Glutamine is essential for epidermal growth factor-stimulated intestinal cell proliferation.
Glutamine stimulates growth of intestinal mucosa in vivo, but the mechanisms involved are unknown. The purpose of this study was to determine whether glutamine is essential for proliferation of enterocytes stimulated by epidermal growth factor (EGF). In addition, we determined which specific mitogenic actions of EGF require glutamine. A nontransformed rat intestinal mucosal cell line (IEC-6) was stimulated with EGF (20 ng/ml) without and with glutamine (0.1 to 10 mmol/L). DNA, RNA, and protein synthesis were quantitated by determining incorporation of tritiated thymidine, tritiated uridine, and 14C-leucine, respectively. Cell numbers and messenger RNA levels of early growth response genes (zif268, jun-B, c-myc) were also determined. Glutamine was required for EGF stimulation of DNA, RNA, and protein synthesis and cell replication; however, EGF-stimulated expression of zif268, jun-B, and c-myc occurred in the absence of glutamine. This study showed that glutamine is essential for EGF-stimulated intestinal mucosal cell proliferation. The mitogenic effects of EGF can be divided into the glutamine-independent, such as the signal transduction pathway leading to the induction of early growth response genes, and the glutamine-dependent, including DNA, RNA, and protein synthesis.


An evaluation of changes over time in serum creatine kinase activity and C-reactive protein concentration in dogs undergoing hemilaminectomy or ovariohysterectomy.
The extent of trauma in a patient can be difficult for a clinician to quantify. A prospective study was performed on 2 groups of dogs undergoing either ovariohysterectomy or hemilaminectomy. The serum activity of creatine kinase and serum concentration of C-reactive protein were evaluated preoperatively and then at 4, 6, 8, 12, 24 and 48 hours postoperatively in both groups. The results were compared statistically both within and between the 2 groups. A wide range of results was found at each time point for both analytes although there were no significant differences for either analyte between the 2 surgical groups preoperatively. Thereafter there were significant differences in creatine kinase activity levels between the 2 groups. C-reactive protein concentration results were very similar in the 2 groups with no statistical difference at any time point. The results of this study suggest that the evaluation of CK and CRP at any one time point in a traumatised animal is of limited value. However, the evaluation of the trend of these 2 analytes, even over a relatively short time period, may allow for useful prognostication in clinical cases.


Premorbid child and family functioning as predictors of post-concussive symptoms in children with mild traumatic brain injuries.
This study sought to determine whether premorbid child and family functioning accounts for or moderates group differences in post-concussive symptoms following mild traumatic brain injury (TBI) in childhood. This prospective, longitudinal cohort study recruited 8- to 15-year-old children, 186 with mild TBI and 99 with orthopedic injuries (OI), from consecutive emergency department admissions. Parents and children rated post-concussive symptoms within 3 weeks of injury and at 1, 3, and 12 months post injury. Parents also provided retrospective ratings of pre-injury symptoms, as well as of premorbid child behavioral adjustment, overall family functioning, and other stressors and resources in the family environment. Children with mild TBI reported more post-concussive symptoms than those with OI, as did their parents, although premorbid child behavioral adjustment and symptoms also were significant predictors of post-concussive symptoms. Group differences in somatic symptoms as reported by parents were more pronounced among children from families that were higher functioning and had more environmental resources. Mild TBI during childhood results in more post-concussive symptoms than OI, even after children's premorbid adjustment is taken into account. Counter to expectations, post-concussive symptoms following mild TBI may actually be more apparent among children from higher-functioning families with greater resources.


Coordination of Metabolism and Virulence Factors Expression of Extraintestinal Pathogenic Escherichia coli Purified from Blood Cultures of Patients with Sepsis.
One of the trademarks of extraintestinal pathogenic Escherichia coli is adaptation of metabolism and basic physiology to diverse host sites. However, little is known how this common human pathogen adapts to permit survival and growth in blood. We used label-free quantitative proteomics to characterize five E. coli strains purified from clinical blood cultures associated with sepsis and urinary tract infections. Further comparison of proteome profiles of the clinical strains and a reference uropathogenic E. coli strain 536 cultivated in blood culture and on two different solid media distinguished cellular features altered in response to the pathogenically relevant condition. The analysis covered nearly 60% of the strains predicted proteomes, and included quantitative description based on label-free intensity scores for 90% of the detected proteins. Statistical comparison of anaerobic and aerobic blood cultures revealed 32 differentially expressed proteins (1.5% of the shared proteins), mostly associated with acquisition and utilization of metal ions critical for anaerobic or aerobic respiration. Analysis of variance identified significantly altered amounts of 47 proteins shared by the strains (2.7%), including proteins involved in vitamin B6 metabolism and virulence. Although the proteomes derived from blood cultures were fairly similar for the investigated strains, quantitative proteomic comparison to the growth on solid media identified 200 proteins with substantially changed levels (11% of the shared proteins). Blood culture was characterized by up-regulation of anaerobic fermentative metabolism and multiple virulence traits, including cell motility and iron acquisition. In a response to the growth on solid media there were increased levels of proteins functional in aerobic respiration, catabolism of medium-specific carbon sources and protection against oxidative and osmotic stresses. These results demonstrate on the expressed proteome level that expression of extraintestinal virulence factors and overall cellular metabolism closely reflects specific growth conditions. Data are available via ProteomeXchange with identifier PXD002912.


Intake of Protein Hydrolysates and Phenolic Fractions Isolated from Flaxseed Ameliorates TNBS-Induced Colitis.
In the attempt to develop new therapeutic treatments for colitis, fractions containing phenolic compound isolate (Phi) and phenolic reduced-flaxseed protein hydrolysate (phr-FPH) from flaxseed are evaluated for their effects on the in vitro production of pro-inflammatory mediators and on the course of experimental colitis. The anti-inflammatory effects of Phi and phr-FPH from flaxseeds are studied in RAW264.7 cells and in trinitrobenzene sulphonic acid (TNBS) colitis model. It is observed that the incubation with Phi or phr-FPH result in lower levels of tumor necrosis factor α and nitric oxide in macrophages stimulated with bacterial lipopolysaccharide + interferon-γ. Prophylactic and therapeutic treatments with Phi and phr-FPH, respectively, greatly contribute to the prevention of weight loss and colon inflammation in colitic BALB/c mice. T cell proliferation, expansion of TH1 and TH17 cells, and pro-inflammatory cytokines are lower, whereas Treg cells are higher in spleen cell cultures from Phi-treated mice. In addition, therapeutic phr-FPH treatment is able to reduce the expansion of TH17 in splenic cell cultures. The consumption of phenolic and protein compounds extracted from flaxseeds has a protective effect on TNBS-induced colitis, and may be useful in the control of other inflammatory disorders.


Brucella abortus L7/L12 recombinant protein induces strong Th1 response in acute brucellosis patients.
Because of high morbidity of the brucellosis in humans and the potential use of the microorganism as an agent of biologic warfare, protection of effective vaccines and specific diagnostic reagents become necessary to eradicate brucellosis. In this study we aimed to investigate the cytokine responses and changes in peripheral blood lymphocyte subgroups of acute brucellosis patients in response to L7/L12 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) recombinant proteins derived from Brucella abortus. levels of IFN-γ, IL-4 and IL-10 secreted from PBMCs of 25 acute brucellosis patients and 15 healthy controls, stimulated with Phytohemagglutinin (PHA), L7/L12 or GAPDH were measured by ELISA. Furthermore alterations in lymphocyte subgroups in response to these Brucella antigens were determined by flow cytometry. Extracellular IFN-γ levels were found to be elevated after stimulation with L7/L12 in patients with acute brucellosis, whereas no significant changes were found in IL-4 and IL-10 levels. Similar data was also obtained with GAPDH, but the stimulation of IFN-γ production was not observed in all patients and was not as strong as that observed for L7/L12. Moreover, when the distribution of lymphocytes subgroups (CD3+, CD3+ CD4+, CD3+ CD8+, CD4+ CD25+, CD3+ CD69+ and CD3+ CD152+) was evaluated, it was found that the stimulation with L7/L12 and GAPDH only led to an increase in the percentage of CD3+ CD69+ lymphocytes. These data indicate that Brucella abortus L7/L12 or GAPDH induce a Th1 type immune response in acute brucellosis patients. Additionally, these recombinant proteins, especially L7/L12, may be used in new vaccine preparations and diagnostic tests.


Thyroid-stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges.
To estimate a normal reference range for thyroid-stimulating hormone (TSH) at each point in gestation in singleton and twin pregnancies. All women enrolling for prenatal care from December 2000 through November 2001 underwent prospective TSH screening at their first visit. Separate nomograms were constructed for singleton and twin pregnancies using regression analysis. Values were converted to multiples of the median (MoM) for singleton pregnancies at each week of gestation. Thyroid-stimulating hormone was evaluated in 13,599 singleton and 132 twin pregnancies. Thyroid-stimulating hormone decreased significantly during the first trimester, and the decrease was greater in twins (both P < .001). Had a nonpregnant reference (0.4-4.0 mU/L) been used rather than our nomogram, 28% of 342 singletons with TSH greater than 2 standard deviations above the mean would not have been identified. For singleton first-trimester pregnancies, the approximate upper limit of normal TSH was 4.0 MoM, and for twins, 3.5 MoM. Thereafter, the approximate upper limit was 2.5 MoM for singleton and twin pregnancies. If thyroid testing is performed during pregnancy, nomograms that adjust for fetal number and gestational age may greatly improve disease detection. Values expressed as multiples of the median may facilitate comparisons across different laboratories and populations.


