Behçet disease, new insights in disease associations and manifestations: a next-generation sequencing study.

Behçet disease is a multi-system disease associated with human leukocyte antigen (HLA) class I polymorphism. High-resolution next-generation sequencing (NGS) with haplotype analysis has not been performed previously for this disease. Sixty Egyptian patients diagnosed according to the International Study Group (ISG) criteria for Behçet disease and 160 healthy geographic and ethnic-matched controls were genotyped for HLA class I loci (HLA-A, B, C). For HLA class II loci (DRB1, DRB3/4/5, DQA1, DQB1, DPA1, DPB1), 40 control samples were genotyped. High-resolution HLA genotyping was performed using NGS and the results were analyzed. Clinical manifestations were oral ulcers (100%), genital ulcers (100%), eye (55%) and neurological (28%) and vascular involvement (35%). HLA-B*51:08 [odds ratio (OR) = 19·75, 95% confidence interval (CI) = 6·5-79; P < 0·0001], HLA-B*15:03 (OR = 12·15, 95% CI = 3·7-50·7; P < 0·0001), HLA-C*16:02 (OR = 6·53, 95% CI = 3-14; P < 0·0001), HLA-A*68:02 (OR = 3·14, 95% CI = 1·1-8·9; P < 0·01) were found to be associated with Behçet disease, as were HLA-DRB1*13:01 and HLA-DQB1*06:03 (OR = 3·39, 95% CI = 0·9-18·9; P = 0·04 for both). By contrast, HLA-A*03:01 (OR = 0·13, 95% CI = 0-0·8; P = 0·01) and HLA-DPB1*17:01 were found to be protective (OR = 0·27, 95% CI = 0·06-1·03; P = 0·02). We identified strong linkage disequilibrium between HLA-B*51:08 and C*16:02 and A*02:01 in a haplotype associated with Behçet disease. HLA-B*51:08 was significantly associated with legal blindness (OR = 2·98, 95% CI = 1·06-8·3; P = 0·01). In Egyptian Behçet patients, HLA-B*51:08 is the most common susceptibility allele and holds poor prognosis for eye involvement.

Presentation outside office hours does not negatively influence treatment times for reperfusion therapy for acute ischemic stroke.

BACKGROUND: Treatment outside office hours has been associated with increased workflow times for intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). Limited data suggest that this "off-hours effect" also exists for endovascular treatment (EVT). We investigated this phenomenon in a well-organized acute stroke care region in the Netherlands. METHODS: Retrospective, observational cohort study of consecutive patients with AIS who received reperfusion therapy in the Greater Amsterdam Area, consisting of 14 primary stroke centers and 1 comprehensive stroke center (IVT: 2009-2015, EVT: 2014-2017). Office hours were defined as presentation during weekdays between 8 AM and 5 PM, excluding National Festive days. Primary outcome was door-to-treatment time (door-to-needle [DNT] for IVT, door-to-groin [DGT] for EVT). For DGT, we used the door time of the first hospital. Other outcomes were in-hospital mortality, modified Rankin Scale (mRS) score at 90 days and symptomatic intracranial hemorrhage (sICH). We performed multivariable linear and logistic regression analyses and used multiple imputation to account for missing values. RESULTS: In total, 59% (2450/4161) and 61% (239/395) of patients treated with IVT and EVT, respectively, presented outside office hours. Median DNT was minimally longer outside office hours (32 vs. 30 min, p = 0.024, adjusted difference 2.5 min, 95% CI 0.7-4.2). Presentation outside office hours was not associated with a longer DGT (median 130 min for both groups, adjusted difference 7.0 min, 95% CI - 4.2 to 18.1). Clinical outcome and sICH rate also did not differ. CONCLUSION: Presentation outside office hours did not lead to clinically relevant treatment delays for reperfusion therapy in patients with AIS.

Mitochondrial dysfunction increases pro-inflammatory cytokine production and impairs repair and corticosteroid responsiveness in lung epithelium.

