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1.  Recombinant influenza H7 hemagglutinins induce lower neutralizing antibody titers in mice than do seasonal hemagglutinins 
Vaccines against avian influenza viruses often require high hemagglutinin (HA) doses or adjuvants to achieve serological titers associated with protection against disease. In particular, viruses of the H7 subtype frequently do not induce strong antibody responses following immunization.
To evaluate whether poor immunogenicity of H7 viruses is an intrinsic property of the H7 hemagglutinin.
We compared the immunogenicity, in naïve mice, of purified recombinant HA from two H7 viruses [A/Netherlands/219/2003(H7N7) and A/New York/107/2003(H7N2)] to that of HA from human pandemic [A/California/07/2009(H1N1pdm09)] and seasonal [A/Perth16/2009(H3N2)] viruses.
After two intramuscular injections with purified hemagglutinin, mice produced antibodies to all HAs, but the response to the human virus HAs was greater than to H7 HAs. The difference was relatively minor when measured by ELISA, greater when measured by hemagglutination inhibition assays, and more marked still by microneutralization assays. H7 HAs induced little or no neutralizing antibody response in mice at either dose tested. Antibodies induced by H7 were of significantly lower avidity than for H3 or H1N1pdm09.
We conclude that H7 HAs may be intrinsically less immunogenic than HA from seasonal human influenza viruses.
PMCID: PMC4262278  PMID: 25213778
H7 influenza viruses; hemagglutinin; immunogenicity; influenza; influenza pandemics; influenza vaccines
2.  Mcam Silencing With RNA Interference Using Magnetofection has Antitumor Effect in Murine Melanoma 
The melanoma cell adhesion molecule (MCAM) is involved in melanoma development and its progression, including invasiveness, metastatic potential and angiogenesis. Therefore, MCAM represents a potential target for gene therapy of melanoma, whose expression could be hindered with posttranscriptional specific gene silencing with RNA interference technology. In this study, we constructed a plasmid DNA encoding short hairpin RNA against MCAM (pMCAM) to explore the antitumor and antiangiogenic effects. The experiments were performed in vitro on murine melanoma and endothelial cells, as well as in vivo on melanoma tumors in mice. The antiproliferative, antimigratory, antiangiogenic and antitumor effects were examined after gene therapy with pMCAM. Gene delivery was performed by magnetofection, and its efficacy compared to gene electrotransfer. Gene therapy with pMCAM has proved to be an effective approach in reducing the proliferation and migration of melanoma cells, as well as having antiangiogenic effect in endothelial cells and antitumor effect on melanoma tumors. Magnetofection as a developing nonviral gene delivery system was effective in the transfection of melanoma cells and tumors with pMCAM, but less efficient than gene electrotransfer in in vivo tumor gene therapy due to the lack of antiangiogenic effect after silencing Mcam by magnetofection.
PMCID: PMC4217080  PMID: 25350580
3.  Segmentation of hepatic vessels from MRI images for planning of electroporation-based treatments in the liver 
Radiology and Oncology  2014;48(3):267-281.
Electroporation-based treatments rely on increasing the permeability of the cell membrane by high voltage electric pulses delivered to tissue via electrodes. To ensure that the whole tumor is covered by the sufficiently high electric field, accurate numerical models are built based on individual patient geometry. For the purpose of reconstruction of hepatic vessels from MRI images we searched for an optimal segmentation method that would meet the following initial criteria: identify major hepatic vessels, be robust and work with minimal user input.
Materials and methods.
We tested the approaches based on vessel enhancement filtering, thresholding, and their combination in local thresholding. The methods were evaluated on a phantom and clinical data.
Results show that thresholding based on variance minimization provides less error than the one based on entropy maximization. Best results were achieved by performing local thresholding of the original de-biased image in the regions of interest which were determined through previous vessel-enhancement filtering. In evaluation on clinical cases the proposed method scored in average sensitivity of 93.68%, average symmetric surface distance of 0.89 mm and Hausdorff distance of 4.04 mm.
The proposed method to segment hepatic vessels from MRI images based on local thresholding meets all the initial criteria set at the beginning of the study and necessary to be used in treatment planning of electroporation-based treatments: it identifies the major vessels, provides results with consistent accuracy and works completely automatically. Whether the achieved accuracy is acceptable or not for treatment planning models remains to be verified through numerical modeling of effects of the segmentation error on the distribution of the electric field.
