Difference of motor overflow depending on the impaired or unimpaired hand in stroke patients.
The aim of this study was to investigate the patterns of contralateral motor overflow (i.e. mirror movement) between the homologous body parts on the right and left side, in stroke patients during single-finger and multi-finger maximum force production tasks. Forty subjects, including stroke (n=20) and normal subjects (n=20), participated in this study. The stroke subjects maximally pressed force sensors with their fingers in a flexed position using a single (index, middle, ring, or little) or all fingers (all 4 fingers) using the impaired (IH) or unimpaired (UIH) hand, while the non-patient subjects used their right hands for the same tasks. The maximal voluntary forces in the ipsilateral and unintended pressing forces of each contralateral finger were recorded during the tasks. The magnitude of motor overflow to the contralateral side was calculated using the index of contralateral independence (CI). During the single finger tasks, the finger CI was significantly decreased in the UIH (91%) compared with that in the IH (99%) or normal hands (99%). Likewise, the multiple finger tasks showed that the CI was significantly lower in the UIH (84%) compared with that in the IH (96%) or normal hands (99%). However, the maximal forces were significantly lower in the IH relative to those in the UIH and normal hands. These data demonstrate that stroke patients have greater motor overflow from the UIH to the IH.


Cross-talk between phospho-STAT3 and PLCγ1 plays a critical role in colorectal tumorigenesis.
Hyperphosphorylation at the Y705 residue of signal transducer and activator of transcription 3 (STAT3) is implicated in tumorigenesis of leukemia and some solid tumors. However, its role in the development of colorectal cancer is not well defined. To rigorously test the impact of this phosphorylation on colorectal tumorigenesis, we engineered a STAT3 Y705F knock-in to interrupt STAT3 activity in HCT116 and RKO colorectal cancer cells. These STAT3 Y705F mutant cells fail to respond to cytokine stimulation and grow slower than parental cells. These mutant cells are also greatly diminished in their abilities to form colonies in culture, to exhibit anchorage-independent growth in soft agar, and to grow as xenografts in nude mice. These observations strongly support the premise that STAT3 Y705 phosphorylation is crucial in colorectal tumorigenesis. Although it is generally believed that STAT3 functions as a transcription factor, recent studies indicate that transcription-independent functions of STAT3 also play an important role in tumorigenesis. We show here that wild-type STAT3, but not STAT3 Y705F mutant protein, associates with phospholipase Cγ1 (PLCγ1). PLCγ1 is a central signal transducer of growth factor and cytokine signaling pathways that are involved in tumorigenesis. In STAT3 Y705F mutant colorectal cancer cells, PLCγ1 activity is reduced. Moreover, overexpression of a constitutively active form of PLCγ1 rescues the transformation defect of STAT3 Y705F mutant cells. In aggregate, our study identifies previously unknown cross-talk between STAT3 and the PLCγ signaling pathways that may play a critical role in colorectal tumorigenesis.


Neurodevelopmental implications of ocular motor apraxia.
Ocular motor apraxia (OMA), a disorder of saccadic initiation, may be congenital or acquired. While the acquired form is frequently associated with significant neuropathology, the congenital form is often regarded as relatively benign. Many children with congenital OMA who were observed clinically have shown neurodevelopmental disturbance over time. A retrospective review was taken of 34 consecutive patients (22 males and 12 females), seen over a 20-year period, to evaluate the frequency and type of associated neurodevelopmental problems. Age at presentation ranged from 8 weeks to 14 years, with a mean age of 10 years. Of 29 children with congenital OMA, 15 had imaging evidence of structural central nervous system abnormalities (with cerebellar hypoplasia the most frequent abnormality detected). Eleven of the 14 patients with no structural abnormality showed abnormal neurodevelopment. This study suggests that congenital OMA is not a benign diagnosis, even in the absence of overt neurological disturbance at the time of presentation.


Role of diversity on the singular values of linear scattering operators: the case of strip objects.
The singular value decomposition of the far-zone scattering operator for weak strip-like scattering objects is studied under multiple view and/or multiple frequency illuminations. The aim is to highlight how such diversities impact the number of degrees of freedom (NDF) of the scattering problem. When the angles of incidence and/or frequencies vary within discrete finite sets, the singular values are analytically determined. It is shown that they exhibit a multistep behavior. For the continuous case, upper and lower bounds are found, which allows us to obtain estimations for the NDF dependending on the parameters of the configuration.


Algal toxin impairs sea lion memory and hippocampal connectivity, with implications for strandings.
Domoic acid (DA) is a naturally occurring neurotoxin known to harm marine animals. DA-producing algal blooms are increasing in size and frequency. Although chronic exposure is known to produce brain lesions, the influence of DA toxicosis on behavior in wild animals is unknown. We showed, in a large sample of wild sea lions, that spatial memory deficits are predicted by the extent of right dorsal hippocampal lesions related to natural exposure to DA and that exposure also disrupts hippocampal-thalamic brain networks. Because sea lions are dynamic foragers that rely on flexible navigation, impaired spatial memory may affect survival in the wild.


From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure.
Manganism is a distinct medical condition from Parkinson's disease. Manganese exposure scenarios in the last century generally have changed from the acute, high-level exposure conditions responsible for the occurrence of manganism to chronic exposure to much lower levels. Such chronic exposures may progressively extend the site of manganese deposition and toxicity from the globus pallidus to the entire area of the basal ganglia, including the substantia nigra pars compacta involved in Parkinson's disease. The mechanisms of manganese neurotoxicity from chronic exposure to very low levels are not well understood, but promising information is based on the concept of susceptibility that may place individuals exposed to manganese at a higher risk for developing Parkinsonian disturbances. These conditions include mutations of genes which play important pathogenetic roles in both Parkinsonism and in the regulation of manganese transport and metabolism. Liver function is also important in manganese-related neurotoxicity and sub-clinical impairment may increase the risk of Parkinsonism. The purpose and scope of this report are to explore the literature concerning manganese exposure and potential subclinical effects and biological pathways, impairment, and development of diseases such as Parkinsonism and manganism. Inhalation and ingestion of manganese will be the focus of this report.


Human dignity of patients with cardiovascular disease admitted to hospitals of Kerman, Iran, in 2015.
The human dignity of patients with cardiovascular disease (CVD) is an important issue, because of patients' dependence upon caregivers, and because it impacts all aspects of their quality of life (QOL). Therefore, understanding and improving the status of dignity among these patients is of great importance. This study aimed to determine the status of dignity in patients with CVD admitted to cardiac intensive care units (CICUs) in Iran. This cross-sectional descriptive study was performed in 2015 on 200 patients admitted to the CICUs of hospitals affiliated to Kerman University of Medical Sciences, Iran. The participants were selected using random sampling method. Patients' understanding of dignity was assessed through the reliable and valid Persian version of the Patient Dignity Inventory (PDI). Patients who were able to read and write or speak Persian and were conscious were included in the study. Data were analyzed using descriptive statistics tests, independent t-test, and one-way ANOVA in SPSS software. The mean age of the study participants was 59.0 ± 17.0. The mean score of human dignity was 3.60 ± 1.39. The mean scores of the factors of loss of independence, emotional distress and uncertainty, changes in ability and mental image, and the loss of human dignity were 3.94 ± 1.06, 3.63 ± 1.37, 3.57 ± 1.20, and 3.30 ± 2.08, respectively. A significant statistical correlation was observed between human dignity and the demographic characteristics of gender and frequency of hospitalizations in a CICU and a significant difference between those who lived alone and those who lived with family was observed (P < 0.05). Patients hospitalized in CICUs experience numerous problems associated with human dignity in each of its four dimensions. It is recommended that a study be conducted to investigate the relationship between the human dignity of patients with CVD and their QOL, anxiety, and depression.


Covert singing in anticipatory auditory imagery.
To date, several fMRI studies reveal activation in motor planning areas during musical auditory imagery. We addressed whether such activations may give rise to peripheral motor activity, termed subvocalization or covert singing, using surface electromyography. Sensors placed on extrinsic laryngeal muscles, facial muscles, and a control site on the bicep measured muscle activity during auditory imagery that preceded singing, as well as during the completion of a visual imagery task. Greater activation was found in laryngeal and lip muscles for auditory than for visual imagery tasks, whereas no differences across tasks were found for other sensors. Furthermore, less accurate singers exhibited greater laryngeal activity during auditory imagery than did more accurate singers. This suggests that subvocalization may be used as a strategy to facilitate auditory imagery, which appears to be degraded in inaccurate singers. Taken together, these results suggest that subvocalization may play a role in anticipatory auditory imagery, and possibly as a way of supplementing motor associations with auditory imagery.


Creating Hierarchical Topographies on Fibrous Platforms Using Femtosecond Laser Ablation for Directing Myoblasts Behavior.
Developing an artificial extracellular matrix that closely mimics the native tissue microenvironment is important for use as both a cell culture platform for controlling cell fate and an in vitro model system for investigating the role of the cellular microenvironment. Electrospinning, one of the methods for fabricating structures that mimic the native ECM, is a promising technique for creating fibrous platforms. It is well-known that align or randomly distributed electrospun fibers provide cellular contact guidance in a single pattern. However, native tissues have hierarchical structures, i.e., topographies on the micro- and nanoscales, rather than a single structure. Thus, we fabricated randomly distributed nanofibrous (720 ± 80 nm in diameter) platforms via a conventional electrospinning process, and then we generated microscale grooves using a femtosecond laser ablation process to develop engineered fibrous platforms with patterned hierarchical topographies. The engineered fibrous platforms can regulate cellular adhesive morphology, proliferation, and distinct distribution of focal adhesion proteins. Furthermore, confluent myoblasts cultured on the engineered fibrous platforms revealed that the direction of myotube assembly can be controlled. These results indicate that our engineered fibrous platforms may be useful tools in investigating the roles of nano- and microscale topographies in the communication between cells and ECM.


