Automated 3D Ιnterstitial Lung Disease Εxtent Quantification: Performance Evaluation and Correlation to PFTs

In this study, the performance of a recently proposed computer-aided diagnosis (CAD) scheme in detection and 3D quantification of reticular and ground glass pattern extent in chest computed tomography of interstitial lung disease (ILD) patients is evaluated. CAD scheme performance was evaluated on a dataset of 37 volumetric chest scans, considering five representative axial anatomical levels per scan. CAD scheme reliability analysis was performed by estimating agreement (intraclass correlation coefficient, ICC) of automatically derived ILD pattern extent to semi-quantitative disease extent assessment in terms of 29-point rating scale provided by two expert radiologists. Receiver operating characteristic (ROC) analysis was employed to assess CAD scheme accuracy in ILD pattern detection in terms of area under ROC curve (A_z). Correlation of reticular and ground glass volumetric pattern extent to pulmonary function tests (PFTs) was also investigated. CAD scheme reliability was substantial for ILD extent (ICC = 0.809) and distinct reticular pattern extent (0.806) and moderate for distinct ground glass pattern extent (0.543), performing within inter-observer agreement. CAD scheme demonstrated high accuracy in detecting total ILD (A_z = 0.950 ± 0.018), while accuracy in detecting distinct reticular and ground glass patterns was 0.920 ± 0.023 and 0.883 ± 0.024, respectively. Moderate and statistically significant negative correlation was found between reticular volumetric pattern extent and diffusing capacity, forced expiratory volume in 1 s, forced vital capacity, and total lung capacity (R = −0.581, −0.513, −0.494, and −0.446, respectively), similar to correlations found between radiologists’ semi-quantitative ratings with PFTs. CAD-based quantification of disease extent is in agreement with radiologists’ semi-quantitative assessment and correlates to specific PFTs, suggesting a potential imaging biomarker for ILD staging and management.     

Comparing Performance of the CADstream and the DynaCAD Breast MRI CAD Systems

Computer-aided diagnosis (CAD) systems are software programs that use algorithms to find patterns associated with breast cancer on breast magnetic resonance imaging (MRI). The most commonly used CAD systems in the USA are CADstream (CS) (Merge Healthcare Inc., Chicago, IL) and DynaCAD for Breast (DC) (Invivo, Gainesville, FL). Our primary objective in this study was to compare the CS and DC breast MRI CAD systems for diagnostic accuracy and postprocessed image quality. Our secondary objective was to compare the evaluation times of radiologists using each system. Three radiologists evaluated 30 biopsy-proven malignant lesions and 29 benign lesions on CS and DC and rated the lesions’ malignancy status using the Breast Imaging Reporting and Data System. Image quality was ranked on a 0–5 scale, and mean reading times were also recorded. CS detected 70 % of the malignant and 32 % of the benign lesions while DC detected 81 % of the malignant lesions and 34 % of the benign lesions. Analysis of the area under the receiver operating characteristic curve revealed that the difference in diagnostic performance was not statistically significant. On image quality scores, CS had significantly higher volume rendering (VR) (p < 0.0001) and motion correction (MC) scores (p < 0.0001). There were no statistically significant differences in the remaining image quality scores. Differences in evaluation times between DC and CS were also not statistically significant. We conclude that both CS and DC perform similarly in aiding detection of breast cancer on MRI. MRI CAD selection will likely be based on other factors, such as user interface and image quality preferences, including MC and VR.     

Diagnosis of Solid Breast Tumors Using Vessel Analysis in Three-Dimensional Power Doppler Ultrasound Images

This study aims to evaluate whether the distribution of vessels inside and adjacent to tumor region at three-dimensional (3-D) power Doppler ultrasonography (US) can be used for the differentiation of benign and malignant breast tumors. 3-D power Doppler US images of 113 solid breast masses (60 benign and 53 malignant) were used in this study. Blood vessels within and adjacent to tumor were estimated individually in 3-D power Doppler US images for differential diagnosis. Six features including volume of vessels, vascularity index, volume of tumor, vascularity index in tumor, vascularity index in normal tissue, and vascularity index in surrounding region of tumor within 2 cm were evaluated. Neural network was then used to classify tumors by using these vascular features. The receiver operating characteristic (ROC) curve analysis and Student’s t test were used to estimate the performance. All the six proposed vascular features are statistically significant (p < 0.001) for classifying the breast tumors as benign or malignant. The A_Z (area under ROC curve) values for the classification result were 0.9138. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the diagnosis performance based on all six proposed features were 82.30 (93/113), 86.79 (46/53), 78.33 (47/60), 77.97 (46/59), and 87.04 % (47/54), respectively. The p value of A_Z values between the proposed method and conventional vascularity index method using z test was 0.04.     

