Evaluation of the Measuring and Improving Quality in Palliative Care Survey.
To evaluate the reliability, content validity, and variation among sites of a survey to assess facilitators and barriers to quality measurement and improvement in palliative care programs. We surveyed a sample of diverse US and Canadian palliative care programs and conducted postcompletion discussion groups. The survey included constructs addressing educational support and training, communication, teamwork, leadership, and prioritization for quality measurement and improvement. We tested internal consistency reliability, described variation among sites, and reported descriptive feedback on content validity. Of 103 respondents in 11 sites, the most common roles were attending physician (38.9%) and nurse practitioner, clinical nurse specialist, or physician assistant (16.5%). Internal consistency reliability was acceptable (Cronbach's α = .70 to .99) for all but one construct. Results varied across sites by more than 1 point on the 1 to 5 scales between the 10th and 90th percentiles of sites for two constructs in recognition and focus on quality measurement (score range by site, 1.7 to 4.8), one construct in teamwork (score range, 3.1 to 4.6), and five constructs in quality improvement (score range, 1.8 to 4.6). In descriptive content validity evaluation, respondents described the survey as an opportunity for assessing quality initiatives and discussing potential improvements, particularly improvements in communication, training, and engagement of team members regarding program quality efforts. This survey to assess palliative care team perspectives on barriers and facilitators for quality measurement and improvement demonstrated reliability, content validity, and initial evidence of variation among sites. Our findings highlight how palliative care team members' perspectives may be valuable to plan, evaluate, and monitor quality-of-care initiatives.


Single cell transcriptomics identifies a unique adipose lineage cell population that regulates bone marrow environment.
Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from mesenchymal stem cells, the true identity of progenitors and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing large scale single cell transcriptome analysis, we computationally defined mesenchymal progenitors at different stages and delineated their bi-lineage differentiation paths in young, adult and aging mice. One identified subpopulation is a unique cell type that expresses adipocyte markers but contains no lipid droplets. As non-proliferative precursors for adipocytes, they exist abundantly as pericytes and stromal cells that form a ubiquitous 3D network inside the marrow cavity. Functionally they play critical roles in maintaining marrow vasculature and suppressing bone formation. Therefore, we name them marrow adipogenic lineage precursors (MALPs) and conclude that they are a newly identified component of marrow adipose tissue.


[Right ventricular assistance with a centrifugal pump. Report of two cases].
Acute right ventricular failure after cardiac surgery occurring in the first postoperative hours is associated with a bad prognosis. We have used a centrifugal pump either for left, right or biventricular assistance. However, the use of this device for pure right ventricular assistance is rare. We report a 30 year-old female undergoing a mitral valve replacement and a 42 year-old male undergoing a cardiac transplantation, who had a successful right ventricular assistance using a centrifugal pump, due to a failing right ventricle, as the result of insufficient myocardial protection and severe pulmonary hypertension. These two cases illustrate the value of the mechanical ventricular assist device for the treatment of right heart failure.


Traumatic myocardial infarction with subsequent normal coronary arteriogram.
A 36-yr-old man suffered from transmural anterior myocardial infarction almost immediately after being hit by a football on the chest. There were neither external signs of injury to the chest wall, nor fractures of the thoracic cage. Coronary angiography 6 wk later revealed no demonstrable obstruction in any vessel; therefore, coronary artery injury with subsequent platelet aggregates or thrombosis followed by lysis and recanalization was suspected. Myocardial contusion or coronary spasm are alternative explanations.


Cost-utility estimates in depression: does the valuation method matter?
Depression imposes a substantial burden on society. In view of the economic burden of depression, studies evaluating depression treatment increasingly incorporate a cost-utility analysis. Outcomes of these analyses are used by decision makers to prioritize healthcare. Although generic preference-based instruments have been recommended for measuring utility, depression research often uses a disease-specific method, based on depression-free days (DFD), to measure utilities. The objective of this study was to compare utility measurement techniques in the context of a randomized controlled trial. In particular, we studied the agreement between QALYs measured with the EuroQol (EQ-5D), the Short Form 6D (SF-6D), and the DFD method, using the EQ-5D as the reference method. We also studied whether the use of different techniques leads to different conclusions for decision makers. Data were derived from the Depression in Elderly with Long-Term Afflictions (DELTA) study. This randomized controlled trial was designed to study the effectiveness and cost-effectiveness of a minimal psychological intervention for chronically ill patients with co-occurring minor or mild to moderate major depression. The EQ-5D, SF-6D and Beck Depression Inventory (to estimate DFDs) were assessed at baseline, and at three, six and twelve months after baseline. Poor agreement was found between the EQ-5D and DFD (Kendall's Tau: 0.33; ICC: 0.21 (95% CI:-0.07-0.45)) and moderate agreement between the EQ-5D and SF-6D (Kendall's Tau: 0.60; ICC: 0.47 (95% CI: 0.36-0.57)). The incremental cost-utility ratio led to similar conclusions for decision makers across techniques. In conclusion, utilities from the disease-specific DFD method should not be compared directly with utilities derived from the EQ-5D. Although a disease-specific method might yield similar cost-utility ratios as generic instruments, generic instruments remain the preferred option for prioritizing healthcare. Limitations of this study include the presence of minor depression and chronic illnesses in our study population. Generic instruments remain preferred for cost-utility analyses, especially when results are used to prioritize healthcare. If the DFD method is a way forward, further research is required to validate utility weights assigned to the DFDs.


Steroid-resistant acute rejections after liver transplant.
Liver transplant is the definitive treatment for the end-stage liver disease. Although effective immunosuppressants are available, steroid-resistant acute rejection can be encountered. Between September 2001 and April 2010, 285 adult and pediatric liver transplants were done on 279 patients from deceased donors and living-related donors at our center. All patients received tacrolimus-based immunosuppressive therapy. Steroids were tapered in 3 months. Liver biopsy was done to confirm acute rejection after vascular or biliary complications had been excluded. High-dose steroids were administered for acute rejections. If there was no response to steroids, acute rejection was defined as steroid-resistant acute rejection. After confirming steroid-resistant acute rejection by a second biopsy, antithymocyte globulin was given to patients until liver functions return to normal level with ganciclovir prophylaxis. Acute rejection was detected in 87 liver transplants (30.5%). Steroid-resistant acute rejections were detected in 12 of 87 patients (7 male, 5 female; 8 pediatric, 4 adult patients; mean age, 16.08 +/- 12.1 years) (13.7%). Mean time from transplant to steroid-resistant acute rejection was 73.58 +/- 59.24 days (range, 20-181 days). The predominant cause of liver disease before liver transplant in patients who had steroid-resistant acute rejection was fulminant hepatic failure. Steroid-resistant acute rejection therapy was successful in 10 of 12 patients (83.3%). Two patients did not respond to therapy; therefore, they advanced to chronic rejection. Adverse effects due to cytokine release were the most frequently encountered reactions in the early period of antithymocyte globulin treatment. The mean follow-ups after steroid-resistant acute rejection treatment were 38.2 +/- 26 months (range, 2-85 months). We did not encounter any serious reaction, serious infection, or long-term adverse effect after antithymocyte globulin treatment. According to our experience, antithymocyte globulin can be considered as a good therapeutic option in steroid-resistant acute rejection with acceptable adverse effects.


Combining NMR and EPR methods for homodimer protein structure determination.
There is a general need to develop more powerful and more robust methods for structural characterization of homodimers, homo-oligomers, and multiprotein complexes using solution-state NMR methods. In recent years, there has been increasing emphasis on integrating distinct and complementary methodologies for structure determination of multiprotein complexes. One approach not yet widely used is to obtain intermediate and long-range distance constraints from paramagnetic relaxation enhancements (PRE) and electron paramagnetic resonance (EPR)-based techniques such as double electron electron resonance (DEER), which, when used together, can provide supplemental distance constraints spanning to 10-70 A. In this Communication, we describe integration of PRE and DEER data with conventional solution-state nuclear magnetic resonance (NMR) methods for structure determination of Dsy0195, a homodimer (62 amino acids per monomer) from Desulfitobacterium hafniense. Our results indicate that combination of conventional NMR restraints with only one or a few DEER distance constraints and a small number of PRE constraints is sufficient for the automatic NMR-based structure determination program CYANA to build a network of interchain nuclear Overhauser effect constraints that can be used to accurately define both the homodimer interface and the global homodimer structure. The use of DEER distances as a source of supplemental constraints as described here has virtually no upper molecular weight limit, and utilization of the PRE constraints is limited only by the ability to make accurate assignments of the protein amide proton and nitrogen chemical shifts.


A phenothiazine urea derivative broadly inhibits coronavirus replication via viral protease inhibition.
Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle formation, viral RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two viral cysteine proteases, main protease (Mpro) and papain-like protease (PLpro), that mediate polyprotein cleavage. Using a structure-guided approach, a phenothiazine urea derivative that inhibits both SARS-CoV-2 Mpro and PLpro protease activity was identified. In silico docking studies also predicted the binding of the phenothiazine urea to the active sites of structurally similar Mpro and PLpro proteases from distantly related alphacoronavirus, HCoV-229 E (229 E), and the betacoronavirus, HCoV-OC43 (OC43). The lead phenothiazine urea derivative displayed broad antiviral activity against all three HCoVs tested in cellulo. It was further demonstrated that the compound inhibited 229 E and OC43 at an early stage of viral replication, with diminished formation of viral replication organelles, and the RNAs that are made within them, as expected following viral protease inhibition. These observations suggest that the phenothiazine urea derivative readily inhibits viral replication and may broadly inhibit proteases of diverse coronaviruses.


[Incidence of infectious diseases in children in the 1st 7 years of life].
The dynamics of changes in the occurrence of infectious diseases in 1180 children during the first 7 years of life has been studied. The possibility of dividing children into groups with rare and frequent occurrence of diseases as early as during the first years of life has been demonstrated. The group of children falling ill frequently determines, to a considerable extent, the morbidity level in infectious diseases among children of the corresponding age group.


