DMARD combination therapy in rheumatoid arthritis: 5‐year follow‐up results in a daily practice setting

Aim: To evaluate the overall effect of disease modifying anti‐rheumatic drug (DMARD) combination therapy in daily practice. Methods: In a retrospective study, 161 consecutive files of patients who attended regular follow‐up sessions, seen from 1998, were analysed. Their data were extracted at baseline, 6 months, 1, 2, 3, 4 and 5 years. American College of Rheumatology ACR70 criteria was chosen for the evaluation of the global result. DMARD combination was methotrexate (7.5–15 mg weekly) and chloroquine (150 mg daily), with low‐dose prednisolone (less than 10 mg daily). In cases of remission, methotrexate was gradually tapered, then prednisolone. Chloroquine was discontinued after 1 year if no recurrence occurred at low‐dose (150 mg every other day). In cases of recurrence at any stage, the treatment scheme was stepped back. Results: The data of 161 patients were analysed. One hundred and six were rheumatoid factor positive (RF+) (66%). ACR 70 for all patients at 6 months follow‐up was 72.5% (95% CI = 7.0); at 1 year, 75.8% (95% CI = 6.7); at 2 years, 72.2% (95% CI = 7.2); at 3 years, 78.9% (95% CI = 6.6); at 4 years, 78.4% (95% CI = 6.9); and at 5 years, 70.6% (95% CI = 8.5). Conclusion: The classical DMARD combination therapy, when used with adequate low‐dose prednisolone, gave an ACR70 response from 71–79%. The efficacy of the treatment did not fade over time. RF– patients did better than RF+ patients, but the difference was not statistically significant.     

Association between the DRD2 A1 allele and opium addiction in the Iranian population.

Dysfunction of the central dopaminergic neurotransmission has been suggested to play an important role in the etiology of certain neuropsychiatric disorders such as drug abuse. It has been shown that the dopamine D2 receptor (DRD2) gene dysfunction is associated with multi-drug addiction. Addiction to opium is the most common form of drug abuse in Iran. We studied the allelic association between DRD2 Taq I A polymorphism in 100 opium-dependent Iranian patients and 130 unrelated controls. A 310 bp (base pair) region surrounding Taq I site at the DRD2 locus was amplified by polymerase chain reaction (PCR) and the PCR product was incubated with Taq I restriction enzyme. The A1 allele remained intact while the A2 allele was cut. Significant association was observed between A1 allele and addiction in the patients group (P < 0.0001). Moreover, the frequency of A1A1 genotype was significantly higher in opium users than controls (P < 0.0001). Our result indicates that DRD2 might be involved in the pathophysiology of opium addiction.     

Quantifying the predictability of diaphragm motion during respiration with a noninvasive external marker

The aim of this work was to quantify the ability to predict intrafraction diaphragm motion from an external respiration signal during a course of radiotherapy. The data obtained included diaphragm motion traces from 63 fluoroscopic lung procedures for 5 patients, acquired simultaneously with respiratory motion signals (an infrared camera-based system was used to track abdominal wall motion). During these sessions, the patients were asked to breathe either (i) without instruction, (ii) with audio prompting, or (iii) using visual feedback. A statistical general linear model was formulated to describe the relationship between the respiration signal and diaphragm motion over all sessions and for all breathing training types. The model parameters derived from the first session for each patient were then used to predict the diaphragm motion for subsequent sessions based on the respiration signal. Quantification of the difference between the predicted and actual motion during each session determined our ability to predict diaphragm motion during a course of radiotherapy. This measure of diaphragm motion was also used to estimate clinical target volume (CTV) to planning target volume (PTV) margins for conventional, gated, and proposed four-dimensional (4D) radiotherapy. Results from statistical analysis indicated a strong linear relationship between the respiration signal and diaphragm motion (p<0.001) over all sessions, irrespective of session number (p=0.98) and breathing training type (p=0.19). Using model parameters obtained from the first session, diaphragm motion was predicted in subsequent sessions to within 0.1 cm (1 sigma) for gated and 4D radiotherapy. Assuming a 0.4 cm setup error, superior-inferior CTV-PTV margins of 1.1 cm for conventional radiotherapy could be reduced to 0.8 cm for gated and 4D radiotherapy. The diaphragm motion is strongly correlated with the respiration signal obtained from the abdominal wall. This correlation can be used to predict diaphragm motion, based on the respiration signal, to within 0.1 cm (1 sigma) over a course of radiotherapy.     