Mechanism of oxidative stress-induced ASK1-catalyzed MKK6 phosphorylation.
Apoptosis signal-regulating kinase 1 (ASK1) is a serine/threonine kinase that responds to a plethora of stress-inducing signals. In turn, activation of ASK1 is associated with a number of human pathological conditions, including neurodegenerative disease, inflammation, and heart failure. In response to oxidative stress, ASK1 activates the cell death-associated p38 MAPK pathway by phosphorylating MKK6. Here, we investigated the regulation of oxidative stress-induced ASK1-catalyzed phosphorylation of MKK6. MKK6 phosphorylation levels increased immediately after H(2)O(2) treatment in intact cells and decreased following treatment for 30 min. When expressed in HEK293T cells, ASK1 was reproducibly purified within a high-molecular mass complex ( approximately 1500 kDa) known as the ASK1 signalosome. Measurement of the in vitro kinetic parameters revealed that the catalytic efficiency (k(cat)/K(m)) of ASK1 was 4000-fold greater in cells treated with H(2)O(2) for 3 min than in untreated cells. Interestingly, although the K(m(ATP)) values were found to be unchanged, the K(m(MKK6)) was dramatically decreased ( approximately 1000-fold). The increased affinity was specific for MKK6 and short-lived, as the K(m(MKK6)) returned to basal levels 30 min after treatment. Consistently, endogenous MKK6 was found within the ASK1 signalosome in intact cells and in addition copurified with ASK1 following treatment for 3 min. In contrast, proteins modulating ASK1 activity and degradation were found to interact with the ASK1 signalosome once MKK6 activation was completed. Taken together, these data suggest that oxidative stress rapidly increases ASK1 catalytic efficiency for MKK6 phosphorylation by increasing MKK6 binding affinity within the ASK1 signalosome prior to induction of inactivation and degradation of the complex.


Functional genomics of wood quality and properties.
Genomics promises to enrich the investigations of biology and biochemistry. Current advancements in genomics have major implications for genetic improvement in animals, plants, and microorganisms, and for our understanding of cell growth, development, differentiation, and communication. Significant progress has been made in the understanding of plant genomics in recent years, and the area continues to progress rapidly. Functional genomics offers enormous potential to tree improvement and the understanding of gene expression in this area of science worldwide. In this review we focus on functional genomics of wood quality and properties in trees, mainly based on progresses made in genomics study of Pinus and Populus. The aims of this review are to summarize the current status of functional genomics including: (1) Gene discovery; (2) EST and genomic sequencing; (3) From EST to functional genomics; (4) Approaches to functional analysis; (5) Engineering lignin biosynthesis; (6) Modification of cell wall biogenesis; and (7) Molecular modelling. Functional genomics has been greatly invested worldwide and will be important in identifying candidate genes whose function is critical to all aspects of plant growth, development, differentiation, and defense. Forest biotechnology industry will significantly benefit from the advent of functional genomics of wood quality and properties.


Interferon-gamma is necessary for the expression of hypersensitivity pneumonitis.
Farmers lung disease is a common form of hypersensitivity pneumonitis (HP) and is characterized by inflammation and granuloma formation in the lung. Interferon-gamma is important for the expression of granulomatous diseases caused by infectious agents; however, the role this mediator in regulating expression of the granulomatous response to inhaled antigen is not known. To evaluate this, we compared the response to inhaled antigen of mice that do not express the gene coding for interferon-gamma (GKO) with that of their normal littermates (WT). GKO and WT mice on a BALB/c background were exposed to 150 microg of the thermophilic bacteria Saccharopolyspora rectivirgula or saline alone, for three consecutive days a week, for 3 wk. After exposure to antigen, WT mice developed a marked granulomatous inflammation associated with an increase in lung weight and numbers of cells in bronchoalveolar lavage fluid (BAL). Although GKO mice also exhibited an increase in lung weight and numbers of cells in BAL fluid, they developed minimal inflammation and no granulomas after a similar exposure to antigen. To further evaluate if the lack of a response to antigen in GKO mice was due to lack of IFN-gamma, we replaced this mediator via intraperitoneal injections. When given replacement IFN-gamma, the GKO mice developed granulomatous inflammation in the lung. These studies show that IFN-gamma is essential for the expression of hypersensitivity pneumonitis.


The perceptions of African women regarding natural menopause in Mamelodi, Tshwane district.
The majority of South African aging population are women, who spend late adulthood experiencing natural menopause. Despite the government spending billions of rand on different services for ageing women, menopausal challenges to African women still receive little attention. The aim of the study was to explore and describe the perceptions of African women regarding natural menopause, in order to propose recommendations for health and social support systems for women in Mamelodi, Tshwane district. A qualitative, exploratory, descriptive and contextual design was used to conduct the study. The population of the study consisted of menopausal women, between the ages 45 and 60 years or more, visiting the clinics for collection of chronic medication and othe rhealth assessment. Individual face-to-face interviews were conducted, using a semi-structured interview guide to collect data. Tesch's method of qualitative data analysis was used in the study. The main theme that emerged from the study was 'attitude toward menopause', which was supported by cultural beliefs and experience. The African menopausal women expressed the importance of health support systems that will meet their needs within their context. Women's health programs and educational health information at facilities should include menopausal education to promote and improve health of all African menopausal women during their adulthood. There is a need to establish a women's health support group network within communities to share menopausal experiences with peers. The training and education curriculum of healthcare providers should include detailed menopause in order to provide comprehensive, congruent care.


Small intestinal glucose exposure determines the magnitude of the incretin effect in health and type 2 diabetes.
The potential influence of gastric emptying on the "incretin effect," mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is unknown. The objectives of this study were to determine the effects of intraduodenal (ID) glucose infusions at 2 (ID2) and 4 (ID4) kcal/min (equating to two rates of gastric emptying within the physiological range) on the size of the incretin effect, gastrointestinal glucose disposal (GIGD), plasma GIP, GLP-1, and glucagon secretion in health and type 2 diabetes. We studied 10 male BMI-matched controls and 11 male type 2 patients managed by diet or metformin only. In both groups, GIP, GLP-1, and the magnitude of incretin effect were greater with ID4 than ID2, as was GIGD; plasma glucagon was suppressed by ID2, but not ID4. There was no difference in the incretin effect between the two groups. Based on these data, we conclude that the rate of small intestinal glucose exposure (i.e., glucose load) is a major determinant of the comparative secretion of GIP and GLP-1, as well as the magnitude of the incretin effect and GIGD in health and type 2 diabetes.


Alcohol-related morbidity and mortality following involuntary job loss: evidence from Swedish register data.
The purpose of this study was to assess the association between involuntary job loss and alcohol-attributable morbidity and mortality. Swedish linked employee-employer data were used to identify all establishment closures during 1990-1999, as well as the employees who were laid off and a comparison group. These data were merged with information on alcohol-attributable deaths and hospital admissions from the Causes of Death Register and the National Patient Register. The associations between job loss and alcohol-attributable morbidity and mortality during a follow-up period of 12 years were estimated by propensity score weighting methods. An excess risk of both alcohol-related hospitalization and mortality was found among both displaced men and women. For women, the wholly alcohol-attributable health problems were mainly limited to alcohol use disorders, whereas men also had an increased risk of hospitalization from poisoning and alcohol-induced liver disease and pancreatitis. The findings support previous evidence of increased risks of alcohol-related morbidity/mortality following involuntary job loss, although the estimates presented herein are more conservative. In addition, the findings suggest that alcohol-related problems manifest somewhat differently in men and women.


Macrophage invasion contributes to degeneration of stria vascularis in Pendred syndrome mouse model.
Pendred syndrome, an autosomal-recessive disorder characterized by deafness and goiter, is caused by a mutation of SLC26A4, which codes for the anion exchanger pendrin. We investigated the relationship between pendrin expression and deafness using mice that have (Slc26a4+/+ or Slc26a4+/-) or lack (Slc26a4-/-) a complete Slc26a4 gene. Previously, we reported that stria vascularis of adult Slc26a4-/- mice is hyperpigmented and that marginal cells appear disorganized. Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration. Slc26a4-/- and age-matched control (Slc26a4+/+ or Slc26a4+/-) mice were studied at four postnatal (P) developmental stages: before and after the age that marks the onset of hearing (P10 and P15, respectively), after weaning (P28-41) and adult (P74-170). Degeneration and hyperpigmentation stria vascularis was evaluated by confocal microscopy. Gene expression in stria vascularis was analyzed by microarray and quantitative RT-PCR. In addition, the expression of a select group of genes was quantified in spiral ligament, spleen and liver to evaluate whether expression changes seen in stria vascularis are specific for stria vascularis or systemic in nature. Degeneration of stria vascularis defined as hyperpigmentation and marginal cells disorganization was not seen at P10 or P15, but occurred after weaning and was associated with staining for CD68, a marker for macrophages. Marginal cells in Slc26a4-/-, however, had a larger apical surface area at P10 and P15. No difference in the expression of Lyzs, C3 and Cd45 was found in stria vascularis of P15 Slc26a4+/- and Slc26a4-/- mice. However, differences in expression were found after weaning and in adult mice. No difference in the expression of markers for acute inflammation, including Il1a, Il6, Il12a, Nos2 and Nos3 were found at P15, after weaning or in adults. The expression of macrophage markers including Ptprc (= Cd45), Cd68, Cd83, Lyzs, Lgals3 (= Mac2 antigen), Msr2, Cathepsins B, S, and K (Ctsb, Ctss, Ctsk) and complement components C1r, C3 and C4 was significantly increased in stria vascularis of adult Slc26a4-/- mice compared to Slc26a4+/+ mice. Expression of macrophage markers Cd45 and Cd84 and complement components C1r and C3 was increased in stria vascularis but not in spiral ligament, liver or spleen of Slc26a4-/- compared to Slc26a4+/- mice. The expression of Lyzs was increased in stria vascularis and spiral ligament but not in liver or spleen. The data demonstrate that hyperpigmentation of stria vascularis and marginal cell reorganization in Slc26a4-/- mice occur after weaning, coinciding with an invasion of macrophages. The data suggest that macrophage invasion contributes to tissue degeneration in stria vascularis, and that macrophage invasion is restricted to stria vascularis and is not systemic in nature. The delayed onset of degeneration of stria vascularis suggests that a window of opportunity exists to restore/preserve hearing in mice and therefore possibly in humans suffering from Pendred syndrome.


