Gingival colonization with selective HACEK microbes in children with congenital heart disease.
It was previously shown that children with congenital heart disease (CHD) harbored Hemophilus, Actinobacillus, Cardiobacter, Eikenella, and Kingella (HACEK) microbes to a greater extent and had more severe gingival inflammation than a normal group of children. The purpose of this study was to determine if HACEK microbes are more prevalent in children with CHD than in normal children when there is no difference in gingival inflammation. Two groups of 12 children were matched with respect to gingival inflammation. Each child had a gingival index recorded as described by Massler. The experimental group consisted of 12 children with CHD 2.5-10 years old (average 5.5) and the control group consisted of 12 healthy children 2-13 years old (average 5.6). Subgingival samples were obtained and cultured for HACEK microbes. Fischer's exact test was performed with the significance level defined at P<0.05. The average gingival indices for the experimental and control groups were 6.5 and 6.4, respectively (N.S.). Nine of 12 children with CHD had Eikenella corrodens (E.c.) compared to 3/12 control patients ( P<0.05). Three of 12 CHD patients but no control patient had Actinobacillus actinomycetemcomitans (A.a.) (N.S.). There were no significant differences in E.c. or A.a. presence between cyanotic and acyanotic CHD patients. This study found that the greater extent of specific HACEK microbes harbored by children with CHD is not associated with cyanosis or the degree of gingival inflammation. Further study is needed to delineate fully the medical significance of this observation.


Utility of Doppler echocardiography and tissue Doppler imaging in the estimation of diastolic function in heart failure with normal ejection fraction: a comparative Doppler-conductance catheterization study.
Various conventional and tissue Doppler echocardiographic indexes were compared with pressure-volume loop analysis to assess their accuracy in detecting left ventricular (LV) diastolic dysfunction in patients with heart failure with normal ejection fraction (HFNEF). Diastolic dysfunction was confirmed by pressure-volume loop analysis obtained by conductance catheter in 43 patients (19 men) with HFNEF. Their Doppler indexes were compared with those of 12 control patients without heart failure symptoms and with normal ejection fraction. Invasively measured indexes for diastolic relaxation (tau, dP/dt(min)), LV end-diastolic pressure, and LV end-diastolic pressure-volume relationship (stiffness, b [dP/dV], and stiffness constant, beta) were correlated with several conventional mitral flow and tissue Doppler imaging indexes. Conventional Doppler indexes correlated moderately with the degree of LV relaxation index, tau (E/A: r=-0.36, P=0.013; isovolumic relaxation time: r=0.31, P=0.040) and b (deceleration time: r=0.39, P=0.012) but not with beta, in contrast to the tissue Doppler imaging indexes E'/A'(lateral) (r=-0.37, P=0.008) and E/E'(lateral) (r=0.53, P<0.001). Diastolic dysfunction was detected in 70% of the HFNEF patients by mitral flow Doppler but in 81% and 86% by E'/A'(lateral), and E/E'(lateral), respectively. Of all echocardiographic parameters investigated, the LV filling index E/E'(lateral) was identified as the best index to detect diastolic dysfunction in HFNEF in which the diagnosis of diastolic dysfunction was confirmed by conductance catheter analysis. We recommend its use as an essential tool for noninvasive diagnostics of diastolic function in patients with HFNEF.


Does Resveratrol Prevent Sevoflurane Toxicity in Newborn Rats?
Inhalation anesthetics have been shown to cause neurodevelopmental disorders and neurotoxic effects. In this study, we aimed to investigate the effect of resveratrol on the possible neurotoxic effect of sevoflurane and the brain-derived neurotrophic factor (BDNF) pathway in newborn rats. The animals were divided into four groups: control, sevoflurane, sevoflurane+resveratrol 25 mg/kg, and sevoflurane+resveratrol 50 mg/kg. The groups that received anesthesia were given 3% sevoflurane for 2 h on the postnatal seventh, eighth, and ninth days. Control gas was applied to the control group. The Morris water maze (MWM) test was performed on postnatal 35th day. After performing the open field test on the postnatal 41st day, the animals were dissected, and the hippocampal BDNF levels were determined by Western blot method. In the MWM test, there was a significant decrease in the time spent in the target quadrant in the sevoflurane anesthesia group compared with control group. This reduction was reversed with the resveratrol pretreatment. Sevoflurane exposure significantly decreased hippocampal BDNF levels compared with the control group. The resveratrol 25 mg/kg pretreatment did not reverse this reduction, whereas resveratrol 50 mg/kg ameliorated this impairment. Sevoflurane did not cause any significant difference in the rats' performance in the open field test. However, 50 mg/kg resveratrol pretreatment caused a statistically significant increase in this performance. Our results showed that sevoflurane impaired learning and memory functions in newborn rats and resveratrol reversed this deterioration. Also BDNF might play a role in this beneficial effect of resveratrol.


Lateral versus posterior surgical approach for the treatment of supracondylar humeral fractures in children: a systematic review and meta-analysis.
Background: Supracondylar humeral fracture (SHF) is the most common type of fracture in children. Moreover, lateral and posterior surgical approaches are the most frequently chosen approaches for open reduction surgery in displaced SHF when C-arm is unavailable. However, previous literature showed mixed findings regarding functional and cosmetic outcomes. Currently, no systematic review and meta-analysis has compared these two procedures. Methods: Our protocol was registered at PROSPERO (registration number CRD42021213763). We conducted a comprehensive electronic database search in MEDLINE, EMBASE, and CENTRAL. Two independent reviewers screened the title and abstract, followed by full-text reading and study selection based on eligibility criteria. The quality of the selected studies was analyzed with the ROBINS-I tool. Meta-analysis was carried out to compare the range of motion (functional outcome) and cosmetic outcome according to Flynn's criteria. This systematic review was conducted based on PRISMA and Cochrane handbook guidelines. Results: Our initial search yielded 163 studies, from which we included five comparative studies comprising 231 children in the qualitative and quantitative analysis. The lateral approach was more likely to result in excellent (OR 1.69, 95% CI [0.97-2.93]) and good (OR 1.12, 95% CI [0.61-2.04]) functional outcomes and less likely to result in fair (OR 0.84, 95% CI [0.34-2.13]) and poor (OR 0.42, 95% CI [0.1-1.73]) functional outcomes compared to the posterior approach. In terms of cosmetic results, both approaches showed mixed findings. The lateral approach was more likely to result in excellent (OR 1.11, 95% CI [0.61-2.02]) and fair (OR 1.18, 95% CI [0.49-2.80]) but less likely to result in good (OR 0.79, 95% CI [0.40-1.55]) cosmetic outcomes. However, none of these analyses were statistically significant (p> 0.05). Conclusion: Lateral and posterior surgical approaches resulted in satisfactory functional and cosmetic outcomes. The two approaches are comparable for treating SHF in children when evaluated with Flynn's criteria.


Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers.
The presence of single nucleotide polymorphisms (SNPs) in the REarranged during Transfection (RET) gene has been investigated with regard to their potential role in the development or progression of medullary thyroid cancer or pheochromocytomas (PHEO) in patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome. The aim of this study was to evaluate the spectrum of RET variants in France between 2003 and 2013, and to evaluate the impact of SNPs on the MEN2 A phenotype. In this retrospective cohort study, RET variants were screened in 5109 index cases, and RET pathogenic variants were screened in 2214 relatives. Exons 5, 8, 10, 11, 13, 14, 15, and 16 were characterized by Sanger sequencing. RET pathogenic variants, RET variants with unknown functional significance (VUS), and four RET SNP variants-G691S (rs1799939), L769L (rs1800861), S836S (rs1800862), and S904S (rs1800863)-were characterized and are reported in index cases. In silico analysis and classification following the recommendation of the American College of Medical Genetics and Genomics was performed for RET VUS. Each patient's age at the time of diagnosis, sex, and the endocrine neoplasias present at molecular diagnosis were recorded. Twenty-six single VUS in RET without any well-defined risk profiles were found in 33 patients. Nine of these were considered probably pathogenic, 11 of uncertain significance, and six as probably benign. Three double pathogenic variants found in three patients were classified as pathogenic. A study of the entire cohort showed that patients carrying pathogenic variants or VUS in RET together with PHEO were diagnosed earlier than the others. The presence of the G691S SNP, or a combination of SNPs, increased the risk of developing PHEO but did not modify the date of the diagnosis. No association was found between SNPs and medullary thyroid cancer or hyperparathyroidism. The findings propose a classification of 15 of the 26 VUS in RET without any well-defined risk profiles and suggest that the G691S SNP, or a combination of SNPs, may be associated with the development of PHEO.


Influences on domestic well water testing behavior in a Central Maine area with frequent groundwater arsenic occurrence.
In 2001 the Environmental Protection Agency (EPA) adopted a new standard for arsenic (As) in drinking water of 10 μg/L, replacing the old standard of 50 μg/L. However, for the 12% of the U.S. population relying on unregulated domestic well water, including half of the population of Maine, it is solely the well owner's responsibility to test and treat the water. A mailed household survey was implemented in January 2013 in 13 towns of Central Maine with the goal of understanding the population's testing and treatment practices and the key behavior influencing factors in an area with high well-water dependency and frequent natural groundwater As. The response rate was 58.3%; 525 of 900 likely-delivered surveys to randomly selected addresses were completed. Although 78% of the households reported that their well has been tested, half of it was more than 5 years ago. Among the 58.7% who believe they have tested for As, most do not remember the results. Better educated, higher income homeowners who more recently purchased their homes are most likely to have included As when last testing. While households agree that water and As-related health risks can be severe, they feel low personal vulnerability and there are low testing norms overall. Significant predictors of including As when last testing include: having knowledge that years of exposure increases As-related health risks (risk knowledge), knowing who to contact to test well water (action knowledge), believing that regular testing does not take too much time (instrumental attitude), and having neighbors who regularly test their water (descriptive norm). Homeowners in As-affected communities have the tendency to underestimate their As risks compared to their neighbors. The reasons for this optimistic bias require further study, but low testing behaviors in this area may be due to the influence of a combination of norm, ability, and attitude factors and barriers.


