Exploration of oncologists' attitudes toward and perceived value of patient-reported outcomes.
To understand oncologists' attitudes toward patient-reported outcome (PRO) measures and to learn how PRO data influence their clinical decision-making. Twenty practicing oncologists participated in 1 of 4 semi-structured focus groups. Most oncologists had no experience with PRO measures, but were able to identify several concepts appropriate for patient-reported assessment. Participants agreed that clinical measures such as performance status were more meaningful to them, but acknowledged that PRO measures were more appropriate for assessing patient symptoms and treatment response. All oncologists believed that clinical efficacy and toxicity data were of primary importance, but that PROs become increasingly important when multiple treatments are available, in advanced or incurable disease, and in palliative care. Several issues prevented oncologists from being able to draw meaningful conclusions from PRO data: lack of familiarity with PRO measures, being presented with too much data to process, lack of clarity around a meaningful change in PRO measure scores, and lack of standardization in the use of PRO measures. Oncologists indicated that PRO data are most influential in advanced or incurable disease and in palliative care. Improving the interpretability of PRO measures could increase the usefulness of PRO data in treatment decision-making.


Impact of polystyrene microplastic exposure on lipid profile and oxidative stress status of male and female Wistar rats.
Microplastics (MPs) are currently global environmental pollutants, and their associated health risks cannot be ignored. However, research on MP toxicity in mammals is limited. We investigated the effects of polystyrene microplastic (PS-MP) particles on the lipid profile and oxidative stress markers of Wistar rats. Two forms of PS-MP-pristine polystyrene and Styrofoam microplastics-particles of diameter <5 mm were used in this study. Each form was separately incorporated into rat feed in varying proportions of 1, 5 and 10%. A total of seventy rats (thirty-five male and thirty-five female rats) were used for this study and were separately distributed into seven groups of five rats each. The rats were then randomly assigned to a control group which received normal rat feed and water and six (6) test groups which were fed varying percentages (1, 5 and 10) of polystyrene microplastics diet for a period of 90 days. The rats were sacrificed under mild diethyl ether anesthesia 12 hr after cessation of treatment and blood was collected for lipid profile and oxidative stress analyses. Results obtained showed that oral exposure to microplastics caused decreased high density lipoprotein cholesterol (HDL-C) and increased low density lipoprotein cholesterol (LDL-C) in the rats. In contrast, there were no significant changes in oxidative stress parameters in the rats following microplastics exposure. Atherogenic indices in the PS-MP exposed rats differed according to gender. These results indicated that PS-MP dietary exposure may lead to dyslipidemia and male rats had higher cardiovascular risk.


Incorrect interpretation of moving-filter continuous particulate air monitor responses.
The graphs supplied by the vendors of moving-filter continuous particulate air monitors (CPAMs) in their sales literature show linear curves on a log-log scale, with net count rate on one axis and concentration on the other. The implication is that the monitor user is to read the concentration from the graph, given an observed net count rate, at any time. For the nominal filter speeds commonly used for these monitors, using the graph in this way is incorrect. The graphs do not state the limitations of the calculation: (1) the nuclide measured must be long-lived; (2) the concentration of that nuclide in the sampled air must remain constant; and (3) the reading of the net count rate must be obtained after a specific time, called the "transit time." This time is typically on the order of several hours. Reading the net count rate at any time earlier than this will result in an incorrect concentration estimate. Given that a major purpose of a CPAM is to alert plant personnel to a change in airborne radioactivity concentrations, by definition when this happens the concentration is not constant. Thus, using the supplied curves will result in an incorrect estimate of that concentration. The solution is to use instead a fixed-filter CPAM and a previously-published quantitative method. With this approach, there is no need to attempt to estimate a concentration, much less to assume that it is constant over long periods of time or that it can only change in a stair-step manner. With this alternative to a moving-filter CPAM, a signal proportional to the time-integrated worker intake can be generated continuously for any time-varying air concentration, including the sums-of-exponentials shapes expected during transient events in compartmental systems.


Split-tracrRNA as an efficient tracrRNA system with an improved potential of scalability.
Due to the relatively long sequence, tracrRNAs are chemically less synthesizable than crRNAs, leading to limited scalability of RNA guides for CRISPR-Cas9 systems. To develop shortened versions of RNA guides with improved cost-effectiveness, we have developed a split-tracrRNA system by nicking the 67-mer tracrRNA (tracrRNA(67)). Cellular gene editing assays and in vitro DNA cleavage assays revealed that the position of the nick is critical for maintaining the activity of tracrRNA(67). TracrRNA(41 + 23), produced by nicking in stem loop 2, showed gene editing efficiency and specificity comparable to those of tracrRNA(67). Removal of the loop of stem loop 2 was further possible without compromising the efficiency and specificity when the stem duplex was stabilized via a high GC content. Binding assays and single-molecule experiments suggested that efficient split-tracrRNAs could be engineered as long as their binding affinity to Cas9 and their reaction kinetics are similar to those of tracrRNA(67).


Enzymatic synthesis of complex glycosaminotrioses and study of their molecular recognition by hevein domains.
Hevein, a protein found in Hevea brasiliensis, has a CRD domain, which is known to bind chitin and GlcNAc-containing oligosaccharides. By using NMR and molecular modeling as major tools we have demonstrated that trisaccharides containing GalNAc and ManNAc residues are also recognized by hevein domains. Thus far unknown trisaccharides GlcNAcbeta(1-->4)GlcNAcbeta(1-->4)ManNAc (1) and GalNAcbeta(1-->4)GlcNAcbeta(1-->4)ManNAc (2) were synthesized with the use of beta-N-acetylhexosaminidase from Aspergillus oryzae. This method is based on the rather unique phenomenon that some fungal beta-N-acetylhexosaminidases cannot hydrolyze disaccharide GlcNAcbeta(1-->4)ManNAc (5) contrary to chitobiose GlcNAcbeta(1-->4)GlcNAc (4) that is cleaved and, therefore, cannot be used as an acceptor for further transglycosylation. Both trisaccharides 1 and 2 were prepared by transglycosylation from disaccharidic acceptor in good yields ranging from 35% to 40%. Our observations strongly indicate that the present nature of the modifications of chitotriose (GlcNAcbeta(1-->lcNAcbeta(1-->4)GlcNAc, 3) at either the non-reducing end (GalNAc instead of GlcNAc) or at the reducing end (ManNAc instead of GlcNAc) do not modify the mode of binding of the trisaccharide to hevein. The association constant values indicate that chitotriose (3) binding is better than that of 1 and 2, and that the binding of (with ManNAc at the reducing end) is favored with respect to that of 2 (with ManNAc at the reducing end with a non-reducing GalNAc moiety).


[Clinical significance of plasma renin, testosterone, 17-alpha-hydroxyprogesterone and ACTH activities in the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. A review of 31 cases].
Measurements of urinary steroids do not allow a precise supervision of the evolution and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Thirty-one cases with a 2 year follow-up allowed a trial of estimation of the progress that could be obtained with plasmatic dosages of renine, testosterone, A.C.T.H. and 17-hydroxyprogesterone (17-O.H.P.) activities. The best way for reaching diagnosis is presently 17-O.H.P. However, the amplitude and variability of nyctemeral changes of 17-O.H.P. as well as A.C.T.H. activities do not allow to use these two dosages for a precise supervision of therapeutic effects. On the contrary, the dosage of testosterone allows the appreciation of the risk of virilization and its reliability gives a precise control of the effects of steroid therapy. The dosage of the renine activity disclosed unknown or not well controlled sodium-losses, and allowed to adjust the dosage of 9-alpha-fluorohydro-cortisone, while limiting glucocorticosteroids. It gave also evidence of the usefulness of prolonged steroid therapy until the end of the growth period.


Changing blood donor screening criteria from permanent deferral for men who have sex with men to individual sexual risk assessment: no evidence of a significant impact on the human immunodeficiency virus epidemic in Italy.
In 2001, the criteria for blood donor eligibility in Italy were modified by a ministerial decree from a permanent deferral for "men who have sex with men" to an individual risk assessment of sexual behaviours. The aim of this study was to evaluate the impact of this change in donor screening criteria on the human immunodeficiency virus epidemic among blood donors in Italy. We used the data obtained from the Italian blood donor epidemiological surveillance system. We compared data collected in 2009 and 2010, when the individual risk assessment policy was applied, with data collected in 1999 when permanent deferral was applied for men who have sex with men based on a declaration of sexual orientation. We evaluated the change over time in the relative proportion of HIV antibody-positive donors who likely acquired the infection from men who have sex with men vs heterosexual sexual exposure; the relative risk was calculated using 1999 as the reference year. In all 3 years, the majority of HIV antibody-positive donors reported sexual exposure as a risk factor for HIV infection; this proportion increased over time, although not statistically significantly. Heterosexuals always accounted for at least 40% of all HIV antibody-positive cases. The rate of HIV antibody-positive donors increased similarly in men who have sex with men and heterosexuals; specifically, the rate of HIV antibody-positive cases per 100,000 donors was more than 2-fold higher among men who have sex with men in 2009-2010 than in 1999 (2009-2010 vs 1999, RR =2.8; P =0.06), and that among heterosexuals was 1.5 fold higher (P =0.18). When comparing the period before (1999) and after (2009-2010), the implementation of the individual risk assessment policy in 2001, no significant increase in the proportion of men who have sex with men compared to heterosexuals was observed among HIV antibody-positive blood donors, suggesting that the change in donor deferral policy did not lead to a disproportionate increase of HIV-seropositive men who have sex with men.


Serum beta 2-microglobulin in hepato-biliary diseases.
The levels of serum beta 2-m in hepato-biliary disease have been examined. Significant increase has been observed in various benign and malignant diseases of the liver, but not in jaundice due to acute pancreatitis. The age-dependent relationship of beta 2-m is present in controls, weaker in the malignant diseases and absent in the benign diseases. The level of beta 2-m is not influenced by jaundice. Serum beta 2-m levels have no role as a discriminant in liver disease.


Simvastatin and Muscle: Zebrafish and Chicken Show that the Benefits are not Worth the Damage.
Simvastatin is one of the most common medicines prescribed to treat human hypercholesterolemia. Simvastatin acts through the inhibition of cholesterol synthesis. Unfortunately, simvastatin causes unwanted side effects on muscles, such as soreness, tiredness, or weakness. Therefore, to understand the mechanism of action of simvastatin, it is important to study its physiological and structural impacts on muscle in varied animal models. Here we report on the effects of simvastatin on two biological models: zebrafish embryos and chicken muscle culture. In the last years, our group and others showed that simvastatin treatment in zebrafish embryos reduces fish movements and induces major structural alterations in skeletal muscles. We also showed that simvastatin and membrane cholesterol depletion induce major changes in proliferation and differentiation of muscle cells in chick muscle cultures. Here, we review and discuss these observations considering reported data on the use of simvastatin as a potential therapy for Duchenne muscular dystrophy.