COPD is characterized by chronic lung inflammation and irreversible lung tissue damage. Inhaled noxious gases, including cigarette smoke, are the major risk factor for COPD. Inhaled smoke first encounters the epithelial lining of the lungs, causing oxidative stress and mitochondrial dysfunction. We investigated whether a mitochondrial defect may contribute to increased lung epithelial pro-inflammatory responses, impaired epithelial repair and reduced corticosteroid sensitivity as observed in COPD. We used wild-type alveolar epithelial cells A549 and mitochondrial DNA-depleted A549 cells (A549 Rho-0) and studied pro-inflammatory responses using (multiplex) ELISA as well as epithelial barrier function and repair (real-time impedance measurements), in the presence and absence of the inhaled corticosteroid budesonide. We observed that A549 Rho-0 cells secrete higher levels of pro-inflammatory cytokines than wild-type A549 cells and display impaired repair upon wounding. Budesonide strongly suppressed the production of neutrophil attractant CXCL8, and promoted epithelial integrity in A549 wild-type cells, while A549 Rho-0 cells displayed reduced corticosteroid sensitivity compared to wild-type cells. The reduced corticosteroid responsiveness may be mediated by glycolytic reprogramming, specifically glycolysis-associated PI3K signaling, as PI3K inhibitor LY294002 restored the sensitivity of CXCL8 secretion to corticosteroids in A549 Rho-0 cells. In conclusion, mitochondrial defects may lead to increased lung epithelial pro-inflammatory responses, reduced epithelial repair and reduced corticosteroid responsiveness in lung epithelium, thus potentially contributing to the pathogenesis of COPD.

On the chaotic behavior of the primal-dual affine-scaling algorithm for linear optimization.

We study a one-parameter family of quadratic maps, which serves as a template for interior point methods. It is known that such methods can exhibit chaotic behavior, but this has been verified only for particular linear optimization problems. Our results indicate that this chaotic behavior is generic.

Should internal mammary chain (IMC) sentinel node biopsy be performed? Outcome in 90 consecutive non-biopsied patients with a positive IMC scintigraphy.

INTRODUCTION: Although the status of the regional lymph nodes is an important determinant of prognosis in breast cancer, harvesting sentinel nodes (SN) detected in the internal mammary chain (IMC) is still controversial. AIMS: To determine in how many patients a positive IMC-SN might change the systemic or locoregional adjuvant therapy, with a possible benefit in outcome. PATIENTS AND METHODS: During 6 1/2 years data of T1-2 breast cancer patients, having an SN procedure, were prospectively collected. Our policy was not to explore the IMC even if it was the only localization of an SN. RESULTS: In 86 of 571 patients lymphoscintigraphy showed an IMC-SN. In 64 of these, the axillary SN was negative and only 25 of these patients did not have an indication for adjuvant systemic treatment based on their tumor characteristics. In the literature, IMC metastases are found in 0-10% of axillary negative patients. Routine IMC-SN biopsies would have resulted in an indication for adjuvant systemic therapy in 2-3 of our patients. Four parasternal recurrences were found during a median follow-up of 51 months. CONCLUSIONS: Harvesting IMC-SNs is a procedure of which only a limited number of patients have therapeutical benefit. Even with a thorough selection of patients, the extra morbidity of the procedure should be weighed against the potential benefit for the patient.

Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression.

To determine the frequency of progressive MRI lesions shortly after radiotherapy for glioma with spontaneous improvement or stabilization, the authors studied a cohort of patients treated within two prospective phase III trials with radiotherapy only. In 9 out of 32 patients, the first post-radiotherapy MRI showed progressive enhancement. In 3 of these 9 the MRI improved or stabilized for 6 months without additional treatment. The authors conclude that patients with progressive lesions within 3 months after radiotherapy should not be eligible for phase II trials on recurrent glioma.

Minute-by-minute differences in co-activation during treadmill walking in cerebral palsy.

The primary purpose of this study was to determine, in children and adolescents with mild spastic cerebra palsy (CP); 1) minute-by-minute differences in lower limb antagonist muscle co-activation and stride length (SL) during treadmill walking following 12-15 minutes of treadmill walking practice, and 2) if the minute-by-minute pattern of co-activation is affected by site (thigh or lower leg) and lower limb dominance. A secondary purpose was to determine if overall there is a difference in co-activation between the dominant and non-dominant lower limbs. Eight independently ambulatory children and adolescents with mild spastic CP (9.2-15.7 yr) participated in the study. Minute-by-minute lower limb antagonist muscle co-activation and SL were measured during a 3-minute treadmill walk at 90% of individually determined fastest treadmill walking speed. Non-dominant thigh (quadriceps, hamstring muscles) co-activation decreased between minute 1 and a) minute 2 (6%), b) minute 3 (7.2%). Co-activation for the dominant lower leg (tibialis anterior, triceps surae muscles) decreased between minute 1 and minute 3 (11.3%). Non-dominant thigh co-activation was on average 27.3% higher than for the dominant thigh. Thigh co-activation was on average 27.7% higher than for the lower leg, independent of dominance or time. SL increased between minute 1 and minute 3 by 2.1%. Twelve to 15 minutes of treadmill walking practice may be sufficient time to obtain stable co-activation and SL values by minute 2 of a fast treadmill walk. Dominance and site affect the magnitude of co-activation.