Improving Recognition of Antimicrobial Peptides and Target Selectivity through Machine Learning and Genetic Programming.
Growing bacterial resistance to antibiotics is spurring research on utilizing naturally-occurring antimicrobial peptides (AMPs) as templates for novel drug design. While experimentalists mainly focus on systematic point mutations to measure the effect on antibacterial activity, the computational community seeks to understand what determines such activity in a machine learning setting. The latter seeks to identify the biological signals or features that govern activity. In this paper, we advance research in this direction through a novel method that constructs and selects complex sequence-based features which capture information about distal patterns within a peptide. Comparative analysis with state-of-the-art methods in AMP recognition reveals our method is not only among the top performers, but it also provides transparent summarizations of antibacterial activity at the sequence level. Moreover, this paper demonstrates for the first time the capability not only to recognize that a peptide is an AMP or not but also to predict its target selectivity based on models of activity against only Gram-positive, only Gram-negative, or both types of bacteria. The work described in this paper is a step forward in computational research seeking to facilitate AMP design or modification in the wet laboratory.


Hydrogelation Induced by Change in Hydrophobicity of Amino Acid Side Chain in Fmoc-Functionalised Amino Acid: Significance of Sulfur on Hydrogelation.
Although a few Fmoc-functionalised amino acids (Fmoc-AA) are capable of forming hydrogels, the exact levels of hydrophobicity, hydrogen bonding, and ionic nature of the Fmoc-AA gelator required for hydrogel formation remains uncertain. Here, the role of hydrophobicity of amino acid side chain, particularly in the formation of hydrogel, was studied by using Fmoc-norleucine (Fmoc-Nle) and its simple sulfur analogues such as Fmoc-methionine (Fmoc-M) in which the γCH2 of Fmoc-Nle is replaced by sulfur. Results indicate that Fmoc-M forms thermally reversible hydrogels in water (pH ca. 6.8), whereas Fmoc-Nle fails to display any gelation under similar conditions. The result suggests that substitution of the sulfur atom likely reduces the hydrophobicity of the alkyl side chain in Fmoc-Nle to the optimum level, which is sufficient to induce supramolecular hydrogelation in Fmoc-M. The difference in the self-association behaviour of Fmoc-M and Fmoc-Nle emphasise the importance of weak noncovalent interaction between side chains (in addition to the hydrogen-bond and aromatic interactions) to stabilise supramolecular self-assembly of Fmoc-functionalised compounds. The current observations provide a lead to the design of new sulfur-based low molecular weight gelators for various potential applications.


Inflammatory reactions in rainbow trout fins and gills exposed to biocides.
Several biocides are widely used in rainbow trout aquaculture against various ectoparasites and ectobionts, but the inflammation induced in treated fish is less well described. Dose-response studies were conducted to elucidate the effects on rainbow trout (gills and fins) induced by a series of biocides including formalin, hydrogen peroxide (H2O2), peracetic acid (PAA) and the surfactant SPH6, which was isolated from the bacterium Pseudomonas H6. The compounds have documented antiparasitic effects, but the specific effects on fish needs further documentation. This study was performed over 24 h, and inflammatory reactions were evaluated in gills and fins. A dose-dependent effect was noted for expression of immune genes encoding for IL-1β, TNFα, IFNγ, IL-10, IL-8, lysozyme, serum amyloid A (SAA), hepcidin, precerebellin and complement factor C3. PAA induced the strongest upregulation of cytokine and acute phase reactant genes followed by H2O2 and formalin. SPH6 showed a lower effect, and in several cases the compound induced downregulation of several genes. Gills showed a stronger response compared to fins. The mucous cell density in fins showed a range of changes which varied by compound. PAA, and to a lesser degree H2O2 and formalin, initially induced mucous cell hyperplasia, whereas SPH6 immediately decreased the number of cells containing mucus.


Mechanism of self-assembly process and seeded supramolecular polymerization of perylene bisimide organogelator.
The mechanism of supramolecular polymerization has been elucidated for an archetype organogelator molecule composed of a perylene bisimide aromatic scaffold and two amide substituents. This molecule self-assembles into elongated one-dimensional nanofibers through a cooperative nucleation-growth process. Thermodynamic and kinetic analyses have been applied to discover conditions (temperature, solvent, concentration) where the spontaneous nucleation can be retarded by trapping of the monomers in an inactive conformation, leading to lag times up to more than 1 h. The unique kinetics in the nucleation process was confirmed as a thermal hysteresis in a cycle of assembly and disassembly processes. Under appropriate conditions within the hysteresis loop, addition of preassembled nanofiber seeds leads to seeded polymerization from the termini of the seeds in a living supramolecular polymerization process. These results demonstrate that seeded polymerizations are not limited to special situations where off-pathway aggregates sequester the monomeric reactant species but may be applicable to a large number of known and to be developed molecules from the large family of molecules that self-assemble into one-dimensional nanofibrous structures. Generalizing from the mechanistic insight into our seeded polymerization, we assert that a cooperative nucleation-growth supramolecular polymerization accompanied by thermal hysteresis can be controlled in a living manner.


Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience.
Until recently, treatment options for patients with progressive, radioactive iodine-resistant differentiated thyroid cancer (DTC) have been limited. In our clinical practice, we have begun to use sorafenib and sunitinib for patients with progressive DTC who are not able or willing to participate in clinical trials. In this paper, we describe the University of Texas M. D. Anderson Cancer Center's experience with the off-label use of these tyrosine kinase inhibitors for DTC. Adult patients were included if they had a diagnosis of radioactive iodine-refractory DTC, were treated with single agent sorafenib or sunitinib, and had both baseline and at least one follow-up scan for restaging purposes. All imaging data were collected, as well as the TSH-suppressed thyroglobulin (Tg) levels corresponding to each scan date. The primary endpoints were radiographic response and progression-free survival (PFS). Secondary objectives were tissue-specific radiographic responses and correlation of Tg with overall response. We identified 33 patients from our clinical database. Fifteen patients (nine women, six men) met inclusion criteria, with a median age of 61 yr (range, 38-83 yr). Eight patients had papillary and seven had follicular thyroid carcinoma. Sorafenib was used in 13 and sunitinib in two, including one patient who failed prior sorafenib therapy. All patients had evidence of progressive disease (PD) before start of therapy, with a median PFS of only 4 months. Best response in target lesions was: partial response (PR) in three (20%), stable disease (SD) in nine (60%), and PD in three (20%). Clinical benefit (PR+SD) was 80%. The sunitinib patient previously refractory to sorafenib had a 38% reduction in tumor size. The most noticeable organ-specific response was observed in lung (median change, -22%) compared to lymph nodes (median change, 0%). Pleural disease and nonirradiated bone metastases demonstrated PD. All histological subtypes had similar responses. The median PFS was 19 months. The median overall survival has not yet been reached, but at 2 yr of follow-up, overall survival is 67%. Log Tg correlated with radiographic response (P = 0.0005). Sorafenib and sunitinib appear to be effective in patients with widely metastatic, progressive DTC, with most patients achieving SD or PR, despite having PD at baseline. The most noticeable responses occurred in the lungs in contrast with minimal changes in nodal metastases and PD in pleural and nonirradiated bone metastases, suggesting a tissue-specific response to therapy. Log Tg significantly correlated with response to treatment and therefore may have value as a surrogate marker of response.


Central odontogenic fibroma of the gingiva: a case report.
In this paper, we present a case of an uncommon and slow-growing tumor known as a central odontogenic fibroma (COF). The patient in question is a 53-year-old African-American man who was referred for periodontal evaluation of asymptomatic space formation between the mandibular central incisors. Clinical and radiological evaluations disclosed tumor-like tissue expanding the alveolar ridge in the buccolingual dimension, along with thinning of the cortical plates. Surgical excision was performed, and the specimen was sent for histopathology, which later confirmed that the lesion was a COF. Periodontal regenerative therapy was performed to rebuild the hard and soft tissue that had been compromised as a result of tumor expansion. The site was grafted, with excellent results.


Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis.
Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.


[A new approach to the problem of cardio-vascular regulation: the endocrine function of the heart (review of the literature)].
Besides generally known functions, the heart has also an endocrine function. Atrial cardiocytes, being typical secretory cells, released peptide hormones into the blood stream: atrial natriuretic peptide containing 28 amino acids and cardiodiolatin. The structure of atrial peptides was determined. It was shown that both derived from their common precursor, a protein containing 151 amino acid. The presence of specific receptors was demonstrated on plasmatic membranes of cells of kidney epithelium, arterial smooth muscle, arterial endothelium, kidney cortex and hypophysis. The interaction of atrial peptides with these receptors activated the guanylate cyclase system. The biological action of atrial peptides manifested itself in the quick, massive and instantaneous increase of diuresis and electrolyte excretion, elevation of clearance of creatinine, decrease of kidney vascular resistance, intensification of glomerular filtration, inhibition of stimulated secretion of aldosterone, relaxation of blood vessels, elimination of arterial and intestinal spasm induced by various endogenous and exogenous vasoconstrictors and correction of kidney hypertension. Various radioimmunoassays for detection of atrial peptides in human blood plasma were developed; it was shown that in patients with congestive failure the atrial peptide content was increased.


Optimized and validated HPLC method for alpha- and gamma-tocopherol measurement in Laurus nobilis leaves. New data on tocopherol content.
Extraction and chromatographic conditions for measuring tocopherols from Laurus nobilis were optimized. Newly harvested leaves were dried in a microwave oven and crushed; then, alpha- and gamma-tocopherol and tocol, added as internal standard, were directly extracted from portions of ground material with acetone, by probe sonication. After centrifugation and filtration, the acetonic extract was directly analyzed by HPLC using a gradient elution with a Discovery C18 column (25 x 0.46 cm) at 35 degrees C. UV and fluorescence detections were employed simultaneously. Validation parameters of the method for linearity, accuracy, and precision can be considered to be adequate for both detection modes. After validation, a number of samples selected from different geographical areas in the Iberian peninsula were measured, and results compared with those in the literature gave surprisingly high values.


