Candidate circulating biomarkers for the cardiovascular disease continuum.
The early identification of susceptibility to adverse cardiovascular outcomes and risk stratification amongst asymptomatic individuals, as well as amongst those with overt disease continues to be one of the major priorities of clinically-orientated research in the field of atherothrombosis. Available data from epidemiological studies indicate that traditional risk factors do not fully explain the predisposition to cardiovascular disease, its dynamics in different population groups and treatment responses. The pressing need for the development and clinical implementation of new markers of atherothrombotic disease has fuelled rapidly expanding research into cardiac biomarkers. This review outlines the main principles of biomarker qualification that have entered clinical practice, as well as an overview of the development of targeted biomarkers across the cardiovascular "continuum". We discuss in detail the evidence from epidemiological and clinical studies advocating the potential clinical use of the most promising candidate plasma biomarkers (more specifically, C-reactive protein, coagulation and inflammatory mediators and natriuretic peptides). Such an application of biomarkers to aid clinical risk assessment would be important in our efforts to improve risk stratification of subjects at risk of cardiovascular events.


Hair removal.
Hair removal with optical devices has become a popular mainstream treatment that today is considered the most efficient method for the reduction of unwanted hair. Photothermal destruction of hair follicles constitutes the fundamental concept of hair removal with red and near-infrared wavelengths suitable for targeting follicular and hair shaft melanin: normal mode ruby laser (694 nm), normal mode alexandrite laser (755 nm), pulsed diode lasers (800, 810 nm), long-pulse Nd:YAG laser (1,064 nm), and intense pulsed light (IPL) sources (590-1,200 nm). The ideal patient has thick dark terminal hair, white skin, and a normal hormonal status. Currently, no method of lifelong permanent hair eradication is available, and it is important that patients have realistic expectations. Substantial evidence has been found for short-term hair removal efficacy of up to 6 months after treatment with the available systems. Evidence has been found for long-term hair removal efficacy beyond 6 months after repetitive treatments with alexandrite, diode, and long-pulse Nd:YAG lasers, whereas the current long-term evidence is sparse for IPL devices. Treatment parameters must be adjusted to patient skin type and chromophore. Longer wavelengths and cooling are safer for patients with darker skin types. Hair removal with lasers and IPL sources are generally safe treatment procedures when performed by properly educated operators. However, safety issues must be addressed since burns and adverse events do occur. New treatment procedures are evolving. Consumer-based treatments with portable home devices are rapidly evolving, and presently include low-level diode lasers and IPL devices.


Adolescent BMI at Northern Israel: From Trends, to Associated Variables and Comorbidities, and to Medical Signatures.
The increasing prevalence of abnormal body mass index (BMI), mainly obesity, is becoming a significant public health problem. This cross-sectional study aimed to provide a comprehensive view of secular trends of BMI, and the associated socio-demographic variables and comorbidities among adolescents with abnormal BMI. Individuals of the study population were born mainly between 1970 and 1993, and were examined at 16 to 19 years of age during the years 1987 to 2010, at 1 conscription center in the northern district of Israel.The study population included 113,694 adolescents. Univariate and multivariable logistic regression models were used to investigate the associations between BMI categories, socio-demographic variables, and medical conditions.A downward trend in the prevalence of normal BMI among both male and female adolescents was obtained, while trends of overweight and obesity (in both genders) and underweight (only among females) rose. Socio-demographic variables such as religion, education, family-related parameters, residential environment, country of birth, and origin were all associated with different risks for abnormal BMI. Obesity was associated with higher risk for hyperlipidemia, endocrine disorders (only in males), knee disorders, and hypertension type I + II (in both genders). Overweight was associated with knee disorders (only in females). Underweight, exclusively in males, was associated with increased risk for endocrine disorders, proteinuria, and cardiac disorders. Hierarchical clustering analysis revealed the intricate relations between gender, BMI, and medical signatures. It brought to light novel clusters of diseases that were abundant among populations having above-normal BMI or underweight males. Furthermore, above-normal BMI was associated with a lower rate of cardiac anomalies and scoliosis/kyphosis, whereas being underweight was associated with a lower risk for hypertension and flat foot.This study provides a reliable and in-depth view of secular trends in height, weight, and BMI of male and female adolescents. It supports previous associations between abnormal BMI and demographic variables and comorbidities, while uncovering novel associations, mainly regarding medical signatures of each gender-BMI group. This might lead to better monitoring, early detection, prevention, and treatment of various conditions associated to abnormal BMI categories and gender groups.


The NgAOX1a gene cloned from Nicotiana glutinosa is implicated in the response to abiotic and biotic stresses.
A novel gene, named NgAOX1a, was isolated from Nicotiana glutinosa by RT-PCR (reverse transcription-PCR). The full-length cDNA of NgAOX1a was 1448 bp, including a 1062-bp ORF (open reading frame), a 124 bp 5' UTR (untranslated region) and a 262 bp 3' UTR. The ORF encodes a 353-amino-acid protein which contains two conserved cysteine residues, four iron-binding motifs, five alpha-helix regions and six conserved histidine residues. The phylogenetic tree showed that NgAOX1a belongs to the AOX1 (alternative oxidase 1)-type group. Alignment analysis showed that NgAOX1a shares a high similarity with other known AOXs. Four exons and three introns were detected in the genomic DNA sequence, and Southern-blotting analysis suggested that NgAOX1a is a single-copy gene. A series of putative cis-acting elements were examined in the 5'-flanking region of NgAOX1a. Northern-blotting analysis showed that the transcript levels of NgAOX1a can be markedly accumulated when tobacco seedlings are treated with various abiotic stimuli, such as exogenous signalling molecules for plant defence response, salicylic acid and H(2)O(2), and the exogenous TCA (tricarboxylic acid) cycle metabolite citrate. However, it could be suppressed by abiotic stress, such as CoCl(2), an inhibitor of ethylene, which indicates that the expression of NgAOX1a may be regulated by ethylene. In addition, NgAOX1a can also be strongly induced by three viral pathogens, tobacco mosaic virus, potato virus X and potato virus Y. These results indicate that NgAOX1a may be involved in multi-signal transduction pathways and may play an important role in defence response.


Pluripotency and lineages in the mammalian blastocyst: an evolutionary view.
Early mammalian development is characterized by a highly specific stage, the blastocyst, by which embryonic and extraembryonic lineages have been determined, but pattern formation has not yet begun. The blastocyst is also of interest because cell precursors of the embryo proper retain for a certain time the capability to generate all the cell types of the adult animal. This embryonic pluripotency is established and maintained by a regulatory network under the control of a small set of transcription factors, comprising Oct4, Sox2 and Nanog. This network is largely conserved in eutherian mammals, but there is scarce information about how it arose in vertebrates. We have analysed the conservation of gene regulatory networks controlling blastocyst lineages and pluripotency in the mouse by comparison with the chick. We found that few of elements of the network are novel to mammals; rather, most of them were present before the separation of the mammalian lineage from other amniotes, but acquired novel expression domains during early mammalian development. Our results strongly support the hypothesis that mammalian blastocyst regulatory networks evolved through rewiring of pre-existing components, involving the co-option and duplication of existing genes and the establishment of new regulatory interactions among them.


Effect of high-dose thiamine and pyridoxine on advanced glycation end products and other oxidative stress markers in hemodialysis patients: a randomized placebo-controlled study.
To study the effect of high doses of thiamine (250 mg/day) and pyridoxine (200 mg/day) supplementation on plasma levels of advanced glycation end products and other oxidative stress markers in hemodialysis patients. An interventional survey. This study was conducted at an outpatient nephrology clinic. INTERVENTION AND PATIENTS: We performed a randomized placebo-controlled study over 8 weeks in 50 patients (53% men, age 52.9 +/- 3.4 years) on regular hemodialysis. The patients were divided into 2 groups of 25 patients in each arm. Before starting the study, the patients in both groups were matched by age, gender, inflammatory profile (plasma interleukin [IL]-6 and high-sensitivity C-reactive protein [hsCRP]), and nutritional status (subjective global assessment and protein nitrogen appearance). In all, 40 of 50 patients completed the study (19 patients in the vitamin group and 21 in the placebo group). Serum albumin, plasma hsCRP, IL-6, advanced oxidation protein products, pentosidine and 8-hydroxy-2'-deoxyguanosine were measured before and after treatment in each group. In both groups, over 8 weeks of follow-up, no significant differences could be observed in oxidative stress, inflammatory, or nutritional markers. There was no evidence showing that high doses of thiamine and pyridoxine affects oxidative stress in hemodialysis patients.


The Prevalence of Dry Eye Syndrome's and the Likelihood to Develop Sjögren's Syndrome in Taiwan: A Population-Based Study.
Dry eye syndrome (DES) is one of the key clinical features and possibly an early clinical presentation of Sjögren's syndrome (SS). We explore DES prevalence and assess the likelihood of DES patients to develop SS in Taiwan through the National Health Insurance Research Database (NHIRD). Through a cohort comparison study, longitudinal data from the NHIRD (2000 to 2008) in Taiwan was used to probe the prevalence of DES and the odds that DES patients would later develop SS. The prevalence of DES in the present study is 4.87%. The incidence rates of developing SS were 4.8% for the DES group and 1.5% for comparison group. The median age and interquartile range of DES and comparison patients was 49.8 (10) and 48.7 (15) years old, respectively. The crude hazard ratio (with 95% confidence interval) for DES patients to develop SS was 3.13 (3.10-3.50) for the DES group, and the adjusted hazard ratio (with 95% confidence interval) was 3.64 (3.43-3.87). The observation period and interquartile range for DES and comparison patients to develop SS later were 1418 (781-2316) versus 1641 (971-2512) days respectively. DES patients carried a higher risk for developing SS (hazard ratio 3.13) and presented for SS 3.88 years earlier than comparison group patients in this study.