PMCID: PMC4110083  PMID: 25177241
electrochemotherapy; non-thermal irreversible electroporation; treatment planning; hepatic vessel segmentation; non-invasive tumor treatments; MRI of liver
4.  DNA packaging intermediates of bacteriophage Φ174 
Like many viruses, bacteriophage ΦX174 packages its I)NA genome into a procapsid that is assembled from structural intermediates and scaffolding proteins. The procapsid contains the structural proteins F, G and H, as well as the scaffolding proteins B and D. Provirions are formed by packaging of DNA together with the small internal J proteins, while losing at least some of the B scaffolding proteins. Eventually, loss of the I) scaffolding proteins and the remaining B proteins leads to the formation of mature virions.
ΦX174 108S 'procapsids' have been purified in milligram quantities by removing 114S (mature virion) and 70S (abortive capsid) particles from crude lysates by differential precipitation with polyethylene glycol. 132S 'provirions' were purified on sucrose gradients in the presence of EDTA. Cryo-electron microscopy (cryo-EM) was used to obtain reconstructions of procapsids and provirions. Although these are very similar to each other, their structures differ greatly from that of the virion. The F and G proteins, whose atomic structures in virions were previously determined from X-ray crystallography, were fitted into the cryo-EM reconstructions. This showed that the pentamer of G proteins on each five-fold vertex changes its conformation only slightly during DNA packaging and maturation, whereas major tertiary and quaternary structural changes occur in the F protein. The procapsids and provirions were found to contain 120 copies of the I) protein arranged as tetramers on the twofold axes. IDNA might enter procapsids through one of the 30 Å diameter holes on the icosahedral three-fold axes.
Combining cryo-EM image reconstruction and X-ray crystallography has revealed the major conformational changes that can occur in viral assembly. The function of the scaffolding proteins may be, in part, to support weak interactions between the structural proteins in the procapsids and to cover surfaces that are subsequently required for subunit–subunit interaction in the virion. The structures presented here are, therefore, analogous to chaperone proteins complexed with folding intermediates of a substrate.
PMCID: PMC4142697  PMID: 7613866
cryo-electron microscopy; DNA packaging; icosahedral capsid; scaffolding proteins; viral assembly
5.  A patient with a painless neck tumour revealed as a carotid paraganglioma: a case report 
Carotid paragangliomas are usually slowly enlarging and painless lateral neck masses. These mostly benign lesions are recognized due to their typical location, vessel displacement and specific blood supply, features that are usually seen on different imaging modalities. Surgery for carotid paraganglioma can be associated with immediate cerebrovascular complications or delayed neurological impairment.
We are reporting the case of a 36-year-old man who presented with a painless mass on the right side of his neck 11 months after being treated for testicular cancer. After a fine-needle aspiration biopsy, he was diagnosed with a testicular cancer lymph node metastasis. Neck US and fluorine [F-18]-fluorodeoxy-D-glucose (FDG) PET-CT showed no signs of hypervascularity or vessel displacement. The patient underwent a level II to V functional neck dissection. During the procedure, suspicion of a carotid paraganglioma was raised and the tumour was carefully dissected from the walls of the carotid arteries with minimal blood loss and no cranial nerve dysfunction.
The histology report revealed carotid paraganglioma with no metastasis in the rest of the lymph nodes. The patient’s history of testicular germ cell tumour led to a functional neck dissection during which a previously unrecognized carotid paraganglioma was removed.
Surgery for carotid PG can be associated with complications that have major impact on quality of life. A thorough assessment of the patient and neck mass must therefore be performed preoperatively in order to perform the surgical procedure under optimal conditions.
PMCID: PMC4153909  PMID: 25141773
Paraganglioma; Carotid body tumour; Head and neck surgery
6.  Influenza Vaccination Accelerates Recovery of Ferrets from Lymphopenia 
PLoS ONE  2014;9(6):e100926.
Ferrets are a useful animal model for human influenza virus infections, since they closely mimic the pathogenesis of influenza viruses observed in humans. However, a lack of reagents, especially for flow cytometry of immune cell subsets, has limited research in this model. Here we use a panel of primarily species cross-reactive antibodies to identify ferret T cells, cytotoxic T lymphocytes (CTL), B cells, and granulocytes in peripheral blood. Following infection with seasonal H3N2 or H1N1pdm09 influenza viruses, these cell types showed rapid and dramatic changes in frequency, even though clinically the infections were mild. The loss of B cells and CD4 and CD8 T cells, and the increase in neutrophils, were especially marked 1–2 days after infection, when about 90% of CD8+ T cells disappeared from the peripheral blood. The different virus strains led to different kinetics of leukocyte subset alterations. Vaccination with homologous vaccine reduced clinical symptoms slightly, but led to a much more rapid return to normal leukocyte parameters. Assessment of clinical symptoms may underestimate the effectiveness of influenza vaccine in restoring homeostasis.