A comparison of Monte Carlo dropout and bootstrap aggregation on the performance and uncertainty estimation in radiation therapy dose prediction with deep learning neural networks.
Recently, artificial intelligence technologies and algorithms have become a major focus for advancements in treatment planning for radiation therapy. As these are starting to become incorporated into the clinical workflow, a major concern from clinicians is not whether the model is accurate, but whether the model can express to a human operator when it does not know if its answer is correct. We propose to use Monte Carlo Dropout (MCDO) and the bootstrap aggregation (bagging) technique on deep learning (DL) models to produce uncertainty estimations for radiation therapy dose prediction. We show that both models are capable of generating a reasonable uncertainty map, and, with our proposed scaling technique, creating interpretable uncertainties and bounds on the prediction and any relevant metrics. Performance-wise, bagging provides statistically significant reduced loss value and errors in most of the metrics investigated in this study. The addition of bagging was able to further reduce errors by another 0.34% for [Formula: see text] and 0.19% for [Formula: see text] on average, when compared to the baseline model. Overall, the bagging framework provided significantly lower mean absolute error (MAE) of 2.62, as opposed to the baseline model's MAE of 2.87. The usefulness of bagging, from solely a performance standpoint, does highly depend on the problem and the acceptable predictive error, and its high upfront computational cost during training should be factored in to deciding whether it is advantageous to use it. In terms of deployment with uncertainty estimations turned on, both methods offer the same performance time of about 12 s. As an ensemble-based metaheuristic, bagging can be used with existing machine learning architectures to improve stability and performance, and MCDO can be applied to any DL models that have dropout as part of their architecture.


The Experience of Locomotor Training From the Perspectives of Therapists and Parents of Children With Cerebral Palsy.
Objective: The objective of this study was to explore the experiences of intensive locomotor training from the perspective of therapists and parents of children with cerebral palsy. Design: A qualitative study using semi-structured interviews was employed to capture perspectives following an intensive locomotor training intervention. Data were analyzed thematically, systematically coding and interpreted by grouping information into themes and sub-theme categories. Participants: Five therapists and seven parents of children with high daily physical assistance and equipment needs participated in the study. Setting: A pediatric tertiary hospital. Results: Experiences of locomotor training were described with relation to the suitability of locomotor training with sub-themes of intervention length and time, engagement within sessions, the importance of support, and the utility of locomotor training beyond a research context. Motivation for participating in locomotor training was described in relation to the enjoyment of movement and for increasing activity level. The barriers and facilitators who participated in locomotor training provided environmental and personal factor subthemes. Finally, the outcomes from the intervention were related to improvements in physical health, sleep, affect and emotion, and ambulation in daily activities. Conclusion: The experience of intensive locomotor training from the perspectives of parents of children who have high physical assistance and equipment needs and the therapists providing the intervention was described. Future studies should consider outcome measures beyond motor capacity to quantify the perceived outcomes of interventions that are meaningful to families.


In vitro and in vivo study of hazardous effects of Ag nanoparticles and Arginine-treated multi walled carbon nanotubes on blood cells: application in hemodialysis membranes.
One of the novel applications of the nanostructures is the modification and development of membranes for hemocompatibility of hemodialysis. The toxicity and hemocompatibility of Ag nanoparticles and arginine-treated multiwalled carbon nanotubes (MWNT-Arg) and possibility of their application in membrane technology are investigated here. MWNT-Arg is prepared by amidation reactions, followed by characterization by FTIR spectroscopy, Raman spectroscopy, and thermogravimetric analysis. The results showed a good hemocompatibility and the hemolytic rates in the presence of both MWNT-Arg and Ag nanoparticles. The hemolytic rate of Ag nanoparticles was lower than that of MWNT-Arg. In vivo study revealed that Ag nanoparticle and MWNT-Arg decreased Hematocrit and mean number of red blood cells (RBC) statistically at concentration of 100 µg mL(-1) . The mean decrease of RBC and Hematocrit for Ag nanoparticles (18% for Hematocrit and 5.8 × 1,000,000/µL) was more than MWNT-Arg (20% for Hematocrit and 6 × 1000000/µL). In addition, MWNT-Arg and Ag nanoparticles had a direct influence on the White Blood Cell (WBC) drop. Regarding both nanostructures, although the number of WBC increased in initial concentration, it decreased significantly at the concentration of 100 µg mL(-1) . It is worth mentioning that the toxicity of Ag nanoparticle on WBC was higher than that of MWNT-Arg. Because of potent antimicrobial activity and relative hemocompatibility, MWNT-Arg could be considered as a new candidate for biomedical applications in the future especially for hemodialysis membranes.


Restricted Epstein-Barr virus protein expression in Burkitt lymphoma is due to a different Epstein-Barr nuclear antigen 1 transcriptional initiation site.
Epstein-Barr virus (EBV) expresses six nuclear antigens (EBNAs) and three integral latent membrane proteins (LMPs) in latently infected growth-transformed B lymphoblastoid cell lines (LCLs). In contrast, EBV protein expression in Burkitt lymphoma tissue or in newly established Burkitt lymphoma cell lines is frequently restricted to the EBV genome maintenance protein, EBNA-1. EBNA-1 expression in the absence of other EBNAs and LMP-1 has been an enigma since, in LCLs, all EBNA mRNAs are processed from a single transcript. We now show that the basis for restricted EBV expression in Burkitt lymphoma cells is selective EBNA-1 mRNA transcription from a hitherto unrecognized promoter that is 50 kb closer to the EBNA-1-encoding exon than previously described EBNA-1 promoters. Infected cells with EBNA-1-restricted expression could preferentially persist in vivo in the face of EBV-immune T-cell responses, which are frequently directed against other EBNAs and are also dependent on LMP-1 expression.


EVIDENCE OF EPSTEIN-BARR VIRUS ASSOCIATION WITH HEAD AND NECK CANCERS: A REVIEW.
Epstein-Barr virus (EBV) is ubiquitous: over 90% of the adult population is infected with this virus. EBV is capable of infecting both B lymphocytes and epithelial cells throughout the body including the head and neck region. Transmission occurs mainly by exchange of saliva. The infection is asymptomatic or mild in children but, in adolescents and young adults, it causes infectious mononucleosis, a self-limiting disease characterized by lethargy, sore throat, fever and lymphadenopathy. Once established, the virus often remains latent and people become lifelong carriers without experiencing disease. However, in some people, the latent virus is capable of causing malignant tumours, such as nasopharyngeal carcinoma and various B- and T-cell lymphomas, at sites including the head, neck and oropharyngeal region. As lymphoma is the second-most common malignant disease of the head, neck and oral region after squamous cell carcinoma, oral health care workers including dentists and specialists have a responsibility to carry out a thorough clinical examination of this anatomical region with a view to identifying and diagnosing lesions that may represent lymphomas. Early detection allows early treatment resulting in better prognosis. The focus of this review is on the morphology, transmission and carcinogenic properties of EBV and clinical and diagnostic aspects of a range of EBV-associated malignancies occurring in the head, neck and oral region. As carcinogenic agents, viruses contribute to a significant proportion of the global cancer burden: approximately 15% of all human cancers, worldwide, are attributable to viruses.1,2 Serologic and epidemiologic studies are providing mounting evidence of an etiologic association between viruses and head and neck malignancies.3 To update oral and maxillofacial surgeons and oral medicine specialists and raise awareness of this association, we recently reviewed the evidence of the etiologic role of human papillomavirus in oral disease.4 In this paper, we review the current state of knowledge of the association of Epstein-Barr virus (EBV) with malignant diseases in the head and neck region.


De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease.
Hirschsprung disease (HSCR) is a common congenital abnormality characterized by absence of the enteric ganglia in the hind gut. In 10-40% of HSCR cases, mutations of the RET receptor tyrosine kinase have been found. The recent identification of a multimeric RET ligand/receptor complex suggested that mutations of genes encoding other components of this complex might also occur in HSCR. To investigate this role, we examined the gene for glial cell line-derived neurotrophic factor (GDNF), the circulating ligand of the RET receptor complex, for mutations in a panel of sporadic and familial HSCR. We identified GDNF sequence variants in 2/36 HSCR patients. The first of these was a conservative change which did not affect the GDNF protein sequence. The second variant was a de novo missense mutation in a family with no history of HSCR and without mutation of the RET gene. Thus, our data are consistent with a causative role for GDNF mutations in some HSCR cases.


THE ACTION OF CERTAIN HORMONES AS DIETARY CONSTITUENTS.
The sex organs of the male are more resistant to dietary deficiencies, the animals showing only retrogression along with a significant loss in weight. Testosterone and gonadotropic hormone (of pregnant mare serum) produce a small but definite restorative effect. Oral administration of estrin to females depresses the food intake, while testosterone, and less so the gonadotropic hormone in males produces the opposite effect. This effect can be regarded as evidence of the dietary significance of these two hormones. The expenses of the present investigation were defrayed by the U. S. Vitamin Corporation, of New York City.


Self-decorating cells via surface-initiated enzymatic controlled radical polymerization.
Through the innovative use of surface-displayed horseradish peroxidase, this work explores the enzymatic catalysis of both bioRAFT polymerization and bioATRP to prompt polymer synthesis on the surface of Saccharomyces cerevisiae cells, with bioATRP outperforming bioRAFT polymerization. The resulting surface modification of living yeast cells with synthetic polymers allows for a significant change in yeast phenotype, including growth profile, aggregation characteristics, and conjugation of non-native enzymes to the clickable polymers on the cell surface, opening new avenues in bioorthogonal cell-surface engineering.


Conservation Genomics of the Threatened Western Spadefoot, Spea hammondii, in Urbanized Southern California.
Populations of the western spadefoot (Spea hammondii) in southern California occur in one of the most urbanized and fragmented landscapes on the planet and have lost up to 80% of their native habitat. Orange County is one of the last strongholds for this pond-breeding amphibian in the region, and ongoing restoration efforts targeting S. hammondii have involved habitat protection and the construction of artificial breeding ponds. These efforts have successfully increased breeding activity, but genetic characterization of the populations, including estimates of effective population size and admixture between the gene pools of constructed artificial and natural ponds, has never been undertaken. Using thousands of genome-wide single-nucleotide polymorphisms, we characterized the population structure, genetic diversity, and genetic connectivity of spadefoots in Orange County to guide ongoing and future management efforts. We identified at least 2, and possibly 3 major genetic clusters, with additional substructure within clusters indicating that individual ponds are often genetically distinct. Estimates of landscape resistance suggest that ponds on either side of the Los Angeles Basin were likely interconnected historically, but intense urban development has rendered them essentially isolated, and the resulting risk of interruption to natural metapopulation dynamics appears to be high. Resistance surfaces show that the existing artificial ponds were well-placed and connected to natural populations by low-resistance corridors. Toad samples from all ponds (natural and artificial) returned extremely low estimates of effective population size, possibly due to a bottleneck caused by a recent multi-year drought. Management efforts should focus on maintaining gene flow among natural and artificial ponds by both assisted migration and construction of new ponds to bolster the existing pond network in the region.