Wilderness Medical Society practice guidelines for the prevention and treatment of acute altitude illness: 2014 update.
To provide guidance to clinicians about best practices, the Wilderness Medical Society convened an expert panel to develop evidence-based guidelines for prevention and treatment of acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema. These guidelines present the main prophylactic and therapeutic modalities for each disorder and provide recommendations about their role in disease management. Recommendations are graded based on the quality of supporting evidence and balance between the benefits and risks/burdens according to criteria put forth by the American College of Chest Physicians. The guidelines also provide suggested approaches to prevention and management of each disorder that incorporate these recommendations. This is an updated version of the original WMS Consensus Guidelines for the Prevention and Treatment of Acute Altitude Illness published in Wilderness & Environmental Medicine 2010;21(2):146-155.


Effects of 2-substitution on 14-epi-19-nortachysterol-mediated biological events: based on synthesis and X-ray co-crystallographic analysis with the human vitamin D receptor.
Both 2α- and 2β-hydroxypropyl substituted 14-epi-1α,25-dihydroxy-19-nortachysterols were synthesized to study the human vitamin D receptor (hVDR) binding affinity, binding configurations, and interactions with amino acid residues in the ligand binding domain of hVDR by X-ray co-crystallographic analysis. In conjunction with our previous results on 14-epi-19-nortachysterol, 2-methylidene-, 2α-methyl-, 2β-methyl, and 2α-hydroxypropoxy-14-epi-19-nortachysterol, we propose a variety of effects of substitution at the C2 position in the 14-epi-19-nortachysterol skeleton on biological activities.


Robust Reference Intervals for Serum Kappa and Lambda Free Light Chains from a Multi Centre Study Population from Hyderabad, India: Myeloma Diagnostic Implications.
The International Myeloma Working Group considers the serum free light chain (SFLC) assay to be an adjunct to traditional tests. Apart from the FLC ratio, the absolute values of individual free light chains also are gaining importance as they appear to be more relevant in certain clinical settings. Automated assays are available for their determination. As laboratories put new test systems into use catering to different disease populations, they are required by accreditation and certification bodies to verify or establish performance specifications, including reference intervals (RIs) representative of their population. Our aim was to establish local RIs for SFLC in a multicentre representative healthy population using a robust method. There was no significant relationship between SFLC levels and age, gender and creatinine levels. The 95% RI for κSFLC was 4.81 to 33.86mg/L, for ? SFLC was 5.19 to 23.67mg/L and for κ/?SFLC was 0.36 to 2.33, significantly higher than the values given by the manufacturer. The κ/? SFLC ratio at 2.23, covering 100% of the data, showed 72% sensitivity (95% CI=39.0 - 94.0), 100% specificity (95% CI=71.5 - 100.0), 100% PPV (95% CI=21.5 - 100.0), 95% NPV (95% CI=75.4 - 99.9), and 79% accuracy (95% CI=56.0 - 93.0). In the patient group, kit RI for κ /? SFLC ratio classified 45.5% (n=5) as positive vs 9.1% (n=1) positive by the study RI, while the kit RI for kappa FLC classified 90.9% (n=10) as positive vs 54.5% (n=6) , indicating increased probability of false positive test results with the kit RI when applied to our patient population. Appropriate and specific reference intervals and criteria values result in fewer false-positive and false-negative results which means fewer wrong or missed diagnoses.


Metallic artifact mitigation and organ-constrained tissue assignment for Monte Carlo calculations of permanent implant lung brachytherapy.
To investigate methods of generating accurate patient-specific computational phantoms for the Monte Carlo calculation of lung brachytherapy patient dose distributions. Four metallic artifact mitigation methods are applied to six lung brachytherapy patient computed tomography (CT) images: simple threshold replacement (STR) identifies high CT values in the vicinity of the seeds and replaces them with estimated true values; fan beam virtual sinogram replaces artifact-affected values in a virtual sinogram and performs a filtered back-projection to generate a corrected image; 3D median filter replaces voxel values that differ from the median value in a region of interest surrounding the voxel and then applies a second filter to reduce noise; and a combination of fan beam virtual sinogram and STR. Computational phantoms are generated from artifact-corrected and uncorrected images using several tissue assignment schemes: both lung-contour constrained and unconstrained global schemes are considered. Voxel mass densities are assigned based on voxel CT number or using the nominal tissue mass densities. Dose distributions are calculated using the EGSnrc user-code BrachyDose for (125)I, (103)Pd, and (131)Cs seeds and are compared directly as well as through dose volume histograms and dose metrics for target volumes surrounding surgical sutures. Metallic artifact mitigation techniques vary in ability to reduce artifacts while preserving tissue detail. Notably, images corrected with the fan beam virtual sinogram have reduced artifacts but residual artifacts near sources remain requiring additional use of STR; the 3D median filter removes artifacts but simultaneously removes detail in lung and bone. Doses vary considerably between computational phantoms with the largest differences arising from artifact-affected voxels assigned to bone in the vicinity of the seeds. Consequently, when metallic artifact reduction and constrained tissue assignment within lung contours are employed in generated phantoms, this erroneous assignment is reduced, generally resulting in higher doses. Lung-constrained tissue assignment also results in increased doses in regions of interest due to a reduction in the erroneous assignment of adipose to voxels within lung contours. Differences in dose metrics calculated for different computational phantoms are sensitive to radionuclide photon spectra with the largest differences for (103)Pd seeds and smallest but still considerable differences for (131)Cs seeds. Despite producing differences in CT images, dose metrics calculated using the STR, fan beam + STR, and 3D median filter techniques produce similar dose metrics. Results suggest that the accuracy of dose distributions for permanent implant lung brachytherapy is improved by applying lung-constrained tissue assignment schemes to metallic artifact corrected images.


Life cycle adapted upstream open reading frames (uORFs) in Trypanosoma congolense: A post-transcriptional approach to accurate gene regulation.
The presented work explores the regulatory influence of upstream open reading frames (uORFs) on gene expression in Trypanosoma congolense. More than 31,000 uORFs in total were identified and characterized here. We found evidence for the uORFs' appearance in the transcriptome to be correlated with proteomic expression data, clearly indicating their repressive potential in T. congolense, which has to rely on post-transcriptional gene expression regulation due to its unique genomic organization. Our data show that uORF's translation repressive potential does not only correlate with elemental sequence features such as length, position and quantity, but involves more subtle components, in particular the codon and amino acid profiles. This corresponds with the popular mechanistic model of a ribosome shedding initiation factors during the translation of a uORF, which can prevent reinitiation at the downstream start codon of the actual protein-coding sequence, due to the former extensive consumption of crucial translation components. We suggest that uORFs with uncommon codon and amino acid usage can slow down the translation elongation process in T. congolense, systematically deplete the limited factors, and restrict downstream reinitiation, setting up a bottleneck for subsequent translation of the protein-coding sequence. Additionally we conclude that uORFs dynamically influence the T. congolense life cycle. We found evidence that transition to epimastigote form could be supported by gain of uORFs due to alternative trans-splicing, which down-regulate housekeeping genes' expression and render the trypanosome in a metabolically reduced state of endurance.


Percutaneous Valve in Valve Implantation for Dysfunctional Bioprosthetic Valves: A Case Report.
Percutaneous valve-in-valve therapy is a life-saving procedure for patients at high risk of reoperation due to dysfunctional bioprosthetic valves. We have reviewed 3 typical cases of a valve-in-valve procedure using high-quality images to demonstrate the suitability of this method for aortic, mitral, and tricuspid positions. Three-dimensional transesophageal echocardiography combined with other modalities such as computerized tomography and fluoroscopy are key elements for anesthesia and procedural guidance, especially as immediate tools to assess valvular function and specific procedure-related complications.


The effects of backward walking training on balance and mobility in an individual with chronic incomplete spinal cord injury: A case report.
Individuals with incomplete spinal cord injuries (ISCIs) commonly face persistent gait impairments. Backward walking training may be a useful rehabilitation approach, providing novel gait and balance challenges. However, little is known about the effects of this approach for individuals with ISCIs. The purpose of this case report was to describe the effects of backward walking training on strength, balance, and upright mobility in an individual with chronic ISCI. A 28-year-old female, 11-years post ISCI (C4, AIS D) completed 18-sessions of backward walking training on a treadmill with partial body-weight support and overground. Training emphasized stepping practice, speed, and kinematics. Outcome measures included: Lower Extremity Motor Score, Berg Balance Scale (BBS), Sensory Organization Test (SOT), 10-Meter Walk Test (10MWT), 3-meter backward walking test, Timed Up and Go (TUG), and Activities-Specific Balance Confidence (ABC) Scale. Strength did not change. Improved balance was evident based on BBS (20 to 37/56) and SOT scores (27 to 40/100). Upright mobility improved based on TUG times (57 to 32.7 s), increased 10MWT speed (0.23 to 0.31 m/s), and backward gait speed (0.07 to 0.12 m/s). Additionally, self-reported balance confidence (ABC Scale) increased from 36.9% to 49.6%. The results suggest that backward walking may be a beneficial rehabilitation approach; examination of the clinical efficacy is warranted.


Distinct mechanisms for the pro-apoptotic conformational transition and alkaline transition in cytochrome c.
We demonstrate for the first time that cytochrome c undergoes a distinct pathway in the alkaline conformational transition from its pro-apoptotic conformational transition, which may have important functional consequences in vivo.


The collateral blood flow and hippuran clearance of the rabbit kidney after occlusion of the renal artery.
The collateral blood flow to the rabbit kidney was determined by two methods: (1) measurement of the venous flow after clamping of the renal artery and (2) Hippuran clearance of the clamped kidney. The collateral blood flow was found to be 0.012 ml/min/g kidney equivalent to 0.2% of the entire blood flow to the rabbit kidney. Compared with collateral blood flow in other mammals (as humans and dogs) with a collateral flow of 6.2% of the normal flow, the collateral blood flow in the rabbit is very modest. The cranial ureteric artery contributes more than 90% of the entire blood flow, while capsular perforants, important in other mammals, play no role in the supply of the rabbit kidney. Only 50% of the collateral blood flow passes the tubular system. Flow to the medulla calculated from Hippuran clearance was 35% greater than flow to the cortical part of the kidney. The subcapsular cortical tubuli were able to absorb Hippuran from the peritoneal fluid and surrounding tissues after the kidney was dissected free from its surroundings and all vessels severed. Absorption corresponded to an arbitrary serum flow of 0.0002 ml/min/g.