Structural strain energy function applied to the ageing of the human aorta.
Stiffening of the aorta with progressing age leads to decrease of aortic compliance and thus to an increase of pulse pressure amplitude. Using a strain energy function (SEF) which takes into account the composition of the arterial wall, we have studied the evolution of key structural components of the human thoracic aorta using data obtained from the literature. The SEF takes into account the wavy nature of collagen, which upon gradual inflation of the blood vessel is assumed to straighten out and become engaged in bearing load. The engagement of the individual fibers is assumed to be distributed log-logistically. The use of a SEF enables the consideration of axial stretch (lambda(z)) and residual strain (opening angle) in the biomechanical analysis. Both lambda(z) and opening angle are known to change with age. Results obtained from applying the SEF to the measurements of aortic pressure-diameter curves indicate that the changes in aortic biomechanics with progressing age are not to be sought in the elastic constants of elastin and collagen or their volume fractions of the aortic wall but moreover in alterations of the collagen mesh arrangement and the waviness of the collagen fibers. In old subjects, the collagen fiber ensemble engages in load bearing much more abruptly than in young subjects. Reasons for this change in collagen fiber dynamics may include fiber waviness remodeling or cross-linkage by advanced glycation end-products (AGE). The abruptness of collagen fiber engagement is also the model parameter that is most responsible for the decreased compliance at progressed ages.


Serial analysis of gene expression provides new insights into regulatory T cells.
It is now possible to induce donor-specific transplantation tolerance in adult rodents using a number of therapeutic strategies. Such peripheral tolerance is maintained by regulatory CD4+ T cells, not only in transplantation models, but also in autoimmunity. Differential gene expression analyses have been used to identify potential new markers for regulatory T cells, aiming to reveal new insights into their mechanisms of action, and to find novel targets for therapeutic manipulation of the immune system.


Accounting for female space sharing in St. Kilda Soay sheep (Ovis aries) results in little change in heritability estimates.
When estimating heritability in free-living populations, it is common practice to account for common environment effects, because of their potential to generate phenotypic covariance among relatives thereby biasing heritability estimates. In quantitative genetic studies of natural populations, however, philopatry, which results in relatives being clustered in space, is rarely accounted for. The two studies that have been carried out so far suggest absolute declines in heritability estimates of up to 43% when accounting for space sharing by relatives. However, due to methodological limitations these estimates may not be representative. We used data from the St. Kilda Soay sheep population to estimate heritabilities with and without accounting for space sharing for five traits for which there is evidence for additive genetic variance (birthweight, birth date, lamb August weight, and female post-mortem jaw and metacarpal length). We accounted for space sharing by related females by separately incorporating spatial autocorrelation, and a home range similarity matrix. Although these terms accounted for up to 18% of the variance in these traits, heritability estimates were only reduced by up to 7%. Our results suggest that the bias caused by not accounting for space sharing may be lower than previously thought. This suggests that philopatry does not inevitably lead to a large bias if space sharing by relatives is not accounted for. We hope our work stimulates researchers to model shared space when relatives in their study population share space, as doing so will enable us to better understand when bias may be of particular concern.


Anaesthesia: what a surgeon needs to know.
Surgeons and anaesthetists work closely together, sometimes in challenging circumstances. To help surgeons cooperate with anaesthetists to deliver high quality care for patients, a working knowledge of modern anaesthetic practice is useful. The specialty of anaesthetics is developing rapidly, and periodic updating of this knowledge is likely to be required. This article provides an update of anaesthetic practice for surgeons, covering the varied roles of anaesthetists, preoperative assessment, management on the day of surgery (induction, maintenance and reversal of anaesthetic), general anaesthesia, the role of regional blocks and sedation. It also discusses safety issues, the management of frail patients and future challenges.


Effect of seven-valent pneumococcal conjugate vaccine on Staphylococcus aureus colonisation in a randomised controlled trial.
Heptavalent pneumococcal conjugate vaccine (PCV7) shifts nasopharyngeal colonisation with vaccine serotype pneumococci towards nonvaccine serotypes. Because of the reported negative association of vaccine serotype pneumococci and Staphylococcus aureus in the nasopharynx, we explored the effect of PCV7 on nasopharyngeal colonisation with S. aureus in children and parents. This study was part of a randomised controlled trial on the effect of PCV7 on pneumococcal carriage, enrolling healthy newborns who were randomly assigned (1:1:1) to receive PCV7 (1) at 2 and 4 months of age (2) at 2, 4 and 11 months or (3) no PCV7 (controls). Nasopharyngeal colonisation of S. aureus was a planned secondary outcome. Nasopharyngeal swabs were obtained from all children over a 2-year period with 6-months interval and from one parent at the child's age of 12 and 24 months and cultured for Streptococcus pneumoniae and S. aureus. Between July 2005 and February 2006, 1005 children were enrolled and received either 2-doses of PCV7 (n = 336), 2+1-doses (336) or no dose (n = 333) before PCV7 implementation in the Dutch national immunization program. S. aureus colonisation had doubled in children in the 2+1-dose group at 12 months of age compared with unvaccinated controls (10.1% versus 5.0%; p = 0.019). A negative association for co-colonisation of S. pneumoniae and S. aureus was observed for both vaccine serotype (adjusted odds ratio (aOR) 0.53, 95% confidence interval (CI) 0.38-0.74) and nonvaccine serotype pneumococci (aOR 0.67, 95% CI 0.52-0.88). PCV7 induces a temporary increase in S. aureus colonisation in children around 12 months of age after a 2+1-dose PCV7 schedule. The potential clinical consequences are unknown and monitoring is warranted. ClinicalTrials.gov NCT00189020.


Publication rates of scientific presentations in Turkish national radiology congresses.
To investigate the publication rates of scientific presentations in Turkish radiology congresses. The abstracts of presentations at Turkish national radiology congresses between 1995-2002 were reviewed. According to the congress abstract booklets, types of the presentation (oral or poster presentation), as well as body system-based categorization were used. The presentations were searched for publication in Medline(R) indexed journals using the PubMed server. The rates of publication of the abstracts, the journals in which the presentations have been published and the time between the presentation and publication were investigated. An overall number of 521 publications were found originating from 4,413 presentations (11.81%). The publication numbers of 2,116 scientific research, 1,995 case report and 302 educational exhibit type presentations were 261 (12.33%), 249 (12.49%) and 11 (3.64%), respectively. For oral presentations the publication ratio was found as 15.38% (116/754) and for posters it was 11.06% (405/3,659). The number of presentations and the number of publications were found to increase by years, however the ratio of publication to presentation remained the same. Mean time to publication was calculated as 24.4 months. In frequency of publication, Tanisal ve Girisimsel Radyoloji, European Radiology, European Journal of Radiology were the first three publication media of the presentations. The publication rates of abstracts presented at Turkish national radiology congresses are lower than the previously reported publication rates in radiology and other specialties.


Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy.
This phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA). Utilizing a dose-escalation design, we delivered between 10 and 200 million adipose-derived autologous MSCs intrathecally to patients with early MSA. Patients were closely followed with clinical, laboratory, and imaging surveillance. Primary endpoints were frequency and type of adverse events; key secondary endpoint was the rate of disease progression assessed by the Unified MSA Rating Scale (UMSARS). Twenty-four patients received treatment. There were no attributable serious adverse events, and injections were generally well-tolerated. At the highest dose tier, 3 of 4 patients developed low back/posterior leg pain, associated with thickening/enhancement of lumbar nerve roots. Although there were no associated neurologic deficits, we decided that dose-limiting toxicity was reached. A total of 6 of 12 patients in the medium dose tier developed similar, but milder and transient discomfort. Rate of progression (UMSARS total) was markedly lower compared to a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004) with an apparent dose-dependent effect. Intrathecal MSC administration in MSA is safe and well-tolerated but can be associated with a painful implantation response at high doses. Compelling dose-dependent efficacy signals are the basis for a planned placebo-controlled trial. This phase I/II study provides Class IV evidence that for patients with early MSA, intrathecal MSC administration is safe, may result in a painful implantation response at high doses, and is associated with dose-dependent efficacy signals.


Crystal orientation and plate structure in echinoid skeletal units.
The submicroscopic morphology of magnesian calcite skeletal units of echinoids, revealed by scanning electron microscopy, was compared with crystal orientation data obtained by x-ray methods and with macroscopic morphology. The Perischoechinoidea and the Euechinoidea differ with regard to the shapes of their trabeculae. Nearly all plates and spines are single crystals. A variety of diJfferent directional relations of c- and a-axes to the main morphological directions are found for different species; adjacent plates with identical c-axis orientation differ strongly in orientation of their a-axes. Fracture surfaces of single trabeculae show cleavage planes and zonal layers attributed to changes in secretion conditions.