High normal levels of albuminuria and risk of hypertension in Indo-Asian population.
Urine albumin excretion in the high normal range [urine albumin to creatinine ratio (UACR) 10-29 mg/g)] predicts hypertension in European-origin populations. However, the prognostic significance of UACR in the high normal range for incident hypertension is unclear in Indo-Asians. The objective of this study was to examine the relationship of normal to high normal levels of UACR and incident hypertension. We conducted a nested cohort study within a cluster randomized controlled trial in Pakistan on 1272 normotensive non-diabetic adults aged ≥ 40 years with UACR <30 mg/g. Incident hypertension was defined as new onset of systolic blood pressure (SBP) ≥ 140 mmHg or diastolic ≥ 90 mmHg or initiation of antihypertensive therapy. A total of 920 (72.3%) participants completed the 2-year final follow-up. During this time, 105 (11.4%) developed incident hypertension. In the multivariable model, the odds [95% confidence interval (CI)] for incident hypertension were 2.45(1.21-4.98) for those in the fourth (top) quartile (≥ 6.1 mg/g) and 2.12 (1.04-4.35) in the third quartile (3.8-6.1 mg/g) compared to those in the lowest quartile (<2.8 mg/g). In addition, a significant interaction between UACR and baseline SBP was observed suggesting that the odds (95% CI) of incident hypertension with UACR were greater at lower baseline SBP (interaction P = 0.044). High normal levels of albuminuria as measured by UACR predict hypertension in non-diabetic Indo-Asians, and this relationship may be enhanced in individuals with low baseline SBP. Further research is needed to assess the clinical applicability of these findings.


Role of gefitinib in patients with recurrent or metastatic cervical carcinoma ineligible or refractory to systemic chemotherapy: first study from Asia.
There are limited options for patients with recurrent or metastatic cervical carcinoma who are either refractory to or ineligible for systemic chemotherapy. We conducted a clinical study to evaluate the role of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in such patients. Eligible patients were enrolled into the study and were treated with gefitinib at a dose of 250 mg/day orally until disease progression, development of intolerable adverse effects, or withdrawal of consent. The primary end point of the study was progression-free survival. The secondary end points were stable disease, overall survival, and toxicity. From January 2008 to June 2011, a total of 20 patients were enrolled. Median age was 52 years and median disease-free interval was 15 months. Twelve patients presented with locoregional recurrence, 2 patients presented with distant metastases, and 6 patients presented with both locoregional recurrence and distant metastasis. Median duration of gefitinib therapy was 4 months. One patient had complete response, 1 patient had partial response, 4 patients had stable disease, and 14 patients had progressive disease. The median progression-free survival and overall survival were 4 months and 5 months, respectively. Only 1 patient had severe drug-related toxicity. Gefitinib is safe and seems to be effective in recurrent or metastatic cervical carcinoma. Further studies are warranted to identify the subgroup of patients, based on epidermal growth factor receptor mutations, who are more likely to benefit.


Thrombosis, physical activity, and acute coronary syndromes.
Acute coronary syndromes (ACS) are common, life-threatening cardiac disorders that typically are triggered by rupture or erosion of an atherosclerotic plaque. Platelet deposition and activation of the blood coagulation cascade in response to plaque disruption lead to the formation of a platelet-fibrin thrombus, which can grow rapidly, obstruct coronary blood flow, and cause myocardial ischemia and/or infarction. Several clinical studies have examined the relationship between physical activity and ACS, and numerous preclinical and clinical studies have examined specific effects of sustained physical training and acute physical activity on atherosclerotic plaque rupture, platelet function, and formation and clearance of intravascular fibrin. This article reviews the available literature regarding the role of physical activity in determining the incidence of atherosclerotic plaque rupture and the pace and extent of thrombus formation after plaque rupture.


Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases?
To compare a restrictive red blood cell transfusion strategy with a more liberal strategy in volume-resuscitated critically ill patients with cardiovascular disease. Twenty-two academic and three community critical care units across Canada. Randomized controlled clinical trial. Three hundred fifty-seven critically ill patients with cardiovascular diseases from the Transfusion Requirements in Critical Care trial who had a hemoglobin concentration of <90 g/L within 72 hrs of admission to the intensive care unit. Patients were randomized to a restrictive strategy to receive allogeneic red blood cell transfusions at a hemoglobin concentration of 70 g/L (and maintained between 70 and 90 g/L) or a liberal strategy to receive red blood cells at 100 g/L (and maintained between 100 and 120 g/L). Baseline characteristics in the restrictive (n = 160) and the liberal group (n = 197) were comparable, except for the use of cardiac and anesthetic drugs (p <.02). Average hemoglobin concentrations (85 +/- 6.2 vs. 103 +/- 6.7 g/L; p <.01) and red blood cell units transfused (2.4 +/- 4.1 vs. 5.2 +/- 5.0 red blood cell units; p <.01) were significantly lower in the restrictive compared with the liberal group. Overall, all mortality rates were similar in both study groups, including 30-day (23% vs. 23%; p = 1.00), 60-day, hospital, and intensive care unit rates. Changes in multiple organ dysfunction from baseline scores were significantly less in the restrictive transfusion group overall (0.2 +/- 4.2 vs. 1.3 +/- 4.4; p =.02). In the 257 patients with severe ischemic heart disease, there were no statistically significant differences in all survival measures, but this is the only subgroup where the restrictive group had lower but nonsignificant absolute survival rates compared with the patients in the liberal group. A restrictive red blood cell transfusion strategy generally appears to be safe in most critically ill patients with cardiovascular disease, with the possible exception of patients with acute myocardial infarcts and unstable angina.


Bullying Victimization and Associations With Substance Use Among US Middle School Students: 2019 Youth Risk Behavior Survey.
Research shows associations between bullying victimization and substance use for teens. However, more research about this relationship for younger adolescents and across race/ethnicity is needed. Prevalence and pooled logistic regression analyses of 2019 Middle School Youth Risk Behavior Survey data from 13 states (N = 74,059 students) examined associations between self-reported bulling victimization (at school, electronically, and both) and having ever tried cigarette smoking, alcohol, or marijuana; used an electronic vapor product; or misused prescription pain medicine. Regression analyses were adjusted by age and sex/race/ethnicity. All 3 measures of bullying victimization were significantly associated (p < .05) with the 5 substance use behaviors examined (adjusted prevalence ratios ranged from 1.29 to 2.32). These associations held across sexes. Significant associations were found within all 7 race/ethnicity categories, with the most associations reported for the non-Hispanic (NH) white, NH black or African American, Hispanic/Latino, and NH Asian groups. The association between bullying and substance use by middle school is a highly relevant issue to consider as students return to classrooms.


[Psychiatric emergencies and family crisis. A possible systemic approach at a general hospital].
Psychiatric emergencies concern not only sectorized psychiatric organizations but general hospitals as well, especially in large cities. No set-ups for long-term management are available in general hospitals and means for short-term intermittent action should be evolved. Family crisis may be responsible for psychiatric emergencies as they may lead to decompensation due to the breaking-up of familial relationships. When confronted with such situations, practitioners must of course face the emergency by using various specific chemotherapeutic agents or by hospitalizing the patient. However, practitioners should also concern themselves with acting upon the whole family in order to help them to develop solutions to the crisis. The modalities of this global approach of psychiatric disorders are delineated in the family crisis therapeutic technique.


Interleukin (IL)-12-driven primary hypothyroidism: the contrasting roles of two Th1 cytokines (IL-12 and interferon-gamma).
IL-12, a prototypic T helper 1 cytokine, has been implicated in the pathogenesis of organ-specific autoimmune diseases, such as Hashimoto's thyroiditis, but reported to give conflicting results in murine models of lymphocytic thyroiditis. To determine the effects of chronic, local production of IL-12 within the thyroid gland, we created transgenic mice that express IL-12 p70 under the transcriptional control of the thyroglobulin promoter. Transgenics developed growth retardation, moderate primary hypothyroidism, and mild lymphocytic infiltration of the thyroid gland. The hypothyroidism was associated with increased mRNA levels of the sodium-iodide symporter, an increase partly due to a direct effect of IL-12 on the thyrocyte. Upon immunization with a suboptimal dose of mouse thyroglobulin, IL-12 transgenic mice developed a lymphocytic thyroiditis that was more frequent and severe than that observed in wild-type littermates. The disease-promoting effect of IL-12 was independent of interferon-gamma, as shown by the similar interferon-gamma levels in transgenics and controls. These findings highlight the contrasting roles of two T helper 1 cytokines and report a novel role of IL-12 on thyroid hormonogenesis.


Vitamin C reduces the severity of common colds: a meta-analysis.
Randomized trials have shown that vitamin C shortens the duration of common colds. Some trials reported greater effects on severe cold symptoms compared with mild symptoms. This review systematically compares the effects of vitamin C on severe and mild common cold symptoms. We included all placebo-controlled trials of orally administered vitamin C in doses of at least 1 g/day for the common cold for people in good health at baseline. The analysis was restricted to trials which reported both the total duration of the common cold, and the severity of the common cold measured using severity scales, the duration of more severe stages of the cold, or proxies for severe colds such as days indoors. Findings were pooled using the inverse variance, fixed effect options of the metacont function of the R package meta to calculate the ratio of means estimate. Fifteen comparisons from 10 trials which reported both mild and severe symptoms were identified. All trials were randomized and double-blind. Compared to placebo, vitamin C significantly decreased the severity of the common cold by 15% (95% CI 9-21%). The direct comparison of the effect of vitamin C on mild and severe symptoms was limited to five comparisons which found that vitamin C had a significant benefit on the duration of severe symptoms. In this subset, there was a significant difference in the size of the effect of vitamin C on the overall duration of colds versus the duration of severe colds (P = 0.002), and vitamin C had no significant effect on the duration of mild symptoms. The common cold is the leading cause of acute morbidity and a major cause of absenteeism from work and school. However, absenteeism is dependent on the severity of symptoms. The finding that vitamin C may have a greater effect on more severe measures of the common cold is therefore important. Further research on the therapeutic effects of vitamin C on the common cold should measure outcomes of differing levels of severity.