Pre-steady-state kinetics of RB69 DNA polymerase and its exo domain mutants: effect of pH and thiophosphoryl linkages on 3'-5' exonuclease activity.
DNA polymerases from the A and B families with 3'-5' exonucleolytic activity have exonuclease domains with similar three-dimensional structures that require two divalent metal ions for catalysis. B family DNA polymerases that are part of a replicase generally have a more potent 3'-5' exonuclease (exo) activity than A family DNA polymerases that mainly function in DNA repair. To investigate the basis for these differences, we determined pH-activity profiles for the exonuclease reactions of T4, RB69, and phi29 DNA polymerases as representatives of B family replicative DNA polymerases and the Klenow fragment (KF) as an example of a repair DNA polymerase in the A family. We performed exo assays under single-turnover conditions and found that excision rates exhibited by the B family DNA polymerases were essentially independent of pH between pH 6.5 and 8.5, whereas the exo activity of KF increased 10-fold for each unit increase in pH. Three exo domain mutants of RB69 polymerase had much lower exo activities than the wild-type enzyme and exhibited pH-activity profiles similar to that of KF. On the basis of pH versus activity data and elemental effects obtained using short double-stranded DNA substrates terminating in phosphorothioate linkages, we suggest that the rate of the chemical step is reduced to the point where it becomes limiting with RB69 pol mutants K302A, Y323F, and E116A, in contrast to the wild-type enzyme where chemistry is faster than the rate-determining step that precedes it.


Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.
The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.


Tobacco industry research on smoking cessation. Recapturing young adults and other recent quitters.
Smoking rates are declining in the United States, except for young adults (age 18 to 24). Few organized programs target smoking cessation specifically for young adults, except programs for pregnant women. In contrast, the tobacco industry has invested much time and money studying young adult smoking patterns. Some of these data are now available in documents released through litigation. Review tobacco industry marketing research on smoking cessation to guide new interventions and improve clinical practice, particularly to address young adult smokers' needs. Analysis of previously secret tobacco industry documents. Compared to their share of the smoking population, young adult smokers have the highest spontaneous quitting rates. About 10% to 30% of smokers want to quit; light smokers and brand switchers are more likely to try. Tobacco companies attempted to deter quitting by developing products that appeared to be less addictive or more socially acceptable. Contrary to consumer expectations, "ultra low tar" cigarette smokers were actually less likely to quit. Tobacco industry views of young adult quitting behavior contrast with clinical practice. Tobacco marketers concentrate on recapturing young quitters, while organized smoking cessation programs are primarily used by older smokers. As young people have both the greatest propensity to quit and the greatest potential benefits from smoking cessation, targeted programs for young adults are needed. Tobacco marketing data suggest that aspirational messages that decrease the social acceptability of smoking and support smoke-free environments resonate best with young adult smokers' motivations.


Subcapsular liver hematoma after fibrinolytic therapy for acute myocardial infarction: a rare case report.
Hemorrhagic complications of thrombolytic therapy are rare but also serious and sometimes life-threatening. Liver hematoma is a very uncommon complication following thrombolytic therapy. We present a rare case of sub-capsular liver hematoma following streptokinase therapy of acute myocardial infarction as a challenging condition. This case report highlights that emergency physicians and cardiologists should be familiar with the significant and uncommon complications of thrombolytic agents, particularly streptokinase which is used generally in under- developed countries.


Grading and interpretation of white matter hyperintensities using statistical maps.
We aimed to generate rigorous graphical and statistical reference data based on volumetric measurements for assessing the relative severity of white matter hyperintensities (WMHs) in patients with stroke. We prospectively mapped WMHs from 2699 patients with first-ever ischemic stroke (mean age=66.8±13.0 years) enrolled consecutively from 11 nationwide stroke centers, from patient (fluid-attenuated-inversion-recovery) MRIs onto a standard brain template set. Using multivariable analyses, we assessed the impact of major (age/hypertension) and minor risk factors on WMH variability. We have produced a large reference data library showing the location and quantity of WMHs as topographical frequency-volume maps. This easy-to-use graphical reference data set allows the quantitative estimation of the severity of WMH as a percentile rank score. For all patients (median age=69 years), multivariable analysis showed that age, hypertension, atrial fibrillation, and left ventricular hypertrophy were independently associated with increasing WMH (0-9.4%, median=0.6%, of the measured brain volume). For younger (≤69) hypertensives (n=819), age and left ventricular hypertrophy were positively associated with WMH. For older (≥70) hypertensives (n=944), age and cholesterol had positive relationships with WMH, whereas diabetes mellitus, hyperlipidemia, and atrial fibrillation had negative relationships with WMH. For younger nonhypertensives (n=578), age and diabetes mellitus were positively related to WMH. For older nonhypertensives (n=328), only age was positively associated with WMH. We have generated a novel graphical WMH grading (Kim statistical WMH scoring) system, correlated to risk factors and adjusted for age/hypertension. Further studies are required to confirm whether the combined data set allows grading of WMH burden in individual patients and a tailored patient-specific interpretation in ischemic stroke-related clinical practice.


Smartphone use and smartphone addiction among young people in Switzerland.
Smartphone addiction, its association with smartphone use, and its predictors have not yet been studied in a European sample. This study investigated indicators of smartphone use, smartphone addiction, and their associations with demographic and health behaviour-related variables in young people. A convenience sample of 1,519 students from 127 Swiss vocational school classes participated in a survey assessing demographic and health-related characteristics as well as indicators of smartphone use and addiction. Smartphone addiction was assessed using a short version of the Smartphone Addiction Scale for Adolescents (SAS-SV). Logistic regression analyses were conducted to investigate demographic and health-related predictors of smartphone addiction. Smartphone addiction occurred in 256 (16.9%) of the 1,519 students. Longer duration of smartphone use on a typical day, a shorter time period until first smartphone use in the morning, and reporting that social networking was the most personally relevant smartphone function were associated with smartphone addiction. Smartphone addiction was more prevalent in younger adolescents (15-16 years) compared with young adults (19 years and older), students with both parents born outside Switzerland, persons reporting lower physical activity, and those reporting higher stress. Alcohol and tobacco consumption were unrelated to smartphone addiction. Different indicators of smartphone use are associated with smartphone addiction and subgroups of young people have a higher prevalence of smartphone addiction. The study provides the first insights into smartphone use, smartphone addiction, and predictors of smartphone addiction in young people from a European country, which should be extended in further studies.


Tailoring Porphyrin Conjugation for Nanoassembly-Driven Phototheranostic Properties.
Lipoprotein mimetic nanostructures, which consist of an amphiphilic lipid shell, a hydrophobic core, and an apolipoprotein mimetic peptide, serve as a versatile platform for the design of drug delivery vehicles as well as the investigation of supramolecular assemblies. Porphyrin incorporation into biomimetic lipoproteins allows one to take advantage of the inherent multimodal photophysical properties of porphyrins, yielding various fluorescence, photoacoustic, and photodynamic agents. To facilitate their incorporation into a lipoprotein structure, porphyrins have been conjugated through a variety of strategies. However, the effects of the conjugate structure on the associated nanoparticle's phototherapeutic properties warrants further investigation. Herein, we systematically investigated the effects of two widely utilized porphyrin conjugates, oleylamide and lipid, on biophotonic properties of their resultant porphyrin-lipoprotein nanoparticles in vitro and in vivo. Specifically, we demonstrated that incorporation of the porphyrin moiety as an oleylamide conjugate leads to a highly stable J-aggregate with strong photoacoustic contrast, while incorporation as an ampiphilic lipid moiety into the lipid shell yields an effective fluorescent and photodynamic agent. The current study proposes a rational design strategy for next-generation lipoprotein-based phototheranostic agents, for which nanoassembly-driven biophotonic and therapeutic properties can be tailored through the specific selection of porphyrin conjugate structures.


Regulation of protein turnover by heat shock proteins.
Protein turnover reflects the balance between synthesis and degradation of proteins, and it is a crucial process for the maintenance of the cellular protein pool. The folding of proteins, refolding of misfolded proteins, and also degradation of misfolded and damaged proteins are involved in the protein quality control (PQC) system. Correct protein folding and degradation are controlled by many different factors, one of the most important of which is the heat shock protein family. Heat shock proteins (HSPs) are in the class of molecular chaperones, which may prevent the inappropriate interaction of proteins and induce correct folding. On the other hand, these proteins play significant roles in the degradation pathways, including endoplasmic reticulum-associated degradation (ERAD), the ubiquitin-proteasome system, and autophagy. This review focuses on the emerging role of HSPs in the regulation of protein turnover; the effects of HSPs on the degradation machineries ERAD, autophagy, and proteasome; as well as the role of posttranslational modifications in the PQC system.