Emergency Colorectal Surgery in a COVID-19 Pandemic Epicenter.
Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a considerable risk during emergency colorectal surgery in a pandemic epicenter. It is well known that the primary route of SARS-CoV-2 transmission is through respiratory droplets. However, little is known about shedding of the virus in bodily fluids and associated risks. Although the current moratorium on elective surgery addresses multiple ongoing concerns, including the management of precious resources as well as unknown exposure risks, surgeons undeniably must face and mitigate risks related to exposure to patient airway management-related aerosols, bodily fluids, surgical smoke, contaminated insufflation, and specimen handling in emergency colorectal surgery. Given the significant concern of airborne transmission, the authors recommend conventional, in lieu of laparoscopic, access in emergency colorectal surgery in a COVID-19 pandemic epicenter.


Thiosulfoxide (sulfane) sulfur: new chemistry and new regulatory roles in biology.
The understanding of sulfur bonding is undergoing change. Old theories on hypervalency of sulfur and the nature of the chalcogen-chalcogen bond are now questioned. At the same time, there is a rapidly expanding literature on the effects of sulfur in regulating biological systems. The two fields are inter-related because the new understanding of the thiosulfoxide bond helps to explain the newfound roles of sulfur in biology. This review examines the nature of thiosulfoxide (sulfane, S0) sulfur, the history of its regulatory role, its generation in biological systems, and its functions in cells. The functions include synthesis of cofactors (molybdenum cofactor, iron-sulfur clusters), sulfuration of tRNA, modulation of enzyme activities, and regulating the redox environment by several mechanisms (including the enhancement of the reductive capacity of glutathione). A brief review of the analogous form of selenium suggests that the toxicity of selenium may be due to over-reduction caused by the powerful reductive activity of glutathione perselenide.


Compartmentalized human immunodeficiency virus type 1 present in cerebrospinal fluid is produced by short-lived cells.
Human immunodeficiency virus type 1 (HIV-1) invades the central nervous system (CNS) during primary infection and persists in this compartment by unknown mechanisms over the course of infection. In this study, we examined viral population dynamics in four asymptomatic subjects commencing antiretroviral therapy to characterize cellular sources of HIV-1 in the CNS. The inability to monitor viruses directly in the brain poses a major challenge in studying HIV-1 dynamics in the CNS. Studies of HIV-1 in cerebrospinal fluid (CSF) provide a useful surrogate for the sampling of virus in the CNS, but they are complicated by the fact that infected cells in local CNS tissues and in the periphery contribute to the population pool of HIV-1 in CSF. We utilized heteroduplex tracking assays to differentiate CSF HIV-1 variants that were shared with peripheral blood plasma from those that were compartmentalized in CSF and therefore presumably derived from local CNS tissues. We then tracked the relative decline of individual viral variants during the initial days of antiretroviral therapy. We found that HIV-1 variants compartmentalized in CSF declined rapidly during therapy, with maximum half-lives of approximately 1 to 3 days. These kinetics emulate the decline in HIV-1 produced from short-lived CD4+ T cells in the periphery, suggesting that a similarly short-lived, HIV-infected cell population exists within the CNS. We propose that short-lived CD4+ T cells trafficking between the CNS and the periphery play an important role in amplifying and maintaining HIV-1 populations in the CNS during the asymptomatic phase of infection.


Water sorption and dimensional changes of denture base polymer reinforced with glass fibers in continuous unidirectional and woven form.
The aim of this study was to determine the dimensional accuracy and water sorption of a denture base polymer that was reinforced with glass fibers in continuous unidirectional and woven form in different weight fractions. Ten rhombic brass plates were prepared with reference points, and 70 heat-cured denture base polymer specimens were produced using these brass models. Ten of 70 were used for controls, and 60 were reinforced with glass fibers in continuous parallel and woven form. The dimensional changes of polymer and fiber-reinforced composite specimens after processing, drying for 4 days at 37 degrees C, and storage in 37 degrees C water for 90 days were calculated by the change of the distance vector. The measurements were made between the reference points on the specimens and were compared with those on the brass model at 4 different stages. The water sorption calculations were made at 10 different time intervals on 70 specimens, which were immersed in a 37 degrees C distilled water bath and weighed. The polymerization shrinkage and water sorption of denture base polymers is lower when the specimens are reinforced with glass fibers in continuous unidirectional and woven form. The highest fiber content showed the smallest dimensional change (0.069 mm, or 0.25%), and the unreinforced group showed the largest change (0.139 mm, or 0.54%). Water sorption occurred mainly during the first 14 days. As the fiber content increases, the dimensional change and water sorption decrease.


[Factors related with the severity of injuries in public streets of an urban area in Cuernavaca, Morelos,Mexico].
To identify risk factors associated with severity of injuries occurring in public streets of an urban area. Between February and April 2001, a cross-sectional survey was conducted among injured people seeking emergency care at three hospitals in Cuernavaca, Morelos, Mexico. Information was also obtained for those who died on accident sites. Data on the following variables were collected: age, sex, alcohol intake, day and time of injury, prehospital care, external cause and nature of injury. The Abbreviated Injury Scale (AIS) was used to define severity of injuries. Data analysis consisted of descriptive, bivariate, and multivariate regression models. A total of 492 injured people were included in the study; 23 of them died on site. The main cause of injuries was road traffic accidents (52%); 72% of injuries were not severe. Variables associated with the severity of injuries were: Road traffic accidents (odds ratio [OR] 6.59, 95% confidence interval [CI] 2.52, 17.23), adjusted for age and schooling. Road traffic injuries are the main cause of severe injuries. TheAIS is useful to assess the frequency and distribution of injury severity.


Screening for family and intimate partner violence: recommendation statement.
This statement summarizes the U.S. Preventive Services Task Force (USPSTF) recommendations on screening for family and intimate partner violence based on the USPSTF's examination of evidence specific to family and intimate partner violence. It updates the 1996 recommendations contained in the Guide to Clinical Preventive Services, second edition. In 1996, the USPSTF found insufficient evidence to recommend for or against the use of specific instruments to detect domestic violence (a "C" recommendation according to 1996 grade definitions). The Task Force now uses an explicit process in which the balance of benefits and harms is determined exclusively by the quality and magnitude of the evidence. As a result, current letter grades are based on different criteria than those in 1996. Current explanations of the ratings and of the strength of overall evidence are given in Appendix A and in Appendix B, respectively. The complete information on which this statement is based, including evidence tables and references, is available in the summary article and in the Systematic Evidence Review, "Screening for Family and Intimate Partner Violence: Systematic Evidence Review for the U.S. Preventive Services Task Force." The USPSTF recommendations, the accompanying summary article, and complete Systematic Evidence Review are available through the USPSTF web site (http://www.preventiveservices.ahrq.gov). The summary article and the USPSTF recommendation statement are available in print through the AHRQ Publications Clearinghouse (call 1-800-358-9295 or e-mail email@example.com).


Assessing ethics and professionalism in dental education.
The foundation for the development of ethical sensitivity and the capacity for reflective reasoning about ethical dilemmas must be established early during professional training. At Indiana University School of Dentistry, two assessment tools, the Dental Ethical Sensitivity Test (DEST) and the Defining Issues Test (DIT) are being employed to help measure student achievement and enhance their skills in this area. Evidence suggests that both small-group discussion and case-based problem solving involving ethical issues improve scores on these measures. It is imperative that opportunities to recognize, analyze, and discuss ethical issues are integrated throughout the dental student's educational program.


Prospects for elucidating the phylogeny of the Apicomplexa.
The Apicomplexa is traditionally considered to contain four clearly defined groups, but the phylogenetic relationships among these groups, and their subsequent taxonomic arrangement, are currently unclear. Here, I consider five of the important criteria that need to be met before radical taxonomic changes are made, in relation to phylogenetic analyses. Unfortunately, at least four of these criteria indicate that the prospects for elucidating the phylogeny and taxonomy of the Apicomplexa are not good in the short term. A lot more pertinent data need to be collected, both in terms of taxa sampled and genes sequenced, before any concordance among phylogenies is likely to emerge; and someone (e.g. a consortium) needs to coordinate the active collection and analysis of these data if any worthwhile progress is to be made.


Intrahepatic peripheral cholangiocarcinoma: CT evaluation.
The purpose of our study was to evaluate the imaging features and patterns of contrast enhancement in peripheral cholangiocarcinomas with computed tomography (CT) and correlate these features with histologic findings when available. We reviewed the CT scans of 24 patients with 25 peripheral cholangiocarcinomas proved by orthotopic liver transplantation (n = 1), liver resection (n = 7), percutaneous needle biopsy (n = 10), and fine needle aspiration biopsy (n = 6). Incremental dynamic nonhelical CT was performed in four cases and helical CT in 21 cases. Portal venous phase images were obtained in all 25 cases. Fourteen patients underwent helical CT during arterial and portal phases. Delayed images were obtained in 20 patients. The size of the tumors ranged from 1.2 to 17 cm. Bile duct dilatation was present in 13 patients (52%), and regional lymph node enlargement was observed in six patients (24%). Retraction of the liver capsule was present in nine patients (36%). In eight patients (32%), satellite nodules were also detected. All tumors were globally hypodense during the portal phase. In 14 patients (70%), delayed images disclosed hyperattenuating tumors. Rimlike contrast enhancement was the most frequent pattern observed in either arterial (57% of patients) or portal (60% of patients) phase imaging. Portal venous encasement was seen in 10 patients (40%). In the proper clinical setting, detection of a hypodense hepatic lesion with peripheral enhancement, biliary dilatation, and contrast enhancement on delayed images are highly suggestive of peripheral intrahepatic cholangiocarcinoma.


Prevalence of chronic kidney disease and associated risk factors--United States, 1999-2004.
Chronic kidney disease (CKD) is a serious condition associated with premature mortality, decreased quality of life, and increased health-care expenditures. Untreated CKD can result in end-stage renal disease and necessitate dialysis or kidney transplantation. Risk factors for CKD include cardiovascular disease, diabetes, hypertension, and obesity. To estimate the prevalence of CKD in the United States (overall and by health risk factors and other characteristics), CDC analyzed the most recent data from the National Health and Nutrition Examination Survey (NHANES). This report summarizes the results of that analysis, which determined that 16.8% of the U.S. population aged >/=20 years had CKD, according to 1999-2004 NHANES data, compared with 14.5% from the 1988-1994 NHANES (i.e., NHANES III), an increase of 15.9% based on crude estimates of prevalence. Persons with diabetes or cardiovascular disease had a greater prevalence of CKD than persons without those conditions. The results underscore the need to continue surveillance for CKD and its risk factors in the United States and to implement new strategies to reduce the number of persons with this condition.