Building genomic profiles for uncovering segmental homology in the twilight zone.
The identification of homologous regions within and between genomes is an essential prerequisite for studying genome structure and evolution. Different methods already exist that allow detecting homologous regions in an automated manner. These methods are based either on finding sequence similarities at the DNA level or on identifying chromosomal regions showing conservation of gene order and content. Especially the latter approach has proven useful for detecting homology between highly divergent chromosomal regions. However, until now, such map-based approaches required that candidate homologous regions show significant collinearity with other segments to be considered as being homologous. Here, we present a novel method that creates profiles combining the gene order and content information of multiple mutually homologous genomic segments. These profiles can be used to scan one or more genomes to detect segments that show significant collinearity with the entire profile but not necessarily with individual segments. When applying this new method to the combined genomes of Arabidopsis and rice, we find additional evidence for ancient duplication events in the rice genome.


An Eye-Tracking Study of Receptive Verb Knowledge in Toddlers.
We examined receptive verb knowledge in 22- to 24-month-old toddlers with a dynamic video eye-tracking test. The primary goal of the study was to examine the utility of eye-gaze measures that are commonly used to study noun knowledge for studying verb knowledge. Forty typically developing toddlers participated. They viewed 2 videos side by side (e.g., girl clapping, same girl stretching) and were asked to find one of them (e.g., "Where is she clapping?"). Their eye-gaze, recorded by a Tobii T60XL eye-tracking system, was analyzed as a measure of their knowledge of the verb meanings. Noun trials were included as controls. We examined correlations between eye-gaze measures and score on the MacArthur-Bates Communicative Development Inventories (CDI; Fenson et al., 1994), a standard parent report measure of expressive vocabulary to see how well various eye-gaze measures predicted CDI score. A common measure of knowledge-a 15% increase in looking time to the target video from a baseline phase to the test phase-did correlate with CDI score but operationalized differently for verbs than for nouns. A 2nd common measure, latency of 1st look to the target, correlated with CDI score for nouns, as in previous work, but did not for verbs. A 3rd measure, fixation density, correlated for both nouns and verbs, although the correlation went in different directions. The dynamic nature of videos depicting verb knowledge results in differences in eye-gaze as compared to static images depicting nouns. An eye-tracking assessment of verb knowledge is worthwhile to develop. However, the particular dependent measures used may be different than those used for static images and nouns.


Knowledge of prenatal health care among Costa Rican and Panamanian women.
There is evidence that health care during pregnancy is a crucial component in ensuring a safe delivery. Because the infant mortality rate in Costa Rica is almost half the rate of Panama, the researchers tested the hypothesis that women in Costa Rica are more knowledgeable about prenatal health care than women in neighboring Panama. A multiple-choice survey was used to evaluate women's knowledge of prenatal care using WHO recommendations as the nominal standard. Oral surveys were administered to 320 women in Costa Rican and Panamanian health care clinics. The surveys consisted of multiple-choice questions designed to assess four specific domains of knowledge in prenatal care: nutrition, danger signs, threats from illness, and acceptable activities during pregnancy. Survey answers were scored, and significant factors in assessing women's knowledge of prenatal care were determined using analysis of variance and general linear models. Costa Rican women scored higher than Panamanian women in most domains of knowledge in prenatal health care. Only country of origin and educational level were significant factors in determining knowledge of prenatal care. However, country of origin was a stronger predictor of knowledge of prenatal care than was having completed high school. These data suggest that Costa Rican women are more knowledgeable about necessary prenatal care than Panamanian women, and that this difference is probably related to direct education about and promotion of prenatal care in Costa Rica. This suggests an influence of cultural health care awareness that extends beyond the previously established negative correlation between maternal educational level and infant mortality.


Molecular architecture of botulinum neurotoxin E revealed by single particle electron microscopy.
Clostridial botulinum neurotoxin (BoNT) causes a neuroparalytic condition recognized as botulism by arresting synaptic vesicle exocytosis. Although the crystal structures of full-length BoNT/A and BoNT/B holotoxins are known, the molecular architecture of the five other serotypes remains elusive. Here, we present the structures of BoNT/A and BoNT/E using single particle electron microscopy. Labeling of the particles with three different monoclonal antibodies raised against BoNT/E revealed the positions of their epitopes in the electron microscopy structure, thereby identifying the three hallmark domains of BoNT (protease, translocation, and receptor binding). Correspondingly, these antibodies selectively inhibit BoNT translocation activity as detected using a single molecule assay. The global structure of BoNT/E is strikingly different from that of BoNT/A despite strong sequence similarity. We postulate that the unique architecture of functionally conserved modules underlies the distinguishing attributes of BoNT/E and contributes to differences with BoNT/A.


A special local clustering algorithm for identifying the genes associated with Alzheimer's disease.
Clustering is the grouping of similar objects into a class. Local clustering feature refers to the phenomenon whereby one group of data is separated from another, and the data from these different groups are clustered locally. A compact class is defined as one cluster in which all similar elements cluster tightly within the cluster. Herein, the essence of the local clustering feature, revealed by mathematical manipulation, results in a novel clustering algorithm termed as the special local clustering (SLC) algorithm that was used to process gene microarray data related to Alzheimer's disease (AD). SLC algorithm was able to group together genes with similar expression patterns and identify significantly varied gene expression values as isolated points. If a gene belongs to a compact class in control data and appears as an isolated point in incipient, moderate and/or severe AD gene microarray data, this gene is possibly associated with AD. Application of a clustering algorithm in disease-associated gene identification such as in AD is rarely reported.


The research agenda for improving health policy, systems performance, and service delivery for tuberculosis control: a WHO perspective.
The development of WHO's DOTS strategy for the control of tuberculosis (TB) in 1995 led to the expansion, adaptation and improvement of operational research in this area. From being a patchwork of small-scale studies concerned with aspects of service delivery, TB operational research shifted to larger-scale, often multicountry projects that were also concerned with health policy and the needs of health systems. The results are now being put into practice by national TB control programmes. In 1998 an ad hoc committee identified the chief factors inhibiting the expansion of DOTS: lack of political will and commitment, poor financial support for TB control, poor organization and management of health services, inadequate human resources, irregular drug supplies, the HIV epidemic, and the rise of multidrug resistance. An analysis of current operational research on TB is presented on the basis of these constraints, and examples of successful projects are outlined in the article. We discuss the prerequisites for success, the shortcomings of this WHO- supported programme, and future challenges and needs.


The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation.
Oligodendrogliomas are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with oligodendrogliomas; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster ortholog of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here, we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell-cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in oligodendrogliomas prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth.Significance: Inactivation of CIC inhibits its direct repression of MAPK pathway genes, leading to their increased expression and mitogen-independent growth.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4114/F1.large.jpg Cancer Res; 78(15); 4114-25. ©2018 AACR.


Implications of quantum metabolism and natural selection for the origin of cancer cells and tumor progression.
Empirical studies give increased support for the hypothesis that the sporadic form of cancer is an age-related metabolic disease characterized by: (a) metabolic dysregulation with random abnormalities in mitochondrial DNA, and (b) metabolic alteration - the compensatory upregulation of glycolysis to offset mitochondrial impairments. This paper appeals to the theory of Quantum Metabolism and the principles of natural selection to formulate a conceptual framework for a quantitative analysis of the origin and proliferation of the disease. Quantum Metabolism, an analytical theory of energy transduction in cells inspired by the methodology of the quantum theory of solids, elucidates the molecular basis for differences in metabolic rate between normal cells, utilizing predominantly oxidative phosphorylation, and cancer cells utilizing predominantly glycolysis. The principles of natural selection account for the outcome of competition between the two classes of cells. Quantum Metabolism and the principles of natural selection give an ontogenic and evolutionary rationale for cancer proliferation and furnish a framework for effective therapeutic strategies to impede the spread of the disease.


9-(2'-Deoxy-2'-Fluoro-β-d-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance.
Current chemotherapy against African sleeping sickness, a disease caused by the protozoan parasite Trypanosoma brucei, is limited by toxicity, inefficacy, and drug resistance. Nucleoside analogues have been successfully used to cure T. brucei-infected mice, but they have the limitation of mainly being taken up by the P2 nucleoside transporter, which, when mutated, is a common cause of multidrug resistance in T. brucei We report here that adenine arabinoside (Ara-A) and the newly tested drug 9-(2'-deoxy-2'-fluoro-β-d-arabinofuranosyl) adenine (FANA-A) are instead taken up by the P1 nucleoside transporter, which is not associated with drug resistance. Like Ara-A, FANA-A was found to be resistant to cleavage by methylthioadenosine phosphorylase, an enzyme that protects T. brucei against the antitrypanosomal effects of deoxyadenosine. Another important factor behind the selectivity of nucleoside analogues is how well they are phosphorylated within the cell. We found that the T. brucei adenosine kinase had a higher catalytic efficiency with FANA-A than the mammalian enzyme, and T. brucei cells treated with FANA-A accumulated high levels of FANA-A triphosphate, which even surpassed the level of ATP and led to cell cycle arrest, inhibition of DNA synthesis, and the accumulation of DNA breaks. FANA-A inhibited nucleic acid biosynthesis and parasite proliferation with 50% effective concentrations (EC50s) in the low nanomolar range, whereas mammalian cell proliferation was inhibited in the micromolar range. Both Ara-A and FANA-A, in combination with deoxycoformycin, cured T. brucei-infected mice, but FANA-A did so at a dose 100 times lower than that of Ara-A.