An Overview of Pulmonary Atresia and Major Aortopulmonary Collateral Arteries.
Pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (PA/VSD/MAPCAs) is a rare and complex congenital cardiac lesion that has historically carried a poor prognosis. With advancements in surgical management, we have seen an improvement in the outcomes for children affected by this disease. However, this population continues to present challenges due to the complex anatomy and physiology associated with PA/VSD/MAPCA. This summary of material presented during one of the nursing sessions of the 2014 Meeting of the Pediatric Cardiac Intensive Care Society provides an overview for those in cardiac intensive care units who do not have a large experience with this lesion. We will review the anatomy, physiology, surgical approach, postoperative management strategies, and cardiac catheter intervention options for PA/VSD/MAPCAs. We will also discuss recent innovations that may lead to continued improvement in outcomes for this challenging patient population.


Subsequent pregnancy outcomes after abdominal vs. laparoscopic myomectomy.
To determine whether abdominal (open) vs. laparoscopic myomectomy affects the obstetrical outcomes of subsequent pregnancies. A retrospective cohort study was conducted at a tertiary university medical center. The study population included women who had a documented birth following a myomectomy at our institution between the years 1997 and 2018. The obstetrical characteristics and immediate perinatal outcomes of the subsequent pregnancy following open vs. laparoscopic myomectomy were collected and compared. Data were retrieved from patients' medical records via the institutional computerized database. Cases that lacked detailed surgery and delivery reports were excluded. Data were analyzed using a chi-square test for categorical variables and one-way ANOVA for continuous variables. A p-value <.05 was considered statistically significant. During the study period, 57 women met the inclusion criteria, of whom 66.6% (38/57) had an open and 33.3% (19/57) had a laparoscopic myomectomy. Women who underwent an open myomectomy had a higher rate of cesarean birth than those in the laparoscopic group (89.5 vs. 42.1%, p < .001). No cases of severe maternal or perinatal complications, uterine ruptures, or placental abruptions were identified in either study group. No other significant differences were noted between the two types of myomectomy. Open myomectomy is associated with a higher rate of cesarean delivery than laparoscopic. No severe adverse maternal or neonatal outcomes were detected in either study group.


Erythema dyschromicum perstans in a Caucasian pediatric patient.
Erythema dyschromicum perstans (EDP), or ashy dermatosis, is characterized by oval, blue-gray macules, which are completely asymptomatic. In adults, the condition is primarily seen in patients of color, most commonly those of Hispanic descent, and typically follows a chronic course. We describe a pediatric case of EDP in a Caucasian patient. In the pediatric population, EDP is more commonly observed in Caucasian patients and often shows significant recovery or complete resolution in a matter of years. This case report outlines the differences in EDP between adult and pediatric patients.


Which "weigh" to Go? Alternative Vancomycin Dosing Strategies in Obese Patients.
PurposeThis study aims to compare the performance of alternative weight-based vancomycin dosing strategies to traditional dosing in obese patients using area under the curve (AUC) monitoring. Methods: This retrospective study compared target attainment of an AUC between 400-600mcg*H/mL using alternative vancomycin dosing strategies. All patients received allometrically dosed vancomycin, with patient-specific AUCs calculated using 2 post-infusion steady-state vancomycin serum concentrations using the trapezoidal rule. Predicted AUCs were calculated using the following: 15 mg/kg total body weight (TBW), 15 mg/kg corrected body weight (CBW), and 12.5 mg/kg TBW. Predicted AUCs from the traditional 15 mg/kg TBW dosing were then compared to alternative dosing strategies using the predicted AUCs from 12.5 mg/kg TBW, 15 mg/kg CBW, and the actual AUCs calculated using allometrically scaled vancomycin dosing. The primary outcome was attainment of initial AUC within the target range of 400-600mcg*H/mL for each dosing method. Results: Eighty-four patients were included. When AUCs were compared to traditional 15 mg/kg dosing strategy, the CBW, 12.5 mg/kg, and allometric dosing strategies were significantly more likely to result in initial attainment of an AUC within a target range of 400-600 mcg*H/mL (P = 0.0003, 0.0135, and 0.0088, respectively). No significant differences were seen between each of the alternative dosing methods (P = 0.73). Conclusion: The 3 alternative vancomycin dosing strategies examined were all significantly more likely to achieve an initial AUC within the target range compared to traditional vancomycin dosing in obese patients. Clinicians should strongly consider one of these alternative dosing strategies for obese patients as opposed to traditional vancomycin dosing.


Zinc in growth and development and spectrum of human zinc deficiency.
Growth retardation is seen in experimental animals as a result of severe dietary restriction of several essential trace elements. However, in humans, the effect of zinc deficiency is most pronounced. Growth failure and hypogonadism in males, related to a deficiency of zinc, have been recognized in many developing countries. A mild deficiency of zinc, affecting growth and development in children and adolescents, has been reported from developed countries as well. Zinc deficiency in humans may manifest as severe, moderate, or mild. The manifestations of severe zinc deficiency include bullous pustular dermatitis, alopecia, diarrhea, emotional disorder, weight loss, intercurrent infections due to cell-mediated immune dysfunctions, hypogonadism in males, neurosensory disorders, and problems with healing of ulcers. This condition can be fatal. A moderate level of zinc deficiency has been reported in a variety of conditions. Clinical manifestations include growth retardation and male hypogonadism in adolescence, rough skin, poor appetite, mental lethargy, delayed wound healing, cell-mediated immune dysfunctions, and abnormal neurosensory changes. A mild level of zinc deficiency may manifest with decreased serum testosterone level and oligospermia in males, decreased lean body mass, hyper-ammonemia, neurosensory changes, anergy, decreased serum thymulin activity, and decreased IL-2 activity. Although the clinical aspects of severe and moderate levels of zinc deficiency are well known, the recognition of mild levels of zinc deficiency has been difficult. Currently plasmas zinc appears to be the most widely used parameter for assessment of human zinc status, and it is known to be decreased in cases of severe and moderate deficiency of zinc.(ABSTRACT TRUNCATED AT 250 WORDS)


Qualitative Analysis of Emotional Distress in Cardiac Patients From the Perspectives of Cognitive Behavioral and Metacognitive Theories: Why Might Cognitive Behavioral Therapy Have Limited Benefit, and Might Metacognitive Therapy Be More Effective?
Introduction: Cognitive behavioral therapy (CBT) alleviates emotional distress in mental health settings, but has only modest effects in cardiac patients. Metacognitive therapy (MCT) also alleviates depression and anxiety in mental health settings and is in its initial stages of evaluation for cardiac patients. Aim: Our objective is to compare how CBT and MCT models conceptualize cardiac patients' distress, and to explore why CBT has had limited benefit for cardiac patients and whether MCT has the potential to be more efficacious. Method: Forty-nine cardiac rehabilitation patients, who screened positively for anxiety and/or depression, provided semi-structured interviews. We analyzed transcripts qualitatively to explore the "fit" of patients' accounts of their distress with the main elements of cognitive behavioral and metacognitive theories. Four illustrative cases, representative of the diverse presentations in the broader sample, were analyzed in detail and are presented here. Results: Conceptualizing patients' distress from the perspective of CBT involved applying many distinct categories to describe specific details of patients' talk, particularly the diversity of their concerns and the multiple types of cognitive distortion. It also required distinction between realistic and unrealistic thoughts, which was difficult when thoughts were associated with the risk or consequences of cardiac events. From the perspective of MCT a single category-perseverative negative thinking-was sufficient to understand all this talk, regardless of whether it indicated realistic or unrealistic thoughts, and could also be applied to some talk that did not seem relevant from a CBT perspective. Discussion: Conceptualizing distress from the perspective of CBT presents multiple, diverse therapeutic targets, not all of which a time-limited therapy would be able to address. Given the difficulty of identifying them as unrealistic or not, thoughts about disease, death or disability may not be amenable to classic CBT techniques such as reality testing. MCT proved more parsimonious and, because it did not distinguish between realistic and unrealistic thoughts, might prove a better fit to emotional distress in cardiac patients.


Characterization of distinct functions for growth factors in murine transitional epithelial cells in primary organotypic culture.
Although previous studies indicate that growth factors can affect several physiological processes in epithelia, their role in the biological dynamics of transitional epithelium of the bladder is not yet established. This study investigates the functional consequences of a direct action of EGF, TGF beta, FGF-1, FGF-2, PDGF-AA, and PDGF-BB on mouse urothelium in organoid-like primary cultures. Confluent and nonconfluent cultures served as a model for intact and regenerating urothelium, respectively. EGF and FGF-1 stimulated in both models under serum-free conditions the BrdU and [3H]-thymidine incorporation. This resulted in an increase in the number of cell layers, but the cultures assumed a less organoid-like morphology. In addition, EGF and FGF-1 stimulated the expansion of nonconfluent cultures. TGF beta inhibited proliferation, caused a decrease in the number of cell layers, and blocked expansion. Moreover, TGF beta induced the terminal differentiation and apoptosis of urothelial cells. In nonconfluent cultures PDGF-BB slightly stimulated the increase in the outgrowth area, but no other effect on the parameters for proliferation and differentiation was observed. FGF-2 and PDGF-AA did not affect any of the studied parameters. These data are consistent with the hypothesis that EGF and FGF-1 can promote wound healing and/or hyperplasia through direct action on the epithelial cells, while TGF beta promotes the development of a normal, differentiated transitional epithelium.


[Giant cell granulomatous angiitis of the central nervous system].
The case is described of a coloured woman of 58, previously affected by filaria, who presented with meningo-encephalitis which proved fatal within a month. Pathological anatomy showed granylomatous angiitis with giant cells scattered throughout the brain and the meninges but confined exclusively to the nervous system. Biological and anatomopathological tests were unable to connect this condition with any precise aetiology. The aetiology of granulomatous angiitis is discussed in this connection and the clinical and anatomopathological charateristics peculiar to giant cell granulomatous angiitis of the nervous system are recalled.


Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts.
Carbon monoxide (CO), a byproduct of heme catabolism by heme oxygenase (HO), confers potent antiinflammatory effects. Here we demonstrate that CO derived from HO-1 inhibited Toll-like receptor (TLR) 2, 4, 5, and 9 signaling, but not TLR3-dependent signaling, in macrophages. Ligand-mediated receptor trafficking to lipid rafts represents an early event in signal initiation of immune cells. Trafficking of TLR4 to lipid rafts in response to LPS was reactive oxygen species (ROS) dependent because it was inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase, and in gp91(phox)-deficient macrophages. CO selectively inhibited ligand-induced recruitment of TLR4 to lipid rafts, which was also associated with the inhibition of ligand-induced ROS production in macrophages. TLR3 did not translocate to lipid rafts by polyinosine-polycytidylic acid (poly(I:C)). CO had no effect on poly(I:C)-induced ROS production and TLR3 signaling. The inhibitory effect of CO on TLR-induced cytokine production was abolished in gp91(phox)-deficient macrophages, also indicating a role for NADPH oxidase. CO attenuated LPS-induced NADPH oxidase activity in vitro, potentially by binding to gp91(phox). Thus, CO negatively controlled TLR signaling pathways by inhibiting translocation of TLR to lipid rafts through suppression of NADPH oxidase-dependent ROS generation.


Probing Tumour Proteostasis and the UPR with Serum Markers.
Tumour proteostasis and the unfolded protein response (UPR) are emerging drivers of tumour progression and important determinants of clinical efficacy of cancer therapy. Recent findings indicate that they also regulate the production of protein tumour markers. Here, we discuss how this new knowledge opens up new perspectives for cancer therapeutics.


Posterior Staphylomas in Pathologic Myopia Imaged by Widefield Optical Coherence Tomography.
To examine posterior staphylomas by widefield optical coherence tomography (WF-OCT) and three-dimensional magnetic resonance imaging (3D-MRI). Highly myopic patients (myopic refractive error >8.0 diopters or axial length >26.5 mm) who had previously undergone orbital 3D-MRI were examined by WF-OCT. The study included 100 eyes of 57 patients with a mean age of 67.9 ± 10.7 years (range, 44-85 years) and mean axial length of 30.0 ± 2.3 mm (range, 25.1-36.5 mm). All staphylomas detected on the 3D-MRI, except for two very large staphylomas, were visualized on the WF-OCT images. Morphologic hallmarks of the staphylomas were smoothly configured staphyloma border with a gradual thinning of the choroid and an inward protrusion of the sclera at the staphyloma edge. Comparing the detectability of the staphylomas on the WF-OCT images versus 3D-MRI revealed no significant difference between both techniques (P = 0.12; χ2 test). Comparing the staphyloma classification between both techniques showed a good concordance with a concordance index kappa of 0.61 (95% confidence interval: 0.50-0.72). A spatial relationship between the staphylomatous areas and the macula and optic nerve head was observed by WF-OCT. WF-OCT can provide tomographic images of posterior staphylomas in a resolution and size unachievable so far, and may replace 3D-MRI in assessing posterior staphylomas. Future studies using WF-OCT may explore the detailed morphologic characteristics of posterior staphylomas and give clues to the etiology of staphylomas.


Protospacer-Adjacent Motif Specificity during Clostridioides difficile Type I-B CRISPR-Cas Interference and Adaptation.
CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems provide prokaryotes with efficient protection against foreign nucleic acid invaders. We have recently demonstrated the defensive interference function of a CRISPR-Cas system from Clostridioides (Clostridium) difficile, a major human enteropathogen, and showed that it could be harnessed for efficient genome editing in this bacterium. However, molecular details are still missing on CRISPR-Cas function for adaptation and sequence requirements for both interference and new spacer acquisition in this pathogen. Despite accumulating knowledge on the individual CRISPR-Cas systems in various prokaryotes, no data are available on the adaptation process in bacterial type I-B CRISPR-Cas systems. Here, we report the first experimental evidence that the C. difficile type I-B CRISPR-Cas system acquires new spacers upon overexpression of its adaptation module. The majority of new spacers are derived from a plasmid expressing Cas proteins required for adaptation or from regions of the C. difficile genome where generation of free DNA termini is expected. Results from protospacer-adjacent motif (PAM) library experiments and plasmid conjugation efficiency assays indicate that C. difficile CRISPR-Cas requires the YCN consensus PAM for efficient interference. We revealed a functional link between the adaptation and interference machineries, since newly adapted spacers are derived from sequences associated with a CCN PAM, which fits the interference consensus. The definition of functional PAMs and establishment of relative activity levels of each of the multiple C. difficile CRISPR arrays in present study are necessary for further CRISPR-based biotechnological and medical applications involving this organism. IMPORTANCE CRISPR-Cas systems provide prokaryotes with adaptive immunity for defense against foreign nucleic acid invaders, such as viruses or phages and plasmids. The CRISPR-Cas systems are highly diverse, and detailed studies of individual CRISPR-Cas subtypes are important for our understanding of various aspects of microbial adaptation strategies and for the potential applications. The significance of our work is in providing the first experimental evidence for type I-B CRISPR-Cas system adaptation in the emerging human enteropathogen Clostridioides difficile. This bacterium needs to survive in phage-rich gut communities, and its active CRISPR-Cas system might provide efficient antiphage defense by acquiring new spacers that constitute memory for further invader elimination. Our study also reveals a functional link between the adaptation and interference CRISPR machineries. The definition of all possible functional trinucleotide motifs upstream protospacers within foreign nucleic acid sequences is important for CRISPR-based genome editing in this pathogen and for developing new drugs against C. difficile infections.


Combining xanthan and chitosan membranes to multipotent mesenchymal stromal cells as bioactive dressings for dermo-epidermal wounds.
The association between tridimensional scaffolds to cells of interest has provided excellent perspectives for obtaining viable complex tissues in vitro, such as skin, resulting in impressive advances in the field of tissue engineering applied to regenerative therapies. The use of multipotent mesenchymal stromal cells in the treatment of dermo-epidermal wounds is particularly promising due to several relevant properties of these cells, such as high capacity of proliferation in culture, potential of differentiation in multiple skin cell types, important paracrine and immunomodulatory effects, among others. Membranes of chitosan complexed with xanthan may be potentially useful as scaffolds for multipotent mesenchymal stromal cells, given that they present suitable physico-chemical characteristics and have adequate tridimensional structure for the adhesion, growth, and maintenance of cell function. Therefore, the purpose of this work was to assess the applicability of bioactive dressings associating dense and porous chitosan-xanthan membranes to multipotent mesenchymal stromal cells for the treatment of skin wounds. The membranes showed to be non-mutagenic and allowed efficient adhesion and proliferation of the mesenchymal stromal cells in vitro. In vivo assays performed with mesenchymal stromal cells grown on the surface of the dense membranes showed acceleration of wound healing in Wistar rats, thus indicating that the use of this cell-scaffold association for tissue engineering purposes is feasible and attractive.


Bone resorption assessed by immunoassay of urinary cross-linked collagen peptides in patients with osteogenesis imperfecta.
Urinary excretion of type I collagen cross-linked N-telopeptides was studied in 52 children and adolescents with osteogenesis imperfecta (OI) and found to be above the 75th percentile of controls in 44 of the patients. OI patients suffering from fractures during the preceding 6 months had significantly higher values (p < 0.05). In contrast, patients with better motor performance tended to have lower values (p = 0.059). The concentration of urinary type I collagen cross-linked N-telopeptides was positively correlated with urinary calcium excretion (p < 0.05), which was found to be elevated in 20 of the patients. Our results show that during childhood and adolescence in OI not only the synthesis but also the turnover of mature cross-linked type I collagen is disturbed and provide evidence that bone resorption rates are elevated.


[Study on morphology and acid secretion in cultured-parietal cells from rabbit gastric mucosa].
In order to investigate the morphological characteristics and functions of gastric parietal cells, excluding factors which affect acid secretion, parietal cells were isolated from a rabbit's gastric mucosa and cultured for several days. The long-term effects of H2-receptor antagonists on morphological characteristics and functions of the parietal cells were also investigated, using primary-cultured cells. Immediately after isolation, the parietal cells showed morphological diversity, especially in terms of the numbers and the sizes of secretory canaliculi as seen by electron microscopy. Forty-eight hours after implantation, the morphological characteristics of the cultured-parietal cells showed homogeneity, characterized by the round-shape, a few of the slightly dilated secretory canaliculi around the nucleus. When stimulated by histamine, cultured-parietal cells displayed remarkably dilated secretory canaliculi with a special type of margin on the surroundings of the canaliculi 5 min after the stimulation took place. Acid secretion from cultured-parietal cells was almost the same as that of freshly-isolated parietal cells when stimulated by histamine up to, at least, 72 hours after implantation. Cultured-parietal cells exhibited acid secretion after stimulation by carbachol, but showed no response for gastrin, the same as freshly-isolated parietal cells. When isolated parietal cells were cultured for 48 hours with cimetidine, cell viability measured by MTT assay was significantly higher than those cultured without cimetidine. However in morphological examination, the primary culture of parietal cells with three types of H2-blocker (cimetidine, ranitidine, famotidine) induced same damage to the cells. Our results indicate that primary culture of isolated parietal cells is a useful method for the study of morphology and the functions of parietal cells, because of homogeneity in morphology and sustained function of acid secretion for, at least, 72 hours. It is also a useful method for the investigation of long-term effects of drugs which specifically affect parietal cells.


Suppressors of a UGG missense mutation in Escherichia coli.
As part of our investigation of tRNA structure-function relationships, we isolated and preliminarily characterized translational suppressors of the tryptophan codon UGG in a trpA missense mutant of Escherichia coli. the parent strain also contained two other mutant alleles relevant to the suppressor search; these were supD, which codes for a serine-inserting amber suppressor tRNA, and gly V55, the gene for a GGA/G-reading mutationally altered glycine tRNA. On the basis of map location, reversed-phase (RPC-5) column chromatography of glycyl-tRNA, and codon response, several classes have been distinguished so far. The number of suppressors in each class, their codon responses, and their apparent genic identities, respectively, are as follows: class 1--4 suppressors, UGG, supD; class 2--12 suppressors, UGG, glyU; class 3--9 suppressors, UGA and UGG, glyT; class 4--2 suppressors, UGG, glyT; class 5--7 suppressors, UGG, gly V55. Besides these, one suppressor retains supD activity, but so far its map location has not been distinguished from that of supD. Another suppressor clearly does not map near supD or any of the glycine tRNA genes mentioned. These last two suppressors may represent novel missense suppressors such as misacylated tRNA's or mutationally altered aminoacyl-tRNA synthetases, tRNA modification enzymes, or ribosomes. Finally, three other suppressors were obtained from a strain containing glyT56, the gene for an AGA/G-reading form of glyT tRNA. All three occurred at the expense of glyT56 activity and exhibited the the transductional linkage to argH that is characteristic of glyT.