Reduced hippocampal field potentials during administration of fluoropyrimidines in vitro.
Toxic effects on the central nervous system have been reported in patients treated with fluoropyrimidines for cancer. In the present study we have investigated the earliest effects of these drugs at the cellular level using slices of hippocampal cortex maintained in vitro. Doxyfluridine (5'-dFUrd; 50 mg/l and 500 mg/l) caused a dose dependent, reversible depression of neuronal activity. The main effect was on the pyramidal cells (population spike reduced by 14 and 25% respectively) and the afferent unmyelinated fibres (afferent fibre volley reduced by 7 and 12% respectively). Excitatory synaptic transmission was affected only by the highest concentration (field-EPSP reduced by 10%). 5-FU caused similar but less marked changes. The drugs did not cause epileptiform activity.


Hapten Synthesis, Antibody Development, and a Highly Sensitive Indirect Competitive Chemiluminescent Enzyme Immunoassay for Detection of Dicamba.
Although dicamba has long been one of the most widely used selective herbicides, some U.S. states have banned the sale and use of dicamba because of farmers complaints of drift and damage to nonresistant crops. To prevent illegal use of dicamba and allow monitoring of nonresistant crops, a rapid and sensitive method for detection of dicamba is critical. In this paper, three novel dicamba haptens with an aldehyde group were synthesized, conjugated to the carrier protein via a reductive-amination procedure and an indirect competitive chemiluminescent enzyme immunoassay (CLEIA) for dicamba was developed. The assay showed an IC50 of 0.874 ng/mL which was over 15 times lower than that of the conventional enzyme immunoassay. The immunoassay was used to quantify dicamba concentrations in field samples of soil and soybean obtained from fields sprayed with dicamba. The developed CLEIA showed an excellent correlation with LC-MS analysis in spike-and-recovery studies, as well as in real samples. The recovery of dicamba ranged from 86 to 108% in plant samples and from 105 to 107% in soil samples. Thus, this assay is a rapid and simple analytical tool for detecting and quantifying dicamba levels in environmental samples and potentially a great tool for on-site crop and field monitoring.


Human platelet surface binding of endogenous secreted factor VIII-von Willebrand factor and platelet factor 4.
Washed human platelets in buffers containing either 2 mM Ca++ or 4 mM EDTA were stimulated by human alpha-thrombin to induce secretion. The binding of two endogenous secreted proteins, factor-VIII-related protein (VIII-R) (von Willebrand factor) and platelet factor 4, was measured by reacting thrombin-treated and control platelets with specific antibodies to these proteins, then quantifying antibody binding with 125I-staphylococcal protein A. Both of these granule proteins were associated with the platelet membrane surface by a calcium-dependent mechanism after thrombin-induced secretion. This ability to bind endogenous secreted proteins to the plasma membrane surface may provide a mechanism by which the platelet can concentrate and organize its secreted proteins for subsequent physiologic reactions.


Haemostatic changes during dialysis associated with thrombus formation on dialysis membranes.
Platelet counts, coagulation factors, and the fibrinolytic system were studied in seven regular dialysis patients during the course of haemodialysis by parallel flow (Gambro-Alwall) and coil (Travenol Ultra-Flo 100) dialysers. Significant falls in the patients' platelet counts and rises in their factor V levels were found with both dialysis systems. The changes were more pronounced over the course of a Gambro-Alwall dialysis, when significant falls in the partial thromboplastin clotting time and in the plasminogen levels were also noted. These haemostatic changes were associated with the retention of platelets on the dialysis membranes and, in the case of the Gambro-Alwall dialyser, with the formation of platelet-fibrin thrombus. This thrombus formation may take place in spite of efficient heparin anticoagulation and may cause excessive blood loss to the regular dialysis patient.


Predictors of Quality of Life in Young Adults Diagnosed With Cancer.
A cross-section correlational study was conducted to evaluate the overall quality of life in young adults (AYAs) diagnosed with cancer, and the impact of health-related and non-health-related factors on their quality of life. Fifty-six AYA cancer survivors were recruited to elicit the impact of biological function (cancer type and comorbidity), symptoms, functional status, general perception of health status, gender, and characteristics of the environment on quality of life. Participants experienced higher than average quality of life. Symptoms, functional status, and general perception of health status were significant predictors of quality of life in this group of AYAs diagnosed with cancer. In delivering quality cancer care, nurses must be able to thoroughly assess symptom status, AYA cancer survivors' perception of their health status, and functioning in order to implement supportive measures to help improve their quality of life.


Investigations on X-ray luminescence CT for small animal imaging.
X-ray Luminescence CT (XLCT) is a hybrid imaging modality combining x-ray and optical imaging in which x-ray luminescent nanophosphors (NPs) are used as emissive imaging probes. NPs are easily excited using common CT energy x-ray beams, and the NP luminescence is efficiently collected using sensitive light based detection systems. XLCT can be recognized as a close analog to fluorescence diffuse optical tomography (FDOT). However, XLCT has remarkable advantages over FDOT due to the substantial excitation penetration depths provided by x-rays relative to laser light sources, long term photo-stability of NPs, and the ability to tune NP emission within the NIR spectral window. Since XCLT uses an x-ray pencil beam excitation, the emitted light can be measured and back-projected along the x-ray path during reconstruction, where the size of the X-ray pencil beam determines the resolution for XLCT. In addition, no background signal competes with NP luminescence (i.e., no auto fluorescence) in XLCT. Currently, no small animal XLCT system has been proposed or tested. This paper investigates an XLCT system built and integrated with a dual source micro-CT system. Two novel sampling paradigms that result in more efficient scanning are proposed and tested via simulations. Our preliminary experimental results in phantoms indicate that a basic CT-like reconstruction is able to recover a map of the NP locations and differences in NP concentrations. With the proposed dual source system and faster scanning approaches, XLCT has the potential to revolutionize molecular imaging in preclinical studies.


Familial intelligence as an estimate of expected ability in children.
Estimation of premorbid or expected IQ in children from IQs of family members was evaluated for precision, sensitivity, and diagnostic efficiency. Prediction of a child's IQ from familial ability has limited precision, and the sizable discrepancies from familial IQ estimates required for statistical significance reduce their sensitivity. In a Monte Carlo simulation, familial IQ discrepancies had stronger positive than negative predictive power for distinguishing severely head-injured from normal children, with acceptable predictive power being obtained over a limited range of circumstances. Thus, while a significant discrepancy may be meaningful, the absence of one is often inconclusive. Familial IQ discrepancies should be used very cautiously, if at all, and are not substantially more accurate than discrepancies from demographic IQ estimates.


Evidence for the lack of base-change and small-deletion mutation induction by trichloroethylene in lacZ transgenic mice.
Trichloroethylene (TCE) is a widely used industrial solvent employed mainly for degreasing and cold-cleaning metal parts. It is also used for dry cleaning, and in the production of a number of chemical products. It has been shown to induce liver and lung tumors in rodents, and have a variety of positive and negative results using in vitro and in vivo mutagenicity tests. In order to assist in the interpretation of the mechanism of carcinogenicity, TCE was tested for the ability to induce gene mutations and small deletions using the lacZ transgenic mouse model (MutaMouse). Male and female animals were exposed by inhalation to 0, 203, 1153, and 3141 ppm TCE, 6 h per day for 12 days. 14 and 60 days following the last exposure, animals were sacrificed and the mutation frequency in bone marrow, kidney, spleen, liver, lung, and testicular germ cells determined. The results of this study indicate that TCE did not induce base-change or small-deletion mutations as detected in this assay in any of the tissues examined. Environ. Mol. Mutagen. 34: 190-194, 1999. Published 1999 Wiley-Liss, Inc.


Host translation machinery is not a barrier to phages that interact with both CPR and non-CPR bacteria.
Here, we profiled putative phages of Saccharibacteria, which are of particular importance as Saccharibacteria influence some human oral diseases. We additionally profiled putative phages of Gracilibacteria and Absconditabacteria, two Candidate Phyla Radiation (CPR) lineages of interest given their use of an alternative genetic code. Among the phages identified in this study, some are targeted by spacers from both CPR and non-CPR bacteria and others by both bacteria that use the standard genetic code as well as bacteria that use an alternative genetic code. These findings represent new insights into possible phage replication strategies and have relevance for phage therapies that seek to manipulate microbiomes containing CPR bacteria.


Support vector machine-based prediction of local tumor control after stereotactic body radiation therapy for early-stage non-small cell lung cancer.
Several prognostic factors for local tumor control probability (TCP) after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) have been described, but no attempts have been undertaken to explore whether a nonlinear combination of potential factors might synergistically improve the prediction of local control. We investigated a support vector machine (SVM) for predicting TCP in a cohort of 399 patients treated at 13 German and Austrian institutions. Among 7 potential input features for the SVM we selected those most important on the basis of forward feature selection, thereby evaluating classifier performance by using 10-fold cross-validation and computing the area under the ROC curve (AUC). The final SVM classifier was built by repeating the feature selection 10 times with different splitting of the data for cross-validation and finally choosing only those features that were selected at least 5 out of 10 times. It was compared with a multivariate logistic model that was built by forward feature selection. Local failure occurred in 12% of patients. Biologically effective dose (BED) at the isocenter (BED(ISO)) was the strongest predictor of TCP in the logistic model and also the most frequently selected input feature for the SVM. A bivariate logistic function of BED(ISO) and the pulmonary function indicator forced expiratory volume in 1 second (FEV1) yielded the best description of the data but resulted in a significantly smaller AUC than the final SVM classifier with the input features BED(ISO), age, baseline Karnofsky index, and FEV1 (0.696 ± 0.040 vs 0.789 ± 0.001, P<.03). The final SVM resulted in sensitivity and specificity of 67.0% ± 0.5% and 78.7% ± 0.3%, respectively. These results confirm that machine learning techniques like SVMs can be successfully applied to predict treatment outcome after SBRT. Improvements over traditional TCP modeling are expected through a nonlinear combination of multiple features, eventually helping in the task of personalized treatment planning.