[Assessment of the formation of interferon neutralizing antibodies and their influence on the effectiveness of interferon therapy in children with juvenile respiratory papillomatosis].
Formation of neutralizing antibodies (NAB) to alpha-interferon (aINF) was assessed in the reaction of antiviral activity neutralization in 36 children with severe juvenile respiratory papillomatosis (JRP). Surgical removal of papillomas was combined with administration of recombinant aINF preparations (reaferon, intron A, viferon). High and moderate neutralizing activity was determined in 22 (61.1%) patients. 7, 2 and 13 of them received reaferon, intron A and viferon, respectively. NAB were not registered in the rest 14 (38.9%) patients. The frequency of NAB formation was not related to the preparation used, only in the group on reaferon it was insignificantly higher. It was found that the highest response to therapy occurred in children with low NAB titer (8 of 12 children, 66.7%), while children with high NAB titer (3 of 4 children, 75%) did not respond.


Feasibility of shortening respiratory isolation with a single sputum nucleic acid amplification test.
Serial smear analysis to guide respiratory isolation (RI) of patients with suspected tuberculosis (TB), the majority of whom will be found not to have TB, leads to expensive and unnecessary isolation, and may potentially result in decreased vigilance of subjects with respiratory compromise. To compare the performance of a single first-sputum, Mycobacterium tuberculosis-specific nucleic acid amplification (NAA) test with three sputum smears for assessing the need for RI. Prospective evaluation of 493 patients with suspected TB (74% HIV positive) admitted to RI in a major county hospital in the United States, who had at least three sputum smears and material available from the first sample for additional NAA testing. Accuracy of the first sputum NAA result and serial smears for identifying patients with potentially infectious TB who truly require RI was determined. Forty-six patients (9.3%) had TB confirmed by culture. First-sputum NAA test detected all patients with TB who had a positive smear (n = 35), even when the first of the three specimens was smear negative. In addition, when compared with serial smears, the first-sputum NAA had a higher sensitivity (0.87; 95% confidence interval [CI], 0.74-0.95) and specificity (1.0) in the detection of subjects with positive M. tuberculosis cultures (smear sensitivity, 0.76; 95% CI, 0.61-0.87; and specificity, 0.96; 95% CI, 0.94-0.98). A single first-sputum NAA testing can rapidly and accurately identify the subset of patients with suspected TB who require RI according to serial sputum smears. Its potential use to shorten RI time does not preclude the need to obtain subsequent specimens for culture.


More that unites us than divides us? A qualitative study of integration of community health and social care services.
The integration of community health and social care services has been widely promoted nationally as a vital step to improve patient centred care, reduce costs, reduce admissions to hospital and facilitate timely and effective discharge from hospital. The complexities of integration raise questions about the practical challenges of integrating health and care given embedded professional and organisational boundaries in both sectors. We describe how an English city created a single, integrated care partnership, to integrate community health and social care services. This led to the development of 12 integrated neighbourhood teams, combining and co-locating professionals across three separate localities. The aim of this research is to identify the context and the factors enabling and hindering integration from a qualitative process evaluation. Twenty-four semi-structured interviews were conducted with equal numbers of health and social care staff at strategic and operational level. The data was subjected to thematic analysis. We describe three key themes: 1) shared vision and leadership; 2) organisational factors; 3) professional workforce factors. We found a clarity of vision and purpose of integration throughout the partnership, but there were challenges related to the introduction of devolved leadership. There were widespread concerns that the specified outcome measures did not capture the complexities of integration. Organisational challenges included a lack of detail around clinical and service delivery planning, tensions around variable human resource practices and barriers to data sharing. A lack of understanding and trust meant professional workforce integration remained a key challenge, although integration was also seen as a potential solution to engender relationship building. Given the long-term national policy focus on integration this ambitious approach to integrate community health and social care has highlighted implications for leadership, organisational design and inter-professional working. Given the ethos of valuing the local assets of individuals and networks within the new partnership we found the integrated neighbourhood teams could all learn from each other. Many of the challenges of integration could benefit from embracing the inherent capabilities across the integrated neighbourhood teams and localities of this city.


Analysis of noise in quartz crystal oscillators by using slowly varying functions method.
By using formal manipulation capability of commercially available symbolic calculation code, it is possible to automatically derive the characteristic polynomial describing the conditions for oscillation of a circuit. The analytical expression of the characteristic polynomial is obtained through an encapsulation process starting from the SPICE netlist description of the circuit: by using a limited number of simple transformations, the initial circuit is progressively transformed in a simplified standard form. In this method, the nonlinear component is described by its large signal admittance parameters obtained from a set of SPICE transient simulations of larger and larger amplitude. The encapsulation process involving linear and nonlinear components as well as noise sources leads to a perturbed characteristic polynomial. In the time domain, the perturbed characteristic polynomial becomes a nonlinear nonautonomous differential equation. By using an extension of the slowly varying functions method, this differential equation is transformed into a nonlinear differential system with perturbation terms as the right-hand side. Eventually, solving this system with classical algorithms allows one to obtain both amplitude and phase noise spectra of the oscillator.


Digital gene expression analysis of two life cycle stages of the human-infective parasite, Trypanosoma brucei gambiense reveals differentially expressed clusters of co-regulated genes.
The evolutionarily ancient parasite, Trypanosoma brucei, is unusual in that the majority of its genes are regulated post-transcriptionally, leading to the suggestion that transcript abundance of most genes does not vary significantly between different life cycle stages despite the fact that the parasite undergoes substantial cellular remodelling and metabolic changes throughout its complex life cycle. To investigate this in the clinically relevant sub-species, Trypanosoma brucei gambiense, which is the causative agent of the fatal human disease African sleeping sickness, we have compared the transcriptome of two different life cycle stages, the potentially human-infective bloodstream forms with the non-human-infective procyclic stage using digital gene expression (DGE) analysis. Over eleven million unique tags were generated, producing expression data for 7360 genes, covering 81% of the genes in the genome. Compared to microarray analysis of the related T. b. brucei parasite, approximately 10 times more genes with a 2.5-fold change in expression levels were detected. The transcriptome analysis revealed the existence of several differentially expressed gene clusters within the genome, indicating that contiguous genes, presumably from the same polycistronic unit, are co-regulated either at the level of transcription or transcript stability. DGE analysis is extremely sensitive for detecting gene expression differences, revealing firstly that a far greater number of genes are stage-regulated than had previously been identified and secondly and more importantly, this analysis has revealed the existence of several differentially expressed clusters of genes present on what appears to be the same polycistronic units, a phenomenon which had not previously been observed in microarray studies. These differentially regulated clusters of genes are in addition to the previously identified RNA polymerase I polycistronic units of variant surface glycoproteins and procyclin expression sites, which encode the major surface proteins of the parasite. This raises a number of questions regarding the function and regulation of the gene clusters that clearly warrant further study.


Elevation of a specific mRNA in longissimus muscle of steers fed ractopamine.
To address the hypothesis that some classes of growth promoters stimulate muscle protein synthesis in growing cattle, 23 crossbred steers were fed diets containing the phenethanolamine growth promoter ractopamine in a 140-d feeding trial. Steers received either no ractopamine, .18 or .36 mg.kg BW-1.d-1 ractopamine for 140 d or .36 or .72 mg.kg BW-1.d-1 ractopamine for 56 d. Longissimus muscle was obtained at slaughter and frozen in liquid N2. RNA was extracted by homogenization of pulverized frozen muscle in guanidinium isothiocyanate and centrifugation through cesium chloride. Polyadenylated mRNA was extracted by capture on oligo-dT columns. Ractopamine had no effect on total RNA or mRNA concentrations (P greater than .25). Hybridization of the RNA to a putative myosin light chain-1/3 (MLC-1/3) cDNA clone in a Northern blot indicated one heavy band (approximately 1 kb) with no evidence of extensive destruction of the RNA. A second, minor band (approximately 3 kb) also was observed in some samples. The MLC-1/3 cDNA clone was hybridized to 1- or 5-micrograms samples of total RNA, and the intensity of the resultant autoradiographs was quantified by laser densitometry. There was a statistical correlation between MLC-1/3 mRNA-micrograms RNA-1 and longissimus cross-sectional area (P less than .05) and average daily gain (P less than .025). The results suggest that ractopamine either increased the transcription of the putative MLC-1/3 gene and(or) increased the stability of MLC-1/3 mRNA in bovine longissimus muscle, either of which could result in an increase in specific myofibrillar protein synthesis.


Metamemory accuracy: effects of feedback and the stability of individual differences.
This study addressed two questions about metamemory accuracy: how feedback about recall performance affects confidence-recall accuracy and whether individual differences in confidence-recall accuracy are stable across different sets of test items. College students answered general knowledge questions and made confidence ratings about the correctness of the answers. Half the students were told whether their answers were correct. All students answered half the questions a second time. The results show that feedback did not produce a general improvement in metamemory accuracy; the improvement was specific to the questions for which feedback was provided. Also, individual students' metamemory accuracy showed moderate alternate-forms stability when each test was made up of 250 items. Therefore, researchers studying individual differences in metamemory accuracy on recall tasks should use tests that yield several hundred responses.