A long noncoding RNA connects c-Myc to tumor metabolism.
Long noncoding RNAs (lncRNAs) have been implicated in a variety of physiological and pathological processes, including cancer. In prostate cancer, prostate cancer gene expression marker 1 (PCGEM1) is an androgen-induced prostate-specific lncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenic potential has been recently shown to be in part due to its ability to activate androgen receptor (AR). Here, we report a novel function of PCGEM1 that provides growth advantages for cancer cells by regulating tumor metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with the pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates metabolism at a transcriptional level that affects multiple metabolic pathways, including glucose and glutamine metabolism, the pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and the tricarboxylic acid cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation, regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified a c-Myc binding domain on PCGEM1 that contributes to the PCGEM1-dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cells. By being a coactivator for both c-Myc and AR, PCGEM1 reprograms the androgen network and the central metabolism in a tumor-specific way, making it a promising target for therapeutic intervention.


Evaluation of a classroom-based psychosocial intervention in conflict-affected Nepal: a cluster randomized controlled trial.
In situations of ongoing violence, childhood psychosocial and mental health problems require care. However, resources and evidence for adequate interventions are scarce for children in low- and middle-income countries. This study evaluated a school-based psychosocial intervention in conflict-affected, rural Nepal. A cluster randomized controlled trial was used to evaluate changes on a range of indicators, including psychiatric symptoms (depression, anxiety, posttraumatic stress disorder), psychological difficulties, resilience indicators (hope, prosocial behavior) and function impairment. Children (n = 325) (mean age = 12.7, SD = 1.04, range 11-14 years) with elevated psychosocial distress were allocated to a treatment or waitlist group. Comparisons of crude change scores showed significant between-group differences on several outcome indicators, with moderate effect sizes (Cohen d = .41 to .58). After correcting for nested variance within schools, no evidence for treatment effects was found on any outcome variable. Additional analyses showed gender effects for treatment on prosocial behavior (mean change difference: 2.70; 95% CI, .97 to 4.44), psychological difficulties (-2.19; 95% CI, -3.82 to -.56), and aggression (-4.42; 95% CI, -6.16 to -2.67). An age effect for treatment was found for hope (.90; 95% CI, -1.54 to -.26). A school-based psychosocial intervention demonstrated moderate short-term beneficial effects for improving social-behavioral and resilience indicators among subgroups of children exposed to armed conflict. The intervention reduced psychological difficulties and aggression among boys, increased prosocial behavior among girls, and increased hope for older children. The intervention did not result in reduction of psychiatric symptoms.


Exercise training and NR supplementation to improve muscle mass and fitness in adolescent and young adult hematopoietic cell transplant survivors: a randomized controlled trial {1}.
Advances in hematopoietic cell transplantation (HCT) have led to marked improvements in survival. However, adolescents and young adults (AYAs) who undergo HCT are at high risk of developing sarcopenia (loss of skeletal muscle mass) due to the impact of HCT-related exposures on the developing musculoskeletal system. HCT survivors who have sarcopenia also have excess lifetime risk of non-relapse mortality. Therefore, interventions that increase skeletal muscle mass, metabolism, strength, and function are needed to improve health in AYA HCT survivors. Skeletal muscle is highly reliant on mitochondrial energy production, as reflected by oxidative phosphorylation (OXPHOS) capacity. Exercise is one approach to target skeletal muscle mitochondrial OXPHOS, and in turn improve muscle function and strength. Another approach is to use "exercise enhancers", such as nicotinamide riboside (NR), a safe and well-tolerated precursor of nicotinamide adenine dinucleotide (NAD+), a cofactor that in turn impacts muscle energy production. Interventions combining exercise with exercise enhancers like NR hold promise, but have not yet been rigorously tested in AYA HCT survivors. We will perform a randomized controlled trial testing 16 weeks of in-home aerobic and resistance exercise and NR in AYA HCT survivors, with a primary outcome of muscle strength via dynamometry and a key secondary outcome of cardiovascular fitness via cardiopulmonary exercise testing. We will also test the effects of these interventions on i) muscle mass via dual energy x-ray absorptiometry; ii) muscle mitochondrial OXPHOS via an innovative non-invasive MRI-based technique, and iii) circulating correlates of NAD+ metabolism via metabolomics. Eighty AYAs (ages 15-30y) will be recruited 6-24 months post-HCT and randomized to 1 of 4 arms: exercise + NR, exercise alone, NR alone, or control. Outcomes will be collected at baseline and after the 16-week intervention. We expect that exercise with NR will produce larger changes than exercise alone in key outcomes, and that changes will be mediated by increases in muscle OXPHOS. We will apply the insights gained from this trial to develop individualized, evidence-supported precision initiatives that will reduce chronic disease burden in high-risk cancer survivors. ClinicalTrials.gov, NCT05194397. Registered January 18, 2022, https://clinicaltrials.gov/ct2/show/NCT05194397 {2a}.


PEPCK gene as model of inhibitory effects of insulin on gene transcription.
Regulation of gene transcription is a major action of insulin. Most of the greater than 20 examples of this effect involve the stimulation of transcription, but a few involve an inhibition. The inhibition of transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene has been studied in detail. Most of this effect is exerted at the level of transcription initiation. Hormone effects on transcription are thought to be mediated through cis-acting DNA sequences located in the 5'-flanking sequence adjacent to the transcription initiation site. The techniques of transient and stable transfection of fusion genes containing various segments of the PEPCK-gene promoter are being used to locate the insulin-responsive sequences.


Human alveolar macrophages: HLA-DR-positive macrophages that are poor stimulators of a primary mixed leukocyte reaction.
Previous studies demonstrated that alveolar macrophages (AM) from most normal human volunteers failed to stimulate the antigen-induced proliferation of peripheral blood T lymphocytes although greater than 90% of AM expressed HLA-DR antigens. The current studies establish that AM also fail to induce allogeneic peripheral blood mononuclear cells to proliferate in a mixed leukocyte reaction (MLR). Suppressive activity by AM was not an explanation for their failure to induce an MLR. Indirect immunofluorescence established the presence of both HLA-DR and DQ antigens on the majority of AM and the persistence of these antigens on cells in culture for up to 6 days, the period of time required to observe a maximal MLR. Metabolic labeling experiments also demonstrated that HLA-DR antigens were synthesized by AM. It was recently reported that AM secrete relatively small amounts of IL 1, an important ancillary signal provided by accessory cells to enhance the stimulation of lymphocyte proliferation. However, addition of optimal concentrations of IL 1 to cultures containing AM failed to enhance the MLR. Thus, there is at least one additional, but as yet undefined, requirement for an accessory cell to induce an optimal MLR besides the display of HLA-D region antigens and the secretion of IL 1. In contrast, AM were effective in specifically stimulating proliferation of alloreactive T cell lines, suggesting that at least some cell lines do not require this nonspecific undefined second signal. We speculate that although AM may not initiate primary immune responses in the lung, they may be important in maintaining immune-mediated inflammatory responses by specifically restimulating already activated T cells.


Influence of the fusiform gyrus on amygdala response to emotional faces in the non-clinical range of social anxiety.
Social anxiety often involves a combination of hypervigilance and avoidance to potentially warning signals including the facial expression of emotions. Functional imaging has demonstrated an increase in amygdala response to emotional faces in subjects with social anxiety. Nevertheless, it is unclear to what extent visual areas processing faces influence amygdala reactivity in different socially anxious individuals. We assessed the influence of the fusiform gyrus activation on amygdala response to emotional faces in the non-clinical range of social anxiety. Twenty-two normal subjects showing a wide range in social anxiety scores were examined using functional magnetic resonance imaging (fMRI) during the processing of happy and fearful faces. A dimensional analysis approach was used involving voxel-wise mapping of the correlation between subjects' social anxiety scores and amygdala activation, before and after controlling for fusiform gyrus activation. We observed that only after controlling for subjects' level of activation of the fusiform gyrus was there an association between social anxiety ratings and amygdala response to both happy and fearful faces. The fusiform gyrus influence was more robust during the fear condition. Of note, fusiform gyrus response to fearful faces showed a negative correlation with additional behavioral assessments related to avoidance, including social anxiety scores, harm avoidance and sensitivity to punishment. Relevant interactions among the emotional face-processing stages exist in the non-clinical range of social anxiety that may ultimately attenuate amygdala responses. Future research will help to establish the role of this effect in a clinical context.


The effects of compression garments on performance of prolonged manual-labour exercise and recovery.
This study investigated the effects of wearing compression garments during and 24 h following a 4-h exercise protocol simulating manual-labour tasks. Ten physically trained male participants, familiar with labouring activities, undertook 4 h of work tasks characteristic of industrial workplaces. Participants completed 2 testing sessions, separated by at least 1 week. In the experimental condition, participants wore a full-length compression top and compression shorts during the exercise protocol and overnight recovery, with normal work clothes worn in the control condition. Testing for serum creatine kinase and C-reactive protein, handgrip strength, knee flexion and extension torque, muscle stiffness, perceived muscle soreness and fatigue as well as heart rate and rating of perceived exertion (RPE) responses to 4-min cycling were performed before, following, and 24 h after exercise. Creatine kinase, muscle soreness, and rating of perceived fatigue increased following the exercise protocol (p < 0.05) as did RPE to a standardised cycling warm-up bout. Conversely, no postexercise changes were observed in C-reactive protein, handgrip strength, peak knee flexion torque, or stiffness measures (p > 0.05). Knee extension torque was significantly higher in the control condition at 24 h postexercise (3.1% ± 5.4% change; compression: 2.2% ± 11.1% change), although no other variables were different between conditions at any time. However, compression demonstrated a moderate-large effect (d > 0.60) to reduce perceived muscle soreness, fatigue, and RPE from standardised warm-up at 24 h postexercise. The current findings suggest that compression may assist in perceptual recovery from manual-labour exercise with implications for the ability to perform subsequent work bouts.


