Methodological challenges when doing research that includes ethnic minorities: a scoping review.
There are challenging methodological issues in obtaining valid and reliable results on which to base occupational therapy interventions for ethnic minorities. The aim of this scoping review is to describe the methodological problems within occupational therapy research, when ethnic minorities are included. A thorough literature search yielded 21 articles obtained from the scientific databases PubMed, Cinahl, Web of Science and PsychInfo. Analysis followed Arksey and O'Malley's framework for scoping reviews, applying content analysis. The results showed methodological issues concerning the entire research process from defining and recruiting samples, the conceptual understanding, lack of appropriate instruments, data collection using interpreters to analyzing data. In order to avoid excluding the ethnic minorities from adequate occupational therapy research and interventions, development of methods for the entire research process is needed. It is a costly and time-consuming process, but the results will be valid and reliable, and therefore more applicable in clinical practice.


Concentration-dependent photophysical switching in mixed self-assembled monolayers of pentacene and perylenediimide on gold nanoclusters.
Photophysical control and switching on organic-inorganic hybrid interfaces are of great interest in diverse fundamental and applicative research areas. 6,13-Bis(triisopropylsilylethynyl)pentacene (TP) is well-known to exhibit efficient singlet fission (SF) for generation of high-yield triplet excited states in aggregated forms, whereas perylenediimide (PDI) ensembles show the characteristic excimer formation. Additionally, a combination of pentacene (electron donor: D) and PDI (electron acceptor: A) is expected to undergo an efficient photoinduced electron transfer (PET), and absorption of two chromophores combined covers the entire visible region. Therefore, the concentration-dependent mixed self-assembled monolayers (SAMs) composed of two chromophores enable us to control and switch the photophysical processes on a surface. In this work, a series of mixed SAMs composed of TP and PDI units on gold nanoclusters (GNCs) were newly synthesized by changing the relative molecular concentration ratios. Structural control of mixed SAMs on a gold surface based on the concentration ratios was successfully achieved. Time-resolved femtosecond and nanosecond transient absorption measurements clearly demonstrate photophysical control and switching of the above competitive reactions such as SF, electron transfer (ET) and excimer formation. The maximum quantum yields of triplet states (ΦT = ∼170%) and electron transfer (ΦET = ∼95%) were quantitatively evaluated by changing the concentration ratios. The rate constants of SF and excimer processes are largely dependent on the concentration ratios, whereas the rate constants of ET processes approximately remain constant. These findings are also discussed based on the statistical framework of the assembly of chromophores on the gold surface.


The anterior cingulate cortex mediates processing selection in the Stroop attentional conflict paradigm.
Regional cerebral blood flow, an index of local neuronal activity, was measured using positron emission tomography (PET) during the performance of the classic Stroop color/word task in eight healthy right-handed subjects. In the first condition of this paradigm, subjects name the color of the words presented on a video monitor. All the words are the color names congruent to the color presented (e.g., the noun "red" displayed in red color). In the second condition, subjects also name the color of the words presented on the monitor. However, during these trials all words are color names incongruent to the color presented (e.g., the noun "red" displayed in green color). The difference in brain activity between these two conditions (i.e., incongruent minus congruent) could reveal brain systems involved in the attentionally mediated resolution of the conflict between the habitual response of reading words vs. the task demands of naming the color of the words--i.e., the Stroop interference effect. The most robust responses occurred in the anterior cingulate cortex. Other responses noted were in the left premotor cortex, left postcentral cortex, left putamen, supplementary motor area, right superior temporal gyrus, and bilateral peristriate cortices. These data provide support for the role of the anterior cingulate cortex in attentional processing through the selection and recruitment of processing centers appropriate for task execution. Furthermore, the extensive distributed network of activated regions suggests that the Stroop interference effect cannot be explained simply in terms of stimulus encoding or response interference.


Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis.
We have previously shown that the expression of a semaphorin, known as a repelling cue in axon guidance, Sema3E, correlates with the ability to form lung metastasis in murine adenocarcinoma cell models. Now, besides providing evidence for the relevance of SEMA3E to human disease by showing that SEMA3E is frequently expressed in human cancer cell lines and solid tumors from breast cancer patients, we show biological activities of Sema3E, which support the implication of Sema3E in tumor progression and metastasis. In vivo, expression of Sema3E in mammary adenocarcinoma cells induces the ability to form experimental lung metastasis, and in vitro, the Sema3E protein exhibits both migration and growth promoting activity on endothelial cells and pheochromocytoma cells. This represents the first evidence of a metastasis-promoting function of a class 3 semaphorin, as this class of genes has hitherto been implicated in tumor biology only as tumor suppressors and negative regulators of growth. Moreover, we show that the full-size Sema3E protein is converted into a p61-Sema3E isoform due to furin-dependent processing, and by analyzing processing-deficient and truncated forms, we show that the generation of p61-Sema3E is required and sufficient for the function of Sema3E in lung metastasis, cell migration, invasive growth, and extracellular signal-regulated kinase 1/2 activation of endothelial cells. These findings suggest that certain breast cancer cells may increase their lung-colonizing ability by converting the growth repellent, Sema3E, into a growth attractant and point to a type of semaphorin signaling different from the conventional signaling induced by full-size dimeric class 3 semaphorins.


ADHD symptoms in children with FXS.
Parent- and teacher-report of attention-deficit/hyperactivity disorder (ADHD) symptoms were examined using problem behavior and DSM-IV symptom inventory questionnaires for 63 children with full mutation fragile X syndrome (FXS) and 56 children without disabilities matched on mental age (MA). Prevalence rates of ADHD symptoms varied depending on type of measure (problem behavior or DSM-IV criteria), subscale (ADHD-inattentive or ADHD-hyperactive), scoring method (continuous T-scores or categorical scores based on DSM-IV algorithm), and rater (parent or teacher). Overall, 54-59% of boys with FXS met diagnostic behavioral criteria for either ADHD-inattentive type only, ADHD-hyperactive type only, or ADHD-combined type based on parent or teacher report. Boys with FXS were rated as having clinically high scores or met diagnostic criteria at higher rates than expected for the general population and had higher raw scores than their MA-matched peers. Parent ratings of boys with FXS resulted in higher ADHD-inattentive type and ADHD-hyperactive type T-scores than teachers. Boys who were rated as meeting DSM-IV criteria were more likely to be taking psychotropic medication and to have younger mental ages. Parents were substantially more likely than teachers to rate boys as meeting DSM-IV criteria for ADHD-inattentive type, while teachers were only slightly more likely than parents to rate boys as meeting DSM-IV criteria for ADHD-hyperactive type. Teachers were more likely than parents to rate boys as meeting DSM-IV criteria for ADHD when boys had lower levels of FMRP.


Reproducible fiber optofluidic laser for disposable and array applications.
Disposable sensors are widely used in biomedical detection due to their inherent safety, ease of use and low cost. An optofluidic laser is a sensitive bioassay platform; however, demonstrating its fabrication cheaply and reproducibly enough for disposable use has been challenging. Here, we report a low-cost, reproducible fiber optofluidic laser (FOFL) using a microstructured optical fiber (MOF). The MOF not only supports the whispering gallery modes for lasing but also serves as a microfluidic channel for sampling the liquid gain medium via capillary force. Because of the precise control of its geometry (δ < 0.4%) during the fiber-drawing process, good reproducibility in laser intensity (δ = 6.5%) was demonstrated by changing 10 sections of the MOF. The strong coupling between the in-fiber resonator and gain medium enables a low threshold of 3.2 μJ mm-2. The angular dependence of the laser emission was observed experimentally and analyzed with numerical simulations. An array of the FOFLs was also demonstrated. This technology has great potential for low-cost bioassay applications.


Serum 25-Hydroxyvitamin D Levels are not Associated with Adverse Outcomes in Clostridium Difficile Infection.
Clostridium difficile infection (CDI) is a significant source of healthcare-associated morbidity and mortality. This study investigated whether serum 25-hydroxyvitamin D is associated with adverse outcomes from CDI. Patients with CDI were prospectively enrolled. Charts were reviewed and serum 25-hydroxyvitamin D was measured. The primary outcome was a composite definition of severe disease: fever (temperature >38°C), acute organ dysfunction, or serum white blood cell count >15,000 cells/µL within 24-48 hours of diagnosis; lack of response to therapy by day 5; and intensive care unit admission; colectomy; or death within 30 days. Sixty-seven patients were included in the final analysis. Mean (±SD) serum 25-hydroxyvitamin D was 26.1 (±18.54) ng/mL. Severe disease, which occurred in 26 (39%) participants, was not associated with serum 25-hydroxyvitamin D [odds ratio (OR) 1.00; 95% confidence interval (CI) 0.96-1.04]. In the adjusted model for severe disease only serum albumin (OR 0.12; 95%CI 0.02-0.64) and diagnosis by detection of stool toxin (OR 5.87; 95%CI 1.09-31.7) remained independent predictors. We conclude that serum 25-hydroxyvitamin D is not associated with the development of severe disease in patients with CDI.


Gradient Index Microlens Implanted in Prefrontal Cortex of Mouse Does Not Affect Behavioral Test Performance over Time.
Implanted gradient index lenses have extended the reach of standard multiphoton microscopy from the upper layers of the mouse cortex to the lower cortical layers and even subcortical regions. These lenses have the clarity to visualize dynamic activities, such as calcium transients, with subcellular and millisecond resolution and the stability to facilitate repeated imaging over weeks and months. In addition, behavioral tests can be used to correlate performance with observed changes in network function and structure that occur over time. Yet, this raises the questions, does an implanted microlens have an effect on behavioral tests, and if so, what is the extent of the effect? To answer these questions, we compared the performance of three groups of mice in three common behavioral tests. A gradient index lens was implanted in the prefrontal cortex of experimental mice. We compared their performance with mice that had either a cranial window or a sham surgery. Three presurgical and five postsurgical sets of behavioral tests were performed over seven weeks. Behavioral tests included rotarod, foot fault, and Morris water maze. No significant differences were found between the three groups, suggesting that microlens implantation did not affect performance. The results for the current study clear the way for combining behavioral studies with gradient index lens imaging in the prefrontal cortex, and potentially other regions of the mouse brain, to study structural, functional, and behavioral relationships in the brain.