Smoking History Is Associated With Adverse Outcomes for Kidney Allograft Recipients.
Donor kidney measurements may affect outcomes of transplanted allografts. We tested allograft and recipient measurements on kidney allograft outcomes. In this study, we compared the effects of kidney allograft volumes, which were measured using computed tomographic angiography before transplant, and allograft weight, which was measured during surgery, in relation to the recipient's body weight and body mass index on kidney function at 6 and 12 months after transplant. We included 74 patients (40 female and 34 male patients, mean age of 50.42 ±; 9.75 y) in this study. Intraoperative allograft weight was 182.68 ± 40.33 g (range, 104-266 g). The allograft volume measured using computed tomographic angiography scanning was 123.34 ± 24.26 mL (range, 78-181 mL). The estimated glomerular filtration rates of the recipients at 6 and 12 months after transplant correlated negatively with age and recipient body mass index but correlated positively with allograft volume/recipient body weight, allograft volume/recipient body mass index, allograft weight, allograft weight/recipient body weight, and allograft weight/recipient body mass index values, as concluded by univariate analyses. From multivariate analyses, we found variables of interest presumed to significantly affect the 12-month estimated glomerular filtration rates, including recipient age, allograft volume/recipient body weight, allograft volume/recipient body mass index, allograft weight, allograft weight/recipient body weight, and allograft weight/recipient body mass index. Transplanted allograft and recipient body values may be used as predictors of estimated glomerular filtration rates 6 and 12 months after transplant.


Pathogenic bacteria as vaccine vectors: teaching old bugs new tricks.
As our scientific knowledge of bacteria grows, so does our ability to manipulate these bacteria to protect rather than infect mammalian hosts from a diverse group of diseases. The old axiom that the best way to protect from a disease is to get infected in the first place is not feasible in the face of the diverse group of pathogens that infect humans. Therefore, reprogramming bacteria to protect against diverse bacterial, viral, and parasitic diseases as well as cancer is a new reality in the field of vaccines.


[Brivudine as an alternative systemic therapy to aciclovir and ganciclovir in acute retinal necrosis syndrome due to varicella-zoster virus].
Two cases of acute retinal necrosis (ARN-) syndrome caused by an infection with varicella zoster virus (VZV) are demonstrated. VZV-DNA was detected in vitreous biopsies by polymerase-chain-reaction (PCR). The course of retinal necrosis was decisively improved by changing antiviral therapy from aciclovir and/or ganciclovir to brivudine. Patient 1: 51 years, male, initial visual acuity 20/40; patient 2: 17 years, female, initial visual acuity 20/30. Both patients were immunocompetent and presented with an unilateral acute retinal necrosis syndrome with peripheral chorioretinitis, retinal vasculitis, vitreous inflammation and optic disc swelling, which resulted in progressive visual loss in a few days. In both patients VZV-DNA was detected in vitreous biopsies with PCR. A regression of intraocular inflammation and necrotic retinal foci was only observed after changing the initial systemic therapy from aciclovir (Zovirax) intravenously 1500 mg/day) and/or ganciclovir (Cymeven) intravenously 250 mg/day) to brivudine (Zostex) per os 500 mg/day). Vitreoretinal surgery was necessary in both patients because of rhegmatogenous retinal detachment. Visual acuity stabilised in patient 1 to 20/200 and in patient 2 to 20/25 during a follow-up of 16 or 32 months, respectively. Brivudine represents an alternative therapy, if standard treatment with aciclovir and/or ganciclovir failed in cases of ARN-syndrome due to presumed drug-resistant varicella zoster virus-subtypes. Complete remission and preservation of a satisfactory function can be achieved.


Label-free measurement of the yeast short chain TAG lipase activity by ESI-MS after one-step esterification.
Triacylglycerol (TAG) lipases hydrolyze ester bonds in TAG and release diacylglycerol (DAG), monoacylglycerol (MAG), and FA. We present a one-step chemical derivatization method for label-free quantification of a mixture of TAG, DAG, and MAG following lipase assay by ESI-MS. Because the ionization efficiencies of TAG, DAG, and MAG are not identical, lipase reaction products, DAG and MAG, are derivatized to TAG species by esterifying their hydroxyl groups using acyl chloride, whose acyl chain contains one less (or one more) -CH2 group than that of substrate TAG. This resulted in three TAG species that were separated by 14 Da from one another and exhibited similar ion responses representing their molar amounts in the mass spectra. A good linear correlation was observed between peak intensity ratios and molar ratios in calibration curve. This method enables simultaneous quantification of TAG, DAG, and MAG in lipase assay and, in turn, allows stoichiometric determination of the concentrations of FAs released from TAG and DAG separately. By applying this strategy to measure both TAG and DAG lipolytic activities of the yeast Tgl2 lipase, we demonstrated its usefulness in studying enzymatic catalysis, as lipase enzymes often show dissimilar activities toward these lipids.


Mechanochemical subcellular-element model of crawling cells.
Constructing physical models of living cells and tissues is an extremely challenging task because of the high complexities of both intra- and intercellular processes. In addition, the force that a single cell generates vanishes in total due to the law of action and reaction. The typical mechanics of cell crawling involve periodic changes in the cell shape and in the adhesion characteristics of the cell to the substrate. However, the basic physical mechanisms by which a single cell coordinates these processes cooperatively to achieve autonomous migration are not yet well understood. To obtain a clearer grasp of how the intracellular force is converted to directional motion, we develop a basic mechanochemical model of a crawling cell based on subcellular elements with the focus on the dependence of the protrusion and contraction as well as the adhesion and de-adhesion processes on intracellular biochemical signals. By introducing reaction-diffusion equations that reproduce traveling waves of local chemical concentrations, we clarify that the chemical dependence of the cell-substrate adhesion dynamics determines the crawling direction and distance with one chemical wave. Finally, we also perform multipole analysis of the traction force to compare it with the experimental results. Our present work sheds light on how intracellular chemical reactions are converted to a directional cell migration under the force-free condition. Although the detailed mechanisms of actual cells are far more complicated than our simple model, we believe that this mechanochemical model is a good prototype for more realistic models.


Two HCl-Elimination Channels and Two CO-Formation Channels Detected with Time-Resolved Infrared Emission upon Photolysis of Acryloyl Chloride [CH2CHC(O)Cl] at 193 nm.
Following photodissociation of gaseous acryloyl chloride, CH2CHC(O)Cl, at 193 nm, temporally resolved vibration-rotational emission spectra of HCl (v ≤ 7, J ≤ 35) in region 2350-3250 cm(-1) and of CO (v ≤ 4, J ≤ 67) in region 1865-2300 cm(-1) were recorded with a step-scan Fourier-transform spectrometer. The HCl emission shows a minor low-J component for v ≤ 4 with average rotational energy Erot = 9 ± 3 kJ mol(-1) and vibrational energy Evib = 28 ± 7 kJ mol(-1) and a major high-J component for v ≤ 7 with average rotational energy Erot = 36 ± 6 kJ mol(-1) and vibrational energy Evib = 49 ± 9 kJ mol(-1); the branching ratio of these two channels is ∼0.2:0.8. Using electronic structure calculations to characterize the transition states and each intrinsic reaction coordinate, we find that the minor pathway corresponds to the four-center HCl-elimination of CH2ClCHCO following a 1,3-Cl-shift of CH2CHC(O)Cl, whereas the major pathway corresponds to the direct four-center HCl-elimination of CH2CHC(O)Cl. Although several channels are expected for CO produced from the secondary dissociation of C2H3CO and H2C═C═C═O, each produced from two possible dissociation channels of CH2CHC(O)Cl, the CO emission shows a near-Boltzmann rotational distribution with average rotational energy Erot = 21 ± 4 kJ mol(-1) and average vibrational energy Evib = 10 ± 4 kJ mol(-1). Consideration of the branching fractions suggests that the CO observed with greater vibrational excitation might result from secondary decomposition of H2C═C═C═O that was produced via the minor low-J HCl-elimination channel, while the internal state distributions of CO produced from the other three channels are indistinguishable. We also introduce a method for choosing the correct point along the intrinsic reaction coordinate for a roaming HCl elimination channel to generate a Franck-Condon prediction for the HCl vibrational energy.


Observations on the Foliar Nematode, Aphelenchoides besseyi, Infecting Tuberose and Rice in India.
The foliar nematode Aphelenchoides besseyi causes white tip disease in rice (Oryza sativa L.) and floral malady in tuberose (Polianthes tuberosa L.). This nematode is widely distributed in the rice fields of many states of India, including West Bengal (WB), Andhra Pradesh (AP), Madhya Pradesh (MP) and Gujarat (GT). In order to generate information on intraspecific variations of A. besseyi as well as to confirm the identity of the nematode species infecting these important crops, morphological observation was undertaken of A. besseyi isolated from tuberose and rice from WB and rice from AP, MP and GT. The molecular study was only done for rice and tuberose populations from AP and WB. The variations were observed among the populations in the tail, esophageal and anterior regions, including the occurrence of four as well as six lateral lines in the lateral fields. The morphometrics of observed populations showed variations and those could be regarded as a consequence of host-induced or geographical variations. PCR amplification of the rDNA ITS 1 and 2 region of rice (AP) and tuberose (WB) populations of A. besseyi generated one fragment of approximately 830 bp, and the size of the ITS region was 788 bp and 791 bp for tuberose and rice population, respectively. Alignment of the two sequences showed almost 100% similarity. Blast analysis revealed a very high level of similarity of both the Indian strains to a Russian population. The Indian and Russian strains could be differentiated using restriction enzyme Bccl. Host tests revealed that rice (cv. IET 4094), oat (cv. OS-6) and teosinte (cv. TL-1) showed a typical distortion due to the infection of A. besseyi. Five germplasm lines of oat showed no infection of the nematode under field conditions. Local cultivars of onion, maize, chrysanthemum, gladiolus, and Sorghum halepense were also not infected by A. besseyi.