Primary cutaneous marginal zone lymphoma in children: a report of 3 cases and review of the literature.
: Primary cutaneous marginal zone lymphoma (PCMZL) is one of the most common cutaneous B-cell lymphomas. It affects mostly patients in their fourth decade and manifests with multifocal nodules mostly on the arms and upper trunk in more than half of the patients. PCMZL is, however, rare in children and adolescents, with only 20 cases reported in patients aged 20 and younger. The authors present 3 cases of PCMZL in teenagers. The patients were 2 girls aged 18 and 13 and a 17-year-old boy. Two patients presented with multiple lesions involving various anatomic sites, whereas in 1 patient, 2 small closely opposed papules on the abdomen were seen. Histopathologically, the characteristic appearance of PCMZL was found in 3 of 4 specimens, with nodular infiltrates composed of small lymphocytes in the interfollicular compartment, reactive germinal centers, and plasma cells in small clusters mainly at the periphery of the infiltrates, whereas 1 specimen showed a dense lymphocytic infiltrate with small granulomas. Clonality was demonstrated by monotypic immunoglobulin light chain expression and/or monoclonal rearrangement of the immunoglobulin heavy chain genes. No Borrelia burgdorferi was identified on serology or by polymerase chain reaction in any of the cases. Treatment included excision or administration of antibiotics with complete remission in all the 3 patients indicating that PCMZL in children and young adolescents follows the same indolent course with a tendency for recurrences, but excellent prognosis as in adults. The pertinent literature on PCZL in childhood and adolescence is reviewed.


A multiscale lattice Boltzmann model of macro- to micro-scale transport, with applications to gut function.
Nutrient absorption in the small intestine cannot occur until molecules are presented to the epithelial cells that line intestinal villi, finger-like protrusions under enteric control. Using a two-dimensional multiscale lattice Boltzmann model of a lid-driven cavity flow with 'villi' at the lower surface, we analyse the hypothesis that muscle-induced oscillatory motions of the villi generate a controlled 'micro-mixing layer' (MML) that couples with the macro-scale flow to enhance absorption. Nutrient molecules are modelled as passive scalar concentrations at high Schmidt number. Molecular concentration supplied at the cavity lid is advected to the lower surface by a lid-driven macro-scale eddy. We find that micro-scale eddying motions enhance the macro-scale advective flux by creating an MML that couples with the macro-scale flow to increase absorption rate. We show that the MML is modulated by its interactions with the outer flow through a diffusion-dominated layer that separates advection-dominated macro-scale and micro-scale mixed layers. The structure and strength of the MML is sensitive to villus length and oscillation frequency. Our model suggests that the classical explanation for the existence of villi--increased absorptive surface area--is probably incorrect. The model provides support for the potential importance of villus motility in the absorptive function of the small intestine.


Herpes Simplex Virus 1 (HSV-1) ICP22 protein directly interacts with cyclin-dependent kinase (CDK)9 to inhibit RNA polymerase II transcription elongation.
The Herpes Simplex Virus 1 (HSV-1)-encoded ICP22 protein plays an important role in viral infection and affects expression of host cell genes. ICP22 is known to reduce the global level of serine (Ser)2 phosphorylation of the Tyr1Ser2Pro3Thr4Ser5Pro6Ser7 heptapeptide repeats comprising the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase (pol) II. Accordingly, ICP22 is thought to associate with and inhibit the activity of the positive-transcription elongation factor b (P-TEFb) pol II CTD Ser2 kinase. We show here that ICP22 causes loss of CTD Ser2 phosphorylation from pol II engaged in transcription of protein-coding genes following ectopic expression in HeLa cells and that recombinant ICP22 interacts with the CDK9 subunit of recombinant P-TEFb. ICP22 also interacts with pol II in vitro. Residues 193 to 256 of ICP22 are sufficient for interaction with CDK9 and inhibition of pol II CTD Ser2 phosphorylation but do not interact with pol II. These results indicate that discrete regions of ICP22 interact with either CDK9 or pol II and that ICP22 interacts directly with CDK9 to inhibit expression of host cell genes.


Insight into the interaction mechanism of iron ions with soil humic acids. The effect of the pH and chemical properties of humic acids.
The main aim of this work was to study the mechanisms of interaction between iron(II) ions and humic acids as a function of pH, iron concentration and various humic acids chemical properties, including the degree of humification, elemental composition, aromaticity and content of acidic functional groups. The results indicated that iron was bound by humic acids at pH 7 in amounts ∼2 times higher than at pH 5 (averaged capacities: 117 and 57 cmol/kg, respectively). Iron binding at pH 7 increased with increasing the total carboxylic and phenolic groups content and the degree of humification of humic acids (R-coefficients: 0.99 and 0.95, respectively). The stability of humic acid-iron complexes at pH 7 were only slightly lower than at pH 5 due to iron hydroxides formed at pH > 5 (averaged stability constants: 5.18 and 5.26, respectively). Iron coordination mode varied depending on pH: at pH 5, the bidentate (chelate) mode dominated, whereas at pH 7 the bridging mode appeared prevalent. The total amount of bound iron was much smaller than the content of the carboxylic and phenolic groups in humic acids, on average by ∼80 (pH 7) and ∼90.1% (pH 5) indicating the occurrence of steric effects in humic acid structure i.e. the reduction of the complexation capacity of free functional groups by adjacent groups occupied by iron and/or the formation of intramolecular aggregates with iron hindering the access of further metal ions. At pH 5 the complexes were soluble in the iron concentration range positively correlated to carboxylic and phenolic groups content, showing the protective nature of negatively charged functional groups on the stability of the solution. At this pH, the destabilization of the system was governed by the neutralization of humic acid charged structures by metal cations and the compression of the double electric layer. At pH 7 the stability of the humic acid-iron solution was largely determined by the form of iron, mainly by the precipitation of metal hydroxides acting as a flocculant destabilizing the solution by co-precipitation of humic acid-iron complexes.


Human leukocytic pyrogen induces release of specific granule contents from human neutrophils.
The ability of highly purified human leukocytic pyrogen (LP) to induce neutrophil lysosomal protein release is described. Human peripheral blood neutrophils isolated by Ficoll-Hypaque and dextran sedimentation were exposed to purified human LP. The specific granule-associated proteins, lysozyme and lactoferrin were selectively released, whereas primary granule (beta-glucuronidase) and cytoplasmic (lactic dehydrogenase) enzyme markers were not. Optimum release was observed after 45 min in the presence of Ca++ and Mg++. Cytochalasin B (5 microgram/ml) had no effect on LP-induced lysosomal enzyme release. Since the pyrogenicity of LP is dependent on prostaglandin synthesis, the effect of two potent inhibitors of prostaglandin synthesis on lysozyme release was studied. Both indomethacin and naproxen failed to inhibit specific granule protein release. These observations suggest that the concommitance of fever, elevated serum or urine lysozyme and hypoferremia may, in part, be explained by the interaction of LP and peripheral blood neutrophils.


Analysis of a tobacco vector and its actions in china: the activities of japan tobacco.
Japan Tobacco (JT) is the third largest tobacco company in the world, and China, the world's largest tobacco consumer, is one of the most important targets for JT. To provide information for tobacco control, we reviewed and analyzed JT and its tactics and strategies in the Chinese market mainly by systematic examination of documents which are made available in the University of California, San Francisco Legacy Tobacco Documents Library. As a result, JT has had a special interest to expand sales of its cigarettes in the Chinese market.


The Saccharomyces cerevisiae gene SDS22 encodes a potential regulator of the mitotic function of yeast type 1 protein phosphatase.
In higher eukaryotes, the activity and specificity of the type 1 protein serine-threonine phosphatase (PP1) catalytic subunit is thought to be controlled by its association with a number of regulatory or targeting subunits. Here we describe the characterization of a gene encoding one such potential polypeptide in the yeast Saccharomyces cerevisiae. The gene which we have isolated (termed SDS22) encodes a product with a high degree of sequence identity to the fission yeast sds22 protein, a known regulator of the mitotic function of PP1 in Schizosaccharomyces pombe. Using two different criteria, we have demonstrated that Sds22p and the catalytic subunit of PP1 (Glc7p) interact in yeast cells. We have also generated a temperature-sensitive allele of GLC7 (glc7-12) which causes a block to the completion of mitosis at the restrictive temperature. Additional copies of SDS22 lead to allele-specific suppression of the glc7-12 mutant, strongly suggesting that the interaction between the two proteins is of functional significance. Sds22p is therefore likely to be the second example of a PP1 regulatory subunit identified in S. cerevisiae.


Tris(1,3-dichloro-2-propyl) phosphate disrupts axonal growth, cholinergic system and motor behavior in early life zebrafish.
Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) could have neurotoxic effects and alter motor behaviors in zebrafish (Danio rerio) larvae, however, the underlying mechanisms are still unknown. In this study, zebrafish embryos were subjected to waterborne exposure of TDCIPP at 100, 300, 600, 900μg/L from 2 to 120-h post-fertilization (hpf). Behavioral measurements indicate that TDCIPP exposure significantly elevated spontaneous movement, and altered swimming behavior response of larvae to both light and dark stimulation. Interestingly, in accordance with these motor effects, TDCIPP significantly decreased expression of the neuron-specific GFP in transgenic (HuC-GFP) zebrafish larvae as well as decreased expression of the neural marker genes elavl3 and ngn1, inhibited the axonal growth of the secondary motoneurons and altered the expressions of axon-related genes (α1-tubulin, shha and netrin2) in zebrafish larvae. Furthermore, TDCIPP exposure at 900μg/L significantly increased the activity of acetylcholinesterase (AChE) enzyme, and decreased the total acetylcholine (ACh) concentration. Our data indicate that the alteration in motor neuron and inhibition of cholinergic system could together lead to the TDCIPP induced motor behavior alterations in zebrafish larvae.