PMCID: PMC4072694  PMID: 24968319
7.  Capsular Sialic Acid of Streptococcus suis Serotype 2 Binds to Swine Influenza Virus and Enhances Bacterial Interactions with Virus-Infected Tracheal Epithelial Cells 
Infection and Immunity  2013;81(12):4498-4508.
Streptococcus suis serotype 2 is an important swine bacterial pathogen, and it is also an emerging zoonotic agent. It is unknown how S. suis virulent strains, which are usually found in low quantities in pig tonsils, manage to cross the first host defense lines to initiate systemic disease. Influenza virus produces a contagious infection in pigs which is frequently complicated by bacterial coinfections, leading to significant economic impacts. In this study, the effect of a preceding swine influenza H1N1 virus (swH1N1) infection of swine tracheal epithelial cells (NTPr) on the ability of S. suis serotype 2 to adhere to, invade, and activate these cells was evaluated. Cells preinfected with swH1N1 showed bacterial adhesion and invasion levels that were increased more than 100-fold compared to those of normal cells. Inhibition studies confirmed that the capsular sialic acid moiety is responsible for the binding to virus-infected cell surfaces. Also, preincubation of S. suis with swH1N1 significantly increased bacterial adhesion to/invasion of epithelial cells, suggesting that S. suis also uses swH1N1 as a vehicle to invade epithelial cells when the two infections occur simultaneously. Influenza virus infection may facilitate the transient passage of S. suis at the respiratory tract to reach the bloodstream and cause bacteremia and septicemia. S. suis may also increase the local inflammation at the respiratory tract during influenza infection, as suggested by an exacerbated expression of proinflammatory mediators in coinfected cells. These results give new insight into the complex interactions between influenza virus and S. suis in a coinfection model.
PMCID: PMC3837972  PMID: 24082069
8.  Ethical pharmaceutical promotion and communications worldwide: codes and regulations 
The international pharmaceutical industry has made significant efforts towards ensuring compliant and ethical communication and interaction with physicians and patients. This article presents the current status of the worldwide governance of communication practices by pharmaceutical companies, concentrating on prescription-only medicines. It analyzes legislative, regulatory, and code-based compliance control mechanisms and highlights significant developments, including the 2006 and 2012 revisions of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Code of Practice.
Developments in international controls, largely built upon long-established rules relating to the quality of advertising material, have contributed to clarifying the scope of acceptable company interactions with healthcare professionals. This article aims to provide policy makers, particularly in developing countries, with an overview of the evolution of mechanisms governing the communication practices, such as the distribution of promotional or scientific material and interactions with healthcare stakeholders, relating to prescription-only medicines.
PMCID: PMC3974225  PMID: 24679064
Pharmaceutical industry; Self-regulation; Code compliance; Promotion of medicines
9.  Correlation Between Change in Air Humidity and the Incidence of Stroke 
Materia Socio-Medica  2013;25(4):242-245.
According to the World Health Organization estimates annually in the world die due to CVI every sixth women and 10th man. This paper is the research of the correlation between changes in relative air humidity and stroke (CVA) in the Sarajevo Canton. Included are patients who experienced an acute stroke in the Canton of Sarajevo and treated in the pre hospital phase by the staff of the Institute for Emergency Medicine. Days with stroke and those without cases of stroke were compared within three years and meteorological data for those days were obtained by the Weather Bureau of Federation of Bosnia and Herzegovina. Meteorological data include measurements of average humidity every day at 7, 14 and 21 o’clock in three years.
To evaluate the significance of the influence of humidity on the incidence of CVI’s. Show the trend towards CVI in the reporting period and is it correlated with the trend of change in relative humidity in those days. Correlate the incidence of stroke as determined in relation to gender, age and selected climatic parameter.
Material and Methods:
This article presents a retrospective study. Subjects were patients of Emergency Medical Care Institute in Sarajevo, which in the period from 2004 to 2006 had a CVI. Included are patients who had a working diagnosis of stroke for the first time or as a repeated stroke. Analysis of cases of stroke was carried out by gender, age, days and seasons by descriptive-analytical epidemiological methods.
In total were registered 1930 patients during three years period. According to years of research in 2004–635, 2005-616 and 2006 – 679. It was found that when testing the null hypothesis about the effects of humidity in two months with a maximum stroke in the year and days without CVI and relative humidity only in 2005 had a statistically significant effect on the incidence of stroke, while during the other two years of the study there was no impacts. It turned out that the extreme values of relative humidity of the day whether there was a rapid increase or decrees in humidity increases the incidence of stroke in all three years of research.