Numerical analysis for a discontinuous rotation of the torus.

In this paper, we study a class of piecewise rotations on the square. While few theoretical results are known about them, we numerically compute box-counting dimensions, correlation dimensions and complexity of the symbolic language produced by the system. Our results seem to confirm a conjecture that the fractal dimension of the exceptional set is two, as well as indicate that the dynamics on it is not ergodic. We also explore a relationship between the piecewise rotations and discretized rotations on lattices Z(2n).

Bacteriophages and Clostridium spores as indicator organisms for removal of pathogens by passage through saturated dune sand.

In a field study on the efficiency of dune recharge for drinking water production, bacteriophage MS2 was shown to be removed 8 log(10) by passage through the dune sand. The question of whether pathogenic viruses would be removed as much as MS2 was studied by comparing complete breakthrough curves of MS2 with those of the human viruses Coxsackievirus B4 (CB4) and Poliovirus 1 (PV1) in laboratory columns. The columns were designed to closely simulate the field conditions: same sand, water, porewater velocity and temperature. Employing a two-site kinetic model to simulate breakthrough curves, attachment/detachment to two types of kinetic sites as well as inactivation of free and attached viruses were evaluated. It was found that attachment to only one of the sites is of significance for determining overall removal. At field scale, removal of the less negatively charged PV1 was extrapolated to be about 30 times greater than that of MS2, but removal of CB4 would be only as much as that of MS2. Also, removal of spores of Clostridium perfringens D10, a potential surrogate for Cryptosporidium oocysts, was studied. The attachment rate coefficient of the spores was 7.5 times greater than that of MS2. However, this does not imply that the removal of the spores is 7.5 times greater than that of MS2. Due to negligible inactivation in combination with detachment of previously attached spores, the actual removal rate of the spores depends on the duration of contamination and eventually all spores will break through. Provided no irreversible attachment or physical straining occurs, this may also be the case for other persistent microorganisms, like oocysts of Cryptosporidium.

Cerebral venous and sinus thrombosis with cerebrospinal fluid circulation block after the first methotrexate administration by lumbar puncture.

We report a patient treated for small lymphocytic lymphoma/leukemia with cerebral venous and sinus thrombosis (CVST) after lumbar puncture with intrathecal administration of methotrexate (MTX). He also developed a cerebrospinal fluid flow block. This is the first report of an association between lumbar puncture and intrathecally administered MTX and the development of CVST. Intrathecal treatment in this patient was discontinued and he was successfully treated with high-dose low-molecular-weight heparin subcutaneously.

Column experiments to study nonlinear removal of bacteriophages by passage through saturated dune sand.

In a recent field study on dune recharge, bacteriophages MS2 and PRD1 were found to be removed 3 log10 over the first 2.4 m and only 5 log10 over the next 27 m. To understand the causes of this nonlinear removal, column experiments were carried out under conditions similar to the field: same recharge water, temperature (5 +/- 3 degrees C) and pore water velocity (1.5 m day(-1)). Soil samples were taken along a streamline between the recharge canal and the first monitoring well. Bacteriophage phiX174 was included for comparison. The high initial removal in the field was found not to be due to heterogeneity of phage suspensions but to soil heterogeneity. Phage removal rates correlated strongly positively with soil organic carbon content, and relatively strongly positively with silt content and the presence of ferric oxyhydroxides. Soil organic carbon content, silt content and the presence of ferric oxyhydroxides were found to decrease exponentially with travel distance. Removal rates of phiX174 were found to be 3-10 times higher than those of MS2 and PRD1 due to the lower electrostatic repulsion that the less negatively charged phiX174 experiences. It is suggested that the high initial removal in the field is due to the presence of favorable sites for attachment formed by ferric oxyhydroxides that decrease exponentially with travel distance. Similar removal rates may be found at both laboratory and field scale. However, due to local variations at field scale detailed knowledge on soil heterogeneity may be needed to enable a reliable prediction of removal.

Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma.

UNLABELLED: Malignant pleural mesothelioma is a notoriously chemoresistant tumour. However, a recent single institution study showed an impressive activity of gemcitabine and cisplatin. Our aim is to investigate the efficacy and toxicity of a gemcitabine and cisplatin combination in selected and chemo-naive patients with histologically proven malignant pleural mesothelioma. METHOD: Gemcitabine 1250 mg m(-2) was administered on day 1 and day 8 and cisplatin 80 mg m(-2) was administered on day 1 in a 3-week cycle with a maximum of six cycles. Response and toxicity evaluations were performed according to WHO and NCIC-CTC criteria. Pathology and radiology were centrally reviewed. Results show that in 25 evaluable patients, four PR were observed (ORR 16%, 95% CI 1-31%). Responses of seven patients were unevaluable. No unexpected toxicity occurred. Time to progression was 6 months (5-7 months) with a median survival from registration of 9.6 months (95% CI 8-12 months). In conclusion this trial excludes with 90% power a response rate of greater than 30% in patients with malignant pleural mesothelioma using a combination of gemcitabine and cisplatin at the proposed dose and schedule.