Cerebral palsy and intrauterine growth in single births: European collaborative study.
Cerebral palsy seems to be more common in term babies whose birthweight is low for their gestational age at delivery, but past analyses have been hampered by small datasets and Z-score calculation methods. We compared data from ten European registers for 4503 singleton children with cerebral palsy born between 1976 and 1990 with the number of births in each study population. Weight and gestation of these children were compared with reference standards for the normal spread of gestation and weight-for-gestational age at birth. Babies of 32-42 weeks' gestation with a birthweight for gestational age below the 10th percentile (using fetal growth standards) were 4-6 times more likely to have cerebral palsy than were children in a reference band between the 25th and 75th percentiles. In children with a weight above the 97th percentile, the increased risk was smaller (from 1.6 to 3.1), but still significant. Those with a birthweight about 1 SD above average always had the lowest risk of cerebral palsy. A similar pattern was seen in those with unilateral or bilateral spasticity, as in those with a dyskinetic or ataxic disability. In babies of less than 32 weeks' gestation, the relation between weight and risk was less clear. The risk of cerebral palsy, like the risk of perinatal death, is lowest in babies who are of above average weight-for-gestation at birth, but risk rises when weight is well above normal as well as when it is well below normal. Whether deviant growth is the cause or a consequence of the disability remains to be determined.


Leprosy affects facial nerves in a scattered distribution from the main trunk to all peripheral branches and neurolysis improves muscle function of the face.
Current literature rejects nerve release in leprous facial neuropathy and states that lesions are restricted to the peripheral zygomatic branches. Since there are approximately 500,000 patients with this disease throughout the world, we wanted to clarify the precise location of facial nerve's affection and the benefit of neurolysis. Our study showed that in patients with leprosy, the facial nerve's main trunk, the peripheral zygomatic branches, and all other branches were affected. Follow-up showed improvement in lagophthalmos and in misreinnervation, with no improvement in the control cohort. Nerve release improves muscle function in leprous facial neuropathy, provided surgery is performed on all affected segments. Intraoperative electroneurodiagnostics is an effective tool for detecting the most proximal site of lesion and ensuring effective surgery.


Musical Dogs: A Review of the Influence of Auditory Enrichment on Canine Health and Behavior.
Music therapy yields many positive health outcomes in humans, but the effects of music on the health and welfare of nonhuman animals vary greatly with the type of music played, the ethology of the species, and the personality and learning history of individual animals. One context in which music therapy may be used to enhance animal welfare is to alleviate stress in domestic environments. Here, we review studies of the effects of music exposure on dogs as a case study for the implementation of music therapy in veterinary medicine. Nine reports of experimental testing for the therapeutic effects of music on dogs were found, with most of these studies focusing on changes in behavior. Overall, exposure to classical music appears to have a calming influence on dogs in stressful environments, with no additional benefit observed from any music purposely designed for dogs (specifically "Through a dog's ear"). Given the cost effectiveness and ease of implementation, music therapy holds promise in veterinary medicine and animal welfare. However, to address precise research questions, further studies must use clearly defined characteristics of stimulus music in the experimental design, and consider the variability of each individual animal's physical characteristics and past experience in the selection of candidates.


The 2009 Late Blight Pandemic in the Eastern United States - Causes and Results.
The tomato late blight pandemic of 2009 made late blight into a household term in much of the eastern United States. Many home gardeners and many organic producers lost most if not all of their tomato crop, and their experiences were reported in the mainstream press. Some CSAs (Community Supported Agriculture) could not provide tomatoes to their members. In response, many questions emerged: How did it happen? What was unusual about this event compared to previous late blight epidemics? What is the current situation in 2012 and what can be done? It's easiest to answer these questions, and to understand the recent epidemics of late blight, if one knows a bit of the history of the disease and the biology of the causal agent, Phytophthora infestans.


Role for C-MPL and its ligand thrombopoietin in early hematopoiesis.
Proto-oncogene c-mpl is structurally homologous with the hematopoietic growth factor receptor superfamily. The ligand for c-mpl was purified and its gene cloned. Extensive functional studies revealed that the ligand for c-mpl plays a crucial role in megakaryocytopoiesis and platelet production, hence, this ligand proved to be the long-sought hematopoietin, thrombopoietin (TPO). We briefly review here the role for TPO in early hematopoiesis, based on our in vitro data obtained using a serum-free culture system. TPO in combination with the ligand for c-kit (SF) or interleukin-3 (IL-3) but not TPO alone supported the growth of murine primitive hematopoietic progenitors. Studies on lineage expression indicated that the progenitors supported by TPO plus SF or TPO plus IL-3 are multipotential. Delayed addition experiments demonstrated that TPO has the potential to effectively support the survival of primitive hematopoietic progenitors. TPO also hastened IL-3-dependent growth of progenitors by shortening the time required for cell-cycling. While size of the colonies did not differ between colonies supported by IL-3 alone and those supported by IL-3 plus TPO, the incidence of megakaryocyte-containing colonies in cultures supported by IL-3 plus TPO was higher than that in cultures supported by IL-3 alone. Taken together, TPO as a single factor can support the survival of hematopoietic progenitors and TPO synergizes with SF or IL-3 to be active on early multipotential hematopoietic progenitors. These findings suggest that the function of TPO initially thought to be restricted to the megakaryocytic lineage proved to be greater in hematopoiesis. Reports from other laboratories regarding the involvement of TPO in early hematopoiesis are also discussed.


HDL cholesterol: trends in two southeastern New England communities, 1981-1993.
Although public health interventions have not specifically targeted high density lipoprotein (HDL) cholesterol, observed changes in the prevalence of other cardiovascular risk factors would be expected to have differential effects on HDL. This study examined secular trends in HDL in relation to changes in other cardiovascular risk factors for the years 1981 through 1993 in the Pawtucket Heart Health Program (PHHP) study communities. Nonfasting HDL levels were assessed in 12,223 respondents to six biennial population random sample surveys. Between 1981 and 1993, mean HDL cholesterol declined by 0.08 mmol/L in both men and women after adjustment for age, city, education, hormone use, medications, recent alcohol use, smoking, regular exercise, body mass index (BMI), and total cholesterol, (p for trend < 0.001). There was no apparent laboratory explanation for the trend which occurred concurrent with decreased smoking prevalence, increasing BMI and decreased prevalence of recent alcohol use. Decreasing HDL cholesterol was observed consistently across subgroups defined by smoking, alcohol use and BMI. Although several favorable cardiovascular risk factor trends have been observed in recent decades, declining HDL cholesterol is also of interest, particularly in conjunction with population increases in BMI.


Quantitative assessment of levodopa-induced dyskinesia using automated motion sensing technology.
The objective was to capture levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD) using body-worn motion sensors. Dopaminergic treatment in PD can induce abnormal involuntary movements, including choreatic dyskinesia (brief, rapid, irregular movements). Adjustments in medication to reduce LID often sacrifice control of motor symptoms, and balancing this tradeoff poses a significant challenge for management of advanced PD. Fifteen PD subjects with known LID were recruited and instructed to perform two stationary motor tasks while wearing a compact wireless motion sensor unit positioned on each hand over the course of a levodopa dose cycle. Videos of subjects performing the motor tasks were later scored by expert clinicians to assess global dyskinesia using the modified Abnormal Involuntary Rating Scale (m-AIMS). Kinematic features were extracted from motion data in different frequency bands (1-3Hz and 3-8Hz) to quantify LID severity and to distinguish between LID and PD tremor. Receiver operator characteristic analysis was used to determine thresholds for individual features to detect the presence of LID. A sensitivity of 0.73 and specificity of 1.00 were achieved. A neural network was also trained to output dyskinesia severity on a 0 to 4 scale, similar to the m-AIMS. The model generalized well to new data (coefficient of determination= 0.85 and mean squared error= 0.3). This study demonstrated that hand-worn motion sensors can be used to assess global dyskinesia severity independent of PD tremor over the levodopa dose cycle.


Localized reduction of graphene oxide by electrogenerated naphthalene radical anions and subsequent diazonium electrografting.
Herein, we describe a new localized functionalization method of graphene oxide (GO) deposited on a silicon oxide surface. The functionalization starts with the reduction of GO by electrogenerated naphthalene radical anions. The source of reducers is a microelectrode moving close to the substrate in a typical scanning electrochemical microscopy (SECM) configuration. Then, the recovery of electronic conductivity upon reduction enables the selective electrochemical functionalization of the patterns. The illustrative example is the electrografting of reduced-GO with a diazonium salt bearing a protonated amino group that can further immobilize gold nanoparticles by simple immersion. This study opens new routes for the construction of multifunctional patterned surfaces.


Contribution of water pollution from inadequate sanitation and housing quality to diarrheal disease in low-cost housing settlements of Cape Town, South Africa.
We investigated the effects of failing sanitation, poor housing conditions, and fecal pollution in runoff water on the health-particularly the incidence of diarrheal disease-of residents of low-cost housing settlements in Cape Town, South Africa. In November 2009, we conducted a cross-sectional survey with structured interviews in 4 communities (n = 336 dwellings; 1080 persons). We used Colilert defined-substrate technology to determine Escherichia coli levels in runoff water samples taken from the study communities. Almost 15% of households disposed of soiled products in storm water drains and 6% disposed of soiled products in the street. In only 26% of the dwellings were toilets washed daily. Approximately 59% of dwellings lacked a tap near the toilet for hand washing, and 14% of respondents suffered 1 or more attacks of diarrhea in the 2 weeks preceding their interview. E.coli counts of runoff environmental water samples ranged from 750 to 1 580 000 000 per 100 milliliters. A holistic and integrated approach is needed to improve housing quality and sanitation among Cape Town's low-income citizens.