An ABC approach to cardiothoracic complications and sequelae of COVID-19: a tertiary centre experience.
The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused unprecedented challenges to healthcare professionals (HCPs) worldwide. HCPs faced an unknown disease causing many complications, including now well-established acute respiratory distress syndrome (ARDS) and pulmonary artery thromboembolic disease, and some not so well known, for instance, tracheobronchomalacia, tracheal tear or dehiscence, granulation tissue formation and pulmonary hypertension. Many of these complications require highly specialist care warranting early recognition of complications and involvement of appropriately trained professionals. Here, we review the complications and sequelae encountered at our tertiary care centre with follow-up data and potential management strategies using the A (Airway), B (Breathing), C (Circulation) approach. This will not only familiarise HCPs with the different complications of COVID-19, but also arm them with a systematic approach to these complications.


Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination.
Class switch recombination (CSR) is the process by which B cells alter the effector function properties of their Ig molecules. The decision to switch to a particular Ig isotype is determined primarily by the mode of B cell activation and cytokine exposure. More recent work indicates that the likelihood or probability of switching increases with successive cell divisions and is largely independent of time. We have analyzed different molecular features of CSR using cell division as a reference point in an attempt to gain insight into the mechanism of division-linked switching. Our results indicated that the accessibility of Ig heavy chain constant regions targeted for CSR was established after the cells had undergone a single cell division and did not vary significantly with subsequent cell divisions. In contrast, expression of activation-induced cytidine deaminase (AID) mRNA was found to increase with successive divisions, exhibiting a striking correlation with the frequency of CSR. Levels of AID in a given division remained constant at different time points, strongly suggesting that the regulation of AID expression was division-linked and independent of time. In addition, constitutive AID expression from a transgene accelerated division-linked CSR. Thus, we propose that the division-linked increase in AID expression provides an underlying molecular explanation for division-linked CSR.


MicroRNAs in endothelial senescence and atherosclerosis.
Aging is an important risk factor for the development of many cardiovascular diseases as atherosclerosis and is accompanied by the decline of endothelial function. Senescence of endothelial cells has been proposed to be involved in endothelial dysfunction and atherogenesis. Therefore, the study of new target therapies to prevent or reverse this process represents a field of great interest. MicroRNAs (miRNAs), a class of short RNAs, play key roles in various biological processes and in the development of human disease through specific posttranscriptional downregulation of gene expression. In particular, miRNAs that are highly expressed by endothelial cells can be detected in high concentration in human atherosclerotic plaques and in the circulation, suggesting their potential translation to bedside to determine the dysfunction of specific signaling pathways which play a role in coronary artery disease in the individual patient, a path towards a stratified medicine approach for early preventive treatment of disease. Here, we review the most recent advances in the field of atherosclerosis that implicate a role for miRNAs with a special emphasis on endothelial senescence and its involvement in the atherosclerotic process. Finally, we briefly discuss the potential use of miRNAs signatures to map atherosclerosis progression and in particular underlying the relevance of circulating plasma miRNAs that can be used clinically as biomarkers of vascular pathology.


Oxidative stress evaluation of ischemia and reperfusion in kidneys under various degrees of hypothermia in rats.
To design an animal model of ischemia-reperfusion (I/R) in kidneys and evaluate the role that predetermined ranges of local hypothermia plays on markers of stress-oxydative as well as on histologic sections. Twenty eight male rats Wistar, under general anesthesia, undergone right nephrectomy (G0, control group) followed by left kidney ischemia during 40 min. Four temperatures groups were designed, with seven animals randomized for each group: normothermic (G1, ±37ºC), mild hypothermia (G2, 26ºC), moderate hypothermia (G3, 15ºC) and deep hypothermia (G4, 4ºC). Left kidney temperature was assessed with an intraparenchymal probe. Left nephrectomy was performed after 240 min of reperfusion. After I/R a blood sample was obtained for f2-IP. Half of each kidney was sent to pathological evaluation and half to analyze CAT, SOD, TBARS, NO3, NO2. Histopathology showed that all kidneys under I/R were significantly more injured than the G0 (p<0.001). TBARS had increased levels in all I/R groups compared with the G0 (p<0.001). CAT had a significant difference (p<0.03) between G1 and G4. Finally, no difference was found on SOD, NO3, NO2 nor on f2-IP. This model of I/R was efficient to produce oxidative-stress in the kidney, showing that 4ºC offered significant decrease in free radicals production, although tissue protection was not observed.


Protection of Kidney Function with Human Antioxidation Protein α1-Microglobulin in a Mouse 177Lu-DOTATATE Radiation Therapy Model.
Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α1-microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT. We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 (177Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term), 177Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term), 177Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment.


[Cholinoreception in Ascaris suum (Nematoda) ascarids and the liver fluke Fasciola hepatica (Trematoda)].
Homogenates of synaptically rich structures of the body (the anterior end of A. suum and F. hepatica, as well as narrow strips of the anterior part of A. suum with median nerves and innervation processes of muscle cells) have been tested for the presence of acetylcholine receptor protein (AchR). Strips of the A. suum muscle tissue with low content of synaptic structures served as a control. AchR was detected by the decrease in the optic density at 260 nm and by the decrease in the reactivity of AchR SH-groups in the presence of Ach. Using both methods, AchR was found in water-soluble fraction of tissue homogenates rich in synaptic structures. No AchR was detected in tissues which do not contain synpatic structures. The data obtained are discussed in relation to the function of Ach as a mediator in helminths.


[Effect of serum fractions from cancer patients on leukocyte migration out of capillary tubes].
Blood serum of patients suffering from cancer of the stomach and urinary bladder inhibited in vitro migration of autologous leukocytes, leukocytes of donors and control patients, and also guinea pig macrophages in over half of cases. In chromatography of these sera on Sephadex G-100 the activity inhibiting the leukocyte migration was revealed in fraction I (Mol. wt. over 100000) and in fractions IV and V (Mol. wt under 30 000). The blood serum and its fractions from cancer patients failed to eliminate the leukocyte migration inhibition caused by the tumour antigens in comparison with the leukocyte migration in the medium with control serum without any antigens. As suggested, the activity of fraction I inhibiting the leukocyte migration was due to the antigen-antibody complex, and of fraction IV and V--to a factor similar by its properties to the factor produced in vitro by lymphocytes stimulated by the antigens or mitogens.


Updates in non-small cell lung cancer.
Lung cancer is the leading cause of cancer death in both men and women. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, representing more than 80% of lung cancer diagnoses. Five-year survival remains at 15%, but new strategies for prevention, early detection, and treatment may improve survival rates. This article provides an overview of updates in NSCLC, with an emphasis on advances in treatment strategies. Newer targeted therapies, as well as advances in genetic blueprinting, will be discussed. Nurses play a pivotal role in the assessment and management of patients with NSCLC and, therefore, must remain abreast of the most current prevention, screening, and treatment options.


MCP-1-MCP-3-Eotaxin gene cluster influences HIV-1 transmission.
MCP-1 (CCL2), MCP-3 (CCL7), and eotaxin (CCL11) are genes for CC chemokines clustered on the long arm of chromosome 17. Previous studies have implicated these chemokines in monocyte recruitment, viral replication, and anti-HIV cytotoxic T cell responses. An epidemiological analysis identified genetic variants influencing HIV-1 transmission and disease progression. Genomic DNA from over 3000 participants enrolled in five natural history cohorts in the United States were analyzed. Nine single nucleotide polymorphisms (SNP) covering 33 kb containing these three genes were genotyped using the polymerase chain reaction. Distortions in allele, genotype, and haplotype frequencies were assessed with respect to HIV-1 transmission and rates of disease progression using categorical and survival analyses. Extensive linkage disequilibrium was observed. Three SNP (-2136T located in the MCP-1 promoter region, 767G in intron 1 of MCP-1, and -1385A in the Eotaxin promoter) were nearly always found together on a 31 kb haplotype (H7) containing the three genes. Frequencies of the three variants and the H7 haplotype were significantly elevated (odds ratio, 0.6; P = 0.005-0.01) in uninfected European-Americans repeatedly exposed to HIV-1 through high-risk sexual behavior or contaminated blood products. Although the extensive linkage disequilibrium precludes positive identification of the causal variant, the results suggest that genetic variation in the H7 region influences susceptibility to HIV-1 infection. Since these chemokines do not bind the primary HIV-1 coreceptors CCR5 or CXCR4, the observed influence on transmission may result from activation of the immune system in response to infection rather than receptor blockage.


Blood pressure and flow rate in the giraffe jugular vein.
Experimental measurements in the jugular veins of upright giraffes have shown that the internal pressure is somewhat above atmospheric and increases with height above the heart. A simple model of steady viscous flow in an inverted U-tube shows that these observations are inconsistent with a model in which the blood vessels in the head and neck are effectively rigid and the system resembles a siphon. Instead, the observations indicate that the veins are collapsed and have a high resistance to flow. However, laboratory experiments with collapsible drain tubing in place of the down arm of the U-tube show internal pressure to be exactly atmospheric and uniform with height. A model of viscous flow in a collapsible tube with non-uniform properties is used to suggest that the observed pressure distribution may be a consequence of the intrinsic cross-sectional area and/or compliance of the veins increasing with distance towards the heart, or the external, tissue pressure falling. Finally, the effect of fluid inertia on steady flow in vertical collapsible tubes with uniform intrinsic properties is analysed, and it is shown that a phenomenon of flow limitation is theoretically possible, in which the supercritical flow in the collapsed vein cannot return to the presumably subcritical flow in the open vena cava, even with the help of an 'elastic jump', if the flow rate is too large. The computed critical flow-rate, of about 80 ml s-1, is about twice the flow-rate estimated to be present in the normal giraffe jugular vein. If there were circumstances in which flow limitation occurred in the jugular veins, it would mean that the cerebral blood flow would be limited by downstream conditions, not directly by local requirements.