Transcriptional and posttranslational regulation of insulin-like growth factor binding protein-3 by Akt3.
Insulin-like growth factor (IGF)-dependent and -independent antitumor activities of insulin-like growth factor binding protein-3 (IGFBP-3) have been proposed in human non-small cell lung cancer (NSCLC) cells. However, the mechanism underlying regulation of IGFBP-3 expression in NSCLC cells is not well understood. In this study, we show that activation of Akt, especially Akt3, plays a major role in the mRNA expression and protein stability of IGFBP-3 and thus antitumor activities of IGFBP-3 in NSCLC cells. When Akt was activated by genomic or pharmacologic approaches, IGFBP-3 transcription and protein stability were decreased. Conversely, suppression of Akt increased IGFBP-3 mRNA levels and protein stability in NSCLC cell lines. Characterization of the effects of constitutively active form of each Akt subtype (HA-Akt-DD) on IGFBP-3 expression in NSCLC cells and a xenograft model indicated that Akt3 plays a major role in the Akt-mediated regulation of IGFBP-3 expression and thus suppression of Akt effectively enhances the antitumor activities of IGFBP-3 in NSCLC cells with Akt3 overactivation. Collectively, these data suggest a novel function of Akt3 as a negative regulator of IGFBP-3, indicating the possible benefit of a combined inhibition of IGFBP-3 and Akt3 for the treatment of patients with NSCLC.


Transgenic expression of cyclin-dependent kinase 4 results in epidermal hyperplasia, hypertrophy, and severe dermal fibrosis.
In a previous report we have described the effects of expression of D-type cyclins in epithelial tissues of transgenic mice. To study the involvement of the D-type cyclin partner cyclin-dependent kinase 4 (CDK4) in epithelial growth and differentiation, transgenic mice were generated carrying the CDK4 gene under the control of a keratin 5 promoter. As expected, transgenic mice showed expression of CDK4 in the epidermal basal-cell layer. Epidermal proliferation increased dramatically and basal cell hyperplasia and hypertrophy were observed. The hyperproliferative phenotype of these transgenic mice was independent of D-type cyclin expression because no overexpression of these proteins was detected. CDK4 and CDK2 kinase activities increased in transgenic animals and were associated with elevated binding of p27(Kip1) to CDK4. Expression of CDK4 in the epidermis results in an increased spinous layer compared with normal epidermis, and a mild hyperkeratosis in the cornified layer. In addition to epidermal changes, severe dermal fibrosis was observed and part of the subcutaneous adipose tissue was replaced by connective tissue. Also, abnormal expression of keratin 6 associated with the hyperproliferative phenotype was observed in transgenic epidermis. This model provides in vivo evidence for the role of CDK4 as a mediator of proliferation in epithelial cells independent of D-type cyclin expression.


Maternal-related deaths and impoverishment among adolescent girls in India and Niger: findings from a modelling study.
High levels of maternal mortality and large associated inequalities exist in low-income and middle-income countries. Adolescent pregnancies remain common, and pregnant adolescent women face elevated risks of maternal mortality and poverty. We examined the distribution across socioeconomic groups of maternal deaths and impoverishment among adolescent girls (15-19 years old) in Niger, which has the highest total fertility rate globally, and India, which has the largest number of maternal deaths. In Niger and India, among adolescent girls, we estimated the distribution per income quintile of: the number of maternal deaths; and the impoverishment, measured by calculating the number of cases of catastrophic health expenditure incurred, caused by complicated pregnancies. We also examined the potential impact on maternal deaths and poverty of increasing adolescent girls' level of education by 1 year. We used epidemiological and cost inputs sourced from surveys and the literature. The number of maternal deaths would be larger among the poorer adolescents than among the richer adolescents in Niger and India. Impoverishment would largely incur among the richer adolescents in Niger and among the poorer adolescents in India. Increasing educational attainment of adolescent girls might avert both a large number of maternal deaths and a significant number of cases of catastrophic health expenditure in the 2 countries. Adolescent pregnancies can lead to large equity gaps and substantial impoverishment in low-income and middle-income countries. Increasing female education can reduce such inequalities and provide financial risk protection and poverty alleviation to adolescent girls.


A physician-focused intervention to reduce potentially inappropriate medication prescribing in older people: a 3-year, Italian, prospective, proof-of-concept study.
Potentially inappropriate medications (PIMs) are a preventable cause of negative clinical and economic consequences in older people. A range of educational interventions have attempted to address this in the past and have produced mixed results. The objective of this study was to assess the effect of a physician-focused, multi-factorial, quality-improvement intervention on PIM prescribing in older patients in primary care. This 3-year, multi-phase, prospective, proof-of-concept project introduced in 2007 was aimed at engaging all 303 general practitioners (GPs) in the Local Health Authority (LHA) of Parma, Italy, to positively influence the quality of prescribing to the entire older outpatient population (those aged at least 65 years) served by these physicians. The intervention focused on increasing GPs' awareness of prescribing for older people and included three key elements: (1) initial dissemination of a developed list of PIMs to always be avoided, along with a list of alternative drugs; (2) annual reviews of PIM incidence data; and (3) educational sessions on PIMs via academic detailing and case study reviews. Quarterly incidence rates of PIM exposure were calculated among all Parma LHA older outpatients who had received a prescription for any medication from their GP in a given quarter. The intervention was assessed by evaluating the changes in these rates between the study baseline (2007 fourth quarter [Q4]) and the end of the study (post-intervention: 2009 Q4). To reduce bias and confounding from background influences that may have acted to reduce PIM incidence rates independent of the intervention, these rate changes were also compared with those drawn from a similar neighbouring LHA over the same time period. Quarterly PIM exposure incidence rates among the older Parma LHA patients declined 31.4 % (7.8 % baseline to 5.3 % post-intervention), compared with 21.6 % in the comparator LHA (7.7 % to 6.1 %). The reduction in rates was significantly greater in the Parma LHA (p < 0.001), where the intervention resulted in 608 older patients (12.4 % of expected) being spared PIM exposure during 2009 Q4. PIM exposure rate reductions for NSAIDs and digoxin were each significantly greater in the Parma LHA than in the comparator LHA. By reaching out to GPs and maintaining contact with them, this quality intervention appears to have positively impacted physicians' awareness and prescribing behaviour, which led to significant reductions in PIM exposures and likely translated to significant population health benefits among their older patients. Similar interventions tailored to target specific PIMs or focus on certain subpopulations of GPs may further improve prescribing quality among older people.


Mild cognitive impairment after adjuvant chemotherapy in breast cancer patients--evaluation of appropriate research design and methodology to measure symptoms.
The development of new chemotherapeutic agents and regimens has contributed to reduced risk of cancer recurrence and prolonged patient survival. However, mild cognitive impairment (MCI), also known as ''chemofog'' or ''chemobrain'' following adjuvant chemotherapy for breast cancer has been reported since the late 1980s. Unfortunately, little is known about it's mechanism, type, severity, and episode length. This article reviewed related studies on the subject, and found that chemotherapy-induced MCI appears to occur in 10-40% of patients, and memory loss and lack of concentration are the most frequent symptoms. The symptoms are apparently transient, but take at least several years to disappear. Reviewed studies show a lack of clear understanding of what causes MCI directly. There is also a lack of consistency in symptom measurement. We point to the need to conduct well-designed studies which begin with a proper hypothesis. Future research needs to be randomized and longitudinal with a base measurement point before the chemotherapy cycle starts. Future studies must adopt an effective and sensitive method to measure MCI. The latest imaging technique, positron emission tomography (PET) may be a powerful tool. Also, all confounding factors, such as age, education, intelligence quotient (IQ), fatigue and depression, hormonal therapy and other treatments should be controlled within the study design. It is hoped that the results of such future studies will allow medical professionals to contemplate effective prevention, treatment and rehabilitation for MCI.


Posttreatment low-risk drinking as a predictor of future drinking and problem outcomes among individuals with alcohol use disorders.
Treatment for alcohol disorders has traditionally been abstinence-oriented, but evaluating the merits of a low-risk drinking outcome as part of a primary treatment endpoint is a timely issue given new pertinent regulatory guidelines. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and problem severity outcomes among individuals with alcohol use disorders in a large private, not for profit, integrated care health plan. Study participants include adults with alcohol use disorders at 6 months (N = 995) from 2 large randomized studies. Logistic regression models were used to explore the relationship between past 30-day drinker status at 6 months posttreatment (abstinent [66%], low-risk drinking [14%] defined as nonabstinence and no days of 5+ drinking, and heavy drinking [20%] defined as 1 or more days of 5+ drinking) and 12-month outcomes, including drinking status and Addiction Severity Index measures of medical, psychiatric, family/social, and employment severity, controlling for baseline covariates. Compared to heavy drinkers, abstinent individuals and low-risk drinkers at 6 months were more likely to be abstinent or low-risk drinkers at 12 months (adj. ORs = 16.7 and 3.4, respectively; p < 0.0001); though, the benefit of abstinence was much greater than that of low-risk drinking. Compared to heavy drinkers, abstinent and low-risk drinkers were similarly associated with lower 12-month psychiatric severity (adj. ORs = 1.8 and 2.2, respectively, p < 0.01) and family/social problem severity (adj. OR = 2.2; p < 0.01). While abstinent individuals had lower 12-month employment severity than heavy drinkers (adj. OR = 1.9; p < 0.01), low-risk drinkers did not differ from heavy drinkers. The drinking groups did not differ on 12-month medical problem severity. Compared to heavy drinkers, low-risk drinkers did as well as abstinent individuals for many of the outcomes important to health and addiction policy. Thus, an endpoint that allows low-risk drinking may be tenable for individuals undergoing alcohol specialty treatment.