Influence of flavonoids on long-term bonding stability on caries-affected dentin.
To evaluate the effect of experimental dentin pre-treatment solutions formulated with different flavonoids on microtensile bond strength (μTBS), nanohardness (NH) and ultra-morphological characteristics of artificial caries-affected dentin (CAD) bonded using a universal bonding system. A microbiological method was used to create an artificial CAD in 91 human molars. Five experimental pre-treatment solutions were created using the following flavonoids: quercetin (QUE); hesperidin (HES); rutin (RUT); naringin (NAR), or proanthocyanidin (PRO). A placebo solution (PLA) with no flavonoids added was also evaluated. The flavonoids or placebo solutions were applied to the CAD prior to the application and photoactivation of a universal adhesive (Scotchbond Universal, 3M Oral Care). A control group (CON), in which only the bonding agent was applied without any flavonoid solution, was also evaluated. A 3-mm-thick block of resin composite (Opallis, FGM) was built up on the flat bonded CAD surfaces and was light-cured following the manufacturer's instructions. Specimens were sectioned to obtain resin-dentin slices and sticks (cross-sectional area of 0.8 mm2). The μTBS, NH, and confocal ultramorphology analysis of resin-dentin interface was evaluated at 24 h and after thermo-cycling aging (25,000 cycles). The results were analyzed using 2-way ANOVA followed by Bonferroni's post hoc test (pre-set α = 0.05). The specimens from groups QUE, NAR, and RUT presented greater μTBS values than those from CON group (p<0.05). Specimens from some of these experimental groups presented greater nanomechanical properties (p<0.05), and no morphological degradation at the resin-dentin interface after aging. The use of exogenous cross-linkers as dentin pre-treatment before bonding procedures may represent a suitable strategy to improve the longevity of universal adhesive systems applied to caries-affected dentin.


COVID-19 and cardiac arrhythmias.
Early studies suggest that coronavirus disease 2019 (COVID-19) is associated with a high incidence of cardiac arrhythmias. Severe acute respiratory syndrome coronavirus 2 infection may cause injury to cardiac myocytes and increase arrhythmia risk. The purpose of this study was to evaluate the risk of cardiac arrest and arrhythmias including incident atrial fibrillation (AF), bradyarrhythmias, and nonsustained ventricular tachycardia (NSVT) in a large urban population hospitalized for COVID-19. We also evaluated correlations between the presence of these arrhythmias and mortality. We reviewed the characteristics of all patients with COVID-19 admitted to our center over a 9-week period. Throughout hospitalization, we evaluated the incidence of cardiac arrests, arrhythmias, and inpatient mortality. We also used logistic regression to evaluate age, sex, race, body mass index, prevalent cardiovascular disease, diabetes, hypertension, chronic kidney disease, and intensive care unit (ICU) status as potential risk factors for each arrhythmia. Among 700 patients (mean age 50 ± 18 years; 45% men; 71% African American; 11% received ICU care), there were 9 cardiac arrests, 25 incident AF events, 9 clinically significant bradyarrhythmias, and 10 NSVTs. All cardiac arrests occurred in patients admitted to the ICU. In addition, admission to the ICU was associated with incident AF (odds ratio [OR] 4.68; 95% confidence interval [CI] 1.66-13.18) and NSVT (OR 8.92; 95% CI 1.73-46.06) after multivariable adjustment. Also, age and incident AF (OR 1.05; 95% CI 1.02-1.09) and prevalent heart failure and bradyarrhythmias (OR 9.75; 95% CI 1.95-48.65) were independently associated. Only cardiac arrests were associated with acute in-hospital mortality. Cardiac arrests and arrhythmias are likely the consequence of systemic illness and not solely the direct effects of COVID-19 infection.


In vitro assessment of asbestos genotoxicity.
Asbestos fibers are highly cytotoxic to cultured mammalian cells and produce chromosomal aberrations in several rodent cell types. There is some uncertainty in the literature as to whether these fibers are clastogenic to cultured human cells. Asbestos fibers do not produce either DNA damage or back mutations in prokaryotic assay systems, and they do not appear to cause DNA strand breaks in either rodent or human cells. The evidence that these fibers can produce either forward mutation or neoplastic transformation of mammalian cells is weak. Asbestos fibers are clearly oncogenic to humans and animals, but, except for clastogenic effects in rodent cells, there is little evidence for genotoxicity of fibers. It is reasonable to expect, therefore, that these materials may be oncogenic by virtue of mechanisms rather than as tumor initiators.


Relationship of job strain to standard coronary risk factors and psychological characteristics in women and men of the Family Heart Study.
This study reports on standard coronary risk factors (plasma lipids and lipoproteins, blood pressure, heart rate, age, body mass index) and psychosocial variables (job strain, Type A behavior, hostility, illnesses, medical and psychological symptoms, health-damaging behavior) in a community sample of 324 employed men, 203 employed women, and 155 female homemakers. Employed women reported less hostility and fewer illnesses than homemakers and had lower cholesterol levels than homemakers and men. Job characteristics were unrelated to standard coronary risk factor levels in both sexes, but predicted medical symptoms and health-damaging behavior in men. These findings suggest that employment is associated with enhanced medical and physical well-being among women and point to possible behavioral and psychological pathways by which job strain may adversely influence men's health.


Late results of gelatin-resorcin-formalin glue-aided repair in acute type A aortic dissection.
Gelatin-resorcin-formalin (GRF) glue has been used to obliterate the false lumen of dissected aortas, resulting in reduced mortality. However, because of the cytotoxicity of formalin, the application of GRF remains controversial. In this study, a total of 138 consecutive patients with acute type A dissection since 1995, who underwent emergency graft replacement, were reviewed. The mean age was 65.5 years. The hospital mortality rate was 6.5%. In-hospital re-exploration rate and patency rate of the false lumen were 6.5% and 24.7%, respectively. The actuarial survival rates were 81.5% after 5 years and 54.8% after 10 years. Reoperation-free rates were 87.9% after 5 years and 72.3% after 10 years. Tissue necrosis or aneurismal degeneration was not demonstrated at reoperation. In conclusion, GRF glue demonstrats excellent tissue adhesion and hemostasis capability, and contributes to improve surgical results.


Prognostic factors versus markers of response to treatment versus surrogate endpoints: Three different concepts.
Multiple sclerosis is a highly heterogeneous disease; the quantitative assessment of disease progression is problematic for many reasons, including the lack of objective methods to measure disability and the long follow-up times needed to detect relevant and stable changes. For these reasons, the importance of prognostic markers, markers of response to treatments and of surrogate endpoints, is crucial in multiple sclerosis research. Aim of this report is to clarify some basic definitions and methodological issues about baseline factors to be considered prognostic markers or markers of response to treatment; to define the dynamic role that variables must have to be considered surrogate markers in relation to specific treatments.


Hot topics from the Assemblies.
Syncope is a transient loss of consciousness typically due to cerebral hypoperfusion with many causes, including pulmonary embolism. The prevalence of pulmonary embolism in patients with syncope is unknown; hence, in a prospective study, Prandoni et al. and the PESIT investigators report in the New England Journal of Medicine the prevalence of pulmonary embolism in 560 patients admitted for a first episode of syncope at 11 medical centres in Italy.


Pyruvate metabolism by a nitrogen-fixing bacterium.
1. The major products of pyruvate dissimilation by washed intact cells of Achromobacter N4-B under nitrogen-fixing conditions are acetate and formate. The formation of succinate and isocitrate and the assimilated amino acids requires carbon dioxide fixation. 2. The products formed by cells incubated with pyruvate in an atmosphere of nitrogen were compared with those formed by cells incubated in an atmosphere of helium. Production of hydrogen and the formation of succinate were greater under helium than under nitrogen. Production of acetate and formate and the utilization of pyruvate were the same in both atmospheres. 3. Cell-free preparations, unlike intact cells of Achromobacter N4-B, do not evolve hydrogen, but do produce lactate. 4. It is suggested that, in cell-free preparations incapable of fixing nitrogen, electrons are accepted from pyruvate to form lactate rather than being used for the reductive formation of ammonia and hydrogen.


Linkage disequilibrium and physical mapping of X-linked juvenile retinoschisis.
X-linked juvenile retinoschisis (RS) is a recessively inherited disorder resulting in poor visual acuity. Affected males typically show retinal degeneration and intraretinal splitting. The prevalence of RS is 1:15,000-1:30,000. Elsewhere we have mapped the RS gene between the markers DXS43 and DXS274 in Xp22.1-p22.2. To narrow the RS region, we analyzed 31 Finnish RS families with the markers DXS418, DXS999, DXS7161, and DXS365 and a new polymorphic microsatellite marker, HYAT1. Multipoint linkage analysis allowed us to localize the RS gene between the markers DXS418 and DXS7161 (LOD score = 31.3). We have covered this region with nine YAC clones. On the basis of the sizes of the YACs, sequence-tagged site (STS) content mapping, and restriction mapping, the physical distance between DXS418 and DXS7161 is approximately 0.9 Mb. A total of five potential CpG islands could be identified. For haplotype analysis, eight additional Finnish RS families were analyzed with the markers DXS1195, DXS418, HYAT1, DXS999, DXS7161, and DXS365. On the basis of the linkage-disequilibrium data that were derived from the genetically isolated Finnish population, the critical region for RS could be narrowed to 0.2-0.3 cM, between the markers DXS418 and HYAT1.


End-of-Life Care in Latin America.
Cancer has become a global pandemic with disproportionately higher mortality rates in low- and middle- income countries, where a large fraction of patients present in advanced stages and in need of end-of-life care. Globally, the number of adults needing end-of-life care is greater than 19 million, and up to 78% of these patients are living in low- and middle- income countries. In the Americas alone, more than one million people are in need of end-of-life care, placing an enormous burden on local health systems, which are often unprepared to meet the challenge presented by this complex patient population. In Latin America, cancer care is characterized by the presence of vast inequalities between and within countries, and the provision of end-of-life care is no exception. Disparities in access to advanced care planning, with a lack of provision of adequate palliative care and pain medication, are common in the region. These shortcomings are related in large part to inadequate or inappropriate legislation, lack of comprehensive national palliative care plans, insufficient infrastructure, lack of opportunities for clinical training, unreliable reporting of data, and cultural barriers. This report reviews the current status of end-of-life care in Latin America, focusing on identifying existing deficiencies and providing a framework for improvement.