Altered Na,K-ATPase pattern in gamma-crystallin mutant mice.
Na,K-adenosine triphosphatase (ATPase) activity is elevated in the lenses of murine cataract Cryge(t) and Cryge(ns) mutant mice. In the present study, the expression of Na,K-ATPase alpha1, alpha2, and alpha3 catalytic subunit polypeptides was examined in the lenses of these mutant mice. Membrane material was isolated from lenses and brain of 3-week-old wild-type mice, as well as heterozygous and homozygous mutant mice. Microsomal membranes were prepared by centrifugation of the homogenized material, and Na,K-ATPase polypeptides were detected by immunoblot analysis with antibodies directed against the Na,K-ATPase isoforms alpha1, alpha2, and alpha3. For the Na,K-ATPase isoforms alpha2 and alpha3, membrane material obtained from the homozygous cataract mutants showed dense immunoblot bands that were not detected in material obtained from wild-type mice. An apparent increase of the alpha1 Na,K-ATPase isoform band density was also detected in lens material from the homozygous mutant mice. The Na,K-ATPase alpha3 polypeptide was also detected in lens membrane material obtained from heterozygous mice of both mutant strains. The alpha2 Na,K-ATPase polypeptide was observed in lens membrane material obtained from heterozygous Cryge(t) mice, and a less dense band was detected in heterozygous Cryge(ns) mice. Band densities of Na,K-ATPase subunits alpha1, alpha2, and alpha3 detected in brain membrane material were similar in both mutant and wild-type mice. The immunoblot results suggest that the abundance of Na,K-ATPase polypeptide is increased in the lens of the cataract mouse mutant but is not altered in the brain. The expression of the alpha2 and alpha3 isoform proteins of Na,K-ATPase is markedly upregulated in the cataractous lens.


Influence of dietary protein and lipid on weight loss in obese ovariohysterectomized cats.
To determine effects of dietary lipid and protein on development of hepatic lipidosis (HL) and on physical and biochemical indices following rapid weight loss in cats. 24 ovariohysterectomized cats. Cats were fed a high energy diet until they gained 30% of their ideal body weight and then randomly assigned to receive 1 of 4 weight-reduction diets (6 cats/diet) at 25% of maintenance energy requirements per day. Diets contained a low or high quality protein source and a lipid source deficient or sufficient in long chain essential fatty acids (LCEFA). Serum and plasma samples and liver biopsy specimens were obtained for biochemical analyses and determination of hepatic lipid content before and after weight gain and during and after weight loss. Irrespective of weight-reduction diet fed, all cats lost weight at a comparable rate (4.51 to 5.00 g/d/kg of obese body weight). Three cats developed hepatic lipidosis. Significant changes in plasma insulin, cholesterol, triglyceride, and serum glucose concentrations were detected after weight gain and weight loss in all diet groups, but values for these variables did not differ among groups. Cats can lose 25 to 30% of their obese body weight over 7 to 9 weeks without developing overt clinical signs of HL, provided that weight-reduction diets are highly palatable, contain a high quality protein, have a source of LCEFA, and are fortified with vitamins and microminerals. However, rapid weight loss may increase risk factors associated with development of diabetes mellitus.


The influence of alloxan-induced diabetes on Müller cell contraction-promoting activities in vitreous.
Previous studies from this laboratory revealed that vitreous insulin-like growth factor biological activity increases in diabetes and that this change can precede the onset of proliferative diabetic retinopathy. The goal of this study was to characterize this phenomenon in an animal model of alloxan-induced diabetes. Swine made diabetic with intravenous alloxan were euthanized at times varying from 0 to 90 days. Vitreous samples from normal and diabetic swine were evaluated for changes in Müller cell contraction-promoting activity, the presence of insulin-like growth factor binding protein (IGFBP), and carbonic anhydrase-I and -II. Ocular tissues from these animals were also evaluated for changes in contraction-promoting growth factors and IGFBP message levels. Alloxan-induced diabetes is associated with significant increases in vitreous Müller cell contraction-promoting activity that are present in as few as 30 days and are sustained for at least 90 days. Biochemical studies revealed that the increases cannot be attributed to loss of growth factor-attenuating IGFBPs, changes in local expression of contraction-promoting growth factors, or vitreous hemorrhage. The previously reported increases in Müller cell contraction-promoting activity detected in human diabetic vitreous are present in diabetic swine within 30 days of chemical induction. The increase does not appear to be attributable to loss of growth factor control, increases in local growth factor expression, or vitreous hemorrhage, suggesting that other mechanisms are involved. It is the authors' speculation that diabetes induces blood-vitreous barrier changes that allow a different subset of plasma proteins to enter vitreous fluids.


Association between albumin infusion and outcomes in patients with acute kidney injury and septic shock.
Septic shock with acute kidney injury (AKI) is common in critically ill patients. Our aim was to evaluate the association between albumin infusion and outcomes in patients with septic shock and AKI. Medical Information Mart for Intensive Care (MIMIC)-III was used to identify patients with septic shock and AKI. Propensity score matching (PSM) was employed to balance the baseline differences. Cox proportional hazards model, Wilcoxon rank-sum test, and logistic regression were utilized to determine the associations of albumin infusion with mortality, length of stay, and recovery of kidney function, respectively. A total of 2861 septic shock patients with AKI were studied, including 891 with albumin infusion, and 1970 without albumin infusion. After PSM, 749 pairs of patients were matched. Albumin infusion was associated with improved 28-day survival (HR 0.72; 95% CI 0.59-0.86; P = 0.002), but it was not difference in 90-day mortality between groups (HR 0.94; 95% CI 0.79-1.12; P = 0.474). Albumin infusion was not associated with the renal function recovery (HR 0.91; 95% CI 0.73-1.13; P = 0.393) in either population. Nevertheless, subgroup analysis showed that albumin infusion was distinctly associated with reduced 28-day mortality in patients with age > 60 years. The results need to be validated in more randomized controlled trials.


Effects of pectic polysaccharides isolated from leek on the production of reactive oxygen and nitrogen species by phagocytes.
The current survey investigates the effect of four polysaccharides isolated from fresh leek or alcohol insoluble substances (AIS) of leek on the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) from phagocytes. The ability of the polysaccharides to activate serum complement was also investigated. Despite the lack of antioxidant activity, the pectic polysaccharides significantly decreased the production of ROS by human neutrophils. Polysaccharides isolated from AIS markedly activated RAW 264.7 macrophages for RNS production in a concentration-dependent manner. The Western blot analysis revealed that this effect was due to the stimulation of the inducible nitric oxide synthase protein expression of macrophages. The polysaccharides extracted from AIS with water showed the ability to fix serum complement, especially through the alternative pathway. It was found that the polysaccharide that has the highest complement-fixing effect is characterized by the highest content of uronic acids and the highest molecular weight.


Factors facilitating a national quality registry to aid clinical quality improvement: findings of a national survey.
While national quality registries (NQRs) are suggested to provide opportunities for systematic follow-up and learning opportunities, and thus clinical improvements, features in registries and contexts triggering such processes are not fully known. This study focuses on one of the world's largest stroke registries, the Swedish NQR Riksstroke, investigating what aspects of the registry and healthcare organisations facilitate or hinder the use of registry data in clinical quality improvement. Following particular qualitative studies, we performed a quantitative survey in an exploratory sequential design. The survey, including 50 items on context, processes and the registry, was sent to managers, physicians and nurses engaged in Riksstroke in all 72 Swedish stroke units. Altogether, 242 individuals were presented with the survey; 163 responded, representing all but two units. Data were analysed descriptively and through multiple linear regression. A majority (88%) considered Riksstroke data to facilitate detection of stroke care improvement needs and acknowledged that their data motivated quality improvements (78%). The use of Riksstroke for quality improvement initiatives was associated (R2=0.76) with 'Colleagues' call for local results' (p=<0.001), 'Management Request of Registry data' (p=<0.001), and it was said to be 'Simple to explain the results to colleagues' (p=0.02). Using stepwise regression, 'Colleagues' call for local results' was identified as the most influential factor. Yet, while 73% reported that managers request registry data, only 39% reported that their colleagues call for the unit's Riksstroke results. While an NQR like Riksstroke demonstrates improvement needs and motivates stakeholders to make progress, local stroke care staff and managers need to engage to keep the momentum going in terms of applying registry data when planning, performing and evaluating quality initiatives.


Hacking the host: exploitation of macrophage polarization by intracellular bacterial pathogens.
Macrophages play an integral role in host defenses against intracellular bacterial pathogens. A remarkable plasticity allows for adaptation to the needs of the host to orchestrate versatile innate immune responses to a variety of microbial threats. Several bacterial pathogens have adapted to macrophage plasticity and modulate the classical (M1) or alternative (M2) activation bias towards a polarization state that increases fitness for intracellular survival. Here, we summarize the current understanding of the host macrophage and intracellular bacterial interface; highlighting the roles of M1/M2 polarization in host defense and the mechanisms employed by several important intracellular pathogens to modulate macrophage polarization to favor persistence or proliferation. Understanding macrophage polarization in the context of disease caused by different bacterial pathogens is important for the identification of targets for therapeutic intervention.


Evolutionary and dispersal history of Eurasian house mice Mus musculus clarified by more extensive geographic sampling of mitochondrial DNA.
We examined the sequence variation of mitochondrial DNA control region and cytochrome b gene of the house mouse (Mus musculus sensu lato) drawn from ca. 200 localities, with 286 new samples drawn primarily from previously unsampled portions of their Eurasian distribution and with the objective of further clarifying evolutionary episodes of this species before and after the onset of human-mediated long-distance dispersals. Phylogenetic analysis of the expanded data detected five equally distinct clades, with geographic ranges of northern Eurasia (musculus, MUS), India and Southeast Asia (castaneus, CAS), Nepal (unspecified, NEP), western Europe (domesticus, DOM) and Yemen (gentilulus). Our results confirm previous suggestions of Southwestern Asia as the likely place of origin of M. musculus and the region of Iran, Afghanistan, Pakistan, and northern India, specifically as the ancestral homeland of CAS. The divergence of the subspecies lineages and of internal sublineage differentiation within CAS were estimated to be 0.37-0.47 and 0.14-0.23 million years ago (mya), respectively, assuming a split of M. musculus and Mus spretus at 1.7 mya. Of the four CAS sublineages detected, only one extends to eastern parts of India, Southeast Asia, Indonesia, Philippines, South China, Northeast China, Primorye, Sakhalin and Japan, implying a dramatic range expansion of CAS out of its homeland during an evolutionary short time, perhaps associated with the spread of agricultural practices. Multiple and non-coincident eastward dispersal events of MUS sublineages to distant geographic areas, such as northern China, Russia and Korea, are inferred, with the possibility of several different routes.