Pharmacological interventions for promoting smoking cessation during pregnancy.
Tobacco smoking in pregnancy causes serious health problems for the developing fetus and mother. When used by non-pregnant smokers, pharmacotherapies (nicotine replacement therapy (NRT), bupropion, and varenicline) are effective for increasing smoking cessation, however their efficacy and safety in pregnancy remains unknown. Electronic cigarettes (ECs) are becoming widely used, but their efficacy and safety when used for smoking cessation in pregnancy are also unknown. To determine the efficacy and safety of smoking cessation pharmacotherapies and ECs used during pregnancy for smoking cessation in later pregnancy and after childbirth, and to determine adherence to smoking cessation pharmacotherapies and ECs for smoking cessation during pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 May 2019), trial registers, and grey literature, and checked references of retrieved studies. Randomised controlled trials (RCTs) conducted in pregnant women, comparing smoking cessation pharmacotherapy or EC use with either placebo or no pharmacotherapy/EC control. We excluded quasi-randomised, cross-over, and within-participant designs, and RCTs with additional intervention components not matched between trial arms. We followed standard Cochrane methods. The primary efficacy outcome was smoking cessation in later pregnancy; safety was assessed by 11 outcomes (principally birth outcomes) that indicated neonatal and infant well-being. We also collated data on adherence to trial treatments. We calculated the risk ratio (RR) or mean difference (MD) and the 95% confidence intervals (CI) for each outcome for each study, where possible. We grouped eligible studies according to the type of comparison. We carried out meta-analyses where appropriate. We included 11 trials that enrolled a total of 2412 pregnant women who smoked at enrolment, nine trials of NRT and two trials of bupropion as adjuncts to behavioural support, with comparable behavioural support provided in the control arms. No trials investigated varenicline or ECs. We assessed four trials as at low risk of bias overall. The overall certainty of the evidence was low across outcomes and comparisons as assessed using GRADE, with reductions in confidence due to risk of bias, imprecision, and inconsistency. Compared to placebo and non-placebo (behavioural support only) controls, there was low-certainty evidence that NRT increased the likelihood of smoking abstinence in later pregnancy (RR 1.37, 95% CI 1.08 to 1.74; I² = 34%, 9 studies, 2336 women). However, in subgroup analysis by comparator type, there was a subgroup difference between placebo-controlled and non-placebo controlled RCTs (test for subgroup differences P = 0.008). There was unclear evidence of an effect in placebo-controlled RCTs (RR 1.21, 95% CI 0.95 to 1.55; I² = 0%, 6 studies, 2063 women), whereas non-placebo-controlled trials showed clearer evidence of a benefit (RR 8.55, 95% CI 2.05 to 35.71; I² = 0%, 3 studies, 273 women). An additional subgroup analysis in which studies were grouped by the type of NRT used found no difference in the effectiveness of NRT in those using patches or fast-acting NRT (test for subgroup differences P = 0.08). There was no evidence of a difference between NRT and control groups in rates of miscarriage, stillbirth, premature birth, birthweight, low birthweight, admissions to neonatal intensive care, caesarean section, congenital abnormalities, or neonatal death. In one study infants born to women who had been randomised to NRT had higher rates of 'survival without developmental impairment' at two years of age compared to the placebo group. Non-serious adverse effects observed with NRT included headache, nausea, and local reactions (e.g. skin irritation from patches or foul taste from gum), but data could not be pooled. Adherence to NRT treatment regimens was generally low. We identified low-certainty evidence that there was no difference in smoking abstinence rates observed in later pregnancy in women using bupropion when compared to placebo control (RR 0.74, 95% CI 0.21 to 2.64; I² = 0%, 2 studies, 76 women). Evidence investigating the safety outcomes of bupropion use was sparse, but the existing evidence showed no difference between the bupropion and control group. NRT used for smoking cessation in pregnancy may increase smoking cessation rates in late pregnancy. However, this evidence is of low certainty, as the effect was not evident when potentially biased, non-placebo-controlled RCTs were excluded from the analysis. Future studies may therefore change this conclusion. We found no evidence that NRT has either positive or negative impacts on birth outcomes; however, the evidence for some of these outcomes was also judged to be of low certainty due to imprecision and inconsistency. We found no evidence that bupropion may be an effective aid for smoking cessation during pregnancy, and there was little evidence evaluating its safety in this population. Further research evidence on the efficacy and safety of pharmacotherapy and EC use for smoking cessation in pregnancy is needed, ideally from placebo-controlled RCTs that achieve higher adherence rates and that monitor infants' outcomes into childhood. Future RCTs of NRT should investigate higher doses than those tested in the studies included in this review.


Comparison of two high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone derived regimens in patients aged under 60 years with low-intermediate risk aggressive lymphoma: a final analysis of the multicenter LNH93-2 protocol.
One-third of patients aged <or=60 years with aggressive lymphoma are at low-intermediate risk (LIR). Before the rituximab era, we prospectively compared ACVBP with ECVBP, a similar regimen including epirubicin instead of doxorubicin and increased dose intensity of cyclophosphamide, followed by conventional consolidation with an increased amount and dose intensity of cytosine-arabinoside, methotrexate, etoposide, and ifosfamide, in 652 patients with LIR aggressive lymphoma. The overall response rate, 5-year event-free survival (EFS), and survival were estimated to be 86%, 60%, and 74%, respectively, with no differences between the two arms. In patients with diffuse large B-cell lymphoma (DLBCL) who received ACVBP, the 5-year EFS and survival were estimated at 69% and 82%. These findings do not support the use of a chemotherapy regimen more intensive than ACVBP in patients aged <or=60 years with LIR aggressive lymphoma. The results in the control arm, without rituximab, have led to a randomized comparison of R-ACVBP and R-CHOP in this patient population.


Covalent modification and inhibition of an epithelial sodium channel by tyrosine-reactive reagents.
This study sought to elucidate the molecular mechanism involved in the Na+ entry across the apical membrane of the urinary bladder of the toad. Na+ transport, as measured by short-circuit current (SCC), was irreversibly inhibited by three tyrosine-specific reagents: N-acetylimidazole (ID50, 4.6 x 10(-2)M), tetranitromethane (1.8 x 10(-4) M), and 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl; 3.4 x 10(-5) M). The functional specificity of NBD-Cl to block Na+ entry via Na+ channels was attested by the following: 1) NBD-Cl produced comparable inhibition of SCC and Na+ influx under aerobic and anaerobic conditions; 2) amphotericin B produced complete recovery of inhibited SCC; 3) vasopressin increased SCC only in proportion to the uninhibited SCC; 4) Km for Na+ was not changed; and 5) the half time for the inhibition varied as a function of amiloride concentration or pharmacologic activity of its analogues. On the basis of the above findings, these tyrosine-specific reagents are believed to be useful chemical probes for the identification and characterization of Na+ channel protein.


A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration.
Semaphorin 4A (Sema4A) has an essential role in photoreceptor survival. In humans, mutations in Sema4A are thought to contribute to retinal degenerative diseases. Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes. The F350C mutation results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival. Additionally, protein structural modelling reveals that the side chain of the 350th amino acid is critical to retain the proper protein conformation. Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A(F350C/F350C) and Sema4A(-/-) mice. Thus, our findings not only indicate the importance of the Sema4A protein conformation in human and mouse retina homeostasis but also identify a novel therapeutic target for retinal degenerative diseases.


Incidence of remission and relapse of proteinuria, end-stage kidney disease, mortality, and major outcomes in primary nephrotic syndrome: the Japan Nephrotic Syndrome Cohort Study (JNSCS).
Despite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan. A 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model. Immunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ≥ 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN. Patients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome.


Premature peripheral vascular disease: clinical profile and abnormal lipid peroxidation.
The aim of this study was to determine any biochemical differences between early-onset peripheral vascular disease and typical onset atherosclerosis, and age-matched controls. A subset of patients present at a young age ( < 50 years) with peripheral vascular disease which pursues an aggressive course. As lipid oxidation seems important in atherosclerosis, total lipid peroxides, oxidized subfractions, and Trolox equivalent antioxidant capacity (TEAC) were studied in patients with premature peripheral vascular disease. Charts were reviewed of patients operated on for vascular occlusive disease over a 5-year period. Patients with early-onset peripheral vascular disease (group I) were evaluated for biochemical abnormalities and compared with typical onset atherosclerotics (group II) and age-matched controls (group III). Sixteen patients with early-onset peripheral vascular disease underwent biochemical evaluation. Conventional lipid profiles did not differ statistically from those of age-matched controls, except for mild elevations in LDL and VLDL in patients with vascular occlusive disease (207 and 195 mg/dl in groups I and 11 versus 157 mg/dl in group III). Total oxidative potential was significantly elevated (P = 0.006) 3.04, 2.15 and 2.04 nmol/ml in groups I, II and III, respectively. Levels of oxidized LDL and VLDL were even more significantly elevated (P = 0.0009) for premature peripheral vascular disease, (1.2, 0.58 and 0.47 nmol/ml in groups I-II). TEAC values did not differ significantly between groups (0.83, 0.82, 0.82 nmol/ml) and did not correlate with total lipid peroxide values for individual patients. In conclusion, lipid peroxides were significantly elevated in patients with premature peripheral vascular disease, the most marked changes being seen in oxidized LDL and VLDL subfractions. Lipid peroxides were elevated when standard lipid profiles were only mildly abnormal. The poor long-term prognosis in these patients suggests the need for aggressive evaluation and treatment of lipid abnormalities.


The di-leucine motif in the cytoplasmic tail of CD4 is not required for binding to human immunodeficiency virus type 1 Nef, but is critical for CD4 down-modulation.
The human immunodeficiency virus type 1 (HIV-1) nef gene encodes a 205 residue, myristoylated phosphoprotein that has been shown to play a critical role in the replication and pathogenesis of the virus. One of the most studied functions of the Nef protein is the down-modulation of cell surface CD4. Nef has been reported to interact with both the cytoplasmic tail of CD4 and proteins that are components of the endocytic machinery, thereby enhancing the endocytosis of CD4 through clathrin-coated pits. A di-leucine motif in the cytoplasmic tail of CD4 (residues 413/414) was reported to be essential both for Nef mediated down-modulation and for Nef binding. In order to further characterize the involvement of this di-leucine motif in CD4 down-modulation we generated a CD4 mutant in which the leucines were substituted by alanines, termed CD4(LL-AA). We demonstrate here that, contrary to previous data obtained with the cytoplasmic tail of CD4 alone, full-length CD4(LL-AA) bound to Nef both in vivo, in recombinant baculovirus-infected Sf9 cells, and in vitro. In contrast the di-leucine motif was required for both Nef-mediated and phorbol ester-induced CD4 down-modulation, suggesting that the essential requirement for the di-leucine motif in CD4 down-modulation reflects the fact that this motif is needed for the interactions of CD4 with the endocytic machinery, not for the interaction with Nef. We have also exploited the observation that CD4(LL-AA) is refractory to Nef-mediated down-modulation to provide the first experimental evidence for a physical interaction between Nef and CD4 in intact mammalian cells.


