asians. The distributions of the SNPs/haplotypes and their associations with TG levels in Uyghur population, an admixture population of Caucasians and East Asians, have not been reported to date. Here, we performed a cross-sectional study to address these. Genotyping of four SNPs in APOA5 (rs662799, rs3135506, rs2075291, and rs2266788) was performed in 1174 unrelated Uyghur subjects. SNP/haplotype and TG association analyses were conducted. The frequencies of the SNPs in Uyghurs were in between those in Caucasians and East Asians. The LD between rs662799 and rs2266788 in Uyghurs was stronger than that in East Asians but weaker than that in Caucasians, and the four SNPs resulted in four haplotypes (TGGT, CGGC, TCGT, and CGTT arranged in the order of rs662799, rs3135506, rs2075291, and rs2266788) representing 99.2% of the population. All the four SNPs were significantly associated with TG levels. Compared with non-carriers, carriers of rs662799-C, rs3135506-C, rs2075291-T, and rs2266788-C alleles had 16.0%, 15.1%, 17.1%, and 12.4% higher TG levels, respectively. When haplotype TGGT was defined as the reference, the haplotypes CGGC, TCGT, and CGTT resulted in 16.1%, 19.0%, and 19.8% higher TG levels, respectively. The proportions of variance in TG explained by APOA5 locus were 2.5%, 0.3%, 0.4%, and 1.9% for single SNP rs662799, rs3135506, rs2075291, and rs2266788, respectively, and 3.0% for the haplotypes constructed by them. The association profiles between the SNPs and haplotypes at APOA5 locus and TG levels in this admixture population differed from those in Caucasians and East Asians. The functions of these SNPs and haplotypes need to be elucidated comprehensively.


Formulation study and evaluation of matrix and three-layer tablet sustained drug delivery systems based on Carbopols with isosorbite mononitrate.
The purpose of this research was to develop and evaluate different preparations of sustained delivery systems, using Carbopols as carriers, in the form of matrices and three-layer tablets with isosorbite mononitrate. Matrix tablets were prepared by direct compression whereas three-layer tablets were prepared by compressing polymer barrier layers on both sides of the core containing the drug. The findings of the study indicated that all systems demonstrated sustained release. The properties of the polymer used and the structure of each formulation appear to considerably affect drug release and its release rate. The three-layer formulations exhibit lower drug release compared to the matrices. This was due to the fact that the barrier-layers hindered the penetration of liquid into the core and modified drug dissolution and release. The geometrical characteristics/structure of the tablets as well as the weight/thickness of the barriers-layers considerably influence the rate of drug release and the release mechanisms. Kinetic analysis of the data indicated that drug release from matrices was mainly attributed to Fickian diffusion while three-layer tablets exhibited either anomalous diffusion or erosion/relaxation mechanisms. The advantage of Carbopol formulations is that a range of release profiles can easily be obtained through variations in tablet structure and thus Carbopols are appropriate carriers of oral sustained drug delivery systems for soluble drugs such as the isosorbite mononitrate.


Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up.
Seventy detoxified heroin-addicted patients were randomly assigned to one of two groups receiving ketamine psychotherapy (KPT) involving two different doses of ketamine. The patients of the experimental group received existentially oriented psychotherapy in combination with a hallucinogenic ("psychedelic") dose of ketamine (2.0 mg/kg im). The patients of the control group received the same psychotherapy combined with a low, non-hallucinogenic (non-psychedelic), dose of ketamine (0.2 mg/kg im). Both the psychotherapist and patient were blind to the dose of ketamine. The therapy included preparation for the ketamine session, the ketamine session itself, and the post session psychotherapy aimed to help patients to integrate insights from their ketamine session into everyday life. The results of this double blind randomized clinical trial of KPT for heroin addiction showed that high dose (2.0 mg/kg) KPT elicits a full psychedelic experience in heroin addicts as assessed quantitatively by the Hallucinogen Rating Scale. On the other hand, low dose KPT (0.2 mg/kg) elicits "sub-psychedelic" experiences and functions as ketamine-facilitated guided imagery. High dose KPT produced a significantly greater rate of abstinence in heroin addicts within the first two years of follow-up, a greater and longer-lasting reduction in craving for heroin, as well as greater positive change in nonverbal unconscious emotional attitudes than did low dose KPT.


Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy.
Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy. This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus. Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss. Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.


A Multicenter Consortium to Define the Epidemiology and Outcomes of Pediatric Solid Organ Transplant Recipients With Inpatient Respiratory Virus Infection.
Respiratory virus infection (RVI) in pediatric solid organ transplant (SOT) recipients poses a significant risk; however, the epidemiology and effects of an RVI after pediatric SOT in the era of current molecular diagnostic assays are unclear. A retrospective observational cohort of pediatric SOT recipients (January 2010 to June 2013) was assembled from 9 US pediatric transplant centers. Charts were reviewed for RVI events associated with hospitalization within 1 year after the transplant. An RVI diagnosis required respiratory symptoms and detection of a virus (ie, human rhinovirus/enterovirus, human metapneumovirus, influenza virus, parainfluenza virus, coronavirus, and/or respiratory syncytial virus). The incidence of RVI was calculated, and the association of baseline SOT factors with subsequent pulmonary complications and death was assessed. Of 1096 pediatric SOT recipients (448 liver, 289 kidney, 251 heart, 66 lung, 42 intestine/multivisceral), 159 (14.5%) developed RVI associated with hospitalization within 12 months after their transplant. RVI occurred at the highest rates in intestine/abdominal multivisceral (38%), thoracic (heart/lung) (18.6%), and liver (15.6%) transplant recipients and a lower rate in kidney (5.5%) transplant recipients. RVI was associated with younger median age at transplant (1.72 vs 7.89 years; P < .001) and among liver or kidney transplant recipients with the receipt of a deceased-donor graft compared to a living donor (P = .01). The all-cause and attributable case-fatality rates within 3 months of RVI onset were 4% and 0%, respectively. Multivariable logistic regression models revealed that age was independently associated with increased risk for a pulmonary complication (odds ratio, 1.24 [95% confidence interval, 1.02-1.51]) and that receipt of an intestine/multivisceral transplant was associated with increased risk of all-cause death (odds ratio, 24.54 [95% confidence interval, 1.69-327.96]). In this study, hospital-associated RVI was common in the first year after pediatric SOT and associated with younger age at transplant. All-cause death after RVI was rare, and no definitive attributable death occurred.


Playfulness in Children with Limited Motor Abilities When Using a Robot.
Children with limited gross motor and manual abilities have fewer opportunities to engage in free play. We investigated the effect of a robotic intervention on the playfulness of children with cerebral palsy (CP). We used a partially nonconcurrent multiple baseline design with four children and their mothers. Children were classified in level IV or V on the Gross Motor Function and Manual Ability Classification Systems. The intervention was the availability of an adapted Lego robot during a 15-min free play session between the child and mother. There were two sessions per week for about 14 weeks. Playfulness was measured using the Test of Playfulness. Statistical comparisons using the 2 SD band and X-moving range chart methods revealed that all the children's levels of playfulness increased significantly while they played with the robot. Comparison of baseline and follow-up phase indicated that three children had retention of improved level of playfulness. Play with adapted Lego robots increased the level of playfulness in all four children during free play with their mothers. The findings have implications for providing children with limitations in motor abilities opportunities for free play with family and friends.


Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosis.
Recently, the Intracellular pathogen resistance 1 (Ipr1) gene was shown to control susceptibility to Mycobacterium tuberculosis in mice. We examined whether common sequence variants of its human orthologue, the SP110 gene, are associated with susceptibility to tuberculosis in a human population. We resequenced SP110 exons in 96 individuals and identified new polymorphisms. Then, we combined our sequence and HapMap data for 83 distinct polymorphisms and selected tags that capture information for all common variants in the 100 kb region around SP110. We genotyped 29 single nucleotide polymorphisms including seven amino-acid changing variants in 1,912 HIV-negative culture-confirmed adult pulmonary tuberculosis patients and 2,104 adult healthy controls from Russia and found no evidence of association. Our results indicate that common polymorphisms of the SP110 gene have no major effect on susceptibility to tuberculosis in this population.