An update on noninvasive follicular thyroid neoplasm with papillary-like nuclear features.
Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) has been established in the literature as a clinically indolent tumor. Despite this, it was traditionally treated like all other PTCs. In an attempt to reduce overtreatment of this entity, a panel of experts reclassified this entity as noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP). This reclassification has led to a flurry of literature elucidating the molecular, cytologic and clinical parameters of this 'new' entity and the implications for patient management. The purpose of this review is to examine the latest literature on this tumor and explore how its emergence has impacted our current understanding of the diagnosis, management and outcomes in this entity. NIFTP is a low grade tumor with an indolent clinical course. Recent studies have begun to document the variable incidence of NIFTP, the ultrasound and cytologic findings, and the impact of the NIFTP terminology on established rates of malignancy in fine-needle aspiration and clinical outcome studies. The recent literature on molecular, radiographic and cytologic characteristics of NIFTP are building our understanding of this neoplasm and support its indolent nature.


The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial.
Itolizumab is a humanized anti-CD6 monoclonal antibody (mAb) that has previously shown encouraging results, in terms of safety and positive clinical effects, in a 6-week monotherapy clinical trial conducted in rheumatoid arthritis (RA) patients. The current Phase I study evaluated the safety and clinical response for a longer treatment of 12 itolizumab intravenous doses in subjects with active RA despite previous disease-modifying anti-rheumatic drug (DMARD) therapy. Twenty-one subjects were enrolled into four dosage groups (0·1, 0·2, 0·4 and 0·8 mg/kg). Efficacy end-points including American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates and disease activity score in 28 joints (DAS28) were monitored at baseline and at specific time-points during a 10-week follow-up period. Itolizumab was well tolerated up to the highest tested dose. No related serious adverse events were reported and most adverse events were mild. Remarkably, itolizumab treatment did not produce lymphopenia and, therefore, was not associated with infections. All patients achieved a clinical response (ACR20) at least once during the study. Eleven subjects (55%) achieved at least a 20% improvement in ACR just 1 week after the first itolizumab administration. The clinical response was observed from the beginning of the treatment and was sustained during 24 weeks. The efficacy profile of this 12-week treatment was similar to that of the previous study (6-week treatment). These results reinforce the safety profile of itolizumab and provide further evidence on the clinical benefit from the use of this anti-CD6 mAb in RA patients.


Incidence and characterization of acute pulmonary embolism in patients with SARS-CoV-2 pneumonia: A multicenter Italian experience.
Several studies reported a high incidence of pulmonary embolism (PE) among patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, but detailed data about clinical characteristics, risk factors of these patients and prognostic role of PE are still lacking. We aim to evaluate the occurrence of pulmonary embolism among patients with SARS-CoV-2 infection, and to describe their risk factors, clinical characteristics, and in-hospital clinical outcomes. This is a multicenter Italian study including 333 consecutive SARS-CoV-2 patients admitted to seven hospitals from February 22 to May 15, 2020. All the patients underwent computed tomography pulmonary angiography (CTPA) for PE detection. In particular, CTPA was performed in case of inadequate response to high-flow oxygen therapy (Fi02≥0.4 to maintain Sp02≥92%), elevated D-dimer (>0.5μg/mL), or echocardiographic signs of right ventricular dysfunction. Clinical, laboratory and radiological data were also analyzed. Among 333 patients with laboratory confirmed SARS-CoV-2 pneumonia and undergoing CTPA, PE was detected in 109 (33%) cases. At CTPA, subsegmental, segmental, lobar and central thrombi were detected in 31 (29%), 50 (46%), 20 (18%) and 8 (7%) cases, respectively. In-hospital death occurred in 29 (27%) patients in the PE-group and in 47 (21%) patients in the non-PE group (p = 0.25). Patients in PE-group had a low rate of traditional risk factors and deep vein thrombosis was detected in 29% of patients undergoing compression ultrasonography. In 71% of cases with documented PE, the thrombotic lesions were located in the correspondence of parenchymal consolidation areas. Despite a low rate of risk factors for venous thromboembolism, PE is present in about 1 out 3 patients with SARS-CoV-2 pneumonia undergoing CTPA for inadequate response to oxygen therapy, elevated D-dimer level, or echocardiographic signs of right ventricular dysfunction. In most of the cases, the thromboses were located distally in the pulmonary tree and were mainly confined within pneumonia areas.


A pilot study adapting and validating the Harvard Trauma Questionnaire (HTQ) and PTSD checklist-5 (PCL-5) with Indian women from slums reporting gender-based violence.
Despite high rates of gender-based violence (GBV) in India, culturally sensitive measures that examine universal and culturally relevant trauma reactions are lacking. Although the Harvard Trauma Questionnaire (HTQ) has been used in India, no study has adapted the measure in full for use with this population. Similarly, the PTSD checklist-5 (PCL-5) has not yet been validated in India. This study describes the adaptation, validation, and results from the adapted HTQ, and embedded PCL-5, for Indian women from slums reporting GBV. This study used the adaptation framework proposed by the HTQ measure developers. The adapted HTQ contained a (1) trauma screen relevant for stressors faced by Indian women from slums, (2) description of the index trauma, (3) description of any ongoing stressors, (4) universal trauma reactions (i.e., PTSD measured by the PCL-5), and culturally relevant trauma reactions (i.e., idioms of distress measured by a scale developed for the study). This measure was piloted on 111 women from Indian slums in face-to-face interviews. Trauma characteristics, types of ongoing stressors, and psychometric properties of the PCL-5 and idioms of distress scale were explored. These scales were validated against measures of depression (PHQ-9), anxiety (GAD-7), and somatic complaints (PHQ-15). The majority of participants (77%) reported physical beatings, 18% reported unwanted sexual touch, and 28.8% reported infidelity as the primary emotional abuse. Further, 96.7% of GBV was perpetrated by partner or family member and over half reported ongoing stressors (e.g., poverty-related strain). The PCL-5 embedded in the HTQ yielded good internal consistency (Cronbach's alpha = .88) as did the idioms of distress scale with deletion of one item (Cronbach's alpha = .80). Both scales were externally valid, yielding large correlations with depression, anxiety, and somatic complaints (rs between .54 and .80, ps < .05). This is the first study to develop a comprehensive measure of trauma exposure with universal and culturally relevant trauma reactions in India. This study also enhances HTQ usage in India by delineating all the steps in the adaptation process. Results can inform the development of trauma-focused interventions for Indian women from slums.


IMMUNOLOGIC RELATION OF STREPTOCOCCAL AND TISSUE ANTIGENS. II. CROSS-REACTION OF ANTISERA TO MAMMALIAN HEART TISSUE WITH A CELL WALL CONSTITUENT OF CERTAIN STRAINS OF GROUP A STREPTOCOCCI.
Further evidence of a cross-reactive relationship between a cell wall antigen of certain Group A streptococcal strains and mammalian heart tissue is provided by the demonstration that goat antisera to washed human or rabbit heart tissue homogenates exhibit precipitation with cell wall extract preparations. A single line of precipitation was observed in agar gel diffusion tests. Precipitating activity of goat antiheart sera was related to the gamma-globulin fraction in zone electrophoresis. The cell wall antigen was demonstrated in cell wall extracts of a Type 5 and Type 19 but not of a Type 12 strain. Antigenic activity was concentrated in the same neutral salt and chromatographic fractions of acid extracts of cell wall previously reported to exhibit this activity by immunofluorescent inhibition of the cross-reaction of antistreptococcal serum with heart tissue.


Impact of Fatty-Acid Labeling of Bacillus subtilis Membranes on the Cellular Lipidome and Proteome.
Developing cultivation methods that yield chemically and isotopically defined fatty acid (FA) compositions within bacterial cytoplasmic membranes establishes an in vivo experimental platform to study membrane biophysics and cell membrane regulation using novel approaches. Yet before fully realizing the potential of this method, it is prudent to understand the systemic changes in cells induced by the labeling procedure itself. In this work, analysis of cellular membrane compositions was paired with proteomics to assess how the proteome changes in response to the directed incorporation of exogenous FAs into the membrane of Bacillus subtilis. Key findings from this analysis include an alteration in lipid headgroup distribution, with an increase in phosphatidylglycerol lipids and decrease in phosphatidylethanolamine lipids, possibly providing a fluidizing effect on the cell membrane in response to the induced change in membrane composition. Changes in the abundance of enzymes involved in FA biosynthesis and degradation are observed; along with changes in abundance of cell wall enzymes and isoprenoid lipid production. The observed changes may influence membrane organization, and indeed the well-known lipid raft-associated protein flotillin was found to be substantially down-regulated in the labeled cells - as was the actin-like protein MreB. Taken as a whole, this study provides a greater depth of understanding for this important cell membrane experimental platform and presents a number of new connections to be explored in regard to modulating cell membrane FA composition and its effects on lipid headgroup and raft/cytoskeletal associated proteins.


A survey of surgical management of the sentinel node positive melanoma patient in the post-MSLT2 era.
The evidence-based management of melanoma patients with a positive sentinel lymph node biopsy (SLNB) has undergone a dramatic shift following publication of practice-changing surgical trials demonstrating no melanoma-specific survival advantage for completion lymph node dissection (CLND) in this scenario. We aimed to survey how surgeons' clinical practice had shifted in response to new evidence from these trials, and at a time when there was starting to become available systemic adjuvant treatments for AJCC Stage III melanoma patients. A web-based survey consisting of practice-based questions and hypothetical clinical scenarios about current melanoma practice with regard to positive sentinel node biopsy was developed and sent to the surgical members of a Melanoma and Skin Cancer (MASC) Trials group in December 2018. Responses were analysed using descriptive statistics. There were 212 invitations sent and 65 respondents (31%). Respondents were from 17 countries, 94% of whom practice in specialist melanoma centres or at referral centres. Of these 97% were familiar with the MSLT2 and DeCOG-SLT clinical trials. At survey, 5% of respondents reported routinely recommending CLND and 55% recommend CLND in selected cases. Respondents were most likely to recommend CLND when multiple SLNs were positive. Important factors for surgical decision-making mentioned included size of SLN deposit, number of positive SLNs and likely compliance with the recommended surveillance regimen. In line with rapid adoption of published evidence, surgical management of Stage III melanoma has altered significantly, with few surgeons within the cohort now performing routine CLNDs after positive SLNB.