Mammographic Image Denoising and Enhancement Using the Anscombe Transformation, Adaptive Wiener Filtering, and the Modulation Transfer Function

A new restoration methodology is proposed to enhance mammographic images through the improvement of contrast features and the simultaneous suppression of noise. Denoising is performed in the first step using the Anscombe transformation to convert the signal-dependent quantum noise into an approximately signal-independent Gaussian additive noise. In the Anscombe domain, noise is filtered through an adaptive Wiener filter, whose parameters are obtained by considering local image statistics. In the second step, a filter based on the modulation transfer function of the imaging system in the whole radiation field is applied for image enhancement. This methodology can be used as a preprocessing module for computer-aided detection (CAD) systems to improve the performance of breast cancer screening. A preliminary assessment of the restoration algorithm was performed using synthetic images with different levels of quantum noise. Afterward, we evaluated the effect of the preprocessing on the performance of a previously developed CAD system for clustered microcalcification detection in mammographic images. The results from the synthetic images showed an increase of up to 11.5 dB (p = 0.002) in the peak signal-to-noise ratio. Moreover, the mean structural similarity index increased up to 8.3 % (p < 0.001). Regarding CAD performance, the results suggested that the preprocessing increased the detectability of microcalcifications in mammographic images without increasing the false-positive rates. Receiver operating characteristic analysis revealed an average increase of 14.1 % (p = 0.01) in overall CAD performance when restored image sets were used.     

Eigenspace Template Matching for Detection of Lacunar Infarcts on MR Images

Detection of lacunar infarcts is important because their presence indicates an increased risk of severe cerebral infarction. However, accurate identification is often hindered by the difficulty in distinguishing between lacunar infarcts and enlarged Virchow-Robin spaces. Therefore, we developed a computer-aided detection (CAD) scheme for the detection of lacunar infarcts. Although our previous CAD method indicated a sensitivity of 96.8 % with 0.71 false positives (FPs) per slice, further reduction of FPs remained an issue for the clinical application. Thus, the purpose of this study is to improve our CAD scheme by using template matching in the eigenspace. Conventional template matching is useful for the reduction of FPs, but it has the following two pitfalls: (1) It needs to maintain a large number of templates to improve the detection performance, and (2) calculation of the cross-correlation coefficient with these templates is time consuming. To solve these problems, we used template matching in the lower dimension space made by a principal component analysis. Our database comprised 1,143 T₁- and T₂-weighted images obtained from 132 patients. The proposed method was evaluated by using twofold cross-validation. By using this method, 34.1 % of FPs was eliminated compared with our previous method. The final performance indicated that the sensitivity of the detection of lacunar infarcts was 96.8 % with 0.47 FPs per slice. Therefore, the modified CAD scheme could improve FP rate without a significant reduction in the true positive rate.     

MRI-Based Breast Volumetry—Evaluation of Three Different Software Solutions

As lipofilling of the female breast is becoming more popular in plastic surgery, the use of MRI to assess breast volume has been employed to control postoperative results. Therefore, we sought to evaluate the accuracy of magnetic resonance imaging (MRI)-based breast volumetry software tools by comparing the measurements of silicone implant augmented breasts with the actual implant volume specified by the manufacturer. MRI-based volume analysis was performed in eight bilaterally augmented patients (46 ± 9 years) with three different software programs (Brainlab© I plan 2.6 neuronavigation software; mass analysis, version 5.3, Medis©; and OsiriX© v.3.0.2. 32-bit). The implant volumes analysed by the BrainLab© software had a mean deviation of 2.2 ± 1.7% (r = 0.99) relative to the implanted prosthesis. OsiriX© software analysis resulted in a mean deviation of 2.8 ± 3.0% (r = 0.99) and the Medis© software had a mean deviation of 3.1 ± 3.0% (r = 0.99). Overall, the volumes of all analysed breast implants correlated very well with the real implant volumes. Processing time was 10 min per breast with each system and 30 s (OsiriX©) to 5 min (BrainLab© and Medis©) per silicone implant. MRI-based volumetry is a powerful tool to calculate both native breast and silicone implant volume in situ. All software solutions performed well and the measurements were close to the actual implant sizes. The use of MRI breast volumetry may be helpful in: (1) planning reconstructive and aesthetic surgery of asymmetric breasts, (2) calculating implant size in patients with missing documentation of a previously implanted device and (3) assessing post-operative results objectively.Key words: MRI, volumetry, mamma, breast, lipofilling, silicone implant, BrainLab, OsiriX, Medis     