The role of vestibular and somatosensory systems in intersegmental control of upright stance.
Upright stance was perturbed using sinusoidal platform rotations to see how vestibular and somatosensory information are used to control segment and intersegmental dynamics in subjects with bilateral vestibular loss (BVL) and healthy controls (C). Subjects stood with eyes closed on a rotating platform (+/-1.2 degrees) for frequencies ranging from 0.01-0.4 Hz in the presence and absence of light fingertip touch. Trunk movement relative to the platform of BVLs was higher than Cs at higher platform frequencies whereas leg movement relative to the platform was similar for both groups. With the addition of light touch, both groups showed similar trunk and leg segment movement relative to the platform. Trunk-leg coordination was in-phase for frequencies below 1 Hz and anti-phase above 1 Hz. Interestingly, BVLs showed evidence of a "legs-leading-trunk" relationship in the shift from in-phase to anti-phase around 1 Hz. Controls showed no preference for either segment to lead the coordinative shift from in- to anti-phase. The results suggest that the balance instability of BVL subjects stems from high variability of the trunk, rather than the legs. The high trunk variability may emerge from the "legs-leading" intersegmental relationship upon which BVLs rely. Because BVLs derive information about self-orientation primarily from the support surface when their eyes are closed, the legs initiate the shift to anti-phase trunk-leg coordination that is necessary for stable upright stance control. Higher trunk variability suggests that this strategy results in lower overall postural stability. Light touch substitutes for vestibular information, leading to lower trunk variability along with a trunk-leg phase shift similar to controls, without a preference for either segment to lead the shift. The results suggest that vestibulospinal control acts primarily to stabilize the trunk in space and to facilitate intersegmental dynamics.


New insights into Lyme disease.
Lyme borreliosis is transmitted through the bite of a tick that is infected by the bacterial spirochete Borrelia burgdorferi. Clinical manifestation of the disease can lead to heart conditions, neurological disorders, and inflammatory disorders. Oxidative stress has been implicated in the pathogenesis of many human diseases. The aim of this study was to investigate the mechanisms of oxidative stress and intracellular communication in Lyme borreliosis patients. Mitochondrial superoxide and cytosolic ionized calcium was measured in peripheral blood mononuclear cells (PBMCs) of Lyme borreliosis patients and healthy controls. Mitochondrial superoxide levels were significantly higher (p<0.0001) in Lyme borreliosis patients (n=32) as compared to healthy controls (n=30). Significantly low (p<0.0001) levels of cytosolic ionized calcium were also observed in Lyme borreliosis patients (n=11) when compared to healthy controls (n=11). These results indicate that there is an imbalance of reactive oxygen species and cytosolic calcium in Lyme borreliosis patients. The results further suggest that oxidative stress and interrupted intracellular communication may ultimately contribute to a condition of mitochondrial dysfunction in the immune cells of Lyme borreliosis patients.


Container contamination as a possible source of a diarrhoea outbreak in Abou Shouk camp, Darfur province, Sudan.
Diarrhoea is one of the five major causes of death in an emergency setting and one of the three main causes of death in children (Curtis and Cairncross, 2003). In June 2004, an outbreak of shigellosis was confirmed in Abou Shouk camp in the Northern Darfur province of Sudan. As water testing showed no contamination, it was assumed that post-collection contamination was happening. The decision was taken to launch a programme of mass disinfection of all water containers in order to break the contamination cycle. Diarrhoea figures from the clinics showed a fall in cases following the cleaning campaign. It is extremely difficult to obtain good and statistically rigorous data in an emergency setting, the priority being to intervene rapidly to prevent further cases of diarrhoea. However, the results do appear to indicate that the disinfection programme has had an impact on the prevalence of bloody and watery diarrhoea.


Exact solution to simultaneous intensity and phase encryption with a single phase-only hologram.
A phase-only hologram applies a modal transformation to an optical transverse spatial mode via phase encoding and intensity masking. Accurate control of the optical field crucially depends on the method employed to encode the hologram. In this Letter, we present a method to encode the amplitude and the phase of an optical field into a phase-only hologram, which allows the exact control of spatial transverse modes. Any intensity masking method modulates the amplitude and alters the phase of the optical field. Our method consists in correcting for this unwanted phase alteration by modifying the phase encryption accordingly. We experimentally verify the accuracy of our method by applying it to the generation and detection of transverse spatial modes in mutually unbiased bases of dimension two and three.


Defining the Landscape of the Pauling-Corey Rippled Sheet: An Orphaned Motif Finding New Homes.
When peptides are mixed with their mirror images in an equimolar ratio, two-dimensional periodic structural folds can form, in which extended peptide strands are arrayed with alternating chirality. The resultant topography class, termed the rippled β-sheet, was introduced as a theoretical concept by Pauling and Corey in 1953. Unlike other fundamental protein structural motifs identified around that time, including the α-helix and the pleated β-sheet, it took several decades before conclusive experimental data supporting the proposed rippled β-sheet motif were gained. Much of the key experimental evidence was provided over the course of the past decade through the concurrent efforts of our three laboratories. Studies that focused on developing new self-assembling hydrogel materials have shown that certain amphiphilic peptides form fibrils and hydrogel networks that are more rigid and have a higher thermodynamic stability when made from racemic peptide mixtures as opposed to pure enantiomers. Related interrogation of assemblies composed of mixtures of l- and d-amphiphilic peptides confirmed that the resulting fibrils were composed of alternating l/d peptides consistent with rippled β-sheets. It was also demonstrated that mirror-image amyloid beta (Aβ) could act as a molecular chaperone to promote oligomer-to-fibril conversion of the natural Aβ enantiomer, which was found to reduce Aβ neurotoxicity against different neuronal cell models. With a cross-disciplinary approach that combines experiment and theory, our three laboratories have demonstrated the unique biophysical, biochemical, and biological properties that arise upon mixing of peptide enantiomers, in consequence of rippled β-sheet formation. In this Account, we give an overview of the early history of the rippled β-sheet and provide a detailed structural description/definition of this motif relative to the pleated β-sheet. We then summarize the key findings, obtained on three unique sets of aggregating mirror-image peptide pairs through independent efforts of our three laboratories, and use these results to delineate the landscape of the rippled β-sheet structural motif to inspire future studies. Peptide sequence parameters that favor rippled β-sheet assembly are described, along with the accompanying kinetic and thermodynamic properties, as well as the resulting emergent physical properties of the assemblies. The Account then concludes with a brief overview of some key unresolved challenges in this nascent field. There is much potential for future applications of this unique supramolecular motif in the realm of materials design and biomedical research. We hope this Account will stimulate much-needed discussion of this fascinating structural class to eventually produce a fully quantitative, rational framework for the molecular engineering of rippled β-sheets in the future.


Host Genetics and Environment Drive Divergent Responses of Two Resource Sharing Gall-Formers on Norway Spruce: A Common Garden Analysis.
A central issue in the field of community genetics is the expectation that trait variation among genotypes play a defining role in structuring associated species and in forming community phenotypes. Quantifying the existence of such community phenotypes in two common garden environments also has important consequences for our understanding of gene-by-environment interactions at the community level. The existence of community phenotypes has not been evaluated in the crowns of boreal forest trees. In this study we address the influence of tree genetics on needle chemistry and genetic x environment interactions on two gall-inducing adelgid aphids (Adelges spp. and Sacchiphantes spp.) that share the same elongating bud/shoot niche. We examine the hypothesis that the canopies of different genotypes of Norway spruce (Picea abies L.) support different community phenotypes. Three patterns emerged. First, the two gallers show clear differences in their response to host genetics and environment. Whereas genetics significantly affected the abundance of Adelges spp. galls, Sacchiphantes spp. was predominately affected by the environment suggesting that the genetic influence is stronger in Adelges spp. Second, the among family variation in genetically controlled resistance was large, i.e. fullsib families differed as much as 10 fold in susceptibility towards Adelges spp. (0.57 to 6.2 galls/branch). Also, the distribution of chemical profiles was continuous, showing both overlap as well as examples of significant differences among fullsib families. Third, despite the predicted effects of host chemistry on galls, principal component analyses using 31 different phenolic substances showed only limited association with galls and a similarity test showed that trees with similar phenolic chemical characteristics, did not host more similar communities of gallers. Nonetheless, the large genetic variation in trait expression and clear differences in how community members respond to host genetics supports our hypothesis that the canopies of Norway spruce differ in their community phenotypes.


Noribogaine is a G-protein biased κ-opioid receptor agonist.
Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicate that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50=9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6'-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations>1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.


Vitamin A supplementation among children in India: Does their socioeconomic status and the economic and social development status of their State of residence make a difference?
India has the largest percentage/number of vitamin A deficient children in the world. However, the effectiveness of a program of vitamin A supplementation at the population level has been rarely examined. We aim to examine the status of vitamin A supplementation among preschool children in India and its association with their socioeconomic and demographic characteristics and the social and economic development level of the State in which they reside. Data are from a cross-sectional study of 20,802 children aged 12-35 months whose mothers participated in the National Family Health Survey 3 (NFHS-3) conducted during 2005-2006. The association between the socioeconomic and demographic characteristics of the children, the social and economic development status of the State in which they reside and vitamin A supplementation status was examined by means of unadjusted and adjusted logistic regression models. Only 25% of the children in India received vitamin A supplementation, indicating a poor coverage, and the differences between the States were wide (<10% to >45%). Rural children (OR: 1.20; 95% CI: 1.10-1.30; P < 0.0001) and children of educated mothers (OR: 2.40; 95% CI: 2.04-2.83; P < 0.0001) were more likely to receive vitamin A supplementation than others. Children born in a higher birth order (6+) (OR: 0.54; 95% CI: 0.46-0.63; P < 0.0001) and those residing in states with low levels of social and economic development (OR: 0.51; 95% CI: 0.46-0.57; P < 0.0001) were only about half as likely to receive vitamin A supplementation as their counterparts. The national vitamin A supplementation program in India did not reach a majority of preschool children in 2005. Greater maternal formal education, higher household wealth status and high social development status of their State of residence appears to be an important determinant for receipt of a vitamin A supplementation by preschool children in India.