PCR-based methods in detection and identification of dermatophytes in dogs and cats with suspected dermatophytosis in 2021 in Poland.
Dermatophytes from Microsporum, Trichophyton and Epidermophyton genera are divided into geophilic, zoophilic and anthropophilic species which cause skin infection in humans and wide group of animals, mainly mammals. Main species causing dermatophytosis in dogs and cats are Microsporum and Trichophyton. Conventional mycological diagnostic technique includes Saburaud Dextrose Agar (SAD) and others medium cultures, 10% KOH mount and direct microscopy of hairs and scraping. Molecular diagnostic become more frequent in veterinary practice due to shortening of waiting time. In this study we based on two PCR methods. The nested PCR amplified CHS1 gene for dermatophytes detection, and multiplex PCR coding ITS1 and ITS2 fragments for species identification of detected derpatophytes. Most frequently detected species was Microsporum canis, mainly in young cats. Geophilic Microsporum gypseum and anthropophilic Trichophyton rubrum was found primarily in dogs. Molecular methods in dermatophytosis identification are rapid in contrast to routinely, long lasting culture.


Two-dimensional electromagnetic cloaks with arbitrary geometries.
Transformation optics opens an exciting gateway to design electromagnetic "invisibility" cloaks with anisotropic and inhomogeneous medium. In this paper, we establish a generalized transformation procedure to highly improve the flexibilities for the design of two-dimensional (2D) cloaks. The general expressions for the complex medium parameters are developed, which can be readily applied to design 2D cloaks with arbitrary geometries. An example of 2D cloak with irregular cross section is designed and studied by full-wave simulations. The Huygens' Principle is applied to quantitatively evaluate its unusual electromagnetic behaviors. All the theoretical and numerical results verify the effectiveness of the proposed approach. The generalization in this Paper makes a great step forward for the flexible design of electromagnetic cloaks with arbitrary shapes.


Reverse genetic studies of homologous DNA recombination using the chicken B-lymphocyte line, DT40.
DT40 is an avian leucosis virus-transformed chicken B-lymphocyte line which exhibits high ratios of targeted to random integration of transfected DNA constructs. This efficient targeted integration may be related to the ongoing diversification of the variable segment of the immunoglobulin gene through homologous DNA recombination-controlled gene conversion. DT40s are a convenient model system for making gene-targeted mutants. Another advantage is the relative tractability of these cells, which makes it possible to disrupt multiple genes in a single cell and to generate conditionally gene-targeted mutants including temperature-sensitive mutants. There are strong phenotypic similarities between murine and DT40 mutants of various genes involved in DNA recombination. These similarities confirm that the DT40 cell line is a reasonable model for the analysis of vertebrate DNA recombination, despite obvious concerns associated with the use of a transformed cell line, which may have certain cell-line-specific characteristics. Here we describe our studies of homologous DNA recombination in vertebrate somatic cells using reverse genetics in DT40 cells.


Pediatric cardiovascular risk factors.
The dominant cause of mortality, morbidity and hospitalization worldwide is cardiac complications, and are the major public health problem in adult populations. The worldwide research is being focused on the idea that cardiovascular disease is an early life pathological state. Early unfavorable exposures, acting in different periods of fetal and early postnatal life, have been observed to be responsible for permanent editions in the cardiac system. This idea has been confirmed by preclinical experimental studies confirming the early life growth restriction leading to developmental adaptations in cardiovascular form and system. All these editions results in elevated susceptibility to cardiovascular disease. The present review article will put emphasis on these risk factors, which lead to the deadly cardiac pathology state in young infants.


A steady-state biofilm model for simultaneous reduction of nitrate and perchlorate, part 1: model development and numerical solution.
A multispecies biofilm model is developed for simultaneous reduction of nitrate and perchlorate in the H(2)-based membrane biofilm reactor. The one-dimension model includes dual-substrate Monod kinetics for a steady-state biofilm with five solid and five dissolved components. The solid components are autotrophic denitrifying bacteria, autotrophic perchlorate-reducing bacteria, heterotrophic bacteria, inert biomass, and extracellular polymeric substances (EPS). The dissolved components are nitrate, perchlorate, hydrogen (H(2)), substrate-utilization-associated products, and biomass-associated products (BAP). The model explicitly considers four mechanisms involved in how three important operating conditions (H(2) pressure, nitrate loading, and perchlorate loading) affect nitrate and perchlorate removals: (1) competition for H(2), (2) promotion of PRB growth due to having two electron acceptors (nitrate and perchlorate), (3) competition between nitrate and perchlorate reduction for the same resources in the PRB: electrons and possibly reductase enzymes, and (4) competition for space in the biofilm. Two other special features are having H(2) delivered from the membrane substratum and solving directly for steady state using a novel three-step approach: finite-difference for approximating partial differential and/or integral equations, Newton-Raphson for solving nonlinear equations, and an iterative scheme to obtain the steady-state biofilm thickness. An example result illustrates the model's features.


Patterns of Prescribing Sodium-Glucose Cotransporter-2 Inhibitors for Medicare Beneficiaries in the United States.
Evidence from large randomized clinical trials supports the benefit of SGLT2i (sodium-glucose cotransporter-2 inhibitors) to improve cardiovascular and kidney outcomes in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease or chronic kidney disease. Considering this evidence, which has been expanding since the product label indication for empagliflozin to reduce risk of cardiovascular death in 2016, clinician-level variation in the prescription of SGLT2i among US Medicare beneficiaries was evaluated. Antihyperglycemic medication prescribers were identified as those physicians and advanced practice providers prescribing metformin in Medicare part D prescriber data. In this cross-sectional study, the proportion prescribing SGLT2i was assessed overall and across specialties in 2018, with changes assessed from 2014 to 2018. SGLT2i use was compared with other second-line antihyperglycemic medication classes, sulfonylureas and DPP4is (dipeptidyl peptidase-4 inhibitors). Among 232 523 unique clinicians who prescribed metformin for Medicare beneficiaries in 2018 (diabetes-treating clinicians), 45 255 (19.5%) prescribed SGLT2i. There was substantial variation across specialties-from 72% of endocrinologists to 14% of cardiologists who prescribed metformin also prescribed SGLT2i. Between 2014 and 2018, the number prescribing SGLT2i increased 5-fold from 9048 in 2014 to 45 255 in 2018. Among clinicians who prescribed both sulfonylureas and SGLT2i in 2018, SGLT2i was prescribed to a median 33 beneficiaries for every 100 prescribed sulfonylureas (interquartile range, 18-67). SGLT2i use relative to sulfonylureas increased from 19 (interquartile range, 11-34) per 100 in 2014 to 33 (interquartile range, 18-67) per 100 in 2018 (Ptrend<0.001). Eighty percent of clinicians prescribing metformin to Medicare beneficiaries did not prescribe SGLT2i in 2018. Moreover, sulfonylureas prescriptions were 3 times more frequent than those of SGLT2is, although a pattern of increasing uptake may portend future trends. These findings highlight a baseline opportunity to improve care and outcomes for patients with type 2 diabetes.


Progranulin gene (GRN) promoter methylation is increased in patients with sporadic frontotemporal lobar degeneration.
Mutations in progranulin gene (GRN) are the most common cause of autosomal dominant familial frontotemporal lobar degeneration (FTLD). In addition, GRN variability influences the risk to develop the disease in non-carriers (sporadic FTLD). We evaluated progranulin gene (GRN) promoter methylation levels in peripheral blood mononuclear cells isolated from 38 patients with sporadic FTLD compared with 38 controls, and correlate them with GRN mRNA expression rate. The percentage of methylation of the GRN promoter was increased in patients with FTLD compared with controls (61.5 vs. 46.3 %, P < 0.001). A trend towards decreased GRN relative expression was observed in patients compared with controls (threefold decrease over controls, P > 0.05), together with a negative correlation between the degree of GRN promoter methylation and mRNA GRN levels (ρ = -0.1, P > 0.05). GRN promoter methylation was not correlated with age. In conclusion, the degree of methylation of the GRN promoter is increased in patients with FTLD as compared with controls, likely leading to a decreased expression of GRN.


Teachers' perspectives on nutrition education in boys' public high schools in Riyadh, Saudi Arabia.
Nutrition education in school may positively affect students' eating behaviour. Teachers need to be empowered to teach nutrition, but no studies have investigated teachers' views on this topic in Saudi Arabia. This study investigated the perspective of teachers on nutrition education and their confidence in teaching it in boys' public high schools in Riyadh, Saudi Arabia. In 2015, 80 boys' public high schools were randomly selected from four areas of Riyadh, and 80 teachers (biological sciences, physical education and health education teachers) were interviewed using a validated questionnaire. A Fisher exact test was run to test the relationship between teachers' perspective and confidence level, and their subject taught. Almost all the teachers (98%) agreed that the health education curriculum should be taught as a core subject for high-school students. Most of the teachers (89%) were interested in teaching nutrition. However, 64% indicated that they did not have adequate nutrition curricular materials and 70% considered that they had not received adequate training on nutrition education. However, 89% were confident that their students would be interested in nutrition and that such education would change their dietary behaviour. Science and health education teachers were more interested in teaching nutrition and were more confident in their ability to do so than physical education teachers (P < 0.05). Most of the teachers were interested in teaching nutrition but barriers existed, such as lack of training and teaching materials, which affected teachers' confidence in delivering nutrition education in their curricula.