Potent anti-angiogenesis and anti-tumor activity of a nove human anti-VEGF antibody,MIL60

Angiogenesis is crucial for tumor development, growth and metastasis. Vascular endothelial growth factor （VEGF） has been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis, and blocking the activity of VEGF can starve tumors. Avastin, which is a humanized anti-VEGF antibody, has been successfully applied in clinics since 2004. However, the price of Avastin is extremely high for Chinese people. Here, we report a novel human anti-VEGF neutralizing antibody, MIL60, which shows an affinity comparable to that of Avastin （the KD value of MIL60 was 44.5 pM, while that of Avastin was 42.7 pM）. MIL60 displays favorable actions in inhibiting VEGF-triggered endothelial cell proliferation （the IC5o value of M IL60 was 31-6.4 ng/ml and that of Avastin was 47--.8.1 ng/ml）, migration （8 pg/ml or 0.8 pg/ml MIL60 versusthe control： P〈O.05） and tube formation （2 I~g/ml or 0.2 lzg/ml MIL60 versusthe control： P〈O.05） viathe VEGFR2 signaling pathway. Moreover, MIL60 was shown to inhibit tumor growth and angiogenesis in vivo in xenograft models of human colon carcinoma and ovarian cancer using immunotherapy and immunohistochemistry analysis （MIL60 versus N.S.： P=0.0007; Avastin versus N.S.： P=0.00046）. These data suggest that MIL60 is a potential therapeutic, anti-angiogenic agent. Our work provides a novel anti-VEGF antibody, which can be considered an anti-tumor antibody candidate and a new option for patients with various cancers.     

Cold-Water Immersion and the Treatment of Hyperthermia: Using 38.6��C as a Safe Rectal Temperature Cooling Limit

Context:

Cold-water immersion is recommended for the immediate field treatment of exertional heat stroke. However, concerns exist over potential overcooling of hyperthermic individuals during cold-water immersion.

Objective:

To evaluate the recommendation that removing previously hyperthermic individuals from a cold-water bath at a rectal temperature (T_re) of 38.6°C would attenuate overcooling.

Design:

Controlled laboratory study.

Setting:

University research laboratory.

Patients or Other Participants:

Participants included 6 men and 4 women (age  =  22 ± 3 years, height  =  172 ± 10 cm, mass  =  67.8 ± 10.7 kg, body fat percentage  =  17.1% ± 4.5%, maximum oxygen consumption  =  59.3 ± 8.7 mL·kg⁻¹·min⁻¹).

Intervention(s):

After exercising at an ambient temperature of 40.0°C for 38.5 ± 9.4 minutes, until T_re reached 39.5°C, participants were immersed in a 2.0°C circulated water bath until T_re decreased to either 37.5°C or 38.6°C. Subsequently, participants were removed from the water bath and recovered for 20 minutes at an ambient temperature of 25°C.

Main Outcome Measure(s):

Rectal and esophageal temperatures were measured continuously during the immersion and recovery periods.

Results:

Because of the experimental design, the overall time of immersion was greater during the 37.5°C trial (16.6 ± 5.7 minutes) than the 38.6°C trial (8.8 ± 2.6 minutes) (t₉  =  −4.740, P  =  .001). During the recovery period after cold-water immersion, both rectal (F_1,9  =  50.540, P < .001) and esophageal (F_1,6  =  20.365, P  =  .007) temperatures remained greater in the 38.6°C trial than in the 37.5°C trial. This was evidenced by low points of 36.47°C ± 0.70°C and 37.19°C ± 0.71°C for rectal temperature (t₉  =  2.975, P  =  .016) and of 35.67°C ± 1.27°C and 36.72°C ± 0.95°C for esophageal temperature (t₆  =  3.963, P  =  .007) during the recovery period of the 37.5°C and 38.6°C trials, respectively.