Lentiviral-mediated RNA interference.
RNA interference (RNAi) is a form of posttranscriptional gene silencing mediated by short double-stranded RNA, known as small interfering RNA (siRNA). These siRNAs are capable of binding to a specific mRNA sequence and causing its degradation. The recent demonstration of a plasmid vector that directs siRNA synthesis in mammalian cells prompted us to examine the ability of lentiviral vectors to encode siRNA as a means of providing long-term gene silencing in mammalian cells. The RNA-polymerase III dependent promoter (H1-RNA promoter) was inserted in the lentiviral genome to drive the expression of a small hairpin RNA (shRNA) against enhanced green fluorescent protein (EGFP). This construct successfully silenced EGFP expression in two stable cell lines expressing this protein, as analyzed by fluorescence microscopy, flow cytometry, and Western blotting. The silencing, which is dose dependent, occurs as early as 72 hr postinfection and persists for at least 25 days postinfection. The ability of lentiviruses encoding siRNA to silence genes specifically makes it possible to take full advantage of the possibilities offered by the lentiviral vector and provides a powerful tool for gene therapy and gene function studies.


Genomic imprinting: CTCF protects the boundaries.
The DNA-binding protein CTCF, which acts as a chromatin 'insulator', regulates imprinting of the mammalian Igf2 and H19 genes in a methylation-sensitive manner. It has now been shown that CTCF is also required for protection against de novo methylation of the differentially methylated domain of H19 in the female germline.


Opportunities in theoretical and computational polymeric materials and soft matter.
Soft materials are abundant in nature and ubiquitous in living systems. Elucidating their multi-faceted properties and underlying mechanisms is not only theoretically challenging and important in its own right, but also serves as the foundation for new materials and applications that will have wide-ranging impact on technology and the national economy. Recent initiatives in computation and data-driven materials discovery, such as the Materials Genome Initiative and the National Science Foundation Designing Materials to Revolutionize and Engineer our Future (NSF-DMREF) program, recognize and highlight the many future opportunities in the field. Building upon similar past efforts, a workshop was held at the University of California, Santa Barbara in October 2013 to specifically identify the central challenges and opportunities in theoretical and computational studies of polymeric as well as non-polymeric soft materials. This article presents a summary of the main findings of the workshop.


[Study of death with secondary diagnosis of malnutrition in a third level hospital].
Malnutrition is a major public health problems, according to WHO, is the leading cause of death, when it affects the group of hospitalized patients, making denominating separate entity "hospital malnutrition". The overall objective is to quantify the main diagnoses frequently high, causing exitus, with secondary diagnosis of malnutrition. This is a descriptive study, which included all hospital discharges in 2011 and first half of 2012, which have been exitus and whose secondary diagnosis of malnutrition, with the total of 33. We performed a descriptive analysis, effected the Mann-Whitney nonparametric test (p < 0.05). The most frequent main diagnoses among 33 analyzed are high sepsis (12.1%), liver metastases (9.1%), pneumonia (6.1%), acute respiratory failure (6.1%) and renal acute renal (6.1%). Although the most frequent primary diagnosis of sepsis, by grouping the diagnoses, the most frequent DRG is respiratory disease, so it has to make comprehensive and quality coding to adjust the relative weight of the same reality. It is essential to specify the source of clinical information used for coding, the degree of malnutrition, for greater specificity in the data.


Biological characterization of human fibroblast-derived mitogenic factors for human melanocytes.
To clarify the paracrine linkage between human fibroblasts and melanocytes in cutaneous pigmentation, we studied the effects of human fibroblast-derived factors on the proliferation of human melanocytes. In medium conditioned for 4 days with human fibroblast culture, factors were produced that markedly stimulated DNA synthesis of human melanocytes. The stimulatory effect was higher in medium conditioned with fibroblasts from aged skin than in medium conditioned with fibroblasts from young skin, and was interrupted by inhibitors of tyrosine kinase, such as tyrphostin, genistein and herbimycin, but not by inhibitors of protein kinases C and A, such as H-7 and phloretin. The conditioned medium was also capable of activating mitogen-activated protein kinase of human melanocytes, with old fibroblasts being more effective than young ones. Analysis of factors released into the conditioned medium revealed that levels of hepatocyte growth factor (HGF) and stem cell factor (SCF) were increased in old-fibroblast-conditioned medium compared with young-fibroblast-conditioned medium. In contrast, levels of basic fibroblast growth factor (bFGF) were similar in both media. When the conditioned medium was treated with HGF antibody with or without SCF antibody, the increase in DNA synthesis by human melanocytes was decreased to 20% of the elevated level, whereas antibodies to bFGF had no effect. Analysis of the medium conditioned for 4 days after cytokine application demonstrated that, of the cytokines tested, interleukin 1alpha and tumour necrosis factor alpha are highly effective in stimulating HGF secretion by old fibroblasts. HGF and SCF, but not bFGF, were markedly increased in culture medium in the presence of IL-1alpha, and this stimulatory effect was confined to young human fibroblasts. These findings suggest that SCF and HGF derived from human fibroblasts may play a part in regulating cutaneous pigmentation during inflammation and aging.


Sodium butyrate induces growth inhibition and apoptosis in human prostate cancer DU145 cells by up-regulation of the expression of annexin A1.
Sodium butyrate, a histone deacetylase inhibitor, has emerged as a promising anticancer drug for multiple cancers. Recent studies have indicated that sodium butyrate could inhibit the progression of prostate cancer; however, the exact mechanism is still unclear. The aim of this study was to investigate the mechanism of sodium butyrate action in prostate cancer DU145 cells. The inhibitory effects of NaB on cell growth were detected by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrrazolium bromide assay. Cell apoptosis was determined by flow cytometric analysis of DU145 cells stained with annexin V and PI. Hoechst 33258 and fluorescence microscopes were used to observe the nuclear morphology of DU145 cells after treatment with NaB. ANXA1 knockdown cells were established through transfection with ANXA1 siRNA. ANXA1 mRNA levels were measured by qRT-PCR. Bcl-2, Bax, ANXA1, ERK1/2 and pERK1/2 were detected by western blot. NaB significantly inhibited the growth and induction apoptosis of DU145 and PC3 cells in a dose-dependent manner. Expression of the anti-apoptosis gene Bcl-xl and Bcl-2 in DU145 cells are decreased and expression of the pro-apoptosis gene Bax and Bak increased after NaB treatment. Further studies have demonstrated that NaB up-regulated the expression of ANXA1 and that the tumor inhibition action of NaB was reduced markedly through knockdown of the ANXA1 gene in DU145 cells. Moreover, the siANXA1 cells showed that cell proliferation increased and cell apoptosis was induced by the inactivation of extracellular regulated kinase (ERK). Our results support a significant correlation between NaB functions and ANXA1 expression in prostate cancer, and pave the way for further studying the molecular mechanism of NaB actions in cancers.


Sulforaphane-enriched extracts from glucoraphanin-rich broccoli exert antimicrobial activity against gut pathogens in vitro and innovative cooking methods increase in vivo intestinal delivery of sulforaphane.
Studies on broccoli (Brassica oleracea var. italica) indicate beneficial effects against a range of chronic diseases, commonly attributed to their bioactive phytochemicals. Sulforaphane, the bioactive form of glucoraphanin, is formed by the action of the indigenous enzyme myrosinase. This study explored the role that digestion and cooking practices play in bioactivity and bioavailability, especially the rarely considered dose delivered to the colon. The antimicrobial activity of sulforaphane extracts from raw, cooked broccoli and cooked broccoli plus mustard seeds (as a source myrosinase) was assessed. The persistence of broccoli phytochemicals in the upper gastrointestinal tract was analysed in the ileal fluid of 11 ileostomates fed, in a cross-over design, broccoli soup prepared with and without mustard seeds. The raw broccoli had no antimicrobial activity, except against Bacillus cereus, but cooked broccoli (with and without mustard seeds) showed considerable antimicrobial activity against various tested pathogens. The recovery of sulforaphane in ileal fluids post soup consumption was < 1% but the addition of mustard seeds increased colon-available sulforaphane sixfold. However, when sulforaphane was extracted from the ileal fluid with the highest sulforaphane content and tested against Escherichia coli K12, no inhibitory effects were observed. Analysis of glucosinolates composition in ileal fluids revealed noticeable inter-individual differences, with six "responding" participants showing increases in glucosinolates after broccoli soup consumption. Sulforaphane-rich broccoli extracts caused potent antimicrobial effects in vitro, and the consumption of sulforaphane-enriched broccoli soup may inhibit bacterial growth in the stomach and upper small intestine, but not in the terminal ileum or the colon.