Utility of Magnetic Resonance Imaging in Diagnosis of Prenatal Non-Visualization of the Fetal Gallbladder: A Case-Series Study.
BACKGROUND This study aimed to assess the utility of magnetic resonance imaging (MRI) in the diagnosis of prenatal non-visualization of the fetal gallbladder (PNVGB). MATERIAL AND METHODS The clinical data of 32 pregnant women with PNVGB who underwent MRI examination during the second and third trimester of pregnancy were collected and their outcomes were analyzed. RESULTS MRI showed that 26 patients (81.3%) had isolated PNVGB and 6 (18.8%) had additional malformations. In 26 patients with isolated PNVGB, 7 were found in the gallbladder on MRI and 4 were found on subsequent ultrasonography. One patient had termination of pregnancy (TOP) and 1 patient was lost to follow-up; the remaining 24 patients were known to deliver a healthy child. Among the 6 patients with additional malformations, 3 terminated their pregnancies due to combined severe abnormalities: 1 patient with horseshoe kidney and 1 with fetal echogenic bowel both had a healthy child, while 1 with fetal growth restriction (FGR) delivered a child who walked on tiptoe. CONCLUSIONS MRI contributes to identifying PNVGB detected or suspected by ultrasonography.


Serum IGF-1, IGFBP-3 and growth hormone levels in children with congenital heart disease: relationship with nutritional status, cyanosis and left ventricular functions.
In this study we aimed to evaluate serum insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) and growth hormone (GH) levels in children with congenital heart disease (CHD) and to determine if these parameters have any relationship to the cyanosis, nutritional status and the left ventricular systolic function. This study is prospective-randomized study which conducted in 94 CHD patients (36 girls and 58 boys, aged between one 1-192 months, 19 cyanotic CHD and 75 acyanotic CHD) and age-sex matched 54 children (26 girls and 28 boys) with no CHD. In the study group, 37 out of the 94 CHD patients (39.4%) and 16 out of the 54 controls (29.6%) had malnutrition. The difference between the cyanotic and acyanotic patients in respect to malnutrition was significant (57.9% and 34.6%, p<0.05). Serum IGF-1 levels were lower (41.8+/-3.9 microg/L, 106.9+/-17.9 microg/L respectively, p<0.001) and GH levels were higher (6.43+/-0.9 ng/ml, 3.87+/-0.5 respectively, p<0.05) in CHD patient group than the controls. Serum IGF-1 levels were significantly lower in cyanotic CHD patients than the acyanotic patients (17.2+/-3.2 microg/L, 48.7.0+/-4.6 microg/L respectively, p<0.001) and serum IGF-1 levels were both lower in acyanotic and cyanotic CHD patients than the controls (p<0.001 for both). Serum IGF-1 and GH levels were similar between the well-nourished CHD patients and CHD patients with malnutrition (p>0.05). In total study group, the most effective factors on serum IGF-1 levels was presence of CHD (p<0.001), in CHD patients, the presence of cyanosis is the most effective factor on serum IGF-1 level, the presence of malnutrition is the most effective factor on serum IGFBP-3 levels (p<0.01). In the acyanotic, cyanotic, and the entire CHD patient groups, we find no correlations between the serum IGF-1, IGFBP-3 levels and left ventricular systolic function measurements. But serum GH levels were negatively correlated with diastolic left ventricular interseptum diameter, diastolic left ventricular mass and left ventricular end-diastolic volume measurements in CHD patients. In conclusion, we determined that the most important factor on serum IGF-1 levels is cyanosis. Reduced IGF1 levels and decreased left ventricular mass with an elevated GH levels in CHD patients and these findings are prominent in the cases with cyanosis and malnutrition. For this reason we believe that chronic hypoxia plays a significant role in the pathogenesis of malnutrition and also we believe that IGF-1 deficiency seen in CHD patients may be responsible in the etiology of the decrease in left ventricular mass independently from GH.


A study of spontaneous mutation rates at ten loci detectable by starch gel electrophoresis in Drosophila melanogaster.
Spontaneous mutation rates at ten allozyme loci on chromosomes II and III of Drosophila melanogaster were studied. Over the three and a half years study, one alpha-GPD mutation and two different IDH mutations were obtained. The alpha-GPD mutation was inherited in the Mendelian fashion, as expected. The two IDH mutations were peculiar in that the band of new types appeared only in females. In males, only the original bands were stained, and the positions where mutant alleles' bands should be present were blank. Both IDH mutant homozygotes appeared as null allele homozygotes, while in females clear-cut single bands were present.-The rates of spontaneous mutation varied greatly. Eight loci studied (MDH, ADH, EST-6, APH, EST-C, ODH, XDH, AO) did not give any germ-line mutation. The average germ-line mutation rate over all ten loci was estimated at 4.5 x 10(-6). This rate is considerably smaller than that for sex-linked recessive visible mutations (Muller, Valencia and Valencia 1950), but it is somewhat less than autosomal recessive visible mutations (Glass and Ritterhoff 1956).


F-box only protein 31 (FBXO31) negatively regulates p38 mitogen-activated protein kinase (MAPK) signaling by mediating lysine 48-linked ubiquitination and degradation of mitogen-activated protein kinase kinase 6 (MKK6).
The p38 MAPK signal transduction pathway plays an important role in inflammatory and stress responses. MAPKK6 (MKK6), a dual specificity protein kinase, is a p38 activator. Activation of the MKK6-p38 pathway is kept in check by multiple layers of regulations, including autoinhibition, dimerization, scaffold proteins, and Lys-63-linked polyubiquitination. However, the mechanisms underlying deactivation of MKK6-p38, which is crucial for maintaining the magnitude and duration of signal transduction, are not well understood. Lys-48-linked ubiquitination, which marks substrates for proteasomal degradation, is an important negative posttranslational regulatory machinery for signal pathway transduction. Here we report that the accumulation of F-box only protein 31 (FBXO31), a component of Skp1 · Cul1 · F-box protein E3 ligase, negatively regulated p38 activation in cancer cells upon genotoxic stresses. Our results show that FBXO31 binds to MKK6 and mediates its Lys-48-linked polyubiquitination and degradation, thereby functioning as a negative regulator of MKK6-p38 signaling and protecting cells from stress-induced cell apoptosis. Taken together, our findings uncover a new mechanism of deactivation of MKK6-p38 and substantiate a novel regulatory role of FBXO31 in stress response.


[(18)F]-FDG PET and localized fibrous mesothelioma.
The aim of this article is to present our experience with positron emission tomography (PET) and localized fibrous mesothelioma and to review the literature on this issue. During the past five years we found three patients with a complete clinical history who underwent a CT scan of the thorax and (18)F-fluorodeoxyglucose positron emission tomography ([(18)F]-FDG-PET) and were diagnosed with localized fibrous mesothelioma. Two of the patients were asymptomatic men and the third was a woman with chest pain. The standardized uptake value was 2.1 in one case, and in the other two an absence of FDG uptake was seen. All three had complete resection of the tumor, and in one case the presurgery diagnosis was adenocarcinoma. In one patient the tumor relapsed twice, and the other two patients are alive without any evidence of disease. The value of FDG-PET in the differential diagnosis of pulmonary and pleural abnormalities has gained ground during the last few years. As in most benign tumors, the FDG uptake is usually low (< 2.5) in the localized fibrous mesothelioma. However, more studies are necessary to define the role of FDG-PET in assessing this tumor.


Pulmonary responses of unilateral positive end expiratory pressure (PEEP) on experimental fat embolism.
The role of positive end expiratory pressure (PEEP) was evaluated in preventing the deleterious mechanical respiratory effects of fatty acid pulmonary embolism. One group of animals had ventilation without PEEP, while the second group had PEEP of 10 cm H2O applied only to the right lung. In the right lung, PEEP slightly reduced the blood flow, increased the vascular resistance, but reduced intersititial edema and reduced the degree of shunting to almost normal. Hypoxemia was prevented in the right pulmonary venous system, but was prominent in the left. The hypoxemia and shunting in the left lung were comparable to the Group I animals without PEEP to either lung. These studies confirm the value of PEEP in the therapy of the pulmonary manifestations of fat embolism which are the lethal factors in the fatty embolism syndrome.


Biochemical differences among four inosinate dehydrogenase inhibitors, mycophenolic acid, ribavirin, tiazofurin, and selenazofurin, studied in mouse lymphoma cell culture.
The mechanism of the cellular toxicity of four inosinate dehydrogenase (IMP-DH) inhibitors with different antitumor and antiviral pharmacological profiles was investigated in mouse lymphoma (S-49) cell culture. Drug effects on cell growth, nucleotide pools, and DNA and RNA synthesis were measured in the presence and absence of guanine salvage supplies. Both guanine and guanosine were capable of bypassing the IMP-DH block, while they also demonstrated some growth-inhibitory effects when added alone in high concentrations. All four drugs reduced cellular guanosine triphosphate levels and caused secondary changes of the uridine, cytidine, and adenosine triphosphate pools that were similar among the four drugs. However, several drug effects in addition to IMP-DH inhibition were observed except with mycophenolic acid which may represent a pure IMP-DH inhibitor. Both tiazofurin and selenazofurin interfered with the uptake and/or metabolism of uridine and thymidine tracers; however, this effect appeared not to contribute to their cellular toxicity in vitro. Moreover, selenazofurin and tiazofurin impaired the utilization of exogenous guanine salvage supplies for DNA and RNA synthesis, and guanine was particularly ineffective in reversing the toxic effects of tiazofurin on cell growth. This finding is important in view of the available guanine salvage supplies in vivo. Since tiazofurin, selenazofurin, and their known metabolites failed to inhibit hypoxanthine-guanine-phosphoribosyl transferase, guanosine monophosphate kinase, and guanosine diphosphate kinase in cell extracts or permeabilized cells, these drugs may interfere with salvage transport across cellular membranes. The toxic effects of mycophenolic acid and ribavirin were similarly reversed by salvage supplies of up to 200 microM guanine, which suggests that ribavirin primarily acts as an IMP-DH inhibitor under these conditions. This result could explain the rather low antitumor efficacy of both mycophenolic acid and ribavirin in vivo. However, increasing the guanine salvage supply in the medium above 200 microM further reversed the toxic effects of mycophenolic acid to maximum rescue, while it increased the toxicity of ribavirin (300 microM). This finding suggests the presence of a toxic mechanism of ribavirin at higher concentrations that is dependent upon the presence of guanine supplies sufficient to fully overcome the IMP-DH inhibition. This study documents that each antimetabolite displays a unique spectrum of activities with multiple toxic targets.