Applicatoin of chitosan-based hydrogel in oral tissue engineering.
Pulpitis, periodontitis, jaw bone defect, and temporomandibular joint damage are common oral and maxillofacial diseases in clinic, but traditional treatments are unable to restore the structure and function of the injured tissues. Due to their good biocompatibility, biodegradability, antioxidant effect, anti-inflammatory activity, and broad-spectrum antimicrobial property, chitosan-based hydrogels have shown broad applicable prospects in the field of oral tissue engineering. Quaternization, carboxymethylation, and sulfonation are common chemical modification strategies to improve the physicochemical properties and biological functions of chitosan-based hydrogels, while the construction of hydrogel composite systems via carrying porous microspheres or nanoparticles can achieve local sequential delivery of diverse drugs or bioactive factors, laying a solid foundation for the well-organized regeneration of defective tissues. Chemical cross-linking is commonly employed to fabricate irreversible permanent chitosan gels, and physical cross-linking enables the formation of reversible gel networks. Representing suitable scaffold biomaterials, several chitosan-based hydrogels transplanted with stem cells, growth factors or exosomes have been used in an attempt to regenerate oral soft and hard tissues. Currently, remarkable advances have been made in promoting the regeneration of pulp-dentin complex, cementum-periodontium-alveolar bone complex, jaw bone, and cartilage. However, the clinical translation of chitosan-based hydrogels still encounters multiple challenges. In future, more in vivo clinical exploration under the conditions of oral complex microenvironments should be performed, and the combined application of chitosan-based hydrogels and a variety of bioactive factors, biomaterials, and state-of-the-art biotechnologies can be pursued in order to realize multifaceted complete regeneration of oral tissue.


Striking multiple synergies created by combining reduced graphene oxides and carbon nanotubes for polymer nanocomposites.
The extraordinary properties of carbon nanotubes (CNTs) and graphene stimulate the development of advanced composites. Recently, several studies have reported significant synergies in the mechanical, electrical and thermal conductivity properties of polymer nanocomposites by incorporating their nanohybrids. In this work, we created polypropylene nanocomposites with homogeneous dispersion of CNTs and reduced graphene oxides via a facile polymer-latex-coating plus melt-mixing strategy, and investigated their synergistic effects in their viscoelastic, gas barrier, and flammability properties. Interestingly, the results show remarkable synergies, enhancing their melt modulus and viscosity, O2 barrier, and flame retardancy properties and respectively exhibiting a synergy percentage of 15.9%, 45.3%, and 20.3%. As previously reported, we also observed remarkable synergistic effects in their tensile strength (14.3%) and Young's modulus (27.1%), electrical conductivity (32.3%) and thermal conductivity (34.6%). These impressive results clearly point towards a new strategy to create advanced materials by adding binary combinations of different types of nanofillers.


Multiple roles of BRIT1/MCPH1 in DNA damage response, DNA repair, and cancer suppression.
Mammalian cells are frequently at risk of DNA damage from both endogenous and exogenous sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor and assure the integrity of their genome. In cells, the intact and effective DDR is essential for the maintenance of genomic stability and it acts as a critical barrier to suppress the development of cancer in humans. Two central kinases for the DDR pathway are ATM and ATR, which can phosphorylate and activate many downstream proteins for cell cycle arrest, DNA repair, or apoptosis if the damages are irreparable. In the last several years, we and others have made significant progress to this field by identifying BRIT1 (also known as MCPH1) as a novel key regulator in the DDR pathway. BRIT1 protein contains 3 breast cancer carboxyl terminal (BRCT) domains which are conserved in BRCA1, MDC1, 53BP1, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. Our in vitro studies revealed BRIT1 to be a chromatinbinding protein required for recruitment of many important DDR proteins (ATM, MDC1, NBS1, RAD51, BRCA2) to the DNA damage sites. We recently also generated the BRIT1 knockout mice and demonstrated its essential roles in homologous recombination DNA repair and in maintaining genomic stability in vivo. In humans, BRIT1 is located on chromosome 8p23.1, where loss of hetero-zigosity is very common in many types of cancer. In this review, we will summarize the novel roles of BRIT1 in DDR, describe the relationship of BRIT1 deficiency with cancer development, and also discuss the use of synthetic lethality approach to target cancers with HR defects due to BRIT1 deficiency.


Organic Liquid Fertilizer Coupled With Single Application of Chemical Fertilization Improves Growth, Biomass, and Yield Components of Cotton Under Mulch Drip Irrigation.
Excessive fertilization, low nutrient utilization rate, and continuous deterioration of cotton field environment have adversely affected the sustainable development of cotton in Xinjiang province of China. To overcome these issues, we hypothesized that an appropriate combination of liquid organic fertilizer and chemical fertilizer (CF) would effectively reduce the input of CF without sacrificing the quality and yield of cotton. A 2-year field experiment explores the effects of three fertilization treatments on the growth, biomass accumulation, and yield of cotton. The three fertilization treatments, namely, no application of fertilizer (CK), the single application of CF, and the combined application of organic liquid fertilizer and CF (F0.6-F1.4), were set up in five ratios. Compared with CF treatment, the combined application of organic liquid fertilizer and CF treatments (F0.6-F1.2) speeded the growth period of cotton by 2-7 days with increased plant height, stem diameter, functional leaf width, and more number of branches, with 9.7-23.5 and 8.4-28.5% higher total plant biomass (TPB) and reproductive organs biomass (ROB), respectively. Compared with CF treatment, the rapid growth duration and maximum accumulation rate of reproductive organs were the highest in F0.8 treatment, with an average increase of 4.6 days and 20.3%. Increment in biomass accumulation contributed to an average increase of 21.8 and 18.9% in cotton boll number and yield, respectively, under F0.8 treatment. Principal component analysis shows that the total biomass, ROB, and total bolls per unit area were positively correlated with the yield, while stem diameter and vegetative organ biomass are negatively correlated with the yield. In conclusion, under film mulching with drip irrigation, organic liquid fertilizer combined with CF reduced by 20% (F0.8 treatment: N, P2O5, and K2O were 182, 104, and 76 kg hm-2, respectively) can sustain the normal growth, promote the accumulation rate of ROB, and lead to efficient cotton production.


Single-stranded nucleic acid-induced helical self-assembly of alkynylplatinum(II) terpyridyl complexes.
Single-stranded nucleic acids, which carry multiple negative charges in an aqueous medium at near neutral pH, are found to induce the aggregation and self-assembly of the positively charged alkynylplatinum(II) terpyridyl complexes via electrostatic binding of the platinum complexes to the single-stranded nucleic acids, as revealed by the appearance of new UV-vis absorption and emission bands upon addition of single-stranded nucleic acids to a buffer solution of the complex. Changes in the intensity and pattern of circular dichroism (CD) spectroscopy are also observed, many of which are consistent with the assembly of the platinum complexes into helical structures, via metal...metal and pi...pi stacking interactions. The induced spectroscopic property changes are found to depend on the structural properties of the nucleic acids.


A four-year longitudinal investigation of the social skills and behavior problems of students with learning disabilities.
This longitudinal, prospective study investigated the social skills and behavior problems of three groups of students (10 students per group) from kindergarten through third grade: learning disabilities (LD), low achievement (LA), and average/high achievement (A/HA). Social skills and behavior problem rating scales were completed by teachers on all students during kindergarten through third grade. Students in the LD and LA group exhibited significantly lower social skills and higher levels of behavior problems than their A/HA peers, but no significant differences for either measure were found between the LD and LA groups. Scores on the cooperating/responding factor of the social skills rating scale increased over time, but scores on the outgoing/initiating factor of the social skills rating scale did not change significantly over time. Discussion focused on the finding that students in the LD and LA groups did not differ significantly on social skills or behavior problems over time, though both groups demonstrated more behavior problems and lower social skills than the A/HA students.


The effects of the Cox maze procedure on atrial function.
The effects of the Cox maze procedure on atrial function remain poorly defined. The purpose of this study was to investigate the effects of a modified Cox maze procedure on left and right atrial function in a porcine model. After cardiac magnetic resonance imaging, 6 pigs underwent pericardiotomy (sham group), and 6 pigs underwent a modified Cox maze procedure (maze group) with bipolar radiofrequency ablation. The maze group had preablation and immediate postablation left and right atrial pressure-volume relations measured with conductance catheters. All pigs survived for 30 days. Magnetic resonance imaging was then repeated for both groups, and conductance catheter measurements were repeated for the right atrium in the maze group. Both groups had significantly higher left atrial volumes postoperatively. Magnetic resonance imaging-derived reservoir and booster pump functional parameters were reduced postoperatively for both groups, but there was no difference in these parameters between the groups. The maze group had significantly higher reduction in the medial and lateral left atrial wall contraction postoperatively. There was no change in immediate left atrial elastance or in the early and 30-day right atrial elastance after the Cox maze procedure. Although the initial left atrial stiffness increased after ablation, right atrial diastolic stiffness did not change initially or at 30 days. Performing a pericardiotomy alone had a significant effect on atrial function that can be quantified by means of magnetic resonance imaging. The effects of the Cox maze procedure on left atrial function could only be detected by analyzing segmental wall motion. Understanding the precise physiologic effects of the Cox maze procedure on atrial function will help in developing less-damaging lesion sets for the surgical treatment of atrial fibrillation.


Duplication of a 2,4-dichlorophenoxyacetic acid monooxygenase gene in Alcaligenes eutrophus JMP134(pJP4).
The Alcaligenes eutrophus JMP134 plasmid pJP4 contains genes necessary for the complete degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) and 3-chlorobenzoic acid. tfdA encodes 2,4-D monooxygenase, the initial enzyme in the 2,4-D catabolic pathway. The tfdA locus has recently been localized to a region on pJP4 13 kilobases away from a cluster of five genes, tfdB to tfdF, which encode the enzymes responsible for the further degradation of 2,4-D to chloromaleylacetic acid (W.R. Streber, K. N. Timmis, and M. H. Zenk, J. Bacteriol. 169:2950-2955, 1987). A second, dissimilar locus on pJP4, tfdAII, has been observed which encodes 2,4-D monooxygenase activity. Gas chromatographic analysis of the 2,4-D metabolites of A. eutrophus harboring pJP4 or subclones thereof localized tfdAII to within a 9-kilobase SstI fragment of pJP4 which also carries the genes tfdBCDEF. This fragment was further characterized in Escherichia coli by deletion and subcloning analysis. A region of 2.5 kilobases, adjacent to tfdC, enabled E. coli extracts to degrade 2,4-D to 2,4-dichlorophenol. Hybridization under low-stringency conditions was observed between tfdA and tfdAII, signifying that the 2,4-D monooxygenase gene was present as two related copies on pJP4.