Conclusions:

Immersion for approximately 9 minutes to a rectal temperature cooling limit of 38.6°C negated any risk associated with overcooling hyperthermic individuals when they were immersed in 2°C water.     

Evaluation of an Automated Information Extraction Tool for Imaging Data Elements to Populate a Breast Cancer Screening Registry

Breast cancer screening is central to early breast cancer detection. Identifying and monitoring process measures for screening is a focus of the National Cancer Institute’s Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) initiative, which requires participating centers to report structured data across the cancer screening continuum. We evaluate the accuracy of automated information extraction of imaging findings from radiology reports, which are available as unstructured text. We present prevalence estimates of imaging findings for breast imaging received by women who obtained care in a primary care network participating in PROSPR (n = 139,953 radiology reports) and compared automatically extracted data elements to a “gold standard” based on manual review for a validation sample of 941 randomly selected radiology reports, including mammograms, digital breast tomosynthesis, ultrasound, and magnetic resonance imaging (MRI). The prevalence of imaging findings vary by data element and modality (e.g., suspicious calcification noted in 2.6 % of screening mammograms, 12.1 % of diagnostic mammograms, and 9.4 % of tomosynthesis exams). In the validation sample, the accuracy of identifying imaging findings, including suspicious calcifications, masses, and architectural distortion (on mammogram and tomosynthesis); masses, cysts, non-mass enhancement, and enhancing foci (on MRI); and masses and cysts (on ultrasound), range from 0.8 to1.0 for recall, precision, and F-measure. Information extraction tools can be used for accurate documentation of imaging findings as structured data elements from text reports for a variety of breast imaging modalities. These data can be used to populate screening registries to help elucidate more effective breast cancer screening processes.     

Comparison of rectal and aural core body temperature thermometry in hyperthermic, exercising individuals: a meta-analysis

Objective:

To compare mean differences in core body temperature (T_core) as assessed via rectal thermometry (T_re) and aural thermometry (T_au) in hyperthermic exercising individuals.

Data Sources:

PubMed, Ovid MEDLINE, SPORTDiscus, CINAHL, and Cochrane Library in English from the earliest entry points to August 2009 using the search terms aural, core body temperature, core temperature, exercise, rectal, temperature, thermistor, thermometer, thermometry, and tympanic.

Study Selection:

Original research articles that met these criteria were included: (1) concurrent measurement of T_re and T_au in participants during exercise, (2) minimum mean temperature that reached 38°C by at least 1 technique during or after exercise, and (3) report of means, standard deviations, and sample sizes.

Data Extraction:

Nine articles were included, and 3 independent reviewers scored these articles using the Physiotherapy Evidence Database (PEDro) scale (mean  =  5.1 ± 0.4). Data were divided into time periods pre-exercise, during exercise (30 to 180 minutes), and postexercise, as well as T_re ranges <37.99°C, 38.00°C to 38.99°C, and >39.00°C. Means and standard deviations for both measurement techniques were provided at all time intervals reported. Meta-analysis was performed to determine pooled and weighted mean differences between T_re and T_au.

Data Synthesis:

The T_re was conclusively higher than the T_au pre-exercise (mean difference [MD]  =  0.27°C, 95% confidence interval [CI]  =  0.15°C, 0.39°C), during exercise (MD  =  0.96°C, 95% CI  =  0.84°C, 1.08°C), and postexercise (MD  =  0.71°C, 95% CI  =  0.65°C, 0.78°C). As T_re measures increased, the magnitude of difference between the techniques also increased with an MD of 0.59°C (95% CI  =  0.53°C, 0.65°C) when T_re was <38°C; 0.79°C (95% CI  =  0.72°C, 0.86°C) when T_re was between 38.0°C and 38.99°C; and 1.72°C (95% CI  =  1.54°, 1.91°C) when T_re was >39.0°C.

Conclusions:

The T_re was consistently greater than T_au when T_core was measured in hyperthermic individuals before, during, and postexercise. As T_core increased, T_au appeared to underestimate T_core as determined by T_re. Clinicians should be aware of this critical difference in temperature magnitude between these measurement techniques when assessing T_core in hyperthermic individuals during or postexercise.     