Sexual knowledge and practice in Pakistani young men.
There is a shortage of scientific data on the subject of sexuality from Pakistan. We decided to document misconceptions among Pakistani young men, regarding masturbation and nocturnal emissions and to make a case for sex education in the country. To study the knowledge, attitude and practice of Pakistani young men as regards masturbation and nocturnal emissions and to see any associations with demographic factors like age, marital status, occupation, level of education and socio economic status. A questionnaire was developed, based on the objectives of the study. It was administered to 188 men between the age's 18-30 years, who presented to the outpatient department of the Aga Khan University Hospital. There was double entry of the data from questionnaires and the demographic form into the computer program, using the Fox Pro for windows and the SPSS for windows. We found a high prevalence of misconceptions and guilt associated with both these acts. Eighty percent of the respondents had masturbated while a 94% had experienced nocturnal emissions. 31.4% and 62.8% of the respondents reported association of physical illness and weakness with masturbation. Responses were 14.9% and 42.6% for nocturnal emissions. Association of guilt with masturbation and nocturnal emissions was 68.6% and 32% respectively. We also studied the association of demographic variables with these prevalence figures, in order to point out areas for future studies and interventions. We have documented the misconceptions regarding masturbation and nocturnal emissions among Pakistani young men and have made a case for sex education of our youth.


Lipopolysaccharide and granulocyte colony-stimulating factor delay neutrophil apoptosis and ingestion by guinea pig macrophages.
In previous studies, neutrophil-ingesting macrophages were clearly and easily observed in the peritoneal cavity of guinea pigs after intraperitoneal injection of thioglycolate medium, and phagocytosis of neutrophils by macrophages could be detected in in vitro cultures of peritoneal exudate cells. Using an in vitro system, we examined the effect of bacterial lipopolysaccharide and recombinant human granulocyte colony-stimulating factor on the apoptosis (programmed cell death) of neutrophils and their subsequent ingestion by macrophages. Lipopolysaccharide delayed karyopyknosis and apoptosis of neutrophils, as shown by endogenous endonuclease activity and a high proportion of trypan blue-excluding cells, and subsequent ingestion by autologous macrophages. Granulocyte colony-stimulating factor also delayed neutrophil karyopyknosis and ingestion by macrophages. When a thioglycolate medium was coinjected intraperitoneally with lipopolysaccharide into guinea pigs in the in vivo system, delays in neutrophil disappearance and ingestion by macrophages in the peritoneal cavity were also observed. We suggest that bacterial products and cytokines regulate neutrophil apoptosis and subsequent ingestion by macrophages at inflamed sites.


Cannabinoid receptors as therapeutic targets for autoimmune diseases: where do we stand?
Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).


Expression differentiation of CYC-like floral symmetry genes correlated with their protein sequence divergence in Chirita heterotricha (Gesneriaceae).
CYCLOIDIEA (CYC) and its homologues have been studied intensively in the model organism Antirrhinum majus and related species regarding their function in controlling floral dorsoventral (adaxial-abaxial) asymmetry, including aborting the adaxial and lateral stamens. This raises the question whether the same mechanism underlies the great morphological diversity of zygomorphy in angiosperms, especially in Lamiales sensu lato, a major clade predominantly with zygomorphic flowers. To address this, we selected a representative in Gesneriaceae, the sister to the remainder of Lamiales s.l., to isolate CYC homologues and further investigate their expression patterns using locus-specific semiquantitative reverse transcriptase polymerase chain reaction. Our results showed that four CYC homologues in Chirita heterotricha differentiated spatially and temporally in expression, in which ChCYC1D was only expressed in the adaxial regions, and transcripts of ChCYC1C were distributed in both the adaxial and lateral regions, while ChCYC2A and ChCYC2B transcripts were only detected in the young inflorescences. ChCYC1C expression in the lateral regions correlated with abortion of the lateral stamens in C. heterotricha hinted at its gain of function, i.e., expanding from the adaxial to the lateral regions in expression. Correlatively, the protein sequences of ChCYC genes exhibited remarkable divergences, in which some lineage-specific amino acids between GCYC1 and GCYC2 in conserved functional domains and two sublineage-specific motifs between GCYC1C and GCYC1D in GCYC1 genes had further been identified. Our results indicated that ChCYC genes had probably undergone an expressional differentiation and specialization in establishing the floral dorsoventral asymmetry in C. heterotricha responding to different selective pressure after gene duplication.


Peeping into human renal calcium oxalate stone matrix: characterization of novel proteins involved in the intricate mechanism of urolithiasis.
The increasing number of patients suffering from urolithiasis represents one of the major challenges which nephrologists face worldwide today. For enhancing therapeutic outcomes of this disease, the pathogenic basis for the formation of renal stones is the need of hour. Proteins are found as major component in human renal stone matrix and are considered to have a potential role in crystal-membrane interaction, crystal growth and stone formation but their role in urolithiasis still remains obscure. Proteins were isolated from the matrix of human CaOx containing kidney stones. Proteins having MW>3 kDa were subjected to anion exchange chromatography followed by molecular-sieve chromatography. The effect of these purified proteins was tested against CaOx nucleation and growth and on oxalate injured Madin-Darby Canine Kidney (MDCK) renal epithelial cells for their activity. Proteins were identified by Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF MS) followed by database search with MASCOT server. In silico molecular interaction studies with CaOx crystals were also investigated. Five proteins were identified from the matrix of calcium oxalate kidney stones by MALDI-TOF MS followed by database search with MASCOT server with the competence to control the stone formation process. Out of which two proteins were promoters, two were inhibitors and one protein had a dual activity of both inhibition and promotion towards CaOx nucleation and growth. Further molecular modelling calculations revealed the mode of interaction of these proteins with CaOx at the molecular level. We identified and characterized Ethanolamine-phosphate cytidylyltransferase, Ras GTPase-activating-like protein, UDP-glucose:glycoprotein glucosyltransferase 2, RIMS-binding protein 3A, Macrophage-capping protein as novel proteins from the matrix of human calcium oxalate stone which play a critical role in kidney stone formation. Thus, these proteins having potential to modulate calcium oxalate crystallization will throw light on understanding and controlling urolithiasis in humans.


Decreased expression of dual-specificity phosphatase 9 is associated with poor prognosis in clear cell renal cell carcinoma.
The molecular mechanisms involved in the development and progression of clear cell renal cell carcinomas (ccRCCs) are poorly understood. The objective of this study was to analyze the expression of dual-specificity phosphatase 9 (DUSP-9) and determine its clinical significance in human ccRCCs. The expression of DUSP-9 mRNA was determined in 46 paired samples of ccRCCs and adjacent normal tissues by using real-time qPCR. The expression of the DUSP-9 was determined in 211 samples of ccRCCs and 107 paired samples of adjacent normal tissues by immunohistochemical analysis. Statistical analysis was performed to define the relationship between the expression of DUSP-9 and the clinical features of ccRCC. The mRNA level of DUSP-9, which was determined by real-time RT-PCR, was found to be significantly lower in tumorous tissues than in the adjacent non-tumorous tissues (p < 0.001). An immunohistochemical analysis of 107 paired tissue specimens showed that the DUSP-9 expression was lower in tumorous tissues than in the adjacent non-tumorous tissues (p < 0.001). Moreover, there was a significant correlation between the DUSP-9 expression in ccRCCs and gender (p = 0.031), tumor size (p = 0.001), pathologic stage (p = 0.001), Fuhrman grade (p = 0.002), T stage (p = 0.001), N classification (p = 0.012), metastasis (p = 0.005), and recurrence (p < 0.001). Patients with lower DUSP-9 expression had shorter overall survival time than those with higher DUSP-9 expression (p < 0.001). Multivariate analysis indicated that low expression of the DUSP-9 was an independent predictor for poor survival of ccRCC patients. To our knowledge, this is the first study that determines the relationship between DUSP-9 expression and prognosis in ccRCC. We found that decreased expression of DUSP-9 is associated with poor prognosis in ccRCC. DUSP-9 may represent a novel and useful prognostic marker for ccRCC.


Bioresponsive peptide-inorganic hybrid nanomaterials.
Bioanalytical techniques that enable simple, fast and reliable high sensitivity monitoring of biomolecular interactions are of immense importance for diagnostics and drug development. This tutorial review provides an overview of recent progress in the development of peptide-based hybrid nanomaterials that transduce molecular interactions by exploiting the optical and magnetic properties of nanoparticles. Peptides have emerged as an interesting alternative to conventional biomolecular receptors, such as antibodies, and are facilitating the design of responsive hybrid nanomaterials that are both robust and sensitive for biodiagnostic applications.


Global Surgery Symposium.
This article describes the Global Surgery Symposium held within the 65th British Association of Paediatric Surgeons (BAPS) Annual Congress in 2018. Global surgery is a rapidly expanding and developing field and is of particular importance in paediatrics since children account for up to 50% of the population in low- and middle-income countries (LMICs). It is estimated that up to a third of childhood deaths in LMICs are the result of a surgical condition, and congenital anomalies have risen to become the 5th leading cause of death in children less than 5-years of age globally. Trainees in high-income countries (HICs) are increasingly interested in global surgery engagement through clinical placements, research, or education, or a combination of these. There is considerable controversy regarding the ethics, practicalities, usefulness, safety, and sustainability of these initiatives. In addition, there is debate as to whether such placements should occur within the paediatric surgery training pathway. LEVEL OF EVIDENCE: 5 (Expert Opinion).