Butyrate Production Pathway Abundances Are Similar in Human and Nonhuman Primate Gut Microbiomes.
Over the course of human evolution, shifts in dietary practices such as meat-eating and cooking, have resulted in reduced fiber intake, a trend that has been exaggerated more recently in industrialized populations. Reduced fiber consumption is associated with a loss of gut microbial taxa that degrade fiber, particularly butyrate. Therefore, this dietary shift in humans may have altered the abundance of microbial genes involved in butyrate production. This study uses a gene-targeted alignment approach to quantify the abundance of butyrate production pathway genes from published wild nonhuman primate and human gut metagenomes. Surprisingly, humans have higher diversity and relative abundances of butyrate production pathways compared with all groups of nonhuman primates except cercopithecoids. Industrialized populations of humans also differ only slightly in butyrate pathway abundance from nonindustrialized populations. This apparent resilience of butyrate production pathways to shifts in human diet across both evolutionary and modern populations may signal an evolutionary shift in host-microbe interactions in humans that increased SCFA production. Such a shift could have contributed to meeting the increased energy requirements of humans relative to nonhuman primates.


Linking stable and dynamic features of positive affect to sleep.
Poor sleep contributes to adult morbidity and mortality. The study examined the extent to which trait positive affect (PA) and PA reactivity, defined as the magnitude of change in daily PA in response to daily events, were linked to sleep outcomes. Analyses are based on data from 100 respondents selected from the National Survey of Midlife in the United States. Multilevel analyses indicated that higher levels of trait PA were associated with greater morning rest and better overall sleep quality. In contrast, PA reactivity was associated with diminished sleep efficiency. Finally, interactions between PA reactivity and trait PA emerged on all three sleep measures, such that higher event-related change in daily positive affect was associated with impaired sleep, especially among individuals high in trait PA. Results suggest that high trait PA, when coupled with high PA reactivity, may contribute to poor sleep.


Progress in Programmable DNA-Aided Self-Assembly of the Master Frame of a Drug Delivery System.
Every year cancer causes approximately 10 million deaths globally. Researchers have developed numerous targeted drug delivery systems (DDSs) with nanoparticles, polymers, and liposomes, but these synthetic materials have poor degradability and low biocompatibility. Because DNA nanostructures have good degradability and high biocompatibility, extensive studies have been performed to construct DDSs with DNA nanostructures as the molecular-layer master frame (MF) assembled via programmable DNA-aided self-assembly for targeted drug release. To learn the progressing trend of self-assembly techniques and keep pace with their recent rapid advancements, it is crucial to provide an overview of their past and recent progress. In this review article, we first present the techniques to assemble the MF of a DDS with solely DNA strands; to assemble MFs with one or more additional type of construction materials, e.g., polymers (including RNA and protein), inorganic nanoparticle, or metal ions, in addition to DNA strands; and to assemble the more complex DNA nanocomplexes. It is observed that both the techniques used and the MFs constructed have become increasingly complex and that the DDS constructed has an increasing number of advanced functions. From our focused review, we anticipate that DDSs with the MF of multiple building materials and DNA nanocomplexes will attract an increasing number of researchers' interests. On the basis of knowledge about materials and functional components (e.g., targeting aptamers/peptides/antibodies and stimuli for drug release) obtained from previously performed studies, researchers can combine more materials with DNA strands to assemble more powerful MFs and incorporate more components to endow DDSs with improved or additional properties/functions, thereby subsequently contributing to cancer prevention.


Effect of limb positioning on the radiographic appearance of the distal and proximal interphalangeal joint spaces of the forelimbs of horses during evaluation of dorsopalmar radiographs.
To determine the effect of limb positioning on the radiographic appearance of the distal and proximal interphalangeal joint spaces of the forelimbs of horses during evaluation of dorsopalmar radiographs. Evaluation study. 14 forelimbs from 9 adult horses. Each horse was in standing position with its forelimbs positioned on blocks. Dorsopalmar radiographs of each foot were obtained with the forelimbs positioned squarely (the metacarpus of both forelimbs was perpendicular to the ground as determined by visual examination [abducted 0°]; baseline) and abducted 5° and 10°. The width of the space at the medial and lateral aspects of the distal and proximal interphalangeal joints (medial and lateral joint space width, respectively) was measured. Mediolateral joint balance was calculated as the difference between the widths of the lateral and medial joint spaces, and joint space width and mediolateral joint balance were compared among all 3 positions. As the extent of limb abduction increased, the medial aspect of the proximal and distal interphalangeal joints became narrower, compared with the corresponding lateral aspect of those joints. For both the distal and proximal interphalangeal joints, the mediolateral joint balance differed significantly among all limb positions. Forelimb position significantly affected the mediolateral joint balance of the interphalangeal joints of horses. Thus, it is crucial that the forelimbs of horses be squarely positioned when dorsopalmar radiographs are obtained for accurate evaluation of interphalangeal joint space and balance.


Early posthatch starvation induces myonuclear apoptosis in chickens.
The effect of early posthatch starvation on myonuclear apoptosis was examined in chickens. Male broiler chickens were or were not provided feed for the first 3-d posthatch. Subsequently, all chickens were provided feed for an additional 4-d posthatch. Chickens were killed at 3- and 7-d posthatch, and the pectoralis thoracicus was harvested, fixed and embedded in paraffin. Muscle sections were labeled with the terminal deoxynucleotidyl transferase histochemical staining technique to identify apoptotic nuclei. At 3- and 7-d posthatch, there was a significantly (P < 0.05) smaller myofiber cross-sectional area for the starved compared with the fed chickens. A larger proportion (P < 0.05) of apoptotic nuclei relative to total nuclei was observed in the starved compared to the fed chickens killed at 3-d posthatch, but the proportion of apoptotic nuclei relative to total nuclei did not differ (P > 0.05) between the starved and fed chickens killed at 7-d posthatch. It appears that apoptosis is a mechanism contributing to the smaller myofiber size observed when feed is not provided early posthatch.


Barriers to and Facilitators of Participation in Health and Social Care Governance: Categories and Cross-Cutting Themes from a Survey of SHAPES Project Partners.
Good governance-aligned with human rights and rights-based care, participation, inclusion, and person-centredness-of digital care systems is integral to their ability to meet their objectives. To gain insight into existing governance structures and processes and participation experiences across Europe and lay foundations for the SHAPES Project's network governance (a healthy and active ageing Innovation Action consortium), our objectives included: 1) expand the list of known stakeholders, 2) explore how the range of stakeholders participate in health and social care governance, 3) develop an inventory of barriers and facilitators. Using an empirical, survey method, we consulted SHAPES Project partner organisations, with respondents invited to suggest specific participation barriers and facilitators. 16 organisations responded. Numerous additional stakeholders were identified. Circa 150 unique barriers and facilitators were reported, rationalised into 20 superordinate categories. Six cross-cutting themes were assembled: dimensionality and flux; power; opportunity and environments; interest, motivation, and choice; valuing governance participation, and duality. This work allows consideration of a wide range of stakeholders for the SHAPES collaborative governance model and future research, and for system design with the benefit of a detailed inventory of barriers and facilitators, and thematic contextualisation. Participation is modifiable and we suggest intervention targets and mechanisms.


Prevalence of Campylobacter and Salmonella at a squab (young pigeon) processing plant.
Microbiological testing for Campylobacter and Salmonella was performed at a processing plant for squab (young pigeon) in three separate trials. Live birds, carcasses, and equipment were targeted for sampling during the preslaughter, pre-evisceration, and postevisceration stages of processing. The three trials represented 18 farms (1,110 squab), 1 farm (250 squab), and 23 farms (2,900 squab). The overall prevalence of positive samples in Trial 1 was 1.4% for Salmonella spp. and 11.1% for C. jejuni; in Trial 2, 4.3 and 0% for Salmonella spp. and C. jejuni; and in Trial 3, 4.1 and 4.8% for Salmonella spp. and C. jejuni, respectively. These observations represent a significantly greater likelihood of having a positive sample for Campylobacter (twofold) or Salmonella (eightfold) at processing, compared with prevalences observed in our previous on-farm study. This finding suggests an overall increase in the number of carcasses contaminated or in the concentration of contamination during transport and processing. In the multifarm trials, only Trial 3 demonstrated a significant increase in the prevalence of positive samples from the preslaughter to the postevisceration stages of processing (P = 0.02), and only for Campylobacter. The prevalence of positive cultures from equipment surfaces were not different than carcasses during processing, therefore no additional critical control points were identified within this system. When pooled swabs were compared (Trial 1) to individual swabs (Trials 2 and 3), no statistical difference in the prevalence of Salmonella or Campylobacter was observed between trials. Direct plating from a pooled sample onto selective agar media (Trial 1) and single swab culture with enrichment followed by plating on selective agar (Trials 2 and 3) were compared for Campylobacter isolation. No statistical difference in C. jejuni prevalence was observed using either method; however, when the detection limit of each method was determined, single swabs with enrichment had greater sensitivity.


Psychiatric aspects of fitness for duty.
The above examples illustrate the complex of biologic, psychological, and social factors that result in a fitness for duty referral. Workplace needs set the tolerance limits within which the worker must operate. They are different for a police officer, for a correctional officer, for a schoolteacher, and for a school custodian. Tolerance limits are affected by factors out of the employer's control, e.g., civil service rules, union contracts, and by the culture of the workplace, the latter being a set of unwritten rules. Ideally, the psychiatrist who performs the fitness for duty examination would have all of the information described above, but in most cases does not. The psychiatrist who has this information can begin to put in place one part of the mosaic that is the ethnography of work.