The relationship between thyroid function,serum monokine induced by interferon gamma and soluble interleukin‐2 receptor in thyroid autoimmune diseases

Interactions between cytokines play an important role in the development of thyroid autoimmunity. Using enzyme-linked immunosorbent assay we investigated serum concentrations of soluble interleukin-2 receptor (sIL-2R), interferon-gamma, tumour necrosis factor (TNF)-α, interleukin (IL)-10, CD30, monokine induced by interferon-gamma (MIG), cytotoxic T lymphocyte antigen-4 and markers of apoptosis decoy receptor 3 and Bcl-2 in 28 patients with hyperthyroid Graves'' disease (GD), 24 patients with untreated Hashimoto''s thyroiditis (HT) and 15 healthy controls. TNF-α, IL-10 and sIL-2R were higher in GD compared with HT and controls (TNF-α: 8·79 in GD versus 2·54 pg/ml in HT, P = 0·01; IL-10: 10·00 versus 3·10 versus 3·10 pg/ml, P₁ < 0·001, P₂ = 0·005; sIL-2R: 1·26 versus 0·64 versus 0·46 ng/ml, P < 0·001). MIG and CD30 were higher in HT compared with controls (649·22 ± 262·55 versus 312·95 ± 143·35 pg/ml, P = 0·037, 6·57 ± 2·35 versus 3·03 ± 1·04 U/ml, P = 0·036 respectively). In GD sIL-2R decreased when the euthyroid state was achieved (1·31 ± 0·64 versus 0·260 ± 0·11, n = 12, P < 0·001). sIL-2R correlated positively with free thyroxine (FT4) (R = 0·521, P = 0·000) and negatively with thyroid stimulating hormone (TSH) (R = −0·472, P = 0·00132). MIG correlated negatively with FT4 (R = −0·573, P = 0·00234) and positively with TSH (R = 0·462, P = 0·0179). The results suggest that serum concentrations of sIL-2R and MIG are related to thyroid function rather than to activation of autoimmunity.     

Alterations in immune cell subsets and their cytokine secretion profile in childhood idiopathic thrombocytopenic purpura (ITP)

Immune thrombocytopenic purpura (ITP) is acquired autoimmune disease in children characterized by the breakdown of immune tolerance. This work is designed to explore the contribution of different lymphocyte subsets in acute and chronic ITP children. Imbalance in the T helper type 1 (Th1)/Th2 cytokine secretion profile was investigated. The frequency of T (CD3⁺, CD4⁺, CD8⁺) and B (CD19⁺) lymphocytes, natural killer (NK) (CD16⁺56⁺) and regulatory T (T_reg) [CD4⁺CD25^+highforkhead box protein 3 (FoxP3)⁺] cells was investigated by flow cytometry in 35 ITP children (15 acute and 20 chronic) and 10 healthy controls. Plasma levels of Th1 cytokines [interferon (IFN-γ) and tumour necrosis factor (TNF-α)] and Th2 [interleukin (IL)-4, IL-6 and IL-10)] cytokines were measured using enzyme-linked immunosorbent assay (ELISA). The percentage of T_reg (P < 0·001) and natural killer (NK) (P < 0·001) cells were significantly decreased in ITP patients compared to healthy controls. A negative correlation was reported between the percentage of T_reg cells and development of acute (r = −0·737; P < 0·01) and chronic (r = −0·515; P < 0·01) disease. All evaluated cytokines (IFN-γ, TNF-α, IL-4, IL-6 and IL-10) were elevated significantly in ITP patients (P < 0·001, P < 0·05, P < 0·05, P < 0·05 and P < 0·001, respectively) compared to controls. In conclusion, our data shed some light on the fundamental role of immune cells and their related cytokines in ITP patients. The loss of tolerance in ITP may contribute to the dysfunction of T_regs. Understanding the role of T cell subsets will permit a better control of autoimmunity through manipulation of their cytokine network.     

Two different fatigue protocols and lower extremity motion patterns during a stop-jump task

Context:

Altered neuromuscular control strategies during fatigue probably contribute to the increased incidence of non-contact anterior cruciate ligament injuries in female athletes.

Objective:

To determine biomechanical differences between 2 fatigue protocols (slow linear oxidative fatigue protocol [SLO-FP] and functional agility short-term fatigue protocol [FAST-FP]) when performing a running-stop-jump task.

Design:

Controlled laboratory study.

Setting:

Laboratory.

Patients or Other Participants:

A convenience sample of 15 female soccer players (age = 19.2 ±0.8 years, height = 1.67±0.05m, mass = 61.7 + 8.1 kg) without injury participated.