Comparative genotyping of Campylobacter jejuni strains from patients with Guillain-Barré syndrome in Bangladesh.
Campylobacter jejuni is a common cause of acute gastroenteritis and is associated with post-infectious neuropathies such as the Guillain-Barré syndrome (GBS) and the Miller Fisher syndrome (MFS). We here present comparative genotyping of 49 C. jejuni strains from Bangladesh that were recovered from patients with enteritis or GBS. All strains were serotyped and analyzed by lipo-oligosaccharide (LOS) genotyping, amplified fragment length polymorphism (AFLP) analysis, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). C. jejuni HS:23 was a predominant serotype among GBS patients (50%), and no specific serotype was significantly associated with GBS compared to enteritis. PCR screening showed that 38/49 (78%) of strains could be assigned to LOS classes A, B, C, or E. The class A locus (4/7 vs 3/39; p<0.01) was significantly associated in the GBS-related strains as compared to enteritis strains. All GBS/oculomotor related strains contained the class B locus; which was also detected in 46% of control strains. Overlapping clonal groups were defined by MLST, AFLP and PFGE for strains from patients with gastroenteritis and GBS. MLST defined 22 sequence types (STs) and 7 clonal complexes including 7 STs not previously identified (ST-3742, ST-3741, ST-3743, ST-3748, ST-3968, ST-3969 and ST-3970). C. jejuni HS:23 strains from patients with GBS or enteritis were clonal and all strains belonged to ST-403 complex. Concordance between LOS class B and ST-403 complex was revealed. AFLP defined 25 different types at 90% similarity. The predominant AFLP type AF-20 coincided with the C. jejuni HS:23 and ST-403 complex. LOS genotyping, MLST, AFLP and PFGE helped to identify the HS:23 strains from GBS or enteritis patients as clonal. Overall, genotypes exclusive for enteritis or for GBS-related strains were not obtained although LOS class A was significantly associated with GBS strains. Particularly, the presence of a clonal and putative neuropathogenic C. jejuni HS:23 serotype may contribute to the high prevalence of C. jejuni related GBS in Bangladesh.


Probiotics to prevent or treat excessive infant crying: systematic review and meta-analysis.
IMPORTANCE Excessive infant crying is common, distressing, but without proven effective prevention or management options. Probiotics may be a promising solution. OBJECTIVE To examine whether probiotics are effective in the prevention/management of crying ("colic") in infants 3 months or younger. DATA SOURCES A systematic search of MEDLINE, EMBASE, and the Cochrane Library, supplemented by the metaRegister of Controlled Trials. STUDY SELECTION Studies that randomized infants 3 months or younger to oral probiotics vs placebo or no or standard treatment with the outcome of infant crying, measured as the duration or number of episodes of infant crying/distress or diagnosis of "infant colic." Twelve of the 1180 initially identified studies were selected. DATA EXTRACTION AND SYNTHESIS This review/meta-analysis was conducted according to guidelines from the Cochrane Handbook for Systematic Reviews of Interventions, with reporting following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data were independently extracted by 3 of us. MAIN OUTCOME(S) AND MEASURE(S) Infant crying, measured as the duration or number of episodes of infant crying/distress, or diagnosis of "infant colic." RESULTS Of the 12 trials (1825 infants) reviewed, 6 suggested probiotics reduced crying, and 6 did not. Three of the 5 management trials concluded probiotics effectively treat colic in breastfed babies; 1 suggested possible effectiveness in formula-fed babies with colic, and 1 suggested ineffectiveness in breastfed babies with colic. Meta-analysis of 3 small trials of breastfed infants with colic found that Lactobacillus reuteri markedly reduced crying time at 21 days (median difference, -65 minutes/d; 95% CI, -86 to -44). However, all trials had potential biases. Meanwhile, of 7 prevention trials, 2 suggested possible benefits. Considerable variability in the study populations, study type, delivery mode/dose of probiotic supplementation, and outcomes precluded meta-analysis. CONCLUSIONS AND RELEVANCE Although L reuteri may be effective as treatment for crying in exclusively breastfed infants with colic, there is still insufficient evidence to support probiotic use to manage colic, especially in formula-fed infants, or to prevent infant crying. Results from larger rigorously designed studies applicable to all crying infants will help draw more definitive conclusions.


Imaging and Surgical Management of Anorectal Vaginal Fistulas.
Anorectal vaginal fistulas (ARVFs) can result in substantial morbidity and potentially embarrassing symptoms in adult women of all ages. Despite having what may be obvious clinical manifestations, the fistulas themselves can be difficult to identify with imaging. MRI is the modality of choice for the diagnosis and characterization of ARVFs. A dedicated protocol involving the use of vaginal gel and optimized imaging planes with respect to the vagina, as well as an understanding of the MRI pelvic floor anatomy, is crucial for reporting surgically relevant details. Ancillary findings such as postsurgical changes, inflammation, abscess, sphincter destruction, and neoplasm are well evaluated. Vaginography, contrast enema, endoscopic US, and CT can be highly useful complementary diagnostic examinations. The entities that result in ARVFs may be obstetric, inflammatory (eg, Crohn disease and diverticulitis), neoplastic, iatrogenic, and/or radiation induced. Surgical management is heavily dependent on the cause and complexity of the fistulizing disease, which are related to the location of the fistula in the vagina, the type and extent of fistula branching, the number of fistulas, sphincter tears, inflammation, and abscess. ©RSNA, 2018.


Qualitative research into nurse decision making: factors for consideration in theoretical sampling.
This article details some of the theoretical sampling choices available to researchers considering qualitative approaches to research into nurse decision making and the information that informs it. It draws on the theoretical and empirical literature on decision theory and, in so doing, provides a rationale for the theoretical sampling choices proposed. The final sampling frame is designed to be applied to decision research in nursing but could offer starting points for research into the decisions of other professional clinical groups.


Surface chemistry of cadmium sulfide magic-sized clusters: a window into ligand-nanoparticle interactions.
Optoelectronic properties of nanoparticles are intimately coupled to the complex physiochemical interplay between the inorganic core and the organic ligand shell. Magic-sized clusters, which are predominately surface atoms, provide a promising avenue to clarify these critical surface interactions. Whereas these interactions impact the surface of both nanoparticles and magic-sized clusters, we show here that only clusters manifest a shift in the excitonic peak by up to 0.4 eV upon solvent or ligand treatment. These results highlight the utility of the clusters as a probe of ligand-surface interactions.


Reagent-free and portable detection of Bacillus anthracis spores using a microfluidic incubator and smartphone microscope.
Bacillus anthracis is the causative agent of anthrax and can be contracted by humans and herbivorous mammals by inhalation, ingestion, or cutaneous exposure to bacterial spores. Due to its stability and disease potential, B. anthracis is a recognized biothreat agent and robust detection and viability methods are needed to identify spores from unknown samples. Here we report the use of smartphone-based microscopy (SPM) in combination with a simple microfluidic incubation device (MID) to detect 50 to 5000 B. anthracis Sterne spores in 3 to 5 hours. This technique relies on optical monitoring of the conversion of the ∼1 μm spores to the filamentous vegetative cells that range from tens to hundreds of micrometers in length. This distinguishing filament formation is unique to B. anthracis as compared to other members of the Bacillus cereus group. A unique feature of this approach is that the sample integrity is maintained, and the vegetative biomass can be removed from the chip for secondary molecular analysis such as PCR. Compared with existing chip-based and rapid viability PCR methods, this new approach reduces assay time by almost half, and is highly sensitive, specific, and cost effective.


Rapid versus delayed readmission in first-admission psychosis: quality indicators for managed care?
This study examined clinical correlates of rapid readmission to a psychiatric inpatient service (less than 3 months after discharge) compared to delayed readmissions (3-12 months) in first-admission patients diagnosed with schizophrenia, bipolar disorder with psychosis, and major depression with psychosis. After reviewing the clinical records and research summaries of all patients who were readmitted withine 1 year of discharge, we compared the two readmission groups with respect to demographic and clinical characteristics and subsequent clinical course. Rapid readmission was significantly associated with instability of clinical condition at first discharge (especially mood symptoms) and, to a lesser degree, with failure to prescribe specific medication for affective psychosis patients. Regardless of duration of community tenure, readmission was strongly associated with medication nonprescription or discontinuation. The results suggest that managed care protocols aimed at preventing rapid readmission may require specific symptom assessment and pharmacotherapeutic intervention during the initial hospitalization. Readmission can be used as a quality indicator of both clinical processes (hospital vand outpatient care) so long as duration of community tenure prior to readmission is taken into account.


Phonon spectroscopy in a Bi2Te3 nanowire array.
The lattice dynamics in an array of 56 nm diameter Bi2Te3 nanowires embedded in a self-ordered amorphous alumina membrane were investigated microscopically using (125)Te nuclear inelastic scattering. The element specific density of phonon states is measured on nanowires in two perpendicular orientations and the speed of sound is extracted. Combined high energy synchrotron radiation diffraction and transmission electron microscopy was carried out on the same sample and the crystallinity was investigated. The nanowires grow almost perpendicular to the c-axis, partly with twinning. The average speed of sound in the 56 nm diameter Bi2Te3 nanowires is ~7% smaller with respect to bulk Bi2Te3 and a decrease in the macroscopic lattice thermal conductivity by ~13% due to nanostructuration and to the reduced speed of sound is predicted.