Arabinogalactan glycosyltransferases target to a unique subcellular compartment that may function in unconventional secretion in plants.
We report that fluorescently tagged arabinogalactan glycosyltransferases target not only the Golgi apparatus but also uncharacterized smaller compartments when transiently expressed in Nicotiana benthamiana. Approximately 80% of AtGALT31A [Arabidopsis thaliana galactosyltransferase from family 31 (At1g32930)] was found in the small compartments, of which, 45 and 40% of AtGALT29A [Arabidopsis thaliana galactosyltransferase from family 29 (At1g08280)] and AtGlcAT14A [Arabidopsis thaliana glucuronosyltransferase from family 14 (At5g39990)] colocalized with AtGALT31A, respectively; in contrast, N-glycosylation enzymes rarely colocalized (3-18%), implicating a role of the small compartments in a part of arabinogalactan (O-glycan) biosynthesis rather than N-glycan processing. The dual localization of AtGALT31A was also observed for fluorescently tagged AtGALT31A stably expressed in an Arabidopsis atgalt31a mutant background. Further, site-directed mutagenesis of a phosphorylation site of AtGALT29A (Y144) increased the frequency of the protein being targeted to the AtGALT31A-localized small compartments, suggesting a role of Y144 in subcellular targeting. The AtGALT31A localized to the small compartments were colocalized with neither SYP61 (syntaxin of plants 61), a marker for trans-Golgi network (TGN), nor FM4-64-stained endosomes. However, 41% colocalized with EXO70E2 (Arabidopsis thaliana exocyst protein Exo70 homolog 2), a marker for exocyst-positive organelles, and least affected by Brefeldin A and Wortmannin. Taken together, AtGALT31A localized to small compartments that are distinct from the Golgi apparatus, the SYP61-localized TGN, FM4-64-stained endosomes and Wortmannin-vacuolated prevacuolar compartments, but may be part of an unconventional protein secretory pathway represented by EXO70E2 in plants.


A computational model for predicting nanoparticle accumulation in tumor vasculature.
Vascular targeting of malignant tissues with systemically injected nanoparticles (NPs) holds promise in molecular imaging and anti-angiogenic therapies. Here, a computational model is presented to predict the development of tumor neovasculature over time and the specific, vascular accumulation of blood-borne NPs. A multidimensional tumor-growth model is integrated with a mesoscale formulation for the NP adhesion to blood vessel walls. The fraction of injected NPs depositing within the diseased vasculature and their spatial distribution is computed as a function of tumor stage, from 0 to day 24 post-tumor inception. As the malignant mass grows in size, average blood flow and shear rates increase within the tumor neovasculature, reaching values comparable with those measured in healthy, pre-existing vessels already at 10 days. The NP vascular affinity, interpreted as the likelihood for a blood-borne NP to firmly adhere to the vessel walls, is a fundamental parameter in this analysis and depends on NP size and ligand density, and vascular receptor expression. For high vascular affinities, NPs tend to accumulate mostly at the inlet tumor vessels leaving the inner and outer vasculature depleted of NPs. For low vascular affinities, NPs distribute quite uniformly intra-tumorally but exhibit low accumulation doses. It is shown that an optimal vascular affinity can be identified providing the proper balance between accumulation dose and uniform spatial distribution of the NPs. This balance depends on the stage of tumor development (vascularity and endothelial receptor expression) and the NP properties (size, ligand density and ligand-receptor molecular affinity). Also, it is demonstrated that for insufficiently developed vascular networks, NPs are transported preferentially through the healthy, pre-existing vessels, thus bypassing the tumor mass. The computational tool described here can effectively select an optimal NP formulation presenting high accumulation doses and uniform spatial intra-tumor distributions as a function of the development stage of the malignancy.


Epidural hematomas of the posterior cranial fossa.
The authors present their experience in the management of posterior fossa epidural hematoma (PFEDH), which involved an aggressive diagnostic approach with the extensive use of head computerized tomography (CT) scanning. The authors treated 43 cases of PFEDH in one of the largest health centers in Brazil. Diagnosis was established in all patients with the aid of CT scanning because the clinical manifestations were frequently nonspecific. Cases were stratified by clinical course, Glasgow Coma Scale score, and their radiological status. Based on clinical and radiological parameters the patients underwent surgical or conservative management. Compared with outcomes reported in the available literature, good outcome was found in this series. This is primarily due to the broad use of CT scanning for diagnostic and observational purposes, which, in the authors' opinion, led to early diagnosis and prompt treatment.


Stimulation of 125I-transferrin binding and 59Fe uptake in rat adipocytes by vanadate: treatment time determines apparent tissue sensitivity.
Vanadium compounds have been documented to stimulate a number of insulin biological effects in vitro and in vivo. We previously demonstrated stimulation of glucose transport and insulin-like growth factor-II (IGF-II) binding in rat adipocytes. These actions are associated with translocation of glucose transporters and IGF-II receptors from an intracellular compartment to the plasma membrane. The transferrin receptor is also recruited to the plasma membrane in response to insulin. Freshly isolated rat adipocytes were incubated with vanadate and insulin at 37 degrees C, and after treating the cells with KCN to inhibit further receptor movement, diferric 125I-transferrin binding was assayed. Vanadate stimulated a dose- and time-dependent increase in 125I-transferrin binding, reaching maximum (approximately threefold) stimulation at 1 mmol/L after a 4-hour incubation. This was equivalent to the maximum insulin effect that was obtained with 10(-8) mol/L after 30 minutes. A similar degree of stimulation was achieved with 0.1 mmol/L vanadate after 8 hours of exposure. Dose-response data showed that the apparent sensitivity to vanadate was time-dependent and increased with the duration of exposure (EC50: 30 minutes, 1 mmol/L; 3 hours, 0.35 mmol/L). Scatchard analysis of 125I-transferrin binding showed that both insulin and vanadate increased receptor binding capacity with no effect on receptor affinity. Total cellular transferrin receptor content measured by immunoblotting with monoclonal anti-transferrin receptor antibody (OX-26) was not altered by insulin or vanadate, consistent with receptor translocation. Assessment of 59Fe uptake from 59Fe-labeled diferric transferrin showed that vanadate augmented 59Fe uptake in a dose-dependent manner to an extent similar to insulin, demonstrating the functional activity of the receptors (percent of control: 10(-8) mol/L insulin, 175% +/- 23.8%, P < .02; 0.3 mmol/L vanadate, 188% +/- 17.3%, P < .01). We conclude that vanadate mimics insulin to augment cell surface transferrin receptors and increase Fe uptake in rat adipocytes. The time-dependent apparent increase in sensitivity is consistent with the effectiveness of very low concentrations of vanadate in vivo after several days of administration, and suggests a requirement for vanadate entry into cells to mediate this biological response.


Progress in colorectal cancer survival in Europe from the late 1980s to the early 21st century: the EUROCARE study.
Colorectal cancer (CRC) is the second most common cause of death due to cancer causing death in Europe, accounting for more than 200,000 deaths per year. Prognosis strongly depends on stage at diagnosis, and the disease can be cured in most cases if diagnosed at an early stage. We aimed to assess trends and recent developments in 5-year relative survival in European countries, with a special focus on age, stage at diagnosis and anatomical cancer subsite. Data from 25 population-based cancer registries from 16 European countries collected in the context of the EUROCARE-4 project were analyzed. Using period analysis, age-adjusted and age-specific 5-year relative survival was calculated by country, European region, stage and cancer subsite for time periods from 1988-1990 to 2000-2002. Survival substantially increased over time in all European regions. In general, increases were more pronounced in younger than in older patients, for earlier than for more advanced cancer stages and for rectum than for colon cancer. Substantial variation of CRC survival between European countries and between age groups persisted and even tentatively increased over time. There is a huge potential for reducing the burden of CRC in Europe by more widespread and equal delivery of existing options of effective early detection and curative treatment to the European population.


Changes in prevalence of overweight and in body image among Fijian women between 1989 and 1998.
To investigate changes in prevalence of overweight and obesity and in body image among ethnic Fijian women in Fiji during a period of rapid social change and the relationship between changes in body image and BMI. The study design was a multiwave cohort study of BMI in a traditional Fijian village over a 9.5-year period from 1989 to 1998. Cohorts were identified in 1989 (n=53) and in 1998 (n=50). Selection criteria included Fijian ethnicity, female gender, age of at least 18 years, and residence in a specific coastal Fijian village in 1989 and 1998, respectively. Assessments consisted of measurement of height and weight, collection of demographic data by written survey, and administration of the Nadroga Language Body Image Questionnaire. The prevalence of overweight and obesity was significantly different between the cohorts, increasing from 60% in 1989 to 84% in 1998 (p=0.014). In addition, the age-adjusted mean BMI was significantly higher in 1998 compared with 1989 (p=0.011). Finally, there were significant between-cohort differences in multiple measures of body image, which were mostly independent of BMI. At 84%, the prevalence of overweight and obesity in this community sample of Fijian women is among the highest in the world. The dramatically increased prevalence over the 9.5-year period studied corresponds with rapid social change in Fiji and significant shifts in prevailing traditional attitudes toward body shape.


Cost-effectiveness of extended adjuvant letrozole therapy after 5 years of adjuvant tamoxifen therapy in postmenopausal women with early-stage breast cancer.
To estimate the cost-effectiveness of extended adjuvant letrozole in postmenopausal women with early breast cancer and estrogen or progesterone receptor-positive tumors who had completed 5 years of adjuvant tamoxifen. Cost-effectiveness analysis using a Markov model. Using a Markov model, we estimated the incremental cost per quality-adjusted life-year (QALY) gained with extended adjuvant letrozole vs no extended adjuvant therapy. Probabilities of breast cancer recurrence or new contralateral tumor adverse effects and death were estimated using data from the MA.17 study and other secondary sources. Costs (in 2004 US dollars) and quality-of-life effects (utilities) of breast cancer events and adverse effects were derived from the literature. In base-case analyses, extended adjuvant letrozole vs no extended adjuvant therapy results in an expected gain of 0.34 QALYs per patient (13.62 vs 13.28 QALYs), at an additional lifetime cost of 9699 dollars per patient (55,254 dollars vs 45,555 dollars). The incremental cost per QALY gained with letrozole is 28,728 dollars. Cost-effectiveness is sensitive to the assumed reduction in risk of breast cancer events with letrozole but is insensitive to the risks, costs, and quality-of-life effects of osteoporosis and hip fracture. Cost-effectiveness is less than 100,000 dollars per QALY for node-positive patients younger than 81 years and for node-negative patients younger than 73 years. For postmenopausal women with early breast cancer who have completed 5 years of adjuvant tamoxifen, the cost-effectiveness of extended adjuvant letrozole is within the range of other generally accepted medical interventions in the United States.