Patients gender had no effect on the incidence of CVI. Seasons had no effect on the incidence of CVI. Most CVI in all three years of research was in relation to the old age and occurred in the older age group 70-79 (41.35%), where it was shown that the age of the patient influences the incidence of CVI. Extremely low relative humidity and extremely high, influence on the increase in the number of CVI. Determined is a slight correlation between the average relative humidity and CVI in single day.
PMCID: PMC3914739  PMID: 24511266
ER; air humidity; the incidence of stroke.
10.  An Unusual Case of Rapidly Progressive Hyperbilirubinemia 
Case Reports in Pediatrics  2013;2013:284029.
We present an unusual case of hyperbilirubinemia with rapid early progression leading to bilirubin encephalopathy in a term neonate. Despite early recognition and intervention, the total serum bilirubin reached a maximum level of 39 mg/dL at 32 hours of life. Prior to an emergent exchange transfusion, the patient's diagnostic evaluation was significant for Coombs-negative microangiopathic hemolytic anemia and thrombocytopenia. Further testing revealed a deficiency of ADAMTS13 protein, or von Willebrand factor-cleaving protease, a finding diagnostic of congenital thrombotic thrombocytopenic purpura, or Upshaw-Schulman syndrome. This rare disease is often misdiagnosed, especially in the newborn period.
PMCID: PMC3830790  PMID: 24288641
11.  Magnetofection: A Reproducible Method for Gene Delivery to Melanoma Cells 
BioMed Research International  2013;2013:209452.
Magnetofection is a nanoparticle-mediated approach for transfection of cells, tissues, and tumors. Specific interest is in using superparamagnetic iron oxide nanoparticles (SPIONs) as delivery system of therapeutic genes. Magnetofection has already been described in some proof-of-principle studies; however, fine tuning of the synthesis of SPIONs is necessary for its broader application. Physicochemical properties of SPIONs, synthesized by the co-precipitation in an alkaline aqueous medium, were tested after varying different parameters of the synthesis procedure. The storage time of iron(II) sulfate salt, the type of purified water, and the synthesis temperature did not affect physicochemical properties of SPIONs. Also, varying the parameters of the synthesis procedure did not influence magnetofection efficacy. However, for the pronounced gene expression encoded by plasmid DNA it was crucial to functionalize poly(acrylic) acid-stabilized SPIONs (SPIONs-PAA) with polyethyleneimine (PEI) without the adjustment of its elementary alkaline pH water solution to the physiological pH. In conclusion, the co-precipitation of iron(II) and iron(III) sulfate salts with subsequent PAA stabilization, PEI functionalization, and plasmid DNA binding is a robust method resulting in a reproducible and efficient magnetofection. To achieve high gene expression is important, however, the pH of PEI water solution for SPIONs-PAA functionalization, which should be in the alkaline range.
PMCID: PMC3686069  PMID: 23862136
12.  Life Satisfaction and Risk-taking Behavior in Secondary Schools Adolescents 
Materia Socio-Medica  2013;25(3):178-181.
Life satisfaction involves cognitive component that allows evaluation of the life and accomplishments of life, and emotional component that includes an evaluation of emotions and mood that followed these accomplishments.
To examine the life satisfaction of young people who attend secondary school, examine the level of satisfaction with life according to sex, to academic achievement, the presence of siblings and to examine the relationship between levels of life satisfaction and risk-taking behaviors.
Results and Discussion:
The results showed that there was no relationship between life satisfaction and preferences of delinquency, as well as life satisfaction and achieved academic success. The results confirmed the relationship between life satisfaction and sex as well as the relationship between life satisfaction and the presence of siblings in the family.
PMCID: PMC3804387  PMID: 24167431
life satisfaction; risk behaviors; adolescence.
13.  Identification of a new cell line permissive to porcine reproductive and respiratory syndrome virus infection and replication which is phenotypically distinct from MARC-145 cell line 
Virology Journal  2012;9:267.
Airborne transmitted pathogens, such as porcine reproductive and respiratory syndrome virus (PRRSV), need to interact with host cells of the respiratory tract in order to be able to enter and disseminate in the host organism. Pulmonary alveolar macrophages (PAM) and MA104 derived monkey kidney MARC-145 cells are known to be permissive to PRRSV infection and replication and are the most studied cells in the literature. More recently, new cell lines developed to study PRRSV have been genetically modified to make them permissive to the virus. The SJPL cell line origin was initially reported to be epithelial cells of the respiratory tract of swine. Thus, the goal of this study was to determine if SJPL cells could support PRRSV infection and replication in vitro.