Effect of salt depletion and propranolol on blood pressure and plasma renin activity in various forms of hypertension.
The effect of propranolol therapy on the mean arterial pressure (MAP) and plasma renin activity (PRA) was studied in three groups of hypertensive patients who were also treated with saliuretics. Group A: In 14 patients with essential hypertension on chlorthalidone treatment, an additional daily dose of 640 mg propranolol for two months led to a significant reduction of the MAP (from 124 to 105 mm Hg) and PRA (from 5.3 to 2.0 ng AI/ml/hr standing). There was no correlation between MAP reduction and either the original levels or change in PRA. Group B: In 14 patients with essential hypertension and 5 with renal artery stenosis studied on a fixed salt intake, the plasma and extracellular volumes, PRA, and blood pressures were recorded before and after three days of diuretic induced salt depletion and, with maintenance of the depleted state, after three days of propranolol. Salt depletion resulted in a decrease in MAP from 132 to 128 mm Hg (NS), and PRA increased from 3.4 to 22.3 ng AI/ml/hr (P less than 0.01). There was no correlation between change in MAP and PRA control values, PRA change, or any of the volume parameters. Addition of propranolol was followed by a rapid MAP decrease to 111 mm Hg (P less than 0.01), and the PRA dropped to a mean of 8.5 (P less than 0.01). No correlation was found between change in MAP and change in PRA. The patients with renal artery stenosis did not differ in their reactions from those with essential hypertension. Group C: In five patients with moderate renal failure and normal to expanded 82-Br distribution volume, propranolol lowered MAP by 10% and lowered the PRA in all five. Salt depletion by furosemide to 82-Br volumes below normal resulted in a 10% decrease of MAP and a marked rise in PRA. In this state propranolol was followed by a further MAP reduction of 18% and a decrease in PRA. There was no quantitative relationship between MAP and PRA change during either of the treatment regimes. It is concluded that in various forms of hypertension, the blood pressure can be effectively lowered by combining diuretics and propranolol regardless of the pretreatment PRA level.


Glucose metabolism in vivo in four commonly used inbred mouse strains.
To characterize differences in whole-body glucose metabolism between commonly used inbred mouse strains. Hyperinsulinemic-euglycemic (approximately 8.5 mmol/l) and -hypoglycemic (approximately 3.0 mmol/l) clamps were done in catheterized, 5-h-fasted mice to assess insulin action and hypoglycemic counter-regulatory responsiveness. Hyperglycemic clamps (approximately 15 mmol/l) were done to assess insulin secretion and compared with results in perifused islets. Insulin action and hypoglycemic counter-regulatory and insulin secretory phenotypes varied considerably in four inbred mouse strains. In vivo insulin secretion was greatest in 129X1/Sv mice, but the counter-regulatory response to hypoglycemia was blunted. FVB/N mice in vivo showed no increase in glucose-stimulated insulin secretion, relative hepatic insulin resistance, and the highest counter-regulatory response to hypoglycemia. In DBA/2 mice, insulin action was lowest among the strains, and islets isolated had the greatest glucose-stimulated insulin secretion in vitro. In C57BL/6 mice, in vivo physiological responses to hyperinsulinemia at euglycemia and hypoglycemia were intermediate relative to other strains. Insulin secretion by C57BL/6 mice was similar to that in other strains in contrast to the blunted glucose-stimulated insulin secretion from isolated islets. Strain-dependent differences exist in four inbred mouse strains frequently used for genetic manipulation and study of glucose metabolism. These results are important for selecting inbred mice to study glucose metabolism and for interpreting and designing experiments.


The status of genetic material and genetic information in The Netherlands.
The moral status of genetic material and information, and the ethics of controlling and manipulating them, is a topic of hot debate in many European countries, including The Netherlands. That heat is due partly to the complexity of the topic, and partly to researchers' fear that their investigations will be hampered by restrictions on the use of personal data or body material. But there is little doubt that manifold diverging interpretations about the status of the human body, body materials, and personal information in Dutch law, written and unwritten, contribute to the intensity of the debates. This article intends to structure the debate by creating more clarity at the conceptual level. By carefully examining relevant articles of the Constitution and Civil Codes, as well as policy documents and authoritative publications, notably in reference to prominent legal concepts such as property, ownership and privacy, and answer should be provided to the following crucial question: is the status of genetic material and information in any sense special in comparison with other body parts and other kinds of information about a person? This paper first discusses the status of human body materials and personal information in general, and then continues with a more specific discussion about the status of genetic material and information. It concludes that the Dutch legislature had carefully avoided (or not felt the need to employ) the concept of ownership in regulating biomedical research; rather, privacy is found to be the prime regulatory concept.


Hispanic physicians' tobacco intervention practices: a cross-sectional survey study.
U.S. Hispanic physicians constitute a considerable professional collective, and they may be most suited to attend to the health education needs of the growing U.S. Hispanic population. These educational needs include tobacco use prevention and smoking cessation. However, there is a lack of information on Hispanic physicians' tobacco intervention practices, their level of awareness and use of cessation protocols, and the type of programs that would best address their tobacco training needs. The purpose of this study was to assess the tobacco intervention practices and training needs of Hispanic physicians. Data was collected through a validated survey instrument among a cross-sectional sample of self-reported Hispanic physicians. Data analyses included frequencies, descriptive statistics, and factorial analyses of variance. The response rate was 55.5%. The majority of respondents (73.3%) were middle-age males. Less than half of respondents routinely performed the most basic intervention: asking patients about smoking status (44.4%) and advising smoking patients to quit (42.2%). Twenty-five percent assisted smoking patients by talking to them about the health risks of smoking, providing education materials or referring them to cessation programs. Only 4.4% routinely arranged follow-up visits or phone calls for smoking patients. The majority of respondents (64.4%) indicated that they prescribe cessation treatments to less than 20% of smoking patients. A few (4.4%) routinely used behavioral change techniques or programs. A minority (15.6%) indicated that they routinely ask their patients about exposure to tobacco smoke, and 6.7% assisted patients exposed to secondhand smoke in understanding the health risks associated with environmental tobacco smoke (ETS). The most frequently encountered barriers preventing respondents from intervening with patients who smoke included: time, lack of training, lack of receptivity by patients, and lack of reimbursement by third party payers. There was no significant main effect of type of physician, nor was there an interaction effect (gender by type of physician), on tobacco-related practices. The results indicate that Hispanic physicians, similarly to U.S. physicians in general, do not meet the level of intervention recommended by health care agencies. The results presented will assist in the development of tobacco training initiatives for Hispanic physicians.


The role of iron uptake in pathogenicity and symbiosis in Photorhabdus luminescens TT01.
Photorhabdus are Gram negative bacteria that are pathogenic to insect larvae whilst also having a mutualistic interaction with nematodes from the family Heterorhabditis. Iron is an essential nutrient and bacteria have different mechanisms for obtaining both the ferrous (Fe2+) and ferric (Fe3+) forms of this metal from their environments. In this study we were interested in analyzing the role of Fe3+ and Fe2+ iron uptake systems in the ability of Photorhabdus to interact with its invertebrate hosts. We constructed targeted deletion mutants of exbD, feoABC and yfeABCD in P. luminescens TT01. The exbD mutant was predicted to be crippled in its ability to obtain Fe3+ and we show that this mutant does not grow well in iron-limited media. We also show that this mutant was avirulent to the insect but was unaffected in its symbiotic interaction with Heterorhabditis. Furthermore we show that a mutation in feoABC (encoding a predicted Fe2+ permease) was unaffected in both virulence and symbiosis whilst the divalent cation transporter encoded by yfeABCD is required for virulence in the Tobacco Hornworm, Manduca sexta (Lepidoptera) but not in the Greater Wax Moth, Galleria mellonella (Lepidoptera). Moreover the Yfe transporter also appears to have a role during colonization of the IJ stage of the nematode. In this study we show that iron uptake (via the TonB complex and the Yfe transporter) is important for the virulence of P. luminescens to insect larvae. Moreover this study also reveals that the Yfe transporter appears to be involved in Mn2+-uptake during growth in the gut lumen of the IJ nematode. Therefore, the Yfe transporter in P. luminescens TT01 is important during colonization of both the insect and nematode and, moreover, the metal ion transported by this pathway is host-dependent.


Peripheral arterial disease: a guide for nephrologists.
Cardiovascular disease is a major source of morbidity and mortality for patients with chronic kidney disease (CKD). Peripheral arterial disease (PAD) is a strong predictor of coronary artery disease and a risk factor for mortality in the general population. This is of particular interest to nephrologists because the risk for PAD is increased in CKD. Often, PAD is overlooked as a source of morbidity and as a cardiovascular risk factor in this population. This review serves as an overview of the epidemiology, screening, diagnosis, and treatment of PAD with an emphasis on CKD.


Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation.
The abundance of energy metabolites is intimately interconnected with the activity of chromatin-modifying enzymes in order to guarantee the finely tuned modulation of gene expression in response to cellular energetic status. Metabolism-induced epigenetic gene regulation is a key molecular axis for the maintenance of cellular homeostasis, and its deregulation is associated with several pathological conditions. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) using the universal methyl donor S-adenosyl methionine (SAM), directly linking one-carbon metabolism with a cell's methylation balance and nicotinamide adenine dinucleotide (NAD+) levels. NNMT expression and activity are regulated in a tissue-specific-manner, and the protein can act either physiologically or pathologically depending on its distribution. While NNMT exerts a beneficial effect by regulating lipid parameters in the liver, its expression in adipose tissue correlates with obesity and insulin resistance. NNMT upregulation has been observed in a variety of cancers, and increased NNMT expression has been associated with tumor progression, metastasis and worse clinical outcomes. Accordingly, NNMT represents an appealing druggable target for metabolic disorders as well as oncological and other diseases in which the protein is improperly activated. This review examines emerging findings concerning the complex NNMT regulatory network and the role of NNMT in both NAD metabolism and cell methylation balance. We extensively describe recent findings concerning the physiological and pathological regulation of NNMT with a specific focus on the function of NNMT in obesity, insulin resistance and other associated metabolic disorders along with its well-accepted role as a cancer-associated metabolic enzyme. Advances in strategies targeting NNMT pathways are also reported, together with current limitations of NNMT inhibitor drugs in clinical use. NNMT is emerging as a key point of intersection between cellular metabolism and epigenetic gene regulation, and growing evidence supports its central role in several pathologies. The use of molecules that target NNMT represents a current pharmaceutical challenge for the treatment of several metabolic-related disease as well as in cancer.