Intervention(s):

Five successful trials of a running–stop-jump task were obtained prefatigue and postfatigue during the 2 protocols. For the SLO-FP, a peak oxygen consumption (V˙o₂peak) test was conducted before the fatigue protocol. Five minutes after the conclusion of the V˙o₂peak test, participants started the fatigue protocol by performing a 30-minute interval run. The FAST-FP consisted of 4 sets of a functional circuit. Repeated 2 (fatigue protocol) × 2 (time) analyses of variance were conducted to assess differences between the 2 protocols and time (prefatigue, postfatigue).

Main Outcome Measure(s):

Kinematic and kinetic measures of the hip and knee were obtained at different times while participants performed both protocols during prefatigue and postfatigue.

Results:

Internal adduction moment at initial contact (IC) was greater during FAST-FP (0.064 ±0.09 Nm/kgm) than SLO-FP (0.024±0.06 Nm/kgm) (F_1,14 = 5.610, P=.03). At IC, participants had less hip flexion postfatigue (44.7°±8.1°) than prefatigue (50.1°±9.5°) (F_1,14 = 16.229, P=.001). At peak vertical ground reaction force, participants had less hip flexion postfatigue (44.7°±8.4°) than prefatigue (50.4°±10.3°) (F_1,14 = 17.026, P=.001). At peak vertical ground reaction force, participants had less knee flexion postfatigue (−35.9°±6.5°) than prefatigue (−38.8°±5.03°) (F_1,14 = 11.537, P=.001).

Conclusions:

Our results demonstrated a more erect landing posture due to a decrease in hip and knee flexion angles in the postfatigue condition. The changes were similar between protocols; however, the FAST-FP was a clinically applicable 5-minute protocol, whereas the SLO-FP lasted approximately 45 minutes.     

Regulatory T cells and chronic immune activation in human immunodeficiency virus 1 (HIV-1)-infected children

The function of CD4⁺ T cells with regulatory activity (T_regs) is the down-regulation of immune responses. This suppressive activity may limit the magnitude of effector responses, resulting in failure to control human immunodeficiency virus 1 (HIV-1) infection, but may also suppress chronic immune activation, a characteristic feature of HIV-1 disease. We evaluated the correlation between viral load, immune activation and T_regs in HIV-1-infected children. Eighty-nine HIV-1-infected children (aged 6–14 years) were included in the study and analysed for HIV-1 plasmaviraemia, HIV-1 DNA load, CD4 and CD8 cell subsets. T_reg cells [CD4⁺ CD25^highCD127^lowforkhead box P3 (FoxP3^high)] and CD8-activated T cells (CD8⁺CD38⁺) were determined by flow cytometry. Results showed that the number of activated CD8⁺CD38⁺ T cells increased in relation to HIV-1 RNA plasmaviraemia (r = 0·403, P < 0·0001). The proportion of T_regs also correlated positively with HIV-1 plasmaviraemia (r = 0·323, P = 0·002), but correlated inversely with CD4⁺ cells (r = −0·312, P = 0·004), thus suggesting a selective expansion along with increased viraemia and CD4⁺ depletion. Interestingly, a positive correlation was found between the levels of T_regs and CD8⁺CD38⁺ T cells (r = 0·305, P = 0·005), and the percentage of T_regs tended to correlate with HIV-1 DNA load (r = 0·224, P = 0·062). Overall, these findings suggest that immune activation contributes to the expansion of T_reg cells. In turn, the suppressive activity of T_regs may impair effector responses against HIV-1, but appears to be ineffective in limiting immune activation.     

Nitric oxide production by polymorphonuclear leucocytes in infected cystic fibrosis sputum consumes oxygen

Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients is characterized by persisting mucoid biofilms in hypoxic endobronchial mucus. These biofilms are surrounded by numerous polymorphonuclear leucocytes (PMNs), which consume a major part of present molecular oxygen (O₂) due to production of superoxide (O₂⁻). In this study, we show that the PMNs also consume O₂ for production of nitric oxide (NO) by the nitric oxide synthases (NOS) in the infected endobronchial mucus. Fresh expectorated sputum samples (n = 28) from chronically infected CF patients (n = 22) were analysed by quantifying and visualizing the NO production. NO production was detected by optode measurements combined with fluorescence microscopy, flow cytometry and spectrophotometry. Inhibition of nitric oxide synthases (NOS) with N^G-monomethyl-L-arginine (L-NMMA) resulted in reduced O₂ consumption (P < 0·0008, n = 8) and a lower fraction of cells with fluorescence from the NO-indicator 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM) (P < 0·002, n = 8). PMNs stained with DAF-FM and the superoxide indicator hydroethidine (HE) and host cells with inducible NOS (iNOS) were identified in the sputum. In addition, the production of the stable end-products of NO in CF sputum was correlated with the concentration of PMNs; NO₃⁻ (P < 0·04, r = 0·66, n = 10) and NO₂⁻ (P< 0·006, r = 0·78, n = 11). The present study suggests that besides consumption of O₂ for production of reactive oxygen species, the PMNs in CF sputum also consume O₂ for production of NO.     