The SJPL cell growth was significantly slower than MARC-145 cell growth. The SJPL cells were found to express the CD151 protein but not the CD163 and neither the sialoadhesin PRRSV receptors. During the course of the present study, the SJPL cells have been reported to be of monkey origin. Nevertheless, SJPL cells were found to be permissive to PRRSV infection and replication even if the development of the cytopathic effect was delayed compared to PRRSV-infected MARC-145 cells. Following PRRSV replication, the amount of infectious viral particles produced in SJPL and MARC-145 infected cells was similar. The SJPL cells allowed the replication of several PRRSV North American strains and were almost efficient as MARC-145 cells for virus isolation. Interestingly, PRRSV is 8 to 16 times more sensitive to IFNα antiviral effect in SJPL cell in comparison to that in MARC-145 cells. PRRSV induced an increase in IFNβ mRNA and no up regulation of IFNα mRNA in both infected cell types. In addition, PRRSV induced an up regulation of IFNγ and TNF-α mRNAs only in infected MARC-145 cells.
In conclusion, the SJPL cells are permissive to PRRSV. In addition, they are phenotypically different from MARC-145 cells and are an additional tool that could be used to study PRRSV pathogenesis mechanisms in vitro.
PMCID: PMC3546013  PMID: 23148668
Porcine reproductive and respiratory syndrome virus; PRRSV; SJPL cells; Virus replication; Cell permissivity; Type 1 IFN; IFNγ; TNF-α; Cytokines
14.  Longitudinal relationship between physical activity and cardiometabolic factors in overweight and obese adults 
Few studies have reported longitudinal relationships between physical activity (PA) and cardiometabolic risk factors over time using repeated assessments in overweight or obese adults. We conducted a longitudinal study in 127 participants (81% with body mass index > 30 kg/m2) who completed a 12-month behavioral intervention for weight loss between 2003 and 2005 in Pittsburgh, PA, USA. Using absolute change scores from baseline to each time point (i.e., 6 and 12 months) for all studied variables (Δ = time point – baseline), we performed mixed effects modeling to examine relationships between PA and cardiometabolic risk factors, after adjusting for body weight, energy intake and other covariates (i.e., age, gender, and ethnicity). PA was assessed as energy expenditure (kcal/week) using the Paffenbarger activity questionnaire. Over the 12-month period, energy expenditure increased (Δ1,370 kcal/week at 6 months vs. Δ886 kcal/week at 12 months); body weight decreased (Δ8.9 kg at 6 months vs. Δ8.4 kg at 12 months). The average increase in energy expenditure over 12 months was significantly and independently related to reductions in total cholesterol (F = 6.25, p = 0.013), low-density lipoprotein cholesterol (LDL-C) (F = 5.08, p = 0.025) and fasting blood glucose (F = 5.10, p = 0.025), but not to other risk factors (i.e., fasting insulin, high-density lipoprotein cholesterol, triglycerides, and waist circumference). In conclusion, among overweight and obese adults undergoing a weight loss intervention, increased energy expenditure over 12 months may improve total cholesterol and LDL-C, important coronary risk factors, and fasting blood glucose, a metabolic risk factor.
PMCID: PMC3319046  PMID: 19806358
Physical activity; Obesity; Longitudinal studies; Lipids; Weight loss
15.  Lower tumour burden and better overall survival in melanoma patients with regional lymph node metastases and negative preoperative ultrasound 
Radiology and Oncology  2011;46(1):60-68.
The purpose of the study was to evaluate the ability of ultrasound (US) and fine needle aspiration biopsy (FNAB) in reducing the number of melanoma patients requiring a sentinel node biopsy (SNB); to compare the amount of metastatic disease in regional lymph nodes in SNB candidates with clinically uninvolved lymph nodes and of those with US uninvolved lymph nodes; and to compare the overall survival (OS) of both groups.
Between 2000 and 2007, a SNB was successfully performed in 707 patients with melanoma. The preoperative US of the regional lymph node basins was performed in 405 SNB candidates. In 14 of these patients, the US-guided FNAB was positive and they proceeded directly to lymph node dissection. In 391 patients, the preoperative US was either negative (343 patients) or suspicious (48 patients) (US group). In the remaining 316 patients the preoperative US was not performed (non-US group).