What is the role of empirical research in bioethical reflection and decision-making? An ethical analysis.
The field of bioethics is increasingly coming into contact with empirical research findings. In this article, we ask what role empirical research can play in the process of ethical clarification and decision-making. Ethical reflection almost always proceeds in three steps: the description of the moral question, the assessment of the moral question and the evaluation of the decision-making. Empirical research can contribute to each step of this process. In the description of the moral object, first of all, empirical research has a role to play in the description of morally relevant facts. It plays a role in answering the "reality-revealing questions" (what, why, how, who, where and when), in assessing the consequences and in proposing alternative courses of action. Secondly, empirical research plays a role in assessing the moral question. It must be acknowledged that research possesses "the normative power of the factual," which can also become normative by suppressing other norms. However, inductive normativity should always be balanced out by a deductive form of normativity. Thirdly, empirical research also has a role to play in evaluating the decision-making process. It can rule out certain moral choices by pointing out the occurrence of certain unexpected consequences or effects. It can also be useful, however, as a sociology of bioethics in which the discipline of bioethics itself becomes an object of research.


Mechanical behavior of in-situ alloyed Ti6Al4V(ELI)-3 at.% Cu lattice structures manufactured by laser powder bed fusion and designed for implant applications.
In the present study, cellular lattice structures for implant applications are reported for the first-time incorporating copper directly by in-situ alloying in the laser powder bed fusion process. The aim to incorporate 3 at.% Cu into Ti6Al4V(ELI) is selected for improved antibacterial properties while maintaining appropriate mechanical properties. Previously, topologically optimized Ti6Al4V(ELI) lattice structures were successfully designed, manufactured and studied for implant applications. The development of a new alloy produced by in-situ alloying of elemental powder mixture of Ti6Al4V(ELI) and pure Cu powders was used here for the production of identical lattice structures with improved antibacterial properties. One of the same as-designed CAD models was used for the manufacturing of these lattices compared to previous work on pure Ti6Al4V(ELI) lattices, making direct comparison of mechanical properties possible. Similar manufacturability highlights the applicability of this alloying technique to other lattice designs. Microstructural characterization was performed by optical and electron microscopies, as well as microCT. Mechanical characterization was performed by means of compression tests and hardness measurements. Results showed that in-situ alloying with copper leads to the formation of localized Cu-rich regions, refinement of martensitic phase and the formation of CuTi2 intermetallic precipitates, which increased the hardness and strength of the material. Deviations in wall thickness between the as-designed and as-manufactured lattices led to anisotropy of the mechanical properties of the lattices. Higher compressive strength values were obtained when thicker walls were oriented along the loading direction. Nevertheless, alloying with Cu had a higher impact on the compressive strength of lattice structure than the wall thickness deviations. The direct in-situ alloying of copper in Ti6Al4V(ELI) is a promising route for direct manufacturing of antibacterial implants.


Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10.
Human umbilical vein endothelial (HUVE) cells have been previously reported to express the genes for the A and B chains of PDGF and to secrete PDGF-related factors into culture media. Antihuman PDGF IgG affinity chromatography was used to purify PDGF-related activity from HUVE cell-conditioned media. Immunoblot analysis of the affinity-purified proteins with anti-PDGF IgG and antibodies specific for the A or B chain peptides of PDGF combined with chemotactic and mitogenic assays revealed that the major PDGF immunorelated molecule secreted by HUVE cells is a monomer of approximately 36-38 kD and that less than 10% of the purified biologically active molecules are PDGF A or B chain peptides. Screening of an HUVE cell cDNA library in the expression vector lambda gtl 1 with the anti-PDGF antibody resulted in the cloning and sequencing of a cDNA with an open reading frame encoding a 38-kD cysteine-rich secreted protein which we show to be the major PDGF-related mitogen secreted by human vascular endothelial cells. The protein has a 45% overall homology to the translation product of the v-src-induced CEF-10 mRNA from chick embryo fibroblasts. We have termed this new mitogen connective tissue growth factor.


Spectrum of Imported Infectious Diseases: A Comparative Prevalence Study of 16,817 German Travelers and 977 Immigrants from the Tropics and Subtropics.
The aim of this study was to assess the spectrum of imported infectious diseases (IDs) among patients consulting the University of Munich, Germany, between 1999 and 2014 after being in the sub-/tropics. The analysis investigated complete data sets of 16,817 diseased German travelers (2,318 business travelers, 4,029 all-inclusive travelers, and 10,470 backpackers) returning from Latin America (3,225), Africa (4,865), or Asia (8,727), and 977 diseased immigrants, originating from the same regions (112, 654 and 211 respectively). The most frequent symptoms assessed were diarrhea (38%), fever (29%), and skin disorder (22%). The most frequent IDs detected were intestinal infections with species of Blastocystis(900),Giardia(730),Campylobacter(556),Shigella(209), and Salmonella(183). Also frequently observed were cutaneous larva migrans (379), dengue (257), and malaria (160). The number of IDs with significantly elevated proportions was higher among backpackers (18) and immigrants (17), especially among those from Africa (18) and Asia (17), whereas it was lower for business travelers (5), all-inclusive travelers (1), and those from Latin America (5). This study demonstrates a large spectrum of imported IDs among returning German travelers and immigrants, which varies greatly based not only on travel destination and origin of immigrants, but also on type of travel.


Correlates of stimulus-response congruence in the posterior parietal cortex.
Primate behavior is flexible: The response to a stimulus often depends on the task in which it occurs. Here we study how single neurons in the posterior parietal cortex (PPC) respond to stimuli which are associated with different responses in different tasks. Two rhesus monkeys performed a task-switching paradigm. Each trial started with a task cue instructing which of two tasks to perform, followed by a stimulus requiring a left or right button press. For half the stimuli, the associated responses were different in the two tasks, meaning that the task context was necessary to disambiguate the incongruent stimuli. The other half of stimuli required the same response irrespective of task context (congruent). Using this paradigm, we previously showed that behavioral responses to incongruent stimuli are significantly slower than to congruent stimuli. We now demonstrate a neural correlate in the PPC of the additional processing time required for incongruent stimuli. Furthermore, we previously found that 29% of parietal neurons encode the task being performed (task-selective cells). We now report differences in neuronal timing related to congruency in task-selective versus task nonselective cells. These differences in timing suggest that the activity in task nonselective cells reflects a motor command, whereas activity in task-selective cells reflects a decision process.


Morbidity and mortality associated with injuries: results of the Global Burden of Disease study in Brazil, 2008.
The aim of this study was to estimate the global burden of disease from external causes in 2008 in Brazil, based on DALYs (disability-adjusted life years). YLLs (years of life lost) were estimated according to the method proposed by Murray & Lopez (1996). Meanwhile, the method for estimating YLDs (years lived with disability) included methodological adjustments taking the Brazilian reality into account. The study showed a total of 195 DALYs per 100 thousand inhabitants, of which 19 DALYs were related to external causes. Among YLLs, 48% were from unintentional causes and 52% from intentional causes. Among YLDs, unintentional causes predominated, with 95%. The share of YLLs in DALYs was 90%. The cause with the highest proportion of YLLs was "homicide and violence" (43%), followed by "road traffic accidents" (31%). Falls accounted for the highest share of YLDs (36%). The sex ratio (male-to-female) was 4.8 for DALYs, and the predominant age bracket was 15-29 years. Since external causes are avoidable, the study provides potentially useful information for policymakers in public security and health.


Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial.
Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28. Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI -11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups. The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice. Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research.


Supplementary abbreviated supine breast MRI following a standard prone breast MRI with single contrast administration: is it effective in detecting the initial contrast-enhancing lesions?
We aimed to evaluate the detectability of contrast enhancing lesions, initially demonstrated in standard prone dynamic contrast-enhanced MRI (DCE-MRI), in a supplementary supine breast MRI examination performed following the standard prone DCE-MRI examination and to show the correlation of spatial displacement of the lesions with breast size and density. Forty-two patients with 45 lesions were prospectively evaluated. Supine breast MRI was acquired with a 6-channel body coil following a standard DCE-MRI in prone position after repositioning the patient. No additional contrast media was administered. Images were evaluated by two radiologists in consensus for the visibility of the lesions. Lesion localization relative to the sternal midline, chest wall and nipple was measured in both prone and supine positions. Correlations between lesion displacement and breast size or breast density were analyzed. Of 45 lesions, 23 (52.3%) were masses, 22 (47.7%) were nonmass enhancements (NME). Forty-four lesions (97.8%) could be detected on supine images. One linear NME of 33 mm in length could not be seen on supine images. Twenty (46.5%) of the detected lesions in supine position were equal to or smaller than 10 mm (11 NME [55%] and 9 masses [45%]). Lesion displacement relative to the chest wall increased with increasing breast size (P < 0.001). An abbreviated supine sequence following a standard prone DCE-MRI with single contrast media administration is an effective method for defining the lesion location in supine position.