Dissecting popliteal cyst: an unusual complication of Reiter's syndrome.
A case of Reiter's syndrome associated with a dissecting popliteal cyst mimicking deep vein thrombophlebitis is reported. The cyst was diagnosed by arthrography and responded to intra-articular injection of corticosteroids. The diagnosis of a dissecting popliteal cyst should be considered in a patient with arthritis of the knee joint from any cause and who develops signs and symptoms of thrombophlebitis.


Exploring the Relationships Between Eating Disorders and Mental Health in Women Attending Residential Substance Use Treatment.
Objective: Comorbid eating disorders (EDs) and ED symptoms are highly prevalent among women with substance use disorders and may be a barrier to recovery. Higher rates of psychiatric illness are common when more than one disorder is present. Yet little is known about the rates and risk factors for EDs/ED symptoms in women attending treatment centers in Australia. The primary aim is to examine the prevalence of ED symptoms among women attending treatment centers. This study also examines past physical and sexual abuse and mental health as specific predictors of EDs/ED symptoms. Methods: Participants were 1,444 women attending residential treatment for substance use issues provided by the Salvation Army in Australia. Measures included the Addiction Severity Index, the Eating Disorder Screen for Primary Care, medication use, hospitalization, mental health, and past abuse. Results: Alcohol was the primary substance of concern for 53.3% of the women, followed by amphetamines (17.5%), and the mean age was 37.83 years (SD = 10.8). Nearly 60% of women screened positive for ED symptoms and 32% reported a previous or current ED. Women with a history of sexual abuse had significantly greater odds (1.96) of positive screening for an ED compared to those without a history of sexual abuse. Similarly, compared to women without a history of physical abuse, those who did have a history had significantly higher odds (1.59) of a positive screen for an ED. These women were also significantly more likely to have had a health care provider recommend they take medications for psychological or emotional problems in the past 30 days, χ2(1) = 8.42, p = .004, and during their lifetime, χ2(1) = 17.89, p < .001. They also had a significantly greater number of overnight hospitalizations for medical problems compared to those who screened negative, t(137) = -2.19, p = .03. Conclusions: Women with comorbid substance use issues and EDs are highly likely to have a history of past abuse. This combination of comorbidities makes treatment and recovery difficult. Increased awareness and research are required to explore integrated approaches to treatment that accommodate these vulnerabilities and improve long-term outcomes.


The ADAMTS131239-1253 peptide is a dominant HLA-DR1-restricted CD4+ T-cell epitope.
Acquired thrombotic thrombocytopenic purpura is a rare and severe disease characterized by auto-antibodies directed against "A Disintegrin And Metalloproteinase with Thrombospondin type 1 repeats, 13th member" (ADAMTS13), a plasma protein involved in hemostasis. Involvement of CD4+ T cells in the pathogenesis of the disease is suggested by the IgG isotype of the antibodies. However, the nature of the CD4+ T-cell epitopes remains poorly characterized. Here, we determined the HLA-DR-restricted CD4+ T-cell epitopes of ADAMTS13. Candidate T-cell epitopes were predicted in silico and binding affinities were confirmed in competitive enzyme-linked immunosorbent assays. ADAMTS13-reactive CD4+ T-cell hybridomas were generated following immunization of HLA-DR1 transgenic mice (Sure-L1 strain) and used to screen the candidate epitopes. We identified the ADAMTS131239-1253 peptide as the single immunodominant HLA-DR1-restricted CD4+ T-cell epitope. This peptide is located in the CUB2 domain of ADAMTS13. It was processed by dendritic cells, stimulated CD4+ T cells from Sure-L1 mice and was recognized by CD4+ T cells from an HLA-DR1-positive patient with acute thrombotic thrombocytopenic purpura. Interestingly, the ADAMTS131239-1253 peptide demonstrated promiscuity towards HLA-DR11 and HLA-DR15. Our work paves the way towards the characterization of the ADAMTS13-specific CD4+ T-cell response in patients with thrombotic thrombocytopenic purpura using ADAMTS131239-1253-loaded HLA-DR tetramers.


Magnetic resonance imaging of the hand for the diagnosis of rheumatoid arthritis in the absence of anti-cyclic citrullinated peptide antibodies: a prospective study.
To assess the practical usefulness of magnetic resonance imaging (MRI) in establishing a positive diagnosis of rheumatoid arthritis (RA) in a cohort of patients with early inflammatory polyarthralgia, in the absence of anti-cyclic citrullinated peptide (anti-CCP) antibodies. We prospectively followed 30 outpatients with inflammatory polyarthralgia and/or synovitis of at least one joint. Patients were disease modifying antirheumatic drug-naive and received no corticosteroids. At the initial visit a clinical examination, radiographs of hands, wrists and feet, and MRI of hands were performed. Rheumatoid factor and anti-CCP antibodies were assessed. The MRI procedure was T1 fat saturation with gadolinium injection [scores were established on the basis of the axial view of the carpal and metacarpal joints, using the RA MRI scoring system (RAMRIS) defined in the OMERACT study]. In all patients, radiographs at baseline were normal and anti-CCP antibodies were negative. At one-year followup, the final diagnosis was: 16 RA; the non-RA group was composed of 4 cases of spondyloarthropathy, 2 cases of fibromyalgia, 4 cases of undifferentiated arthritis (3 of which were self-limiting), 1 sicca syndrome, 1 hemochromatosis, 1 polymyositis, and 1 paraneoplastic syndrome. No statistical difference was found between patients with and without RA for carpal erosion, synovitis, and tenosynovitis. However, a statistical difference was observed between the RA and non-RA group where metacarpophalangeal (MCP) erosion scores were concerned (p = 0.024). This difference persisted when we compared erosions of the second and third MCP in the 2 groups (p = 0.044). ROC curve analysis revealed a positive MCP score at 15, with a specificity of 70% and a sensitivity of 64%. In our population of 30 anti-CPP negative patients with normal radiographs, MRI of hands, showing MCP erosions, can be helpful for the diagnosis of RA.


Do Sideline Tests of Vestibular and Oculomotor Function Accurately Diagnose Sports-Related Concussion in Adults? A Systematic Review and Meta-analysis.
Sports-related concussion (SRC) assessment tools are primarily based on subjective assessments of somatic, cognitive, and psychosocial/emotional symptoms. SRC symptoms remain underreported, and objective measures of SRC impairments would be valuable to assist diagnosis. Measurable impairments to vestibular and oculomotor processing have been shown to occur after SRC and may provide valid objective assessments. Determine the diagnostic accuracy of sideline tests of vestibular and oculomotor dysfunction to identify SRC in adults. Systematic review; Level of evidence, 4. Electronic databases and gray literature were searched from inception until February 12, 2020. Physically active individuals (>16 years of age) who participated in sports were included. The reference standard for SRC was a combination of clinical signs and symptoms (eg, the Sport Concussion Assessment Tool [SCAT]), and index tests included any oculomotor assessment tool. The QUADAS tool was used to assess risk of bias, with the credibility of the evidence being rated according to GRADE. A total of 8 studies were included in this review. All included studies used the King-Devick test, with no other measures being identified. Meta-analysis was performed on 4 studies with a summary sensitivity and specificity of 0.77 and 0.82, respectively. The overall credibility of the evidence was rated as very low. Caution must be taken when interpreting these results given the very low credibility of the evidence, and the true summary sensitivity and specificity may substantially differ from the values calculated within this systematic review. Therefore, we recommend that clinicians using the King-Devick test to diagnose SRC in adults do so in conjunction with other tools such as the SCAT. CRD42018106632.


Characteristics of tumour-specific antigens.
It is clear that an essential and detailed body of knowledge is now becoming available through recent investigations in the experimental animal and in humans concerning the biochemical and genetic characteristics of tumour antigens, especially tumour-specific antigens. Hopefully, through this knowledge, we shall be able to improve the diagnosis and control of cancer. To summarize the recent findings in our laboratory, proteins p82 and p86 have been isolated and apparently purified from MC-induced sarcomas and from an SV40-induced sarcoma of BALB/c mice. Each protein, where assayed, shows a specific immunogenicity for the tumour from which it was isolated. Both p82 and p86 are present on the several sarcomas we studied and have been purified using the isolation and chromatographic procedures used initially for Meth A. On the basis of information obtained to date, p82 and p86 appear to be separate entities as determined by their chromatographic patterns, molecular masses, isoelectric points, amino acid compositions and reactivities to the specific antisera raised against the purified antigens. Each appears to be a well-conserved protein. Partial amino acid sequences obtained from p82 indicate that p82 is a unique protein. The answer to whether p82 and p86 are related or unrelated molecules, however, must wait for more complete structural studies. Such studies will hopefully lead to a molecular characterization and identification of the genetic mechanisms responsible for diversity of TATA, and will determine whether TATA within a group (for example among carcinogen-induced sarcomas) represent a family of structurally related molecules with polymorphic epitopes coded for by a single locus, or unrelated molecules coded for by several loci.


Antagonism of group III metabotropic glutamate receptors results in impairment of LTD but not LTP in the hippocampal CA1 region, and prevents long-term spatial memory.
Recently it has emerged that hippocampal long-term depression (LTD) may play an important role in the acquisition and storage of spatial memories. This form of synaptic plasticity is tightly regulated by metabotropic glutamate receptors (mGluRs) that negatively couple to adenylyl cyclase. Activation of group III mGluRs is necessary for persistent hippocampal LTD, but is not required for depotentiation or long-term potentiation (LTP) in the dentate gyrus in vivo. In the CA1 region antagonism of group III mGluRs prevents LTD in vivo. Effects on LTP in vivo are as yet unknown. We investigated the effects of group III mGluR antagonism on LTP and LTD at Schaffer collateral-CA1 synapses, and on spatial learning in the eight-arm radial maze. Daily application of the group III mGluR antagonist (R,S)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) resulted in impairment of long-term (reference) memory, with effects becoming apparent 4 days after training and drug treatment began. Short-term (working) memory was unaffected throughout the 10-day study. Application of CPPG prevented LTD, but not LTP, in the CA1 region. These data suggest that activation of group III mGluRs is required for the establishment of spatial long-term memory. Their exclusive role in mediating hippocampal LTD provides correlational evidence for a role for LTD in the type of spatial learning studied.