Can influenza epidemics be prevented by voluntary vaccination?
Previous modeling studies have identified the vaccination coverage level necessary for preventing influenza epidemics, but have not shown whether this critical coverage can be reached. Here we use computational modeling to determine, for the first time, whether the critical coverage for influenza can be achieved by voluntary vaccination. We construct a novel individual-level model of human cognition and behavior; individuals are characterized by two biological attributes (memory and adaptability) that they use when making vaccination decisions. We couple this model with a population-level model of influenza that includes vaccination dynamics. The coupled models allow individual-level decisions to influence influenza epidemiology and, conversely, influenza epidemiology to influence individual-level decisions. By including the effects of adaptive decision-making within an epidemic model, we can reproduce two essential characteristics of influenza epidemiology: annual variation in epidemic severity and sporadic occurrence of severe epidemics. We suggest that individual-level adaptive decision-making may be an important (previously overlooked) causal factor in driving influenza epidemiology. We find that severe epidemics cannot be prevented unless vaccination programs offer incentives. Frequency of severe epidemics could be reduced if programs provide, as an incentive to be vaccinated, several years of free vaccines to individuals who pay for one year of vaccination. Magnitude of epidemic amelioration will be determined by the number of years of free vaccination, an individuals' adaptability in decision-making, and their memory. This type of incentive program could control epidemics if individuals are very adaptable and have long-term memories. However, incentive-based programs that provide free vaccination for families could increase the frequency of severe epidemics. We conclude that incentive-based vaccination programs are necessary to control influenza, but some may be detrimental. Surprisingly, we find that individuals' memories and flexibility in adaptive decision-making can be extremely important factors in determining the success of influenza vaccination programs. Finally, we discuss the implication of our results for controlling pandemics.


Glycoluril derived cucurbituril analogues and the emergence of the most recent example: tiarauril.
Cucurbituril analogues can bear some of the chemical and physical characteristics of their parental origin and are derived wholly or in part from glycolurils (including homologues). The development of analogues is discussed from their earliest origins to the most recent developments, which includes deviations in binding properties and the inclusion of alternative molecular units in conjunction with glycolurils. Examples of alternative guest binding are discussed and compared to the behaviour of conventional cucurbituril.


Prostate cancer with perineural spread and dural extension causing bilateral lumbosacral plexopathy: case report.
Perineural tumor spread in prostate cancer is emerging as a mechanism to explain select cases of neurological dysfunction and as a cause of morbidity and tumor recurrence. Perineural spread has been shown to extend from the prostate bed to the lumbosacral plexus and then distally to the sciatic nerve or proximally to the sacral and lumbar nerves and even intradurally. The authors present a case of a bilateral neoplastic lumbosacral plexopathy that can be explained anatomically as an extension of the same process: from one lumbosacral plexus to the contralateral one utilizing the dural sac as a bridge between the opposite sacral nerve roots. Their theory is supported by sequential progression of symptoms and findings on clinical examinations as well as high-resolution imaging (MRI and PET/CT scans). The neoplastic nature of the process was confirmed by a sciatic nerve fascicular biopsy. The authors believe that transmedian dural spread allows continuity of a neoplastic process from one side of the body to the other.


Assessing the effectiveness of intuitive eating for weight loss - pilot study.
The obesity epidemic is widely recognized as a major public health issue resulting in chronic diseases. Calorie restriction (CR) is frequently used for most weight loss programs. The intuitive eating (IE) approach uses an individual's response to internal cues of hunger, satiety, and appetite and replaces CR. The study was a randomized controlled trial with two groups that assessed the anthropometric measurements of obese adults using CR and IE to achieve weight loss. The participants were sedentary obese individuals with no history of chronic diseases. They engaged in physical activity three times per week for 30 minutes and recorded their daily food intake in a food diary. Instructions were given for the CR and IE at the start and midpoint of the study. The duration of the study was 6 weeks. Weight and waist circumference were measured and body mass index calculated. total weight loss was significantly (p=0.03) lower in the CR group than in the IE group. The CR group lost weight consistently throughout the study, whereas weight loss in the IE group was significantly less at the endpoint than at the midpoint. Calorie restriction is a superior approach to weight management than IE.


Monitoring immediate-early gene expression through firefly luciferase imaging of HRS/J hairless mice.
Gene promoters fused to the firefly luciferase gene (luc) are useful for examining gene regulation in live transgenic mice and they provide unique views of functioning organs. The dynamics of gene expression in cells and tissues expressing luciferase can be observed by imaging this enzyme's bioluminescent oxidation of luciferin. Neural pathways involved in specific behaviors have been identified by localizing expression of immediate-early genes such as c-fos. A transgenic mouse line with luc controlled by the human c-fos promoter (fos::luc) has enabled gene expression imaging in brain slice cultures. To optimize imaging of immediate-early gene expression throughout intact mice, the present study examined fos::luc mice and a second transgenic mouse containing luc controlled by the human cytomegalovirus immediate-early gene 1 promoter and enhancer (CMV::luc). Because skin pigments and hair can significantly scatter light from underlying structures, the two transgenic lines were crossed with a hairless albino mouse (HRS/J) to explore which deep structures could be imaged. Furthermore, live anesthetized mice were compared with overdosed mice. Bioluminescence imaging of anesthetized mice over several weeks corresponded with expression patterns in mice imaged rapidly after a lethal overdose. Both fos::luc and CMV::luc mice showed quantifiable bright bioluminescence in ear, nose, paws, and tail whether they were anesthetized or overdosed. CMV::luc and fos::luc neonates had bioluminescence patterns similar to those of adults, although intensity was significantly higher in neonates. CMV::luc mice crossed with HRS/J mice had high expression in bone, claws, head, pancreas, and skeletal muscle, but less in extremities than haired CMV::luc mice. Imaging of brain bioluminescence through the neonatal skull was also practical. By imaging luciferin autofluorescence it was clear that substrate distribution did not restrict bioluminescence imaging to capillaries after injection. Luciferin treatment and anesthesia during imaging did not adversely affect circadian rhythms in locomotor activity. Imaging of gene expression patterns with luciferase can be extended from studies of live animals to rapid imaging of mice following a pentobarbital overdose before significant effects from postmortem changes occurs. Bioluminescent transgenic mice crossed with HRS/J mice are valuable for examining gene expression in deep tissues.


Evidence that IGF-binding protein-5 functions as a growth factor.
Recent studies support the concept that IGF-binding protein-5 (IGFBP-5) stimulates bone formation, at least in part, via IGF-independent mechanisms. To evaluate this hypothesis further, we evaluated in vitro and in vivo effects of IGFBP-5 on bone formation parameters using the IGF-I knockout (KO) mouse. Treatment of serum-free cultures of osteoblast clones derived from IGF-I KO mice with recombinant human IGFBP-5 increased both proliferation and alkaline phosphatase (ALP) activity in a dose-dependent manner, an effect comparable to that seen with IGF-I. IGF-II levels from media conditioned by osteoblasts derived from IGF-I KO mouse were below those detectable by RIA. To eliminate possible actions of IGF-II, if any was produced by osteoblasts derived from IGF-I knockout mice, the IGFBP-5 effect was studied in the presence of exogenously added IGFBP-4, a potent inhibitor of IGF-II actions in bone cells. Addition of IGFBP-4 blocked IGF-I- but not IGFBP-5-induced cell proliferation in osteoblasts derived from IGF-I knockout mice. Consistent with in vitro results, a single local injection of IGFBP-5 to the outer periosteum of the parietal bone of IGF-I KO mice increased ALP activity and osteocalcin levels of calvarial bone extracts. The magnitudes of IGFBP-5-induced increases in ALP and osteocalcin in parietal bone extracts of IGF-I KO mice were comparable to those seen in C3H mice. In contrast to IGFBP-5, local administration of IGFBP-4 had no significant effect on bone formation in C3H and IGF-I KO mice. These results provide the first direct evidence to our knowledge that IGFBP-5 functions as a growth factor that stimulates its actions in part via an IGF-independent mechanism.