Ulk4, a Newly Discovered Susceptibility Gene for Schizophrenia, Regulates Corticogenesis in Mice.
Schizophrenia (SCZ) is a chronic and severe mental disease that affects around 1% of the population. The precise etiology of SCZ still remains largely unknown, and no conclusive mechanisms are firmly established. Recent advances in epidemiological and clinical investigation support an overwhelmingly strong neurodevelopmental origin for SCZ. Here, we demonstrated that Unc-51-like kinase 4 (Ulk4), a novel risk factor for major mental disorders including schizophrenia, is involved in the corticogenesis. Deletion of Ulk4 in mice led to significantly thinner layers of II-III, and V in the cerebral cortex, which was confirmed in conditional Ulk4 deletion mice achieved by Cre-loxp strategy. This abnormality might be caused by decreased intermediate neural progenitors and increased apoptosis. Thus, our data suggest that Ulk4 manipulates the behaviors of neural progenitors during brain development and, when functionally defective, leads to the reduction of specific cortical layers. This anomaly may increase predisposition to a range of neurodevelopmental disorders, including SCZ.


Long-duration effect of multi-factor stresses on the cellular biochemistry, oil-yielding performance and morphology of Nannochloropsis oculata.
Microalga Nannochloropsis oculata is a promising alternative feedstock for biodiesel. Elevating its oil-yielding capacity is conducive to cost-saving biodiesel production. However, the regulatory processes of multi-factor collaborative stresses (MFCS) on the oil-yielding performance of N. oculata are unclear. The duration effects of MFCS (high irradiation, nitrogen deficiency and elevated iron supplementation) on N. oculata were investigated in an 18-d batch culture. Despite the reduction in cell division, the biomass concentration increased, resulting from the large accumulation of the carbon/energy-reservoir. However, different storage forms were found in different cellular storage compounds, and both the protein content and pigment composition swiftly and drastically changed. The analysis of four biodiesel properties using pertinent empirical equations indicated their progressive effective improvement in lipid classes and fatty acid composition. The variation curve of neutral lipid productivity was monitored with fluorescent Nile red and was closely correlated to the results from conventional methods. In addition, a series of changes in the organelles (e.g., chloroplast, lipid body and vacuole) and cell shape, dependent on the stress duration, were observed by TEM and LSCM. These changes presumably played an important role in the acclimation of N. oculata to MFCS and accordingly improved its oil-yielding performance.


Anti-inflammatory strategies in the treatment of schizophrenia.
Schizophrenia is a major mental illness with a lifetime prevalence of about 1%. Antipsychotic drugs, with a primary mechanism of action that involves dopamine receptor blockade, are the mainstay in the treatment of the disorder. However, despite optimum antipsychotic treatment, few patients return to pre-morbid levels; the treatment deficit includes refractory positive symptoms, negative symptoms, mood impairments, cognitive impairments, social impairments, and/or a variety of medication-related adverse effects, including extrapyramidal symptoms, metabolic disturbances, hyperprolactinemia, and others. To address these, antipsychotic treatment has been augmented with psychosocial interventions, cognitive rehabilitation, different kinds of electrical and magnetic brain stimulation, and a large range of drugs from the neuropsychiatric as well as, surprise, the general medical pharmacopeia. The pleomorphic pathophysiology of schizophrenia includes abnormalities in immunological and inflammatory pathways, and so it is not surprising that anti-inflammatory drugs have also been trialed as augmentation agents in schizophrenia. This article critically examines the outcomes after augmentation with conventional anti-inflammatory interventions; results from randomized controlled trials do not encourage the use of either aspirin (1000 mg/day) or celecoxib (400 mg/day), both of which have been studied for this indication during the past decade and a half.


Dendritic cells as targets or therapeutics in rheumatic autoimmune disease.
Antigen-specific immunotherapy is a major goal for improvement in the treatment of autoimmune rheumatic disease. Dendritic cells are professional antigen-presenting cells, abundant at mucosal surfaces and in tissues. They also play a critical role in self-tolerance. This review covers recent advances in the field of dendritic cells as targets or therapeutics in rheumatic autoimmune disease. Key themes include the phenotypic and functional characterization, lineage relationships and transcription factors involved in the development of the various dendritic cell subsets. Phenotype and function of mouse and human subsets has now been much better mapped. Progress in the elucidation of targeting ligands and routes for induction of antigen-specific tolerance using either antigen-antibody fusion constructs or particulate conjugates is described. Various inflammatory molecules made by dendritic cells, including type I interferon, are important therapeutic targets in autoimmune rheumatic diseases. Approaches to block this and clinical trials in this area are discussed. There are considerable basic science developments in the field of dendritic cells and tolerance that will speed translation to human of the large amount of knowledge generated in mouse in-vivo systems. Various antigen-specific therapy approaches are in the process of translation to the clinic.


Production of monoclonal antibody alpha Pro3 recognizing a human prostatic carcinoma antigen.
The monoclonal antibody alpha Pro3 recognizes an antigen concentrated in human primary prostatic carcinoma tissue removed surgically. Although the antigen was detectable in extracts of human normal and malignant nonprostatic tissue, as well as in benign prostate tissue, quantitative absorption analysis revealed a substantially greater quantity of the antigen in malignant prostate tissue. The antigen recognized by alpha Pro3 in primary prostatic carcinoma has an apparent nonreduced molecular weight of 175,000 and an apparent subunit molecular weight of 54,000. This antigen, p54, appears to be present on the surface of cultured prostatic tumor cells of the PC-3 cell line, but its location in vivo has not been defined. Successful competition between alpha Pro3 and prostatic carcinoma patient serum immunoglobulin for a Mr 54,000 antigen (reduced molecular weight) present in prostatic carcinoma tissue extract suggests that p54 may play a significant role in the immunobiology of prostatic carcinoma. alpha Pro3 has potential as a sensitive probe for an antigen relevant to human tumor biology.


The influence of the soil on spring and autumn phenology in European beech.
Tree phenology is a key discipline in forest ecology linking seasonal fluctuations of photoperiod and temperature with the annual development of buds, leaves and flowers. Temperature and photoperiod are commonly considered as main determinants of tree phenology while little is known about interactions with soil chemical characteristics. Seedlings of 12 European beech (Fagus sylvatica L.) provenances were transplanted in 2011 to model ecosystems and grown for 4 years on acidic or calcareous forest soil. Spring bud burst and autumnal leaf senescence were assessed in the last 2 years, 2013 and 2014, which were characterized by contrasting annual temperatures with a very warm spring and autumn in 2014. In 2013, spring bud burst and autumnal leaf senescence were advanced on acidic soil with a greater effect on leaf senescence. Hence, the vegetation period 2013 was shorter on this soil type compared with that on calcareous soil. In 2014, a similar soil effect was observed for spring bud burst while autumnal leaf senescence and the length of the vegetation period were not affected, probably due to interferences with the overall extension of the vegetation period in this exceptionally warm year. A different soil responsiveness was observed among the provenances with early bursting or senescing provenances being more sensitive than late bursting or senescing provenances. The findings of this study highlight the soil as an ecologically relevant factor in tree phenology and might help explain existing uncertainties in current phenology models.


Susceptibility of human fetal mesenchymal stem cells to Kaposi sarcoma-associated herpesvirus.
Recent reports link Kaposi sarcoma-associated herpesvirus (KSHV) infection of bone marrow cells to bone marrow failure and lymphoproliferative syndromes. The identity of the infected marrow cells, however, remains unclear. Other work has demonstrated that circulating mononuclear cells can harbor KSHV where its detection predicts the onset and severity of Kaposi sarcoma. In either setting, bone marrow precursors may serve as viral reservoirs. Since mesenchymal stem cells (MSCs) in human bone marrow regulate the differentiation and proliferation of adjacent hematopoietic precursors, we investigated their potential role in KSHV infection. Our results indicate that primary MSCs are susceptible to both cell-free and cell-associated KSHV in culture. Moreover, infection persisted within nearly half of the cells for up to 6 weeks. Thus, MSCs possess a clear capacity to support KSHV infection and warrant further exploration into their potential role in KSHV-related human disease.


Glycan evolution in response to collaboration, conflict, and constraint.
Glycans, oligo- and polysaccharides secreted or attached to proteins and lipids, cover the surfaces of all cells and have a regulatory capacity and structural diversity beyond any other class of biological molecule. Glycans may have evolved these properties because they mediate cellular interactions and often face pressure to evolve new functions rapidly. We approach this idea two ways. First, we discuss evolutionary innovation. Glycan synthesis, regulation, and mode of chemical interaction influence the spectrum of new forms presented to evolution. Second, we describe the evolutionary conflicts that arise when alleles and individuals interact. Glycan regulation and diversity are integral to these biological negotiations. Glycans are tasked with such an amazing diversity of functions that no study of cellular interaction can begin without considering them. We propose that glycans predominate the cell surface because their physical and chemical properties allow the rapid innovation required of molecules on the frontlines of evolutionary conflict.


Embracing excellence in healthcare: the role of positive feedback.
Embracing failure for the purpose of learning is a key trait in successful teams. Failure, however, is not the only source of learning. The majority of interventions in healthcare are successful, yet our prevailing efforts to extract learning intelligence tend to focus almost exclusively on failures, such as harm and errors. By considering the learning potential across the whole landscape of work from success to failure, we can widen the range of learning opportunities. The key steps to learn from excellence are first to recognise excellence, which can be highly subjective, and second to provide positive feedback. Positive feedback enhances learning through a number of routes, including increasing self-efficacy and intrinsic motivation. It may also help to improve relationships within teams and to offset negativity associated with blame cultures.