Displacement of the hyoid bone by muscle paralysis and lung volume increase: the effects of obesity and obstructive sleep apnea.
Animal studies suggest a pivotal role of the hyoid bone in obstructive sleep apnea (OSA). We aimed to explore the role of the hyoid bone in humans by testing the hypotheses that muscle paralysis and lung volume (LV) changes displace the hyoid bone position particularly in people with obesity and/or OSA. Fifty patients undergoing general anesthesia participated in this study (20 participants with nonobese, non-OSA; 8 people with nonobese OSA; and 22 people with obese OSA). Three lateral neck radiographs to assess the hyoid position (primary variable) and craniofacial structures were taken during wakefulness, complete muscle paralysis under general anesthesia, and LV increase under general anesthesia. LV was increased by negative extrathoracic pressure application and LV changes were measured with a spirometer. Analysis of covariance was used to identify statistical significance. Muscle paralysis under general anesthesia significantly displaced the hyoid bone posteriorly (95% CI: 1.7 to 4.6, 1.5 to 5.2, and 1.1 to 4.0 mm in nonobese non-OSA, nonobese OSA, and obese OSA groups, respectively), and this was more prominent in people with central obesity. LV increase significantly displaced the hyoid bone caudally in all groups (95% CI: 0.2 to 0.7, 0.02 to 0.6, and 0.2 to 0.6 mm/0.1 liter LV increase in nonobese non-OSA, nonobese OSA, and obese OSA groups, respectively). Waist-hip ratio was directly associated with the caudal displacement during LV increase. The hyoid bone plays an important role in the pathophysiology of pharyngeal airway obstruction due to muscle paralysis and LV reduction, particularly in people with obesity. UMIN Clinical Trial Registry, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=cR000022635&language=E, UMIN000019578.


Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs.
Rheumatoid arthritis (RA) is characterised by breach of self-tolerance towards citrullinated antigens with generation of anti-citrullinated peptide/proteins antibodies (ACPA). Currently, the nature and source of citrullinated antigens driving the humoral autoimmune response within synovial ectopic lymphoid structures (ELS) is a crucial unknown aspect of RA pathogenesis. Here we characterised the autoreactive B-cell response of lesional B cells isolated from ELS+RA synovium. Single synovial tissue CD19+cells were Fluorescence Activated Cell Sorting (FACS)-sorted and VH/VL Ig genes cloned to generate recombinant monoclonal antibodies (rmAbs) from patients with ELS+/ACPA+RA. RA-rmAbs immunoreactivity analysis provided the following key findings: (1) in a chIP-based array containing 300 autoantigens and in a 'citrullinome' multiplex assay, a strong reactivity against citrullinated histones H2A/H2B (citH2A/H2B) was observed in ∼40% of RA-rmAbs, followed by cit-fibrinogen and cit-vimentin; (2) anti-citH2A/H2B-reactive RA-rmAbs (but not anti-citH2A/H2B negative) selectively recognised neutrophil extracellular traps (NETs) from peripheral blood and/or RA joint neutrophils; (3) anti-citH2A/citH2B and anti-NET immunobinding was dependent on affinity maturation and was completely abrogated following reversion of hypermutated IgVH/VL genes to germline sequences; (4) ELS+ (not ELS-) RA synovial tissues engrafted into Severe Combined ImmunoDeficiency (SCID) mice released human anti-citH2A/citH2B and anti-NET antibodies in association with the intra-graft expression of CXCL13 and lymphotoxin (LT)-β, two master regulators of ELS. We provided novel evidence that B cells differentiated within synovial ELS in the RA joints frequent target deiminated proteins which could be generated during NETosis of RA synovial neutrophils including histones. Thus, NETs could represent a source of citrullinated antigens fuelling the ACPA autoimmune response within the RA synovium.


Comparison of microsurgical and macrosurgical technique using bioactive synthetic bone graft and collagen membrane for an implant site development: A randomized controlled clinical trial.
Implant site development can be effective in minimizing postextraction alveolar ridge resorption in the esthetic region. Microsurgical approach has demonstrated substantial improvement in soft-tissue architecture. The aim of the present study was to evaluate and compare the efficacy of microsurgical technique with conventional one for implant site development utilizing biphasic hydroxyapatite/beta-tricalcium phosphate bone graft substitute and collagen membrane. Thirty extraction sites were planned for implant placement and randomly divided into control (macrosurgical/conventional) and test (microsurgery) sites. Clinical measurements were recorded at four different points of extraction socket, i.e., mesiobuccal, midbuccal, distobuccal, and midlingual/palatal at baseline, 3, 6, and 9 months. Postoperative neovascularization at control and test site was evaluated by ultrasound Doppler flowmetry at baseline, 10th day, and 1 month. Radiological assessment of bone density (Hounsfield units) was measured at control and test sites at baseline, 6 and 9 months by computed tomography. Data was subjected to statistical analysis. Significant socket fill at all the four different sites was observed and found to be statistically significant at test as compared to control group with better tissue contour after 3, 6, and 9 months. Test group demonstrated better neovascularization (P < 0.05) with significantly higher bone density (P = 0.000) at different time intervals. The results indicate that the augmentation of extraction sockets, not only improved the quality of bone in both the techniques but the utilization of microsurgical instruments and microsutures under magnification definitely enhanced the quality of soft tissues which is imperative for successful implant placement and its survival.


A strategy for full interrogation of prognostic gene expression patterns: exploring the biology of diffuse large B cell lymphoma.
Gene expression profiling yields quantitative data on gene expression used to create prognostic models that accurately predict patient outcome in diffuse large B cell lymphoma (DLBCL). Often, data are analyzed with genes classified by whether they fall above or below the median expression level. We sought to determine whether examining multiple cut-points might be a more powerful technique to investigate the association of gene expression with outcome. We explored gene expression profiling data using variable cut-point analysis for 36 genes with reported prognostic value in DLBCL. We plotted two-group survival logrank test statistics against corresponding cut-points of the gene expression levels and smooth estimates of the hazard ratio of death versus gene expression levels. To facilitate comparisons we also standardized the expression of each of the genes by the fraction of patients that would be identified by any cut-point. A multiple comparison adjusted permutation p-value identified 3 different patterns of significance: 1) genes with significant cut-point points below the median, whose loss is associated with poor outcome (e.g. HLA-DR); 2) genes with significant cut-points above the median, whose over-expression is associated with poor outcome (e.g. CCND2); and 3) genes with significant cut-points on either side of the median, (e.g. extracellular molecules such as FN1). Variable cut-point analysis with permutation p-value calculation can be used to identify significant genes that would not otherwise be identified with median cut-points and may suggest biological patterns of gene effects.


Patient co-payments and use of prescription medicines.
To investigate how prescription co-payments influence the medicine use of Australian patients. Two surveys and an in-depth interview study were conducted in the Newcastle/Hunter region of New South Wales (NSW). A community-based survey explored how often prescription cost posed a barrier to prescription use. A general practice patient survey investigated the impact of prescription cost on the timing of medical consultations and prescription collection. Quantitative data were summarised using descriptive statistics; associations between household characteristics and outcomes were explored using odds ratios and chi square analysis. In-depth interviews were conducted to explore the role of prescription cost in medicine use. The interview data were qualitatively analysed for relevant themes using 'grounded theory'. 420 of 950 households (44%) participated in the community survey: 110 (26%) reported delaying visiting a GP, 85 (20%) not buying all of their prescription medicines and 77 (18%) not refilling a prescription because of cost. Sixty-two (15%) households reported significant difficulties with prescription costs. Households with children had twice the odds of reporting significant difficulties than those without (OR= 2.0, 95% CI 1.2-3.5). Of the 442 (43%) GP patients who participated, 25 (6%) patients reported prescription cost as the reason for delaying their visit. Of the 291 patients who received a prescription, 26 (9%) patients reported cost as the reason for not collecting some or all of their prescriptions. Given the wide variation in patients' capacity to manage increased out-of-pocket costs, co-payments may add to patients' burden and place a potential barrier to safe and timely prescription use.


Metoprolol in acute myocardial infarction. Other clinical findings and tolerability. The MIAMI Trial Research Group.
Fifteen minutes after injection there was a fall in mean heart rate (18%, p less than 0.001), systolic blood pressure (10%, p less than 0.001) and rate-pressure product (27%, p less than 0.0001) in the metoprolol group of patients in the MIAMI trial. Hypotension and bradycardia not necessarily associated with withdrawal of drug were more common in the metoprolol group (p less than 0.001). Atrioventricular block I was more common in the metoprolol group (p less than 0.03), whereas no such difference was observed for atrioventricular block II and III, asystole or pacemaker implantations. Left ventricular failure was observed no more often in the metoprolol group. The occurrence of cardiogenic shock also did not differ between the groups. Cardiac glycosides were used more in the placebo group, but diuretic and furosemide usage did not differ. For all patients mean furosemide doses and number of diuretic injections were similar in both treatment groups. Atropine (4.1 vs 6.4%) and sympathomimetic (3.2 vs 4.6%) agents were used more often in the metoprolol group during days 0 to 5 (p less than 0.05). The trial medication was withdrawn temporarily more often in the metoprolol than in the placebo group (p less than 0.001). However, permanent withdrawal of trial medication occurred with a similar frequency overall in both groups. More patients were withdrawn from the study because of cardiovascular reasons in the metoprolol group (9%) than in the placebo group (5%, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


A stochastic multicellular model identifies biological watermarks from disorders in self-organized patterns of phyllotaxis.
Exploration of developmental mechanisms classically relies on analysis of pattern regularities. Whether disorders induced by biological noise may carry information on building principles of developmental systems is an important debated question. Here, we addressed theoretically this question using phyllotaxis, the geometric arrangement of plant aerial organs, as a model system. Phyllotaxis arises from reiterative organogenesis driven by lateral inhibitions at the shoot apex. Motivated by recurrent observations of disorders in phyllotaxis patterns, we revisited in depth the classical deterministic view of phyllotaxis. We developed a stochastic model of primordia initiation at the shoot apex, integrating locality and stochasticity in the patterning system. This stochastic model recapitulates phyllotactic patterns, both regular and irregular, and makes quantitative predictions on the nature of disorders arising from noise. We further show that disorders in phyllotaxis instruct us on the parameters governing phyllotaxis dynamics, thus that disorders can reveal biological watermarks of developmental systems.