The augmented neutrophil respiratory burst in response to Escherichia coli is reduced in liver cirrhosis during infection

Several functional abnormalities in phagocytes from patients with liver cirrhosis contribute to an increased risk of infection. An increased resting respiratory burst has been observed in neutrophils from cirrhotic patients. We investigated whether an infection in cirrhosis affects the respiratory burst capacity of neutrophils and monocytes in response to Escherichia coli. This study included 45 hospitalized patients with liver cirrhosis and clinical signs of infection, 39 patients with liver cirrhosis in the absence of infection and 29 healthy subjects. Respiratory burst, lipopolysaccharide-binding protein (LBP), and immunoglobulin (Ig)G-autoantibodies against oxidized low-density lipoproteins (ab-oxLDL) were measured. The fraction of neutrophils spontaneously producing reactive oxygen species (ROS) was elevated in liver cirrhosis (P < 0·01). The neutrophil resting burst increased with Child–Pugh stage (P = 0·02) and correlated with augmented ROS release in response to opsonized E. coli (P < 0·05). Although LBP was increased in patients with cirrhosis (P < 0·01), higher LBP levels correlated with a lower resting burst in neutrophils (r_s = –0·395; P < 0·01). In the presence of infection, the resting burst was unaltered. However, neutrophil ROS release in response to E. coli was reduced markedly (P = 0·01), and it decreased as serum C-reactive protein (CRP) concentration rose (r_s = −0·437; P < 0·01), indicating the development of a sepsis-like immune paralysis. A positive correlation between ab-oxLDL and ROS release was observed (P < 0·01). In conclusion, the respiratory burst increases with severity of liver cirrhosis but is restrained by increasing LBP levels. Augmented ROS release in response to E. coli is accompanied by elevated markers of oxidative damage and becomes exhausted in the presence of infection.     

Peripheral Artery Disease in Korean Patients Undergoing Percutaneous Coronary Intervention: Prevalence and Association with Coronary Artery Disease Severity

Peripheral artery disease (PAD) is an important marker for the risk stratification of patients with coronary artery disease (CAD). We investigated the prevalence of PAD in patients undergoing percutaneous coronary intervention (PCI) with CAD and the relationship between ankle-brachial pressure index (ABPI) and CAD severity. A total of 711 patients undergoing PCI for CAD from August 2009 to August 2011 were enrolled. PAD diagnosis was made using the ABPI. The prevalence of PAD was 12.8%. In PAD patients, mean values of right and left ABPI were 0.71 ± 0.15 and 0.73 ± 0.15. Patients with PAD had a higher prevalence of left main coronary disease (14.3% vs 5.8%, P = 0.003), more frequently had multivessel lesions (74.9% vs 52.1%, P < 0.001) and had higher SYNTAX score (18.2 ± 12.3 vs 13.1 ± 8.26, P = 0.002). Using multivariate analysis, we determined that left main CAD (OR, 2.954; 95% CI, 1.418-6.152, P = 0.004) and multivessel CAD (OR, 2.321; 95% CI, 1.363-3.953, P = 0.002) were both independently associated with PAD. We recommend that ABPI-based PAD screening should be implemented in all patients undergoing PCI with CAD, especially in severe cases.     