Gene expression profiling of women with varying degrees of cervical intraepithelial neoplasia.
A pilot study to determine genomic microarray differences in patients with normal cervical tissue and cervical intraepithelial neoplasia (CIN) 3. After institutional review board approval, patients referred to the University of Alabama at Birmingham Colposcopy Clinic for a loop electrosurgical excisional procedure were identified. Tissue biopsies of both normal tissue and CIN 3 from fresh loop electrosurgical excisional procedure specimens were obtained and sent to pathology for histological confirmation. Procurement of these 2 types of tissue from the same patient controls for different types of human papillomavirus infection, smoking and nutritional status, age, immunocompetency, and other microenvironment factors (i.e., the patient serves as their own control). Standard RNA extraction techniques (Qiagen, Inc., Valencia, CA) were used to prepare the tissue specimens for microarray analysis with the Affymetrix GeneChip U133A expression array (Affymetrix, Inc., Santa Clara, CA). Paired samples were eligible for microarray analysis only when both normal tissue and CIN 3 were confirmed by pathology. The data were then subsequently subjected to a log-like transformation and analyzed with a t test. For this study, p<.001 was determined to be statistically significant. Twenty-one pairs of both normal and CIN tissues were obtained and underwent histological evaluation followed by RNA extraction. Within the normal group, 86% were confirmed as true normals and 14% as CIN. Within the CIN group, 28.5% were found to have CIN 2, 62% were found to have CIN 3, and 9.5% had no evidence of CIN. Mean RNA content of normal samples was 2.0 microg, whereas the mean RNA content of CIN samples was significantly higher at 7.4 microg (p=006). Ultimately, 5 pairs of normal and neoplastic tissues were subjected to microarray analysis. Using a cutoff of p<.001, 24 candidate genes were identified from more than 18,000 genes. In the CIN 3 group, 14 genes were overexpressed and 10 genes were underexpressed. Of the 14 overexpressed genes, 9 were noted to have identities listed in the National Center for Biotechnology Information public domain. Five (56%) of these 9 genes were directly related to immunity-related pathways, and 3 (33%) of the 9 genes were found to be involved in cell cycle function/control. One overexpressed gene was identified as p53. The presence of CIN is marked by increased transcriptional activity, evident by an almost 4-fold increase in mean RNA content obtained from our CIN samples versus normal cervical tissue. Furthermore, a number of statistically significant overexpressed genes of interest related to immune function/response and cell cycle control were identified in our pilot microarray study. This data have the ability to direct future research endeavors in cervical neoplasia. Future endeavors include the use of laser capture microdissection to evaluate genomic changes strictly at the epithelial level and, as such, exclude stromal response contributions.


Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding-fasting response and the circadian clock.
RNA polymerase III (Pol III) synthesizes short noncoding RNAs, many of which are essential for translation. Accordingly, Pol III activity is tightly regulated with cell growth and proliferation by factors such as MYC, RB1, TRP53, and MAF1. MAF1 is a repressor of Pol III transcription whose activity is controlled by phosphorylation; in particular, it is inactivated through phosphorylation by the TORC1 kinase complex, a sensor of nutrient availability. Pol III regulation is thus sensitive to environmental cues, yet a diurnal profile of Pol III transcription activity is so far lacking. Here, we first use gene expression arrays to measure mRNA accumulation during the diurnal cycle in the livers of (1) wild-type mice, (2) arrhythmic Arntl knockout mice, (3) mice fed at regular intervals during both night and day, and (4) mice lacking the Maf1 gene, and so provide a comprehensive view of the changes in cyclic mRNA accumulation occurring in these different systems. We then show that Pol III occupancy of its target genes rises before the onset of the night, stays high during the night, when mice normally ingest food and when translation is known to be increased, and decreases in daytime. Whereas higher Pol III occupancy during the night reflects a MAF1-dependent response to feeding, the rise of Pol III occupancy before the onset of the night reflects a circadian clock-dependent response. Thus, Pol III transcription during the diurnal cycle is regulated both in response to nutrients and by the circadian clock, which allows anticipatory Pol III transcription.


Effects of CBD-Enriched Cannabis sativa Extract on Autism Spectrum Disorder Symptoms: An Observational Study of 18 Participants Undergoing Compassionate Use.
Autism Spectrum Disorders comprise conditions that may affect cognitive development, motor skills, social interaction, communication, and behavior. This set of functional deficits often results in lack of independence for the diagnosed individuals, and severe distress for patients, families, and caregivers. There is a mounting body of evidence indicating the effectiveness of pure cannabidiol (CBD) and CBD-enriched Cannabis sativa extract (CE) for the treatment of autistic symptoms in refractory epilepsy patients. There is also increasing data support for the hypothesis that non-epileptic autism shares underlying etiological mechanisms with epilepsy. Here we report an observational study with a cohort of 18 autistic patients undergoing treatment with compassionate use of standardized CBD-enriched CE (with a CBD to THC ratio of 75/1). Among the 15 patients who adhered to the treatment (10 non-epileptic and five epileptic) only one patient showed lack of improvement in autistic symptoms. Due to adverse effects, three patients discontinued CE use before 1 month. After 6-9 months of treatment, most patients, including epileptic and non-epileptic, showed some level of improvement in more than one of the eight symptom categories evaluated: Attention Deficit/Hyperactivity Disorder; Behavioral Disorders; Motor Deficits; Autonomy Deficits; Communication and Social Interaction Deficits; Cognitive Deficits; Sleep Disorders and Seizures, with very infrequent and mild adverse effects. The strongest improvements were reported for Seizures, Attention Deficit/Hyperactivity Disorder, Sleep Disorders, and Communication and Social Interaction Deficits. This was especially true for the 10 non-epileptic patients, nine of which presented improvement equal to or above 30% in at least one of the eight categories, six presented improvement of 30% or more in at least two categories and four presented improvement equal to or above 30% in at least four symptom categories. Ten out of the 15 patients were using other medicines, and nine of these were able to keep the improvements even after reducing or withdrawing other medications. The results reported here are very promising and indicate that CBD-enriched CE may ameliorate multiple ASD symptoms even in non-epileptic patients, with substantial increase in life quality for both ASD patients and caretakers.


Population analysis of subsaturated 172-12 nucleosomal arrays by atomic force microscopy detects nonrandom behavior that is favored by histone acetylation and short repeat length.
Concatameric 5 S rDNA templates reconstituted in vitro into nucleosomal arrays provide very popular chromatin models for many kinds of studies. Here, atomic force microscopy is used to determine the population distributions for one such nucleosomal array, the 172-12, reconstituted to various subsaturated levels with nonacetylated or hyperacetylated HeLa histones. This array is a model for short linker length genomes and transcriptionally active and newly replicated chromatins. The analysis shows that as input histone levels increase, template occupation increases progressively as discrete population distributions. The distributions are random at low (n(av) < 4) and high (n(av) > 8) loadings but display specific nonrandom features, such as a deficit of molecules with one nucleosome more or less than the peak species in the distribution and enhanced distribution breadths, in the mid-range (n(av) = 4-8). Thus, the mid-range of occupation on polynucleosomal arrays may be a special range for chromatin structure and/or assembly. The mid-range nonrandom features are enhanced in distributions from short repeat (172-12) arrays, particularly for unacetylated chromatin, and in distributions from hyperacetylated chromatin, particularly for long repeat (208-12) arrays. Thus, short repeat length and acetylation can affect basic chromatin properties, like population tendencies, in very similar ways and therefore may cause similar changes in chromatin structure. Some possible effects are suggested. The data also indicate that it is thermodynamically more difficult for hyperacetylated nucleosomes to assemble onto the 172-12 templates, a result having implications for in vivo chromatin assembly.


Anomalies of the corpus callosum: correlation with further anomalies of the brain.
The MR imaging studies of 68 patients who had brain anomalies were reviewed retrospectively to evaluate specific anatomic abnormalities of the corpus callosum. The corpus callosum was abnormal in 32 (47%) of the 68 patients. Excluding patients with the Chiari I malformation, callosal anomalies were present in 30 (68%) of 44 patients. Callosal dysgenesis was most common, followed by callosal atrophy or hypoplasia and complete agenesis. The anterior commissure was present in all patients. On the basis of the known temporal sequence of brain and callosal embryogenesis, we deduced the following regarding the pathogenesis of developmental anomalies: (1) callosal dysgenesis occurs as a result of insults during the formation of its precursors, not during formation of the corpus callosum itself; (2) the Dandy-Walker malformation sometimes occurs as a result of an insult in the eighth week of gestation, several weeks later than has been generally accepted; (3) sphenoidal encephaloceles probably occur as a result of faulty disjunction of neuroectoderm and cutaneous ectoderm at the anterior neuropore; and (4) a complete but atrophic corpus callosum results from an insult to the cortex or white matter after formation of the corpus callosum is complete (18-20 weeks). Callosal anomalies, easily identified on MR, are an important indicator of additional brain anomalies. Analysis of the corpus callosum provides important information about the embryogenesis of brain anomalies and may assist in distinguishing between in utero and perinatal brain insults.


Personal Identity Development in Hispanic Immigrant Adolescents: Links with Positive Psychosocial Functioning, Depressive Symptoms, and Externalizing Problems.
The present study was designed to examine trajectories of personal identity coherence and confusion among Hispanic recent-immigrant adolescents, as well as the effects of these trajectories on psychosocial and risk-taking outcomes. Personal identity is extremely important in anchoring young immigrants during a time of acute cultural change. A sample of 302 recently immigrated (5 years or less in the United States at baseline) Hispanic adolescents (Mage = 14.51 years at baseline; SD = 0.88 years, range 14-17) from Miami and Los Angeles (47 % girls) completed measures of personal identity coherence and confusion at the first five waves of a six-wave longitudinal study; and reported on positive psychosocial functioning, depressive symptoms, and externalizing problems at baseline and at Time 6. Results indicated that identity coherence increased linearly across time, but that there were no significant changes in confusion over time and no individual differences in confusion trajectories. Higher baseline levels of, and improvements in, coherence predicted higher levels of self-esteem, optimism, and prosocial behavior at the final study timepoint. Higher baseline levels of confusion predicted lower self-esteem, greater depressive symptoms, more aggressive behavior, and more rule breaking at the final study timepoint. These results are discussed in terms of the importance of personal identity for Hispanic immigrant adolescents, and in terms of implications for intervention.