Mineral and vitamin status on high-fiber diets: long-term studies of diabetic patients.
High-fiber diets have a beneficial impact on glucose metabolism of selected persons with diabetes mellitus. A major concern is the long-term effects of fiber intake on mineral and vitamin status. We measured serum concentrations of selected minerals and vitamins and also assessed three fat-soluble vitamins in 15 patients fed high-fiber diets for an average of 21 mo. Average values for serum calcium, phosphorus, alkaline phosphatase, iron-binding capacity, magnesium, and hemoglobin values were normal. Vitamin B12 and folic acid concentrations in serum were also normal. Indirect assessment suggested that these patients had adequate intakes of the fat-soluble vitamins A, D, and K. These preliminary observations suggest that high-fiber diets containing a wide variety of natural foods are well tolerated for up to 51 mo; we failed to detect evidence suggesting mineral or vitamin deficiency in these patients.


The Mouse-Specific Splice Variant mRAGE_v4 Encodes a Membrane-Bound RAGE That Is Resistant to Shedding and Does Not Contribute to the Production of Soluble RAGE.
The receptor for advanced glycation end-products (RAGE) is involved in the onset and progression of several inflammatory diseases. The RAGE primary transcript undergoes numerous alternative splicing (AS) events, some of which are species-specific. Here, we characterize the mouse-specific mRAGE_v4 splice variant, which is conserved in rodents and absent in primates. mRAGE_v4 derives from exon 9 skipping and encodes a receptor (M-RAGE) that lacks 9 amino acids between the transmembrane and the immunoglobulin (Ig) domains. RNA-Seq data confirm that in mouse lung mRAGE_v4 is the most abundant RAGE mRNA isoform after mRAGE, which codes for full-length RAGE (FL-RAGE), while in heart all RAGE variants are almost undetectable. The proteins M-RAGE and FL-RAGE are roughly equally abundant in mouse lung. Contrary to FL-RAGE, M-RAGE is extremely resistant to shedding because it lacks the peptide motif recognized by both ADAM10 and MMP9, and does not contribute significantly to soluble cRAGE formation. Thus, a cassette exon in RAGE corresponds to a specific function of the RAGE protein-the ability to be shed. Given the differences in RAGE AS variants between rodents and humans, caution is due in the interpretation of results obtained in mouse models of RAGE-dependent human pathologies.


Multiplexed Nucleic Acid Hybridization Assays Using Single-FRET-Pair Distance-Tuning.
Multiplexed photoluminescence (PL) detection plays an important role in chemical and biological sensing. Here, it is shown that time-gated (TG) detection of a single terbium-donor-based Förster resonance energy transfer (FRET) pair can be used to selectively quantify low nanomolar concentrations of multiple DNAs or microRNAs in a single sample. This study demonstrates the applicability of single-TG-FRET-pair multiplexing for molecular (Tb-to-dye) and nanoparticle (Tb-to-quantum-dot) biosensing. Both systems use acceptor-sensitization and donor-quenching for quantifying biomolecular recognition and modification of the donor-acceptor distance for tuning the PL decays. TG intensity detection provides extremely low background noise and a quick and simple one-step assay format. Single-TG-FRET-pair multiplexing can be combined with spectral and spatial resolution, paving the way for biosensing with unprecedented high-order multiplexing capabilities.


[Evolution of the immunoglobulins].
Review. All vertebrates, so far tested, possess immunoglobulins of IgM class similar to the IgM of mammals in structure and function. On the phylogenetic level of anuran amphibians a low-molecular weight 7S immunglobulin type appears occurring in the representatives of reptiles and birds, too. These 7S immunoglobulins (earlier called IgY-like immunoglobulins) show physico-chemical and antigenic properties common to the mammalian IgA. Therefore, they can be considered the precursors of mammalian IgA. The immunoglobulins of IgG, IgD, and IgE classes represent phylogenetically modern molecules appearing during the evolution on the level of mammals. Besides, some special developments can be observed amongst the immunoglobulins.


Immunotherapies inducing immunogenic cell death in cancer: insight of the innate immune system.
Cancer immunotherapies include monoclonal antibodies, cytokines, oncolytic viruses, cellular therapies, and other biological and synthetic immunomodulators. These are traditionally studied for their effect on the immune system's role in eliminating cancer cells. However, some of these therapies have the unique ability to directly induce cytotoxicity in cancer cells by inducing immunogenic cell death (ICD). Unlike general immune stimulation, ICD triggers specific therapy-induced cell death pathways, based on the release of damage-associated molecular patterns (DAMPs) from dying tumour cells. These activate innate pattern recognition receptors (PRRs) and subsequent adaptive immune responses, offering the promise of sustained anticancer drug efficacy and durable antitumour immune memory. Exploring how onco-immunotherapies can trigger ICD, enhances our understanding of their mechanisms and potential for combination strategies. This review explores the complexities of these immunotherapeutic approaches that induce ICD, highlighting their implications for the innate immune system, addressing challenges in cancer treatment, and emphasising the pivotal role of ICD in contemporary cancer research.


A combination of new screening assays for prioritization of transmission-blocking antimalarials reveals distinct dynamics of marketed and experimental drugs.
The development of drugs to reduce malaria transmission is an important part of malaria eradication plans. We set out to develop and validate a combination of new screening assays for prioritization of transmission-blocking molecules. We developed high-throughput assays for screening compounds against gametocytes, the parasite stages responsible for onward transmission to mosquitoes. An existing gametocyte parasitic lactate dehydrogenase (pLDH) assay was adapted for use in 384-well plates, and a novel homogeneous immunoassay to monitor the functional transition of female gametocytes into gametes was developed. A collection of 48 marketed and experimental antimalarials was screened and subsequently tested for impact on sporogony in Anopheles mosquitoes, to directly quantify the transmission-blocking properties of antimalarials in relation to their effects on gametocyte pLDH activity or gametogenesis. The novel screening assays revealed distinct stage-specific kinetics and dynamics of drug effects. Peroxides showed the most potent transmission-blocking effects, with an intermediate speed of action and IC50 values that were 20-40-fold higher than the IC50s against the asexual stages causing clinical malaria. Finally, the novel synthetic peroxide OZ439 appeared to be a promising drug candidate as it exerted gametocytocidal and transmission-blocking effects at clinically relevant concentrations.


In vitro stimulation of alkaline phosphatase activity in immature embryonic chick pelvic cartilage by adenosine 3'5'-monophosphate.
Cyclic AMP content in embryonic chick pelvic cartilage increases significantly as the embryo ages from 8 to 10 d. This in ovo elevation in cyclic AMP content precedes maximal cartilage alkaline phosphatase activity by some 24 h. We studied whether this temporal relationship may be causally related, using an in vitro organ culture. Incubation of pelvic cartilage from 9- and 10-d embryos in medium containing monobutyryl cyclic AMP (BtcAMP) resulted in significant increases in alkaline phosphatase activity (220 and 66 percent, respectively) as compared to that of cartilages incubated in medium alone. This stimulation was both concentration- and time-dependent with maximal response at 0.5 mM BtcAMP and 4-h incubation, respectively. Similar incubations of cartilage in medium containing 1-methyl-3-isobutyl xanthine (MIX), 0.25 mM, also resulted in increased alkaline phosphatase activity (114 percent). However, pelvic cartilage from 11-d embryos incubated in medium containing BtcAMP or MIX showed no increase in alkaline phosphatase activity. We postulated that developmental age was the factor responsible for this difference in response and that immature cartilage (that with little or no alkaline phosphatase activity) would respond to BtcAMP whereas mature cartilage (that with significant alkaline phosphatase activity) would not. This was tested by incubating end sections of 11-d cartilage, which have little alkaline phosphatase activity, and center sections, which have significantly alkaline phosphatase activity, with both BtcAMP and MIX. Alkaline phosphatase activity in end sections (immature cartilage) was stimulated by BtcAMP and MIX, whereas it was not stimulated in the center sections. Actinomycin D and cycloheximide inhibited BtcAMP and MIX stimulation of alkaline phosphatase activity. Thus, the in vitro data suggest that cyclic AMP is a mediator for the stimulation of alkaline phosphatase activity in embryonic cartilage.


Unravelling the mechanism of glycerol hydrogenolysis over rhodium catalyst through combined experimental-theoretical investigations.
We report herein a detailed and accurate study of the mechanism of rhodium-catalysed conversion of glycerol into 1,2-propanediol and lactic acid. The first step of the reaction is particularly debated, as it can be either dehydration or dehydrogenation. It is expected that these elementary reactions can be influenced by pH variations and by the nature of the gas phase. These parameters were consequently investigated experimentally. On the other hand, there was a lack of knowledge about the behaviour of glycerol at the surface of the metallic catalyst. A theoretical approach on a model Rh(111) surface was thus implemented in the framework of density functional theory (DFT) to describe the above-mentioned elementary reactions and to calculate the corresponding transition states. The combination of experiment and theory shows that the dehydrogenation into glyceraldehyde is the first step for the glycerol transformation on the Rh/C catalyst in basic media under He or H(2) atmosphere.