[Autonomy: to what extent is the concept relevant in psychiatry?].
Autonomy is an important concept in psychiatry, but because it is a somewhat abstract and ambiguous notion, it is not applicable in its entirety in a psychiatric context. This becomes obvious in situations where patients are receiving long term care and treatment. To modify the concept of autonomy in such a way that it acquires an extra dimension that renders it applicable to daily psychiatric practice. The literature was reviewed in order to find articles that reveal the tensions that arise between autonomy and dependence in psychiatry and that reflect the human characteristics that are concealed behind the modern concepts of autonomy, freedom and respect for autonomy. Concepts such as person, identity, acknowledgement, dialogical ethics and life histories are used as an addition to the concepts of autonomy of Kant and Mill. A phenomenological and a context sensitive conception of autonomy is needed within the perspective of dialogical ethics. A dialogical perspective requires from psychiatric professionals a susceptibility for what the patient as a human being really has to say. On the basis of a dialogue where there is space and attention for life histories, backgrounds and the potentials of patients, a new perspective can be developed that is shared by the persons involved. In psychiatry, statements about real autonomy and genuine respect for autonomy are only truly meaningful within the context of doctors, nurses and patients. A hermeneutic approach to patients which involves dialogue creates new opportunities in the field of staff-patient relations.


Phenylpropanoids in Silybum marianum cultures treated with cyclodextrins coated with magnetic nanoparticles.
The glucose oligosaccharide-derived cyclodextrins (CDs) are used for improving bioactive compound production in plant cell cultures because, in addition to their elicitation activity, CDs promote product removal from cells. However, despite these advantages, the industrial application of CDs is hampered by their high market price. A strategy to overcome this constraint was recently tested, in which reusable CD polymers coated with magnetic Fe3O4 nanoparticles were harnessed in Vitis vinifera cell cultures to produce t-resveratrol (t-R). In this study, we applied hydroxypropyl-β-CDs (HPCD) and HPCDs coated with magnetic nanoparticles (HPCD-EPI-MN) in methyl jasmonate (MJ)-treated transgenic Silybum marianum cultures ectopically expressing either a stilbene synthase gene (STS) or a chalcone synthase gene (CHS), and compared their effects on the yields of t-R and naringenin (Ng), respectively. HPCD-EPI-MN at 15 g/L stimulated the accumulation of metabolites in the culture medium of the corresponding transgenic cell lines, with up to 4 mg/L of t-R and 3 mg/L of Ng released after 3 days. Similar amounts were produced in cultures treated with HPCD. Concentrations higher than 15 g/L of HPCD-EPI-MN and prolonged incubation periods negatively affected cell growth and viability in both transgenic cell lines. Reutilization of HPCD-EPI-MN was possible in three elicitation cycles (72 h each), after which the polymer retained 25-30% of its initial efficiency, indicating good stability and reusability. Due to their capacity to adsorb metabolites and their recyclability, the application of magnetic CD polymers may reduce the costs of establishing efficient secondary metabolite production systems on a commercial scale. KEY POINTS: • Long-term transgenic S. marianum suspensions stably produce transgene products • t-R and Ng accumulated extracellularly in cultures elicited with HPCD and HPCD-EPI-MN • The recyclability of HPCD-EPI-MN for metabolite production was proven.


Diagnostic peritoneal lavage in blunt abdominal trauma.
A prospective study to determine the reliability of diagnostic peritoneal lavage in blunt abdominal trauma was carried on during the 11 year period January 1978 to February 1989. Abdominal injury was correctly diagnosed by peritoneal lavage in 1,275 of 1,305 patients (97.7%). In the present study the charts of these patients were reviewed. Of the 555 patients in whom peritoneal lavage was positive and who underwent laparotomy, only 396 patients had an intraabdominal injury that required operation according to our new criteria for the treatment of blunt abdominal trauma. Sixty of the 555 patients had minor injuries that were treated conservatively. The remainder had either little (n = 78) or no (n = 21) intra-abdominal damage except a small amount of free blood about 20 ml in the peritoneal cavity. Diagnostic peritoneal lavage is accurate (97.7%) in detecting free blood in the abdominal cavity. On the other hand, it results in a high percentage of unnecessary laparotomies (28.6%). Patients with blunt abdominal trauma in whom peritoneal lavage shows the presence of blood should be investigated further to reduce the number of unnecessary laparotomies.


Multicenter retrospective assessment of thiazolidinedione monotherapy and combination therapy in patients with type 2 diabetes: comparative subgroup analyses of glycemic control and blood lipid levels.
Thiazolidinediones (TZDs) have contributed to the management of patients with type 2 diabetes mellitus as unique insulin-sensitizing agents. When used as monotherapy or in combination therapy, these drugs not only reduce glycosylated hemoglobin (HbA(1c)) levels, but also effect changes in blood lipid concentrations and have the potential to ameliorate cardiovascular disease risk. Although drugs in the TZD class are perceived to be equivalent clinically, prospective and retrospective studies have demonstrated their ability to modify blood lipid levels. We evaluated and compared the effects of pioglitazone and rosiglitazone monotherapy and combination therapy on blood lipid levels and HbA(1c) in patients with type 2 diabetes. We conducted a multicenter retrospective chart review of 1115 records of patients with type 2 diabetes who received pioglitazone or rosiglitazone, alone or in combination with other antidiabetic agents, between August 1, 1999, and August 31, 2000. The review was conducted to evaluate pretreatment and posttreatment levels of triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and HbA(1c). All observed demographic characteristics, comorbidities, and concomitant drug use were similar in both treatment cohorts. Of the patients who received pioglitazone, 83% also received >/=1 other antihyperglycemic agent and 59% received some form of antihyperlipidemic therapy. Among those who received rosiglitazone, 81% received concomitant antihyperglycemic medication and 60% received some form of antihyperlipidemic therapy. With pioglitazone, mean levels of serum triglyceride, total cholesterol, and LDL-C decreased and HDL-C increased in most patients, with or without concomitant antihyperglycemic medications; with rosiglitazone, with or without other antidiabetic agents, triglyceride and HDL-C levels decreased, whereas total cholesterol and LDL-C levels increased in most patients. Reductions in HbA(1c) levels and increases in body weight related to each study drug were comparable. This comparative assessment of pioglitazone and rosiglitazone, based on observational data, reveals that use of these TZDs with other antidiabetic agents was similar in 605 primary care practices in the United States. In both monotherapy and combination treatment regimens, pioglitazone was associated with greater beneficial effects on lipids than was rosiglitazone. Additional studies are needed to determine the long-term outcomes of TZD therapy with concomitant antihyperglycemic medications.


2,6-Dibenzyl-1,2,3,5,6,7-hexahydro-2,4,6,8-tetraaza-s-indacene and 2,6-bis(4-methoxybenzyl)-1,2,3,5,6,7-hexahydro-2,4,6,8-tetraaza-s-indacene.
The title compounds, C22H22N4 and C24H26N4O2 [alternative names: 2,6-dibenzyl-2,3,6,7-tetrahydro-1H,5H-dipyrrolo[3,4-b; 3',4'-e]pyrazine and 2,6-bis(4-methoxybenzyl)-2,3,6,7-tetrahydro-1H,5H-dipyrolo[3,4-b;3',4'-e]pyrazine], two 1,2,3,5,6,7-hexahydro-2,4,6,8-tetraaza-s-indacene derivatives, are both centrosymmetric and have similar S-shaped structures. In the former, there are two independent molecules (A and B), both of which possess Ci symmetry. These two molecules are arranged such that the benzene ring substituent of molecule B is directed towards the plane of the benzene ring substituent of molecule A, with a dihedral angle of 55.4 (2) degrees between their planes. The shortest C-H...C distance is, however, only 3.21 (1) A. In both compounds, the benzene ring substituents are almost perpendicular to the plane of the central pyrazine ring, and the pyrrolidine rings have perfect envelope conformations. In the crystal structures of both compounds, the molecules pack in a herring-bone arrangement.


The Clinical Added Value of Imaging: A Perspective From Outcome Prediction.
Objective measures of psychiatric health would be of benefit in clinical practice. Despite considerable research in the area of psychiatric neuroimaging outcome prediction, translating putative neuroimaging markers (neuromarkers) of a disorder into clinical practice has proven challenging. We reviewed studies that used neuroimaging measures to predict treatment response and disease outcomes in major depressive disorder, substance use, autism spectrum disorder, psychosis, and dementia. The majority of studies sought to predict psychiatric outcomes rather than develop a specific biological index of future disease trajectory. Studies varied widely with respect to sample size and quantification of out-of-sample prediction model performance. Many studies were able to predict psychiatric outcomes with moderate accuracy, with neuroimaging data often augmenting the prediction compared to clinical or psychometric data alone. We make recommendations for future research with respect to methods that can increase the generalizability and reproducibility of predictions. Large sample sizes in conjunction with machine learning methods, such as feature selection, cross-validation, and random label permutation, provide significant improvement to and quantification of generalizability. Further refinement of neuroimaging protocols and analysis methods will likely facilitate the clinical applicability of predictive imaging markers in psychiatry. Such clinically relevant neuromarkers need not necessarily be grounded in the pathophysiology of the disease, but identifying these neuromarkers may suggest targets for future research into disease mechanisms. The ability of imaging prediction models to augment clinical judgments will ultimately depend on the personal and economic costs and benefits to the patient.


Psychosocial care for the caregivers of primary malignant brain tumor patients.
Despite clinical experience that suggests a high burden of care among relatives of individuals with a primary malignant brain tumor (PMBT), little is known about their actual needs. In this study, the caregivers' personal experiences, quality of life, burden of care, and psychological well-being were examined. Fifty-nine percent did not receive any financial aid for home care, 33% had increased risk for psychosomatic problems, 45% had anxiety, and 33% increased depression levels. The caregiver's quality of life was most strongly affected by the burden of care (p < .001) and the patient's mental state (p < .03). To improve the situation, empathetic professionals and an early implementation of palliative care and social work are required.


Test-retest reliability of the 50-foot timed walk and 30-second chair stand test in patients with total hip arthroplasty.
The purpose was to investigate the test-retest reliability of the 50-Foot Timed Walk (50FWT), and 30-Second Chair Stand Test (30CST) in the patients with total hip arthroplasty (THA). The study was a test-retest study. Thirty-seven patients with THA performed two trials for both the 30CTS and 50FWT on the same day with one hour interval. To assess reliability, the intra-class correlation coefficient [ICC(2,1)], standard error of measurement (SEM), the smallest real difference at the 95% confidence level (SRD95) were calculated. The ICCs for the 50FWT and 30CTS were 0.98 and 0.94, respectively. The SEM and SRD95 for the 50FWT and 30CTS were 0.3 and 0.8 seconds and 0.4 and 1.2 repeats, respectively. The test-retest reliability of the tests was very high. The 50FWT and 30CST are very reliable to measure the functional performance in patients with THA in the clinical settings.