The proportion of macrometastatic sentinel lymph nodes (SN), number of metastatic lymph nodes per patient and proportion of nonsentinel lymph node metastases were found to be lower in the US group compared to the non-US group. The smaller tumour burden of the US group was reflected in a significantly better OS of patients with SN metastases.
The preoperative US of regional lymph nodes spares some patients with melanoma from undergoing a SNB. Patients with regional metastases and a negative preoperative US have a significantly lower tumour burden in comparison to those with clinically negative lymph nodes, which is also reflected in a better OS.
PMCID: PMC3423764  PMID: 22933981
melanoma; ultrasound; tumour burden; overall survival
16.  Correlation of Barometer Pressure and Incidence of Cerebrovascular Insult 
Materia Socio-Medica  2012;24(4):232-237.
The intention of this work is to research whether the link between the barometer pressure and the cerebrovascular insult (CVI) exists. The stroke is the first cause of non-traumatic disability and third illness by mortality in the majority of available relevant literature.
Goal of the sudy was to research all the cases of the patients who suffered from the acute stroke in the Canton of Sarajevo and those who were treated in the pre-hospital phase by Emergency Medical Institute staff and their working diagnosis was established as CVI ac.
Material and methods:
The criteria in the research were established for inclusion and exclusion of cases. The days with and without CVI cases were compared with the meteorological data obtained from the Hydro-meteorological Institute of Federation of Bosnia and Herzegovina . Since the approval was requested and obtained from the Hydro-meteorological Institute, all the meteorological data could be compared. The meteorological data comprise the barometer pressure measuring every day at 7 h, 14 h and 21 h.
Results and discussion:
In the retrospective study, there will be followed, during three years (2004, 2005 and 2006), the cases of the patients who suffered from the stroke, and, the emergency medical care was offered to them by the side of the Emergency Medical Institute of Canton of Sarajevo staff. All the cases in the Canton of Sarajevo were followed regardless of the place of incidence: whether the help was offered in Institute’s outpatient departments, patient’s flat or at public place. Due to the extensiveness of data (in the analysis comprising three years, there was the total of 1930 cases), the test of normal distribution was used. Since it was about the pre-hospital research, the acute stroke was looked at generally without division by types. The certain diagnostics by types can only be established in the hospital.
The results in the research indicate that the extreme values of barometer pressure, regardless of their being increased ones or decreased ones, influence the increase of CVI incidence, while by comparing the average values in the days with CVI and without CVI, they did not have any influence on the CVI incidence.
PMCID: PMC3732370  PMID: 23922533
emergency medical care; barometer pressure; CVI.
17.  Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study 
Preoperative capecitabine-based chemoradiation is a standard treatment for locally advanced rectal cancer (LARC). Here, we explored the safety and efficacy of the addition of bevacizumab to capecitabine and concurrent radiotherapy for LARC.
Patients with MRI-confirmed stage II/III rectal cancer received bevacizumab 5 mg/kg i.v. 2 weeks prior to neoadjuvant chemoradiotherapy followed by bevacizumab 5 mg/kg on Days 1, 15 and 29, capecitabine 825 mg/m2 twice daily on Days 1-38, and concurrent radiotherapy 50.4 Gy (1.8 Gy/day, 5 days/week for 5 weeks + three 1.8 Gy/day), starting on Day 1. Total mesorectal excision was scheduled 6-8 weeks after completion of chemoradiotherapy. Tumour regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was pathological complete response (pCR).
61 patients were enrolled (median age 60 years [range 31-80], 64% male). Twelve patients (19.7%) had T3N0 tumours, 1 patient T2N1, 19 patients (31.1%) T3N1, 2 patients (3.3%) T2N2, 22 patients (36.1%) T3N2 and 5 patients (8.2%) T4N2. Median tumour distance from the anal verge was 6 cm (range 0-11). Grade 3 adverse events included dermatitis (n = 6, 9.8%), proteinuria (n = 4, 6.5%) and leucocytopenia (n = 3, 4.9%). Radical resection was achieved in 57 patients (95%), and 42 patients (70%) underwent sphincter-preserving surgery. TRG 4 (pCR) was recorded in 8 patients (13.3%) and TRG 3 in 9 patients (15.0%). T-, N- and overall downstaging rates were 45.2%, 73.8%, and 73.8%, respectively.
This study demonstrates the feasibility of preoperative chemoradiotherapy with bevacizumab and capecitabine. The observed adverse events of neoadjuvant treatment are comparable with those previously reported, but the pCR rate was lower.