Mapping brain asymmetry in health and disease through the ENIGMA consortium.
Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA-Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average asymmetry was achieved, including an intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi-dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive-compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.


A longitudinal assessment of the victim-offender overlap.
Although research has established an offending/victimization overlap and that offenders and victims share similar characteristics, much less work has examined the longitudinal sequencing of victimization and offending in the same developmental period and whether key risk/protective factors significantly distinguish both offenders and victims.This study uses longitudinal data from a large sample of adolescents to examine these issues and does so using a novel methodological approach, the trajectory methodology, which allows for the examination of covariation between offending and victimization. Results indicate that there is a considerable degree of overlap between victims of physical violence and offenders over time and that certain covariates including school commitment, parental monitoring, low self-control, and sex significantly discriminate victim and offender groups. Furthermore, low self-control appears to be the most salient risk factor for distinguishing both victimization and delinquency trajectories.Theoretical and policy implications and directions for future research are identified.


[A unique psychopharmacologic profile of adrafinil in mice].
The following psychopharmacological effects of adrafinil have been observed in mice: increase in locomotor activity (64-256 mg.kg-1), antagonism (16-128 mg.kg-1) of the hypnotic effects of barbitone but not of pentobarbitone, reduction of immobility duration in the forced swimming test (16-256 mg.kg-1); slight antagonism (256 mg.kg-1) of electroshock-induced convulsions; no modification of rectal temperature; no stereotyped or climbing behaviour; no increase in lethality in aggregated mice (LD50 isolated = 1022 mg.kg-1, LD50 aggregated = 859 mg.kg-1); lack of effects on the provisional tests for antidepressants: no interaction with reserpine-, oxotremorine-, or apomorphine-induced hypothermia but potentiation of yohimbine-induced toxicity; lack of peripheral sympathetic effects (no mydriasis, no salivation, no contraction of the pilomotor muscles, no antagonism of reserpine-induced ptosis); lack of peripheral anticholinergic effects (no mydriasis, no antagonism of oxotremorine-induced salivation or lacrimation). As compared to no analeptic, anticholinergic or antidepressant drugs, adrafinil shows a unique behavioural profile in mice defined on the one hand by a specific stimulant activity associated with antidepressant-like effects that do no seem related to a beta-adrenergic mechanism and on the other hand by a lack of dopaminergic effects. Most adrafinil-induced effects (increase in locomotor activity, reduction of immobility duration in the forced swimming test) may correspond to a central alpha 1-adrenergic stimulation, but the unexpected lack of peripheral sympathetic effects remains unexplained.


Outcomes of vascular access for hemodialysis: A systematic review and meta-analysis.
The decision about the type and location of a hemodialysis vascular access is challenging and can be affected by multiple factors. We explored the effect of several a priori chosen patient characteristics on access outcomes. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through November 13, 2014. We included studies that evaluated patency, mortality, access infection, and maturation of vascular access in adults requiring long-term dialysis. Pairs of reviewers working independently selected the studies and extracted the data. Outcomes were pooled across studies using the random-effects model. Two hundred studies met the eligibility criteria reporting on 875,269 vascular accesses. Overall, studies appeared to have provided incidence rates at low to moderate risk of bias. The overall primary patency at 2 years was higher for fistulas than for grafts and catheters (55%, 40%, and 50%, respectively). Patency was lower in individuals with diabetes, coronary artery disease, older individuals, and in women. Mortality at 2 years was highest with catheters, followed by grafts then fistulas (26%, 17%, and 15%, respectively). The current evidence remains in support of autogenous access as the best approach when feasible. We provide incidence rates in various subgroups to inform shared decision making and facilitate the conversation with patients about access planning.


Effectiveness of a mass media campaign in promoting HIV testing information seeking among African American women.
"Take Charge. Take the Test." (TCTT), a media campaign promoting HIV testing among African American women, was piloted in Cleveland and Philadelphia from October 2006 to October 2007. This study assesses TCTT's effectiveness in promoting HIV testing information seeking among target audiences in each pilot city. The authors analyzed data on telephone hotlines promoted by the campaign and the www.hivtest.org Web site to examine trends in hotline calls and testing location searches before, during, and after the campaign. Cleveland hotline data were available from October 1, 2005, through February 28, 2008, for a total of 29 months (N = 126 weeks). Philadelphia hotline data were available from May 1, 2006, through February 28, 2008, for a total of 22 months (N = 96 weeks). The authors assessed the relation between market-level measures of the campaign's advertising activities and trends in hotline call volume and testing location searches. They found a significant relation between measures of TCTT advertising and hotline calls. Specifically, they found that increases in advertising gross ratings points were associated with increases in call volume, controlling for caller demographics and geographic location. The campaign had similar effects on HIV testing location searches. Overall, it appears the campaign generated significant increases in HIV information seeking. Results are consistent with other studies that have evaluated the effects of media campaigns on similar forms of information seeking. This study illustrates useful methods for evaluating campaign effects on information seeking with data on media implementation, hotline calls, and zip code-based searches for testing locations.


Quantitative and qualitative consequences of reduced pollen loads in a mixed-mating plant.
Greater pollination intensity can enhance maternal plant fitness by increasing seed set and seed quality as a result of more intense pollen competition or enhanced genetic sampling. We tested experimentally these effects by varying the pollen load from a single pollen donor on stigmas of female flowers of Dalechampia scandens (Euphorbiaceae) and measuring the effects on seed number and seed mass. Seed set increased rapidly with pollen number at low to moderate pollen loads, and a maximum set of three seeds occurred with a mean pollen load of 19 pollen grains. We did not detect a trade-off between the number of seeds and seed mass within a fruit. Seed mass increased with increasing pollen load, supporting the hypothesis of enhanced seed quality via increased pollen-competition intensity or genetic sampling. These results suggest that maternal fitness increases with larger pollen loads, even when the fertilization success is already high. Our results further highlight the importance of high rates of pollen arrival onto stigmas, as mediated by reliable pollinators. Comparing the pollen-to-seed response curve obtained in this experiment with those observed in natural populations suggests that pollen limitation may be more severe in natural populations than predicted from greenhouse studies. These results also indicate that declines in pollinator abundance may decrease plant fitness through lowered seed quality before an effect on seed set is detected.


Estimating undetected Ebola spillovers.
The preparedness of health systems to detect, treat, and prevent onward transmission of Ebola virus disease (EVD) is central to mitigating future outbreaks. Early detection of outbreaks is critical to timely response, but estimating detection rates is difficult because unreported spillover events and outbreaks do not generate data. Using three independent datasets available on the distributions of secondary infections during EVD outbreaks across West Africa, in a single district (Western Area) of Sierra Leone, and in the city of Conakry, Guinea, we simulated realistic outbreak size distributions and compared them to reported outbreak sizes. These three empirical distributions lead to estimates for the proportion of detected spillover events and small outbreaks of 26% (range 8-40%, based on the full outbreak data), 48% (range 39-62%, based on the Sierra Leone data), and 17% (range 11-24%, based on the Guinea data). We conclude that at least half of all spillover events have failed to be reported since EVD was first recognized. We also estimate the probability of detecting outbreaks of different sizes, which is likely less than 10% for single-case spillover events. Comparing models of the observation process also suggests the probability of detecting an outbreak is not simply the cumulative probability of independently detecting any one individual. Rather, we find that any individual's probability of detection is highly dependent upon the size of the cluster of cases. These findings highlight the importance of primary health care and local case management to detect and contain undetected early stage outbreaks at source.


Regional disparities in the burden of disease attributable to unsafe water and poor sanitation in China.
To estimate the disease burden attributable to unsafe water and poor sanitation and hygiene in China, to identify high-burden groups and to inform improvement measures. The disease burden attributable to unsafe water and poor sanitation and hygiene in China was estimated for diseases resulting from exposure to biologically contaminated soil and water (diarrhoeal disease, helminthiases and schistosomiasis) and vector transmission resulting from inadequate management of water resources (malaria, dengue and Japanese encephalitis). The data were obtained from China's national infectious disease reporting system, national helminthiasis surveys and national water and sanitation surveys. The fraction of each health condition attributable to unsafe water and poor sanitation and hygiene in China was estimated from data in the Chinese and international literature. In 2008, 327 million people in China lacked access to piped drinking water and 535 million lacked access to improved sanitation. The same year, unsafe water and poor sanitation and hygiene accounted for 2.81 million disability-adjusted life years (DALYs) and 62,800 deaths in the country, and 83% of the attributable burden was found in children less than 5 years old. Per capita DALYs increased along an east-west gradient, with the highest burden in inland provinces having the lowest income per capita. Despite remarkable progress, China still needs to conduct infrastructural improvement projects targeting provinces that have experienced slower economic development. Improved monitoring, increased regulatory oversight and more government transparency are needed to better estimate the effects of microbiologically and chemically contaminated water and poor sanitation and hygiene on human health.