Cyclosporin A and PSC 833 prevent up-regulation of MDR1 expression by anthracyclines in a human multidrug-resistant cell line.
We have previously demonstrated that within 24 h of exposure of the CEM/A7R cell line to epirubicin (EPI), MDR1 gene expression is induced. The aim of the current study was to investigate the role of cyclosporin A (CyA) and PSC 833, two biochemical modulators of the classical multidrug-resistant phenotype, in this model. CEM/A7R cells were exposed to EPI in the presence or absence of various concentrations of CyA or PSC 833. MDR1 expression was assessed using Northern blot analysis and quantitated using a phosphorimager. P-glycoprotein (P-gp) expression was analyzed by the determination of MRK16 binding using flow cytometry. P-gp function was measured in an assay of [3H]daunomycin accumulation. The coincubation of CyA or PSC 833 with EPI prevented the increase in MDR1 gene expression induced by EPI alone. This effect of the two modulators was dose dependent. Neither modulator alone had any significant effect on the expression of MDR1. In these experiments, changes in MDR1 expression correlated with changes in P-gp levels (based on MRK16 binding) and P-gp function. Thus, both PSC 833 and CyA appear to prevent the induction of MDR1 gene expression caused by the short-term exposure of CEM/A7R cells to EPI.


HIV in Indian MSM: reasons for a concentrated epidemic & strategies for prevention.
Men who have sex with men (MSM) in India are disproportionately likely to be HIV-infected, and face distinct psychosocial challenges. Understanding the unique socio-cultural issues of MSM in India and how they relate to HIV risk could maximize the utility of future prevention efforts. This review discusses: (i) the importance of addressing co-occurring mental health issues, such as depression, which may interfere with MSM's ability to benefit from traditional risk reduction counselling, (ii) reducing HIV-related stigma among health providers, policymakers and the lay public, and (iii) the role for non-governmental organizations that work with the community to play in providing culturally relevant HIV prevention programmes for MSM.


Topographical variation in glycosaminoglycan content in human articular cartilage.
The weight-bearing status of articular cartilage has been shown to affect its biochemical composition. We have investigated the topographical variation of sulphated glycosaminoglycan (GAG) relative to the DNA content of the chondrocyte in human distal femoral articular cartilage. Paired specimens of distal femoral articular cartilage, from weight-bearing and non-weight-bearing regions, were obtained from 13 patients undergoing above-knee amputation. After papain enzyme digestion, spectrophotometric GAG and fluorometric DNA assays assessed the biochemical composition of the samples. The results were analysed using a paired t-test. Although there were no significant differences in cell density between the regions, the weight-bearing areas showed a significantly higher concentration of GAG relative to DNA when compared with non-weight-bearing areas (p = 0.02). We conclude that chondrocytes are sensitive to their mechanical environment, and that local loading conditions influence the metabolism of the cells and hence the biochemical structure of the tissue.


Cell-free DNA and telomere length among women undergoing in vitro fertilization treatment.
The current research is aimed at finding potential non-invasive bio-markers that will help us learn more about the mechanisms at play in failed assisted reproduction treatment. This exploratory pilot study examined the relationship between cell-free DNA (CFD) in plasma and telomere length in lymphocytes among women undergoing in vitro fertilization (IVF) and compared telomere length and CFD levels to a healthy control group. Blood of 20 women undergoing IVF was collected at three time points during the IVF cycle. We assessed the relationship between CFD and telomere length as well as controlling for morning cortisol levels. We also collected blood of 10 healthy controls at two time points (luteal and follicular phases of the menstrual cycle) and compared mean telomere length, CFD, and cortisol levels between the IVF patients and healthy controls. The results revealed an inverse relationship between CFD levels and telomere lengths at several time points that remained significant even after controlling for cortisol levels. Women undergoing IVF had statistically significant higher levels of CFD and shorter telomeres compared to healthy controls. The relationship between telomere length and CFD should be further explored in larger studies in order to uncover potential mechanisms that cause both shortened telomere length and elevated CFD in women undergoing IVF.


Noninvasive structural, functional, and molecular imaging in drug development.
Modern drug research is mechanism-based and the development of disease modifying therapies involves the identification of molecular key players in the pathological cascade. Today, noninvasive imaging tools enable the visualization and quantitative assessment of the expression of molecular targets, of their interaction with potential ligands, as well as of the functional consequence of this interaction at a molecular (e.g. activation of signaling cascades), cellular, metabolic, physiological, and morphological level in a temporo-spatially resolved manner. The ability to gather such information from the intact organism with all regulatory processes in place renders imaging highly attractive for the biomedical researcher and for the drug developer in particular. Molecular imaging is potentially capable of providing this information. Today, proof-of-principle has been established that imaging is in fact adding value to the drug discovery and development processes. Numerous studies have used structural and functional imaging readouts to document therapy efficacy, mainly during lead optimization. Similarly, major efforts have been devoted to the development and evaluation of imaging biomarkers that might serve as early readouts for therapy response with the potential of being used in the clinical drug evaluation thereby facilitating translational research. In this contribution, we illustrate the role and potential of imaging in modern drug discovery and development with selected examples. Yet, despite its huge potential the impact of imaging on drug discovery has been modest in the past; potential reasons will be discussed. Nevertheless, noninvasive imaging methods are rapidly evolving and it is beyond doubt that their importance for biomedical research will increase.


Heavy-electron metals: new highly correlated States of matter.
Heavy-electron metals exhibit highly correlated electronic behavior at liquid helium temperatures, with conduction-electron masses some hundred times the free-electron mass. Whether "normal," antiferromagnetic, or superconducting, their electronic behavior differs drastically from their ordinary metallic counterparts. The physical origin of the large mass and unusual superconducting and magnetic properties is the strong coupling between the conduction electrons and the local f-electron moment fluctuations characteristic of these materials.


A model for the involvement of neural cell adhesion molecules in stress-related mood disorders.
Critical interactions between genetic and environmental factors -- among which stress is one of the most potent non-genomic factors -- are involved in the development of mood disorders. Intensive work during the past decade has led to the proposal of the network hypothesis of depression [Castren E: Nat Rev Neurosci 2005;6:241-246]. In contrast to the earlier chemical hypothesis of depression that emphasized neurochemical imbalance as the cause of depression, the network hypothesis proposes that problems in information processing within relevant neural networks might underlie mood disorders. Clinical and preclinical evidence supporting this hypothesis are mainly based on observations from depressed patients and animal stress models indicating atrophy (with basic research pointing at structural remodeling and decreased neurogenesis as underlying mechanisms) and malfunctioning of the hippocampus and prefrontal cortex, as well as the ability of antidepressant treatments to have the opposite effects. A great research effort is devoted to identify the molecular mechanisms that are responsible for the network effects of depression and antidepressant actions, with a great deal of evidence pointing at a key role of neurotrophins (notably the brain-derived neurotrophic factor) and other growth factors. In this review, we present evidence that implicates alterations in the levels of the neural cell adhesion molecules of the immunoglobulin superfamily, NCAM and L1, among the mechanisms contributing to stress-related mood disorders and, potentially, in antidepressant action.


Eutrophication and recovery in experimental lakes: implications for lake management.
Combinations of phosphorus, nitrogen, and carbon were added to several small lakes in northwestern Ontario, Canada, at rates similar to those in many culturally eutrophied lakes. Phosphate and nitrate caused rapid eutrophication. A similar result was obtained with phosphate, ammonia, and sucrose, but recovery was almost immediate when phosphate additions only were discontinued. When two basins of one lake were fertilized with equal amounts of nitrate and sucrose, and phosphorus was also added to one of the basins, the phosphateenriched basin quickly became highly eutrophic, while the basin receiving only nitrogen and carbon remained at prefertilization conditions. These results, and the high affinity of sediments for phosphorus indicate that rapid abatement of eutrophication may be expected to follow phosphorus control measures.


Early Career Outcomes of Family Medicine Residency Graduates Exposed to Innovative Flexible Longitudinal Tracks.
The Preparing the Personal Physician for Practice (P4) project used a case series design to study innovations in the content, length, structure, and location of residency training in 14 geographically diverse family medicine programs between 2007 and 2012. We aimed to explore how offering flexible longitudinal tracks (FLT) affected graduates' scope of practice, particularly in maternal child health (MCH), which included at least 17 months of focused training that increased each year over 4 years. We administered a cross-sectional survey to graduates of P4 residencies approximately 18 months after they completed training (2011-2014) and compared graduates of the John Peter Smith (JPS) Family Medicine Residency MCH FLT to all other P4 graduates. The overall response rate was 81.8% (365/446). JPS graduates who completed the flexible MCH track (n=15) compared to all other P4 graduates (n=332) were more likely to deliver babies (13/15, 86.7% versus 48/324, 14.6%) and perform C-sections as the primary surgeon (12/15, 80.0% versus 15/322, 4.7%). Additional areas of expanded scope associated with the MCH track included endoscopy (4/15, 26.7% versus 10/323, 3.1%), the care of hospitalized adults and associated procedures (central lines, eg: 8/15, 53.3% versus 47/322, 14.6%), and the care of hospitalized children (13/15, 86.7% versus 111/323, 34.4%). Graduating from the JPS MCH FLT was associated with a higher provision of maternal, child, and ill adult patient care services, including associated procedures.