Impact of a mailed intervention on annual mammography and physician breast examinations among women at high risk of breast cancer.
Only a few studies have examined repeat annual mammography rates, and most studies find that such regularity is low, ranging from < 5% in the general population to between 14 and 20% of first-degree relatives. The present study tested the effectiveness of a mailed intervention designed to improve compliance with breast cancer screening guidelines among women at elevated familial risk. The study used a pretest-posttest control group design; 369 twin sisters of breast cancer cases were assigned alternately to an intervention or a control group on the basis of sequential registration numbers. The intervention consisted of written materials, an audiotape, and mailed reminders. The posttest was mailed 2.5 years after the intervention in order to provide adequate time to assess the regularity of screening. The intervention and control groups were virtually identical with respect to demographic and baseline screening characteristics. Of those who returned the follow-up questionnaire, annual physician breast examinations were 12.8% higher and annual mammograms were 10.3% higher in the intervention group than in the control group. The probability of annual screening with physician breast examination and mammography was higher in the intervention group, and the probability of annual mammography continued to be higher for women over age 52 years after controlling for baseline screening, year of diagnosis, education, and status of the twin. This result is consistent with improvements found in other studies. Women who did not return follow-up questionnaires were more likely to have had fewer physician breast examinations and mammograms and more likely to be in the intervention group than those who stayed in the study. Additionally, those who dropped out of the intervention arm perceived themselves to be less susceptible and perceived screening to be less effective than did those who dropped out of the control arm. Although the intervention caused many women to be screened more regularly, those who had not been screened in the past and those who held opinions that were not conducive to screening were more likely to drop out. This mailed intervention for high-risk women increased their rate of screening. Characteristics of women resistant to such programs have been identified; alternative strategies need to be developed to reach this small percentage of high-risk women who ignore their elevated susceptibility.


Insulin sensitivity in relation to fat distribution and plasma adipocytokines among abusers of anabolic androgenic steroids.
Abuse of anabolic androgenic steroids (AAS) is prevalent among young men, but information regarding effects on insulin sensitivity and fat distribution is limited. The objective was to investigate insulin sensitivity in relation to fat distribution and adipocytokines among current and former AAS abusers compared with controls. Cross-sectional study among men involved in recreational strength training. Current and former AAS abusers (n=37 and n=33) and controls (n=30) volunteered from the community. We assessed insulin sensitivity by Matsuda index (oral glucose tolerance test). Using overnight fasting blood samples, adiponectin and leptin were measured. Body composition and fat distribution, including visceral adipose tissue (VAT), were assessed by dual energy X-ray absorptiometry. Current and former AAS abusers displayed lower Matsuda index than controls (%-difference (95%CI) from controls, -26% (-45; -1) and -39% (-55; -18)). Testosterone was markedly higher among current AAS abusers and subnormal among former AAS abusers compared with controls. Current AAS abusers displayed higher mean VAT than controls (388 (17) vs 293 (12) cm3 , P<.001) whereas body fat %, adiponectin and leptin concentrations were lower. In contrast, former AAS abusers showed highest leptin concentrations and body fat %. Multivariate linear regressions identified VAT as independent predictor of lower Matsuda index among current AAS abusers compared with controls; while body fat % independently predicted lower Matsuda index among former AAS abusers. Both current and former AAS abusers displayed lower insulin sensitivity which could be mediated by higher VAT and total body fat %, respectively.


Switching of the relative dominance between feedback mechanisms in lipopolysaccharide-induced NF-κB signaling.
A fundamental goal in biology is to gain a quantitative understanding of how appropriate cell responses are achieved amid conflicting signals that work in parallel. Through live, single-cell imaging, we monitored both the dynamics of nuclear factor κB (NF-κB) signaling and inflammatory cytokine transcription in macrophages exposed to the bacterial product lipopolysaccharide (LPS). Our analysis revealed a previously uncharacterized positive feedback loop involving induction of the expression of Rela, which encodes the RelA (p65) NF-κB subunit. This positive feedback loop rewired the regulatory network when cells were exposed to LPS above a distinct concentration. Paradoxically, this rewiring of NF-κB signaling in macrophages (a myeloid cell type) required the transcription factor Ikaros, which promotes the development of lymphoid cells. Mathematical modeling and experimental validation showed that the RelA positive feedback overcame existing negative feedback loops and enabled cells to discriminate between different concentrations of LPS to mount an effective innate immune response only at higher concentrations. We suggest that this switching in the relative dominance of feedback loops ("feedback dominance switching") may be a general mechanism in immune cells to integrate opposing feedback on a key transcriptional regulator and to set a response threshold for the host.


Bone density and mineral metabolism in thyroidectomized patients treated with long-term L-thyroxine.
1. A decreased bone mass has been reported in patients with endogenous hyperthyroidism, but the effect on bone density and mineral metabolism of thyroxine administration in thyroidectomized patients is still controversial. To further contribute to this debate, we studied 25 women thyroidectomized for thyroid cancer on long-term treatment with thyroid-stimulating hormone-suppressive doses of L-thyroxine. Twenty-one sex- and age-matched normal subjects were also studied as a control group. 2. The bone density of the spine and serum calcitonin, calcitriol and parathyroid hormone concentrations were not different when the whole patient group was compared with the control subjects, nor when the patients and control subjects were compared according to their menopausal status. However, post-menopausal thyroidectomized patients showed significantly lower bone mass (P < 0.001) than premenopausal patients. 3. L-Thyroxine-treated patients showed significantly higher levels of bone alkaline phosphatase and urine hydroxyproline excretion than control subjects (P < 0.003 and P < 0.001, respectively). These differences were still present when patients and control subjects were analysed according to their menopausal status. However, bone alkaline phosphatase was significantly higher in postmenopausal than in premenopausal women only in L-thyroxine-treated patients (P < 0.05). In postmenopausal L-thyroxine-treated patients a negative correlation between time since menopause and bone mass (P < 0.05) and a positive correlation between bone alkaline phosphatase and hydroxyproline excretion (P < 0.03) were also found.(ABSTRACT TRUNCATED AT 250 WORDS)


Quantitative analysis of dynamic contrast-enhanced MR images based on Bayesian P-splines.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an important tool for detecting subtle kinetic changes in cancerous tissue. Quantitative analysis of DCE-MRI typically involves the convolution of an arterial input function (AIF) with a nonlinear pharmacokinetic model of the contrast agent concentration. Parameters of the kinetic model are biologically meaningful, but the optimization of the nonlinear model has significant computational issues. In practice, convergence of the optimization algorithm is not guaranteed and the accuracy of the model fitting may be compromised. To overcome these problems, this paper proposes a semi-parametric penalized spline smoothing approach, where the AIF is convolved with a set of B-splines to produce a design matrix using locally adaptive smoothing parameters based on Bayesian penalized spline models (P-splines). It has been shown that kinetic parameter estimation can be obtained from the resulting deconvolved response function, which also includes the onset of contrast enhancement. Detailed validation of the method, both with simulated and in vivo data, is provided.


Cognitive behavior therapy, exercise, or both for treating chronic widespread pain.
The clinical impact of telephone-delivered cognitive behavioral therapy (TCBT), exercise, or a combined intervention in primary care patients with chronic widespread pain (CWP) is unclear. A total of 442 patients with CWP (meeting the American College of Rheumatology criteria) were randomized to receive 6 months of TCBT, graded exercise, combined intervention, or treatment as usual (TAU). The primary outcome, using a 7-point patient global assessment scale of change in health since trial enrollment (range: very much worse to very much better), was assessed at baseline and 6 months (intervention end) and 9 months after randomization. A positive outcome was defined as "much better" or "very much better." Data were analyzed using logistic regression according to the intention-to-treat principle. The percentages reporting a positive outcome at 6 and 9 months, respectively, were TAU group, 8% and 8%; TCBT group, 30% and 33%; exercise group, 35% and 24%; and combined intervention group, 37% and 37% (P < .001). After adjustment for age, sex, center, and baseline predictors of outcome, active interventions improved outcome compared with TAU: TCBT (6 months: odds ratio [OR], 5.0 [95% CI, 2.0-12.5]; 9 months: OR, 5.4 [95% CI, 2.3-12.8]), exercise (6 months: OR, 6.1 [95% CI, 2.5-15.1]; 9 months: OR, 3.6 [95% CI, 1.5-8.5]), and combined intervention (6 months: OR, 7.1 [95% CI, 2.9-17.2]; 9 months: OR, 6.2 [95% CI, 2.7-14.4]). At 6 and 9 months, combined intervention was associated with improvements in the 36-Item Short Form Health Questionnaire physical component score and a reduction in passive coping strategies. Conclusions on cost-effectiveness were sensitive to missing data. TCBT was associated with substantial, statistically significant, and sustained improvements in patient global assessment. clinicaltrials.gov Identifier: ISRCTN67013851.