Four-dimensional (4D) PET/CT imaging of the thorax

We have reported in our previous studies on the methodology, and feasibility of 4D-PET (Gated PET) acquisition, to reduce respiratory motion artifact in PET imaging of the thorax. In this study, we expand our investigation to address the problem of respiration motion in PET/CT imaging. The respiratory motion of four lung cancer patients were monitored by tracking external markers placed on the thorax. A 4D-CT acquisition was performed using a "step-and-shoot" technique, in which computed tomography (CT) projection data were acquired over a complete respiratory cycle at each couch position. The period of each CT acquisition segment was time stamped with an "x-ray ON" signal, which was recorded by the tracking system. 4D-CT data were then sorted into 10 groups, according to their corresponding phase of the breathing cycle. 4D-PET data were acquired in the gated mode, where each breathing cycle was divided into ten 0.5 s bins. For both CT and PET acquisitions, patients received audio prompting to regularize breathing. The 4D-CT and 4D-PET data were then correlated according to respiratory phase. The effect of 4D acquisition on improving the co-registration of PET and CT images, reducing motion smearing, and consequently increase the quantitation of the SUV, were investigated. Also, quantitation of the tumor motions in PET, and CT, were studied and compared. 4D-PET with matching phase 4D-CTAC showed an improved accuracy in PET-CT image co-registration of up to 41%, compared to measurements from 4D-PET with clinical-CTAC. Gating PET data in correlation with respiratory motion reduced motion-induced smearing, thereby decreasing the observed tumor volume, by as much as 43%. 4D-PET lesions volumes showed a maximum deviation of 19% between clinical CT and phase- matched 4D-CT attenuation corrected PET images. In CT, 4D acquisition resulted in increasing the tumor volume in two patients by up to 79%, and decreasing it in the other two by up to 35%. Consequently, these corrections have yielded an increase in the measured SUV by up to 16% over the clinical measured SUV, and 36% over SUV's measured in 4D-PET with clinical-CT Attenuation Correction (CTAC) SUV's. Quantitation of the maximum tumor motion amplitude, using 4D-PET and 4D-CT, showed up to 30% discrepancy between the two modalities. We have shown that 4D PET/CT is clinically a feasible method, to correct for respiratory motion artifacts in PET/CT imaging of the thorax. 4D PET/CT acquisition can reduce smearing, improve the accuracy in PET-CT co-registration, and increase the measured SUV. This should result in an improved tumor assessment for patients with lung malignancies.     