Differentiation of (Mixed) Halogenated Dibenzo-p-Dioxins by Negative Ion Atmospheric Pressure Chemical Ionization.
Brominated and mixed halogenated dibenzo-p-dioxins (PBDDs and PXDDs) may well be as toxic as 2,3,7,8-tetrachloro-dibenzo-p-dioxin (2378-TCDD), a compound reputed as one of the most toxic chemicals known to exist. However, studies on the occurrence of PXDDs have been hampered by a lack of authentic standards as well as separation techniques capable of resolving the enormous number of potential isomers. Electron ionization (EI) mass spectrometry based methods are of limited value due to the lack of isomer specific fragmentation. Negative ion atmospheric pressure chemical ionization (APCI(-)) of 2378-TCDD was described in this journal over 30 years ago. Under these conditions, the reaction between O2(-•) and 2378-TCDD results in structure diagnostic cleavages of the C-O bonds, which can distinguish TCDD isomers on the basis of Cl distribution between the two aromatic rings. In the present study, the analogous ether cleavages of PBDDs and PXDDs were studied using a gas chromatograph-quadrupole time-of-flight (GC-QTOF) mass spectrometer coupled using APCI. The results indicate comparable detection limits for the radical cations [M(•+)] and negative pseudomolecular ions [M-Cl+O](-): approximately 5 fg and 10 fg, respectively, for 2378-TCDD and 5-10 fg and 10-30 fg, respectively, for the 2,3,7,8-substituted PXDDs. Detection limits obtained by monitoring the ether cleavage products were somewhat higher (between 100 and 600 fg) but still acceptable for trace analysis of PXDDs. Such reactions may resolve coeluting isomers, which is crucial for the identification of PXDDs. The technique is demonstrated by differentiating PXDD isomer classes in a sample obtained from a major industrial fire that would not be feasible using EI or positive ion APCI(+).


Simulation to assess the safety of new healthcare teams and new facilities.
: Our institution recently opened a satellite hospital including a pediatric emergency department. The staffing model at this facility does not include residents or subspecialists, a substantial difference from our main hospital. Our previous work and published reports demonstrate that simulation can identify latent safety threats (LSTs) in both new and established settings. Using simulation, our objective was to define optimal staff roles, refine scope of practice, and identify LSTs before facility opening. : Laboratory simulations were used to define roles and scope of practice. After each simulation, teams were debriefed using video recordings. The National Aeronautics and Space Administration-Task Load Index was completed by each participant to measure perceived workload. Simulations were scored for team behaviors by video reviewers using the Mayo High Performance Team Scale. Subsequent in situ simulations focused on identifying LSTs and monitoring for unintended consequences from changes made. : Twenty-four simulations were performed over 3 months before the hospital opening. Laboratory debriefing identified the need to modify provider responsibilities. National Aeronautics and Space Administration-Task Load Index scores and debriefings demonstrated that the medication nurse had the greatest workload during resuscitations. Modifying medication delivery was deemed critical. Lower Mayo High Performance Team Scale scores, implying less teamwork, were noted during in situ simulations. In situ sessions identified 37 LSTs involving equipment, personnel, and resources. : Simulation can help determine provider workload, refine team responsibilities, and identify LSTs. This pilot project provides a template for evaluation of new teams and clinical settings before patient exposure.


Proteomic analysis of barley cell nuclei purified by flow sorting.
Many proteins are present in the nucleus; some are involved with its structural and functional organization, some with gene expression, and some with cell division. The plant nuclear proteome has not been well explored. Its characterization requires extraction methods which minimize both the artifactual alteration of the proteins and the extent of contamination with non-nuclear proteins. The conventional multi-step fractionation procedure is both laborious and prone to contamination. Here, we describe a single-step method based on flow sorting. The method allows the separation of G1, S and G2 phase nuclei and minimizes the risk of contamination by non-nuclear proteins. Preliminary results obtained using G1 phase cell nuclei from barley root tips indicate that flow sorting coupled with a protein/peptide separation and mass spectrometry will permit a comprehensive characterization of the plant nuclear proteome.


The use of dietary supplements and their association with blood pressure in a large Midwestern cohort.
There have been numerous studies assessing the association of diet and blood pressure but little is known about the association between less commonly used nutritional supplements and blood pressured. The purpose of this study was to quantify the use of dietary supplements and their potential association with blood pressure in a large population-based cohort of adults in the Midwest. The Personalized Medicine Research Project cohort was the population source for the current study. The current study includes subjects with Dietary History Questionnaire (DHQ) data available as well as at least one clinical blood pressure measurement recorded in their electronic medical record. After excluding extreme outlying measurements, median systolic and diastolic blood pressure measurements were calculated for each individual and were compared for subjects who did and did not report taking one of a list of 37 different supplements listed on the DHQ more than once per week over the previous 12 months. 9,732 subjects had both blood pressure and DHQ data available. They ranged in age from 18 to 98 years (mean 56 years) and 3,625 (37%) were male. Nine of 37 supplements showed evidence for association with blood pressure: coenzyme Q10, fish oil, iron, bilberry, echinacea, evening primrose oil, garlic, goldenseal and milk thistle. With the exception of the mineral iron, mean systolic and diastolic blood pressures were higher for users of the specific supplements than non-users. These results should not be interpreted as causal, nor can the direction of the association be assumed to be correct because the temporality of the association is unknown. We hope the observed significant associations will foster future research to evaluate blood pressure effects of dietary supplements.


Intralesional injection of 2% zinc sulfate solution in the treatment of acute old world cutaneous leishmaniasis: a randomized, double-blind, controlled clinical trial.
Several in vitro and in vivo studies have shown inhibitory effects of zinc sulfate (ZnSO4) on Leishmania parasites. The objective of this study was to compare the efficacy of intralesional injections of 2% ZnSO4 solution with meglumine antimonate (Glucantime) in the treatment of acute Old World cutaneous leishmaniasis (CL). Seventy-two patients with CL lesions less than 8 weeks were recruited in a randomized, double-blind, clinical trial in an area endemic for Leishmania major after giving written informed consent. They were treated with 6 weekly intralesional injections of either drug. Among 36 patients with 53 lesions treated with ZnSO4 and 36 patients with 53 lesions treated with Glucantime, 13 patients with 19 lesions and 22 patients with 31 lesions completed the trial, respectively. Inadequacy of treatment was the main reason for drop-out in 12 (33.3%) and 2 (5.5%) patients in ZnSO4 and Glucantime groups, respectively (P < .05). Complete re-epithelialization was observed in 2 (10.5%) and 19 (61.3%) lesions 1 week after the end of treatment in the ZnSO4 and Glucantime groups, respectively (P < .05). In conclusion a 6-week course of weekly intralesional injections of 2% ZnSO4 solution was less effective than Glucantime in the treatment of acute Old World CL.


lncRNA SNHG8 Promotes the Tumorigenesis and Metastasis by Sponging miR-149-5p and Predicts Tumor Recurrence in Hepatocellular Carcinoma.
Long noncoding RNAs (lncRNAs) are aberrantly expressed in multiple malignant tumors involved in tumor growth and metastasis. Accumulating data show that small nucleolar RNA host gene (SNHG) 1/12/20 plays a key role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanisms by which SNHG8 contributes to HCC remain elusive and merit exploration. The association between SNHG8 expression and the clinicopathological characteristics and prognoses in HCC patients was analysed by using qRT-PCR analysis and the data from The Cancer Genome Atlas. Cell growth and metastatic potential were determined by MTT, colony formation, Transwell assays, and the mouse xenograft tumor model and lung metastasis model. Epithelial-mesenchymal transition markers were detected by western blot analysis. The binding capacity of SNHG8 with miRNAs was evidenced by bioinformatic analysis and a luciferase reporter assay. In addition, the rescue experiments were performed based on co-transfection with sh-SNHG8 and a miR-149 inhibitor in HCC cells. The expression levels of lncRNA SNHG8 were dramatically increased in HCC tissues and cell lines as compared with the adjacent normal tissues, and SNHG8 expression was an independent prognostic factor of tumor recurrence in HCC patients. Furthermore, knockdown of SNHG8 inhibited cell proliferation, invasion, and lung metastasis in vitro and in vivo, whereas overexpression of SNHG8 reversed these effects. SNHG8 acted as a sponge of miR-149 and counteracted the tumor suppressive effects of mi R-149 in HCC cells. Expression of phosphatase, Mg2+/Mn2+ dependent 1F, a target of R-149, displayed a negative correlation with miR-149 expression but a positive correlation with SNHG8 expression in HCC specimens. As lncRNA SNHG8 may promote HCC tumorigenesis and metastasis by sponging miR-149, it is a potential candidate marker and therapeutic target for HCC.