Disordered hyperuniform heterogeneous materials.
Disordered hyperuniform many-body systems are distinguishable states of matter that lie between a crystal and liquid: they are like perfect crystals in the way they suppress large-scale density fluctuations and yet are like liquids or glasses in that they are statistically isotropic with no Bragg peaks. These systems play a vital role in a number of fundamental and applied problems: glass formation, jamming, rigidity, photonic and electronic band structure, localization of waves and excitations, self-organization, fluid dynamics, quantum systems, and pure mathematics. Much of what we know theoretically about disordered hyperuniform states of matter involves many-particle systems. In this paper, we derive new rigorous criteria that disordered hyperuniform two-phase heterogeneous materials must obey and explore their consequences. Two-phase heterogeneous media are ubiquitous; examples include composites and porous media, biological media, foams, polymer blends, granular media, cellular solids, and colloids. We begin by obtaining some results that apply to hyperuniform two-phase media in which one phase is a sphere packing in d-dimensional Euclidean space [Formula: see text]. Among other results, we rigorously establish the requirements for packings of spheres of different sizes to be 'multihyperuniform'. We then consider hyperuniformity for general two-phase media in [Formula: see text]. Here we apply realizability conditions for an autocovariance function and its associated spectral density of a two-phase medium, and then incorporate hyperuniformity as a constraint in order to derive new conditions. We show that some functional forms can immediately be eliminated from consideration and identify other forms that are allowable. Specific examples and counterexamples are described. Contact is made with well-known microstructural models (e.g. overlapping spheres and checkerboards) as well as irregular phase-separation and Turing-type patterns. We also ascertain a family of autocovariance functions (or spectral densities) that are realizable by disordered hyperuniform two-phase media in any space dimension, and present select explicit constructions of realizations. These studies provide insight into the nature of disordered hyperuniformity in the context of heterogeneous materials and have implications for the design of such novel amorphous materials.


Uniform growth and neuronal integration.
1. The cable equations were analyzed to determine the effects of two patterns of uniform growth on the passive and active integrative properties of neurons. 2. During uniform isoelectrotonic growth, the diameters of all neuronal processes increase as the square of their increase in length, while the specific electrical properties and branch terminal conditions of the neuron remain constant. An analytic inductive proof is given to show that, for any neuron, uniform isoelectrotonic growth increases the input conductance everywhere by the cube of the growth factor, but leaves the active and passive spread of membrane potential within the neuron unchanged. The spread of membrane voltage is unchanged because this pattern of growth enables both the axial and membrane currents everywhere in the cell to increase by the cube of the growth factor. Synaptic inputs would evoke the same responses in the isoelectrotonically larger cell as in the smaller cell if the total postsynaptic conductance of the synapse increased with the dendritic membrane area. 3. During uniform isometric growth, the diameter and lengths of all processes increase by the same factor, while the specific electrical properties and branch terminal conditions remain constant. This pattern of uniform growth increases the input conductance by the square of the growth factor, and also increases the attenuation, delay, and low-pass filtering of the cell's responses. Voltage attenuation increases with isometric growth because the axial current increases in proportion to growth, while the membrane current increases in proportion to the square of the growth factor. Isometric growth reduces the ability of distal synaptic inputs to affect the membrane potential at proximal integrating sites, even after the synaptic conductance has increased to compensate for the increased input conductance. 4. These two patterns of uniform growth help define the consequences of all types of uniform growth for neuronal integration and responsiveness.


Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates.
Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival and functioning of dopamine neurons in a variety of animal models and some recent human trials. However, delivery of any protein to the brain remains a challenge due to the blood/brain barrier. Here we show that human neural progenitor cells (hNPC) can be genetically modified to release glycosylated GDNF in vitro under an inducible promoter system. hNPC-GDNF were transplanted into the striatum of rats 10 days following a partial lesion of the dopamine system. At 2 weeks following transplantation, the cells had migrated within the striatum and were releasing physiologically relevant levels of GDNF. This was sufficient to increase host dopamine neuron survival and fiber outgrowth. At 5 weeks following grafting there was a strong trend towards functional improvement in transplanted animals and at 8 weeks the cells had migrated to fill most of the striatum and continued to release GDNF with transport to the substantia nigra. These cells could also survive and release GDNF 3 months following transplantation into the aged monkey brain. No tumors were found in any animal. hNPC can be genetically modified, and thereby represent a safe and powerful option for delivering growth factors to specific targets within the central nervous system for diseases such as Parkinson's.


Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options.
Diabetic cardiomyopathy is the presence of myocardial dysfunction in the absence of coronary artery disease and hypertension. Hyperglycemia seems to be central to the pathogenesis of diabetic cardiomyopathy and to trigger a series of maladaptive stimuli that result in myocardial fibrosis and collagen deposition. These processes are thought to be responsible for altered myocardial relaxation characteristics and manifest as diastolic dysfunction on imaging. Sophisticated imaging technologies also have permitted the detection of subtle systolic dysfunction in the diabetic myocardium. In the early stages, these changes appear reversible with tight metabolic control, but as the pathologic processes become organized, the changes are irreversible and contribute to an excess risk of heart failure among diabetic patients independently of common comorbidities, such as coronary artery disease and hypertension. Therapeutic agents specifically targeting processes that lead to these pathophysiologic changes are in the early stages of development. Although glycemic control and early administration of neurohormonal antagonists remain the cornerstones of therapeutic approaches, newer treatment targets are currently being explored.


Domain-General and Domain-Specific Electrophysiological Markers of Cognitive Distance Coding for What, Where, and When Memory Retrieval.
The what, where, and when components of episodic memory can be differentiated based on their distinctive domain-specific underlying neural correlates. However, recent studies have proposed that a common neural mechanism of conceptual mapping may be involved in the coding of cognitive distance across all domains. In this study, we provide evidence that both domain-specific and domain-general processes occur simultaneously during memory retrieval by identifying distinctive and common neural representations for mapping what (i.e., semantic distance), where (i.e., spatial distance), and when (i.e., temporal distance) using scalp EEG from 47 healthy participants (age 21-30, 26 male and 21 female). First, we found that all three components commonly showed a positive correlation between cognitive distance and slow theta power (2.5-5 Hz) in parietal channels. Meanwhile, fast theta power (5-8.5 Hz) specifically represented spatial and temporal distance in occipital and parietal channels, respectively. Additionally, we identified a unique correlate of temporal distance coding in frontal/parietal slow theta power during the early phase of retrieval. All of the above neural markers of cognitive mapping, both domain-general and specific, were associated with individual differences in what, where, and when memory accuracy.SIGNIFICANCE STATEMENT The Cognitive Map Theory was originally founded to explain how we remember and organize the immense amount of spatial information that we face when we navigate. However, memory research has recently trended in the direction of emphasizing the generalizability of cognitive mapping mechanisms to information in any domain, represented as distances in an abstract conceptual space. In a single study, we show that both common and unique neural coding of semantic distance (i.e., what), spatial distance (i.e., where), and temporal distance (i.e., when) simultaneously support episodic memory retrieval. Our results suggest that our ability to accurately distinguish between memories is achieved through an integration of domain-specific and domain-general neurocognitive mechanisms that work in parallel.


Prognostic factors for duration of sick leave in patients sick listed with acute low back pain: a systematic review of the literature.
The percentages of patients with acute low back pain (LBP) that go on to a chronic state varies between studies from 2% to 34%. In some of these cases low back pain leads to great costs. To evaluate the evidence for prognostic factors for return to work among workers sick listed with acute LBP. Systematic literature search with a quality assessment of studies, assessment of levels of evidence for all factors, and pooling of effect sizes. Inclusion of studies in the review was restricted to inception cohort studies of workers with LBP on sick leave for less than six weeks, with the outcome measured in absolute terms, relative terms, survival curve, or duration of sick leave. Of the studies, 18 publications (14 cohorts) fulfilled all inclusion criteria. One low quality study, four moderate quality studies, and nine high quality studies were identified; 79 prognostic factors were studied and grouped in eight categories for which the evidence was assessed. Specific LBP, higher disability levels, older age, female gender, more social dysfunction and more social isolation, heavier work, and receiving higher compensation were identified as predictors for a longer duration of sick leave. A history of LBP, job satisfaction, educational level, marital status, number of dependants, smoking, working more than 8 hour shifts, occupation, and size of industry or company do not influence duration of sick leave due to LBP. Many different constructs were measured to identify psychosocial predictors of long term sick leave, which made it impossible to determine the role of these factors.


Generation of anti-type III pneumococcal polysaccharide hybridomas from mice with an X-linked B-lymphocyte defect.
(CBA/N X BALB/c male)F1 mice bear on X-linked defect making them totally unresponsive to T-independent (TI), TI-2 antigens such as type III pneumococcal polysaccharide (SSS-III). We found that somatic cell hybrids between CB nonresponder spleen cells and NS1 plasmacytoma cells secreted antibody specific for SSS-III. The solid-phase binding of such antibody was completely inhibited by the addition of free antigen (SSS-III) and the amount of antibody detected in culture fluids ranged from 10 ng/ml to 10 micrograms/ml. Eight hybridoma clones were identified; all make antibody of the IgM class. These results indicate that the X-linked defect does not result in a deletion of a B-cell subset which responds to TI-2 antigens.


Hydrogen saline prevents selenite-induced cataract in rats.
The aim of this study was to investigate the potential antioxidative effect and mechanism for the protective effects of hydrogen saline on selenite-induced cataract in rats. Sprague-Dawley rat pups were divided into the following groups: control (Group A), selenite induced (Group B), and selenite plus hydrogen saline treated (Group C). Rat pups in Groups B and C received a single subcutaneous injection of sodium selenite (25 μmol/kg bodyweight) on postnatal day 12. Group C also received an intraperitoneal injection of H2 saline (5 ml/kg bodyweight) daily from postnatal day 8 to postnatal day 17. The development of cataract was assessed weekly by slit-lamp examination for 2 weeks. After sacrifice, extricated lenses were analyzed for activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, levels of malondialdehyde, reduced glutathione (GSH), and total sulfhydryl contents. The magnitude of lens opacification in Group B was significantly higher than in Group A (p<0.05), while Group C had less opacification than Group B (p<0.05). Compared with Group B, the mean activities of the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, levels of GSH, and total sulfhydryl contents were higher, whereas the level of malondialdehyde was lower following treatment with hydrogen saline(p<0.05). This is an initial report showing that hydrogen saline can prevent selenite-induced cataract in rats. It acts via maintaining antioxidant enzymes and GSH, protecting the sulfhydryl group, and inhibiting lipid peroxidation.