Morbidity and mortality in elderly trauma patients

BACKGROUND: Despite an increasing incidence, relatively few studies have examined the factors that predict morbidity and mortality in older patients and several reports have found standard predictors such as the Injury Severity Score to be less useful in this patient population. Similarly, the effect of skeletal injury has not been examined with regard to complications and mortality. The purpose of this study was to review a large multicenter experience with elderly trauma patients to isolate factors that might predict morbidity and mortality. The potential effect of skeletal long-bone injury was of particular interest. METHODS: The charts of all patients older than 60 years who were admitted to one of four Level I trauma centers after sustaining blunt trauma were reviewed. Mechanisms of injury included in the study were motor vehicle crash, pedestrian struck, fall from a height, and crush injury. Slip-and-fall injuries were excluded. A total of 326 patients met inclusion criteria. Variables studied included age, sex, mechanism of injury, Injury Severity Score (ISS), Revised Trauma Score, Glasgow Coma Scale (GCS) score, blood transfusion, fluid resuscitation, surgery performed (laparotomy, long-bone fracture stabilization, both), and timing of surgery. Outcome variables measured included incidence of adult respiratory distress syndrome, pneumonia, sepsis, myocardial infarction, deep venous thromboembolism, gastrointestinal complications, and death. chi2, logistic regression, t test, and nonparametric analyses were done as appropriate for the type of variable. RESULTS: The average age of the patients was 72.2+/-8 years. Overall, 59 patients (18.1%) died, of whom 52 of 59 survived at least 24 hours. Statistical significance for continuous variables (p < 0.05) using univariate analysis was reached for the following factors for the patients who died: higher ISS (33.1 vs. 16.4), lower GCS score (11.5 vs. 13.9), greater transfusion requirement (10.9 vs. 2.9 U), and more fluid infused (12.4 vs. 4.9 L). Logistic regression analysis was performed to determine the factors that predicted mortality. They included (odds ratios and p values in parentheses) transfusion (1.11, p = 0.01), ISS (1.04, p = 0.008), GCS score (0.87, p = 0.007), and fluid requirement (1.06, p = 0.06). Regarding surgery, orthopedic surgery alone had an odds ratio of 0.53, indicating that orthopedic patients was less likely to die than patients who did not undergo any surgery. Patients who underwent only a general surgical procedure were 2.5 times more likely to die (p = 0.03) and patients who underwent both general and orthopedic procedures were 1.5 times more likely to die (p = 0.32) than patients who did not require surgery. Early (< or =24 hours) versus late (>24 hours) surgery for bony stabilization did not have a statistical effect on mortality (11% early vs. 18% late). Two patients in need of bony stabilization, however, died before these procedures were performed. With regard to complications, regression analysis revealed that ISS predicted adult respiratory distress syndrome, pneumonia, sepsis, and gastrointestinal complications; fluid transfusion predicted myocardial infusion; and need for surgery and transfusion requirements predicted sepsis. These complications, in turn, were significant risk factors for mortality. This large series of elderly patients demonstrates that mortality correlates closely with ISS and is influenced by blood and fluid requirements and by GCS score. The institution-specific mortality was the same when adjusted for ISS. The need for orthopedic surgery and the timing of the surgery was not a risk factor for systemic complications or mortality in this series. CONCLUSION: Mortality is predicted by ISS and by complications in older patients. Seventy-seven percent of the orthopedic injuries were stabilized early, but the timing of surgery did not have any statistical effect on the incidence of complications or mortality. (ABSTRACT TRUNCA     

Evaluation of Non Diseased Specified Outcome Measures in Hand Injuries to Assess Activity and Participation Based on ICF Content

The objective of the study is to provide information about non disease specified outcome measures which evaluate disability in patients who have impairments in hand and upper extremity and to find the extent to which they are evaluating “disability” based on ICF hand Core Set (activity limitation and participation restriction). MEDLINE, CINAHL, GOOGLE SCHOLAR , OVID and SCIENCE DIRECT databases were systematically searched for studies on non disease specified outcome measures used to evaluate upper extremity function; only studies written in English were considered. We reviewed titles and abstracts of the identified studies to determine whether the studies met predefined eligibility criteria (eg, non disease specified out come measures used in hand injured patients). All the outcome measures which had eligibility included. After full text review ,7 non disease specified outcome measures in hand were identified. Studies were extracted, and the information retrieved from them. All the outcome measures which had incuded, were linked with ICF hand core set disability part (activity and participation). All of them only linked to 16 (42 %) components of ICF hand Core Set, which were most activity and less participation from ICF. None of the non disease specified out come measures in hand injuries cover all domains of disability from the ICF Hand Core Set.     

Improved anticancer delivery of paclitaxel by albumin surface modification of PLGA nanoparticles

Background

Nanoparticles (NPs) play an important role in anticancer delivery systems. Surface modified NPs with hydrophilic polymers such as human serum albumin (HSA) have long half-life in the blood circulation system.