PMCID: PMC3179720  PMID: 21880132
capecitabine; chemoradiation; bevacizumab; locally advanced rectal cancer; LARC; phase II study
19.  Summary statement: EHRA Summit 2010 with the Participation of Central-Eastern European Countries: ‘ICD for Life’ Initiative—Fighting against Sudden Cardiac Death in Emerging Economies 
Europace  2011;13(8):1209-1210.
PMCID: PMC3148819  PMID: 21810867
20.  SMART trial: A randomized clinical trial of self-monitoring in behavioral weight management-design and baseline findings 
Contemporary clinical trials  2009;30(6):540-551.
The primary form of treatment for obesity today is behavioral therapy. Self-monitoring diet and physical activity plays an important role in interventions targeting behavior and weight change. The SMART weight loss trial examined the impact of replacing the standard paper record used for self-monitoring with a personal digital assistant (PDA). This paper describes the design, methods, intervention, and baseline sample characteristics of the SMART trial.
The SMART trial used a 3-group design to determine the effects of different modes of self-monitoring on short- and long-term weight loss and on adherence to self-monitoring in a 24-month intervention. Participants were randomized to one of three conditions (1) use of a standard paper record (PR); (2) use of a PDA with dietary and physical activity software (PDA); or (3), use of a PDA with the same software plus a customized feedback program (PDA + FB).
We screened 704 individuals and randomized 210. There were statistically but not clinically significant differences among the three cohorts in age, education, HDL cholesterol, blood glucose and systolic blood pressure. At 24 months, retention rate for the first of three cohorts was 90%.
To the best of our knowledge, the SMART trial is the first large study to compare different methods of self-monitoring in a behavioral weight loss intervention and to compare the use of PDAs to conventional paper records. This study has the potential to reveal significant details about self-monitoring patterns and whether technology can improve adherence to this vital intervention component.
PMCID: PMC2860431  PMID: 19665588
Obesity; Weight loss; Adherence; Technology; Personal digital assistant; Behavioral treatment; Randomized clinical trial
22.  Salivary Gonadal and Adrenal Hormone Differences in Boys and Girls With and Without Disruptive Behavior Disorders: Contextual Variants 
Biological psychology  2009;81(1):31-39.
Hormone differences by psychopathology group and gender may have implications for understanding disruptive behavior disorders (DBD) and complexities of treatment outcomes. Current theoretical models emphasize contextual differences as moderators of hormone-behavior relations. This report examined: a) hormone differences in youth with and without DBD, and b) contextual factors as moderators of behavior problems and hormones. 180 children and adolescents were enrolled (141 boys, mean 9.0 ± 1.7 years). DBD participants met criteria for conduct disorder (CD) and/or oppositional defiant disorder (ODD) (n = 111); 69 were recruited as healthy comparisons (HC). Saliva was collected for testosterone, cortisol, dehydroepiandrosterone and androstenedione. DBD youth had significantly higher androstenedione than the HC group. There was a group by gender interaction for basal cortisol mean with DBD boys and HC girls having lower cortisol. Moderating effects of contextual variables (e.g., family functioning, delinquent peers) were noted for cortisol and adrenal androgens. Findings argue for considering hormones as an influence on DBD beyond simple direct one-to one associations.
PMCID: PMC2680777  PMID: 19428966
cortisol; conduct disorder; disruptive behavior disorders; testosterone; adrenal androgens; context
23.  Adherence to a behavioral weight loss treatment program enhances weight loss and improvements in biomarkers 
To describe participants’ adherence to multiple components (attendance, energy intake, fat gram, exercise goals, and self-monitoring eating and exercise behaviors) of a standard behavioral treatment program (SBT) for weight loss and how adherence to these components may influence weight loss and biomarkers (triglycerides, low density lipoproteins [LDL], high density lipoprotein, and insulin) during the intensive and less-intensive intervention phases.
A secondary analysis of a randomized clinical trial consisting of a SBT with either fat-restricted standard or lacto-ovo vegetarian diet. The 12-month intervention was delivered in 33 group sessions. The first six months reflected the intensive phase; the second six months, the less-intensive intervention phase. We conducted the analysis without regard to treatment assignment. Eligible participants included overweight/obese adults (N = 176; mean body mass index = 34.0 kg/m2). The sample was 86.9% female, 70.5% White, and 44.4 ± 8.6 years old. The outcome measures included weight and biomarkers.
There was a significant decline in adherence to each treatment component over time (P < 0.0001). In the first six months, adherence to attendance, self-monitoring and the energy goal were significantly associated with greater weight loss (P < 0.05). Adherence to attendance and exercise remained significantly associated with weight loss in the second six months (P < 0.05). Adherence to attendance, self-monitoring and exercise had indirect effects through weight loss on LDL, triglycerides, and insulin (P < 0.05).