A multigene phylogeny of Olpidium and its implications for early fungal evolution.
From a common ancestor with animals, the earliest fungi inherited flagellated zoospores for dispersal in water. Terrestrial fungi lost all flagellated stages and reproduce instead with nonmotile spores. Olpidium virulentus (= Olpidium brassicae), a unicellular fungus parasitizing vascular plant root cells, seemed anomalous. Although Olpidium produces zoospores, in previous phylogenetic studies it appeared nested among the terrestrial fungi. Its position was based mainly on ribosomal gene sequences and was not strongly supported. Our goal in this study was to use amino acid sequences from four genes to reconstruct the branching order of the early-diverging fungi with particular emphasis on the position of Olpidium. We concatenated sequences from the Ef-2, RPB1, RPB2 and actin loci for maximum likelihood and Bayesian analyses. In the resulting trees, Olpidium virulentus, O. bornovanus and non-flagellated terrestrial fungi formed a strongly supported clade. Topology tests rejected monophyly of the Olpidium species with any other clades of flagellated fungi. Placing Olpidium at the base of terrestrial fungi was also rejected. Within the terrestrial fungi, Olpidium formed a monophyletic group with the taxa traditionally classified in the phylum Zygomycota. Within Zygomycota, Mucoromycotina was robustly monophyletic. Although without bootstrap support, Monoblepharidomycetes, a small class of zoosporic fungi, diverged from the basal node in Fungi. The zoosporic phylum Blastocladiomycota appeared as the sister group to the terrestrial fungi plus Olpidium. This study provides strong support for Olpidium as the closest living flagellated relative of the terrestrial fungi. Appearing nested among hyphal fungi, Olpidium's unicellular thallus may have been derived from ancestral hyphae. Early in their evolution, terrestrial hyphal fungi may have reproduced with zoospores.


The synaptonemal complex has liquid crystalline properties and spatially regulates meiotic recombination factors.
The synaptonemal complex (SC) is a polymer that spans ~100 nm between paired homologous chromosomes during meiosis. Its striated, periodic appearance in electron micrographs led to the idea that transverse filaments within this structure 'crosslink' the axes of homologous chromosomes, stabilizing their pairing. SC proteins can also form polycomplexes, three-dimensional lattices that recapitulate the periodic structure of SCs but do not associate with chromosomes. Here we provide evidence that SCs and polycomplexes contain mobile subunits and that their assembly is promoted by weak hydrophobic interactions, indicative of a liquid crystalline phase. We further show that in the absence of recombination intermediates, polycomplexes recapitulate the dynamic localization of pro-crossover factors during meiotic progression, revealing how the SC might act as a conduit to regulate chromosome-wide crossover distribution. Properties unique to liquid crystals likely enable long-range signal transduction along meiotic chromosomes and underlie the rapid evolution of SC proteins.


A vital role for complement in heart disease.
Heart diseases are common and significant contributors to worldwide mortality and morbidity. During recent years complement mediated inflammation has been shown to be an important player in a variety of heart diseases. Despite some negative results from clinical trials using complement inhibitors, emerging evidence points to an association between the complement system and heart diseases. Thus, complement seems to be important in coronary heart disease as well as in heart failure, where several studies underscore the prognostic importance of complement activation. Furthermore, patients with atrial fibrillation often share risk factors both with coronary heart disease and heart failure, and there is some evidence implicating complement activation in atrial fibrillation. Moreover, Chagas heart disease, a protozoal infection, is an important cause of heart failure in Latin America, and the complement system is crucial for the protozoa-host interaction. Thus, complement activation appears to be involved in the pathophysiology of a diverse range of cardiac conditions. Determination of the exact role of complement in the various heart diseases will hopefully help to identify patients that might benefit from therapeutic complement intervention.


A Hidden State in Light-Harvesting Complex II Revealed By Multipulse Spectroscopy.
Light-harvesting complex II (LHCII) is pivotal both for collecting solar radiation for photosynthesis, and for protection against photodamage under high light intensities (via a process called nonphotochemical quenching, NPQ). Aggregation of LHCII is associated with fluorescence quenching, and is used as an in vitro model system of NPQ. However, there is no agreement on the nature of the quencher and on the validity of aggregation as a model system. Here, we use ultrafast multipulse spectroscopy to populate a quenched state in unquenched (unaggregated) LHCII. The state shows characteristic features of lutein and chlorophyll, suggesting that it is an excitonically coupled state between these two compounds. This state decays in approximately 10 ps, making it a strong competitor for photodamage and photochemical quenching. It is observed in trimeric and monomeric LHCII, upon re-excitation with pulses of different wavelengths and duration. We propose that this state is always present, but is scarcely populated under low light intensities. Under high light intensities it may become more accessible, e.g. by conformational changes, and then form a quenching channel. The same state may be the cause of fluorescence blinking observed in single-molecule spectroscopy of LHCII trimers, where a small subpopulation is in an energetically higher state where the pathway to the quencher opens up.


The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing.
The coactivator-associated arginine methyltransferase CARM1 is recruited by many different transcription factors as a positive regulator. To understand the mechanism by which CARM1 functions, we sought to isolate its substrates. We developed a small-pool screening approach for this purpose and identified CA150, SAP49, SmB, and U1C as splicing factors that are specifically methylated by CARM1. We further showed that CA150, a molecule that links transcription to splicing, interacts with the Tudor domain of the spinal muscular atrophy protein SMN in a CARM1-dependent fashion. Experiments with an exogenous splicing reporter and the endogenous CD44 gene revealed that CARM1 promotes exon skipping in an enzyme-dependent manner. The identification of splicing factors that are methylated by CARM1, and protein-protein interactions that are regulated by CARM1, strongly implicates this enzyme in the regulation of alternative splicing and points toward its involvement in spinal muscular atrophy pathogenesis.


AN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion.
The infiltrative nature of Glioblastoma (GBM), the most aggressive primary brain tumor, critically prevents complete surgical resection and masks tumor cells behind the blood brain barrier reducing the efficacy of systemic treatment. Here, we use a genome-wide interference screen to determine invasion-essential genes and identify the AN1/A20 zinc finger domain containing protein 3 (ZFAND3) as a crucial driver of GBM invasion. Using patient-derived cellular models, we show that loss of ZFAND3 hampers the invasive capacity of GBM, whereas ZFAND3 overexpression increases motility in cells that were initially not invasive. At the mechanistic level, we find that ZFAND3 activity requires nuclear localization and integral zinc-finger domains. Our findings indicate that ZFAND3 acts within a nuclear protein complex to activate gene transcription and regulates the promoter of invasion-related genes such as COL6A2, FN1, and NRCAM. Further investigation in ZFAND3 function in GBM and other invasive cancers is warranted.


Myocardial injury in scorpion envenomed children: significance of assessment of serum troponin I and interleukin-8.
(1) To investigate the significance of assessment of serum levels of cardiac troponin I (cTnI) and interleukin-8 (IL-8) beside other biomarkers of myocardial injury in scorpion envenomed children. (2) To find the correlation between these biochemical indices with clinical status, prognosis and outcome of these cases. Forty-one children in Upper Egypt were admitted to Pediatric Intensive Care Unit, Assiut University Hospital, for scorpion envenomation. They were compared with fifteen apparently healthy children of matching age as controls. The victims and controls were subjected to complete clinical examination, full blood count and arterial blood gases analysis. According to severity of scorpion envenomation, 17 children had manifestations of severe envenomation and clinical signs of toxic myocarditis (severe cases), 14 children had moderate manifestations of envenomation without clinical evidence of carditis (moderate cases) and 10 cases showing only mild symptoms of envenomation (mild cases). The serum levels of cTnI and IL-8 beside the enzymatic activities of creatine phosphokinase (CPK), CPK-MB isoenzyme (CPK-MB) and lactate dehydrogenase (LDH) were determined once for mild cases and controls on admission and twice for severe and moderate cases on admission and after 24 hrs. The measurements of electrocardiography (ECG), echocardiographic measurement of % fractional shortening of left ventricule (%SF), left ventricular ejection fraction (LVEF) and cardiac chambers dilatation were done for severe and moderate cases. All the envenomed victims showed significantly higher mean values of CPK, CPK-MB, LDH, and IL-8 on admission in comparison to control group. cTnI was not detectable in the sera of control group as well as patients with mild envenomation. The mean values of CPK, CPK-MB, LDH, and IL-8 were significantly higher in severe cases while only IL-8 and CPK-MB were significantly higher in moderate cases in comparison with mild cases. The mean values of IL-8, cTnI, CPK, CPK-MB and LDH were significantly higher in severe cases both on admission and on follow-up comparing with moderate cases. The case fatality rate was 12.5% and all were from severe cases with toxic myocarditis (5/41=12.5%). The non-survivors victims showed significant higher mean values of only cTnI on admission and both cTnI and IL-8 on follow up in comparison to the survivors. Significant reduction of % SF and LVEF were noticed among the non-survivors in comparison to survivors. The cTnI showed 100% specificity and sensitivity for diagnosis of myocardial injury in relation to Echo finding in the envenomed victims. In severe cases, cTnI was positively correlated with IL-8 while negatively correlated with %SF and LVEF. it may be suggested that cTnI is the most specific marker for diagnosis of myocardial injury in scorpion envenomation, which is almost associated with skeletal muscle injury. Other biochemical markers did not show such specificity. Also, IL-8 may be involved in the pathogenesis of myocardial injury of scorpion envenomation. Both cTnI and IL-8 may be useful to forecast the fatal outcome in scorpion envenomation.