Important effects of relative humidity on the formation processes of iodine oxide particles from CH3I photo-oxidation.
In this work, laboratory chamber experiments of gas-phase methyl iodide photolysis in the presence of ozone at three relative humidity conditions were performed to study the formation and physico-chemical properties of iodine oxide particles. The obtained results revealed significant morphological changes of iodine oxide particles that were observed to depend on relative humidity. The formed iodine oxide particles under dry conditions were supposed to be agglomerates of fine hygroscopic crystals. On the other hand, a humid atmosphere was observed to favor the formation of isomeric, tetragonal and orthorhombic hygroscopic crystals potentially composed of HIO3 likely formed from progressive hydration of iodine oxide clusters. This process leads to a release of molecular iodine, I2, which may indicate a potential role of I2O4 in the particles' evolution processes. The obtained results on the iodine oxides' behavior are important to the nuclear power plant safety industry since many of the organic iodides that may be released during a major nuclear power-plant accident contain radioactive isotopes of iodine that are known to have lethal or toxic impacts on human health.


Mirtazapine relieves post-electroconvulsive therapy headaches and nausea: a case series and review of the literature.
Headaches and nausea are the 2 most common adverse effects of electroconvulsive therapy (ECT). These adverse effects have been frequently reported in the postictal period and make it difficult for the patient to continue with the following ECTs. Mirtazapine is an antidepressant with a mechanism that involves activating serotonin (5-HT1) receptors. This mechanism has been hypothesized to be the underlying therapeutic effects for depression and anxiety. In addition, mirtazapine possesses antagonistic effects on the postsynaptic serotonin 5-HT2 and 5-HT3 receptors. The pharmacological actions are hypothesized to be related to its treatment effects of headaches and nausea. Here, we report a case series of patients developing post-ECT headaches and nausea, and the concomitant administration of mirtazapine successfully relieved the ECT-associated adverse effects. This case series suggest that mirtazapine may be an optional treatment for ECT-induced headaches and nausea.


Sociomedical correlates of missed opportunities for immunisation.
Missed opportunity for immunisation is one of the hurdles in the achievement of 85 percent or more immunisation coverage. It is essential to screen every child for immunisation status and advise necessary immunisation at every opportunity otherwise full immunisation coverage may not be possible. Present survey was carried out at Indira Gandhi Medical College and Hospital, Nagpur to study the sociomedical correlates of missed opportunities for immunisation in children below 2 years of age attending the hospital. Missed opportunities for immunisation in these children was found to be 39.9%. It is mostly for B. C. G. (21.8%) and measles (9.8%) and maximum for booster doses of DPT and polio (43%).


The Valsalva maneuver and Alzheimer's disease: is there a link?
Recent research findings provide evidence for Alzheimer's disease-related changes in brain diseases, such as normal pressure hydrocephalus and traumatic brain injury, and in glaucoma at the level of the retinal ganglion cells. This is a group of diseases that affect central nervous system tissue and are characterized by elevation of intracranial or intraocular pressure and/or local shear stress and strain. This strengthens the possibility that Alzheimer-type changes in these diseases may result at least in part from exposure of central nervous system tissue to elevated mechanical load. As activities or diseases with significant Valsalva effort can generate increased intracranial pressures, we hypothesize that individuals who frequently perform strong Valsalva maneuvers (e.g., long hours of repetitive heavy lifting, sequences of blows during the playing of a wind instrument, forceful and repetitive cough, bearing-down efforts during parturition) may be more susceptible to developing Alzheimer's disease. In this paper, we discuss three hypotheses about the mechanisms by which extensive use of the Valsalva maneuver might contribute to the neuropathogenesis of Alzheimer's disease: via mechanical stress-induced events in the hippocampus and/or via changes in the secretory process of the choroid plexus and/or via hemodynamic changes in cerebral blood flow. If confirmed, this hypothesis could have implications in clinical practice.


[An analysis of the immunity indices of patients with indurative diseases of the head of the pancreas].
Based on an analysis of dynamics of immunity indices the authors have revealed differences in the character of their changes in nontumoral and tumoral diseases and in relation to the stage of the malignant process. The optimal minimum of indices of the immunity status in indurative diseases of the pancreas head is proposed which is of significance for differential diagnosis and determination of resectability of the tumor.


[Prevalence of smoking among high school teachers and students in Norway].
The Ministry of Health and Social Affairs has defined "smoke-free schools" and "role models" as priority objectives in a document describing the national strategy to prevent the harmful effects of tobacco. We have investigated smoking policies in upper secondary schools, and to what extent policies support these objectives. Heads of Schools or Counsellors at all 487 upper secondary schools in Norway were contacted by telephone. Up to five calls were placed to reach the right person. A total of 432 interviews were conducted (90% response) in the course of December 1998. 85% of upper secondary schools permit the teachers and 90% permit the students to smoke in the school area. At 35% of the schools students and teachers smoke together on a daily basis. There are geographical differences in levels of restriction. 20% of the schools have prepared a plan of action against use of tobacco. Compared with schools without such a plan, smoking is less frequent among both teachers and students, and tobacco prevention activities are given higher priority. We conclude that public authorities should introduce a set of universal rules for smoking among students and teachers in the upper secondary school.


Erythrocyte deformability and hemorheological profile in multiple myeloma.
The hemorheological profile in multiple myeloma (MM) has been extensively studied. Our investigation regarded the behavior of whole-blood viscosity, plasma viscosity and erythrocyte deformability in MM. We enrolled 24 MM patients; 13 of them had been recently diagnosed and were at the initial stage of therapy, 6 were on consolidation/conservation therapy and 5 had achieved a complete remission. On fasting venous blood we evaluated whole-blood and plasma viscosity at high and low shear rates, haematocrit, the ratios between whole-blood viscosity (at high and low shear rate) and haematocrit×100, the ratio between plasma viscosity at low and high shear rate and the erythrocyte deformability examined by using laser diffractometry and expressed as elongation index. A significant increase in plasma viscosity at low shear rate and a marked decrease in haematocrit were observed in MM patients compared with normal controls. Also the ratio between the high shear rate whole-blood viscosity and haematocrit ×100 and the ratio between the low and high shear rate plasma viscosity were significantly increased in MM patients. A significant decrease in erythrocyte deformability, especially at low shear stresses, was found. We discuss some hypotheses that might explain the behavior of red blood cell deformability in MM, considering that its impairment, in addition to the increase of plasma viscosity, can alter the microcirculatory flow in these patients.


Self-care practices among type II diabetics in rural area of Kancheepuram district, Tamil Nadu.
Type 2 diabetes mellitus is one of the most prevalent noncommunicable diseases in India. The acute and chronic complications of diabetes impact the physical, mental, and social well-being of the patients, thereby, placing a major burden on the health care system. Studies have shown that adequate self-care practices among the patients will facilitate good glycemic control and prevent complications. To study the patterns of self-care practice among diabetic patients and the factors associated with them. This descriptive cross-sectional study was carried out among 250 diabetics in the rural field practice area of a Tertiary Medical College and Hospital in Chennai. The participants were interviewed on their diabetic status and various components of self-care practices adopted from The Summary of Diabetes Self-care Activities (SDSCA) Measure. Adherence to medication was assessed by using Morisky Medication Adherence Scale-4 (MMAS-4). Our study observed that the overall prevalence of good self-care practices was very low (5.6%). Moderate self-care practices were prevalent in 42% of the study participants whereas the majority (52.4%) of the study population had poor self-care practices. In our study, the association between self-care activity with educational status and occupation was found to be statistically significant. Adherence was high for blood sugar testing (75.2%) and medication (70.4%) in the study population whereas adherence for foot care was poor (17.6%). Our study emphasized on the need for knowledge and awareness to be provided in rural areas regarding diabetes care management and self-care practices. Structured programs need to be planned to improve the attitude and practices of diabetic patients to promote better compliance towards diet, exercise, adherence to drugs, and appropriate foot care.


Arteriovenous malformations of the gastrointestinal tract.
During an eight-year period, 17 patients ranging in age from 7 months to 81 years were found to have arteriovenous malformations (AVMs) of the gastrointestinal tract complicated by major hemorrhage. After review of these cases, a clinical classification of AVMs was developed, based on angiographic characteristics, localization, age of the patient, and family history. Type 1 AVMs were solitary, localized lesions within the right side of the colon. They occurred in seven patients 55 years of age or older. None were palpable or visible at operation. Type 2 AVMs occurred in seven patients. They were larger and occasionally visible, most commonly in the small intestine, and probably of congenital origin. Symptoms all began before 50 years of age. Type 3 AVMs were punctate angiomas causing gastrointestinal hemorrhage. They occurred in three patients with the classical findings of hereditary hemorrhagic telangiectasia. The diagnosis of most AVMs can be determined preoperatively only by selective angiographic studies.


rVISTA 2.0: evolutionary analysis of transcription factor binding sites.
Identifying and characterizing the transcription factor binding site (TFBS) patterns of cis-regulatory elements represents a challenge, but holds promise to reveal the regulatory language the genome uses to dictate transcriptional dynamics. Several studies have demonstrated that regulatory modules are under positive selection and, therefore, are often conserved between related species. Using this evolutionary principle, we have created a comparative tool, rVISTA, for analyzing the regulatory potential of noncoding sequences. Our ability to experimentally identify functional noncoding sequences is extremely limited, therefore, rVISTA attempts to fill this great gap in genomic analysis by offering a powerful approach for eliminating TFBSs least likely to be biologically relevant. The rVISTA tool combines TFBS predictions, sequence comparisons and cluster analysis to identify noncoding DNA regions that are evolutionarily conserved and present in a specific configuration within genomic sequences. Here, we present the newly developed version 2.0 of the rVISTA tool, which can process alignments generated by both the zPicture and blastz alignment programs or use pre-computed pairwise alignments of several vertebrate genomes available from the ECR Browser and GALA database. The rVISTA web server is closely interconnected with the TRANSFAC database, allowing users to either search for matrices present in the TRANSFAC library collection or search for user-defined consensus sequences. The rVISTA tool is publicly available at http://rvista.dcode.org/.