Inhibitory effect of telmisartan on the blood pressure response to angiotensin II challenge.

Telmisartan is a new angiotensin receptor antagonist possessing potent, selective, and insurmountable inhibitory activity specific to the angiotensin II type 1 (AT 1 ) receptor. The current study was performed to determine the inhibition of the angiotensin II pressor response by telmisartan in 48 healthy volunteers challenged with hypertension-inducing doses of i.v. angiotensin II. Subjects were challenged with this dose of angiotensin II at intervals between 0.25 and 48 h after double-blind single-dose oral administration of telmisartan 20 mg (n = 12), 40 mg (n = 12), or 80 mg (n = 12) or placebo (n = 12) in parallel groups. Diastolic and systolic blood pressure and pulse rate were recorded continuously using a servophotoplethysmograph. Urine samples were collected during the study for urinalysis. Tolerability of telmisartan, in comparison with placebo, was also monitored throughout the study. Telmisartan 20-80 mg dose dependently inhibited the increase in diastolic and systolic blood pressure induced by angiotensin II. Telmisartan 40 mg produced 80.1% maximum inhibition, and with 80 mg 89.6% maximum inhibition of diastolic blood pressure was achieved. Inhibition was apparent after 0.3-1.1 h and was still observed 48 h after administration for all telmisartan doses. The inhibitory effect of telmisartan 20, 40, and 80 mg, 48 h after dosing was significantly greater than that of placebo. A > 25% inhibition of the angiotensin II response on diastolic blood pressure was detected until 26.9, 35.4, and 40.5 h, respectively, after telmisartan 20 mg, 40 mg, and 80 mg. Anti-clockwise hysteresis was observed, indicating a delay and longer persistence of effect than to be expected from the plasma concentration-time course. The slow dissociation of telmisartan from the receptor probably contributed to this hysteresis. The incidence of adverse events was comparable in telmisartan-and placebo-treated subjects and was not dose dependent. In conclusion, telmisartan 40 mg provides rapid-onset, well-tolerated, and near-maximal inhibition of angiotensin II-induced hypertension, with maintenance of the inhibitory effect for 48 h.

Volume coronary angiography using targeted scans (VCATS): a new strategy in MR coronary angiography.

The aim of this study was to explore the clinical possibilities of a new strategy for magnetic resonance imaging of the coronary arteries. Thirteen patients were studied by volume coronary angiography using targeted scans (VCATS) to visualize the major coronary arteries in a series of breath-holds. The proximal coronary arteries were clearly seen in 92% and the mid segments in 50-70% of the patients. VCATS was able to visualize a total vessel length of the left main (LM) (mean: 9.4+/-3.4 mm), of the left anterior descending (LAD) 69+/-20 mm, of the right coronary artery (RCA) 90+/-33 mm and of the left circumflex (LCX) 41+/-18 mm. There was a reasonable correlation between the VCATS and conventional coronary angiography (CAG) for vessel diameter (r = 0.71), with a slight overestimation of 0.7 mm by VCATS. There were nine significant stenoses present of which six were correctly detected, three were missed and one false positive was present. VCATS is fast strategy for visualizing the major coronary artery branches and has the potential to detect significant stenoses in these branches.

The effect of anisotropy on the potential distribution in biological tissue and its impact on nerve excitation simulations.

We present a finite difference solution of the potential distribution associated with electrical current stimulation in an anisotropic in-homogeneous tissue environment and compare it to the isotropic case. The results demonstrate that there can be significant errors associated with the assumption of isotropic tissue properties in calculating the potential distribution along an axon in nerve excitation simulations. These errors can have a significant impact on predicted nerve fiber recruitment patterns when evaluating the efficacy of specific surface or intramuscular stimulus electrode configurations. The results of this study also suggest when a more comprehensive tissue model should be implemented in an electrode design study. Simulation results indicate that the isotropy assumption is worst under bipolar electrode stimulation as opposed to monopolar stimulation and that the bipolar error increases as the distance between electrodes decreases. In light of these results, it is concluded that in order to avoid large errors in the calculated potential distribution along an axon, the isotropy assumption should only be used when the transverse depth from the electrode to the nerve is relatively small.