Insertional inactivation of the major autolysin gene of Streptococcus pneumoniae.
The lytA gene encoding the major pneumococcal autolysin (N-acetylmuramoyl-L-alanine amidase) was inactivated by inserting the 2-kilobase MspI fragment of pE194 containing the staphylococcal ermC gene. Stable autolysis-deficient (Lyt-) mutants and their isogenic Lyt+ parents were used in experiments designed to test possible physiological functions of the amidase. No autolysis could be induced in the mutants grown at 37 degrees C by deoxycholate, by incubation in stationary phase, or by treatment with penicillin. On the other hand, the Lyt- mutants exhibited normal growth rates and yields and normal adaptive responses during shifts from one growth temperature or nutritional condition to another. There was no evidence for impeded cell separation (chain formation). Colonies of Lyt- insertional mutants produced normal hemolytic zones on blood agar; they showed normal (high) levels of competence for genetic transformation. Lyt- mutants were also able to produce type 3 and 6 capsular polysaccharides, and such strains showed the same degree of virulence in mice as did the isogenic Lyt+ parent. The physiological function(s) of the amidase remains a puzzle.


Involvement of monocytes/macrophages as key factors in the development and progression of cardiovascular diseases.
Emerging evidence points to the involvement of specialized cells of the immune system as key drivers in the pathophysiology of cardiovascular diseases. Monocytes are an essential cell component of the innate immune system that rapidly mobilize from the bone marrow to wounded tissues where they differentiate into macrophages or dendritic cells and trigger an immune response. In the healthy heart a limited, but near-constant, number of resident macrophages have been detected; however, this number significantly increases during cardiac damage. Shortly after initial cardiac injury, e.g. myocardial infarction, a large number of macrophages harbouring a pro-inflammatory profile (M1) are rapidly recruited to the cardiac tissue, where they contribute to cardiac remodelling. After this initial period, resolution takes place in the wound, and the infiltrated macrophages display a predominant deactivation/pro-resolution profile (M2), promoting cardiac repair by mediating pro-fibrotic responses. In the present review we focus on the role of the immune cells, particularly in the monocyte/macrophage population, in the progression of the major cardiac pathologies myocardial infarction and atherosclerosis.


Discovery of melanotransferrin as a serological marker of colorectal cancer by secretome analysis and quantitative proteomics.
To discover serological colorectal cancer (CRC) markers, we analyzed cell line secretome to gather proteins of higher potential to be secreted from tissues into circulation. A total of 898 human proteins were identified, of which 62.2% were predicted to be released or shed from cells. The identified proteins were compared with tissue proteomes to find candidate proteins whose expressions were elevated in tumor tissues compared with normal tissues as revealed by (i) quantitative proteomic analysis based on cICAT and mTRAQ or (ii) data mining of immunohistochemical images piled in Human Protein Atlas database. By applying various stringent criteria, 11 candidate proteins were selected. Among these, we validated an significant increase (p = 0.0018) of melanotransferrin (TRFM) at the plasma level of CRC patients through Western blotting, using 130 plasma samples containing 30 healthy controls, 80 CRC patients, and 20 patients of other diseases. Finally, we measured the expression level of TRFM in 325 plasma samples containing 77 healthy controls and 228 CRC patients (34.6 ± 4.2 ng/mL and 67.0 ± 6.4 ng/mL, p < 0.0001) through ELISA and demonstrated the area under the receiver operating characteristic curve of 0.723 (p < 0.0001) with a 92.5% specificity, 48.2% sensitivity, and 95.7% positive predictive value. Furthermore, unlike CEA and PAI-1, up-regulation of TRFM in pathological stages I & II groups compared with stages III & IV groups lead us to expect the use TRFM for early-stage diagnosis of CRC. In this study, we suggest TRFM as a potential serological marker for CRC and expect our discovery strategy to help identify highly cancer-specific and body-fluid-accessible biomarkers.


Why do A·T and G·C self-sort? Hückel aromaticity as a driving force for electronic complementarity in base pairing.
Density functional theory computations and block-localized wavefunction analyses for 57 hydrogen-bonded base pairs document excellent linear correlation between the gas-phase association energies and the degree of aromaticity gain of paired bases (r = 0.949), challenging prevailing views of factors that underlie the proposed electronic complementarity of A·T(U) and G·C base pairs. Base pairing interactions can polarize the π-electrons of interacting bases to increase (or decrease) cyclic 4n + 2π electron delocalization, resulting in aromaticity gain (or loss) in the paired bases, and become strengthened (or weakened). The potential implications of this reciprocal relationship for improving nucleic acid force-fields and for designing robust unnatural base pairs are discussed.


Influenza, but not HIV-specific CTL epitopes, elicits delayed-type hypersensitivity (DTH) reactions in HIV-infected patients.
The induction of cytotoxic T lymphocytes (CTLs) is believed to be an important defense mechanism against viral infections. The availability of simple, sensitive, specific and physiologically informative in vivo tests, applicable to humans, would greatly elucidate the nature of protective immune responses and facilitate immune monitoring in large vaccine trials. Here we studied the possibility of using defined HLA-A*02:01-restricted CTL epitopes from influenza matrix protein (GL9, GILGFVFTL) and HIV Gag p17 (SL9, SLYNTVATL) to elicit a cutaneous delayed-type hypersensitivity (DTH) reaction. Our results show that the GL9 but not the SL9 epitope was able to induce a DTH reaction. HIV infection status, HIV RNA level and CD4(+) T-cell counts were not predictive of the extent of DTH reactions. However, a markedly reduced expression of skin homing markers CD103 and cutaneous lymphocyte associated Ag (CLA) on epitope-specific CTL populations was associated with a lack of SL9 DTH reactivity. These data demonstrate that DTH reactions can be elicited by optimally defined CTL epitopes per se and point towards specific homing markers that are required for such reactions. These data may offer new insights into the immune pathogenesis of HIV infection and provide the basis of novel immune monitoring approaches for large-scale HIV vaccine trials.


Manuka honey reduces the motility of Pseudomonas aeruginosa by suppression of flagella-associated genes.
Manuka honey is a broad-spectrum antimicrobial agent that seems to affect different bacteria in many different ways. It has been shown to be bactericidal against Pseudomonas aeruginosa by destabilizing the cell wall, but we aimed to investigate whether there were further intracellular target sites. In this study inhibitory effects of manuka honey on P. aeruginosa were investigated using hydrophobicity assays, two-dimensional electrophoresis, quantitative RT-PCR, transmission electron microscopy and motility assays. Exposure of P. aeruginosa to manuka honey reduced both swarming and swimming motility. Moreover, this was a consequence of de-flagellation of the bacterial cell, which was correlated with decreased expression of the major structural flagellin protein, FliC, and concurrent suppression of flagellin-associated genes, including fliA, fliC, flhF, fleN, fleQ and fleR. The differential expression of the flagellar regulon in the presence of manuka honey was mapped schematically. Flagella are integral to bacterial adhesion, the initiation of infection and biofilm formation, and swarming has been associated with increased virulence. By limiting motility in vitro, we infer that manuka honey impacts on the virulence of P. aeruginosa. This deduction must now be tested in vivo.


Attenuation of Infectious Bronchitis Virus in Eggs Results in Different Patterns of Genomic Variation across Multiple Replicates.
The gammacoronavirus infectious bronchitis virus (IBV) causes an acute, highly contagious respiratory disease of poultry. Live attenuated vaccines are traditionally generated by serial passage of a virulent strain in embryonated chicken eggs; however, the molecular mechanism of attenuation is unknown. M41-CK, a virulent lab-adapted strain of IBV, was egg passaged over 100 times in four parallel independent replicates. All four final egg-passaged viruses were attenuated in vivo and exhibited similar growth phenotypes in adult chicken kidney cells and ex vivo tracheal organ cultures. The virus populations were sequenced by 454 pyrosequencing at the end of passaging, and the results showed that overall sequence diversity in the IBV population increased but the four replicates only had between 11 and 17 consensus-level single nucleotide polymorphisms (SNPs). Although hot spots of variation were identified in spike and nucleocapsid structural proteins as well as the 3' untranslated region, each attenuated virus possessed a different pattern of genomic variation. Overall, only a small number of consensus-level SNPs were acquired during egg passage, leaving a potentially short route back to virulence. These results highlight the unpredictable nature of attenuation by serial egg passage and the need to develop mechanisms to rationally attenuate IBV for the next generation of effective vaccines.IMPORTANCE Infectious bronchitis remains a major problem in the global poultry industry, despite the existence of many different vaccines. IBV vaccines are currently developed by serial passage of a virulent strain on embryonated hen's eggs until attenuation; however, little is known about the evolution of the viral population during the process of attenuation. High-throughput sequencing of four replicates of a serially egg-passaged IBV revealed a different pattern of genomic variation in each attenuated replicate and few consensus-level SNPs. This raises concerns that only a small number of genomic mutations are required to revert to a virulent phenotype, which may result in vaccine breakdown in the field. The observed hot spots of variation in the attenuated viruses have the potential to be used in the rational attenuation of virulent IBV for next-generation vaccine design.


Courtship violence: incidence in a national sample of higher education students.
An approximately representative national sample of 2,602 women and 2,105 men was surveyed regarding their frequency of inflicting and sustaining verbal and physical aggression in a heterosexual relationship. Results revealed that approximately 81% of the men inflicted, as well as received, some form of verbal aggression at least once, while the comparable figure for women was 87-88%. The percentage experiencing some form of physical aggression was lower; about 37% of the men and 35% of the women inflicted some form of physical aggression and about 39% of the men and 32% of the women sustained some physical aggression. No differences were found as a function of ethnicity, family income, and institutional characteristics. Regional differences in the use of verbal and physical aggression, and in the receipt of physical aggression, were found for men.