Finite-size and correlation-induced effects in mean-field dynamics.
The brain's activity is characterized by the interaction of a very large number of neurons that are strongly affected by noise. However, signals often arise at macroscopic scales integrating the effect of many neurons into a reliable pattern of activity. In order to study such large neuronal assemblies, one is often led to derive mean-field limits summarizing the effect of the interaction of a large number of neurons into an effective signal. Classical mean-field approaches consider the evolution of a deterministic variable, the mean activity, thus neglecting the stochastic nature of neural behavior. In this article, we build upon two recent approaches that include correlations and higher order moments in mean-field equations, and study how these stochastic effects influence the solutions of the mean-field equations, both in the limit of an infinite number of neurons and for large yet finite networks. We introduce a new model, the infinite model, which arises from both equations by a rescaling of the variables and, which is invertible for finite-size networks, and hence, provides equivalent equations to those previously derived models. The study of this model allows us to understand qualitative behavior of such large-scale networks. We show that, though the solutions of the deterministic mean-field equation constitute uncorrelated solutions of the new mean-field equations, the stability properties of limit cycles are modified by the presence of correlations, and additional non-trivial behaviors including periodic orbits appear when there were none in the mean field. The origin of all these behaviors is then explored in finite-size networks where interesting mesoscopic scale effects appear. This study leads us to show that the infinite-size system appears as a singular limit of the network equations, and for any finite network, the system will differ from the infinite system.


IgE receptors (FcR epsilon) modifications. II. Effect of regulator soluble factors of human IgE synthesis, isolated in polyacrylamide gels.
In a series of works done on humans patterned after animal experimental models, we created an "in vitro" model which allowed us to produce soluble IgE regulator factors. We observed its biological activity in IgE synthesis and constructed changes that protein fractions from affinity chromatography (fractions enriched in soluble regulator IgE factors) exercised on IgE receptor expression. We then decided to determine the molecular weight of each one of the active protein fractions. We performed electrophoresis on the gel of polyacrylamide (Weber-Osborn technique). Protein bands were processed, with the aim of isolating the gel and quantifying the biological activity. The protein fractions obtained from the chromatographies with affinity to CON-A sepharose were subjected to electrophoresis in polyacrylamide gel, with the aim of obtaining molecular weights of proteins comprising it. Using rosette technique, there were no changes seen in Fc epsilon expression just as what happened in the experiment with material fractionated by chromatography. However, these changes are produced and are statistically significant using the immunofluorescence technique. The highest inhibition of rosettes or immunofluorescence is that of the protein band of 10,000 daltons extracted in NaCl and that of 20,000 daltons extracted in PBS. Both effects are similar. The inhibition reached by the 20,000 dalton band in NaCl is less although there are no significant differences. The material extracted in PBS of the band between 6.9 and 7.2 mm of gel (G4) did not have any changes. None of the proteins added to the culture medium had any effects of receptor gamma expression. The average values of the receptor expression was similar to basal levels.


The Latin America and the Caribbean Consortium on Dementia (LAC-CD): From Networking to Research to Implementation Science.
In comparison with other regions, dementia prevalence in Latin America is growing rapidly, along with the consequent clinical, social, and economic burden upon patients and their families. The combination of fragile health care systems, large social inequalities, and isolated clinical and research initiatives makes the coordination of efforts imperative. The Latin America and the Caribbean Consortium on Dementia (LAC-CD) is a regional organization overseeing and promoting clinical and research activities on dementia. Here, we first provide an overview of the consortium, highlighting the antecedents and current mission. Then, we present the consortium's regional research, including the multi-partner consortium to expand dementia research in Latin America (ReDLat), which aims to identify the unique genetic, social, and economic factors that drive Alzheimer's and frontotemporal dementia presentation in LAC relative to the US. We describe an extension of ReDLat which aims to develop affordable markers of disease subtype and severity using high density EEG. We introduce current initiatives promoting regional diagnosis, visibility, and capacity, including the forthcoming launch of the Latin American Brain Health Institute (BrainLat). We discuss LAC-CD-led advances in brain health diplomacy, including an assessment of responses to the impact of COVID-19 on people with dementia and examining the knowledge of public policies among experts in the region. Finally, we present the current knowledge-to-action framework, which paves the way for a future regional action plan. Coordinated actions are crucial to forging strong regional bonds, supporting the implementation of regional dementia plans, improving health systems, and expanding research collaborations across Latin America.


Conversion from cyclosporine to tacrolimus in patients at risk for chronic renal allograft failure: 60-month results of the CRAF Study.
This study compared the long-term effects of switching from cyclosporine to tacrolimus on the incidence, progression, and severity of chronic renal allograft failure in patients with elevated serum creatinine levels. Patients were assigned randomly (2:1) to switch to tacrolimus or remain on cyclosporine. Tacrolimus was initiated at 1/50th of the cyclosporine dose or 0.15 mg/kg/day, whichever dose was lower, to maintain trough concentrations between 5 and 15 ng/mL. Cyclosporine doses were adjusted to achieve trough concentrations between 100 and 300 ng/mL. At 60 months, the median change from baseline in serum creatinine was -0.2 mg/dL in the tacrolimus group and 0.3 mg/dL in the cyclosporine group (P=0.003). Median change in estimated creatinine clearance was 1.2 mL/min in the tacrolimus group and -4.1 mL/min in the cyclosporine group (P=0.019). The incidence of new-onset diabetes, hyperglycemia, hypertension, lymphoma, and malignancies was generally low and comparable between groups. Fewer patients in the tacrolimus group than in the cyclosporine group developed new cardiac conditions (11% vs. 28%, P=0.004), had low-density lipoprotein (LDL) cholesterol values more than 130 mg/dL (29% vs. 57%, P=0.002), or developed hyperlipidemia (24% vs. 67%, P=0.046) during the 60-month follow-up period. Despite these changes, patient and graft survival were similar for both groups. Switching from cyclosporine to tacrolimus resulted in improved renal function and a reduction in the occurrence of new-onset cardiac conditions and hyperlipidemia, with no increase in the incidence of new-onset diabetes or new-onset hyperglycemia. However, after 5 years there was no impact on patient or graft survival.


Relation between Medicare screening reimbursement and stage at diagnosis for older patients with colon cancer.
Medicare's reimbursement policy was changed in 1998 to provide coverage for screening colonoscopies for patients with increased colon cancer risk, and expanded further in 2001 to cover screening colonoscopies for all individuals. To determine whether the Medicare reimbursement policy changes were associated with an increase in either colonoscopy use or early stage colon cancer diagnosis. Patients in the Surveillance, Epidemiology, and End Results Medicare linked database who were 67 years of age and older and had a primary diagnosis of colon cancer during 1992-2002, as well as a group of Medicare beneficiaries who resided in Surveillance, Epidemiology, and End Results areas but who were not diagnosed with cancer. Trends in colonoscopy and sigmoidoscopy use among Medicare beneficiaries without cancer were assessed using multivariate Poisson regression. Among the patients with cancer, stage was classified as early (stage I) vs all other (stages II-IV). Time was categorized as period 1 (no screening coverage, 1992-1997), period 2 (limited coverage, January 1998-June 2001), and period 3 (universal coverage, July 2001-December 2002). A multivariate logistic regression (outcome = early stage) was used to assess temporal trends in stage at diagnosis; an interaction term between tumor site and time was included. Colonoscopy use increased from an average rate of 285/100,000 per quarter in period 1 to 889 and 1919/100,000 per quarter in periods 2 (P<.001) and 3 (P vs 2<.001), respectively. During the study period, 44,924 eligible patients were diagnosed with colorectal cancer. The proportion of patients diagnosed at an early stage increased from 22.5% in period 1 to 25.5% in period 2 and 26.3% in period 3 (P<.001 for each pairwise comparison). The changes in Medicare coverage were strongly associated with early stage at diagnosis for patients with proximal colon lesions (adjusted relative risk period 2 vs 1, 1.19; 95% confidence interval, 1.13-1.26; adjusted relative risk period 3 vs 2, 1.10; 95% confidence interval, 1.02-1.17) but weakly associated, if at all, for patients with distal colon lesions (adjusted relative risk period 2 vs 1, 1.07; 95% confidence interval, 1.01-1.13; adjusted relative risk period 3 vs 2, 0.97; 95% confidence interval, 0.90-1.05). Expansion of Medicare reimbursement to cover colon cancer screening was associated with an increased use of colonoscopy for Medicare beneficiaries, and for those who were diagnosed with colon cancer, an increased probability of being diagnosed at an early stage. The selective effect of the coverage change on proximal colon lesions suggests that increased use of whole-colon screening modalities such as colonoscopy may have played a pivotal role.


Experimental generation of discrete ultraviolet wavelength by cascaded intermodal four-wave mixing in a multimode photonic crystal fiber.
In this Letter, we demonstrate experimentally for the first time, to the best of our knowledge, discrete ultraviolet (UV) wavelength generation by cascaded intermodal FWM when femtosecond pump pulses at 800 nm are launched into the deeply normal dispersion region of the fundamental guided mode of a multimode photonic crystal fiber (MPCF). For pump pulses at average input powers of Pav=450, 550, and 650 mW, the first anti-Stokes waves are generated at the visible wavelength of 538.1 nm through intermodal phase matching between the fundamental and second-order guided mode of the MPCF. The first anti-Stokes waves generated then serve as the secondary pump for the next intermodal FWM process. The second anti-Stokes waves in the form of the third-order guided mode are generated at the UV wavelength of 375.8 nm. The maximum output power is above 10 mW for Pav=650 mW. We also confirm that the influences of fiber bending and intermodal walk-offs on the cascaded intermodal FWM-based frequency conversion process are negligible.