MR coronary angiography with breath-hold targeted volumes: preliminary clinical results.

PURPOSE: To assess the clinical value of a magnetic resonance (MR) coronary angiography strategy involving a small targeted volume to image one coronary segment in a single breath hold for the detection of greater than 50% stenosis. MATERIALS AND METHODS: Thirty-eight patients referred for elective coronary angiography were included. The coronary arteries were localized during single-breath-hold, three-dimensional imaging of the entire heart. MR coronary angiography was then performed along the major coronary branches with a double-oblique, three-dimensional, gradient-echo sequence. Conventional coronary angiography was the reference-standard method. RESULTS: Adequate visualization was achieved with MR coronary angiography in 85%-91% of the proximal coronary arterial branches and in 38%-76% of the middle and distal branches. Overall, 187 (69%) of 272 segments were suitable for comparison between conventional and MR coronary angiography. The diagnostic accuracy of MR coronary angiography for the detection of hemodynamically significant stenoses was 92%; sensitivity, 68%; and specificity, 97%. The sensitivity in individual segments was 50%-77%, whereas the specificity was 94%-100%. CONCLUSION: Adequate visualization of the major coronary arterial branches was possible in the majority of patients. The observed accuracy of MR coronary angiography for detection of hemodynamically significant coronary arterial stenosis is promising, but it needs to be higher before this modality can be used reliably in a clinical setting.

Lymphedema and lymphocysts following lymphadenectomy may be prevented by omentoplasty: A pilot study.

OBJECTIVES: Pelvic lymph node dissection as part of the staging surgery for cervical carcinoma interrupts the afferent lymphatics, so the lymph drains retroperitoneally. New surgical techniques designed to leave the peritoneum open after the retroperitoneal dissection, in particular the application of a pedicled omentoplasty along the dissection route, have been advocated to prevent the formation of lymphocysts and lymphedema. We investigated the possible benefit of pedicled omentoplasty in preventing lymphocysts and lymphedema following pelvic lymph node dissection. METHODS: In this pilot study with historical controls we compared the formation of lymphocysts and lymphedema following two different surgical techniques for pelvic node dissection: group I (historical controls), in which the dorsal peritoneum was left open, and group II, in which the dorsal peritoneum was left open with application of a pedicled omentoplasty. In these two groups of gynecologic patients, we compared the lymph flow patterns and the occurrence of lymphedema following systemic pelvic lymphadenectomy. The two groups were of comparable clinical status and consisted of 12 (group I) and 10 (group II) patients. Lymphocysts, if any, were detected by CT scan, the lymph flow patterns were visualized by dynamic lymphscintography, and lymphedema was visualized by physical examination and magnetic resonance imaging of the groin and the upper leg. RESULTS: In both groups a distinct intraperitoneal absorption of the lymph fluid was observed. Pedicled omentoplasty seemed to facilitate the absorption or transport of lymph fluid, resulting in less lymphedema in the upper leg. CONCLUSION: It appeared that leaving the dorsal peritoneum open to give the lymph stream the opportunity to pour into the abdominal cavity is important in preventing lymphocysts and lymphedema. The dynamic lymphscintigraphy described in this paper showed that the intraabdominal lymph flow is absorbed by the peritoneum and even more quickly by the pedicled omentum.

Magnetic resonance imaging of the coronary arteries: imaging planes and resulting anatomy in two-dimensional imaging.

Magnetic-resonance imaging techniques use different imaging planes than does conventional coronary angiography to acquire longer segments of a coronary artery in a single tomographic slice. At first sight, these planes appear rather puzzling, because the coronary arteries are displayed in unfamiliar orientations. In this article we will review the existing methodology for obtaining the orientations for the proximal coronary arteries and describe the associated anatomical landmarks that can be seen. Additional orientations for the middle segment of the circumflex and distal right coronary artery are introduced. These orientations are used both in various acquisition techniques and for evaluation of three-dimensional data when using multiplanar reformatting.

Basic principles of magnetic resonance imaging.

Magnetic resonance imaging (MRI) is a noninvasive imaging technique that is becoming more and more important in clinical cardiology. Physicians must understand the basic principles of MRI before reliable use in practice is possible. Therefore, we will give an introduction to basic MRI principles necessary to understand the difficulties of cardiac MRI. First the generation of a signal by the combination of a strong magnetic field, radiofrequency pulses, and temporary changes in the magnetic field is explained. Then, the processes of localization of different points in an image, resolution, and signal-to-noise ratio are highlighted. Finally, the influence of tissue characteristics such as T1 and T2 on the contrast of an image are discussed.