Risk factors for Trypanosoma cruzi infection among children in central Brazil: a case-control study in vector control settings.
This population-based case-control study was conducted in northern Goias State, central Brazil, in rural settings under vector control surveillance. One hundred forty-nine children seropositive for Trypanosoma cruzi antibodies, selected in a cross-sectional survey carried out in village schools, were compared with 298 seronegative classmate controls matched for age, sex, and place of residence. Information on potential environmental, familiar, and social economic risk factors for T. cruzi infection was collected during household visits, and interviews with parents and entomologic inspections of domestic and peridomestic environments were conducted. The presence of triatomines in dwellings or evidence of triatomine colonization was found to be statistically associated with seropositivity in children. The presence of exuviae and a report of triatomines indoors or outdoors by householders in the past were strong predictors of an infected child. Children from seropositive mothers had a 3.9-fold increase in the risk of having anti-T. cruzi antibodies after adjusting for the confounding variables, including triatomine capture, mother's age, and family size in multivariate analysis. Parent's report of vector presence showed a 97.7% sensitivity in identifying a dwelling with at least one seropositive child. The possibility of transplacental T. cruzi transmission and its implication for Chagas' disease control were considered.


Perioperative prophylaxis to prevent recurrence following cataract surgery in uveitic patients: a two-centre, prospective, randomized trial.
To compare the postoperative risk of inflammatory relapse in two groups of uveitic patients who underwent cataract surgery: one group had perioperative topical steroids alone and the other used topical and oral steroids. Prospective, randomized, unmasked, duocentric clinical trial conducted at the University of Parma (Italy), and the Jules Gonin Eye Hospital of Lausanne (Switzerland). Patients with a history of non-infectious uveitis requiring cataract surgery in 2009-2013 were assigned to two groups of perioperative prophylaxis: (A) intensive topical steroids alone; (B) the same topical regimen combined with oral steroids. Uveitis relapse over a period of 6 months was assessed. In total, 52 eyes in 50 patients were randomized: 28 eyes were assigned to group A (topical) and 24 eyes to group B (topical + oral). Mean relapse-free survival time was 131 ± 11 days in group A and 150 ± 13 days in group B. This difference was not statistically significant (p = 0.42). At the end of follow-up, the groups were also comparable in terms of significant improvement in visual acuity (p < 0.01), mean central macular thickness (CMT) and IOP variation. Absolute and long-lasting control of ocular, and possibly systemic, inflammation predisposes uveitis patients to satisfactory results after cataract extraction and intraocular lens implantation. Despite a lower rate of recurrences following oral steroid supplementation, the efficacy of an intensive perioperative topical steroid regimen alone in preventing postoperative uveitis relapse was statistically comparable. Secondary outcomes were also comparable between the two groups. Transient IOP elevation should be expected until treatment discontinuation.


The phylogenetic position and ultrastructure of the uncultured bacterium Achromatium oxaliferum.
Achromatium oxaliferum is a large, morphologically conspicuous, sediment-dwelling bacterium. Nothing is known concerning its phylogeny and it has eluded all attempts at laboratory cultivation. The limited physiological description of A. oxaliferum has been based on morphological features of the bacterium such as the presence of intracellular sulphur inclusions. A. oxaliferum cells were purified from a wetland region close to Rydal Water (Cumbria, UK). Scanning and transmission electron microscopy revealed that a number of morphologically distinct A. oxaliferum cell-types, based on cell surface features and the size and abundance of calcite and sulphur inclusions within the cells, were present in a single sample of purified cells. PCR was used to amplify almost full-length 16S rRNA gene sequences from DNA extracted from A. oxaliferum cells directly purified from sediments. The PCR products were cloned and partial sequences (approx. 400 bp) were determined for seven of the clones. Three different sequence clusters were recovered from the clone libraries. A near full-length (1489 bp) 16S rRNA gene sequence was determined for a representative clone of the most dominant sequence-type (52% of the sequences). Comparative sequence analysis showed A. oxaliferum to form a deep branching lineage within the gamma-subdivision of the Proteobacteria. A. oxaliferum was related most closely to the Chromatium assemblage that includes sulphur-oxidizing symbiotic bacteria, purple sulphur bacteria, and sulphur- and iron-oxidizing thiobacilli. Phylogenetic inferences made using distance, parsimony and maximum likelihood methods all placed A. oxaliferum with this group of bacteria. Bootstrap support for a relationship with any particular lineage within the assemblage was weak. The seven clone sequences recovered from the A. oxaliferum cells however formed a monophyletic group well supported by bootstrap analysis (85-100% support depending on the analysis done). It was concluded that A. oxaliferum was related to organisms of the Chromatium assemblage but constituted a novel lineage within this group of bacteria. A. oxaliferum cells were confirmed as the source of the 16S rRNA sequence obtained, by the use of a fluorescently-labelled 16S rRNA-targeted oligonucleotide specific for the A. oxaliferum rRNA sequence.


Completion of Requirements in Iowa's Medicaid Expansion Premium Disincentive Program, 2014-2015.
To evaluate rates of member compliance with Iowa's Medicaid expansion premium disincentive program. We used 2014 to 2015 Iowa Medicaid data to construct rolling 12-month cohorts of Wellness Plan and Marketplace Choice members (Iowa's 2 Medicaid expansion waiver programs for individuals ≤ 100% and 101%-138% of the federal poverty level, respectively), calculated completion rates for required activities (i.e., wellness examinations and health risk assessments), and identified factors associated with program compliance. Overall, 18.5% of Wellness Plan and 12.5% of Marketplace Choice members completed both activities (P < .001). From 2014 to 2015, completion rates for both activities decreased for Wellness Plan members but increased for Marketplace Choice members. Members who were younger, male, or non-White were less likely to complete required activities. Approximately 81% of Wellness Plan members and 87% of Marketplace Choice members failed to comply with program requirements and should have been subject to paying premiums the following year or face disenrollment. Disparities in completion rates may exacerbate disparities in insurance coverage and health outcomes. Public Health Implications. As states consider establishing Medicaid premium disincentive programs, they should anticipate challenges to successful implementation.


Revision total hip arthroplasty with use of a cemented femoral component. Results at a mean of ten years.
Revision of the femoral component of a total hip replacement with use of cement has been associated with early mechanical failure due to aseptic loosening. The purpose of the present study was to determine the long-term survival after revision of the femoral component with cement and to identify factors that were predictive of failure. The results of 129 revision total hip arthroplasties that had been performed with use of a cemented femoral stem were reviewed to determine component survival. Ninety-seven hips that had been followed for a minimum of five years were included in survival analysis and tests of significance. Harris hip scores were used to quantify clinical outcomes. Clinical and surgical factors were analyzed to determine whether they were predictive of failure. The mean Harris hip score improved from 52 points preoperatively to 71 points at the time of the most recent follow-up (p < 0.001). The ten-year survival rate was 91% with rerevision of the femoral component because of aseptic loosening as the end point and 71% with mechanical failure as the end point. Patients who were more than sixty years old had greater long-term component survival and less pain than younger patients did (p < 0.05). A good-quality postoperative cement mantle was associated with better long-term radiographic signs of fixation (p < 0.001). Poor femoral bone quality was associated with an increased rate of rerevision for aseptic loosening (p = 0.021). Revision with use of a cemented femoral component remains an option for selected patients, with an acceptable ten-year survival rate and fair radiographic evidence of fixation. Our patients had acceptable clinical outcomes at ten years, and few had notable pain. The best results may be achieved in older patients (those who are sixty years old or more) with adequate bone stock who are managed with modern cementing techniques.


Human epithelial ovarian cancer allelotype.
To determine which chromosomes and chromosomal regions contain putative tumor suppressor genes important for human epithelial ovarian cancer, we performed loss of heterozygosity (LOH) studies on 37 primary epithelial ovarian tumors. Using 70 polymorphic markers, we examined all chromosome arms (excluding acrocentric arms) on all specimens. Our findings show a high frequency of LOH for the following chromosome arms: 5q (43%); 6p (62%); 6q (57%); 7p (36%); 8p (40%); 9q (54%); 13q (56%); 14q (47%); 15q (36%); 17p (81%); 17q (76%); 18q (43%); 21q (36%); and 22q (71%). When separated into low and high grade tumors, there were statistically significant differences of LOH for the following chromosome arms: 6p (29% versus 70%); 13q (0% versus 72%); 17p (33% versus 90%); and 17q (29% versus 87%). No statistically significant difference was found between different histological subtypes. The average fractional allelic loss for low grade tumors was 0.17 versus 0.40 for high grade and 0.35 for all tumors. In an effort to more specifically localize common regions of molecular genetic deletion, we examined the following chromosomes in greater detail: chromosome 13 (5 markers); chromosome 17 (8 markers); and chromosome 6 (8 polymorphic markers). No tumor showed deletion of only a portion of chromosome 13. When any informative marker for chromosome 13 showed loss, all markers showed loss. Similarly, the tumors of most patients demonstrated LOH of all informative markers that map to chromosome 17; however, regional deletion of 17p markers was observed in 3 tumors. Twelve tumors demonstrated regional deletions of portions of chromosome 6. These tumors suggest that at least 2 regions of chromosome 6 are important for ovarian epithelial carcinogenesis. One region appears to be on distal 6q and a second region is near the centromere of chromosome 6 proximal to the HLA locus.