We observed a decline in adherence to each treatment component as the intervention intensity was reduced. Adherence to multiple treatment components was associated with greater weight loss and improvements in biomarkers. Future research needs to focus on improving and maintaining adherence to all components of the treatment protocol to promote weight loss and maintenance.
PMCID: PMC2778406  PMID: 19936157
adherence; obesity; diet; exercise; self-monitoring; biomarkers
24.  Using Instrumented Paper Diaries to Document Self-Monitoring Patterns in Weight-Loss 
Contemporary clinical trials  2007;29(2):182-193.
Self-monitoring of eating is associated with successful weight loss, but adherence is imperfect and deteriorates over time. Moreover, intentionally or not, many individuals have difficulty keeping faithful records. We used instrumented paper diaries (IPDs) to study self-monitoring in randomly chosen participants in the PREFER trial, a behavioral treatment for weight-loss study. The diaries they used to self-report eating were periodically replaced with IPDs at various times during an 18-month weight-loss program, consisting of three successive phases: intense treatment (n = 35), less-intense treatment (n = 13), and maintenance (n = 16). We compared electronically documented self-monitoring data, showing when and how often IPDs were used, with self-reported data, then compared the electronically validated adherence and weight loss. Self-reported diary usage exceeded IPD-documented usage while the electronic data demonstrated a significant decline in self-monitoring over time. Diary recording often was not timely. Percentage weight lost correlated significantly with frequency of IPD use (p = .001) and the number of diary entries made within 15 minutes of opening the IPD (p = .002). This is the first study to document patterns of self-monitoring among participants in a weight-loss program, which demonstrated that individuals may falsify the times and frequency of self-monitoring. Furthermore, our results showed that adherence to self-monitoring and the timeliness of recording significantly correlate with improved weight loss.
PMCID: PMC2435095  PMID: 17702667
self-monitoring; adherence; obesity; behavioral treatment of obesity; instrumented paper diaries (IPD); self-report; weight loss
25.  Estuary-associated syndrome in North Carolina: an occupational prevalence study. 
Atlantic coast estuaries recently have experienced fish kills and fish with lesions attributed to Pfiesteria piscicida and related dinoflagellates. Human health effects have been reported from laboratory exposure and from a 1997 Maryland fish kill. North Carolina has recorded Pfiesteria-related fish kill events over the past decade, but human health effects from environmental exposure have not been systematically investigated or documented here. At the request of the state health agency, comprehensive examinations were conducted in a cross-sectional prevalence study of watermen working where Pfiesteria exposure may occur: waters where diseased or stressed fish were reported from June to September 1997, and where Pfiesteria had been identified in the past. Controls worked on unaffected waterways. The study was conducted 3 months after the last documented Pfiesteria-related fish kill. The goal was to document any persistent health effects from recent or remote contact with fish kills, fish with lesions, or affected waterways, using the 1997 U.S. Centers for Disease Control and Prevention case description for estuary-associated syndrome (EAS). Examinations included comprehensive medical, occupational, and environmental history, general medical, dermatologic, and neurologic examinations, vision testing, and neuropsychologic evaluations. Seventeen of 22 watermen working in affected waters and 11 of 21 in unaffected waters reported exposure to a fish kill or to fish with lesions. We found no pattern of abnormalities on medical, neurologic, neuropsychologic, or NES-2 evaluation. By history, one subject in each group met the EAS criteria, neither of whom had significant neuropsychological impairment when examined. Watermen from affected waterways had a significant reduction in visual contrast sensitivity (VCS) at the midspatial frequencies, but we did not identify a specific factor or exposure associated with this reduction. The cohorts did not differ in reported occupational exposure to solvents (qualitative) or to other neurotoxicants; however, exposure history was not sufficiently detailed to measure or control for solvent exposure. This small prevalence study in watermen, conducted 3 months after the last documented fish kill related to Pfiesteria, did not identify an increased risk of estuary-associated syndrome in those working on affected waterways. A significant difference between the estuary and ocean watermen was found on VCS, which could not be attributed to any specific factor or exposure. VCS may be affected by chemicals, drugs, alcohol, and several developmental and degenerative conditions; it has not been validated as being affected by known exposure to dinoflagellate secretions. VCS should be considered for inclusion in further studies, together with documentation or quantification of its potential confounders, to assess whether it has utility in relationship to dinoflagellate exposure.
PMCID: PMC1242046  PMID: 11171520

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