Label-aligned multi-task feature learning for multimodal classification of Alzheimer's disease and mild cognitive impairment.
Multimodal classification methods using different modalities of imaging and non-imaging data have recently shown great advantages over traditional single-modality-based ones for diagnosis and prognosis of Alzheimer's disease (AD), as well as its prodromal stage, i.e., mild cognitive impairment (MCI). However, to the best of our knowledge, most existing methods focus on mining the relationship across multiple modalities of the same subjects, while ignoring the potentially useful relationship across different subjects. Accordingly, in this paper, we propose a novel learning method for multimodal classification of AD/MCI, by fully exploring the relationships across both modalities and subjects. Specifically, our proposed method includes two subsequent components, i.e., label-aligned multi-task feature selection and multimodal classification. In the first step, the feature selection learning from multiple modalities are treated as different learning tasks and a group sparsity regularizer is imposed to jointly select a subset of relevant features. Furthermore, to utilize the discriminative information among labeled subjects, a new label-aligned regularization term is added into the objective function of standard multi-task feature selection, where label-alignment means that all multi-modality subjects with the same class labels should be closer in the new feature-reduced space. In the second step, a multi-kernel support vector machine (SVM) is adopted to fuse the selected features from multi-modality data for final classification. To validate our method, we perform experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database using baseline MRI and FDG-PET imaging data. The experimental results demonstrate that our proposed method achieves better classification performance compared with several state-of-the-art methods for multimodal classification of AD/MCI.


Length of Endoprosthetic Reconstruction in Revision Knee Arthroplasty Is Associated With Complications and Reoperations.
Complex revision total knee arthroplasty (TKA) often calls for endoprosthetic reconstruction to address bone loss, poor bone quality, and soft tissue insufficiency. Larger amounts of segmental bone loss in the setting of joint replacement may be associated with greater areas of devascularized tissue, which could increase the risk of complications and worsen functional results. Are longer endoprosthetic reconstructions associated with (1) higher risk of deep infection; (2) increased risk of reoperation and decreased implant survivorship; or (3) poorer ambulatory status? This is a single-institution retrospective case series of nononcologic femoral endoprosthetic reconstructions for revision TKA from 1995 to 2013 (n = 32). Cases were categorized as distal (n = 17) or diaphyseal (n = 15) femoral reconstructions based on extension to or above the supracondylar metaphyseal-diaphyseal junction, respectively. Five patients from each group were lost to followup before 2 years (distal mean 4 years [range, 2-8 years]; diaphyseal mean = 6 years [range, 2-16 years]), and one of the 12 distal reconstructions and two of the 10 diaphyseal reconstructions had not been evaluated within the past 5 years. Clinical outcomes and ambulatory status (able to walk or not) were assessed through chart review by authors not involved in any cases. Prior incidence of periprosthetic joint infection was high in both groups (distal = seven of 12 versus diaphyseal = four of 10; p = 0.670). Patients with diaphyseal femoral replacements were more likely to develop postoperative deep infections than patients with distal femoral replacements (distal = three of 12 versus diaphyseal = nine of 10; p = 0.004). Implant survivorship (revision-free) for diaphyseal reconstructions was worse at 2 years (distal = 100%, 95% confidence interval [CI], 100%-100% versus diaphyseal = 40%, 95% CI, 19%-86%; p = 0.001) and 5 years (distal = 90%, 95% CI, 75%-100% versus diaphyseal = 30%, 95% CI, 12%-73%; p = 0.001). Infection-free, revision-free survival (retention AND no infection) was worse for diaphyseal femoral replacing reconstructions than for distal femoral replacements at 2 years (distal = 70%, 95% CI, 48%-100% versus diaphyseal = 20%, 95% CI, 6%-69%; p = 0.037) and 5 years (distal = 70%, 95% CI, 48%-100% versus diaphyseal = 10%, 95% CI, 2%-64%; p = 0.012). There was no difference with the small numbers available in proportion of patients able to walk (distal reconstruction = eight of 11 versus diaphyseal = seven of 10; p = 1.000), although all but one patient in each group required walking aids. Endoprosthetic femoral reconstruction is a viable salvage alternative to amputation for treatment of failed TKA with segmental distal femoral bone loss. In our small series even with substantial loss to followup and likely best-case estimates of success, extension proximal to the supracondylar metaphyseal-diaphyseal junction results in higher infection and revision risk. In infection, limb salvage remains possible with chronic antibiotic suppression, which we now use routinely for all femoral replacement extending into the diaphysis. Level III, therapeutic study.


Event-related potential evidence of form and meaning coding during online speech recognition.
It is still a matter of debate whether initial analysis of speech is independent of contextual influences or whether meaning can modulate word activation directly. Utilizing event-related brain potentials (ERPs), we tested the neural correlates of speech recognition by presenting sentences that ended with incomplete words, such as To light up the dark she needed her can-. Immediately following the incomplete words, subjects saw visual words that (i) matched form and meaning, such as candle; (ii) matched meaning but not form, such as lantern; (iii) matched form but not meaning, such as candy; or (iv) mismatched form and meaning, such as number. We report ERP evidence for two distinct cohorts of lexical tokens: (a) a left-lateralized effect, the P250, differentiates form-matching words (i, iii) and form-mismatching words (ii, iv); (b) a right-lateralized effect, the P220, differentiates words that match in form and/or meaning (i, ii, iii) from mismatching words (iv). Lastly, fully matching words (i) reduce the amplitude of the N400. These results accommodate bottom-up and top-down accounts of human speech recognition. They suggest that neural representations of form and meaning are activated independently early on and are integrated at a later stage during sentence comprehension.


Temporal accuracy of human cortico-cortical interactions.
The precision in space and time of interactions among multiple cortical sites was evaluated by examining repeating precise spatiotemporal patterns of instances in which cortical currents showed brief amplitude undulations. The amplitudes of the cortical current dipoles were estimated by applying a variant of synthetic aperture magnetometry to magnetoencephalographic (MEG) recordings of subjects tapping to metric auditory rhythms of drum beats. Brief amplitude undulations were detected in the currents by template matching at a rate of 2-3 per second. Their timing was treated as point processes, and precise spatiotemporal patterns were searched for. By randomly teetering these point processes within a time window W, we estimated the accuracy of the timing of these brief amplitude undulations and compared the results with those obtained by applying the same analysis to traces composed of random numbers. The results demonstrated that the timing accuracy of patterns was better than 3 ms. Successful classification of two different cognitive processes based on these patterns suggests that at least some of the repeating patterns are specific to a cognitive process.


Patient age influences perceptions about health care communication.
The study's objective was to determine if a patient's age is independently associated with how he/she perceives interactions with health care providers. We used a secondary, cross-sectional analysis of nationally representative data from the 2002 Medical Expenditure Panel Survey (MEPS). We measured the independent association between patient age and six outcomes pertaining to communication and decision-making autonomy, while simultaneously controlling for gender, race, ethnicity, family income, educational attainment, census region, rural residence, insurance status, and usual source of care. Compared to patients>or=65 years, patients ages 18-64 were less likely to report that their provider "always" listened to them, "always" showed respect for what they had to say, and "always" spent enough time with them. Patient perceptions of health care interactions vary by age. A better understanding of how and why age is associated with patient-provider communication could be useful to design practice-level interventions that enhance services and also to develop national policies that improve health care delivery and health outcomes.


Microfluidic neural probes: in vivo tools for advancing neuroscience.
Microfluidic neural probes hold immense potential as in vivo tools for dissecting neural circuit function in complex nervous systems. Miniaturization, integration, and automation of drug delivery tools open up new opportunities for minimally invasive implants. These developments provide unprecedented spatiotemporal resolution in fluid delivery as well as multifunctional interrogation of neural activity using combined electrical and optical modalities. Capitalizing on these unique features, microfluidic technology will greatly advance in vivo pharmacology, electrophysiology, optogenetics, and optopharmacology. In this review, we discuss recent advances in microfluidic neural probe systems. In particular, we will highlight the materials and manufacturing processes of microfluidic probes, device configurations, peripheral devices for fluid handling and packaging, and wireless technologies that can be integrated for the control of these microfluidic probe systems. This article summarizes various microfluidic implants and discusses grand challenges and future directions for further developments.