Autoimmune Pancreatitis.
Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disease of the pancreas that belongs to the spectrum of immunoglobulin G-subclass4-related diseases (IgG4-RD) and typically presents with obstructive jaundice. Idiopathic duct-centric pancreatitis (IDCP) is a closely related but distinct disease that mimics AIP radiologically but manifests clinically most commonly as recurrent acute pancreatitis in young individuals with concurrent inflammatory bowel disease. IgG4 levels are often elevated in AIP and normal in IDCP. Histologically, lymphoplasmacytic acinar inflammation and storiform fibrosis are seen in both. In addition, the histologic hallmark of IDCP is the granulocyte epithelial lesion: intraluminal and intraepithelial neutrophils in medium-sized and small ducts with or without granulocytic acinar inflammation often associated with destruction of ductal architecture. Initial treatment of both AIP and IDCP is with oral corticosteroids for duration of 4 weeks followed by a gradual taper. Relapses are common in AIP and relatively uncommon in IDCP, a relatively rare disease for which the natural history is not well understood. For patients with relapsing AIP, treatment with immunomodulators and more recently rituximab has been recommended. Although rare instances of pancreaticobiliary malignancy has been reported in patients with AIP, overall the lifetime risk of developing pancreatic cancer does not appear to be elevated.


Thermodynamics, structure and properties of polynuclear lanthanide complexes with a tripodal ligand: insight into their self-assembly.
Self-assembly processes between a tripodal ligand and Ln(III) cations have been investigated by means of supramolecular analytical methods. At an equimolar ratio of components, tetranuclear tetrahedral complexes are readily formed in acetonitrile. The structural analysis of the crystallographic data shows a helical wrapping of binding strands around metallic cations. The properties of this series of highly charged 3D compounds were examined by using NMR spectroscopy and optical methods in solution and in the solid state. In the presence of excess metal, a new trinuclear complex was identified. The X-ray crystal structure elucidated the coordination of metallic cations with two ligands of different conformations. By varying the metal/ligand ratio, a global speciation of this supramolecular system has been evidenced with different spectroscopic methods. In addition, these rather complicated equilibria were successfully characterised with the thermodynamic stability constants. A rational analysis of the self-assembly processes was attempted by using the thermodynamic free energy model and the impact of the ligand structure on the effective concentration is discussed.


Endothelin-1 stimulates tyrosine phosphorylation of p125 focal adhesion kinase in mesangial cells.
Endothelin-1 (ET-1) is known to induce the contraction and proliferation of glomerular mesangial cells. Because ET-1 was found to stimulate the tyrosine phosphorylation of unidentified cellular proteins in cultured mesangial cells, protein tyrosine kinase might serve as one of the important signals leading to various functions of ET-1. Focal adhesion kinase (p125FAK) is a newly identified cytoplasmic protein tyrosine kinase that is activated by the phosphorylation of its own tyrosine residue. Because p125FAK was found to play a role in the signal transduction of not only integrins but also various neurotransmitters, including bombesin, endothelin, and vasopressin in Swiss 3T3 cells and Rat-1 fibroblasts, whether ET-1 could stimulate the tyrosine phosphorylation of p125FAK in glomerular mesangial cells was examined. ET-1 stimulated the tyrosine phosphorylation of p125FAK by threefold to fourfold in cultured mesangial cells. This effect of ET-1 was detected at 1 min and reached a maximum within 5 min and was blocked by BQ-123, an antagonist for ETA receptor. A23187, a calcium ionophore, failed to stimulate the tyrosine phosphorylation of p125FAK, and ET-1 was able to stimulate the tyrosine phosphorylation of p125FAK, even in a calcium-free medium. The activation of protein kinase C (PKC) by phorbol 12, 13-dibutyrate resulted in a stimulation of the tyrosine phosphorylation of p125FAK, and an inhibition of PKC by calphostin C or staurosporine significantly reduced the effect of ET-1. Furthermore, prolonged treatment of the cells with phorbol 12, 13-dibutyrate markedly inhibited the ET-1-induced tyrosine phosphorylation of p125FAK. These results indicate that p125FAK might play a role in a signal transduction system of ET-1 in glomerular mesangial cells and that the ET-1-induced tyrosine phosphorylation of p125FAK is largely dependent on the PKC pathway.


Colloidal Quantum Dots as Photocatalysts for Triplet Excited State Reactions of Organic Molecules.
Triplet excited state chemistry has enabled a range of important organic transformations by accessing reaction pathways inaccessible to photoredox chemistry. Such photoreactions are triggered by triplet photosensitizers, which absorb visible-light photons and transfer the energy to the substrate or to a co-catalyst through triplet-triplet energy transfer (TT EnT). The most popular triplet photosensitizers, metal complexes and organic chromophores, have proven useful in a range of pericyclic reactions, bond dissociations, and isomerizations, but they have several characteristics related to their chemical and electronic structure that limit their selectivity, energy efficiency, and sustainability. This Perspective describes some ways that colloidal quantum dots (QDs) address the limitations of molecular photocatalysts for TT EnT-driven organic transformations. These sub-5-nm particles have the large catalytic surface area and electronic/optical tunability of homogeneous catalysts, and the easy separation and surface templating effects of heterogeneous catalysts. Their optical and electronic properties, small singlet-triplet energy splitting, narrow emission line widths, and high photostability enhance their performance as triplet photosensitizers. This Perspective describes these advantages in the context of published and ongoing investigations of TT EnT-driven reactions, and then highlights the advantages and challenges associated with using related emerging materials, specifically lead halide perovskite QDs and quasi-2D nanoplatelets, as photocatalysts for triplet excited state chemistry.


Expression of epidermal growth factor receptor in human cultured cells and tissues: relationship to cell lineage and stage of differentiation.
Mouse monoclonal antibodies have been used to study the distribution of the epidermal growth factor receptor in human cultured cells and tissues. As expected, most epithelial cells expressed epidermal growth factor receptor (EGFr), whereas cells of hematopoietic origin were EGFr-. However, EGFr was found to be differentially expressed on cultured cells of neuroectodermal origin. Normal melanocytes and a proportion of melanomas are EGFr-, whereas a distinct subset of other melanomas, astrocytomas, and neuroblastomas is EGFr+. Expression of the EGFr in melanomas was closely related to the expression of phenotypic traits of differentiation. Less differentiated melanomas have an epithelioid morphology and are nonpigmented, Ia+, and EGFr+; in contrast, more differentiated melanomas have a dendritic morphology and are pigmented, Ia-, and EGFr-. In the melanoma cell panel used, expression of EGFr did not correlate with rate of proliferation. Expression of EGFr in tissues also showed a lack of correlation with the proliferative state of cells. Our findings indicate that expression of EGFr is related to cell lineage and specific stages of cellular differentiation, rather than only to cell proliferation. The data suggest that receptor content may be elevated in a large number of tumor cell lines.


Health care fraud: recent developments and timeless advice.
Health care fraud has gained increased attention at both the state and federal levels in recent years. The $875 million criminal settlement by TAP Pharmaceutical Products, Inc, in October 2001 and subsequent indictments of physicians involved with the alleged HCA Medicare fraud conspiracy highlight the fact that physicians who are unaware of any wrongdoing may get dragged into the government's battle. The various laws and overlapping enforcement agencies can be complex and daunting to a physician who is falsely accused. This article provides a brief overview of three relevant federal health care fraud statutes: the Prescription Drug Marketing Act, the Medicaid Anti-Kickback Statute, and the False Claims Act. The article also briefly discusses the Texas Medicaid Fraud Prevention Act and the roles of various state agencies responsible for the detection and prevention of health care fraud. Finally, the article provides practical advice about the investigate process and what every prudent physician should do if under investigation.


Films from resistant starch-pectin dispersions intended for colonic drug delivery.
Free films were obtained by the solvent casting method from retrograded starch-pectin dispersions at different polymer proportions and concentrations with and without plasticizer. Film forming dispersions were characterized according to their hardness, birefringence and rheological properties. The polymer dispersions showed a predominantly viscous behavior (G″>G') and the absence of plasticizers lead to building of stronger structures, while the occurrence of Maltese crosses in the retrograded dispersions indicates the occurrence of a crystalline organization. Analyses of the films included mechanical properties, thickness, superficial and cross sectional morphology, water vapor permeability, liquid uptake ability, X-ray diffractometry, in vitro dissolution and enzymatic digestion. The high resistant starch content (65.8-96.8%) assured the resistance of materials against enzymatic digestion by pancreatin. Changes in the X-ray diffraction patterns indicated a more organized and crystalline structure of free films in relation to isolated polymers. Increasing of pectin proportion and pH values favored the dissolution and liquid uptake of films. Films prepared with lower polymer concentration presented better barrier function (WVP and mechanical properties).


The Johns Hopkins Geriatric Summer Scholars Program: a model to increase diversity in geriatric medicine.
The Division of Geriatric Medicine and Gerontology at the Johns Hopkins University strives to create a workforce that represents the racial, ethnic, and sex diversity of U.S. society. To that end, the division has developed a summer program for underrepresented minority first-year medical students to expose them to geriatric medicine and research. The ultimate aim of this initiative is to recruit students to academic medicine, specifically geriatric medicine, where they are drastically underrepresented. Nineteen students participated in the program from the summer of 2002 to the summer of 2004. The participants have continued on to win seven other research fellowships, participate in the National Institute on Aging Technical Assistance Workshop, and present at four national conferences, including the American Geriatrics Society conference and the Gerontological Society of America meeting. One of the students, who is completing medical school in May 2005, is returning to begin the internal medicine residency program at Johns Hopkins Bayview, where the majority of the geriatric faculty practice medicine. Another student who is also graduating is obtaining her Masters in Public Health with a concentration in epidemiology from the Johns Hopkins Bloomberg School of Public Health before starting residency. This article describes the outcomes of the first 3 years of the program, with an emphasis on curriculum development and the recruitment and retention of underrepresented minority medical students.