Shear-induced platelet aggregation increases in patients with proximal and severe coronary artery stenosis.
Shear stress generated in stenosed arteries promotes platelet thrombi formation at the stenosed sites by accelerating the binding of von Willebrand factor (vWF) to platelets. Shear-induced platelet aggregation (SIPA) has been studied in acute coronary syndromes, but not in chronic coronary disease. We investigated the effect of both the site and severity of coronary stenosis on SIPA in patients with chronic coronary artery disease. Shear-induced platelet aggregation was measured using platelet-rich plasma in 49 patients (41 men and 8 women; mean age 61+/-10 years) with coronary artery disease to evaluate the association between the extent of SIPA and coronary angiographic findings. Stenoses > 75% were considered severe. In all, 62 healthy individuals (54 men and 18 women; mean age 45+/-7 years) served as controls. The correlation between SIPA and the site and severity of the coronary lesion, and parameters of coagulation and fibrinolysis were evaluated. Shear-induced platelet aggregation was increased in the stenosis group (69.0+/-10.6%) compared with the controls (57.7+/-10.3%, p < 0.0001). Patients with severe stenosis in the proximal segments had significantly increased SIPA (p< 0.0001) and vWF larger multimer concentration (p<0.0001) compared with the control group. A significant correlation existed between SIPA and the vWF larger multimer concentration in all subjects studied (r = 0.422, p < 0.0001). Shear-induced platelet aggregation is increased in patients with severe stenosis of the proximal coronary arteries and correlates with plasma concentrations of vWF larger multimers, suggesting that severe stenosis in the proximal segments is not only associated with an increased risk of significant myocardial ischemia, but may also generate high shear stress in the stenosed artery and increase plasma vWF larger multimers, thereby promoting the formation of platelet thrombi.


Phytotoxicity associated to microcystins: a review.
Microcystins (MC) are the most studied toxins of cyanobacteria since they are widely distributed and account for several cases of human and animal poisoning, being potent inhibitors of the serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A). The phosphatases PP1 and PP2A are also present in plants, which may also suffer adverse effects due to the inhibition of these enzymes. In aquatic plants, biomass reduction is usually observed after absorption of cyanotoxins, which can bioaccumulate in its tissues. In terrestrial plants, the effects caused by microcystins vary from inhibition to stimulation as the individuals develop from seedling to adult, and include reduction of protein phosphatases 1 and 2A, oxidative stress, decreased photosynthetic activity and even cell apoptosis, as well as bioaccumulation in plant tissues. Thus, the irrigation of crop plants by water contaminated with microcystins is not only an economic problem but becomes a public health issue because of the possibility of food contamination, and this route of exposure requires careful monitoring by the responsible authorities.


At the Bedside: Innate immunity as an immunotherapy tool for hematological malignancies.
The identification of an anti-tumor effect displayed by cells of innate immunity has opened new scenarios, not only in the field of allo-HSCT but also for nontransplanted patients with hematological malignancies or solid tumors. Donor-derived NK cells have been shown to contribute to the eradication of malignant cells after allo-HSCT, when recipients lack ligands for their inhibitory receptors. These alloreactive donor NK cells can also kill recipient APCs and CTLs, thus preventing the occurrence of GvHD and graft rejection. The role of activating receptors on the capacity of NK cells to kill leukemia targets has become evident in the last years. The adoptive infusion of ex vivo-activated NK cells has been investigated recently in Phase I/II trials on patients with hematological malignancies and solid tumors, with promising results. γδ T lymphocytes are also able to display anti-tumor activity-this providing the biological rationale for Phase I/II trials in lymphoproliferative disorders and solid tumors. Aminobisphosphonates are clinically available compounds able to boost γδ T cell function. As γδ T cells do not cause GvHD, they could also be transduced with tumor-associated chimeric antigen receptors and safely infused in allo-HSCT recipients. Basic aspects of innate immunity relevant to the field will be covered by a companion review article.


A 1463 gene cattle-human comparative map with anchor points defined by human genome sequence coordinates.
A second-generation 5000 rad radiation hybrid (RH) map of the cattle genome was constructed primarily using cattle ESTs that were targeted to gaps in the existing cattle-human comparative map, as well as to sparsely populated map intervals. A total of 870 targeted markers were added, bringing the number of markers mapped on the RH(5000) panel to 1913. Of these, 1463 have significant BLASTN hits (E < e(-5)) against the human genome sequence. A cattle-human comparative map was created using human genome sequence coordinates of the paired orthologs. One-hundred and ninety-five conserved segments (defined by two or more genes) were identified between the cattle and human genomes, of which 31 are newly discovered and 34 were extended singletons on the first-generation map. The new map represents an improvement of 20% genome-wide comparative coverage compared with the first-generation map. Analysis of gene content within human genome regions where there are gaps in the comparative map revealed gaps with both significantly greater and significantly lower gene content. The new, more detailed cattle-human comparative map provides an improved resource for the analysis of mammalian chromosome evolution, the identification of candidate genes for economically important traits, and for proper alignment of sequence contigs on cattle chromosomes.


On the role of substrate in light-harvesting experiments.
An analysis of the emitted light distribution for a single emitter located at the planar interface of two optical media was performed. The interface of a varying refractive index substrate with air was considered, which is a common case in luminescence microscopy (spectroscopy) experiments. A modification of the radiative recombination rate induced by the variation of the substrate together with the emitted radiation spatial redistribution were taken into account. Simulation results show that the collection efficiency of the emitted light can vary several times depending on the substrate choice and the emitter intrinsic quantum efficiency.


Selection of an unnatural peptide library for dsDNA binding.
More and more, nucleic acids have become prime targets in the development of new compounds, able to control gene expression. For the development of new sequence selective dsDNA binding ligands, one can learn a lot from existing models such as, lexitropsins, combilexins and actinomycin D. This analysis, together with the knowledge of the details on protein-DNA interactions, has inspired the assembly of unnatural amino acids in a combinatorial way to generate a dsDNA recognition library. The first selection round has led to the selection of new DNA binding molecules, which may lead on the long run to the discovery of new DNA binding motifs.


A Mindful Parenting Program for Parents Concerned About Child Internalizing Problems: a Randomized Controlled Feasibility Study.
This study sought to establish four aspects of feasibility for a mindful parenting program: demand for the program from parents with concerns regarding their child's internalizing problems, acceptability of the program to those parents, preliminary efficacy, and the likelihood of successful expansion of the program to the intended population. The study was a pilot, randomized controlled trial comparing a mindful parenting program to waitlist. Participants were parents (N = 25) of children aged 3-18 years, with self-reported concerns regarding their child's internalizing problems, recruited from the community. Demand was assessed using recruitment and adherence rates. Acceptability was assessed using parent-reported usefulness. Preliminary efficacy was assessed using parent reports of child internalizing problems, mindful parenting, parenting stress, cognitive emotion regulation, parental experiential avoidance, and parent beliefs about child anxiety. Intervention group parents also provided weekly in-session data on coping in stressful parenting situations. The likelihood of successful expansion was assessed using qualitative feedback on whether and how the program had helped parents manage child internalizing problems, particularly anxiety. Feasibility was established for the four aspects assessed. The program was well-attended and acceptable to parents. Moderate to large effects were found in favor of the intervention group for most parent and child outcomes. Weekly data showed improved coping in difficult parenting situations. Qualitative feedback suggested that parents believed that increased acceptance and empathy had helped them cope with child internalizing problems. Mindful parenting programs may assist parents of children with internalizing problems to manage parenting stress and emotionally regulate themselves, even in difficult parenting moments. They may also reduce child internalizing problems, through improved parental emotion regulation, and greater acceptance of and empathy for their child. Australian Clinical Trials Registry, registration number ACTRN12620000690954.


Successful arterial switch operation for transposition of the great arteries with intact ventricular septum and congenital diaphragmatic hernia: A case report.
We report performing a successful arterial switch operation on a full-term male infant with transposition of the great arteries and intact ventricular septum associated with a congenital diaphragmatic hernia. The patient developed severe persistent pulmonary hypertension after successful repair of a left congenital diaphragmatic hernia that restricted pulmonary blood flow into the hypoplastic left lung, and subsequent unilateral pulmonary congestion of the unaffected right lung occurred because of the hemodynamics generated by the transposition of the great arteries. Intravenous epoprostenol with nitric oxide inhalation and mechanical hypoventilation effectively controlled pulmonary vascular resistance before the arterial switch operation was performed. <Learning Objective: The outcome of this case suggests that administration of intravenous epoprostenol with nitric oxide inhalation effectively treats persistent pulmonary hypertension of the newborn. Moreover, the hemodynamics associated with transposition of the great arteries requires controlled mechanical hypoventilation to effectively treat pulmonary congestion.>.


Visualization of airborne droplets generated with dental handpieces and verification of the efficacy of high-volume evacuators: an in vitro study.
The COVID-19 pandemic led to concerns about the potential airborne transmission of the virus during dental procedures, but evidence of actual transmission in clinical settings was lacking. This study aimed to observe the behavior of dental sprays generated from dental rotary handpieces and to evaluate the effectiveness of high-volume evacuators (HVEs) using laser light sheets and water-sensitive papers. A dental manikin and jaw model were mounted in a dental treatment unit. Mock cutting procedures were performed on an artificial tooth on the maxillary left central incisor using an air turbine, a contra-angle electric micromotor (EM), and a 1:5 speed-up contra-angle EM (×5EM). Intraoral vacuum and extraoral vacuum (EOV) were used to verify the effectiveness of the HVEs. The dynamics and dispersal range of the dental sprays were visualized using a laser light sheet. In addition, environmental surface pollution was monitored three-dimensionally using water-sensitive papers. Although the HVEs were effective in both the tests, the use of EOV alone increased vertical dispersal and pollution. The use of various types of HVEs to reduce the exposure of operators and assistants to dental sprays when using dental rotary cutting instruments is beneficial. The study findings will be helpful in the event of a future pandemic caused by an emerging or re-emerging infectious disease.


Thrombophlebitis of the lateral chest wall (Mondor's disease).
Mondor's disease is a rare condition, which involves the thrombophlebitis of the superficial veins of the breast and anterior chest wall. A 37-year-old woman presented with sudden onset of local pain and edema on her right chest wall, accompanied by a longitudinal retraction of the skin during arm abduction in the area. Clinical, histological and ultrasonographic findings confirmed Mondor's disease and the treatment was symptomatic, using pain relievers and warm compresses. The symptomatology remitted within 2 weeks of therapy. Mondor's disease is a rare condition where ultrasound complements the clinical evaluation and allows the characterization of certain abnormalities, which correlated with functional biochemical data and other procedures may substitute the need of biopsy.