MicroRNA-155 in serum-derived extracellular vesicles as a potential biomarker for hematologic malignancies - a short report.
The use of extracellular vesicles (EVs) from body fluids as "liquid biopsies" is emerging as a promising approach for the diagnosis, prognosis and therapeutic monitoring of cancer patients. MicroRNA-155 (miR155), a non-coding transcript of the B-cell integration cluster (BIC) gene, has been reported to play a critical role in the pathogenesis of several types of hematologic malignancies (HMs) in which high miR155 levels have been found. At yet, however, the EV miR155 level and its putative clinical relevance in sera of HM patients have not been reported. EVs from sera of representative patients with eight different HMs and healthy subjects (controls) were isolated using differential centrifugation. The identity and quality of the EVs were verified by atomic force and transmission electron microscopy. The EV miR155 levels were measured by quantitative RT-PCR. The sensitivity, specificity and area under the curve (AUC) of differences in EV miR155 levels were determined using ROC curve analyses. We found that the EV miR155 levels were significantly higher in chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and Waldenström's macroglobulinemia (WM) cases compared to controls. Conversely, we found that the EV miR155 levels were significantly lower in myelodysplastic syndrome (MDS) and multiple myeloma (MM) cases. No differences were found in follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) or Hodgkin's Lymphoma (HL) cases compared to controls. EV miR155 ROC curve analyses revealed significantly different patterns in CLL and AML cases compared to controls, and in AML cases compared to MDS cases (p = 0.004, p = 0.01 and p = 0.04, respectively). In addition, we found that high EV miR155 levels correlated with high white blood cell counts in AML patients. Our data indicate that EV miR155 may serve as an attractive new, non-invasive diagnostic biomarker in human hematologic malignancies.


SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans.
SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.


Analysis and classification of broadband echoes using bio-inspired dolphin pulses.
To date most sonars use narrow band pulses and often only the echo envelope is used for object detection and classification. This paper considers the advantages afforded by bio-inspired sonar for object identification and classification through the analysis and the understanding of the broadband echo structure. Using the biomimetic dolphin based sonar system in conjunction with bio-inspired pulses developed from observations of bottlenose dolphins performing object identification tasks, results are presented from experiments carried out in a wave tank and harbor. In these experiments responses of various targets to two different bio-inspired signals are measured and analyzed. The differences in response demonstrate the strong dependency between signal design and echo interpretation. In the simulations and empirical data, the resonance phenomena of these targets cause strong notches and peaks in the echo spectra. With precision in the localization of these peaks and dips of around 1 kHz, the locations are very stable for broadside insonification of the targets and they can be used as features for classification. This leads to the proposal of a broadband classifier which operates by extracting the notch positions in the target echo spectra.


Interactions of fluoroquinolone antibacterial agents with aqueous chlorine: reaction kinetics, mechanisms, and transformation pathways.
Kinetics, products, and mechanistic aspects of reactions between free available chlorine (HOCl/OCl-), ciprofloxacin (CF), and enrofloxacin (EF) were extensively investigated to elucidate the behavior of fluoroquinolone antibacterial agents during water chlorination processes. Although the molecular structures of these two substrates differ only with respect to degree of N(4) amine alkylation, CF and EF exhibit markedly different HOCl reaction kinetics and transformation pathways. HOCI reacts very rapidly at CF's secondary N(4) amine, forming a chloramine intermediate that spontaneously decays in aqueous solution by concerted piperazine fragmentation. In contrast, HOCl reacts relatively slowly at EF's tertiary N(4) amine, apparently forming a highly reactive chlorammonium intermediate (R3N-(4)Cl+) that can catalytically halogenate EF or other substrates present in solution. Flumequine, a fluoroquinolone that lacks the characteristic piperazine ring, exhibits no apparent reactivity toward HOCI but appears to undergo facile halodecarboxylation in the presence of R3N(4)-Cl+ species derived from EF. Measured reaction kinetics were validated in real water matrixes by modeling CF and EF losses in the presence of free chlorine residuals. Combined chlorine (CC) kinetics were determined under selected conditions to evaluate the potential significance of reactions with chloramines. CF's rapid kinetics in direct reactions with HOCl, and relatively high reactivity toward CC, indicate that secondary amine-containing fluoroquinolones should be readily transformed during chlorination of real waters, whether applied chlorine doses are present as free or combined residuals. However, EF's slower HOCl reaction kinetics, recalcitrance toward CC, and participation in the catalytic halogenation cycle described herein suggest that tertiary amine-containing fluoroquinolones will be comparatively stable during most full-scale water chlorination processes.


Self-sharpening induces jet-like structure in seafloor gravity currents.
Gravity currents are the primary means by which sediments, solutes and heat are transported across the ocean-floor. Existing theory of gravity current flow employs a statistically-stable model of turbulent diffusion that has been extant since the 1960s. Here we present the first set of detailed spatial data from a gravity current over a rough seafloor that demonstrate that this existing paradigm is not universal. Specifically, in contrast to predictions from turbulent diffusion theory, self-sharpened velocity and concentration profiles and a stable barrier to mixing are observed. Our new observations are explained by statistically-unstable mixing and self-sharpening, by boundary-induced internal gravity waves; as predicted by recent advances in fluid dynamics. Self-sharpening helps explain phenomena such as ultra-long runout of gravity currents and restricted growth of bedforms, and highlights increased geohazard risk to marine infrastructure. These processes likely have broader application, for example to wave-turbulence interaction, and mixing processes in environmental flows.


The effects of Vitamin C on sperm quality parameters in laboratory rats following long-term exposure to cyclophosphamide.
Cyclophosphamide is a widely used medication and can cause oxidative stress. This study was conducted to investigate the effects of Vitamin C on reproductive organs' weight and the quality of sperm parameters in laboratory rats. In this experimental study, 40 rats were randomly assigned into five groups of eight each. Distilled water (DW) group received only food and water, Group 2 was administered with drug solvent (DW) by gavage, Group 3 intraperitoneally administered with 1.6 mg/kg cyclophosphamide, Group 4 gavaged Vitamin C at 0.88 mg/kg, and Group 5 administered with effective doses of Vitamin C and cyclophosphamide by gavage with 1-h intervals. Sperm parameters of the samples were taken from distal epididymis and tissues were studied, and the data were analyzed by SPSS version 22. The lowest weight of testicles and epididymis was seen in cyclophosphamide-exposed rats and the highest weight of testicles and epididymis in Vitamin C-exposed rats (P < 0.05). The highest motility, progression, viability, and count of sperm were seen in the Vitamin C-treated group and the lowest in the cyclophosphamide-exposed group. The highest proportion of sperm anomalies was seen in the cyclophosphamide-exposed group. Vitamin C, as an antioxidant, can be effective on some of the sperm parameters and can reduce cyclophosphamide-induced complications in animal model.


Gene Expression Profiling in the APP/PS1KI Mouse Model of Familial Alzheimer's Disease.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-β (Aβ) accumulation, extracellular deposition of Aβ peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aβ in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses.


Resorbable structured porous materials in the healing process of hard tissue defects.
The long-term goal of this research is to assist the resurfacing of damaged articular cartilage. Coralline hydroxyapatite (HA) was coated with a thin film of polylactide (PLa), maintaining pore structural characteristics. Cylindrical plugs (3 x 7 mm) implanted in non-load-bearing femoral and tibial diaphyses of the rabbit indicated substantial bone ingrowth at 3 weeks, with no significant difference between coated and uncoated HA in the amount and distribution of new bone. PLa-epsilon caprolactone polymeric negative replicas of coral Goniopora (G), inserted into the rabbit femur for 4 wks, showed newly formed bone grown deeply into the pores. Tight attachment of new bone to the implant and minimal inflammatory response suggested an osteocompatible reaction. In order to maintain the desirable pore structure of G while introducing controllable degradation rate and mechanical properties, a novel technique was employed to replicate G with PLa and its co-polymers. An intermediary negative replica of G was prepared with aspirin. A co-polymer positive replica of G was then prepared by solution or melt infusion into the negative replica; the aspirin was removed by methanol. A macro- (300-500 microns) and microporous (5-15 microns) structure was prepared by freeze-drying. This replica received appreciable bone ingrowth when implanted in the rabbit tibia for 3 wks. Our results demonstrate the feasibility of creating devices with interconnected pore structures and controlled porosity, elasticity, and mechanical strength sufficient for articular cartilage application, osteocompatibility, and controlled degradation rate.