How do walking, standing, and resting influence transtibial amputee residual limb fluid volume?
The purpose of this research was to determine how fluid volume changes in the residual limbs of people with transtibial amputation were affected by activity during test sessions with equal durations of resting, standing, and walking. Residual limb extracellular fluid volume was measured using biompedance analysis in 24 participants. Results showed that all subjects lost fluid volume during standing with equal weight-bearing, averaging a loss rate of -0.4%/min and a mean loss over the 25 min test session of 2.6% (standard deviation [SD] 1.1). Sixteen subjects gained limb fluid volume during walking (mean gain of 1.0% [SD 2.5]), and fifteen gained fluid volume during rest (mean gain of 1.0% [SD 2.2]). Walking explained only 39.3% of the total session fluid volume change. There was a strong correlation between walk and rest fluid volume changes (-0.81). Subjects with peripheral arterial disease experienced relatively high fluid volume gains during sitting but minimal changes or losses during sit-to-stand and stand-to-sit transitioning. Healthy female subjects experienced high fluid volume changes during transitioning from sit-to-stand and stand-to-sit. The differences in fluid volume response among subjects suggest that volume accommodation technologies should be matched to the activity-dependent fluid transport characteristics of the individual prosthesis user.


[Pharmacological and clinical trial data on a novel phosphate-binding polymer (sevelamer hydrochloride), a medicine for hyperphosphatemia in hemodialysis patients].
Hyperphosphatemia is one of the major complications of hemodialysis patients and plays a key role in the pathogenesis of cardiovascular calcification and secondary hyperparathyroidism. Dietary phosphate restriction and removal of phosphate by dialysis are insufficient to control hyperphosphatemia. Therefore, almost all patients undergoing hemodialysis should take oral phosphate binders. Sevelamer hydrochloride (sevelamer) is a novel phosphate-binding polymer that contains neither aluminum nor calcium, and it is not absorbed from the gastrointestinal tract. In rat models with progressive chronic renal insufficiency, in addition to lowering effects on serum levels of phosphorus, calcium x phosphorus product, and parathyroid hormone, dietary treatment of sevelamer can prevent parathyroid hyperplasia, vascular calcification, high turnover bone lesion, and renal functional deterioration. In clinical studies with hemodialysis patients, sevelamer lowers serum phosphorus and calcium x phosphorus product without any incidence of hypercalcemia. Switching calcium-containing phosphate binders to sevelamer can decrease the percentage of hypoparathyroidism and hyperparathyroidism by negative calcium balance and increased dosage of vitamin D, respectively. Sevelamer also decreases serum low-density lipoprotein cholesterol levels by its bile acid-binding capacity. A long-term clinical study has demonstrated that the progression of coronary and aortic calcification in hemodialysis patients is attenuated by sevelamer. Thus, sevelamer offers the promise of impacting cardiac calcification and thereby reducing morbidity and mortality of hemodialysis patients.


High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy.
Numerous articles and several reviews have been published on the role of antioxidants, and diet and lifestyle modifications in cancer prevention. However, the potential role of these factors in the management of human cancer have been largely ignored. Extensive in vitro studies and limited in vivo studies have revealed that individual antioxidants such as vitamin A (retinoids), vitamin E (primarily alpha-tocopheryl succinate), vitamin C (primarily sodium ascorbate) and carotenoids (primarily polar carotenoids) induce cell differentiation and growth inhibition to various degrees in rodent and human cancer cells by complex mechanisms. The proposed mechanisms for these effects include inhibition of protein kinase C activity, prostaglandin E1-stimulated adenylate cyclase activity, expression of c-myc, H-ras, and a transcription factor (E2F), and induction of transforming growth factor-beta and p21 genes. Furthermore, antioxidant vitamins individually or in combination enhance the growth-inhibitory effects of x-irradiation, chemotherapeutic agents, hyperthermia, and biological response modifiers on tumor cells, primarily in vitro. These vitamins, individually, also reduce the toxicity of several standard tumor therapeutic agents on normal cells. Low fat and high fiber diets can further enhance the efficacy of standard cancer therapeutic agents; the proposed mechanisms for these effects include the production of increased levels of butyric acid and binding of potential mutagens in the gastrointestinal tract by high fiber and reduced levels of growth promoting agents such as prostaglandins, certain fatty acids and estrogen by low fat. We propose, therefore, a working hypothesis that multiple antioxidant vitamin supplements together with diet and lifestyle modifications may improve the efficacy of standard and experimental cancer therapies.


Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34(+)-derived dendritic cell vaccination: a phase I trial in metastatic melanoma.
Six American Joint Committee on Cancer stage IV melanoma patients were enrolled into a Phase I study of vaccination with autologous CD34(+)-derived dendritic cells transduced with a modified vaccinia Ankara virus encoding human tyrosinase gene (MVA-hTyr). Patients received a first intravenous injection of 1 x 10(8) MVA-hTyr-transduced dendritic cells, followed by three s.c. injections at a 14-day interval. Treatment was well tolerated, except for low-grade fever (three of six patients), mild erythema at injection site (five of six), and vitiligo (two of six). A partial response, involving shrinkage of an s.c. nodule, later surgically removed, was observed in 1 patient, who then remained disease-free (>850 days). By human lymphocyte antigen tetramer analysis, significant and often long-lasting increases in frequency of T cells directed to tyrosinase(368-376) but not to gp100(209-217) were documented in periphery of 4 of 5 HLA-A*0201+ patients, a few days after vaccine administration. In addition, maturation phenotype of tyrosinase-specific T cell shifted toward the T effector memory/T terminally differentiate stages (CCR7(-)CD45RA(-/+)) in synchrony with the T-cell frequency peaks. By enzyme-linked immunospot in peripheral blood of five HLA-A*0201+ patients, we found that the vaccine could induce interferon gamma-releasing effector cells directed to HLA-A*0201/tyrosinase(368-376) and to vaccinia virus HLA-A*0201/H3L(184-192) epitopes. Moreover, an interferon gamma response after vaccination was elicited even against the HLA-DRB1-1501/tyrosinase(386-406) epitope in one out of two HLA-A* DRB1-01501+ patients. These results indicate that vaccination with MVA-hTyr-transduced dendritic cells is well tolerated, can possibly produce clinical responses, and activates tyrosinase- and vaccinia virus-specific T cells in vivo. These data suggest a broad utility of the MVA vector for targeting tumor-associated antigens to dendritic cells for tumor immunotherapy.


Using Online Tool (iPrior) for Modeling ToxCast™ Assays Towards Prioritization of Animal Toxicity Testing.
The use of long-term animal studies for human and environmental toxicity estimation is more discouraged than ever before. Alternative models for toxicity prediction, including QSAR studies, are gaining more ground. A recent approach is to combine in vitro chemical profiling and in silico chemical descriptors with the knowledge about toxicity pathways to derive a unique signature for toxicity endpoints. In this study we investigate the ToxCast™ Phase I data regarding their ability to predict long-term animal toxicity. We investigated thousands of models constructed in an effort to predict 61 toxicity endpoints using multiple descriptor packages and hundreds of in vitro assays. We investigated the use of in vitro assays and biochemical pathways on model performance. We identified 10 toxicity endpoints where biologically derived descriptors from in vitro assays or pathway perturbations improved the model prediction ability. In vivo toxicity endpoints proved generally challenging to model. Few models were possible to readily model with a balanced accuracy (BA) above 0.7. We also constructed in silico models to predict the outcome of 144 in vitro assays. This showed better statistical metrics with 79 out of 144 assays having median balanced accuracy above 0.7. This suggests that the in vitro datasets have a better modelability than in vivo animal toxicities for the given datasets. Moreover, we published an online platform (http://iprior.ochem.eu) that automates large-scale model building and analysis.


Left pulmonary artery sling: difference in monochorionic monoamniotic twin presentation.
Pulmonary artery sling (PAS) is a rare congenital vascular anomaly where the left pulmonary artery (LPA) originates from the right pulmonary artery and passes between the trachea and esophagus. Limited literature has been published about PAS in twins. This report demonstrates two different outcomes in mono-mono twins presenting with PAS. Patients with PAS can experience sequelae including wheezing, stridor, atelectasis, or emphysema. Vascular rings occur when the anomalous LPA encircles the airway and esophagus, causing direct compression and respiratory distress. In the case of LPA sling, the sling does not encircle the airway and esophagus but acts as a cradle so the airway which is adjacent to the vessel is not directly compressed. Unfortunately, patients with LPA sling may become severely ill due to airway narrowing even when there is no compression of the adjacent airway. This is the more common presentation in PAS and was seen in Twin A whereas direct airway compression was seen in Twin B. PAS usually presents in patients during their first year of life and high clinical suspicion is important for diagnosis. As this case report demonstrates, presentations and outcomes can be variable in mono-mono twins with LPS and as a result, appropriate investigations should be offered with monitoring of respiratory compromise.


Multi-detector row CT of pancreatic islet cell tumors.
Pancreatic islet cell tumors (ICTs) are neuroendocrine neoplasms that produce and secrete hormones to a variable degree. These neoplasms can present a diagnostic challenge, both clinically and radiologically. ICTs can be classified as either syndromic or nonsyndromic on the basis of their clinical manifestations. Multi-detector row computed tomography (CT) plays an important role in the diagnosis and staging of both syndromic and nonsyndromic ICTs. In general, syndromic ICTs are less than 3 cm in size. They are typically hyperenhancing and are usually best seen on CT scans obtained during the arterial phase. Nonsyndromic ICTs tend to be larger than syndromic ICTs at presentation and are more likely to be cystic or necrotic. It is important for the radiologist to be familiar with appropriate CT protocol for the evaluation of patients with suspected pancreatic ICT and to understand the variable CT appearances of these neoplasms.