Improved emergency myelopoiesis and survival in neonatal sepsis by caspase‐1/11 ablation

Over one million newborns die annually from sepsis with the highest mortality in premature and low-birthweight infants. The inflammasome plays a central role in the regulation of innate immunity and inflammation, and is presumed to be involved in protective immunity, in large part through the caspase-1-dependent activation of interleukin-1β (IL-1β) and IL-18. Studies in endotoxic shock, however, suggest that endogenous caspase-1 activity and the inflammasome contribute to mortality primarily by promoting excessive systemic inflammatory responses. We examined whether caspase-1 and the inflammasome also regulate neonatal inflammation, host protective immunity and myelopoiesis during polymicrobial sepsis. Neonatal (5–7 days) C57BL/6 and caspase-1/11^−/− mice underwent a low-lethality caecal slurry model of intra-abdominal sepsis (LD_25–45). Ablation of caspase-1/11, but not apoptosis-associated speck-like protein containing a CARD domain or nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), improved neonatal survival following septic challenge compared with wild-type mice (P < 0·001), with decreased concentrations of inflammatory cytokines in the serum and peritoneum. Surprisingly, caspase-1/11^−/− neonates also exhibited increased bone marrow and splenic haematopoietic stem cell expansion (P < 0·001), and increased concentrations of granulocyte and macrophage colony-stimulating factors in the peritoneum (P < 0·001) after sepsis. Ablation of caspase-1/11 signalling was also associated with increased recruitment of peritoneal macrophages and neutrophils (P < 0·001), increased phagocytosis by neutrophils (P = 0·003), and decreased bacterial colonization (P = 0·02) in the peritoneum. These findings suggest that endogenous caspase-1/11 activity, independent of the NLRP3 inflammasome, not only promotes the magnitude of the inflammatory response, but also suppresses protective immunity in the neonate, so contributing to innate immune dysfunction and poor survival in neonatal sepsis.     

Observer Performance Using Virtual Pathology Slides: Impact of LCD Color Reproduction Accuracy

The use of color LCDs in medical imaging is growing as more clinical specialties use digital images as a resource in diagnosis and treatment decisions. Telemedicine applications such as telepathology, teledermatology, and teleophthalmology rely heavily on color images. However, standard methods for calibrating, characterizing, and profiling color displays do not exist, resulting in inconsistent presentation. To address this, we developed a calibration, characterization, and profiling protocol for color-critical medical imaging applications. Physical characterization of displays calibrated with and without the protocol revealed high color reproduction accuracy with the protocol. The present study assessed the impact of this protocol on observer performance. A set of 250 breast biopsy virtual slide regions of interest (half malignant, half benign) were shown to six pathologists, once using the calibration protocol and once using the same display in its “native” off-the-shelf uncalibrated state. Diagnostic accuracy and time to render a decision were measured. In terms of ROC performance, Az (area under the curve) calibrated = 0.8570 and Az uncalibrated = 0.8488. No statistically significant difference (p = 0.4112) was observed. In terms of interpretation speed, mean calibrated = 4.895 s; mean uncalibrated = 6.304 s which is statistically significant (p = 0.0460). Early results suggest a slight advantage diagnostically for a properly calibrated and color-managed display and a significant potential advantage in terms of improved workflow. Future work should be conducted using different types of color images that may be more dependent on accurate color rendering and a wider range of LCDs with varying characteristics.     

An Interactive System for Computer-Aided Diagnosis of Breast Masses

Although mammography is the only clinically accepted imaging modality for screening the general population to detect breast cancer, interpreting mammograms is difficult with lower sensitivity and specificity. To provide radiologists “a visual aid” in interpreting mammograms, we developed and tested an interactive system for computer-aided detection and diagnosis (CAD) of mass-like cancers. Using this system, an observer can view CAD-cued mass regions depicted on one image and then query any suspicious regions (either cued or not cued by CAD). CAD scheme automatically segments the suspicious region or accepts manually defined region and computes a set of image features. Using content-based image retrieval (CBIR) algorithm, CAD searches for a set of reference images depicting “abnormalities” similar to the queried region. Based on image retrieval results and a decision algorithm, a classification score is assigned to the queried region. In this study, a reference database with 1,800 malignant mass regions and 1,800 benign and CAD-generated false-positive regions was used. A modified CBIR algorithm with a new function of stretching the attributes in the multi-dimensional space and decision scheme was optimized using a genetic algorithm. Using a leave-one-out testing method to classify suspicious mass regions, we compared the classification performance using two CBIR algorithms with either equally weighted or optimally stretched attributes. Using the modified CBIR algorithm, the area under receiver operating characteristic curve was significantly increased from 0.865 ± 0.006 to 0.897 ± 0.005 (p < 0.001). This study demonstrated the feasibility of developing an interactive CAD system with a large reference database and achieving improved performance.