Methods

The method of modified nanoprecipitation was utilized for encapsulation of paclitaxel (PTX) in poly (lactic-co-glycolic acid) (PLGA). Para-maleimide benzoic hydrazide was conjugated to PLGA for the surface modifications of PLGA NPs, and then HSA was attached on the surface of prepared NPs by maleimide attachment to thiol groups (cysteines) of albumin. The application of HSA provides for the longer blood circulation of stealth NPs due to their escape from reticuloendothelial system (RES). Then the physicochemical properties of NPs like surface morphology, size, zeta potential, and in-vitro drug release were analyzed.

Results

The particle size of NPs ranged from 170 to 190 nm and increased about 20–30 nm after HSA conjugation. The zeta potential was about -6 mV and it decreased further after HSA conjugation. The HSA conjugation in prepared NPs was proved by Fourier transform infrared (FT-IR) spectroscopy, faster degradation of HSA in Differential scanning calorimetry (DSC) characterization, and other evidences such as the increasing in size and the decreasing in zeta potential. The PTX released in a biphasic mode for all colloidal suspensions. A sustained release profile for approximately 33 days was detected after a burst effect of the loaded drug. The in vitro cytotoxicity evaluation also indicated that the HSA NPs are more cytotoxic than plain NPs.

Conclusions

HSA decoration of PLGA NPs may be a suitable method for longer blood circulation of NPs.     

GWAS with longitudinal phenotypes: performance of approximate procedures

Analysis of genome-wide association studies with longitudinal data using standard procedures, such as linear mixed model (LMM) fitting, leads to discouragingly long computation times. There is a need to speed up the computations significantly. In our previous work (Sikorska et al: Fast linear mixed model computations for genome-wide association studies with longitudinal data. Stat Med 2012; 32.1: 165–180), we proposed the conditional two-step (CTS) approach as a fast method providing an approximation to the P-value for the longitudinal single-nucleotide polymorphism (SNP) effect. In the first step a reduced conditional LMM is fit, omitting all the SNP terms. In the second step, the estimated random slopes are regressed on SNPs. The CTS has been applied to the bone mineral density data from the Rotterdam Study and proved to work very well even in unbalanced situations. In another article (Sikorska et al: GWAS on your notebook: fast semi-parallel linear and logistic regression for genome-wide association studies. BMC Bioinformatics 2013; 14: 166), we suggested semi-parallel computations, greatly speeding up fitting many linear regressions. Combining CTS with fast linear regression reduces the computation time from several weeks to a few minutes on a single computer. Here, we explore further the properties of the CTS both analytically and by simulations. We investigate the performance of our proposal in comparison with a related but different approach, the two-step procedure. It is analytically shown that for the balanced case, under mild assumptions, the P-value provided by the CTS is the same as from the LMM. For unbalanced data and in realistic situations, simulations show that the CTS method does not inflate the type I error rate and implies only a minimal loss of power.     

Comparative analysis of Behcet's disease in the APLAR region

Aims: Behcet's disease (BD) was originally a disease of the Silk Road. Some authors think that BD from the Silk Road is different from those seen in other countries. The aim of this study was to analyze the clinical manifestations of BD in APLAR countries, where some of them are in the Silk Road (SR) and some others not (NSR). Methods: Data from Australia (NSR), Hong Kong (NSR), India (SR), Iran (SR), and Singapore (SR) were selected and analyzed under the same protocol. Prior published data from China (SR) Japan (SR) and Korea (SR) were included in the analysis. Results: The mean age at the onset of the disease was under 30 for all countries except Japan and Singapore. The male gender was more frequent except in Australia and Korea. Oral aphthosis was the most frequent manifestation (90–100%). Genital aphthosis was less frequent (57–82%). Skin manifestations were also frequent (61–87%). Ocular manifestations were reported from 21–69% of patients. The difference was mainly due to patients’ selection bias and the low number of patients in some reports. The same was true for joint (30–87%), gastrointestinal (6–38%), neurological (2.5–29%) and vascular manifestations (5–28%). Conclusion: Despite the percentage difference among some countries, the general pattern of the disease was the same, suggesting that the minor differences seen in different parts of the world were not enough to call the disease a syndrome, or to differentiate Behcet's disease of the Silk Road from those seen in Western countries.